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Yashin, Anatoli I.

Positions:

Research Professor in the Social Science Research Institute

Social Science Research Institute
Institutes and Provost's Academic Units

Co-Director of the Biodemographic Research Unit within DuPRI

Center for Population Health & Aging
Institutes and Provost's Academic Units

Faculty Research Scholar of DuPRI's Population Research Center

Duke Population Research Center
Institutes and Provost's Academic Units

Faculty Research Scholar of DuPRI's Center for Population Health & Aging

Center for Population Health & Aging
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.S. 1967

M.S. — Moscow Institure of Physics and Technology

Ph.D. 1970

Ph.D. — Institute of Control Sciences (Russia)

Grants:

Relationships among Genetic Regulators of Aging, Health, and Lifespan

Administered By
SSRI Incubator Projects and Support
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
June 15, 2014
End Date
April 30, 2019

Genetics of Changes in Population Pyramids: Implications for Health Forecasting

Administered By
Center for Population Health & Aging
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
January 01, 2014
End Date
December 31, 2018

Genetic Modulations of Morbidity Compression: A Population-Based Study

Administered By
Social Science Research Institute
AwardedBy
National Institutes of Health
Role
Senior Investigator
Start Date
September 30, 2016
End Date
June 30, 2018

Generating new knowledge to support reversibility interventions

Administered By
Psychology and Neuroscience
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
September 30, 2014
End Date
April 30, 2017

Causal Effects of Time-Dependent Treatment: Optimizing Care of Cancer Patients

Administered By
Center for Population Health & Aging
AwardedBy
National Institutes of Health
Role
Senior Investigator
Start Date
September 30, 2013
End Date
August 31, 2015

Integrating Population and Basic Science in Cancer Research

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Co-Director
Start Date
September 01, 2009
End Date
August 31, 2015

The Future of Major Geriatric Disorders in the US Elderly

Administered By
Duke Population Research Institute
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 2008
End Date
August 31, 2013

Evaluating New Genetic Effects on Health and Aging from Longitudinal Data

Administered By
Center for Population Health & Aging
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 2007
End Date
August 31, 2013

Archiving and Dissemination of NLTCS Medicaid Data

Administered By
Center for Population Health & Aging
AwardedBy
National Institutes of Health
Role
Senior Investigator
Start Date
August 01, 2012
End Date
July 31, 2013

New Methods of Studying Aging, Health and Longevity: Combining Longitudinal Data

Administered By
Center for Population Health & Aging
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 2009
End Date
July 31, 2011

Healthy Life at Risk: The Role of Senesence

Administered By
Social Science Research Institute
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 2005
End Date
June 30, 2011

Dynamic Determinants of Exceptional Health at Late Ages

Administered By
Sociology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
February 15, 2006
End Date
December 31, 2010
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Awards:

Mindel C. Sheps Award. Population Association of America.

Type
National
Awarded By
Population Association of America
Date
January 01, 2012

Publications:

Hidden heterogeneity in Alzheimer's disease: Insights from genetic association studies and other analyses.

Despite evident success in clarifying many important features of Alzheimer's disease (AD) the efficient methods of its prevention and treatment are not yet available. The reasons are likely to be the fact that AD is a multifactorial and heterogeneous health disorder with multiple alternative pathways of disease development and progression. The availability of genetic data on individuals participated in longitudinal studies of aging health and longevity, as well as on participants of cross-sectional case-control studies allow for investigating genetic and non-genetic connections with AD and to link the results of these analyses with research findings obtained in clinical, experimental, and molecular biological studies of this health disorder. The objective of this paper is to perform GWAS of AD in several study populations and investigate possible roles of detected genetic factors in developing AD hallmarks and in other health disorders. The data collected in the Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), Health and Retirement Study (HRS) and Late Onset Alzheimer's Disease Family Study (LOADFS) were used in these analyses. The logistic regression and Cox's regression were used as statistical models in GWAS. The results of analyses confirmed strong associations of genetic variants from well-known genes APOE, TOMM40, PVRL2 (NECTIN2), and APOC1 with AD. Possible roles of these genes in pathological mechanisms resulting in development of hallmarks of AD are described. Many genes whose connection with AD was detected in other studies showed nominally significant associations with this health disorder in our study. The evidence on genetic connections between AD and vulnerability to infection, as well as between AD and other health disorders, such as cancer and type 2 diabetes, were investigated. The progress in uncovering hidden heterogeneity in AD would be substantially facilitated if common mechanisms involved in development of AD, its hallmarks, and AD related chronic conditions were investigated in their mutual connection.

Authors
Yashin, AI; Fang, F; Kovtun, M; Wu, D; Duan, M; Arbeev, K; Akushevich, I; Kulminski, A; Culminskaya, I; Zhbannikov, I; Yashkin, A; Stallard, E; Ukraintseva, S
MLA Citation
Yashin, AI, Fang, F, Kovtun, M, Wu, D, Duan, M, Arbeev, K, Akushevich, I, Kulminski, A, Culminskaya, I, Zhbannikov, I, Yashkin, A, Stallard, E, and Ukraintseva, S. "Hidden heterogeneity in Alzheimer's disease: Insights from genetic association studies and other analyses." Experimental gerontology (October 26, 2017).
PMID
29107063
Source
epmc
Published In
Experimental Gerontology
Publish Date
2017
DOI
10.1016/j.exger.2017.10.020

Telomeres and the natural lifespan limit in humans.

An ongoing debate in demography has focused on whether the human lifespan has a maximal natural limit. Taking a mechanistic perspective, and knowing that short telomeres are associated with diminished longevity, we examined whether telomere length dynamics during adult life could set a maximal natural lifespan limit. We define leukocyte telomere length of 5 kb as the 'telomeric brink', which denotes a high risk of imminent death. We show that a subset of adults may reach the telomeric brink within the current life expectancy and more so for a 100-year life expectancy. Thus, secular trends in life expectancy should confront a biological limit due to crossing the telomeric brink.

Authors
Steenstrup, T; Kark, JD; Verhulst, S; Thinggaard, M; Hjelmborg, JVB; Dalgård, C; Kyvik, KO; Christiansen, L; Mangino, M; Spector, TD; Petersen, I; Kimura, M; Benetos, A; Labat, C; Sinnreich, R; Hwang, S-J; Levy, D; Hunt, SC; Fitzpatrick, AL; Chen, W; Berenson, GS; Barbieri, M; Paolisso, G; Gadalla, SM; Savage, SA; Christensen, K; Yashin, AI; Arbeev, KG; Aviv, A
MLA Citation
Steenstrup, T, Kark, JD, Verhulst, S, Thinggaard, M, Hjelmborg, JVB, Dalgård, C, Kyvik, KO, Christiansen, L, Mangino, M, Spector, TD, Petersen, I, Kimura, M, Benetos, A, Labat, C, Sinnreich, R, Hwang, S-J, Levy, D, Hunt, SC, Fitzpatrick, AL, Chen, W, Berenson, GS, Barbieri, M, Paolisso, G, Gadalla, SM, Savage, SA, Christensen, K, Yashin, AI, Arbeev, KG, and Aviv, A. "Telomeres and the natural lifespan limit in humans." Aging 9.4 (April 6, 2017): 1130-1142.
Website
http://hdl.handle.net/10161/14745
PMID
28394764
Source
epmc
Published In
Aging
Volume
9
Issue
4
Publish Date
2017
Start Page
1130
End Page
1142
DOI
10.18632/aging.101216

Theory of partitioning of disease prevalence and mortality in observational data.

In this study, we present a new theory of partitioning of disease prevalence and incidence-based mortality and demonstrate how this theory practically works for analyses of Medicare data. In the theory, the prevalence of a disease and incidence-based mortality are modeled in terms of disease incidence and survival after diagnosis supplemented by information on disease prevalence at the initial age and year available in a dataset. Partitioning of the trends of prevalence and mortality is calculated with minimal assumptions. The resulting expressions for the components of the trends are given by continuous functions of data. The estimator is consistent and stable. The developed methodology is applied for data on type 2 diabetes using individual records from a nationally representative 5% sample of Medicare beneficiaries age 65+. Numerical estimates show excellent concordance between empirical estimates and theoretical predictions. Evaluated partitioning model showed that both prevalence and mortality increase with time. The primary driving factors of the observed prevalence increase are improved survival and increased prevalence at age 65. The increase in diabetes-related mortality is driven by increased prevalence and unobserved trends in time-periods and age-groups outside of the range of the data used in the study. Finally, the properties of the new estimator, possible statistical and systematical uncertainties, and future practical applications of this methodology in epidemiology, demography, public health and health forecasting are discussed.

Authors
Akushevich, I; Yashkin, AP; Kravchenko, J; Fang, F; Arbeev, K; Sloan, F; Yashin, AI
MLA Citation
Akushevich, I, Yashkin, AP, Kravchenko, J, Fang, F, Arbeev, K, Sloan, F, and Yashin, AI. "Theory of partitioning of disease prevalence and mortality in observational data." Theoretical population biology 114 (April 2017): 117-127.
Website
http://hdl.handle.net/10161/14750
PMID
28130147
Source
epmc
Published In
Theoretical Population Biology
Volume
114
Publish Date
2017
Start Page
117
End Page
127
DOI
10.1016/j.tpb.2017.01.003

stpm: an R package for stochastic process model.

The Stochastic Process Model (SPM) represents a general framework for modeling the joint evolution of repeatedly measured variables and time-to-event outcomes observed in longitudinal studies, i.e., SPM relates the stochastic dynamics of variables (e.g., physiological or biological measures) with the probabilities of end points (e.g., death or system failure). SPM is applicable for analyses of longitudinal data in many research areas; however, there are no publicly available software tools that implement this methodology.We developed an R package stpm for the SPM-methodology. The package estimates several versions of SPM currently available in the literature including discrete- and continuous-time multidimensional models and a one-dimensional model with time-dependent parameters. Also, the package provides tools for simulation and projection of individual trajectories and hazard functions.In this paper, we present the first software implementation of the SPM-methodology by providing an R package stpm, which was verified through extensive simulation and validation studies. Future work includes further improvements of the model. Clinical and academic researchers will benefit from using the presented model and software. The R package stpm is available as open source software from the following links: https://cran.r-project.org/package=stpm (stable version) or https://github.com/izhbannikov/spm (developer version).

Authors
Zhbannikov, IY; Arbeev, K; Akushevich, I; Stallard, E; Yashin, AI
MLA Citation
Zhbannikov, IY, Arbeev, K, Akushevich, I, Stallard, E, and Yashin, AI. "stpm: an R package for stochastic process model." BMC bioinformatics 18.1 (February 23, 2017): 125-.
Website
http://hdl.handle.net/10161/14793
PMID
28231764
Source
epmc
Published In
BMC Bioinformatics
Volume
18
Issue
1
Publish Date
2017
Start Page
125
DOI
10.1186/s12859-017-1538-7

Uncoupling associations of risk alleles with endophenotypes and phenotypes: insights from the ApoB locus and heart-related traits.

Traditionally, genomewide association studies (GWAS) have emphasized the benefits of large samples in the analyses of age-related traits rather than their specific properties. We adopted a realistic concept of genetic susceptibility to inherently heterogeneous, age-related traits driven by the elusive role of evolution in their properties. We analyzed in detail the associations of rs693 and rs562338 polymorphisms representing the Apolipoprotein B locus with endophenotypes (total cholesterol [TC] and high-density lipoprotein cholesterol) and phenotypes (myocardial infarction [MI] and survival) in four large-scale studies, which include 20 748 individuals with 2357 MI events. We showed that a strong, robust predisposition of rs693 and rs562338 to TC (β = 0.72, P = 7.7 × 10-30 for rs693 and β = -1.08, P = 9.8 × 10-42 for rs562338) is not translated into a predisposition to MI and survival. The rs693_A allele influences risks of MI and mortality after MI additively with lipids. This allele shows antagonistic effects-protecting against MI risks (β = -0.18, P = 1.1 × 10-5 ) or increasing MI risks (β = 0.15, P = 2.8 × 10-3 ) and mortality after MI, in different populations. Paradoxically, increased TC concentrations can be protective against MI for the rs693_A allele carriers. Our results uncouple the influences of the same alleles on endophenotypes and phenotypes despite potential causal relationships among the latter. Our strategy reveals virtually genomewide significance for the associations of rs693 with MI (P = 5.5 × 10-8 ) that is contrasted with a weak estimate following the traditional, sample-size-centered GWAS strategy (P = 0.16) in the same sample. These results caution against the use of the traditional GWAS strategy for gaining profound insights into genetic predisposition to healthspan and lifespan.

Authors
Kulminski, AM; Kernogitski, Y; Culminskaya, I; Loika, Y; Arbeev, KG; Bagley, O; Duan, M; Arbeeva, L; Ukraintseva, SV; Wu, D; Stallard, E; Yashin, AI
MLA Citation
Kulminski, AM, Kernogitski, Y, Culminskaya, I, Loika, Y, Arbeev, KG, Bagley, O, Duan, M, Arbeeva, L, Ukraintseva, SV, Wu, D, Stallard, E, and Yashin, AI. "Uncoupling associations of risk alleles with endophenotypes and phenotypes: insights from the ApoB locus and heart-related traits." Aging cell 16.1 (February 2017): 61-72.
Website
http://hdl.handle.net/10161/14747
PMID
27683205
Source
epmc
Published In
Aging Cell
Volume
16
Issue
1
Publish Date
2017
Start Page
61
End Page
72
DOI
10.1111/acel.12526

Modeling of immunosenescence and risk of death from respiratory infections: Evaluation of the role of antigenic load and population heterogeneity

© EDP Sciences, 2017. It is well known that efficacy of immune functions declines with age. It results in an increase of severity and duration of respiratory infections and also in dramatic growth of risk of death due to these diseases after age 65. The goal of this work is to describe and investigate the mechanism underlying the age pattern of the mortality rate caused by infectious diseases and to determine the cause-specific hazard rate as a function of immune system characteristics. For these purposes we develop a three-compartment model explaining observed risk-of-death. The model incorporates up-to-date knowledge about cellular mechanisms of aging, disease dynamics, population heterogeneity in resistance to infections, and intrinsic aging rate. The results of modeling show that the age-trajectory of mortality caused by respiratory infections may be explained by the value of antigenic load, frequency of infections and the rate of aging of the stem cell population (i.e. the population of T-lymphocyte progenitor cells). The deceleration of infection-induced mortality at advanced age can be explained by selection of individuals with a slower rate of stem cell aging. Parameter estimates derived from fitting mortality data indicate that infection burden was monotonically decreasing during the twentieth century, and changes in total antigenic load were gender-specific: it experienced periodic fluctuations in males and increased approximately two-fold in females.

Authors
Sannikova, TE; Romanyukha, AA; Barbi, E; Caselli, G; Franceschi, C; Yashin, AI
MLA Citation
Sannikova, TE, Romanyukha, AA, Barbi, E, Caselli, G, Franceschi, C, and Yashin, AI. "Modeling of immunosenescence and risk of death from respiratory infections: Evaluation of the role of antigenic load and population heterogeneity." Mathematical Modelling of Natural Phenomena 12.5 (January 1, 2017): 48-62.
Source
scopus
Published In
Mathematical Modelling of Natural Phenomena (MMNP)
Volume
12
Issue
5
Publish Date
2017
Start Page
48
End Page
62
DOI
10.1051/mmnp/201712504

The Survival of Spouses Marrying Into Longevity-Enriched Families.

Studies of longevity-enriched families are an important tool to gain insight into the mechanisms of exceptionally long and healthy lives. In the Long Life Family Study, the spouses of the members of the longevity-enriched families are often used as a control group. These spouses could be expected to have better health than the background population due to shared family environment with the longevity-enriched family members and due to assortative mating.A Danish cohort study of 5,363 offspring of long-lived siblings, born 1917-1982, and 4,498 "first spouses" of these offspring. For each offspring and spouse, 10 controls were drawn from a 5% random sample of the Danish population matched on birth year and sex. Mortality was assessed for ages 20-69 years during 1968-2013 based on prospectively collected registry data.During the 45-year follow-up period, 437 offspring deaths and 502 offspring spouse deaths were observed. Compared with the background population, the hazard ratio for male offspring was 0.44 (95% confidence interval [CI]: 0.38-0.50) and for female offspring it was 0.57 (95% CI: 0.49-0.66). For male spouses, the hazard ratio was 0.66 (95% CI: 0.59-0.74), whereas for female spouses it was 0.64 (95% CI: 0.54-0.76). Sensitivity analyses in restricted samples gave similar results.The mortality for ages 20-69 years of spouses marrying into longevity-enriched families is substantially lower than the mortality in the background population, although long-lived siblings participation bias may have contributed to the difference. This finding has implications for the use of spouses as controls in healthy aging and longevity studies, as environmental and/or genetic overmatching may occur.

Authors
Pedersen, JK; Elo, IT; Schupf, N; Perls, TT; Stallard, E; Yashin, AI; Christensen, K
MLA Citation
Pedersen, JK, Elo, IT, Schupf, N, Perls, TT, Stallard, E, Yashin, AI, and Christensen, K. "The Survival of Spouses Marrying Into Longevity-Enriched Families." The journals of gerontology. Series A, Biological sciences and medical sciences 72.1 (January 2017): 109-114.
Website
http://hdl.handle.net/10161/14896
PMID
27540092
Source
epmc
Published In
Journals of Gerontology: Series A
Volume
72
Issue
1
Publish Date
2017
Start Page
109
End Page
114
DOI
10.1093/gerona/glw159

Pleiotropic Associations of Allelic Variants in a 2q22 Region with Risks of Major Human Diseases and Mortality.

Gaining insights into genetic predisposition to age-related diseases and lifespan is a challenging task complicated by the elusive role of evolution in these phenotypes. To gain more insights, we combined methods of genome-wide and candidate-gene studies. Genome-wide scan in the Atherosclerosis Risk in Communities (ARIC) Study (N = 9,573) was used to pre-select promising loci. Candidate-gene methods were used to comprehensively analyze associations of novel uncommon variants in Caucasians (minor allele frequency~2.5%) located in band 2q22.3 with risks of coronary heart disease (CHD), heart failure (HF), stroke, diabetes, cancer, neurodegenerative diseases (ND), and mortality in the ARIC study, the Framingham Heart Study (N = 4,434), and the Health and Retirement Study (N = 9,676). We leveraged the analyses of pleiotropy, age-related heterogeneity, and causal inferences. Meta-analysis of the results from these comprehensive analyses shows that the minor allele increases risks of death by about 50% (p = 4.6×10-9), CHD by 35% (p = 8.9×10-6), HF by 55% (p = 9.7×10-5), stroke by 25% (p = 4.0×10-2), and ND by 100% (p = 1.3×10-3). This allele also significantly influences each of two diseases, diabetes and cancer, in antagonistic fashion in different populations. Combined significance of the pleiotropic effects was p = 6.6×10-21. Causal mediation analyses show that endophenotypes explained only small fractions of these effects. This locus harbors an evolutionary conserved gene-desert region with non-coding intergenic sequences likely involved in regulation of protein-coding flanking genes ZEB2 and ACVR2A. This region is intensively studied for mutations causing severe developmental/genetic disorders. Our analyses indicate a promising target region for interventions aimed to reduce risks of many major human diseases and mortality.

Authors
Kulminski, AM; He, L; Culminskaya, I; Loika, Y; Kernogitski, Y; Arbeev, KG; Loiko, E; Arbeeva, L; Bagley, O; Duan, M; Yashkin, A; Fang, F; Kovtun, M; Ukraintseva, SV; Wu, D; Yashin, AI
MLA Citation
Kulminski, AM, He, L, Culminskaya, I, Loika, Y, Kernogitski, Y, Arbeev, KG, Loiko, E, Arbeeva, L, Bagley, O, Duan, M, Yashkin, A, Fang, F, Kovtun, M, Ukraintseva, SV, Wu, D, and Yashin, AI. "Pleiotropic Associations of Allelic Variants in a 2q22 Region with Risks of Major Human Diseases and Mortality." PLoS genetics 12.11 (November 10, 2016): e1006314-.
PMID
27832070
Source
epmc
Published In
PLoS genetics
Volume
12
Issue
11
Publish Date
2016
Start Page
e1006314
DOI
10.1371/journal.pgen.1006314

Resilience Versus Robustness in Aging.

Authors
Ukraintseva, S; Yashin, AI; Arbeev, KG
MLA Citation
Ukraintseva, S, Yashin, AI, and Arbeev, KG. "Resilience Versus Robustness in Aging." The journals of gerontology. Series A, Biological sciences and medical sciences 71.11 (November 2016): 1533-1534.
Website
http://hdl.handle.net/10161/14748
PMID
27146372
Source
epmc
Published In
Journals of Gerontology: Series A
Volume
71
Issue
11
Publish Date
2016
Start Page
1533
End Page
1534
DOI
10.1093/gerona/glw083

Protective role of the apolipoprotein E2 allele in age-related disease traits and survival: evidence from the Long Life Family Study.

The apolipoprotein E (apoE) is a classic example of a gene exhibiting pleiotropism. We examine potential pleiotropic associations of the apoE2 allele in three biodemographic cohorts of long-living individuals, offspring, and spouses from the Long Life Family Study, and intermediate mechanisms, which can link this allele with age-related phenotypes. We focused on age-related macular degeneration, bronchitis, asthma, pneumonia, stroke, creatinine, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, diseases of heart (HD), cancer, and survival. Our analysis detected favorable associations of the ε2 allele with lower LDL-C levels, lower risks of HD, and better survival. The ε2 allele was associated with LDL-C in each gender and biodemographic cohort, including long-living individuals, offspring, and spouses, resulting in highly significant association in the entire sample (β = -7.1, p = 6.6 × 10-44). This allele was significantly associated with HD in long-living individuals and offspring (relative risk [RR] = 0.60, p = 3.1 × 10-6) but this association was not mediated by LDL-C. The protective effect on survival was specific for long-living women but it was not explained by LDL-C and HD in the adjusted model (RR = 0.70, p = 2.1 × 10-2). These results show that ε2 allele may favorably influence LDL-C, HD, and survival through three mechanisms. Two of them (HD- and survival-related) are pronounced in the long-living parents and their offspring; the survival-related mechanism is also sensitive to gender. The LDL-C-related mechanism appears to be independent of these factors. Insights into mechanisms linking ε2 allele with age-related phenotypes given biodemographic structure of the population studied may benefit translation of genetic discoveries to health care and personalized medicine.

Authors
Kulminski, AM; Raghavachari, N; Arbeev, KG; Culminskaya, I; Arbeeva, L; Wu, D; Ukraintseva, SV; Christensen, K; Yashin, AI
MLA Citation
Kulminski, AM, Raghavachari, N, Arbeev, KG, Culminskaya, I, Arbeeva, L, Wu, D, Ukraintseva, SV, Christensen, K, and Yashin, AI. "Protective role of the apolipoprotein E2 allele in age-related disease traits and survival: evidence from the Long Life Family Study." Biogerontology 17.5-6 (November 2016): 893-905.
Website
http://hdl.handle.net/10161/14754
PMID
27447179
Source
epmc
Published In
Biogerontology
Volume
17
Issue
5-6
Publish Date
2016
Start Page
893
End Page
905
DOI
10.1007/s10522-016-9659-3

High-Resolution Analyses of Effects of Polygenic Risk Scores on Time-to-Event Outcomes in Longitudinal Studies

Authors
Arbeev, KG; Arbeeva, LS; Zhbannikov, IY; Bagley, O; Akushevich, I; Kovtun, M; Kulminski, AM; Culminskaya, IV; Ukraintseva, SV; Yashin, AI
MLA Citation
Arbeev, KG, Arbeeva, LS, Zhbannikov, IY, Bagley, O, Akushevich, I, Kovtun, M, Kulminski, AM, Culminskaya, IV, Ukraintseva, SV, and Yashin, AI. "High-Resolution Analyses of Effects of Polygenic Risk Scores on Time-to-Event Outcomes in Longitudinal Studies." November 2016.
Source
wos-lite
Published In
Genetic Epidemiology
Volume
40
Issue
7
Publish Date
2016
Start Page
622
End Page
622

GENE-LEVEL META-ANALYSIS OF CANDIDATE GENES INVOLVED IN ALZHEIMER’S DISEASE AND LONGEVITY

MLA Citation
"GENE-LEVEL META-ANALYSIS OF CANDIDATE GENES INVOLVED IN ALZHEIMER’S DISEASE AND LONGEVITY." November 2016.
Source
crossref
Published In
The Gerontologist
Volume
56
Issue
Suppl_3
Publish Date
2016
Start Page
104
End Page
104
DOI
10.1093/geront/gnw162.402

ANALYSIS OF INTERACTIONS BETWEEN ALZHEIMER’S DISEASE CANDIDATE GENES AND THEIR IMPACT ON LONGEVITY

MLA Citation
"ANALYSIS OF INTERACTIONS BETWEEN ALZHEIMER’S DISEASE CANDIDATE GENES AND THEIR IMPACT ON LONGEVITY." November 2016.
Source
crossref
Published In
The Gerontologist
Volume
56
Issue
Suppl_3
Publish Date
2016
Start Page
103
End Page
103
DOI
10.1093/geront/gnw162.400

PHYSIOLOGICAL DYSREGULATION AS PROMISING MEASURE OF ROBUSTNESS AND RESILIENCE IN AGING STUDIES

MLA Citation
"PHYSIOLOGICAL DYSREGULATION AS PROMISING MEASURE OF ROBUSTNESS AND RESILIENCE IN AGING STUDIES." November 2016.
Website
http://hdl.handle.net/10161/14812
Source
crossref
Published In
The Gerontologist
Volume
56
Issue
Suppl_3
Publish Date
2016
Start Page
180
End Page
181
DOI
10.1093/geront/gnw162.706

PARTITIONING OF TIME TRENDS IN PREVALENCE OF LUNG CANCER AMONG OLDER U.S. ADULTS

MLA Citation
"PARTITIONING OF TIME TRENDS IN PREVALENCE OF LUNG CANCER AMONG OLDER U.S. ADULTS." November 2016.
Source
crossref
Published In
The Gerontologist
Volume
56
Issue
Suppl_3
Publish Date
2016
Start Page
705
End Page
705
DOI
10.1093/geront/gnw162.2874

TRENDS IN DIABETES MELLITUS AND RELATED HEALTH OUTCOMES 1991–2013: ACHIEVEMENTS AND CHALLENGES

MLA Citation
"TRENDS IN DIABETES MELLITUS AND RELATED HEALTH OUTCOMES 1991–2013: ACHIEVEMENTS AND CHALLENGES." November 2016.
Website
http://hdl.handle.net/10161/14804
Source
crossref
Published In
The Gerontologist
Volume
56
Issue
Suppl_3
Publish Date
2016
Start Page
705
End Page
706
DOI
10.1093/geront/gnw162.2876

RELATIONSHIPS AMONG AGING HEALTH AND LONGEVITY IN HRS: CAUSAL ANALYSES USING MENDELIAN RANDOMIZATION

MLA Citation
"RELATIONSHIPS AMONG AGING HEALTH AND LONGEVITY IN HRS: CAUSAL ANALYSES USING MENDELIAN RANDOMIZATION." November 2016.
Source
crossref
Published In
The Gerontologist
Volume
56
Issue
Suppl_3
Publish Date
2016
Start Page
181
End Page
181
DOI
10.1093/geront/gnw162.707

INTEGRATING GENETIC DATA INTO HEALTH AND MORTALITY FORECASTING USING THE HEALTH AND RETIREMENT STUDY

MLA Citation
"INTEGRATING GENETIC DATA INTO HEALTH AND MORTALITY FORECASTING USING THE HEALTH AND RETIREMENT STUDY." November 2016.
Source
crossref
Published In
The Gerontologist
Volume
56
Issue
Suppl_3
Publish Date
2016
Start Page
660
End Page
660
DOI
10.1093/geront/gnw162.2684

GENETIC PREDISPOSITION TO AGE-RELATED PHENOTYPES IN THE LIGHT OF EVOLUTION

MLA Citation
"GENETIC PREDISPOSITION TO AGE-RELATED PHENOTYPES IN THE LIGHT OF EVOLUTION." November 2016.
Source
crossref
Published In
The Gerontologist
Volume
56
Issue
Suppl_3
Publish Date
2016
Start Page
49
End Page
49
DOI
10.1093/geront/gnw162.204

PLEIOTROPIC META-ANALYSIS IDENTIFIES SHARED GENETIC CONNECTIONS BETWEEN DISTINCT AGE-RELATED TRAITS

MLA Citation
"PLEIOTROPIC META-ANALYSIS IDENTIFIES SHARED GENETIC CONNECTIONS BETWEEN DISTINCT AGE-RELATED TRAITS." November 2016.
Source
crossref
Published In
The Gerontologist
Volume
56
Issue
Suppl_3
Publish Date
2016
Start Page
251
End Page
251
DOI
10.1093/geront/gnw162.1006

GENES WITH PLEIOTROPIC EFFECTS ON AGING-RELATED TRAITS IN HUMANS

MLA Citation
"GENES WITH PLEIOTROPIC EFFECTS ON AGING-RELATED TRAITS IN HUMANS." November 2016.
Source
crossref
Published In
The Gerontologist
Volume
56
Issue
Suppl_3
Publish Date
2016
Start Page
266
End Page
266
DOI
10.1093/geront/gnw162.1074

A NOVEL ALLELIC VARIANT IN A 2Q22 REGION CONFERS RISKS OF MAJOR HUMAN DISEASES AND MORTALITY

MLA Citation
"A NOVEL ALLELIC VARIANT IN A 2Q22 REGION CONFERS RISKS OF MAJOR HUMAN DISEASES AND MORTALITY." November 2016.
Source
crossref
Published In
The Gerontologist
Volume
56
Issue
Suppl_3
Publish Date
2016
Start Page
266
End Page
266
DOI
10.1093/geront/gnw162.1072

Explicating heterogeneity of complex traits has strong potential for improving GWAS efficiency.

Common strategy of genome-wide association studies (GWAS) relying on large samples faces difficulties, which raise concerns that GWAS have exhausted their potential, particularly for complex traits. Here, we examine the efficiency of the traditional sample-size-centered strategy in GWAS of these traits, and its potential for improvement. The paper focuses on the results of the four largest GWAS meta-analyses of body mass index (BMI) and lipids. We show that just increasing sample size may not make p-values of genetic effects in large (N > 100,000) samples smaller but can make them larger. The efficiency of these GWAS, defined as ratio of the log-transformed p-value to the sample size, in larger samples was larger than in smaller samples for a small fraction of loci. These results emphasize the important role of heterogeneity in genetic associations with complex traits such as BMI and lipids. They highlight the substantial potential for improving GWAS by explicating this role (affecting 11-79% of loci in the selected GWAS), especially the effects of biodemographic processes, which are heavily underexplored in current GWAS and which are important sources of heterogeneity in the various study populations. Further progress in this direction is crucial for efficient use of genetic discoveries in health care.

Authors
Kulminski, AM; Loika, Y; Culminskaya, I; Arbeev, KG; Ukraintseva, SV; Stallard, E; Yashin, AI
MLA Citation
Kulminski, AM, Loika, Y, Culminskaya, I, Arbeev, KG, Ukraintseva, SV, Stallard, E, and Yashin, AI. "Explicating heterogeneity of complex traits has strong potential for improving GWAS efficiency." Scientific reports 6 (October 14, 2016): 35390-.
Website
http://hdl.handle.net/10161/14753
PMID
27739495
Source
epmc
Published In
Scientific Reports
Volume
6
Publish Date
2016
Start Page
35390
DOI
10.1038/srep35390

Interaction Between the FOXO1A-209 Genotype and Tea Drinking Is Significantly Associated with Reduced Mortality at Advanced Ages.

On the basis of the genotypic/phenotypic data from Chinese Longitudinal Healthy Longevity Survey (CLHLS) and Cox proportional hazard model, the present study demonstrates that interactions between carrying FOXO1A-209 genotypes and tea drinking are significantly associated with lower risk of mortality at advanced ages. Such a significant association is replicated in two independent Han Chinese CLHLS cohorts (p = 0.028-0.048 in the discovery and replication cohorts, and p = 0.003-0.016 in the combined dataset). We found the associations between tea drinking and reduced mortality are much stronger among carriers of the FOXO1A-209 genotype compared to non-carriers, and drinking tea is associated with a reversal of the negative effects of carrying FOXO1A-209 minor alleles, that is, from a substantially increased mortality risk to substantially reduced mortality risk at advanced ages. The impacts are considerably stronger among those who carry two copies of the FOXO1A minor allele than those who carry one copy. On the basis of previously reported experiments on human cell models concerning FOXO1A-by-tea-compounds interactions, we speculate that results in the present study indicate that tea drinking may inhibit FOXO1A-209 gene expression and its biological functions, which reduces the negative impacts of FOXO1A-209 gene on longevity (as reported in the literature) and offers protection against mortality risk at oldest-old ages. Our empirical findings imply that the health outcomes of particular nutritional interventions, including tea drinking, may, in part, depend upon individual genetic profiles, and the research on the effects of nutrigenomics interactions could potentially be useful for rejuvenation therapies in the clinic or associated healthy aging intervention programs.

Authors
Zeng, Y; Chen, H; Ni, T; Ruan, R; Nie, C; Liu, X; Feng, L; Zhang, F; Lu, J; Li, J; Li, Y; Tao, W; Gregory, SG; Gottschalk, W; Lutz, MW; Land, KC; Yashin, A; Tan, Q; Yang, Z; Bolund, L; Ming, Q; Yang, H; Min, J; Willcox, DC; Willcox, BJ; Gu, J; Hauser, E; Tian, X-L; Vaupel, JW
MLA Citation
Zeng, Y, Chen, H, Ni, T, Ruan, R, Nie, C, Liu, X, Feng, L, Zhang, F, Lu, J, Li, J, Li, Y, Tao, W, Gregory, SG, Gottschalk, W, Lutz, MW, Land, KC, Yashin, A, Tan, Q, Yang, Z, Bolund, L, Ming, Q, Yang, H, Min, J, Willcox, DC, Willcox, BJ, Gu, J, Hauser, E, Tian, X-L, and Vaupel, JW. "Interaction Between the FOXO1A-209 Genotype and Tea Drinking Is Significantly Associated with Reduced Mortality at Advanced Ages." Rejuvenation research 19.3 (June 2016): 195-203.
Website
http://hdl.handle.net/10161/14659
PMID
26414954
Source
epmc
Published In
Rejuvenation Research
Volume
19
Issue
3
Publish Date
2016
Start Page
195
End Page
203
DOI
10.1089/rej.2015.1737

Dynamics of biomarkers in relation to aging and mortality.

Contemporary longitudinal studies collect repeated measurements of biomarkers allowing one to analyze their dynamics in relation to mortality, morbidity, or other health-related outcomes. Rich and diverse data collected in such studies provide opportunities to investigate how various socio-economic, demographic, behavioral and other variables can interact with biological and genetic factors to produce differential rates of aging in individuals. In this paper, we review some recent publications investigating dynamics of biomarkers in relation to mortality, which use single biomarkers as well as cumulative measures combining information from multiple biomarkers. We also discuss the analytical approach, the stochastic process models, which conceptualizes several aging-related mechanisms in the structure of the model and allows evaluating "hidden" characteristics of aging-related changes indirectly from available longitudinal data on biomarkers and follow-up on mortality or onset of diseases taking into account other relevant factors (both genetic and non-genetic). We also discuss an extension of the approach, which considers ranges of "optimal values" of biomarkers rather than a single optimal value as in the original model. We discuss practical applications of the approach to single biomarkers and cumulative measures highlighting that the potential of applications to cumulative measures is still largely underused.

Authors
Arbeev, KG; Ukraintseva, SV; Yashin, AI
MLA Citation
Arbeev, KG, Ukraintseva, SV, and Yashin, AI. "Dynamics of biomarkers in relation to aging and mortality." Mechanisms of ageing and development 156 (June 2016): 42-54. (Review)
Website
http://hdl.handle.net/10161/14756
PMID
27138087
Source
epmc
Published In
Mechanisms of Ageing and Development
Volume
156
Publish Date
2016
Start Page
42
End Page
54
DOI
10.1016/j.mad.2016.04.010

Resistance to stresses and reliability of biological systems: Insights for genetic studies of human aging, health, and longevity

© 2016 IEEE. Connection between stress resistance and longevity in biological organisms is widely discussed and confirmed experimentally. Much less is known about the roles of genetic and non-genetic factors in regulation of such connection. Earlier studies emphasized that mechanism that realizes such connection involves interplay between processes of individual aging and external challenges. As a result of such interplay the parameters of the Gompertz mortality curve are negatively correlated. Such correlation has been also observed in the process of survival improvement in developed part of the world during the first part of the last century. The mortality decline was mainly due to favorable changes in external and living conditions as well as progress in health care. Surprisingly, similar pattern of survival changes is observed in the groups of individuals ranked with respect to the number of «longevity» alleles carried by individuals. We showed that this phenomenon can be interpreted as an increase in resistance to stresses and showed that similar effect is observed in reliability of technical systems when redundancy of their components increases. The availability of longitudinal data for genotyped individuals opens unique opportunity to address more sophisticated questions about roles of genetic and non-genetic factors in connection between aging, stress resistance and longevity in humans. For this purpose the dynamic model of human mortality and aging is used. We show how such model can be used in genetic analyses of fundamental processes of interaction between genetic and non-genetic factors to influence human longevity.

Authors
Yashin, AI; Arbeev, KG; Arbeeva, LS; Wu, D; Akushevich, I; Kulminski, A; Kovtun, M; Zhbannikov, I; Ukraintseva, SV
MLA Citation
Yashin, AI, Arbeev, KG, Arbeeva, LS, Wu, D, Akushevich, I, Kulminski, A, Kovtun, M, Zhbannikov, I, and Ukraintseva, SV. "Resistance to stresses and reliability of biological systems: Insights for genetic studies of human aging, health, and longevity." March 11, 2016.
Website
http://hdl.handle.net/10161/14818
Source
scopus
Published In
Proceedings - 2nd International Symposium on Stochastic Models in Reliability Engineering, Life Science, and Operations Management, SMRLO 2016
Publish Date
2016
Start Page
403
End Page
409
DOI
10.1109/SMRLO.2016.70

Puzzling role of genetic risk factors in human longevity: "risk alleles" as pro-longevity variants.

Complex diseases are major contributors to human mortality in old age. Paradoxically, many genetic variants that have been associated with increased risks of such diseases are found in genomes of long-lived people, and do not seem to compromise longevity. Here we argue that trade-off-like and conditional effects of genes can play central role in this phenomenon and in determining longevity. Such effects may occur as result of: (i) antagonistic influence of gene on the development of different health disorders; (ii) change in the effect of gene on vulnerability to death with age (especially, from "bad" to "good"); (iii) gene-gene interaction; and (iv) gene-environment interaction, among other factors. A review of current knowledge provides many examples of genetic factors that may increase the risk of one disease but reduce chances of developing another serious health condition, or improve survival from it. Factors that may increase risk of a major disease but attenuate manifestation of physical senescence are also discussed. Overall, available evidence suggests that the influence of a genetic variant on longevity may be negative, neutral or positive, depending on a delicate balance of the detrimental and beneficial effects of such variant on multiple health and aging related traits. This balance may change with age, internal and external environments, and depend on genetic surrounding. We conclude that trade-off-like and conditional genetic effects are very common and may result in situations when a disease "risk allele" can also be a pro-longevity variant, depending on context. We emphasize importance of considering such effects in both aging research and disease prevention.

Authors
Ukraintseva, S; Yashin, A; Arbeev, K; Kulminski, A; Akushevich, I; Wu, D; Joshi, G; Land, KC; Stallard, E
MLA Citation
Ukraintseva, S, Yashin, A, Arbeev, K, Kulminski, A, Akushevich, I, Wu, D, Joshi, G, Land, KC, and Stallard, E. "Puzzling role of genetic risk factors in human longevity: "risk alleles" as pro-longevity variants." Biogerontology 17.1 (February 2016): 109-127. (Review)
Website
http://hdl.handle.net/10161/14816
PMID
26306600
Source
epmc
Published In
Biogerontology
Volume
17
Issue
1
Publish Date
2016
Start Page
109
End Page
127
DOI
10.1007/s10522-015-9600-1

How the effects of aging and stresses of life are integrated in mortality rates: insights for genetic studies of human health and longevity.

Increasing proportions of elderly individuals in developed countries combined with substantial increases in related medical expenditures make the improvement of the health of the elderly a high priority today. If the process of aging by individuals is a major cause of age related health declines then postponing aging could be an efficient strategy for improving the health of the elderly. Implementing this strategy requires a better understanding of genetic and non-genetic connections among aging, health, and longevity. We review progress and problems in research areas whose development may contribute to analyses of such connections. These include genetic studies of human aging and longevity, the heterogeneity of populations with respect to their susceptibility to disease and death, forces that shape age patterns of human mortality, secular trends in mortality decline, and integrative mortality modeling using longitudinal data. The dynamic involvement of genetic factors in (i) morbidity/mortality risks, (ii) responses to stresses of life, (iii) multi-morbidities of many elderly individuals, (iv) trade-offs for diseases, (v) genetic heterogeneity, and (vi) other relevant aging-related health declines, underscores the need for a comprehensive, integrated approach to analyze the genetic connections for all of the above aspects of aging-related changes. The dynamic relationships among aging, health, and longevity traits would be better understood if one linked several research fields within one conceptual framework that allowed for efficient analyses of available longitudinal data using the wealth of available knowledge about aging, health, and longevity already accumulated in the research field.

Authors
Yashin, AI; Arbeev, KG; Arbeeva, LS; Wu, D; Akushevich, I; Kovtun, M; Yashkin, A; Kulminski, A; Culminskaya, I; Stallard, E; Li, M; Ukraintseva, SV
MLA Citation
Yashin, AI, Arbeev, KG, Arbeeva, LS, Wu, D, Akushevich, I, Kovtun, M, Yashkin, A, Kulminski, A, Culminskaya, I, Stallard, E, Li, M, and Ukraintseva, SV. "How the effects of aging and stresses of life are integrated in mortality rates: insights for genetic studies of human health and longevity." Biogerontology 17.1 (February 2016): 89-107. (Review)
Website
http://hdl.handle.net/10161/14803
PMID
26280653
Source
epmc
Published In
Biogerontology
Volume
17
Issue
1
Publish Date
2016
Start Page
89
End Page
107
DOI
10.1007/s10522-015-9594-8

Optimal Versus Realized Trajectories of Physiological Dysregulation in Aging and Their Relation to Sex-Specific Mortality Risk.

While longitudinal changes in biomarker levels and their impact on health have been characterized for individual markers, little is known about how overall marker profiles may change during aging and affect mortality risk. We implemented the recently developed measure of physiological dysregulation based on the statistical distance of biomarker profiles in the framework of the stochastic process model of aging, using data on blood pressure, heart rate, cholesterol, glucose, hematocrit, body mass index, and mortality in the Framingham original cohort. This allowed us to evaluate how physiological dysregulation is related to different aging-related characteristics such as decline in stress resistance and adaptive capacity (which typically are not observed in the data and thus can be analyzed only indirectly), and, ultimately, to estimate how such dynamic relationships increase mortality risk with age. We found that physiological dysregulation increases with age; that increased dysregulation is associated with increased mortality, and increasingly so with age; and that, in most but not all cases, there is a decreasing ability to return quickly to baseline physiological state with age. We also revealed substantial sex differences in these processes, with women becoming dysregulated more quickly but with men showing a much greater sensitivity to dysregulation in terms of mortality risk.

Authors
Arbeev, KG; Cohen, AA; Arbeeva, LS; Milot, E; Stallard, E; Kulminski, AM; Akushevich, I; Ukraintseva, SV; Christensen, K; Yashin, AI
MLA Citation
Arbeev, KG, Cohen, AA, Arbeeva, LS, Milot, E, Stallard, E, Kulminski, AM, Akushevich, I, Ukraintseva, SV, Christensen, K, and Yashin, AI. "Optimal Versus Realized Trajectories of Physiological Dysregulation in Aging and Their Relation to Sex-Specific Mortality Risk." Frontiers in public health 4 (January 25, 2016): 3-.
Website
http://hdl.handle.net/10161/14757
PMID
26835445
Source
epmc
Published In
Frontiers in Public Health
Volume
4
Publish Date
2016
Start Page
3
DOI
10.3389/fpubh.2016.00003

How Genes Modulate Patterns of Aging-Related Changes on the Way to 100: Biodemographic Models and Methods in Genetic Analyses of Longitudinal Data.

To clarify mechanisms of genetic regulation of human aging and longevity traits, a number of genome-wide association studies (GWAS) of these traits have been performed. However, the results of these analyses did not meet expectations of the researchers. Most detected genetic associations have not reached a genome-wide level of statistical significance, and suffered from the lack of replication in the studies of independent populations. The reasons for slow progress in this research area include low efficiency of statistical methods used in data analyses, genetic heterogeneity of aging and longevity related traits, possibility of pleiotropic (e.g., age dependent) effects of genetic variants on such traits, underestimation of the effects of (i) mortality selection in genetically heterogeneous cohorts, (ii) external factors and differences in genetic backgrounds of individuals in the populations under study, the weakness of conceptual biological framework that does not fully account for above mentioned factors. One more limitation of conducted studies is that they did not fully realize the potential of longitudinal data that allow for evaluating how genetic influences on life span are mediated by physiological variables and other biomarkers during the life course. The objective of this paper is to address these issues.We performed GWAS of human life span using different subsets of data from the original Framingham Heart Study cohort corresponding to different quality control (QC) procedures and used one subset of selected genetic variants for further analyses. We used simulation study to show that approach to combining data improves the quality of GWAS. We used FHS longitudinal data to compare average age trajectories of physiological variables in carriers and non-carriers of selected genetic variants. We used stochastic process model of human mortality and aging to investigate genetic influence on hidden biomarkers of aging and on dynamic interaction between aging and longevity. We investigated properties of genes related to selected variants and their roles in signaling and metabolic pathways.We showed that the use of different QC procedures results in different sets of genetic variants associated with life span. We selected 24 genetic variants negatively associated with life span. We showed that the joint analyses of genetic data at the time of bio-specimen collection and follow up data substantially improved significance of associations of selected 24 SNPs with life span. We also showed that aging related changes in physiological variables and in hidden biomarkers of aging differ for the groups of carriers and non-carriers of selected variants.. The results of these analyses demonstrated benefits of using biodemographic models and methods in genetic association studies of these traits. Our findings showed that the absence of a large number of genetic variants with deleterious effects may make substantial contribution to exceptional longevity. These effects are dynamically mediated by a number of physiological variables and hidden biomarkers of aging. The results of these research demonstrated benefits of using integrative statistical models of mortality risks in genetic studies of human aging and longevity.

Authors
Yashin, AI; Arbeev, KG; Wu, D; Arbeeva, L; Kulminski, A; Kulminskaya, I; Akushevich, I; Ukraintseva, SV
MLA Citation
Yashin, AI, Arbeev, KG, Wu, D, Arbeeva, L, Kulminski, A, Kulminskaya, I, Akushevich, I, and Ukraintseva, SV. "How Genes Modulate Patterns of Aging-Related Changes on the Way to 100: Biodemographic Models and Methods in Genetic Analyses of Longitudinal Data." North American actuarial journal : NAAJ 20.3 (January 2016): 201-232.
Website
http://hdl.handle.net/10161/14755
PMID
27773987
Source
epmc
Published In
North American Actuarial Journal
Volume
20
Issue
3
Publish Date
2016
Start Page
201
End Page
232
DOI
10.1080/10920277.2016.1178588

Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases.

Age-related diseases may result from shared biological mechanisms in intrinsic processes of aging. Genetic effects on age-related diseases are often modulated by environmental factors due to their little contribution to fitness or are mediated through certain endophenotypes. Identification of genetic variants with pleiotropic effects on both common complex diseases and endophenotypes may reveal potential conflicting evolutionary pressures and deliver new insights into shared genetic contribution to healthspan and lifespan. Here, we performed pleiotropic meta-analyses of genetic variants using five NIH-funded datasets by integrating univariate summary statistics for age-related diseases and endophenotypes. We investigated three groups of traits: (1) endophenotypes such as blood glucose, blood pressure, lipids, hematocrit, and body mass index, (2) time-to-event outcomes such as the age-at-onset of diabetes mellitus (DM), cancer, cardiovascular diseases (CVDs) and neurodegenerative diseases (NDs), and (3) both combined. In addition to replicating previous findings, we identify seven novel genome-wide significant loci (< 5e-08), out of which five are low-frequency variants. Specifically, from Group 2, we find rs7632505 on 3q21.1 in SEMA5B, rs460976 on 21q22.3 (1 kb from TMPRSS2) and rs12420422 on 11q24.1 predominantly associated with a variety of CVDs, rs4905014 in ITPK1 associated with stroke and heart failure, rs7081476 on 10p12.1 in ANKRD26 associated with multiple diseases including DM, CVDs, and NDs. From Group 3, we find rs8082812 on 18p11.22 and rs1869717 on 4q31.3 associated with both endophenotypes and CVDs. Our follow-up analyses show that rs7632505, rs4905014, and rs8082812 have age-dependent effects on coronary heart disease or stroke. Functional annotation suggests that most of these SNPs are within regulatory regions or DNase clusters and in linkage disequilibrium with expression quantitative trait loci, implying their potential regulatory influence on the expression of nearby genes. Our mediation analyses suggest that the effects of some SNPs are mediated by specific endophenotypes. In conclusion, these findings indicate that loci with pleiotropic effects on age-related disorders tend to be enriched in genes involved in underlying mechanisms potentially related to nervous, cardiovascular and immune system functions, stress resistance, inflammation, ion channels and hematopoiesis, supporting the hypothesis of shared pathological role of infection, and inflammation in chronic age-related diseases.

Authors
He, L; Kernogitski, Y; Kulminskaya, I; Loika, Y; Arbeev, KG; Loiko, E; Bagley, O; Duan, M; Yashkin, A; Ukraintseva, SV; Kovtun, M; Yashin, AI; Kulminski, AM
MLA Citation
He, L, Kernogitski, Y, Kulminskaya, I, Loika, Y, Arbeev, KG, Loiko, E, Bagley, O, Duan, M, Yashkin, A, Ukraintseva, SV, Kovtun, M, Yashin, AI, and Kulminski, AM. "Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases." Frontiers in genetics 7 (January 2016): 179-.
Website
http://hdl.handle.net/10161/14749
PMID
27790247
Source
epmc
Published In
Frontiers in Genetics
Volume
7
Publish Date
2016
Start Page
179

Pure and Confounded Effects of Causal SNPs on Longevity: Insights for Proper Interpretation of Research Findings in GWAS of Populations with Different Genetic Structures.

This paper shows that the effects of causal SNPs on lifespan, estimated through GWAS, may be confounded and the genetic structure of the study population may be responsible for this effect. Simulation experiments show that levels of linkage disequilibrium (LD) and other parameters of the population structure describing connections between two causal SNPs may substantially influence separate estimates of the effect of the causal SNPs on lifespan. This study suggests that differences in LD levels between two causal SNP loci within two study populations may contribute to the failure to replicate previous GWAS findings. The results of this paper also show that successful replication of the results of genetic association studies does not necessarily guarantee proper interpretation of the effect of a causal SNP on lifespan.

Authors
Yashin, AI; Zhbannikov, I; Arbeeva, L; Arbeev, KG; Wu, D; Akushevich, I; Yashkin, A; Kovtun, M; Kulminski, AM; Stallard, E; Kulminskaya, I; Ukraintseva, S
MLA Citation
Yashin, AI, Zhbannikov, I, Arbeeva, L, Arbeev, KG, Wu, D, Akushevich, I, Yashkin, A, Kovtun, M, Kulminski, AM, Stallard, E, Kulminskaya, I, and Ukraintseva, S. "Pure and Confounded Effects of Causal SNPs on Longevity: Insights for Proper Interpretation of Research Findings in GWAS of Populations with Different Genetic Structures." Frontiers in genetics 7 (January 2016): 188-.
Website
http://hdl.handle.net/10161/14751
PMID
27877192
Source
epmc
Published In
Frontiers in Genetics
Volume
7
Publish Date
2016
Start Page
188

Coordinated Action of Biological Processes during Embryogenesis Can Cause Genome-Wide Linkage Disequilibrium in the Human Genome and Influence Age-Related Phenotypes.

A role of non-Mendelian inheritance in genetics of complex, age-related traits is becoming increasingly recognized. Recently, we reported on two inheritable clusters of SNPs in extensive genome-wide linkage disequilibrium (LD) in the Framingham Heart Study (FHS), which were associated with the phenotype of premature death. Here we address biologically-related properties of these two clusters. These clusters have been unlikely selected randomly because they are functionally and structurally different from matched sets of randomly selected SNPs. For example, SNPs in LD from each cluster are highly significantly enriched in genes (p=7.1×10-22 and p=5.8×10-18), in general, and in short genes (p=1.4×10-47 and p=4.6×10-7), in particular. Mapping of SNPs in LD to genes resulted in two, partly overlapping, networks of 1764 and 4806 genes. Both these networks were gene enriched in developmental processes and in biological processes tightly linked with development including biological adhesion, cellular component organization, locomotion, localization, signaling, (p<10-4, q<10-4 for each category). Thorough analysis suggests connections of these genetic networks with different stages of embryogenesis and highlights biological interlink of specific processes enriched for genes from these networks. The results suggest that coordinated action of biological processes during embryogenesis may generate genome-wide networks of genetic variants, which may influence complex age-related phenotypes characterizing health span and lifespan.

Authors
Culminskaya, I; Kulminski, AM; Yashin, AI
MLA Citation
Culminskaya, I, Kulminski, AM, and Yashin, AI. "Coordinated Action of Biological Processes during Embryogenesis Can Cause Genome-Wide Linkage Disequilibrium in the Human Genome and Influence Age-Related Phenotypes." Annals of gerontology and geriatric research 3.1 (January 2016).
Website
http://hdl.handle.net/10161/14797
PMID
28357417
Source
epmc
Published In
Annals of gerontology and geriatric research
Volume
3
Issue
1
Publish Date
2016

On Approaches to Improve Power in Analyses of Genetic Effects on Time-To-Event Outcomes in Longitudinal Studies

Authors
Arbeev, KG; Arbeeva, LS; Bagley, O; Duan, H; Akushevich, I; Kulminski, AM; Kovtun, M; Culminskaya, IV; Wu, D; Ukraintseva, SV; Yashin, AI
MLA Citation
Arbeev, KG, Arbeeva, LS, Bagley, O, Duan, H, Akushevich, I, Kulminski, AM, Kovtun, M, Culminskaya, IV, Wu, D, Ukraintseva, SV, and Yashin, AI. "On Approaches to Improve Power in Analyses of Genetic Effects on Time-To-Event Outcomes in Longitudinal Studies." November 2015.
Source
wos-lite
Published In
Genetic Epidemiology
Volume
39
Issue
7
Publish Date
2015
Start Page
530
End Page
530

Unfolding heterogeneity of complex traits has strong potential for advancing GWAS

Authors
Kulminski, AM; Loika, Y; Culminskaya, I; Arbeev, KG; Yashin, AI
MLA Citation
Kulminski, AM, Loika, Y, Culminskaya, I, Arbeev, KG, and Yashin, AI. "Unfolding heterogeneity of complex traits has strong potential for advancing GWAS." November 2015.
Source
wos-lite
Published In
Genetic Epidemiology
Volume
39
Issue
7
Publish Date
2015
Start Page
562
End Page
562

IMPACTS OF CEREBROVASCULAR AND NEURODEGENERATIVE DISEASES ON SURVIVAL OF LUNG CANCER PATIENTS

MLA Citation
"IMPACTS OF CEREBROVASCULAR AND NEURODEGENERATIVE DISEASES ON SURVIVAL OF LUNG CANCER PATIENTS." The Gerontologist 55.Suppl_2 (November 2015): 496-496.
Website
http://hdl.handle.net/10161/14798
Source
crossref
Published In
The Gerontologist
Volume
55
Issue
Suppl_2
Publish Date
2015
Start Page
496
End Page
496
DOI
10.1093/geront/gnv214.03

GENETIC HETEROGENEITY AND ITS ROLE IN GWAS OF HUMAN AGING AND LONGEVITY

MLA Citation
"GENETIC HETEROGENEITY AND ITS ROLE IN GWAS OF HUMAN AGING AND LONGEVITY." November 2015.
Source
crossref
Published In
The Gerontologist
Volume
55
Issue
Suppl_2
Publish Date
2015
Start Page
859
End Page
859
DOI
10.1093/geront/gnv490.04

BIODEMOGRAPHIC APPROACHES TO ANALYSES OF POLYGENETIC EFFECTS ON MORTALITY AND AGING

MLA Citation
"BIODEMOGRAPHIC APPROACHES TO ANALYSES OF POLYGENETIC EFFECTS ON MORTALITY AND AGING." November 2015.
Source
crossref
Published In
The Gerontologist
Volume
55
Issue
Suppl_2
Publish Date
2015
Start Page
200
End Page
200
DOI
10.1093/geront/gnv554.16

PLEIOTROPIC EFFECTS OF GENES ON AGE-RELATED PHENOTYPES: INSIGHTS FROM GERONTOLOGICAL APPROACHES

MLA Citation
"PLEIOTROPIC EFFECTS OF GENES ON AGE-RELATED PHENOTYPES: INSIGHTS FROM GERONTOLOGICAL APPROACHES." November 2015.
Source
crossref
Published In
The Gerontologist
Volume
55
Issue
Suppl_2
Publish Date
2015
Start Page
460
End Page
461
DOI
10.1093/geront/gnv195.07

THE HEALTH OF SPOUSES MARRYING INTO LONGEVITY-ENRICHED FAMILIES

MLA Citation
"THE HEALTH OF SPOUSES MARRYING INTO LONGEVITY-ENRICHED FAMILIES." November 2015.
Source
crossref
Published In
The Gerontologist
Volume
55
Issue
Suppl_2
Publish Date
2015
Start Page
7
End Page
7
DOI
10.1093/geront/gnv507.03

PLEIOTROPIC EFFECTS OF GENES ON PHENOTYPES OF AGING, COMPLEX DISEASE AND LONGEVITY

MLA Citation
"PLEIOTROPIC EFFECTS OF GENES ON PHENOTYPES OF AGING, COMPLEX DISEASE AND LONGEVITY." November 2015.
Source
crossref
Published In
The Gerontologist
Volume
55
Issue
Suppl_2
Publish Date
2015
Start Page
459
End Page
459
DOI
10.1093/geront/gnv195.02

THE ROLE OF BIODEMOGRAPHIC FACTORS IN GENETICS OF AGE-RELATED PHENOTYPES

MLA Citation
"THE ROLE OF BIODEMOGRAPHIC FACTORS IN GENETICS OF AGE-RELATED PHENOTYPES." November 2015.
Source
crossref
Published In
The Gerontologist
Volume
55
Issue
Suppl_2
Publish Date
2015
Start Page
460
End Page
460
DOI
10.1093/geront/gnv195.06

TIME TRENDS OF DISEASE PREVALENCE AMONG OLDER U.S. ADULTS

MLA Citation
"TIME TRENDS OF DISEASE PREVALENCE AMONG OLDER U.S. ADULTS." November 2015.
Source
crossref
Published In
The Gerontologist
Volume
55
Issue
Suppl_2
Publish Date
2015
Start Page
27
End Page
27
DOI
10.1093/geront/gnv205.04

Quantification of biological aging in young adults.

Antiaging therapies show promise in model organism research. Translation to humans is needed to address the challenges of an aging global population. Interventions to slow human aging will need to be applied to still-young individuals. However, most human aging research examines older adults, many with chronic disease. As a result, little is known about aging in young humans. We studied aging in 954 young humans, the Dunedin Study birth cohort, tracking multiple biomarkers across three time points spanning their third and fourth decades of life. We developed and validated two methods by which aging can be measured in young adults, one cross-sectional and one longitudinal. Our longitudinal measure allows quantification of the pace of coordinated physiological deterioration across multiple organ systems (e.g., pulmonary, periodontal, cardiovascular, renal, hepatic, and immune function). We applied these methods to assess biological aging in young humans who had not yet developed age-related diseases. Young individuals of the same chronological age varied in their "biological aging" (declining integrity of multiple organ systems). Already, before midlife, individuals who were aging more rapidly were less physically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biological aging in young adults can be used to identify causes of aging and evaluate rejuvenation therapies.

Authors
Belsky, DW; Caspi, A; Houts, R; Cohen, HJ; Corcoran, DL; Danese, A; Harrington, H; Israel, S; Levine, ME; Schaefer, JD; Sugden, K; Williams, B; Yashin, AI; Poulton, R; Moffitt, TE
MLA Citation
Belsky, DW, Caspi, A, Houts, R, Cohen, HJ, Corcoran, DL, Danese, A, Harrington, H, Israel, S, Levine, ME, Schaefer, JD, Sugden, K, Williams, B, Yashin, AI, Poulton, R, and Moffitt, TE. "Quantification of biological aging in young adults." Proceedings of the National Academy of Sciences of the United States of America 112.30 (July 6, 2015): E4104-E4110.
Website
http://hdl.handle.net/10161/10319
PMID
26150497
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
112
Issue
30
Publish Date
2015
Start Page
E4104
End Page
E4110
DOI
10.1073/pnas.1506264112

GxE interactions between FOXO genotypes and drinking tea are significantly associated with prevention of cognitive decline in advanced age in China.

Logistic regression analysis based on data from 822 Han Chinese oldest old aged 92+ demonstrated that interactions between carrying FOXO1A-266 or FOXO3-310 or FOXO3-292 and tea drinking at around age 60 or at present time were significantly associated with lower risk of cognitive disability at advanced ages. Associations between tea drinking and reduced cognitive disability were much stronger among carriers of the genotypes of FOXO1A-266 or FOXO3-310 or FOXO3-292 compared with noncarriers, and it was reconfirmed by analysis of three-way interactions across FOXO genotypes, tea drinking at around age 60, and at present time. Based on prior findings from animal and human cell models, we postulate that intake of tea compounds may activate FOXO gene expression, which in turn may positively affect cognitive function in the oldest old population. Our empirical findings imply that the health benefits of particular nutritional interventions, including tea drinking, may, in part, depend upon individual genetic profiles.

Authors
Zeng, Y; Chen, H; Ni, T; Ruan, R; Feng, L; Nie, C; Cheng, L; Li, Y; Tao, W; Gu, J; Land, KC; Yashin, A; Tan, Q; Yang, Z; Bolund, L; Yang, H; Hauser, E; Willcox, DC; Willcox, BJ; Tian, X-L; Vaupel, JW
MLA Citation
Zeng, Y, Chen, H, Ni, T, Ruan, R, Feng, L, Nie, C, Cheng, L, Li, Y, Tao, W, Gu, J, Land, KC, Yashin, A, Tan, Q, Yang, Z, Bolund, L, Yang, H, Hauser, E, Willcox, DC, Willcox, BJ, Tian, X-L, and Vaupel, JW. "GxE interactions between FOXO genotypes and drinking tea are significantly associated with prevention of cognitive decline in advanced age in China." The journals of gerontology. Series A, Biological sciences and medical sciences 70.4 (April 2015): 426-433.
Website
http://hdl.handle.net/10161/14682
PMID
24895270
Source
epmc
Published In
Journals of Gerontology: Series A
Volume
70
Issue
4
Publish Date
2015
Start Page
426
End Page
433
DOI
10.1093/gerona/glu060

Trade-offs in the effects of the apolipoprotein E polymorphism on risks of diseases of the heart, cancer, and neurodegenerative disorders: insights on mechanisms from the Long Life Family Study.

The lack of evolutionary established mechanisms linking genes to age-related traits makes the problem of genetic susceptibility to health span inherently complex. One complicating factor is genetic trade-off. Here we focused on long-living participants of the Long Life Family Study (LLFS), their offspring, and spouses to: (1) Elucidate whether trade-offs in the effect of the apolipoprotein E e4 allele documented in the Framingham Heart Study (FHS) are a more general phenomenon, and (2) explore potential mechanisms generating age- and gender-specific trade-offs in the effect of the e4 allele on cancer, diseases of the heart, and neurodegenerative disorders assessed retrospectively in the LLFS populations. The e4 allele can diminish risks of cancer and diseases of the heart and confer risks of diseases of the heart in a sex-, age-, and LLFS-population-specific manner. A protective effect against cancer is seen in older long-living men and, potentially, their sons (>75 years, relative risk [RR]>75=0.48, p=0.086), which resembles our findings in the FHS. The protective effect against diseases of the heart is limited to long-living older men (RR>76=0.50, p=0.016), as well. A detrimental effect against diseases of the heart is characteristic for a normal LLFS population of male spouses and is specific for myocardial infarction (RR=3.07, p=2.1×10(-3)). These trade-offs are likely associated with two inherently different mechanisms, including disease-specific (detrimental; characteristic for a normal male population) and systemic, aging-related (protective; characteristic for older long-living men) mechanisms. The e4 allele confers risks of neurological disorders in men and women (RR=1.98, p=0.046). The results highlight the complex role of the e4 allele in genetic susceptibility to health span.

Authors
Kulminski, AM; Arbeev, KG; Culminskaya, I; Ukraintseva, SV; Stallard, E; Province, MA; Yashin, AI
MLA Citation
Kulminski, AM, Arbeev, KG, Culminskaya, I, Ukraintseva, SV, Stallard, E, Province, MA, and Yashin, AI. "Trade-offs in the effects of the apolipoprotein E polymorphism on risks of diseases of the heart, cancer, and neurodegenerative disorders: insights on mechanisms from the Long Life Family Study." Rejuvenation research 18.2 (April 2015): 128-135.
Website
http://hdl.handle.net/10161/14864
PMID
25482294
Source
epmc
Published In
Rejuvenation Research
Volume
18
Issue
2
Publish Date
2015
Start Page
128
End Page
135
DOI
10.1089/rej.2014.1616

Cardiovascular comorbidities and survival of lung cancer patients: Medicare data based analysis.

To evaluate the role of cardiovascular disease (CVD) comorbidity in survival of patients with non-small cell lung cancer (NSCLC).The impact of seven CVDs (at the time of NSCLC diagnosis and during subsequent follow-up) on overall survival was studied for NSCLC patients aged 65+ years using the Surveillance, Epidemiology, and End Results data linked to the U.S. Medicare data, cancer stage- and treatment-specific. Cox regression was applied to evaluate death hazard ratios of CVDs in univariable and multivariable analyses (controlling by age, TNM statuses, and 78 non-CVD comorbidities) and to investigate the effects of 128 different combinations of CVDs on patients' survival.Overall, 95,167 patients with stage I (n=29,836, 31.4%), II (n=5133, 5.4%), IIIA (n=11,884, 12.5%), IIIB (n=18,020, 18.9%), and IV (n=30,294, 31.8%) NSCLC were selected. Most CVDs increased the risk of death for stages I-IIIB patients, but did not significantly impact survival of stage IV patients. The worse survival of patients was associated with comorbid heart failure, myocardial infarction, and cardiac arrhythmias that occurred during a period of follow-up: HRs up to 1.85 (p<0.001), 1.96 (p<0.05), and 1.67 (p<0.001), respectively, varying by stage and treatment. The presence of hyperlipidemia at baseline (HR down to 0.71, p<0.05) was associated with better prognosis. Having multiple co-existing CVDs significantly increased mortality for all treatments, especially for stages I and II patients treated with surgery (HRs up to 2.89, p<0.05) and stages I-IIIB patients treated with chemotherapy (HRs up to 2.59, p<0.001) and chemotherapy and radiotherapy (HRs up to 2.20, p<0.001).CVDs impact the survival of NSCLC patients, particularly when multiple co-existing CVDs are present; the impacts vary by stage and treatment. This data should be considered in improving cancer treatment selection process for such potentially challenging patients as the elderly NSCLC patients with CVD comorbidities.

Authors
Kravchenko, J; Berry, M; Arbeev, K; Lyerly, HK; Yashin, A; Akushevich, I
MLA Citation
Kravchenko, J, Berry, M, Arbeev, K, Lyerly, HK, Yashin, A, and Akushevich, I. "Cardiovascular comorbidities and survival of lung cancer patients: Medicare data based analysis." Lung cancer (Amsterdam, Netherlands) 88.1 (April 2015): 85-93.
Website
http://hdl.handle.net/10161/14819
PMID
25704956
Source
epmc
Published In
Lung Cancer
Volume
88
Issue
1
Publish Date
2015
Start Page
85
End Page
93
DOI
10.1016/j.lungcan.2015.01.006

Genetics of aging, health, and survival: dynamic regulation of human longevity related traits.

The roles of genetic factors in human longevity would be better understood if one can use more efficient methods in genetic analyses and investigate pleiotropic effects of genetic variants on aging and health related traits.We used EMMAX software with modified correction for population stratification to perform genome wide association studies (GWAS) of female lifespan from the original FHS cohort. The male data from the original FHS cohort and male and female data combined from the offspring FHS cohort were used to confirm findings. We evaluated pleiotropic effects of selected genetic variants as well as gene-smoking interactions on health and aging related traits. Then we reviewed current knowledge on functional properties of genes related to detected variants.The eight SNPs with genome-wide significant variants were negatively associated with lifespan in both males and females. After additional QC, two of these variants were selected for further analyses of their associations with major diseases (cancer and CHD) and physiological aging changes. Gene-smoking interactions contributed to these effects. Genes closest to detected variants appear to be involved in similar biological processes and health disorders, as those found in other studies of aging and longevity e.g., in cancer and neurodegeneration.The impact of genes on longevity may involve trade-off-like effects on different health traits. Genes that influence lifespan represent various molecular functions but may be involved in similar biological processes and health disorders, which could contribute to genetic heterogeneity of longevity and the lack of replication in genetic association studies.

Authors
Yashin, AI; Wu, D; Arbeeva, LS; Arbeev, KG; Kulminski, AM; Akushevich, I; Kovtun, M; Culminskaya, I; Stallard, E; Li, M; Ukraintseva, SV
MLA Citation
Yashin, AI, Wu, D, Arbeeva, LS, Arbeev, KG, Kulminski, AM, Akushevich, I, Kovtun, M, Culminskaya, I, Stallard, E, Li, M, and Ukraintseva, SV. "Genetics of aging, health, and survival: dynamic regulation of human longevity related traits." Frontiers in genetics 6 (January 2015): 122-.
Website
http://hdl.handle.net/10161/14821
PMID
25918517
Source
epmc
Published In
Frontiers in Genetics
Volume
6
Publish Date
2015
Start Page
122
DOI
10.3389/fgene.2015.00122

Birth Cohort, Age, and Sex Strongly Modulate Effects of Lipid Risk Alleles Identified in Genome-Wide Association Studies.

Insights into genetic origin of diseases and related traits could substantially impact strategies for improving human health. The results of genome-wide association studies (GWAS) are often positioned as discoveries of unconditional risk alleles of complex health traits. We re-analyzed the associations of single nucleotide polymorphisms (SNPs) associated with total cholesterol (TC) in a large-scale GWAS meta-analysis. We focused on three generations of genotyped participants of the Framingham Heart Study (FHS). We show that the effects of all ten directly-genotyped SNPs were clustered in different FHS generations and/or birth cohorts in a sex-specific or sex-unspecific manner. The sample size and procedure-therapeutic issues play, at most, a minor role in this clustering. An important result was clustering of significant associations with the strongest effects in the youngest, or 3rd Generation, cohort. These results imply that an assumption of unconditional connections of these SNPs with TC is generally implausible and that a demographic perspective can substantially improve GWAS efficiency. The analyses of genetic effects in age-matched samples suggest a role of environmental and age-related mechanisms in the associations of different SNPs with TC. Analysis of the literature supports systemic roles for genes for these SNPs beyond those related to lipid metabolism. Our analyses reveal strong antagonistic effects of rs2479409 (the PCSK9 gene) that cautions strategies aimed at targeting this gene in the next generation of lipid drugs. Our results suggest that standard GWAS strategies need to be advanced in order to appropriately address the problem of genetic susceptibility to complex traits that is imperative for translation to health care.

Authors
Kulminski, AM; Culminskaya, I; Arbeev, KG; Arbeeva, L; Ukraintseva, SV; Stallard, E; Wu, D; Yashin, AI
MLA Citation
Kulminski, AM, Culminskaya, I, Arbeev, KG, Arbeeva, L, Ukraintseva, SV, Stallard, E, Wu, D, and Yashin, AI. "Birth Cohort, Age, and Sex Strongly Modulate Effects of Lipid Risk Alleles Identified in Genome-Wide Association Studies." PloS one 10.8 (January 2015): e0136319-.
Website
http://hdl.handle.net/10161/14863
PMID
26295473
Source
epmc
Published In
PloS one
Volume
10
Issue
8
Publish Date
2015
Start Page
e0136319
DOI
10.1371/journal.pone.0136319

Aging and health--a systems biology perspective. Introduction.

Authors
Jazwinski, SM; Yashin, AI
MLA Citation
Jazwinski, SM, and Yashin, AI. "Aging and health--a systems biology perspective. Introduction." Interdisciplinary topics in gerontology 40 (January 2015): VII-XII.
Website
http://hdl.handle.net/10161/14905
PMID
25509217
Source
epmc
Published In
Interdisciplinary Topics in Gerontology
Volume
40
Publish Date
2015
Start Page
VII
End Page
XII

Introduction

Authors
Jazwinski, SM; Yashin, AI
MLA Citation
Jazwinski, SM, and Yashin, AI. "Introduction." October 9, 2014. vii-xii.
Source
scopus
Volume
40
Publish Date
2014
Start Page
vii
End Page
xii

Aging and health - A systems biology perspective

© 2015 by S. Karger AG, Basel. All rights reserved. Aging is a major risk factor for chronic diseases, which in turn can provide information about the aging of a biological system. This publication serves as an introduction to systems biology and its application to biological aging. Key pathways and processes that impinge on aging are reviewed, and how they contribute to health and disease during aging is discussed. The evolution of this situation is analyzed, and the consequences for the study of genetic effects on aging are presented. Epigenetic programming of aging, as a continuation of development, creates an interface between the genome and the environment. New research into the gut microbiome describes how this interface may operate in practice with marked consequences for a variety of disorders. This analysis is bolstered by a view of the aging organism as a whole, with conclusions about the mechanisms underlying resilience of the organism to change, and is expanded with a discussion of circadian rhythms in aging. Finally, the book presents an outlook for the development of interventions to delay or to reverse the features of aging. The publication is recommended to students, researchers as well as professionals dealing with public health and public policy related to an aging society.

Authors
Jazwinski, SM; Yashin, AI
MLA Citation
Jazwinski, SM, and Yashin, AI. Aging and health - A systems biology perspective. October 9, 2014.
Source
scopus
Volume
40
Publish Date
2014
Start Page
1
End Page
194
DOI
10.1159/isbn.978-3-318-02730-3

Letter to the editor: Standardization of genetic association studies, pros and cons, reaffirmed.

Authors
Kulminski, A; Culminskaya, I; Yashin, AI
MLA Citation
Kulminski, A, Culminskaya, I, and Yashin, AI. "Letter to the editor: Standardization of genetic association studies, pros and cons, reaffirmed." Age (Dordrecht, Netherlands) 36.2 (April 2014): 945-947. (Letter)
Website
http://hdl.handle.net/10161/14907
PMID
24271844
Source
epmc
Published In
AGE
Volume
36
Issue
2
Publish Date
2014
Start Page
945
End Page
947
DOI
10.1007/s11357-013-9602-3

Age, gender, and cancer but not neurodegenerative and cardiovascular diseases strongly modulate systemic effect of the Apolipoprotein E4 allele on lifespan.

Enduring interest in the Apolipoprotein E (ApoE) polymorphism is ensured by its evolutionary-driven uniqueness in humans and its prominent role in geriatrics and gerontology. We use large samples of longitudinally followed populations from the Framingham Heart Study (FHS) original and offspring cohorts and the Long Life Family Study (LLFS) to investigate gender-specific effects of the ApoE4 allele on human survival in a wide range of ages from midlife to extreme old ages, and the sensitivity of these effects to cardiovascular disease (CVD), cancer, and neurodegenerative disorders (ND). The analyses show that women's lifespan is more sensitive to the e4 allele than men's in all these populations. A highly significant adverse effect of the e4 allele is limited to women with moderate lifespan of about 70 to 95 years in two FHS cohorts and the LLFS with relative risk of death RR = 1.48 (p = 3.6 × 10(-6)) in the FHS cohorts. Major human diseases including CVD, ND, and cancer, whose risks can be sensitive to the e4 allele, do not mediate the association of this allele with lifespan in large FHS samples. Non-skin cancer non-additively increases mortality of the FHS women with moderate lifespans increasing the risks of death of the e4 carriers with cancer two-fold compared to the non-e4 carriers, i.e., RR = 2.07 (p = 5.0 × 10(-7)). The results suggest a pivotal role of non-sex-specific cancer as a nonlinear modulator of survival in this sample that increases the risk of death of the ApoE4 carriers by 150% (p = 5.3 × 10(-8)) compared to the non-carriers. This risk explains the 4.2 year shorter life expectancy of the e4 carriers compared to the non-carriers in this sample. The analyses suggest the existence of age- and gender-sensitive systemic mechanisms linking the e4 allele to lifespan which can non-additively interfere with cancer-related mechanisms.

Authors
Kulminski, AM; Arbeev, KG; Culminskaya, I; Arbeeva, L; Ukraintseva, SV; Stallard, E; Christensen, K; Schupf, N; Province, MA; Yashin, AI
MLA Citation
Kulminski, AM, Arbeev, KG, Culminskaya, I, Arbeeva, L, Ukraintseva, SV, Stallard, E, Christensen, K, Schupf, N, Province, MA, and Yashin, AI. "Age, gender, and cancer but not neurodegenerative and cardiovascular diseases strongly modulate systemic effect of the Apolipoprotein E4 allele on lifespan." PLoS genetics 10.1 (January 30, 2014): e1004141-.
Website
http://hdl.handle.net/10161/14759
PMID
24497847
Source
epmc
Published In
PLoS genetics
Volume
10
Issue
1
Publish Date
2014
Start Page
e1004141
DOI
10.1371/journal.pgen.1004141

Introduction

Authors
Jazwinski, SM; Yashin, AI
MLA Citation
Jazwinski, SM, and Yashin, AI. "Introduction." January 1, 2014. VII-XII.
Source
scopus
Volume
40
Publish Date
2014
Start Page
VII
End Page
XII

Age, Gender, and Cancer but Not Neurodegenerative and Cardiovascular Diseases Strongly Modulate Systemic Effect of the Apolipoprotein E4 Allele on Lifespan

Enduring interest in the Apolipoprotein E (ApoE) polymorphism is ensured by its evolutionary-driven uniqueness in humans and its prominent role in geriatrics and gerontology. We use large samples of longitudinally followed populations from the Framingham Heart Study (FHS) original and offspring cohorts and the Long Life Family Study (LLFS) to investigate gender-specific effects of the ApoE4 allele on human survival in a wide range of ages from midlife to extreme old ages, and the sensitivity of these effects to cardiovascular disease (CVD), cancer, and neurodegenerative disorders (ND). The analyses show that women's lifespan is more sensitive to the e4 allele than men's in all these populations. A highly significant adverse effect of the e4 allele is limited to women with moderate lifespan of about 70 to 95 years in two FHS cohorts and the LL FS with relative risk of death RR = 1.48 (p = 3.6×10 -6 ) in the FHS cohorts. Major human diseases including CVD, ND, and cancer, whose risks can be sensitive to the e4 allele, do not mediate the association of this allele with lifespan in large FHS samples. Non-skin cancer non-additively increases mortality of the FHS women with moderate lifespans increasing the risks of death of the e4 carriers with cancer two-fold compared to the non-e4 carriers, i.e., RR = 2.07 (p = 5.0×10 -7 ). The results suggest a pivotal role of non-sex-specific cancer as a nonlinear modulator of survival in this sample that increases the risk of death of the ApoE4 carriers by 150% (p = 5.3×10 -8 ) compared to the non-carriers. This risk explains the 4.2 year shorter life expectancy of the e4 carriers compared to the non-carriers in this sample. The analyses suggest the existence of age- and gender-sensitive systemic mechanisms linking the e4 allele to lifespan which can non-additively interfere with cancer-related mechanisms. © 2014 Kulminski et al.

Authors
Kulminski, AM; Arbeev, KG; Culminskaya, I; Arbeeva, L; Ukraintseva, SV; Stallard, E; Christensen, K; Schupf, N; Province, MA; Yashin, AI
MLA Citation
Kulminski, AM, Arbeev, KG, Culminskaya, I, Arbeeva, L, Ukraintseva, SV, Stallard, E, Christensen, K, Schupf, N, Province, MA, and Yashin, AI. "Age, Gender, and Cancer but Not Neurodegenerative and Cardiovascular Diseases Strongly Modulate Systemic Effect of the Apolipoprotein E4 Allele on Lifespan." PLoS Genetics 10.1 (January 1, 2014).
Website
http://hdl.handle.net/10161/14866
Source
scopus
Published In
PLoS genetics
Volume
10
Issue
1
Publish Date
2014
DOI
10.1371/journal.pgen.1004141

Letter to the editor: Standardization of genetic association studies, pros and cons, reaffirmed

Authors
Kulminski, A; Culminskaya, I; Yashin, AI
MLA Citation
Kulminski, A, Culminskaya, I, and Yashin, AI. "Letter to the editor: Standardization of genetic association studies, pros and cons, reaffirmed." Age 36.2 (January 1, 2014): 945-947. (Letter)
Website
http://hdl.handle.net/10161/14906
Source
scopus
Published In
AGE
Volume
36
Issue
2
Publish Date
2014
Start Page
945
End Page
947
DOI
10.1007/s11357-013-9602-3

Joint Analyses of Longitudinal and Time-to-Event Data in Research on Aging: Implications for Predicting Health and Survival.

Longitudinal data on aging, health, and longevity provide a wealth of information to investigate different aspects of the processes of aging and development of diseases leading to death. Statistical methods aimed at analyses of time-to-event data jointly with longitudinal measurements became known as the "joint models" (JM). An important point to consider in analyses of such data in the context of studies on aging, health, and longevity is how to incorporate knowledge and theories about mechanisms and regularities of aging-related changes that accumulate in the research field into respective analytic approaches. In the absence of specific observations of longitudinal dynamics of relevant biomarkers manifesting such mechanisms and regularities, traditional approaches have a rather limited utility to estimate respective parameters that can be meaningfully interpreted from the biological point of view. A conceptual analytic framework for these purposes, the stochastic process model of aging (SPM), has been recently developed in the biodemographic literature. It incorporates available knowledge about mechanisms of aging-related changes, which may be hidden in the individual longitudinal trajectories of physiological variables and this allows for analyzing their indirect impact on risks of diseases and death. Despite, essentially, serving similar purposes, JM and SPM developed in parallel in different disciplines with very limited cross-referencing. Although there were several publications separately reviewing these two approaches, there were no publications presenting both these approaches in some detail. Here, we overview both approaches jointly and provide some new modifications of SPM. We discuss the use of stochastic processes to capture biological variation and heterogeneity in longitudinal patterns and important and promising (but still largely underused) applications of JM and SPM to predictions of individual and population mortality and health-related outcomes.

Authors
Arbeev, KG; Akushevich, I; Kulminski, AM; Ukraintseva, SV; Yashin, AI
MLA Citation
Arbeev, KG, Akushevich, I, Kulminski, AM, Ukraintseva, SV, and Yashin, AI. "Joint Analyses of Longitudinal and Time-to-Event Data in Research on Aging: Implications for Predicting Health and Survival." Frontiers in public health 2 (January 2014): 228-. (Review)
Website
http://hdl.handle.net/10161/14758
PMID
25414844
Source
epmc
Published In
Frontiers in Public Health
Volume
2
Publish Date
2014
Start Page
228
DOI
10.3389/fpubh.2014.00228

Biodemographic Analyses of Longitudinal Data on Aging, Health, and Longevity: Recent Advances and Future Perspectives.

Biodemography became one of the most innovative and fastest growing areas in demography. This progress is fueled by the growing variability and amount of relevant data available for analyses as well as by methodological developments allowing for addressing new research questions using new approaches that can better utilize the potential of these data. In this review paper, we summarize recent methodological advances in biodemography and their diverse practical applications. Three major topics are covered: (1) computational approaches to reconstruction of age patterns of incidence of geriatric diseases and other characteristics such as recovery rates at the population level using Medicare claims data; (2) methodological advances in genetic and genomic biodemography and applications to research on genetic determinants of longevity and health; and (3) biodemographic models for joint analyses of time-to-event data and longitudinal measurements of biomarkers collected in longitudinal studies on aging. We discuss how such data and methodology can be used in a comprehensive prediction model for joint analyses of incomplete datasets that take into account the wide spectrum of factors affecting health and mortality transitions including genetic factors and hidden mechanisms of aging-related changes in physiological variables in their dynamic connection with health and survival.

Authors
Arbeev, KG; Akushevich, I; Kulminski, AM; Ukraintseva, SV; Yashin, AI
MLA Citation
Arbeev, KG, Akushevich, I, Kulminski, AM, Ukraintseva, SV, and Yashin, AI. "Biodemographic Analyses of Longitudinal Data on Aging, Health, and Longevity: Recent Advances and Future Perspectives." Advances in geriatrics 2014 (January 2014).
Website
http://hdl.handle.net/10161/14762
PMID
25590047
Source
epmc
Published In
Advances in Geriatrics
Volume
2014
Publish Date
2014
DOI
10.1155/2014/957073

Genetic Structures of Population Cohorts Change with Increasing Age: Implications for Genetic Analyses of Human aging and Life Span.

Correcting for the potential effects of population stratification is an important issue in genome wide association studies (GWAS) of complex traits. Principal component analysis (PCA) of the genetic structure of the population under study with subsequent incorporation of the first several principal components (PCs) in the GWAS regression model is often used for this purpose.For longevity related traits such a correction may negatively affect the accuracy of genetic analyses. This is because PCs may capture genetic structure induced by mortality selection processes in genetically heterogeneous populations.We used the Framingham Heart Study data on life span and on individual genetic background to construct two sets of PCs. One was constructed to separate population stratification due to differences in ancestry from that induced by mortality selection. The other was constructed using genetic data on individuals of different ages without attempting to separate the ancestry effects from the mortality selection effects. The GWASs of human life span were performed using the first 20 PCs from each of the selected sets to control for possible population stratification.The results indicated that the GWAS that used the PC set separating population stratification induced by mortality selection from differences in ancestry produced stronger genetic signals than the GWAS that used PCs without such separation.The quality of genetic estimates in GWAS can be improved when changes in genetic structure caused by mortality selection are taken into account in controlling for possible effects of population stratification.

Authors
Yashin, AI; Wu, D; Arbeev, KG; Arbeeva, LS; Akushevich, I; Kulminski, A; Culminskaya, I; Stallard, E; Ukraintseva, SV
MLA Citation
Yashin, AI, Wu, D, Arbeev, KG, Arbeeva, LS, Akushevich, I, Kulminski, A, Culminskaya, I, Stallard, E, and Ukraintseva, SV. "Genetic Structures of Population Cohorts Change with Increasing Age: Implications for Genetic Analyses of Human aging and Life Span." Annals of gerontology and geriatric research 1.4 (January 2014).
Website
http://hdl.handle.net/10161/14761
PMID
25893220
Source
epmc
Published In
Annals of gerontology and geriatric research
Volume
1
Issue
4
Publish Date
2014

A new algorithm for predicting time to disease endpoints in Alzheimer's disease patients.

The ability to predict the length of time to death and institutionalization has strong implications for Alzheimer's disease patients and caregivers, health policy, economics, and the design of intervention studies.To develop and validate a prediction algorithm that uses data from a single visit to estimate time to important disease endpoints for individual Alzheimer's disease patients.Two separate study cohorts (Predictors 1, N = 252; Predictors 2, N = 254), all initially with mild Alzheimer's disease, were followed for 10 years at three research centers with semiannual assessments that included cognition, functional capacity, and medical, psychiatric, and neurologic information. The prediction algorithm was based on a longitudinal Grade of Membership model developed using the complete series of semiannually-collected Predictors 1 data. The algorithm was validated on the Predictors 2 data using data only from the initial assessment to predict separate survival curves for three outcomes.For each of the three outcome measures, the predicted survival curves fell well within the 95% confidence intervals of the observed survival curves. Patients were also divided into quintiles for each endpoint to assess the calibration of the algorithm for extreme patient profiles. In all cases, the actual and predicted survival curves were statistically equivalent. Predictive accuracy was maintained even when key baseline variables were excluded, demonstrating the high resilience of the algorithm to missing data.The new prediction algorithm accurately predicts time to death, institutionalization, and need for full-time care in individual Alzheimer's disease patients; it can be readily adapted to predict other important disease endpoints. The algorithm will serve an unmet clinical, research, and public health need.

Authors
Razlighi, QR; Stallard, E; Brandt, J; Blacker, D; Albert, M; Scarmeas, N; Kinosian, B; Yashin, AI; Stern, Y
MLA Citation
Razlighi, QR, Stallard, E, Brandt, J, Blacker, D, Albert, M, Scarmeas, N, Kinosian, B, Yashin, AI, and Stern, Y. "A new algorithm for predicting time to disease endpoints in Alzheimer's disease patients." Journal of Alzheimer's disease : JAD 38.3 (January 2014): 661-668.
Website
http://hdl.handle.net/10161/14898
PMID
24064468
Source
epmc
Published In
Journal of Alzheimer's disease : JAD
Volume
38
Issue
3
Publish Date
2014
Start Page
661
End Page
668
DOI
10.3233/jad-131142

Introduction

Authors
Jazwinski, SM; Yashin, AI
MLA Citation
Jazwinski, SM, and Yashin, AI. "Introduction." 2014. VII-XII.
Source
scival
Volume
40
Publish Date
2014
Start Page
VII
End Page
XII

Morbidity risks among older adults with pre-existing age-related diseases.

Multi-morbidity is common among older adults; however, for many aging-related diseases there is no information for U.S. elderly population on how earlier-manifested disease affects the risk of another disease manifested later during patient's lifetime. Quantitative evaluation of risks of cancer and non-cancer diseases for older adults with pre-existing conditions is performed using the Surveillance, Epidemiology, and End Results (SEER) Registry data linked to the Medicare Files of Service Use (MFSU). Using the SEER-Medicare data containing individual records for 2,154,598 individuals, we empirically evaluated age patterns of incidence of age-associated diseases diagnosed after the onset of earlier manifested disease and compared these patterns with those in general population. Individual medical histories were reconstructed using information on diagnoses coded in MFSU, dates of medical services/procedures, and Medicare enrollment/disenrollment. More than threefold increase of subsequent diseases risk was observed for 15 disease pairs, majority of them were i) diseases of the same organ and/or system (e.g., Parkinson disease for patients with Alzheimer disease, HR=3.77, kidney cancer for patients with renal failure, HR=3.28) or ii) disease pairs with primary diseases being fast-progressive cancers (i.e., lung, kidney, and pancreas), e.g., ulcer (HR=4.68) and melanoma (HR=4.15) for patients with pancreatic cancer. Lower risk of subsequent disease was registered for 20 disease pairs, mostly among patients with Alzheimer's or Parkinson's disease, e.g., decreased lung cancer risk among patients with Alzheimer's (HR=0.64) and Parkinson's (HR=0.60) disease. Synergistic and antagonistic dependences in geriatric disease risks were observed among US elderly confirming known and detecting new associations of wide spectrum of age-associated diseases. The results can be used in optimization of screening, prevention and treatment strategies of chronic diseases among U.S. elderly population.

Authors
Akushevich, I; Kravchenko, J; Ukraintseva, S; Arbeev, K; Kulminski, A; Yashin, AI
MLA Citation
Akushevich, I, Kravchenko, J, Ukraintseva, S, Arbeev, K, Kulminski, A, and Yashin, AI. "Morbidity risks among older adults with pre-existing age-related diseases." Experimental gerontology 48.12 (December 2013): 1395-1401.
Website
http://hdl.handle.net/10161/14832
PMID
24064264
Source
epmc
Published In
Experimental Gerontology
Volume
48
Issue
12
Publish Date
2013
Start Page
1395
End Page
1401
DOI
10.1016/j.exger.2013.09.005

MATHEMATICAL MODELS OF PHYSIOLOGICAL DYSREGULATION TRAJECTORIES DURING AGING

Authors
Arbeev, KG; Cohen, AA; Arbeeva, L; Milot, E; Akushevich, I; Kulminski, A; Yashin, AI
MLA Citation
Arbeev, KG, Cohen, AA, Arbeeva, L, Milot, E, Akushevich, I, Kulminski, A, and Yashin, AI. "MATHEMATICAL MODELS OF PHYSIOLOGICAL DYSREGULATION TRAJECTORIES DURING AGING." GERONTOLOGIST 53 (November 2013): 222-222.
Source
wos-lite
Published In
The Gerontologist
Volume
53
Publish Date
2013
Start Page
222
End Page
222

THE ROLE OF THE APOLIPOPROTEIN E4 ALLELE, CANCER, CVD AND NEURODEGENERATIVE DISORDERS IN HUMAN LIFESPAN

Authors
Kulminski, A; Culminskaya, I; Arbeev, KG; Arbeeva, L; Ukraintseva, SV; Yashin, AI
MLA Citation
Kulminski, A, Culminskaya, I, Arbeev, KG, Arbeeva, L, Ukraintseva, SV, and Yashin, AI. "THE ROLE OF THE APOLIPOPROTEIN E4 ALLELE, CANCER, CVD AND NEURODEGENERATIVE DISORDERS IN HUMAN LIFESPAN." GERONTOLOGIST 53 (November 2013): 250-250.
Website
http://hdl.handle.net/10161/14867
Source
wos-lite
Published In
The Gerontologist
Volume
53
Publish Date
2013
Start Page
250
End Page
250

Recovery and survival from aging-associated diseases.

Considering disease incidence to be a main contributor to healthy lifespan of the US elderly population may lead to erroneous conclusions when recovery/long-term remission factors are underestimated. Using two Medicare-based population datasets, we investigated the properties of recovery from eleven age-related diseases.Cohorts of patients who stopped visiting doctors during a five-year follow-up since disease onset were analyzed non-parametrically and using the Cox proportional hazard model resulted in estimated recovery and survival rates and evaluated the health state of recovered individuals by comparing their survival with non-recovered patients and the general population.Recovered individuals had lower death rates than non-recovered patients, therefore, patients who stopped visiting doctors are a healthier subcohort. However, they had higher death rates than in general population for all considered diseases, therefore the complete recovery does not occur.Properties of recovery/long-term remission among the US population of older adults with chronic diseases were uncovered and evaluated. The results allow for a better quantifiable contribution of age-related diseases to healthy life expectancy and improving forecasts of health and mortality.

Authors
Akushevich, I; Kravchenko, J; Ukraintseva, S; Arbeev, K; Yashin, AI
MLA Citation
Akushevich, I, Kravchenko, J, Ukraintseva, S, Arbeev, K, and Yashin, AI. "Recovery and survival from aging-associated diseases." Experimental gerontology 48.8 (August 2013): 824-830.
Website
http://hdl.handle.net/10161/14833
PMID
23707929
Source
epmc
Published In
Experimental Gerontology
Volume
48
Issue
8
Publish Date
2013
Start Page
824
End Page
830
DOI
10.1016/j.exger.2013.05.056

Biogenetic mechanisms predisposing to complex phenotypes in parents may function differently in their children.

This study focuses on the participants of the Long Life Family Study to elucidate whether biogenetic mechanisms underlying relationships among heritable complex phenotypes in parents function in the same way for the same phenotypes in their children. Our results reveal 3 characteristic groups of relationships among phenotypes in parents and children. One group composed of 3 pairs of phenotypes confirms that associations among some phenotypes can be explained by the same biogenetic mechanisms working in parents and children. Two other groups including 9 phenotype pairs show that this is not a common rule. Our findings suggest that biogenetic mechanisms underlying relationships among different phenotypes, even if they are causally related, can function differently in successive generations or in different age groups of biologically related individuals. The results suggest that the role of aging-related processes in changing environment may be conceptually underestimated in current genetic association studies using genome wide resources.

Authors
Kulminski, AM; Arbeev, KG; Christensen, K; Stallard, E; Miljkovic, I; Barmada, M; Yashin, AI
MLA Citation
Kulminski, AM, Arbeev, KG, Christensen, K, Stallard, E, Miljkovic, I, Barmada, M, and Yashin, AI. "Biogenetic mechanisms predisposing to complex phenotypes in parents may function differently in their children." J Gerontol A Biol Sci Med Sci 68.7 (July 2013): 760-768.
Website
http://hdl.handle.net/10161/14870
PMID
23213029
Source
pubmed
Published In
Journals of Gerontology: Series A
Volume
68
Issue
7
Publish Date
2013
Start Page
760
End Page
768
DOI
10.1093/gerona/gls243

Time trends of incidence of age-associated diseases in the US elderly population: Medicare-based analysis.

time trends of age-adjusted incidence rates of 19 ageing-related diseases were evaluated for 1992-2005 period with the National Long Term Care Survey and the Surveillance, Epidemiology and End RESULTS Registry data both linked to Medicare data (NLTCS-Medicare and SEER-Medicare, respectively).the rates were calculated using individual medical histories (34,077 individuals from NLTCS-Medicare and 199,418 from SEER-Medicare) reconstructed using information on diagnoses coded in Medicare data, dates of medical services/procedures and Medicare enrolment/disenrolment.increases of incidence rates were dramatic for renal disease [the average annual percent change (APC) is 8.56%, 95% CI = 7.62, 9.50%], goiter (APC = 6.67%, 95% CI = 5, 90, 7, 44%), melanoma (APC = 6.15%, 95% CI = 4.31, 8.02%) and Alzheimer's disease (APC = 3.96%, 95% CI = 2.67, 5.26%), and less prominent for diabetes and lung cancer. Decreases of incidence rates were remarkable for angina pectoris (APC = -6.17%, 95% CI = -6.96, -5.38%); chronic obstructive pulmonary disease (APC = -5.14%, 95% CI = -6.78,-3.47%), and ulcer (APC = -5.82%, 95% CI = -6.77,-4.86%) and less dramatic for carcinomas of colon and prostate, stroke, hip fracture and asthma. Incidence rates of female breast carcinoma, myocardial infarction, Parkinson's disease and rheumatoid arthritis were almost stable. For most diseases, an excellent agreement was observed for incidence rates between NLTCS-Medicare and SEER-Medicare. A sensitivity analysis proved the stability of the evaluated time trends.time trends of the incidence of diseases common in the US elderly population were evaluated. The results show dramatic increase in incidence rates of melanoma, goiter, chronic renal and Alzheimer's disease in 1992-2005. Besides specifying widely recognised time trends on age-associated diseases, new information was obtained for trends of asthma, ulcer and goiter among the older adults in the USA.

Authors
Akushevich, I; Kravchenko, J; Ukraintseva, S; Arbeev, K; Yashin, AI
MLA Citation
Akushevich, I, Kravchenko, J, Ukraintseva, S, Arbeev, K, and Yashin, AI. "Time trends of incidence of age-associated diseases in the US elderly population: Medicare-based analysis." Age and ageing 42.4 (July 2013): 494-500.
Website
http://hdl.handle.net/10161/14835
PMID
23482353
Source
epmc
Published In
Age and Ageing
Volume
42
Issue
4
Publish Date
2013
Start Page
494
End Page
500
DOI
10.1093/ageing/aft032

Circulatory Diseases in the U.S. Elderly in the Linked National Long-Term Care Survey-Medicare Database: Population-Based Analysis of Incidence, Comorbidity, and Disability.

Incidence rates of acute coronary heart disease (ACHD; including myocardial infarction and angina pectoris), stroke, and heart failure (HF) were studied for their age, disability, and comorbidity patterns in the U.S. elderly population using the National Long Term Care Survey (NLTCS) data linked to Medicare records for 1991-2005. Incidence rates increased with age with a decrease in the oldest old (stroke and HF) or were stable at all ages (ACHD). For all diseases, incidence rates were lower among institutionalized individuals and higher in individuals with higher comorbidity indices. The results could be used for understanding currently debated effects of biomedical research, screening, and therapeutic innovations on changes in disease incidence with advancing age as well as for projecting future Medicare costs.

Authors
Akushevich, I; Kravchenko, J; Ukraintseva, S; Arbeev, K; Yashin, AI
MLA Citation
Akushevich, I, Kravchenko, J, Ukraintseva, S, Arbeev, K, and Yashin, AI. "Circulatory Diseases in the U.S. Elderly in the Linked National Long-Term Care Survey-Medicare Database: Population-Based Analysis of Incidence, Comorbidity, and Disability." Research on aging 35.4 (July 2013): 437-458.
Website
http://hdl.handle.net/10161/14840
PMID
26609189
Source
epmc
Published In
Research on Aging
Volume
35
Issue
4
Publish Date
2013
Start Page
437
End Page
458
DOI
10.1177/0164027512446941

Biogenetic mechanisms predisposing to complex phenotypes in parents may function differently in their children.

This study focuses on the participants of the Long Life Family Study to elucidate whether biogenetic mechanisms underlying relationships among heritable complex phenotypes in parents function in the same way for the same phenotypes in their children. Our results reveal 3 characteristic groups of relationships among phenotypes in parents and children. One group composed of 3 pairs of phenotypes confirms that associations among some phenotypes can be explained by the same biogenetic mechanisms working in parents and children. Two other groups including 9 phenotype pairs show that this is not a common rule. Our findings suggest that biogenetic mechanisms underlying relationships among different phenotypes, even if they are causally related, can function differently in successive generations or in different age groups of biologically related individuals. The results suggest that the role of aging-related processes in changing environment may be conceptually underestimated in current genetic association studies using genome wide resources.

Authors
Kulminski, AM; Arbeev, KG; Christensen, K; Stallard, E; Miljkovic, I; Barmada, M; Yashin, AI
MLA Citation
Kulminski, AM, Arbeev, KG, Christensen, K, Stallard, E, Miljkovic, I, Barmada, M, and Yashin, AI. "Biogenetic mechanisms predisposing to complex phenotypes in parents may function differently in their children." The journals of gerontology. Series A, Biological sciences and medical sciences 68.7 (July 2013): 760-768.
Website
http://hdl.handle.net/10161/14799
Source
epmc
Published In
Journals of Gerontology: Series A
Volume
68
Issue
7
Publish Date
2013
Start Page
760
End Page
768
DOI
10.1093/gerona/gls243

Inter-chromosomal level of genome organization and longevity-related phenotypes in humans.

Studies focusing on unraveling the genetic origin of health span in humans assume that polygenic, aging-related phenotypes are inherited through Mendelian mechanisms of inheritance of individual genes. We use the Framingham Heart Study (FHS) data to examine whether non-Mendelian mechanisms of inheritance can drive linkage of loci on non-homologous chromosomes and whether such mechanisms can be relevant to longevity-related phenotypes. We report on genome-wide inter-chromosomal linkage disequilibrium (LD) and on chromosome-wide intra-chromosomal LD and show that these are real phenomena in the FHS data. Genetic analysis of inheritance in families based on Mendelian segregation reveals that the alleles of single nucleotide polymorphisms (SNPs) in LD at loci on non-homologous chromosomes are inherited as a complex resembling haplotypes of a genetic unit. This result implies that the inter-chromosomal LD is likely caused by non-random assortment of non-homologous chromosomes during meiosis. The risk allele haplotypes can be subject to dominant-negative selection primary through the mechanisms of non-Mendelian inheritance. They can go to extinction within two human generations. The set of SNPs in inter-chromosomal LD (N=68) is nearly threefold enriched, with high significance (p=1.6 × 10(-9)), on non-synonymous coding variants (N=28) compared to the entire qualified set of the studied SNPs. Genes for the tightly linked SNPs are involved in fundamental biological processes in an organism. Survival analyses show that the revealed non-genetic linkage is associated with heritable complex phenotype of premature death. Our results suggest the presence of inter-chromosomal level of functional organization in the human genome and highlight a challenging problem of genomics of human health and aging.

Authors
Kulminski, AM; Culminskaya, I; Yashin, AI
MLA Citation
Kulminski, AM, Culminskaya, I, and Yashin, AI. "Inter-chromosomal level of genome organization and longevity-related phenotypes in humans." Age (Dordrecht, Netherlands) 35.2 (April 2013): 501-518.
Website
http://hdl.handle.net/10161/14910
PMID
22282054
Source
epmc
Published In
AGE
Volume
35
Issue
2
Publish Date
2013
Start Page
501
End Page
518
DOI
10.1007/s11357-011-9374-6

The role of lipid-related genes, aging-related processes, and environment in healthspan.

The inherent complexity of aging-related traits can temper progress in unraveling the genetic origins of healthspan. We focus on two generations in the Framingham Heart Study, the original (FHS) and offspring (FHSO) cohorts, to determine whether aging-related processes in changing environments can substantially impact the role of lipid-related genes discovered in candidate gene (the apolipoprotein E (APOE) e2/3/4 polymorphism) and genome-wide (the APOB rs1042034 (C/T)) studies, in regulation of total cholesterol (TC) and onset of cardiovascular disease (CVD). We demonstrate that the APOE e4 allele and APOB CC genotype can play detrimental, neutral, and protective sex-specific roles in the etiology of CVD at different ages and in different environments. We document antagonistic roles for the e4 allele in the onset of CVD characterized by detrimental effects at younger ages (RR≤ 75 years = 1.49, P = 7.5 × 10(-4) ) and protective effects at older ages (RR76+years = 0.77, P = 0.044) for FHS participants. We found that disregarding the role of aging erroneously nullifies the significant effects of the e4 allele in this sample (RR = 0.92, P = 0.387). The leading biogenetic pathways mediating genetic effects on CVD may be more relevant to lipid metabolism for APOB than APOE. Aging-related processes can modulate the strength of genetic associations with TC in the same individuals at different chronological ages. We found substantial differences in the effects of the same APOE and APOB alleles on CVD and TC across generations. The results suggest that aging-related processes in changing environments may play key roles in the genetics of healthspan. Detailed systemic integrative analyses may substantially advance the progress.

Authors
Kulminski, AM; Culminskaya, I; Arbeev, KG; Ukraintseva, SV; Stallard, E; Arbeeva, L; Yashin, AI
MLA Citation
Kulminski, AM, Culminskaya, I, Arbeev, KG, Ukraintseva, SV, Stallard, E, Arbeeva, L, and Yashin, AI. "The role of lipid-related genes, aging-related processes, and environment in healthspan." Aging cell 12.2 (April 2013): 237-246.
Website
http://hdl.handle.net/10161/14868
PMID
23320904
Source
epmc
Published In
Aging Cell
Volume
12
Issue
2
Publish Date
2013
Start Page
237
End Page
246
DOI
10.1111/acel.12046

Trade-off in the effect of the APOE gene on the ages at onset of cardiocascular disease and cancer across ages, gender, and human generations.

Decades of studies of candidate genes show their complex role in aging-related traits. We focus on apolipoprotein E e2/3/4 polymorphism and ages at onset of cardiovascular diseases (CVD) and cancer in the parental and offspring generations of the Framingham Heart Study participants to gain insights on the role of age and gender across generations in genetic trade-offs. The analyses show that the apolipoprotein E e4 allele carriers live longer lives without cancer than the non-e4 allele carriers in each generation. The role of the e4 allele in onset of CVD is age- and generation-specific, constituting two modes of sexually dimorphic genetic trade-offs. In offspring, the e4 allele confers risk of CVD primarily in women and can protect against cancer primarily in men of the same age. In the parental generation, genetic trade-off is seen in different age groups, with a protective role of the e4 allele against cancer in older men and its detrimental role in CVD in younger women. The puzzling complexity of genetic mechanisms working in different genders, ages, and environments calls for more detail and systemic analyses beyond those adapted in current large-scale genetic association studies.

Authors
Kulminski, AM; Culminskaya, I; Arbeev, KG; Ukraintseva, SV; Arbeeva, L; Yashin, AI
MLA Citation
Kulminski, AM, Culminskaya, I, Arbeev, KG, Ukraintseva, SV, Arbeeva, L, and Yashin, AI. "Trade-off in the effect of the APOE gene on the ages at onset of cardiocascular disease and cancer across ages, gender, and human generations." Rejuvenation research 16.1 (February 2013): 28-34.
Website
http://hdl.handle.net/10161/14872
PMID
23094790
Source
epmc
Published In
Rejuvenation Research
Volume
16
Issue
1
Publish Date
2013
Start Page
28
End Page
34
DOI
10.1089/rej.2012.1362

How lifespan associated genes modulate aging changes: lessons from analysis of longitudinal data.

The influence of genes on human lifespan is mediated by biological processes that characterize body's functioning. The age trajectories of these processes contain important information about mechanisms linking aging, health, and lifespan. The objective of this paper is to investigate regularities of aging changes in different groups of individuals, including individuals with different genetic background, as well as their connections with health and lifespan.To reach this objective we used longitudinal data on four physiological variables, information about health and lifespan collected in the Framingham Heart Study (FHS), data on longevity alleles detected in earlier study, as well as methods of statistical modeling.We found that phenotypes of exceptional longevity and health are linked to distinct types of changes in physiological indices during aging. We also found that components of aging changes differ in groups of individuals with different genetic background.These results suggest that factors responsible for exceptional longevity and health are not necessary the same, and that postponing aging changes is associated with extreme longevity. The genetic factors which increase lifespan are associated with physiological changes typical of healthy and long-living individuals, smaller mortality risks from cancer and CVD and better estimates of adaptive capacity in statistical modeling. This indicates that extreme longevity and health related traits are likely to be less heterogeneous phenotypes than lifespan, and studying these phenotypes separately from lifespan may provide additional information about mechanisms of human aging and its relation to chronic diseases and lifespan.

Authors
Yashin, AI; Arbeev, KG; Wu, D; Arbeeva, LS; Kulminski, A; Akushevich, I; Culminskaya, I; Stallard, E; Ukraintseva, SV
MLA Citation
Yashin, AI, Arbeev, KG, Wu, D, Arbeeva, LS, Kulminski, A, Akushevich, I, Culminskaya, I, Stallard, E, and Ukraintseva, SV. "How lifespan associated genes modulate aging changes: lessons from analysis of longitudinal data." Frontiers in genetics 4 (January 22, 2013): 3-.
Website
http://hdl.handle.net/10161/14839
PMID
23346098
Source
epmc
Published In
Frontiers in Genetics
Volume
4
Publish Date
2013
Start Page
3
DOI
10.3389/fgene.2013.00003

Methodological aspects of studying human aging, health, and mortality

© Springer Science+Business Media Dordrecht 2013. Age trajectories of mortality rates in human populations characterize individuals’ inequality in the duration of life. Various models of mortality rates are used in the analyses of survival data in demographic and epidemiological applications aiming to identify sources of individual differences in life span. Despite existing practice to use estimated model parameters in explanations of differences in mortality rates among different populations, in most cases differences in such estimates are difficult to interpret. The reason for this difficulty is that parameters of many demographic mortality models do not characterize either biological processes developing in aging human organisms or expose to environmental and living conditions. At the same time many processes affecting survival chances are measured in human longitudinal studies of aging, health and longevity, which suggest an opportunity for developing mortality models with parameters that can be interpreted in terms of processes and measured in such studies. The purpose of this paper is to develop an approach to mortality modeling that allows for describing the mortality rate in terms of parameters of physiological processes and declining health status that develops in aging human organisms. In contrast to traditional demographic models, which are difficult to use in the analyses of longitudinal data, our model allows for taking all these data into account. We use diffusion-type continuous time stochastic process for describing evolution of physiological state over the life course and finite-state continuous process for describing changes in health status during this period. We derive equations for respective mortality models, and approximate changes in physiological state by conditional Gaussian process, given health state. We applied this model to the analyses of longitudinal data collected in the Framingham Heart Study. The results of these analyses show that model parameters can be evaluated from longitudinal data and properly interpreted. The analyses indicate important differences in physiological dynamics among healthy and sick individuals.

Authors
Yashin, AI; Akushevich, I; Arbeev, K; Kulminski, A; Ukraintseva, S
MLA Citation
Yashin, AI, Akushevich, I, Arbeev, K, Kulminski, A, and Ukraintseva, S. "Methodological aspects of studying human aging, health, and mortality." Applied Demography and Public Health. January 1, 2013. 337-355.
Source
scopus
Publish Date
2013
Start Page
337
End Page
355
DOI
10.1007/978-94-007-6140-7_19

Why does melanoma metastasize into the brain? Genes with pleiotropic effects might be the key.

Authors
Yashin, AI; Wu, D; Arbeev, KG; Kulminski, AM; Stallard, E; Ukraintseva, SV
MLA Citation
Yashin, AI, Wu, D, Arbeev, KG, Kulminski, AM, Stallard, E, and Ukraintseva, SV. "Why does melanoma metastasize into the brain? Genes with pleiotropic effects might be the key." Frontiers in genetics 4 (January 2013): 75-.
Website
http://hdl.handle.net/10161/14869
PMID
23641255
Source
epmc
Published In
Frontiers in Genetics
Volume
4
Publish Date
2013
Start Page
75
DOI
10.3389/fgene.2013.00075

How the quality of GWAS of human lifespan and health span can be improved.

Authors
Yashin, AI; Arbeev, KG; Wu, D; Arbeeva, LS; Kulminski, AM; Akushevich, I; Culminskaya, I; Stallard, E; Ukraintseva, SV
MLA Citation
Yashin, AI, Arbeev, KG, Wu, D, Arbeeva, LS, Kulminski, AM, Akushevich, I, Culminskaya, I, Stallard, E, and Ukraintseva, SV. "How the quality of GWAS of human lifespan and health span can be improved." Frontiers in genetics 4 (January 2013): 125-.
Website
http://hdl.handle.net/10161/14838
PMID
23825477
Source
epmc
Published In
Frontiers in Genetics
Volume
4
Publish Date
2013
Start Page
125
DOI
10.3389/fgene.2013.00125

Families Enriched for Exceptional Longevity also have Increased Health-Span: Findings from the Long Life Family Study

Authors
Sebastiani, P; Sun, FX; Andersen, SL; Lee, JH; Wojczynski, MK; Sanders, JL; Yashin, A; Newman, AB; Perls, TT
MLA Citation
Sebastiani, P, Sun, FX, Andersen, SL, Lee, JH, Wojczynski, MK, Sanders, JL, Yashin, A, Newman, AB, and Perls, TT. "Families Enriched for Exceptional Longevity also have Increased Health-Span: Findings from the Long Life Family Study." Frontiers in Public Health 1 (2013).
Source
crossref
Published In
Frontiers in Public Health
Volume
1
Publish Date
2013
DOI
10.3389/fpubh.2013.00038

The role of lipid-related genes, aging-related processes, and environment in healthspan

The inherent complexity of aging-related traits can temper progress in unraveling the genetic origins of healthspan. We focus on two generations in the Framingham Heart Study, the original (FHS) and offspring (FHSO) cohorts, to determine whether aging-related processes in changing environments can substantially impact the role of lipid-related genes discovered in candidate gene (the apolipoprotein E (APOE) e2/3/4 polymorphism) and genome-wide (the APOB rs1042034 (C/T)) studies, in regulation of total cholesterol (TC) and onset of cardiovascular disease (CVD). We demonstrate that the APOE e4 allele and APOB CC genotype can play detrimental, neutral, and protective sexspecific roles in the etiology of CVD at different ages and in different environments. We document antagonistic roles for the e4 allele in the onset of CVD characterized by detrimental effects at younger ages (RR≤ 75 years = 1.49, P = 7.5×104) and protective effects at older ages (RR76+years = 0.77, P = 0.044) for FHS participants. We found that disregarding the role of aging erroneously nullifies the significant effects of the e4 allele in this sample (RR = 0.92, P = 0.387). The leading biogenetic pathways mediating genetic effects on CVD may be more relevant to lipid metabolism for APOB than APOE. Aging-related processes can modulate the strength of genetic associations with TC in the same individuals at different chronological ages. We found substantial differences in the effects of the same APOE and APOB alleles on CVD and TC across generations. The results suggest that aging-related processes in changing environments may play key roles in the genetics of healthspan. Detailed systemic integrative analyses may substantially advance the progress. © 2013 The Authors. © 2013 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

Authors
Kulminski, AM; Culminskaya, I; Arbeev, KG; Ukraintseva, SV; Stallard, E; Arbeeva, L; Yashin, AI
MLA Citation
Kulminski, AM, Culminskaya, I, Arbeev, KG, Ukraintseva, SV, Stallard, E, Arbeeva, L, and Yashin, AI. "The role of lipid-related genes, aging-related processes, and environment in healthspan." Aging Cell 12.2 (2013): 237-246.
Website
http://hdl.handle.net/10161/14899
Source
scival
Published In
Aging Cell
Volume
12
Issue
2
Publish Date
2013
Start Page
237
End Page
246
DOI
10.1111/acel.12046

Inter-chromosomal level of genome organization and longevity-related phenotypes in humans

Studies focusing on unraveling the genetic origin of health span in humans assume that polygenic, aging-related phenotypes are inherited through Mendelian mechanisms of inheritance of individual genes. We use the Framingham Heart Study (FHS) data to examine whether non-Mendelian mechanisms of inheritance can drive linkage of loci on non-homologous chromosomes and whether such mechanisms can be relevant to longevity-related phenotypes. We report on genome-wide inter-chromosomal linkage disequilibrium (LD) and on chromosome-wide intra-chromosomal LD and show that these are real phenomena in the FHS data. Genetic analysis of inheritance in families based on Mendelian segregation reveals that the alleles of single nucleotide polymorphisms (SNPs) in LD at loci on non-homologous chromosomes are inherited as a complex resembling haplotypes of a genetic unit. This result implies that the inter-chromosomal LD is likely caused by non-random assortment of non-homologous chromosomes during meiosis. The risk allele haplotypes can be subject to dominant-negative selection primary through the mechanisms of non-Mendelian inheritance. They can go to extinction within two human generations. The set of SNPs in inter-chromosomal LD (N = 68) is nearly threefold enriched, with high significance (p = 1.6 × 10 -9), on non-synonymous coding variants (N = 28) compared to the entire qualified set of the studied SNPs. Genes for the tightly linked SNPs are involved in fundamental biological processes in an organism. Survival analyses show that the revealed non-genetic linkage is associated with heritable complex phenotype of premature death. Our results suggest the presence of inter-chromosomal level of functional organization in the human genome and highlight a challenging problem of genomics of human health and aging. © 2012 American Aging Association.

Authors
Kulminski, AM; Culminskaya, I; Yashin, AI
MLA Citation
Kulminski, AM, Culminskaya, I, and Yashin, AI. "Inter-chromosomal level of genome organization and longevity-related phenotypes in humans." Age 35.2 (2013): 501-518.
Website
http://hdl.handle.net/10161/14908
Source
scival
Published In
AGE
Volume
35
Issue
2
Publish Date
2013
Start Page
501
End Page
518
DOI
10.1007/s11357-011-9374-6

Patterns of Aging-Related changes on the way to 100: An Approach to studying aging, mortality, and longevity from longitudinal data

The objective of this paper is to investigate dynamic properties of age trajectories of physiological indices and their effects on mortality risk and longevity using longitudinal data on more than 5,000 individuals collected in biennial examinations of the Framingham Heart Study (FHS) original cohort during about 50 subsequent years of follow-up. We first performed empirical analyses of the FHS longitudinal data. We evaluated average age trajectories of indices describing physiological states for different groups of individuals and established their connections with mortality risk. These indices include body mass index, diastolic blood pressure, pulse pressure, pulse rate, level of blood glucose, hematocrit, and serum cholesterol. To be able to investigate dynamic mechanisms responsible for changes in the aging human organisms using available longitudinal data, we further developed a stochastic process model of human mortality and aging, by including in it the notions of "physiological norms," "allostatic adaptation and allostatic load," "stress resistance," and other characteristics associated with the internal process of aging and the effects of external disturbances. In this model, the persistent deviation of physiological indices from their normal values contributes to an increase in morbidity and mortality risks. We used the stochastic process model in the statistical analyses of longitudinal FHS data. We found that different indices have different average age patterns and different dynamic properties. We also found that age trajectories of long-lived individuals differ from those of the shorter-lived members of the FHS original cohort for both sexes. Using methods of statistical modeling, we evaluated "normal" age trajectories of physiological indices and the dynamic effects of allostatic adaptation. The model allows for evaluating average patterns of aging-related decline in stress resistance. This effect is captured by the narrowing of the U-shaped mortality risk (considered a function of physiological state) with age. We showed that individual indices and their rates of change with age, as well as other measures of individual variability, manifested during the life course are important contributors to mortality risks. The advantages and limitations of the approach are discussed.

Authors
Yashin, AI; Arbeev, KG; Ukraintseva, SV; Akushevich, I; Kulminski, A
MLA Citation
Yashin, AI, Arbeev, KG, Ukraintseva, SV, Akushevich, I, and Kulminski, A. "Patterns of Aging-Related changes on the way to 100: An Approach to studying aging, mortality, and longevity from longitudinal data." North American Actuarial Journal 16.4 (December 1, 2012): 403-433.
Website
http://hdl.handle.net/10161/14846
Source
scopus
Published In
North American Actuarial Journal
Volume
16
Issue
4
Publish Date
2012
Start Page
403
End Page
433
DOI
10.1080/10920277.2012.10597640

Developmental Processes can Drive Inter-chromosomal Linkage Disequilibrium

Authors
Kulminski, AM; Culminskaya, I; Yashin, AI
MLA Citation
Kulminski, AM, Culminskaya, I, and Yashin, AI. "Developmental Processes can Drive Inter-chromosomal Linkage Disequilibrium." November 2012.
Source
wos-lite
Published In
Genetic Epidemiology
Volume
36
Issue
7
Publish Date
2012
Start Page
725
End Page
726

Relationship Between the APOE Polymorphism and Risks of Cancer and Alzheimer's Disease: Application of the Genetic Stochastic Process Model

Authors
Arbeev, KG; Ukraintseva, SV; Kulminski, AM; Arbeeva, LS; Akushevich, I; Culminskaya, IV; Wu, D; Yashin, AI
MLA Citation
Arbeev, KG, Ukraintseva, SV, Kulminski, AM, Arbeeva, LS, Akushevich, I, Culminskaya, IV, Wu, D, and Yashin, AI. "Relationship Between the APOE Polymorphism and Risks of Cancer and Alzheimer's Disease: Application of the Genetic Stochastic Process Model." November 2012.
Source
wos-lite
Published In
Genetic Epidemiology
Volume
36
Issue
7
Publish Date
2012
Start Page
747
End Page
747

The Role of Genes and Life Course in Late Life Diseases

Authors
Kulminski, AM; Culminskaya, I; Arbeev, KG; Ukraintseva, SV; Arbeeva, L; Yashin, AI
MLA Citation
Kulminski, AM, Culminskaya, I, Arbeev, KG, Ukraintseva, SV, Arbeeva, L, and Yashin, AI. "The Role of Genes and Life Course in Late Life Diseases." November 2012.
Source
wos-lite
Published In
Genetic Epidemiology
Volume
36
Issue
7
Publish Date
2012
Start Page
743
End Page
744

MEDICARE-BASED MULTIMORBIDITY INDEX FOR PROJECTING MORBIDITY AND MORTALITY AMONG OLDER ADULTS IN THE U.S

Authors
Akushevich, I; Kravchenko, J; Whitson, H; Cohen, HJ; Ukraintseva, SV; Arbeev, KG; Yashin, AI
MLA Citation
Akushevich, I, Kravchenko, J, Whitson, H, Cohen, HJ, Ukraintseva, SV, Arbeev, KG, and Yashin, AI. "MEDICARE-BASED MULTIMORBIDITY INDEX FOR PROJECTING MORBIDITY AND MORTALITY AMONG OLDER ADULTS IN THE U.S." GERONTOLOGIST 52 (November 2012): 630-630.
Website
http://hdl.handle.net/10161/14871
Source
wos-lite
Published In
The Gerontologist
Volume
52
Publish Date
2012
Start Page
630
End Page
630

TRADE-OFF IN THE EFFECT OF THE APOLIPOPROTEIN E POLYMORPHISM ON THE AGES AT ONSET OF CVD AND CANCER: THE ROLE OF AGE AND GENDER ACROSS GENERATIONS

Authors
Kulminski, A; Culminskaya, I; Arbeev, KG; Ukraintseva, SV; Arbeeva, L; Yashin, AI
MLA Citation
Kulminski, A, Culminskaya, I, Arbeev, KG, Ukraintseva, SV, Arbeeva, L, and Yashin, AI. "TRADE-OFF IN THE EFFECT OF THE APOLIPOPROTEIN E POLYMORPHISM ON THE AGES AT ONSET OF CVD AND CANCER: THE ROLE OF AGE AND GENDER ACROSS GENERATIONS." GERONTOLOGIST 52 (November 2012): 153-153.
Website
http://hdl.handle.net/10161/14800
Source
wos-lite
Published In
The Gerontologist
Volume
52
Publish Date
2012
Start Page
153
End Page
153

GENES, HEALTH, AGING, AND ENVIRONMENT: HOW ARE THEY RELATED?

Authors
Kulminski, A; Culminskaya, I; Arbeev, KG; Ukraintseva, SV; Arbeeva, L; Yashin, AI
MLA Citation
Kulminski, A, Culminskaya, I, Arbeev, KG, Ukraintseva, SV, Arbeeva, L, and Yashin, AI. "GENES, HEALTH, AGING, AND ENVIRONMENT: HOW ARE THEY RELATED?." GERONTOLOGIST 52 (November 2012): 123-123.
Source
wos-lite
Published In
The Gerontologist
Volume
52
Publish Date
2012
Start Page
123
End Page
123

MUTUAL DEPENDENCE OF RISKS OF CANCER AND CHRONIC NON-CANCER DISEASES: MEDICARE-BASED ANALYSIS

Authors
Akushevich, I; Kravchenko, J; Ukraintseva, SV; Arbeev, KG; Yashin, AI
MLA Citation
Akushevich, I, Kravchenko, J, Ukraintseva, SV, Arbeev, KG, and Yashin, AI. "MUTUAL DEPENDENCE OF RISKS OF CANCER AND CHRONIC NON-CANCER DISEASES: MEDICARE-BASED ANALYSIS." GERONTOLOGIST 52 (November 2012): 372-372.
Source
wos-lite
Published In
The Gerontologist
Volume
52
Publish Date
2012
Start Page
372
End Page
372

GENETIC AND NON-GENETIC FACTORS IN AGING, HEALTH, AND LIFESPAN: INSIGHTS FROM BIODEMOGRAPHIC ANALYSES

Authors
Yashin, AI; Wu, D; Arbeev, KG; Akushevich, I; Kulminski, A; Stallard, P; Arbeeva, L; Ukraintseva, SV
MLA Citation
Yashin, AI, Wu, D, Arbeev, KG, Akushevich, I, Kulminski, A, Stallard, P, Arbeeva, L, and Ukraintseva, SV. "GENETIC AND NON-GENETIC FACTORS IN AGING, HEALTH, AND LIFESPAN: INSIGHTS FROM BIODEMOGRAPHIC ANALYSES." GERONTOLOGIST 52 (November 2012): 123-123.
Source
wos-lite
Published In
The Gerontologist
Volume
52
Publish Date
2012
Start Page
123
End Page
123

CONNECTION BETWEEN INDIVIDUAL AGING AND MORTALITY: THE RESULTS OF BIO-DEMOGRAPHIC ANALYSES

Authors
Yashin, AI; Arbeev, KG; Akushevich, I; Kulminski, A; Stallard, P; Wu, D; Arbeeva, L; Ukraintseva, SV
MLA Citation
Yashin, AI, Arbeev, KG, Akushevich, I, Kulminski, A, Stallard, P, Wu, D, Arbeeva, L, and Ukraintseva, SV. "CONNECTION BETWEEN INDIVIDUAL AGING AND MORTALITY: THE RESULTS OF BIO-DEMOGRAPHIC ANALYSES." GERONTOLOGIST 52 (November 2012): 261-261.
Source
wos-lite
Published In
The Gerontologist
Volume
52
Publish Date
2012
Start Page
261
End Page
261

EVALUATING EFFECTS OF GENES AND AGE TRAJECTORIES OF PHYSIOLOGICAL VARIABLES ON MORTALITY AND MORBIDITY RISKS: APPLICATION OF GENETIC STOCHASTIC PROCESS MODEL

Authors
Arbeev, KG; Akushevich, I; Kulminski, A; Ukraintseva, SV; Arbeeva, L; Culminskaya, I; Wu, D; Yashin, AI
MLA Citation
Arbeev, KG, Akushevich, I, Kulminski, A, Ukraintseva, SV, Arbeeva, L, Culminskaya, I, Wu, D, and Yashin, AI. "EVALUATING EFFECTS OF GENES AND AGE TRAJECTORIES OF PHYSIOLOGICAL VARIABLES ON MORTALITY AND MORBIDITY RISKS: APPLICATION OF GENETIC STOCHASTIC PROCESS MODEL." GERONTOLOGIST 52 (November 2012): 152-152.
Source
wos-lite
Published In
The Gerontologist
Volume
52
Publish Date
2012
Start Page
152
End Page
152

How genes influence life span: the biodemography of human survival.

In genome-wide association studies (GWAS) of human life span, none of the genetic variants has reached the level of genome-wide statistical significance. The roles of such variants in life span regulation remain unclear.A biodemographic analyses was done of genetic regulation of life span using data on low-significance longevity alleles selected in the earlier GWAS of the original Framingham cohort.Age-specific survival curves considered as functions of the number of longevity alleles exhibit regularities known in demography as "rectangularization" of survival curves. The presence of such pattern confirms observations from experimental studies that regulation of life span involves genes responsible for stress resistance.Biodemographic analyses could provide important information about the properties of genes affecting phenotypic traits.

Authors
Yashin, AI; Wu, D; Arbeev, KG; Stallard, E; Land, KC; Ukraintseva, SV
MLA Citation
Yashin, AI, Wu, D, Arbeev, KG, Stallard, E, Land, KC, and Ukraintseva, SV. "How genes influence life span: the biodemography of human survival." Rejuvenation research 15.4 (August 2012): 374-380.
Website
http://hdl.handle.net/10161/14874
PMID
22607627
Source
epmc
Published In
Rejuvenation Research
Volume
15
Issue
4
Publish Date
2012
Start Page
374
End Page
380
DOI
10.1089/rej.2011.1290

Polygenic effects of common single-nucleotide polymorphisms on life span: when association meets causality.

Recently we have shown that the human life span is influenced jointly by many common single-nucleotide polymorphisms (SNPs), each with a small individual effect. Here we investigate further the polygenic influence on life span and discuss its possible biological mechanisms. First we identified six sets of prolongevity SNP alleles in the Framingham Heart Study 550K SNPs data, using six different statistical procedures (normal linear, Cox, and logistic regressions; generalized estimation equation; mixed model; gene frequency method). We then estimated joint effects of these SNPs on human survival. We found that alleles in each set show significant additive influence on life span. Twenty-seven SNPs comprised the overlapping set of SNPs that influenced life span, regardless of the statistical procedure. The majority of these SNPs (74%) were within genes, compared to 40% of SNPs in the original 550K set. We then performed a review of current literature on functions of genes closest to these 27 SNPs. The review showed that the respective genes are largely involved in aging, cancer, and brain disorders. We concluded that polygenic effects can explain a substantial portion of genetic influence on life span. Composition of the set of prolongevity alleles depends on the statistical procedure used for the allele selection. At the same time, there is a core set of longevity alleles that are selected with all statistical procedures. Functional relevance of respective genes to aging and major diseases supports causal relationships between the identified SNPs and life span. The fact that genes found in our and other genetic association studies of aging/longevity have similar functions indicates high chances of true positive associations for corresponding genetic variants.

Authors
Yashin, AI; Wu, D; Arbeev, KG; Ukraintseva, SV
MLA Citation
Yashin, AI, Wu, D, Arbeev, KG, and Ukraintseva, SV. "Polygenic effects of common single-nucleotide polymorphisms on life span: when association meets causality." Rejuvenation research 15.4 (August 2012): 381-394.
Website
http://hdl.handle.net/10161/14873
PMID
22533364
Source
epmc
Published In
Rejuvenation Research
Volume
15
Issue
4
Publish Date
2012
Start Page
381
End Page
394
DOI
10.1089/rej.2011.1257

Increase in circulating levels of IGF-1 and IGF-1/IGFBP-3 molar ratio over a decade is associated with colorectal adenomatous polyps.

High levels of circulating insulin-like growth factor-1 (IGF-1) have been associated with increased risk of several cancers. Regarding colorectal cancer, these associations are generally weak. We hypothesized that an increase in IGF-1 over time would be a stronger risk factor for cancer-related outcomes than the actual levels. In this analysis we utilized existing data from the Insulin Resistance and Atherosclerosis Study (IRAS). Circulating IGF-1 levels and molar ratios of IGF-1 to IGF binding protein 3 (IGFBP-3) were measured at three time points, within a 10-year follow-up period. We examined the associations of increase of the two variables with the presence of colorectal adenoma at the end of follow-up among participants with normal glucose tolerance at baseline. This included 143 individuals, from which 24 were diagnosed with adenomatous polyps. Although the mean levels of IGF-1 and IGF-1/IGFBP-3 decline with age, ~ 30% of the participants showed an increase of at least fifteen percent ("ever increase") in one or both of these variables, compared to baseline. We found a positive association between "ever increase" in IGF-1 or IGF-1/IGFBP-3 and the presence of colorectal adenoma: ORs were 3.81 (95% CI: 1.30-10.8) and 2.83 (95% CI: 1.00-8.22), respectively. No association was found when analyzing the actual levels of both variables at any time point. Our data suggest that an increase in circulating IGF-1 or IGF-1/IGFBP-3 may represent a disturbed GH/IGF1 homeostasis, which could favor the development of precancerous lesions such as colorectal adenoma.

Authors
Soubry, A; Il'yasova, D; Sedjo, R; Wang, F; Byers, T; Rosen, C; Yashin, A; Ukraintseva, S; Haffner, S; D'Agostino, R
MLA Citation
Soubry, A, Il'yasova, D, Sedjo, R, Wang, F, Byers, T, Rosen, C, Yashin, A, Ukraintseva, S, Haffner, S, and D'Agostino, R. "Increase in circulating levels of IGF-1 and IGF-1/IGFBP-3 molar ratio over a decade is associated with colorectal adenomatous polyps." Int J Cancer 131.2 (July 15, 2012): 512-517.
Website
http://hdl.handle.net/10161/14914
PMID
21898383
Source
pubmed
Published In
International Journal of Cancer
Volume
131
Issue
2
Publish Date
2012
Start Page
512
End Page
517
DOI
10.1002/ijc.26393

Modeling longitudinal data on health aging and life span

Authors
Yashin, AI; Arbeev, KG; Akushevich, I; Kulminski, A; Ukraintseva, SV; Stallard, E; Land, KC
MLA Citation
Yashin, AI, Arbeev, KG, Akushevich, I, Kulminski, A, Ukraintseva, SV, Stallard, E, and Land, KC. "Modeling longitudinal data on health aging and life span." Physics of Life Reviews 9.2 (June 2012): 195-197.
Website
http://hdl.handle.net/10161/14848
Source
crossref
Published In
Physics of Life Reviews
Volume
9
Issue
2
Publish Date
2012
Start Page
195
End Page
197
DOI
10.1016/j.plrev.2012.05.018

The quadratic hazard model for analyzing longitudinal data on aging, health, and the life span.

A better understanding of processes and mechanisms linking human aging with changes in health status and survival requires methods capable of analyzing new data that take into account knowledge about these processes accumulated in the field. In this paper, we describe an approach to analyses of longitudinal data based on the use of stochastic process models of human aging, health, and longevity which allows for incorporating state of the art advances in aging research into the model structure. In particular, the model incorporates the notions of resistance to stresses, adaptive capacity, and "optimal" (normal) physiological states. To capture the effects of exposure to persistent external disturbances, the notions of allostatic adaptation and allostatic load are introduced. These notions facilitate the description and explanation of deviations of individuals' physiological indices from their normal states, which increase the chances of disease development and death. The model provides a convenient conceptual framework for comprehensive systemic analyses of aging-related changes in humans using longitudinal data and linking these changes with genotyping profiles, morbidity, and mortality risks. The model is used for developing new statistical methods for analyzing longitudinal data on aging, health, and longevity.

Authors
Yashin, AI; Arbeev, KG; Akushevich, I; Kulminski, A; Ukraintseva, SV; Stallard, E; Land, KC
MLA Citation
Yashin, AI, Arbeev, KG, Akushevich, I, Kulminski, A, Ukraintseva, SV, Stallard, E, and Land, KC. "The quadratic hazard model for analyzing longitudinal data on aging, health, and the life span." Physics of life reviews 9.2 (June 2012): 177-188.
Website
http://hdl.handle.net/10161/14845
PMID
22633776
Source
epmc
Published In
Physics of Life Reviews
Volume
9
Issue
2
Publish Date
2012
Start Page
177
End Page
188
DOI
10.1016/j.plrev.2012.05.002

New stochastic carcinogenesis model with covariates: an approach involving intracellular barrier mechanisms.

In this paper we present a new multiple-pathway stochastic model of carcinogenesis with potential of predicting individual incidence risks on the basis of biomedical measurements. The model incorporates the concept of intracellular barrier mechanisms in which cell malignization occurs due to an inefficient operation of barrier cell mechanisms, such as antioxidant defense, repair systems, and apoptosis. Mathematical formalism combines methodological innovations of mechanistic carcinogenesis models and stochastic process models widely used in studying biodemography of aging and longevity. An advantage of the modeling approach is in the natural combining of two types of measures expressed in terms of model parameters: age-specific hazard rate and means of barrier states. Results of simulation studies allow us to conclude that the model parameters can be estimated in joint analyses of epidemiological data and newly collected data on individual biomolecular measurements of barrier states. Respective experimental designs for such measurements are suggested and discussed. An analytical solution is obtained for the simplest design when only age-specific incidence rates are observed. Detailed comparison with TSCE model reveals advantages of the approach such as the possibility to describe decline in risk at advanced ages, possibilities to describe heterogeneous system of intermediate cells, and perspectives for individual prognoses of cancer risks. Application of the results to fit the SEER data on cancer risks demonstrates a strong predictive power of the model. Further generalizations of the model, opportunities to measure barrier systems, biomedical and mathematical aspects of the new model are discussed.

Authors
Akushevich, I; Veremeyeva, G; Kravchenko, J; Ukraintseva, S; Arbeev, K; Akleyev, AV; Yashin, AI
MLA Citation
Akushevich, I, Veremeyeva, G, Kravchenko, J, Ukraintseva, S, Arbeev, K, Akleyev, AV, and Yashin, AI. "New stochastic carcinogenesis model with covariates: an approach involving intracellular barrier mechanisms." Mathematical biosciences 236.1 (March 2012): 16-30.
Website
http://hdl.handle.net/10161/14847
PMID
22200574
Source
epmc
Published In
Mathematical Biosciences
Volume
236
Issue
1
Publish Date
2012
Start Page
16
End Page
30
DOI
10.1016/j.mbs.2011.12.002

Age patterns of incidence of geriatric disease in the U.S. elderly population: Medicare-based analysis.

To use the Medicare Files of Service Use (MFSU) to evaluate patterns in the incidence of aging-related diseases in the U.S. elderly population.Age-specific incidence rates of 19 aging-related diseases were evaluated using the National Long Term Care Survey (NLTCS) and the Surveillance, Epidemiology, and End Results (SEER) Registry data, both linked to MFSU (NLTCS-M and SEER-M, respectively), using an algorithm developed for individual date at onset evaluation.A random sample from the entire U.S. elderly population (Medicare beneficiaries) was used in NLTCS, and the SEER Registry data covers 26% of the U.S. population.Thirty-four thousand seventy-seven individuals from NLTCS-M and 2,154,598 from SEER-M.Individual medical histories were reconstructed using information on diagnoses coded in MFSU, dates of medical services and procedures, and Medicare enrollment and disenrollment.The majority of diseases (e.g., prostate cancer, asthma, and diabetes mellitus) had a monotonic decline (or decline after a short period of increase) in incidence with age. A monotonic increase in incidence with age with a subsequent leveling off and decline was observed for myocardial infarction, stroke, heart failure, ulcer, and Alzheimer's disease. An inverted U-shaped age pattern was detected for lung and colon carcinomas, Parkinson's disease, and renal failure. The results obtained from the NLTCS-M and SEER-M were in agreement (excluding an excess for circulatory diseases in the NLTCS-M). A sensitivity analysis proved the stability of the incidence rates evaluated.The developed computational approaches applied to the nationally representative Medicare-based data sets allow reconstruction of age patterns of disease incidence in the U.S. elderly population at the national level with unprecedented statistical accuracy and stability with respect to systematic biases.

Authors
Akushevich, I; Kravchenko, J; Ukraintseva, S; Arbeev, K; Yashin, AI
MLA Citation
Akushevich, I, Kravchenko, J, Ukraintseva, S, Arbeev, K, and Yashin, AI. "Age patterns of incidence of geriatric disease in the U.S. elderly population: Medicare-based analysis." Journal of the American Geriatrics Society 60.2 (February 2012): 323-327.
Website
http://hdl.handle.net/10161/14851
PMID
22283485
Source
epmc
Published In
Journal of American Geriatrics Society
Volume
60
Issue
2
Publish Date
2012
Start Page
323
End Page
327
DOI
10.1111/j.1532-5415.2011.03786.x

Trade-Off In The Effects Of The APOE Polymorphism On The Ages At Onset Of CVD And Cancer: Insights From The Genetic Stochastic Process Model

Authors
Arbeev, KG; Kulminski, A; Ukraintseva, SV; Arbeeva, LS; Akushevich, I; Culminskaya, IV; Wu, D; Yashin, AI
MLA Citation
Arbeev, KG, Kulminski, A, Ukraintseva, SV, Arbeeva, LS, Akushevich, I, Culminskaya, IV, Wu, D, and Yashin, AI. "Trade-Off In The Effects Of The APOE Polymorphism On The Ages At Onset Of CVD And Cancer: Insights From The Genetic Stochastic Process Model." February 2012.
Source
wos-lite
Published In
Genetic Epidemiology
Volume
36
Issue
2
Publish Date
2012
Start Page
157
End Page
157

Effect of the APOE Polymorphism and Age Trajectories of Physiological Variables on Mortality: Application of Genetic Stochastic Process Model of Aging.

We evaluated effects of the APOE polymorphism (carriers versus noncarriers of the e4 allele) and age trajectories of total cholesterol (CH) and diastolic blood pressure (DBP) on mortality risk in the Framingham Heart Study (original cohort). We found that long-lived carriers and noncarriers have different average age trajectories and long-lived individuals have consistently higher levels and less steep declines at old ages compared to short-lived individuals. We applied the stochastic process model of aging aimed at joint analyses of genetic and nongenetic subsamples of longitudinal data and estimated different aging-related characteristics for carriers and noncarriers which otherwise cannot be evaluated from data. We found that such characteristics differ in carriers and noncarriers: (1) carriers have better adaptive capacity than noncarriers in case of CH, whereas for DBP the opposite situation is observed; (2) mean allostatic trajectories are higher in carriers and they differ from "optimal" trajectories minimizing mortality risk; (3) noncarriers have lower baseline mortality rates at younger ages but they increase faster than those for carriers resulting in intersection at the oldest ages. Such observations strongly indicate the presence of a genetic component in respective aging-related mechanisms. Such differences may contribute to patterns of allele- and sex-specific mortality rates.

Authors
Arbeev, KG; Ukraintseva, SV; Kulminski, AM; Akushevich, I; Arbeeva, LS; Culminskaya, IV; Wu, D; Yashin, AI
MLA Citation
Arbeev, KG, Ukraintseva, SV, Kulminski, AM, Akushevich, I, Arbeeva, LS, Culminskaya, IV, Wu, D, and Yashin, AI. "Effect of the APOE Polymorphism and Age Trajectories of Physiological Variables on Mortality: Application of Genetic Stochastic Process Model of Aging." Scientifica 2012 (January 2012).
Website
http://hdl.handle.net/10161/14760
PMID
23682334
Source
epmc
Published In
Scientifica
Volume
2012
Publish Date
2012
DOI
10.6064/2012/568628

An age-structured extension to the vectorial capacity model.

BACKGROUND: Vectorial capacity and the basic reproductive number (R(0)) have been instrumental in structuring thinking about vector-borne pathogen transmission and how best to prevent the diseases they cause. One of the more important simplifying assumptions of these models is age-independent vector mortality. A growing body of evidence indicates that insect vectors exhibit age-dependent mortality, which can have strong and varied affects on pathogen transmission dynamics and strategies for disease prevention. METHODOLOGY/PRINCIPAL FINDINGS: Based on survival analysis we derived new equations for vectorial capacity and R(0) that are valid for any pattern of age-dependent (or age-independent) vector mortality and explore the behavior of the models across various mortality patterns. The framework we present (1) lays the groundwork for an extension and refinement of the vectorial capacity paradigm by introducing an age-structured extension to the model, (2) encourages further research on the actuarial dynamics of vectors in particular and the relationship of vector mortality to pathogen transmission in general, and (3) provides a detailed quantitative basis for understanding the relative impact of reductions in vector longevity compared to other vector-borne disease prevention strategies. CONCLUSIONS/SIGNIFICANCE: Accounting for age-dependent vector mortality in estimates of vectorial capacity and R(0) was most important when (1) vector densities are relatively low and the pattern of mortality can determine whether pathogen transmission will persist; i.e., determines whether R(0) is above or below 1, (2) vector population growth rate is relatively low and there are complex interactions between birth and death that differ fundamentally from birth-death relationships with age-independent mortality, and (3) the vector exhibits complex patterns of age-dependent mortality and R(0) ∼ 1. A limiting factor in the construction and evaluation of new age-dependent mortality models is the paucity of data characterizing vector mortality patterns, particularly for free ranging vectors in the field.

Authors
Novoseltsev, VN; Michalski, AI; Novoseltseva, JA; Yashin, AI; Carey, JR; Ellis, AM
MLA Citation
Novoseltsev, VN, Michalski, AI, Novoseltseva, JA, Yashin, AI, Carey, JR, and Ellis, AM. "An age-structured extension to the vectorial capacity model." PLoS One 7.6 (2012): e39479-.
Website
http://hdl.handle.net/10161/14911
PMID
22724022
Source
pubmed
Published In
PloS one
Volume
7
Issue
6
Publish Date
2012
Start Page
e39479
DOI
10.1371/journal.pone.0039479

The second international conference "genetics of aging and longevity".

Authors
Anisimov, VN; Bartke, A; Barzilai, N; Batin, MA; Blagosklonny, MV; Brown-Borg, H; Budovskaya, Y; Campisi, J; Friguet, B; Fraifeld, V; Franceschi, C; Gems, D; Gladyshev, V; Gorbunova, V; Gudkov, AV; Kennedy, B; Konovalenko, M; Kraemer, B; Moskalev, A; Petropoulos, I; Pasyukova, E; Rattan, S; Rogina, B; Seluanov, A; Shaposhnikov, M; Reis, RS; Tavernarakis, N; Vijg, J; Yashin, A; Zimniak, P
MLA Citation
Anisimov, VN, Bartke, A, Barzilai, N, Batin, MA, Blagosklonny, MV, Brown-Borg, H, Budovskaya, Y, Campisi, J, Friguet, B, Fraifeld, V, Franceschi, C, Gems, D, Gladyshev, V, Gorbunova, V, Gudkov, AV, Kennedy, B, Konovalenko, M, Kraemer, B, Moskalev, A, Petropoulos, I, Pasyukova, E, Rattan, S, Rogina, B, Seluanov, A, Shaposhnikov, M, Reis, RS, Tavernarakis, N, Vijg, J, Yashin, A, and Zimniak, P. "The second international conference "genetics of aging and longevity"." Aging 4.5 (2012): 305-317.
Website
http://hdl.handle.net/10161/14909
PMID
22661237
Source
scival
Published In
Aging
Volume
4
Issue
5
Publish Date
2012
Start Page
305
End Page
317

PATTERNS OF AGING-RELATED DISEASES INCIDENCE AND RECOVERY IN US ELDERLY

Authors
Akushevich, I; Kravchenko, J; Ukraintseva, SV; Arbeev, KG; Yashin, AI
MLA Citation
Akushevich, I, Kravchenko, J, Ukraintseva, SV, Arbeev, KG, and Yashin, AI. "PATTERNS OF AGING-RELATED DISEASES INCIDENCE AND RECOVERY IN US ELDERLY." GERONTOLOGIST 51 (November 2011): 229-229.
Website
http://hdl.handle.net/10161/14875
Source
wos-lite
Published In
The Gerontologist
Volume
51
Publish Date
2011
Start Page
229
End Page
229

LIFESTYLE EFFECTS ON MORBIDITY AND MORTALITY IN US ELDERLY POPULATION

Authors
Akushevich, I; Kravchenko, J; Ukraintseva, SV; Arbeev, KG; Yashin, AI
MLA Citation
Akushevich, I, Kravchenko, J, Ukraintseva, SV, Arbeev, KG, and Yashin, AI. "LIFESTYLE EFFECTS ON MORBIDITY AND MORTALITY IN US ELDERLY POPULATION." GERONTOLOGIST 51 (November 2011): 333-333.
Source
wos-lite
Published In
The Gerontologist
Volume
51
Publish Date
2011
Start Page
333
End Page
333

DO EARLY-LIFE AGING-RELATED PHENOTYPES IN ADULTS PREDICT HEALTH TRAITS AT LATE AGES IN FAMILIES? INSIGHTS FROM THE LONG-LIFE FAMILY STUDY

Authors
Kulminski, A; Arbeev, KG; Christensen, K; Newman, AB; Province, MA; Elo, IT; Mayeux, R; Yashin, AI
MLA Citation
Kulminski, A, Arbeev, KG, Christensen, K, Newman, AB, Province, MA, Elo, IT, Mayeux, R, and Yashin, AI. "DO EARLY-LIFE AGING-RELATED PHENOTYPES IN ADULTS PREDICT HEALTH TRAITS AT LATE AGES IN FAMILIES? INSIGHTS FROM THE LONG-LIFE FAMILY STUDY." GERONTOLOGIST 51 (November 2011): 122-122.
Source
wos-lite
Published In
The Gerontologist
Volume
51
Publish Date
2011
Start Page
122
End Page
122

HOW GENES CONTRIBUTE TO AGING RELATED CHANGES AND AFFECT LIFE SPAN IN HUMANS

Authors
Yashin, AI; Wu, D; Arbeev, KG; Ukraintseva, SV
MLA Citation
Yashin, AI, Wu, D, Arbeev, KG, and Ukraintseva, SV. "HOW GENES CONTRIBUTE TO AGING RELATED CHANGES AND AFFECT LIFE SPAN IN HUMANS." GERONTOLOGIST 51 (November 2011): 121-121.
Source
wos-lite
Published In
The Gerontologist
Volume
51
Publish Date
2011
Start Page
121
End Page
121

Joint Analysis of Health Histories, Physiological State, and Survival

Authors
YASHIN, ANATOLYI; AKUSHEVICH, IGOR; ARBEEV, KONSTANTING; KULMINSKI, ALEXANDER; UKRAINTSEVA, SVETLANA
MLA Citation
YASHIN, ANATOLYI, AKUSHEVICH, IGOR, ARBEEV, KONSTANTING, KULMINSKI, ALEXANDER, and UKRAINTSEVA, SVETLANA. "Joint Analysis of Health Histories, Physiological State, and Survival." Mathematical Population Studies 18.4 (October 2011): 207-233.
Website
http://hdl.handle.net/10161/14877
Source
crossref
Published In
Mathematical Population Studies
Volume
18
Issue
4
Publish Date
2011
Start Page
207
End Page
233
DOI
10.1080/08898480.2011.614486

Trade-off in the effects of the apolipoprotein E polymorphism on the ages at onset of CVD and cancer influences human lifespan.

Progress in unraveling the genetic origins of healthy aging is tempered, in part, by a lack of replication of effects, which is often considered a signature of false-positive findings. We convincingly demonstrate that the lack of genetic effects on an aging-related trait can be because of trade-offs in the gene action. We focus on the well-studied apolipoprotein E (APOE) e2/3/4 polymorphism and on lifespan and ages at onset of cardiovascular diseases (CVD) and cancer, using data on 3924 participants of the Framingham Heart Study Offspring cohort. Kaplan-Meier estimates show that the e4 allele carriers live shorter lives than the non-e4 allele carriers (log rank = 0.016). The adverse effect was attributed to the poor survival of the e4 homozygotes, whereas the effect of the common e3/4 genotype was insignificant. The e3/4 genotype, however, was antagonistically associated with onsets of those diseases predisposing to an earlier onset of CVD and a later onset of cancer compared to the non-e4 allele genotypes. This trade-off explains the lack of a significant effect of the e3/4 genotype on survival; adjustment for it in the Cox regression model makes the detrimental effect of the e4 allele highly significant (P = 0.002). This trade-off is likely caused by the lipid-metabolism-related (for CVD) and nonrelated (for cancer) mechanisms. An evolutionary rationale suggests that genetic trade-offs should not be an exception in studies of aging-related traits. Deeper insights into biological mechanisms mediating gene action are critical for understanding the genetic regulation of a healthy lifespan and for personalizing medical care.

Authors
Kulminski, AM; Culminskaya, I; Ukraintseva, SV; Arbeev, KG; Arbeeva, L; Wu, D; Akushevich, I; Land, KC; Yashin, AI
MLA Citation
Kulminski, AM, Culminskaya, I, Ukraintseva, SV, Arbeev, KG, Arbeeva, L, Wu, D, Akushevich, I, Land, KC, and Yashin, AI. "Trade-off in the effects of the apolipoprotein E polymorphism on the ages at onset of CVD and cancer influences human lifespan." Aging cell 10.3 (June 2011): 533-541.
Website
http://hdl.handle.net/10161/14853
PMID
21332925
Source
epmc
Published In
Aging Cell
Volume
10
Issue
3
Publish Date
2011
Start Page
533
End Page
541
DOI
10.1111/j.1474-9726.2011.00689.x

Modeling hematopoietic system response caused by chronic exposure to ionizing radiation.

A new model of the hematopoietic system response in humans chronically exposed to ionizing radiation describes the dynamics of the hematopoietic stem cell compartment as well as the dynamics of each of the four blood cell types (lymphocytes, neutrophiles, erythrocytes, and platelets). The required model parameters were estimated based on available results of human and experimental animal studies. They include the steady-state number of hematopoietic stem cells and peripheral blood cell lines in an unexposed organism, amplification parameters for each blood line, parameters describing proliferation and apoptosis, parameters of feedback functions regulating the steady-state numbers, and characteristics of radiosensitivity related to cell death and non-lethal cell damage. The model predictions were tested using data on hematological measurements (e.g., blood counts) performed in 1950-1956 in the Techa River residents chronically exposed to ionizing radiation since 1949. The suggested model of hematopoiesis is capable of describing experimental findings in the Techa River Cohort, including: (1) slopes of the dose-effect curves reflecting the inhibition of hematopoiesis due to chronic ionizing radiation, (2) delay in effect of chronic exposure and accumulated character of the effect, and (3) dose-rate patterns for different cytopenic states (e.g., leukopenia, thrombocytopenia).

Authors
Akushevich, IV; Veremeyeva, GA; Dimov, GP; Ukraintseva, SV; Arbeev, KG; Akleyev, AV; Yashin, AI
MLA Citation
Akushevich, IV, Veremeyeva, GA, Dimov, GP, Ukraintseva, SV, Arbeev, KG, Akleyev, AV, and Yashin, AI. "Modeling hematopoietic system response caused by chronic exposure to ionizing radiation." Radiation and environmental biophysics 50.2 (May 2011): 299-311.
Website
http://hdl.handle.net/10161/14854
PMID
21259022
Source
epmc
Published In
Radiation and Environmental Biophysics
Volume
50
Issue
2
Publish Date
2011
Start Page
299
End Page
311
DOI
10.1007/s00411-011-0351-3

Do gender, disability, and morbidity affect aging rate in the LLFS? Application of indices of cumulative deficits.

We used an approach of cumulative deficits to evaluate the rate of aging in 4954 participants of the Long-Life Family Study (LLFS) recruited in the U.S. (Boston, New York, and Pittsburgh) and Denmark. We used an array of 85 health-related deficits covering major health dimensions including depression, cognition, morbidity, physical performance, and disability to construct several deficit indices (DIs) with overlapping and complementary sets of deficits to test robustness of the estimates. Our study shows that the DIs robustly characterize accelerated rates of aging irrespective of specific of deficits. When a wider spectrum of health dimensions is considered these rates are better approximated by quadratic law. Exponential rates are more characteristic for more severe health dimensions. The aging rates are the same for males and females. Individuals who contracted major diseases and those who were free of them exhibited the same aging rates as characterized by the DI constructed using mild deficits. Unlike health, disability can qualitatively alter the aging patterns of the LLFS participants. We report on systemic differences in health among the LLFS centenarians residing in New York and Boston. This study highlights importance of aggregated approaches to better understand systemic mechanisms of health deterioration in long-living individuals.

Authors
Kulminski, AM; Arbeev, KG; Christensen, K; Mayeux, R; Newman, AB; Province, MA; Hadley, EC; Rossi, W; Perls, TT; Elo, IT; Yashin, AI
MLA Citation
Kulminski, AM, Arbeev, KG, Christensen, K, Mayeux, R, Newman, AB, Province, MA, Hadley, EC, Rossi, W, Perls, TT, Elo, IT, and Yashin, AI. "Do gender, disability, and morbidity affect aging rate in the LLFS? Application of indices of cumulative deficits." Mechanisms of ageing and development 132.4 (April 2, 2011): 195-201.
Website
http://hdl.handle.net/10161/14878
PMID
21463647
Source
epmc
Published In
Mechanisms of Ageing and Development
Volume
132
Issue
4
Publish Date
2011
Start Page
195
End Page
201
DOI
10.1016/j.mad.2011.03.006

Leukocyte telomere length, breast cancer risk in the offspring: the relations with father's age at birth.

Recent studies have reported that leukocyte telomere length (LTL) is longer in offspring of older fathers. Longer telomeres might increase cancer risk. We examined the relation of father's age at the birth of the offspring (FAB) with LTL in the offspring in 2177 participants of the Family Heart Study and the probability of developing breast cancer in 1405 women from the Framingham Heart Study (offspring cohort). For each year of increase in FAB (adjusted for mother's age at birth), LTLs in the daughters and sons were longer by 19.4bp and 12.2bp, respectively (p<0.0001). Daughters of older fathers were less likely to stay free of breast cancer compared to daughters of younger fathers in empirical (p=0.014) and Cox regression analyses (p=0.0012) adjusted for relevant covariates. We conclude that older fathers endow their offspring with a longer LTL and their daughters with increased susceptibility to breast cancer. These independent observations cannot provide evidence for a causal relationship, mediated by telomere length, between FAB and increased breast cancer risk in daughters. However, with couples delaying having children in today's society, studies exploring the LTL association with increased breast cancer risk in daughters of older fathers might be timely and relevant.

Authors
Arbeev, KG; Hunt, SC; Kimura, M; Aviv, A; Yashin, AI
MLA Citation
Arbeev, KG, Hunt, SC, Kimura, M, Aviv, A, and Yashin, AI. "Leukocyte telomere length, breast cancer risk in the offspring: the relations with father's age at birth." Mechanisms of ageing and development 132.4 (April 2011): 149-153.
Website
http://hdl.handle.net/10161/14876
PMID
21354438
Source
epmc
Published In
Mechanisms of Ageing and Development
Volume
132
Issue
4
Publish Date
2011
Start Page
149
End Page
153
DOI
10.1016/j.mad.2011.02.004

Evaluation of genotype-specific survival using joint analysis of genetic and non-genetic subsamples of longitudinal data.

Small sample size of genetic data is often a limiting factor for desirable accuracy of estimated genetic effects on age-specific risks and survival. Longitudinal non-genetic data containing information on survival or disease onsets of study participants for whom the genetic data were not collected may provide an additional "reserve" for increasing the accuracy of respective estimates. We present a novel method for joint analyses of "genetic" (covering individuals for whom both genetic information and mortality/morbidity data are available) and "non-genetic" (covering individuals for whom only mortality/morbidity data were collected) subsamples of longitudinal data. Our simulation studies show substantial increase in the accuracy of estimates in such joint analyses compared to analyses based on genetic subsample alone. Application of this method to analysis of the effect of common apolipoprotein E (APOE) polymorphism on survival using combined genetic and non-genetic subsamples of the Framingham Heart Study original cohort data showed that female, but not male, carriers of the APOE e4 allele have significantly worse survival than non-carriers, whereas empirical analyses did not produce any significant results for either sex.

Authors
Arbeev, KG; Ukraintseva, SV; Arbeeva, LS; Akushevich, I; Kulminski, AM; Yashin, AI
MLA Citation
Arbeev, KG, Ukraintseva, SV, Arbeeva, LS, Akushevich, I, Kulminski, AM, and Yashin, AI. "Evaluation of genotype-specific survival using joint analysis of genetic and non-genetic subsamples of longitudinal data." Biogerontology 12.2 (April 2011): 157-166.
Website
http://hdl.handle.net/10161/14856
PMID
21193960
Source
epmc
Published In
Biogerontology
Volume
12
Issue
2
Publish Date
2011
Start Page
157
End Page
166
DOI
10.1007/s10522-010-9316-1

Age trajectories of physiological indices in relation to healthy life course.

We analysed relationship between the risk of onset of "unhealthy life" (defined as the onset of cancer, cardiovascular diseases, or diabetes) and longitudinal changes in body mass index, diastolic blood pressure, hematocrit, pulse pressure, pulse rate, and serum cholesterol in the Framingham Heart Study (Original Cohort) using the stochastic process model of human mortality and aging. The analyses demonstrate how decline in resistance to stresses and adaptive capacity accompanying human aging can be evaluated from longitudinal data. We showed how these components of the aging process, as well as deviation of the trajectories of physiological indices from those minimising the risk at respective ages, can lead to an increase in the risk of onset of unhealthy life with age. The results indicate the presence of substantial gender difference in aging related decline in stress resistance and adaptive capacity, which can contribute to differences in the shape of the sex-specific patterns of incidence rates of aging related diseases.

Authors
Arbeev, KG; Ukraintseva, SV; Akushevich, I; Kulminski, AM; Arbeeva, LS; Akushevich, L; Culminskaya, IV; Yashin, AI
MLA Citation
Arbeev, KG, Ukraintseva, SV, Akushevich, I, Kulminski, AM, Arbeeva, LS, Akushevich, L, Culminskaya, IV, and Yashin, AI. "Age trajectories of physiological indices in relation to healthy life course." Mechanisms of ageing and development 132.3 (March 2011): 93-102.
Website
http://hdl.handle.net/10161/14857
PMID
21262255
Source
epmc
Published In
Mechanisms of Ageing and Development
Volume
132
Issue
3
Publish Date
2011
Start Page
93
End Page
102
DOI
10.1016/j.mad.2011.01.001

Health and function of participants in the Long Life Family Study: A comparison with other cohorts.

Individuals from families recruited for the Long Life Family Study (LLFS) (n= 4559) were examined and compared to individuals from other cohorts to determine whether the recruitment targeting longevity resulted in a cohort of individuals with better health and function. Other cohorts with similar data included the Cardiovascular Health Study, the Framingham Heart Study, and the New England Centenarian Study. Diabetes, chronic pulmonary disease and peripheral artery disease tended to be less common in LLFS probands and offspring compared to similar aged persons in the other cohorts. Pulse pressure and triglycerides were lower, high density lipids were higher, and a perceptual speed task and gait speed were better in LLFS. Age-specific comparisons showed differences that would be consistent with a higher peak, later onset of decline or slower rate of change across age in LLFS participants. These findings suggest several priority phenotypes for inclusion in future genetic analysis to identify loci contributing to exceptional survival.

Authors
Newman, AB; Glynn, NW; Taylor, CA; Sebastiani, P; Perls, TT; Mayeux, R; Christensen, K; Zmuda, JM; Barral, S; Lee, JH; Simonsick, EM; Walston, JD; Yashin, AI; Hadley, E
MLA Citation
Newman, AB, Glynn, NW, Taylor, CA, Sebastiani, P, Perls, TT, Mayeux, R, Christensen, K, Zmuda, JM, Barral, S, Lee, JH, Simonsick, EM, Walston, JD, Yashin, AI, and Hadley, E. "Health and function of participants in the Long Life Family Study: A comparison with other cohorts." Aging (Albany NY) 3.1 (January 2011): 63-76.
Website
http://hdl.handle.net/10161/14915
PMID
21258136
Source
pubmed
Published In
Aging
Volume
3
Issue
1
Publish Date
2011
Start Page
63
End Page
76
DOI
10.18632/aging.100242

Medical cost trajectories and onsets of cancer and noncancer diseases in US elderly population.

Time trajectories of medical costs-associated with onset of twelve aging-related cancer and chronic noncancer diseases were analyzed using the National Long-Term Care Survey data linked to Medicare Service Use files. A special procedure for selecting individuals with onset of each disease was developed and used for identification of the date at disease onset. Medical cost trajectories were found to be represented by a parametric model with four easily interpretable parameters reflecting: (i) prediagnosis cost (associated with initial comorbidity), (ii) cost of the disease onset, (iii) population recovery representing reduction of the medical expenses associated with a disease since diagnosis was made, and (iv) acquired comorbidity representing the difference between post- and pre diagnosis medical cost levels. These parameters were evaluated for the entire US population as well as for the subpopulation conditional on age, disability and comorbidity states, and survival (2.5 years after the date of onset). The developed approach results in a family of new forecasting models with covariates.

Authors
Akushevich, I; Kravchenko, J; Akushevich, L; Ukraintseva, S; Arbeev, K; Yashin, AI
MLA Citation
Akushevich, I, Kravchenko, J, Akushevich, L, Ukraintseva, S, Arbeev, K, and Yashin, AI. "Medical cost trajectories and onsets of cancer and noncancer diseases in US elderly population." Computational and mathematical methods in medicine 2011 (January 2011): 857892-.
Website
http://hdl.handle.net/10161/14855
PMID
21687557
Source
epmc
Published In
Computational and Mathematical Methods in Medicine
Volume
2011
Publish Date
2011
Start Page
857892
DOI
10.1155/2011/857892

Heritability estimates of endophenotypes of long and health life: the Long Life Family Study.

Identification of gene variants that contribute to exceptional survival may provide critical biologic information that informs optimal health across the life span.As part of phenotype development efforts for the Long Life Family Study, endophenotypes that represent exceptional survival were identified and heritability estimates were calculated. Principal components (PCs) analysis was carried out using 28 physiologic measurements from five trait domains (cardiovascular, cognition, physical function, pulmonary, and metabolic).The five most dominant PCs accounted for 50% of underlying trait variance. The first PC (PC1), which consisted primarily of poor pulmonary and physical function, represented 14.3% of the total variance and had an estimated heritability of 39%. PC2 consisted of measures of good metabolic and cardiovascular function with an estimated heritability of 27%. PC3 was made up of cognitive measures (h(2) = 36%). PC4 and PC5 contained measures of blood pressure and cholesterol, respectively (h(2) = 25% and 16%).These PCs analysis-derived endophenotypes may be used in genetic association studies to help identify underlying genetic mechanisms that drive exceptional survival in this and other populations.

Authors
Matteini, AM; Fallin, MD; Kammerer, CM; Schupf, N; Yashin, AI; Christensen, K; Arbeev, KG; Barr, G; Mayeux, R; Newman, AB; Walston, JD
MLA Citation
Matteini, AM, Fallin, MD, Kammerer, CM, Schupf, N, Yashin, AI, Christensen, K, Arbeev, KG, Barr, G, Mayeux, R, Newman, AB, and Walston, JD. "Heritability estimates of endophenotypes of long and health life: the Long Life Family Study." The journals of gerontology. Series A, Biological sciences and medical sciences 65.12 (December 2010): 1375-1379.
Website
http://hdl.handle.net/10161/14882
PMID
20813793
Source
epmc
Published In
Journals of Gerontology: Series A
Volume
65
Issue
12
Publish Date
2010
Start Page
1375
End Page
1379
DOI
10.1093/gerona/glq154

Evaluation of Effects of Genetic polymorphisms and Age Trajectories of Physiological Indices on survival

Authors
Arbeev, KG; Ukraintseva, SV; Arbeeva, LS; Akushevich, I; Kulminski, AM; Wu, D; Yashin, AI
MLA Citation
Arbeev, KG, Ukraintseva, SV, Arbeeva, LS, Akushevich, I, Kulminski, AM, Wu, D, and Yashin, AI. "Evaluation of Effects of Genetic polymorphisms and Age Trajectories of Physiological Indices on survival." December 2010.
Source
wos-lite
Published In
Genetic Epidemiology
Volume
34
Issue
8
Publish Date
2010
Start Page
965
End Page
966

Estimation and validation of a multiattribute model of Alzheimer disease progression.

OBJECTIVES: To estimate and validate a multiattribute model of the clinical course of Alzheimer disease (AD) from mild AD to death in a high-quality prospective cohort study, and to estimate the impact of hypothetical modifications to AD progression rates on costs associated with Medicare and Medicaid services. DATA AND METHODS: The authors estimated sex-specific longitudinal Grade of Membership (GoM) models for AD patients (103 men, 149 women) in the initial cohort of the Predictors Study (1989-2001) based on 80 individual measures obtained every 6 mo for 10 y. These models were replicated for AD patients (106 men, 148 women) in the 2nd Predictors Study cohort (1997-2007). Model validation required that the disease-specific transition parameters be identical for both Predictors Study cohorts. Medicare costs were estimated from the National Long Term Care Survey. RESULTS: Sex-specific models were validated using the 2nd Predictors Study cohort with the GoM transition parameters constrained to the values estimated for the 1st Predictors Study cohort; 57 to 61 of the 80 individual measures contributed significantly to the GoM models. Simulated, cost-free interventions in the rate of progression of AD indicated that large potential cost offsets could occur for patients at the earliest stages of AD. CONCLUSIONS: AD progression is characterized by a small number of parameters governing changes in large numbers of correlated indicators of AD severity. The analysis confirmed that the progression of AD represents a complex multidimensional physiological process that is similar across different study cohorts. The estimates suggested that there could be large cost offsets to Medicare and Medicaid from the slowing of AD progression among patients with mild AD. The methodology appears generally applicable in AD modeling.

Authors
Stallard, E; Kinosian, B; Zbrozek, AS; Yashin, AI; Glick, HA; Stern, Y
MLA Citation
Stallard, E, Kinosian, B, Zbrozek, AS, Yashin, AI, Glick, HA, and Stern, Y. "Estimation and validation of a multiattribute model of Alzheimer disease progression." Med Decis Making 30.6 (November 2010): 625-638.
Website
http://hdl.handle.net/10161/14916
PMID
21183754
Source
pubmed
Published In
Medical Decision Making
Volume
30
Issue
6
Publish Date
2010
Start Page
625
End Page
638
DOI
10.1177/0272989X10363479

NEW PREDICTORS OF EXCEPTIONAL HEALTH AND SURVIVAL FROM LONGITUDINAL DATA

Authors
Yashin, AI; Arbeev, KG; Ukraintseva, SV; Akushevich, I; Kulminski, A; Kravchenko, J; Il'yasova, D; Wu, D
MLA Citation
Yashin, AI, Arbeev, KG, Ukraintseva, SV, Akushevich, I, Kulminski, A, Kravchenko, J, Il'yasova, D, and Wu, D. "NEW PREDICTORS OF EXCEPTIONAL HEALTH AND SURVIVAL FROM LONGITUDINAL DATA." GERONTOLOGIST 50 (October 2010): 20-20.
Source
wos-lite
Published In
The Gerontologist
Volume
50
Publish Date
2010
Start Page
20
End Page
20

SYSTEMIC GENETIC DETERMINANTS OF HEALTHY AGING AND EVOLUTIONARY SELECTION IN HUMANS

Authors
Kulminski, A; Culminskaya, I; Ukraintseva, SV; Arbeev, KG; Yashin, AI
MLA Citation
Kulminski, A, Culminskaya, I, Ukraintseva, SV, Arbeev, KG, and Yashin, AI. "SYSTEMIC GENETIC DETERMINANTS OF HEALTHY AGING AND EVOLUTIONARY SELECTION IN HUMANS." GERONTOLOGIST 50 (October 2010): 266-266.
Source
wos-lite
Published In
The Gerontologist
Volume
50
Publish Date
2010
Start Page
266
End Page
266

Joint influence of small-effect genetic variants on human longevity.

The results of genome-wide association studies of complex traits, such as life span or age at onset of chronic disease, suggest that such traits are typically affected by a large number of small-effect alleles. Individually such alleles have little predictive values, therefore they were usually excluded from further analyses. The results of our study strongly suggest that the alleles with small individual effects on longevity may jointly influence life span so that the resulting influence can be both substantial and significant. We show that this joint influence can be described by a relatively simple "genetic dose - phenotypic response" relationship.

Authors
Yashin, AI; Wu, D; Arbeev, KG; Ukraintseva, SV
MLA Citation
Yashin, AI, Wu, D, Arbeev, KG, and Ukraintseva, SV. "Joint influence of small-effect genetic variants on human longevity." Aging 2.9 (September 2010): 612-620.
Website
http://hdl.handle.net/10161/14881
PMID
20834067
Source
epmc
Published In
Aging
Volume
2
Issue
9
Publish Date
2010
Start Page
612
End Page
620

Early hematopoietic effects of chronic radiation exposure in humans.

The major goal of this study is to investigate and quantitatively describe the nature of the relationship between the characteristics of chronic exposure to ionizing radiation and specific patterns of hematopoiesis reduction. The study is based on about 3,200 hemograms taken for inhabitants of the Techa riverside villages over the years 1951-1956, i.e., the period characterized by a gradual decrease in dose rates. The mean cumulative red bone marrow dose was 333.6 + or - 4.6 mGy. The approach to statistical analyses involved both empirical methods and modeling (generalized linear models and logistic regressions). The results of the analyses highlighted a gradual increase in the frequency of cytopenias with dose rate. The impact of exposure on hematopoiesis reduction patterns was found to be more substantial than that of age and health status. Dose rates resulting in a two-fold increase in the frequency of cytopenias have been estimated.

Authors
Akleyev, AV; Akushevich, IV; Dimov, GP; Veremeyeva, GA; Varfolomeyeva, TA; Ukraintseva, SV; Yashin, AI
MLA Citation
Akleyev, AV, Akushevich, IV, Dimov, GP, Veremeyeva, GA, Varfolomeyeva, TA, Ukraintseva, SV, and Yashin, AI. "Early hematopoietic effects of chronic radiation exposure in humans." Health Phys 99.3 (September 2010): 330-336.
Website
http://hdl.handle.net/10161/14860
PMID
20699694
Source
pubmed
Published In
Health Physics
Volume
99
Issue
3
Publish Date
2010
Start Page
330
End Page
336
DOI
10.1097/HP.0b013e3181c2f315

Modeling deterministic effects in hematopoietic system caused by chronic exposure to ionizing radiation in large human cohorts.

A new model of the hematopoietic system for humans chronically exposed to ionizing radiation allows for quantitative description of the initial hematopoiesis inhibition and subsequent increase in the risks of late stochastic effects such as leukemia. This model describes the dynamics of the hematopoietic stem cell compartment as well as the dynamics of each of the three blood cell types (leukocytes, erythrocytes, and platelets). The model parameters are estimated from the results of other experiments. They include the steady-state numbers of hematopoietic stem cells and peripheral blood cell lines for an unexposed organism, amplification parameters for each blood cell line, parameters describing the proliferation and apoptosis, parameters of feedback functions regulating the steady-state numbers, and characteristics of radiosensitivity in respect to cell death and non-lethal cell damages. The dynamic model of hematopoiesis is applied to the data on a subcohort of the Techa River residents with hematological measurements (e.g., blood counts) performed in 1950-1956 (which totals to about 3,500 exposed individuals). Among well-described effects observed in these data are the slope values of the dose-effect curves describing the hematopoietic inhibition and the dose rate patterns of the fractions of cytopenic states (e.g., leukopenia, thrombocytopenia). The model has been further generalized by inclusion of the component describing the risk of late stochastic effects. The risks of the development of late effects (such as leukemia) in population groups with specific patterns of early reactions in hematopoiesis (such as leukopenia induced by ionizing radiation) are investigated using simulation studies and compared to data.

Authors
Akushevich, IV; Veremeyeva, GA; Dimov, GP; Ukraintseva, SV; Arbeev, KG; Akleyev, AV; Yashin, AI
MLA Citation
Akushevich, IV, Veremeyeva, GA, Dimov, GP, Ukraintseva, SV, Arbeev, KG, Akleyev, AV, and Yashin, AI. "Modeling deterministic effects in hematopoietic system caused by chronic exposure to ionizing radiation in large human cohorts." Health physics 99.3 (September 2010): 322-329.
Website
http://hdl.handle.net/10161/14859
PMID
20699693
Source
epmc
Published In
Health Physics
Volume
99
Issue
3
Publish Date
2010
Start Page
322
End Page
329
DOI
10.1097/hp.0b013e3181c61dc1

Trade-offs between cancer and other diseases: do they exist and influence longevity?

Relationships between aging, disease risks, and longevity are not yet well understood. For example, joint increases in cancer risk and total survival observed in many human populations and some experimental aging studies may be linked to a trade-off between cancer and aging as well as to the trade-off(s) between cancer and other diseases, and their relative impact is not clear. While the former trade-off (between cancer and aging) received broad attention in aging research, the latter one lacks respective studies, although its understanding is important for developing optimal strategies of increasing both longevity and healthy life span. In this paper, we explore the possibility of trade-offs between risks of cancer and selected major disorders. First, we review current literature suggesting that the trade-offs between cancer and other diseases may exist and be linked to the differential intensity of apoptosis. Then we select relevant disorders for the analysis (acute coronary heart disease [ACHD], stroke, asthma, and Alzheimer disease [AD]) and calculate the risk of cancer among individuals with each of these disorders, and vice versa, using the Framingham Study (5209 individuals) and the National Long Term Care Survey (NLTCS) (38,214 individuals) data. We found a reduction in cancer risk among old (80+) men with stroke and in risk of ACHD among men (50+) with cancer in the Framingham Study. We also found an increase in ACHD and stroke among individuals with cancer, and a reduction in cancer risk among women with AD in the NLTCS. The manifestation of trade-offs between risks of cancer and other diseases thus depended on sex, age, and study population. We discuss factors modulating the potential trade-offs between major disorders in populations, e.g., disease treatments. Further study is needed to clarify possible impact of such trade-offs on longevity.

Authors
Ukraintseva, SV; Arbeev, KG; Akushevich, I; Kulminski, A; Arbeeva, L; Culminskaya, I; Akushevich, L; Yashin, AI
MLA Citation
Ukraintseva, SV, Arbeev, KG, Akushevich, I, Kulminski, A, Arbeeva, L, Culminskaya, I, Akushevich, L, and Yashin, AI. "Trade-offs between cancer and other diseases: do they exist and influence longevity?." Rejuvenation research 13.4 (August 2010): 387-396.
Website
http://hdl.handle.net/10161/14858
PMID
20426618
Source
epmc
Published In
Rejuvenation Research
Volume
13
Issue
4
Publish Date
2010
Start Page
387
End Page
396
DOI
10.1089/rej.2009.0941

Leukocyte telomere length is associated with disability in older u.s. Population.

To determine whether mean leukocyte telomere length (LTL) serves as a biomarker of disability assessed according to activities of daily living (ADLs) and what factors may modify this relationship.Retrospective cross-sectional study.A subset of the National Long Term Care Survey (NTLCS), a Medicare-based U.S. population longitudinal study focused on trends of overall health and functional status in older adults.Six hundred and twenty-four individuals from the 1999 wave of the NTLCS cohort.Relative LTL determined according to quantitative polymerase chain reaction. LTL has previously been shown to correlate with common age-related disorders and mortality, as well as with socioeconomic status.A sex difference in LTL was observed but not age-dependent shortening or association with socioeconomic status. LTL was associated with disability and functional status assessed according to ADLs. The association between ADLs and LTL was stronger in subjects without diabetes mellitus, whereas associations were not seen when only subjects with diabetes mellitus were analyzed. Associations between LTL and cardiovascular disease (CVD) and cancer were also present in the group without diabetes mellitus but not in the group with diabetes mellitus.These findings support the concept that LTL is a biomarker of overall well-being that is predictive of disability of older individuals in the U.S. population. Diabetes mellitus plays an important role as a modifier of the association between LTL and disability, CVD, and cancer. These associations have clinical implications because of the potential predictive value of LTL and deserve further investigation.

Authors
Risques, RA; Arbeev, KG; Yashin, AI; Ukraintseva, SV; Martin, GM; Rabinovitch, PS; Oshima, J
MLA Citation
Risques, RA, Arbeev, KG, Yashin, AI, Ukraintseva, SV, Martin, GM, Rabinovitch, PS, and Oshima, J. "Leukocyte telomere length is associated with disability in older u.s. Population." Journal of the American Geriatrics Society 58.7 (July 2010): 1289-1298.
Website
http://hdl.handle.net/10161/14880
PMID
20579170
Source
epmc
Published In
Journal of American Geriatrics Society
Volume
58
Issue
7
Publish Date
2010
Start Page
1289
End Page
1298
DOI
10.1111/j.1532-5415.2010.02948.x

Exceptional survivors have lower age trajectories of blood glucose: lessons from longitudinal data.

Exceptional survival results from complicated interplay between genetic and environmental factors. The effects of these factors on survival are mediated by the biological and physiological variables, which affect mortality risk. In this paper, we evaluated the role of blood glucose (BG) in exceptional survival using the Framingham heart study data for the main (FHS) and offspring (FHSO) cohorts. We found that: (1) the average cross-sectional age patterns of BG change over time; (2) the values of BG level among the longest lived individuals in this study differ for different sub-cohorts; (3) the longitudinal age patterns of BG differ from those of cross-sectional ones. We investigated mechanisms forming average age trajectories of BG in the FHS cohort. We found that the two curves: one, characterizing the average effects of allostatic adaptation, and another, minimizing mortality risk for any given age, play the central role in this process. We found that the average BG age trajectories for exceptional survivors are closer to the curve minimizing mortality risk than those of individuals having shorter life spans. We concluded that individuals whose age trajectories of BG are located around the curve minimizing chances of premature death at each given age have highest chances of reaching exceptional longevity.

Authors
Yashin, AI; Arbeev, KG; Akushevich, I; Ukraintseva, SV; Kulminski, A; Arbeeva, LS; Culminskaya, I
MLA Citation
Yashin, AI, Arbeev, KG, Akushevich, I, Ukraintseva, SV, Kulminski, A, Arbeeva, LS, and Culminskaya, I. "Exceptional survivors have lower age trajectories of blood glucose: lessons from longitudinal data." Biogerontology 11.3 (June 2010): 257-265.
PMID
19644762
Source
epmc
Published In
Biogerontology
Volume
11
Issue
3
Publish Date
2010
Start Page
257
End Page
265
DOI
10.1007/s10522-009-9243-1

Early hematopoiesis inhibition under chronic radiation exposure in humans.

The major goal of this study was to identify and quantitatively describe the association between the characteristics of chronic (low-dose rate) exposure to (low LET) ionizing radiation and cellularity of peripheral blood cell lines. About 3,200 hemograms (i.e., spectra of blood counts) obtained over the years of maximal exposure to ionizing radiation (1950-1956) for inhabitants of the Techa River were used in analyses. The mean cumulative red bone marrow dose (with standard errors), calculated using Techa River Dosimetry System-2000, was 333.6 +/- 4.6 mGy (SD = 259.9 mGy, max = 1151 mGy) to the year 1956. The statistical approach included both empirical methods for estimating frequencies of cytopenic states of the investigated blood cell lines (e.g. neutrophile, platelets, erythrocyte, etc.), and regression methods, including generalized linear models and logistic regressions which allowed taking into account confounding factors (e.g., attained age, age at maximal exposure, presence of concomitant diseases, and demographic characteristics). The results of the analyses demonstrated hematopoiesis inhibition manifested by a decrease in peripheral blood cellularity and an increase in the frequency of cytopenia in all blood cell lines (leukocytes, including lymphocytes, monocytes, neutrophiles, as well as platelets and erythrocytes). The intensity of hematopoiesis inhibition in the period of maximal exposures is determined by the combined influence of the dose rate and cumulative dose. The contribution of specific confounding factors was quantified and shown to be much less important than dose characteristics. The best predictor among dose characteristics was identified for each blood cell line. A 2-fold increase in dose rate is assumed to be a characteristic of radiosensitivity and a quantitative characteristic of the effect.

Authors
Akleyev, AV; Akushevich, IV; Dimov, GP; Veremeyeva, GA; Varfolomeyeva, TA; Ukraintseva, SV; Yashin, AI
MLA Citation
Akleyev, AV, Akushevich, IV, Dimov, GP, Veremeyeva, GA, Varfolomeyeva, TA, Ukraintseva, SV, and Yashin, AI. "Early hematopoiesis inhibition under chronic radiation exposure in humans." Radiat Environ Biophys 49.2 (May 2010): 281-291.
Website
http://hdl.handle.net/10161/14861
PMID
20340030
Source
pubmed
Published In
Radiation and Environmental Biophysics
Volume
49
Issue
2
Publish Date
2010
Start Page
281
End Page
291
DOI
10.1007/s00411-010-0269-1

Beta2-adrenergic receptor gene polymorphisms as systemic determinants of healthy aging in an evolutionary context.

The Gln(27)Glu polymorphism but not the Arg(16)Gly polymorphism of the beta2-adrenergic receptor (ADRB2) gene appears to be associated with a broad range of aging-associated phenotypes, including cancers at different sites, myocardial infarction (MI), intermittent claudication (IC), and overall/healthy longevity in the Framingham Heart Study Offspring cohort. The Gln(27)Gln genotype increases risks of cancer, MI and IC, whereas the Glu(27) allele or, equivalently, the Gly(16)Glu(27) haplotype tends to be protective against these diseases. Genetic associations with longevity are of opposite nature at young-old and oldest-old ages highlighting the phenomenon of antagonistic pleiotropy. The mechanism of antagonistic pleiotropy is associated with an evolutionary-driven advantage of carriers of a derived Gln(27) allele at younger ages and their survival disadvantage at older ages as a result of increased risks of cancer, MI and IC. The ADRB2 gene can play an important systemic role in healthy aging in evolutionary context that warrants exploration in other populations.

Authors
Kulminski, AM; Culminskaya, I; Ukraintseva, SV; Arbeev, KG; Land, KC; Yashin, AI
MLA Citation
Kulminski, AM, Culminskaya, I, Ukraintseva, SV, Arbeev, KG, Land, KC, and Yashin, AI. "Beta2-adrenergic receptor gene polymorphisms as systemic determinants of healthy aging in an evolutionary context." Mechanisms of ageing and development 131.5 (May 2010): 338-345.
Website
http://hdl.handle.net/10161/14883
PMID
20399803
Source
epmc
Published In
Mechanisms of Ageing and Development
Volume
131
Issue
5
Publish Date
2010
Start Page
338
End Page
345
DOI
10.1016/j.mad.2010.04.001

"Predicting" parental longevity from offspring endophenotypes: data from the Long Life Family Study (LLFS).

While there is evidence that longevity runs in families, the study of long-lived families is complicated by the fact that longevity-related information is available only for the oldest old, many of whom may be deceased and unavailable for testing, and information on other living family members, primarily descendents, is censored. This situation requires a creative approach for analyzing determinants of longevity in families. There are likely biomarkers that predict an individual's longevity, suggesting the possibility that those biomarkers which are heritable may constitute valuable endophenotypes for exceptional survival. These endophenotypes could be studied in families to identify human longevity genes and elucidate possible mechanisms of their influence on longevity. In this paper, we analyze data collected in the Long Life Family Study (LLFS) investigating whether indicators of physiological state, cognitive functioning and health/well-being among offspring predict longevity in parents. Good predictors can be used as endophenotypes for exceptional survival. Our analyses revealed significant associations between cumulative indices describing physiological state, as well as a number of offspring phenotypes, and parental lifespan, supporting both their familial basis and relevance to longevity. We conclude that the study of endophenotypes within families is a valid approach to the genetics of human longevity.

Authors
Yashin, AI; Arbeev, KG; Kulminski, A; Borecki, I; Christensen, K; Barmada, M; Hadley, E; Rossi, W; Lee, JH; Cheng, R; Elo, IT
MLA Citation
Yashin, AI, Arbeev, KG, Kulminski, A, Borecki, I, Christensen, K, Barmada, M, Hadley, E, Rossi, W, Lee, JH, Cheng, R, and Elo, IT. ""Predicting" parental longevity from offspring endophenotypes: data from the Long Life Family Study (LLFS)." Mechanisms of ageing and development 131.3 (March 2010): 215-222.
PMID
20184914
Source
epmc
Published In
Mechanisms of Ageing and Development
Volume
131
Issue
3
Publish Date
2010
Start Page
215
End Page
222
DOI
10.1016/j.mad.2010.02.001

Trends in survival and recovery from stroke: evidence from the National Long-Term Care Survey/Medicare data.

Improvements in recovery rates may contribute to an increase in healthy life expectancy. It is unclear, however, whether such changes take place because health researchers traditionally deal with changes in incidence and survival from diseases. The purpose of this study was to test for the presence of time trends in the recovery rate from stroke.We compared age patterns of recovery rates from stroke evaluated in 2 subcohorts represented in the National Long-Term Care Survey data linked with the Medicare service use files.We found a statistically significant increase in recovery rate between 1994 and 1999 for females but not for males.Time trends in recovery rate from stroke exist and can be detected from available data. The roles of influential factors and causes of sex difference in recovery improvement deserve further studies.

Authors
Yashin, A; Akushevich, I; Ukraintseva, S; Akushevich, L; Arbeev, K; Kulminski, A
MLA Citation
Yashin, A, Akushevich, I, Ukraintseva, S, Akushevich, L, Arbeev, K, and Kulminski, A. "Trends in survival and recovery from stroke: evidence from the National Long-Term Care Survey/Medicare data." Stroke 41.3 (March 2010): 563-565. (Letter)
PMID
20093634
Source
epmc
Published In
Stroke
Volume
41
Issue
3
Publish Date
2010
Start Page
563
End Page
565
DOI
10.1161/strokeaha.109.572339

Polymorphisms in the ACE and ADRB2 genes and risks of aging-associated phenotypes: the case of myocardial infarction.

Multiple functions of the beta2-adrenergic receptor (ADRB2) and angiotensin-converting enzyme (ACE) genes warrant studies of their associations with aging-related phenotypes. We focus on multimarker analyses and analyses of the effects of compound genotypes of two polymorphisms in the ADRB2 gene, rs1042713 and rs1042714, and 11 polymorphisms of the ACE gene, on the risk of such an aging-associated phenotype as myocardial infarction (MI). We used the data from a genotyped sample of the Framingham Heart Study Offspring (FHSO) cohort (n = 1500) followed for about 36 years with six examinations. The ADRB2 rs1042714 (C-->G) polymorphism and two moderately correlated (r(2) = 0.77) ACE polymorphisms, rs4363 (A-->G) and rs12449782 (A-->G), were significantly associated with risks of MI in this aging cohort in multimarker models. Predominantly linked ACE genotypes exhibited opposite effects on MI risks, e.g., the AA (rs12449782) genotype had a detrimental effect, whereas the predominantly linked AA (rs4363) genotype exhibited a protective effect. This trade-off occurs as a result of the opposite effects of rare compound genotypes of the ACE polymorphisms with a single dose of the AG heterozygote. This genetic trade-off is further augmented by the selective modulating effect of the rs1042714 ADRB2 polymorphism. The associations were not altered by adjustment for common MI risk factors. The results suggest that effects of single specific genetic variants of the ADRB2 and ACE genes on MI can be readily altered by gene-gene or/and gene-environmental interactions, especially in large heterogeneous samples. Multimarker genetic analyses should benefit studies of complex aging-associated phenotypes.

Authors
Kulminski, AM; Culminskaya, IV; Ukraintseva, SV; Arbeev, KG; Akushevich, I; Land, KC; Yashin, AI
MLA Citation
Kulminski, AM, Culminskaya, IV, Ukraintseva, SV, Arbeev, KG, Akushevich, I, Land, KC, and Yashin, AI. "Polymorphisms in the ACE and ADRB2 genes and risks of aging-associated phenotypes: the case of myocardial infarction." Rejuvenation research 13.1 (February 2010): 13-21.
Website
http://hdl.handle.net/10161/3300
PMID
20230274
Source
epmc
Published In
Rejuvenation Research
Volume
13
Issue
1
Publish Date
2010
Start Page
13
End Page
21
DOI
10.1089/rej.2009.0905

Dynamic determinants of longevity and exceptional health.

It is well known from epidemiology that values of indices describing physiological state in a given age may influence human morbidity and mortality risks. Studies of connection between aging and life span suggest a possibility that dynamic properties of age trajectories of the physiological indices could also be important contributors to morbidity and mortality risks. In this paper we use data on longitudinal changes in body mass index, diastolic blood pressure, pulse pressure, pulse rate, blood glucose, hematocrit, and serum cholesterol in the Framingham Heart Study participants, to investigate this possibility in depth. We found that some of the variables describing individual dynamics of the age-associated changes in physiological indices influence human longevity and exceptional health more substantially than the variables describing physiological state. These newly identified variables are promising targets for prevention aiming to postpone onsets of common elderly diseases and increase longevity.

Authors
Yashin, AI; Arbeev, KG; Akushevich, I; Arbeeva, L; Kravchenko, J; Il'yasova, D; Kulminski, A; Akushevich, L; Culminskaya, I; Wu, D; Ukraintseva, SV
MLA Citation
Yashin, AI, Arbeev, KG, Akushevich, I, Arbeeva, L, Kravchenko, J, Il'yasova, D, Kulminski, A, Akushevich, L, Culminskaya, I, Wu, D, and Ukraintseva, SV. "Dynamic determinants of longevity and exceptional health." Current gerontology and geriatrics research (January 2010).
PMID
20953403
Source
epmc
Published In
Current Gerontology and Geriatrics Research
Publish Date
2010
DOI
10.1155/2010/381637

A new approach to individual prognostication of cancer development under conditions of chronic radiation exposure

This paper describes a new approach to modelling carcinogenesis, including that induced by ionising radiation. The specific feature of the developed approach is that the model, still adhering to the mutational theory of carcinogenesis, includes parameters of intracellular processes which can be measured for any individual. The assumptions laying the basis for this approach are that cell malignisation results from inefficient functioning of a number of barrier mechanisms on the cell's way from the primary DNA damage to phenotypically manifested mutation/aberration initiating or promoting carcinogenesis, and inefficient functioning of the barrier mechanisms is caused, in turn, by one or several genetic and/or epigenetic events, the number and type of which are of no importance for this approach. The paper points out the necessity and possibility to include model parameters that reflect the status of such intercellular mechanisms as the system of antioxidant protection, repair and apoptosis. The theoretical formalism of the model structure is presented as the generalisation of the concepts of multiple-stage and multiple-pathway models for describing the new biological approach to modelling. Also, the paper discusses issues such as schemes for measuring the parameters included in the model, approaches to individual risk estimation and further generalisation of the model. Copyright © 2010 Inderscience Enterprises Ltd.

Authors
Veremeyeva, GA; Akushevich, IV; Ukraintseva, SV; Yashin, AI; Epifanova, SB; Blinova, EA; Akleyev, AV
MLA Citation
Veremeyeva, GA, Akushevich, IV, Ukraintseva, SV, Yashin, AI, Epifanova, SB, Blinova, EA, and Akleyev, AV. "A new approach to individual prognostication of cancer development under conditions of chronic radiation exposure." International Journal of Low Radiation 7.1 (2010): 53-80.
Source
scival
Published In
International Journal of Low Radiation
Volume
7
Issue
1
Publish Date
2010
Start Page
53
End Page
80
DOI
10.1504/IJLR.2010.032771

A bivariate survival model with compound Poisson frailty

A correlated frailty model is suggested for analysis of bivariate time-to-event data. The model is an extension of the correlated power variance function (PVF) frailty model (correlated three-parameter frailty model) (J. Epidemiol. Biostat. 1999; 4:53-60). It is based on a bivariate extension of the compound Poisson frailty model in univariate survival analysis (Ann. Appl. Probab. 1992; 4:951-972). It allows for a non-susceptible fraction (of zero frailty) in the population, overcoming the common assumption in survival analysis that all individuals are susceptible to the event under study. The model contains the correlated gamma frailty model and the correlated inverse Gaussian frailty model as special cases. A maximum likelihood estimation procedure for the parameters is presented and its properties are studied in a small simulation study. This model is applied to breast cancer incidence data of Swedish twins. The proportion of women susceptible to breast cancer is estimated to be 15 per cent. Copyright © 2009 John Wiley & Sons, Ltd.

Authors
Wienke, A; Ripatti, S; Palmgren, J; Yashin, A
MLA Citation
Wienke, A, Ripatti, S, Palmgren, J, and Yashin, A. "A bivariate survival model with compound Poisson frailty." Statistics in Medicine 29.2 (2010): 275-283.
PMID
19856276
Source
scival
Published In
Statistics in Medicine
Volume
29
Issue
2
Publish Date
2010
Start Page
275
End Page
283
DOI
10.1002/sim.3749

Evaluation of Genotype-specific Age Patterns of Hazard Rates Using Joint Analysis of Genetic and Non-genetic Subsamples of Longitudinal Data

Authors
Arbeev, KG; Ukraintseva, SV; Arbeeva, LS; Kulminski, AM; Akushevich, I; Yashin, AI
MLA Citation
Arbeev, KG, Ukraintseva, SV, Arbeeva, LS, Kulminski, AM, Akushevich, I, and Yashin, AI. "Evaluation of Genotype-specific Age Patterns of Hazard Rates Using Joint Analysis of Genetic and Non-genetic Subsamples of Longitudinal Data." December 2009.
Source
wos-lite
Published In
Genetic Epidemiology
Volume
33
Issue
8
Publish Date
2009
Start Page
822
End Page
822

Date of eclosion modulates longevity: insights across dietary-restriction gradients and female reproduction in the mexfly Anastrepha ludens.

We use unique experimental data on daily reproduction and survival of individual fruit flies from eight cohorts eclosed at different dates in 2004 and 2005 who were treated with varying proportions of sugar and yeast and subject to different caloric restrictions (CR). We investigate the relationship between eclosion date and longevity across diets and reproduction in Anastrepha ludens. We show that eclosion date can be associated with uncontrolled external or internal factor(s) which can modulate longevity of males and females independently of diet and reproduction to the extent similar to the effect of diet on longevity. The effect of diet manipulation on longevity is sensitive to date of eclosion with the role of CR in life extension ranging from beneficial to harmful. Interaction of date of eclosion with compositional changes of sugar and yeast but not with CR is responsible for life extension. Highly protein-enriched diets reliably maximize reproduction but not life span. Decreased longevity of flies treated with high-protein diets may be associated with harmful consequences of protein ingestion but is unlikely a result of high reproduction rates. We present evidence for the presence of two frailty-sensitive weakly interacting mechanisms of longevity in female flies associated with differences in predisposed fitness.

Authors
Kulminski, AM; Molleman, F; Culminskaya, IV; Arbeev, KG; Ukraintseva, SV; Carey, JR; Yashin, AI
MLA Citation
Kulminski, AM, Molleman, F, Culminskaya, IV, Arbeev, KG, Ukraintseva, SV, Carey, JR, and Yashin, AI. "Date of eclosion modulates longevity: insights across dietary-restriction gradients and female reproduction in the mexfly Anastrepha ludens." Experimental gerontology 44.11 (November 2009): 718-726.
PMID
19716408
Source
epmc
Published In
Experimental Gerontology
Volume
44
Issue
11
Publish Date
2009
Start Page
718
End Page
726
DOI
10.1016/j.exger.2009.08.007

Hormesis against aging and diseases: using properties of biological adaptation for health and survival improvement.

The idea of using hormesis for postponing aging and improving human health has been recently discussed in scientific literature. This paper shows that redundancy in renewal capacity, some portion of which become activated and manifested in hormesis effects, may originate as a result of interaction between living organisms and their environment. It is shown that such redundancy may normally exist for organisms in the wild, and not only in domesticated and laboratory animals. Further development of the hormesis idea requires: (i) investigating regularities of response to multiple stimuli; (ii) studying slow-time responses (e.g., physiological adaptation) to repeated stimuli; (iii) studying connection between slow and fast (e.g., developing at the cellular and sub-cellular levels) stress responses; (iv) translating knowledge accumulated in studies of animal model systems to humans; (v) evaluating unrealized potential for improving health and longevity using hormetic mechanisms. The use of mathematical and computer modeling for translating experimental knowledge about hormesis effects to humans, as well as connection between studying hormetic mechanisms and analyses of the age trajectories of physiological and biological indices affecting U-shapes curves of morbidity-mortality risks using longitudinal data on aging, health, and longevity are discussed.

Authors
Yashin, AI
MLA Citation
Yashin, AI. "Hormesis against aging and diseases: using properties of biological adaptation for health and survival improvement. (Published online)" Dose Response 8.1 (October 8, 2009): 41-47.
PMID
20221287
Source
pubmed
Published In
Dose-response : a publication of International Hormesis Society
Volume
8
Issue
1
Publish Date
2009
Start Page
41
End Page
47
DOI
10.2203/dose-response.09-024.Yashin

DYNAMIC DETERMINANTS OF EXCEPTIONAL HEALTH AND LONGEVITY

Authors
Yashin, AI; Arbeev, KG; Akushevich, I; Ukraintseva, SV; Kulminski, A; Arbeeva, L; Culminskaya, I
MLA Citation
Yashin, AI, Arbeev, KG, Akushevich, I, Ukraintseva, SV, Kulminski, A, Arbeeva, L, and Culminskaya, I. "DYNAMIC DETERMINANTS OF EXCEPTIONAL HEALTH AND LONGEVITY." GERONTOLOGIST 49 (October 2009): 183-183.
Source
wos-lite
Published In
The Gerontologist
Volume
49
Publish Date
2009
Start Page
183
End Page
183

DATE OF ECLOSION AS A DETERMINANT OF LONG LIFE IN THE MEXFLY ANASTREPHA LUDENS: INSIGHTS ACROSS DIET, CALORIC RESTRICTION AND REPRODUCTION

Authors
Kulminski, A; Molleman, F; Culminskaya, I; Arbeev, K; Ukraintseva, S; Carey, J; Yashin, AI
MLA Citation
Kulminski, A, Molleman, F, Culminskaya, I, Arbeev, K, Ukraintseva, S, Carey, J, and Yashin, AI. "DATE OF ECLOSION AS A DETERMINANT OF LONG LIFE IN THE MEXFLY ANASTREPHA LUDENS: INSIGHTS ACROSS DIET, CALORIC RESTRICTION AND REPRODUCTION." GERONTOLOGIST 49 (October 2009): 141-141.
Source
wos-lite
Published In
The Gerontologist
Volume
49
Publish Date
2009
Start Page
141
End Page
141

PHYSIOLOGICAL CHANGES DURING THE LIFE COURSE: INSIGHTS FOR AGING, HEALTH, AND LONGEVITY

Authors
Yashin, AI; Arbeev, KG; Akushevich, I; Ukraintseva, SV; Kulminski, A; Arbeeva, L; Culminskaya, I
MLA Citation
Yashin, AI, Arbeev, KG, Akushevich, I, Ukraintseva, SV, Kulminski, A, Arbeeva, L, and Culminskaya, I. "PHYSIOLOGICAL CHANGES DURING THE LIFE COURSE: INSIGHTS FOR AGING, HEALTH, AND LONGEVITY." GERONTOLOGIST 49 (October 2009): 90-90.
Source
wos-lite
Published In
The Gerontologist
Volume
49
Publish Date
2009
Start Page
90
End Page
90

SYSTEMIC BIOLOGICAL ROLE OF THE BETA2-ADRENERGIC RECEPTOR GENE POLYMORPHISMS IN HEALTHY AGING

Authors
Kulminski, A; Culminskaya, I; Ukraintseva, SV; Arbeev, KG; Land, K; Yashin, AI
MLA Citation
Kulminski, A, Culminskaya, I, Ukraintseva, SV, Arbeev, KG, Land, K, and Yashin, AI. "SYSTEMIC BIOLOGICAL ROLE OF THE BETA2-ADRENERGIC RECEPTOR GENE POLYMORPHISMS IN HEALTHY AGING." GERONTOLOGIST 49 (October 2009): 90-90.
Source
wos-lite
Published In
The Gerontologist
Volume
49
Publish Date
2009
Start Page
90
End Page
90

Multiple mild heat-shocks decrease the Gompertz component of mortality in Caenorhabditis elegans.

Exposure to mild heat-stress (heat-shock) can significantly increase the life expectancy of the nematode Caenorhabditis elegans. A single heat-shock early in life extends longevity by 20% or more and affects life-long mortality by decreasing initial mortality only; the rate of increase in subsequent mortality (Gompertz component) is unchanged. Repeated mild heat-shocks throughout life have a larger effect on life span than does a single heat-shock early in life. Here, we ask how multiple heat-shocks affect the mortality trajectory in nematodes and find increases of life expectancy of close to 50% and of maximum longevity as well. We examined mortality using large numbers of animals and found that multiple heat-shocks not only decrease initial mortality, but also slow the Gompertz rate of increase in mortality. Thus, multiple heat-shocks have anti-aging hormetic effects and represent an effective approach for modulating aging.

Authors
Wu, D; Cypser, JR; Yashin, AI; Johnson, TE
MLA Citation
Wu, D, Cypser, JR, Yashin, AI, and Johnson, TE. "Multiple mild heat-shocks decrease the Gompertz component of mortality in Caenorhabditis elegans." Experimental gerontology 44.9 (September 2009): 607-612.
PMID
19580861
Source
epmc
Published In
Experimental Gerontology
Volume
44
Issue
9
Publish Date
2009
Start Page
607
End Page
612
DOI
10.1016/j.exger.2009.06.007

Maintaining physiological state for exceptional survival: What is the normal level of blood glucose and does it change with age?

The levels of blood glucose (BG) in humans tend to increase with age deviating from the norm specified for the young adults. Such elevation is often considered as a factor contributing to an increase in risks of disease and death. The proper use of intervention strategies coping with or preventing consequences of BG elevation requires understanding the roles of external forces and intrinsic senescence in this process. To address these issues, we performed analyses of longitudinal data on BG collected in the Framingham Heart Study using methods of descriptive statistics and statistical modeling. The approach allows us to separate effects of persistent external disturbances from "normal" aging-related changes due to the senescence process. We found that the BG level corresponding to the lowest mortality risk tends to increase with age. The changes in the shape of the mortality risk with age indicate the aging-related decline in resistance to stresses affecting the BG level. The results show that analyzing longitudinal data using advanced methods may substantially increase our knowledge on factors and mechanisms responsible for aging-related changes in humans.

Authors
Yashin, AI; Ukraintseva, SV; Arbeev, KG; Akushevich, I; Arbeeva, LS; Kulminski, AM
MLA Citation
Yashin, AI, Ukraintseva, SV, Arbeev, KG, Akushevich, I, Arbeeva, LS, and Kulminski, AM. "Maintaining physiological state for exceptional survival: What is the normal level of blood glucose and does it change with age?." Mechanisms of ageing and development 130.9 (September 2009): 611-618.
PMID
19635493
Source
epmc
Published In
Mechanisms of Ageing and Development
Volume
130
Issue
9
Publish Date
2009
Start Page
611
End Page
618
DOI
10.1016/j.mad.2009.07.004

Genetic model for longitudinal studies of aging, health, and longevity and its potential application to incomplete data.

Many longitudinal studies of aging collect genetic information only for a sub-sample of participants of the study. These data also do not include recent findings, new ideas and methodological concepts developed by distinct groups of researchers. The formal statistical analyses of genetic data ignore this additional information and therefore cannot utilize the entire research potential of the data. In this paper, we present a stochastic model for studying such longitudinal data in joint analyses of genetic and non-genetic sub-samples. The model incorporates several major concepts of aging known to date and usually studied independently. These include age-specific physiological norms, allostasis and allostatic load, stochasticity, and decline in stress resistance and adaptive capacity with age. The approach allows for studying all these concepts in their mutual connection, even if respective mechanisms are not directly measured in data (which is typical for longitudinal data available to date). The model takes into account dependence of longitudinal indices and hazard rates on genetic markers and permits evaluation of all these characteristics for carriers of different alleles (genotypes) to address questions concerning genetic influence on aging-related characteristics. The method is based on extracting genetic information from the entire sample of longitudinal data consisting of genetic and non-genetic sub-samples. Thus it results in a substantial increase in the accuracy of statistical estimates of genetic parameters compared to methods that use only information from a genetic sub-sample. Such an increase is achieved without collecting additional genetic data. Simulation studies illustrate the increase in the accuracy in different scenarios for datasets structurally similar to the Framingham Heart Study. Possible applications of the model and its further generalizations are discussed.

Authors
Arbeev, KG; Akushevich, I; Kulminski, AM; Arbeeva, LS; Akushevich, L; Ukraintseva, SV; Culminskaya, IV; Yashin, AI
MLA Citation
Arbeev, KG, Akushevich, I, Kulminski, AM, Arbeeva, LS, Akushevich, L, Ukraintseva, SV, Culminskaya, IV, and Yashin, AI. "Genetic model for longitudinal studies of aging, health, and longevity and its potential application to incomplete data." Journal of theoretical biology 258.1 (May 2009): 103-111.
PMID
19490866
Source
epmc
Published In
Journal of Theoretical Biology
Volume
258
Issue
1
Publish Date
2009
Start Page
103
End Page
111
DOI
10.1016/j.jtbi.2009.01.023

Studying health histories of cancer: a new model connecting cancer incidence and survival.

The results of recent experimental and epidemiological studies provide evidence on the connection between carcinogenesis, cancer progression, and aging. Existing models, however, are traditionally focused only on one of these aspects of health deterioration. In this paper, we derive a new model of cancer, which describes the connection between the ages at disease onset, the duration of disease, and life span of respective individuals. The model combines ideas used in the two hits model of carcinogenesis with those used in the Le Bras multistate model of aging with constant transition intensities. The model is used in the joint analyses of the US demographic mortality data and SEER data for selected cancers. The results show that the developed approach is capable of explaining links among health history data and provides useful insights on mechanisms of cancer occurrence, disease progression, other aging-related changes, and mortality. Further developments of this model are discussed.

Authors
Yashin, AI; Akushevich, I; Arbeev, K; Akushevich, L; Kulminski, A; Ukraintseva, S
MLA Citation
Yashin, AI, Akushevich, I, Arbeev, K, Akushevich, L, Kulminski, A, and Ukraintseva, S. "Studying health histories of cancer: a new model connecting cancer incidence and survival." Mathematical biosciences 218.2 (April 2009): 88-97.
PMID
19167410
Source
epmc
Published In
Mathematical Biosciences
Volume
218
Issue
2
Publish Date
2009
Start Page
88
End Page
97
DOI
10.1016/j.mbs.2008.12.007

Mathematical modeling of immunosenescence: Scenarios, processes and limitations

© 2009 Springer Science+Business Media B.V. Mathematical modeling of immunosenescence is the new area of research emerging at the interface of the immunology, gerontology, and mathematics. In this paper we outline basic variables important for modeling aging immunity. We discuss the role of evolution in shaping pattern of aging in the immune system of modern humans. We investigate mathematical models of postnatal changes in the population of peripheral T-cells, effects of the antigenic load during development on the body growth, and contribution of immunosenescence to the old age increase in the risk of death from respiratory infections.

Authors
Romanyukha, AA; Rudnev, SG; Sannikova, TA; Yashin, AI
MLA Citation
Romanyukha, AA, Rudnev, SG, Sannikova, TA, and Yashin, AI. "Mathematical modeling of immunosenescence: Scenarios, processes and limitations." Handbook on Immunosenescence: Basic Understanding and Clinical Applications. January 1, 2009. 145-163.
Source
scopus
Publish Date
2009
Start Page
145
End Page
163
DOI
10.1007/978-1-4020-9063-9-8

Health-related phenotypes and longevity in danish twins.

Aging studies can be facilitated by refocusing from longevity phenotypes to their proxies (intermediate phenotypes). Robust selection of the intermediate phenotypes requires data on such phenotypes and life span measured in the same individuals, which is not always the case in aging studies. A promising approach is to select intermediate phenotypes using information on longevity measured in related individuals. We evaluated feasibility of this approach focusing on 32 geriatric diseases as potential intermediate phenotypes of longevity assessed in the Longitudinal Study of Aging Danish Twins. Our analyses reveal that geriatric diseases measured in some family members can predict life span in the other family members both individually and cumulatively ensuring that this approach for selection of intermediate phenotypes is feasible. The cumulative-trait approach is more promising for such studies compared with the individual-trait approach. Heritable health dimensions contributing to a decrease of life span have sex-insensitive and sex-specific components.

Authors
Kulminski, AM; Arbeev, KG; Culminskaya, IV; Ukraintseva, SV; Christensen, K; Yashin, AI
MLA Citation
Kulminski, AM, Arbeev, KG, Culminskaya, IV, Ukraintseva, SV, Christensen, K, and Yashin, AI. "Health-related phenotypes and longevity in danish twins." The journals of gerontology. Series A, Biological sciences and medical sciences 64.1 (January 2009): 1-8.
PMID
19211549
Source
epmc
Published In
Journals of Gerontology: Series A
Volume
64
Issue
1
Publish Date
2009
Start Page
1
End Page
8
DOI
10.1093/gerona/gln051

Trade-off between cancer and aging: what role do other diseases play? Evidence from experimental and human population studies.

The potential gain in life expectancy which could result from the complete elimination of mortality from cancer in the U.S. would not exceed 3 years if one were to consider cancer independently of other causes of death. In this paper, we review evidence of trade-offs between cancer and aging as well as between cancer and other diseases, which, if taken into account, may substantially increase estimates of gain in life expectancy resulting from cancer eradication. We also used the Multiple Causes of Death (MCD) data to evaluate correlations among mortalities from cancer and other major disorders including heart disease, stroke, diabetes, Alzheimer's, Parkinson's diseases, and asthma. Our analyses revealed significant negative correlations between cancer and other diseases suggesting stronger population effects of cancer eradication. Possible mechanisms of the observed dependencies and emerging perspectives of using dependent competing risks models for evaluating the effects of reduction of mortality from cancer on life expectancy are discussed.

Authors
Yashin, AI; Ukraintseva, SV; Akushevich, IV; Arbeev, KG; Kulminski, A; Akushevich, L
MLA Citation
Yashin, AI, Ukraintseva, SV, Akushevich, IV, Arbeev, KG, Kulminski, A, and Akushevich, L. "Trade-off between cancer and aging: what role do other diseases play? Evidence from experimental and human population studies." Mechanisms of ageing and development 130.1-2 (January 2009): 98-104.
PMID
18452970
Source
epmc
Published In
Mechanisms of Ageing and Development
Volume
130
Issue
1-2
Publish Date
2009
Start Page
98
End Page
104
DOI
10.1016/j.mad.2008.03.006

Leukocyte telomere dynamics and human hematopoietic stem cell kinetics during somatic growth

Objective: A central question in stem cell research is knowing the frequency of human hematopoietic stem cells (HSC) replication in vivo. Materials and Methods: We have constructed a model that characterizes HSC kinetics and the relative sizes of the hematopoietic progenitor cell (HPC) and HSC pools from birth onward. The model capitalizes on leukocyte telomere length (LTL) data and body weight-gain charts from birth to the age of 20 years. The core premise of the model is that during human growth, LTL dynamics (birth LTL and age-dependent LTL shortening afterward) chronicle the expansions of the HSC and HPC pools. Results: The model estimates that by the end of the first year of life, HSC have replicated ∼17 times and they replicate ∼2.5 times/year between the ages of 3 and 13 years. Subsequently, HSC replication slows considerably. In adults HSC replicate at a rate of ∼0.6 times/year. In addition, the model predicts that newborns with small birth weight would have shorter LTL as adults and that women would have longer LTL than men. Conclusion: Our findings will be useful in bone marrow transplantations and might explain a body of clinical observations related to LTL distribution in the general population. © 2009 ISEH - Society for Hematology and Stem Cells.

Authors
Sidorov, I; Kimura, M; Yashin, A; Aviv, A
MLA Citation
Sidorov, I, Kimura, M, Yashin, A, and Aviv, A. "Leukocyte telomere dynamics and human hematopoietic stem cell kinetics during somatic growth." Experimental Hematology 37.4 (2009): 514-524.
PMID
19216021
Source
scival
Published In
Experimental Hematology
Volume
37
Issue
4
Publish Date
2009
Start Page
514
End Page
524
DOI
10.1016/j.exphem.2008.11.009

Linear latent structure analysis and modelling of multiple categorical variables

Linear latent structure analysis is a new approach for investigation of population heterogeneity using high-dimensional categorical data. In this approach, the population is represented by a distribution of latent vectors, which play the role of heterogeneity variables, and individual characteristics are represented by the expectation of this vector conditional on individual response patterns. Results of the computer experiments demonstrating a good quality of reconstruction of model parameters are described. The heterogeneity distribution estimated from 1999 National Long Term Care Survey (NLTCS) is discussed. A predictive power of the heterogeneity scores on mortality is analysed using vital statistics data linked to NLTCS.

Authors
Akushevich, I; Kovtun, M; Manton, KG; Yashin, AI
MLA Citation
Akushevich, I, Kovtun, M, Manton, KG, and Yashin, AI. "Linear latent structure analysis and modelling of multiple categorical variables." Computational and Mathematical Methods in Medicine 10.3 (2009): 203-218.
Source
scival
Published In
Computational and Mathematical Methods in Medicine
Volume
10
Issue
3
Publish Date
2009
Start Page
203
End Page
218
DOI
10.1080/17486700802259798

Circulatory diseases and aging

Age patterns of incidence rates of major circulatory diseases (CDs), their time trends, risk factors, and other characteristics capable of contributing to the debates on the role of aging in the deterioration of human health are investigated using standard statistical methods. The need for approaches capable of addressing more sophisticated questions about the connection between CD and aging-related changes in the human organism are discussed. Methods of statistical modeling are considered an efficient tool for studying the effects of the complex interplay between external and internal processes contributing to deterioration of the status of health, well-being, and survival. Their strength, limitations, and perspectives on their application to available data sets are described. © 2008 Copyright © 2008 Elsevier Inc. All rights reserved.

Authors
Akushevich, I; Yashin, AI
MLA Citation
Akushevich, I, and Yashin, AI. "Circulatory diseases and aging." (December 1, 2008): 717-726. (Chapter)
Source
scopus
Publish Date
2008
Start Page
717
End Page
726
DOI
10.1016/B978-012373960-5.00111-8

Sex-specific health deterioration and mortality: the morbidity-mortality paradox over age and time.

The traditional sex morbidity-mortality paradox that females have worse health but better survival than males is based on studies of major health traits. We applied a cumulative deficits approach to study this paradox, selecting 34 minor health deficits consistently measured in the 9th (1964) and 14th (1974) Framingham Heart and 5th (1991-1995) Offspring Study exams focusing on the 55-78 age range. We constructed four deficit indices (DIs) using all 34 deficits as well as subsets of these deficits characterizing males' (DI(M)) and females' (DI(F)) health disadvantages, and no relative sex-disadvantages. The DI(34)-specific age patterns are sex-insensitive within the 55-74 age range. The DI(34), however, tends to selectively increase the risk of death for males. The DI(F)-associated health dimension supports the traditional morbidity paradox, whereas the DI(M)-associated dimension supports the inverse paradox, wherein males have worse health but better survival than females. The traditional paradox became less pronounced, whereas the inverse paradox became more pronounced from the 1960s to the 1990 s. The sex-specific excess in minor health deficits may vary according to particular set of deficits, thus providing evidence for traditional and inverse morbidity paradoxes. The time-trends suggest the presence of a strong exogenous effect modifier affecting the rate of health deterioration and mortality risk.

Authors
Kulminski, AM; Culminskaya, IV; Ukraintseva, SV; Arbeev, KG; Land, KC; Yashin, AI
MLA Citation
Kulminski, AM, Culminskaya, IV, Ukraintseva, SV, Arbeev, KG, Land, KC, and Yashin, AI. "Sex-specific health deterioration and mortality: the morbidity-mortality paradox over age and time." Experimental gerontology 43.12 (December 2008): 1052-1057.
PMID
18835429
Source
epmc
Published In
Experimental Gerontology
Volume
43
Issue
12
Publish Date
2008
Start Page
1052
End Page
1057
DOI
10.1016/j.exger.2008.09.007

Effects of ACE D/I Polymorphism and 11 SNPs Heterozygosity in the Same Gene on Health Risks in Framingham Study

Authors
Yashin, AI; Culminskaya, IV; Arbeev, KG; Ukraintseva, SV; Akushevich, I; Kulminski, A
MLA Citation
Yashin, AI, Culminskaya, IV, Arbeev, KG, Ukraintseva, SV, Akushevich, I, and Kulminski, A. "Effects of ACE D/I Polymorphism and 11 SNPs Heterozygosity in the Same Gene on Health Risks in Framingham Study." November 2008.
Source
wos-lite
Published In
Genetic Epidemiology
Volume
32
Issue
7
Publish Date
2008
Start Page
722
End Page
722

Stochastic Model for Joint Analysis of Genetic and Non-Genetic Data from Longitudinal Studies of Aging, Health and Longevity

Authors
Arbeev, KG; Yashin, AI; Akushevich, I; Kulminski, AM; Arbeeva, LS; Akushevich, L; Ukraintseva, SV
MLA Citation
Arbeev, KG, Yashin, AI, Akushevich, I, Kulminski, AM, Arbeeva, LS, Akushevich, L, and Ukraintseva, SV. "Stochastic Model for Joint Analysis of Genetic and Non-Genetic Data from Longitudinal Studies of Aging, Health and Longevity." November 2008.
Source
wos-lite
Published In
Genetic Epidemiology
Volume
32
Issue
7
Publish Date
2008
Start Page
678
End Page
678

Interacting Effect of ACE D/I Polymorphism and Smoking on Health Risks in Framingham Study

Authors
Yashin, AI; Ukraintseva, SV; Arbeev, KG; Culminskaya, IV; Akushevich, I; Kulminski, A
MLA Citation
Yashin, AI, Ukraintseva, SV, Arbeev, KG, Culminskaya, IV, Akushevich, I, and Kulminski, A. "Interacting Effect of ACE D/I Polymorphism and Smoking on Health Risks in Framingham Study." November 2008.
Source
wos-lite
Published In
Genetic Epidemiology
Volume
32
Issue
7
Publish Date
2008
Start Page
722
End Page
723

Heritability of Endophenotypes of Pulmonary & Physical Function in Long Life Family Study

Authors
Matteini, AM; Fallin, MD; Kammerer, CM; Schupf, N; Yashin, AI; Mayeux, R; Barr, RG; Arbeev, KG; Christensen, K; Hadley, EC; Newman, AB; Walston, JD
MLA Citation
Matteini, AM, Fallin, MD, Kammerer, CM, Schupf, N, Yashin, AI, Mayeux, R, Barr, RG, Arbeev, KG, Christensen, K, Hadley, EC, Newman, AB, and Walston, JD. "Heritability of Endophenotypes of Pulmonary & Physical Function in Long Life Family Study." November 2008.
Source
wos-lite
Published In
Genetic Epidemiology
Volume
32
Issue
7
Publish Date
2008
Start Page
706
End Page
707

Cumulative deficits and physiological indices as predictors of mortality and long life.

We evaluated the predictive potential for long-term (24-year) survival and longevity (85+ years) of an index of cumulative deficits (DI) and six physiological indices (pulse pressure, diastolic blood pressure, pulse rate, serum cholesterol, blood glucose, and hematocrit) measured in mid- to late life (44-88 years) for participants of the 9th and 14th Framingham Heart Study examinations. For all ages combined, the DI, pulse pressure, and blood glucose are the strongest determinants of both long-term survival and longevity, contributing cumulatively to their explanation. Diastolic blood pressure and hematocrit are less significant determinants of both of these outcomes. The pulse rate is more relevant to survival, whereas serum cholesterol is more relevant to longevity. Only the DI is a significant predictor of longevity and mortality for each 5-year age group ranging from 45 to 85 years. The DI appears to be a more important determinant of long-term risks of death and longevity than are the physiological indices.

Authors
Kulminski, AM; Ukraintseva, SV; Culminskaya, IV; Arbeev, KG; Land, KC; Akushevich, L; Yashin, AI
MLA Citation
Kulminski, AM, Ukraintseva, SV, Culminskaya, IV, Arbeev, KG, Land, KC, Akushevich, L, and Yashin, AI. "Cumulative deficits and physiological indices as predictors of mortality and long life." The journals of gerontology. Series A, Biological sciences and medical sciences 63.10 (October 2008): 1053-1059.
PMID
18948555
Source
epmc
Published In
Journals of Gerontology: Series A
Volume
63
Issue
10
Publish Date
2008
Start Page
1053
End Page
1059
DOI
10.1093/gerona/63.10.1053

Changes in health status among participants of the Framingham Heart Study from the 1960s to the 1990s: application of an index of cumulative deficits.

Health of the general population is improving along a number of major health dimensions. Using a cumulative deficits approach, we investigated whether such improvements were evident at the level of minor health traits.We selected 37 small-effect traits consistently measured in the 9th (performed in 1964) and 14th (1974) Framingham Heart and 5th (1991-1995) Offspring Study exams to construct indices of cumulative deficits (DIs).We identified deficits-specific DIs characterizing health dimensions associated with no health changes (DI(NHC)), health worsening (DI(WRS)), and health improving (DI(IMP)) between the 1960s and 1990s. The risks of death attributable to the DI(NHC) dominate within shorter time horizons. For longer time horizons, both the DI(NHC) and DI(IMP) provide the same contribution to the risks of death. The mortality risks associated with the DI(WRS) are the weakest and least significant.The analyses show that the cumulative deficits approach might be an efficient tool for analyzing the effects of a large number of health characteristics for which the individual effects are small, inconsistent, or non-significant. They show favorable trends such that health of the Framingham studies participants either did not change or improved over time for the most serious small-effect traits.

Authors
Kulminski, AM; Arbeev, KG; Ukraintseva, SV; Culminskaya, IV; Land, K; Yashin, AI
MLA Citation
Kulminski, AM, Arbeev, KG, Ukraintseva, SV, Culminskaya, IV, Land, K, and Yashin, AI. "Changes in health status among participants of the Framingham Heart Study from the 1960s to the 1990s: application of an index of cumulative deficits." Annals of epidemiology 18.9 (September 2008): 696-701.
PMID
18794010
Source
epmc
Published In
Annals of Epidemiology
Volume
18
Issue
9
Publish Date
2008
Start Page
696
End Page
701
DOI
10.1016/j.annepidem.2008.06.005

The U-shaped response of initial mortality in Caenorhabditis elegans to mild heat shock: does it explain recent trends in human mortality?

U-shaped dose-response relationships (hormesis) have been documented in numerous biological, toxicological, and pharmacological investigations. For example, in response to a mild 35 degrees C heat shock, the longevity of Caenorhabditis elegans exhibits an inverted U-shaped dose-response. By applying the demographic concept of heterogeneity, we find that this U-shaped curve for longevity response is driven by a U-shaped dose-response of initial mortality. When worms are subjected to mild heat shock, the initial mortality decreases compared to the control. This initial mortality benefit increases with moderate increases in the length of heat shock, peaking at a point that coincides with the induction of damage to the worms. The dose of heat shock that coincided with this benefit in initial mortality did not affect the rate of increase in mortality.

Authors
Wu, D; Cypser, JR; Yashin, AI; Johnson, TE
MLA Citation
Wu, D, Cypser, JR, Yashin, AI, and Johnson, TE. "The U-shaped response of initial mortality in Caenorhabditis elegans to mild heat shock: does it explain recent trends in human mortality?." The journals of gerontology. Series A, Biological sciences and medical sciences 63.7 (July 2008): 660-668.
PMID
18693219
Source
epmc
Published In
Journals of Gerontology: Series A
Volume
63
Issue
7
Publish Date
2008
Start Page
660
End Page
668
DOI
10.1093/gerona/63.7.660

Cumulative deficits better characterize susceptibility to death in elderly people than phenotypic frailty: lessons from the Cardiovascular Health Study.

To compare how well frailty measures based on a phenotypic frailty approach proposed in the Cardiovascular Health Study (CHS) and a cumulative deficits approach predict mortality.Cohort study.The main cohort of the CHS.Four thousand seven hundred twenty-one individuals.A phenotypic frailty index (PFI) was defined in the same way as proposed in the CHS: assessing weight loss, exhaustion, low physical activity, slowness, and poor grip strength. A cumulative deficit index (DI) was defined based on 48 elderly deficits (signs, symptoms, impairments, diseases) included in the index, with equal weights.Of the 1,073 frailest individuals with the lowest survival, the PFI, categorized as proposed in the CHS into robust, prefrail, and frail categories, underestimated the risk of death for 720 persons, whereas the DI categorized into the same three frailty categories underestimated the mortality risk for 134 persons. The higher power of the DI for discriminating frail individuals in their susceptibility to death also followed from comparison of quasi-instantaneous values of both indices. The three-level DI identified 219 individuals as frail of 361 individuals identified as frail according to the three-level PFI.The DI can more precisely evaluate chances of death because it assesses a broader spectrum of disorders than the PFI. Both indices appear to be frailty related. Integration of both approaches is highly promising for increasing the precision of discrimination of the risk of death and especially for identification of the most vulnerable elderly people.

Authors
Kulminski, AM; Ukraintseva, SV; Kulminskaya, IV; Arbeev, KG; Land, K; Yashin, AI
MLA Citation
Kulminski, AM, Ukraintseva, SV, Kulminskaya, IV, Arbeev, KG, Land, K, and Yashin, AI. "Cumulative deficits better characterize susceptibility to death in elderly people than phenotypic frailty: lessons from the Cardiovascular Health Study." Journal of the American Geriatrics Society 56.5 (May 2008): 898-903.
PMID
18363679
Source
epmc
Published In
Journal of American Geriatrics Society
Volume
56
Issue
5
Publish Date
2008
Start Page
898
End Page
903
DOI
10.1111/j.1532-5415.2008.01656.x

Association between APOE epsilon 2/epsilon 3/epsilon 4 polymorphism and disability severity in a national long-term care survey sample.

early studies reported controversial findings on association of apolipoprotein E (APOE) polymorphism with disability.to analyse sex-specific associations of APOE genotypes with impairments in (instrumental) activities of daily living [(I)ADL] and mortality.population-based 1999 National Long Term Care Survey (NLTCS) of the US older (65+) individuals.genetic data are available for 1,805 individuals.each of six genotypes of three common alleles of the APOE locus (epsilon 2, epsilon 3 and epsilon 4) was tested on the association with a disability index or mortality.APOE epsilon 3/epsilon 3 genotype significantly decreases odds ratio (OR) for IADL disability in males [OR = 0.48; 95% Confidence Interval (CI) 0.31-0.76] while it exhibits no association in females. The OR for ADL disability is 0.19 (CI 0.04-0.99) for epsilon 4/epsilon 4 female carriers. The epsilon 2/epsilon 3 genotype increases the chances of IADL disability for males (OR = 2.33; CI 1.28-4.25). No significant association between APOE polymorphism and mortality was found. A surprising observation was that epsilon 4/epsilon 4 female carriers have a 5.3 times lower chance of having ADL disability than non-epsilon 4/epsilon 4-carriers.association of the APOE polymorphism with disability and lack of association with mortality support the view that APOE gene actions may be more significant as modulators of frailty than of longevity.

Authors
Kulminski, A; Ukraintseva, SV; Arbeev, KG; Manton, KG; Oshima, J; Martin, GM; Yashin, AI
MLA Citation
Kulminski, A, Ukraintseva, SV, Arbeev, KG, Manton, KG, Oshima, J, Martin, GM, and Yashin, AI. "Association between APOE epsilon 2/epsilon 3/epsilon 4 polymorphism and disability severity in a national long-term care survey sample." Age and ageing 37.3 (May 2008): 288-293.
PMID
18250093
Source
epmc
Published In
Age and Ageing
Volume
37
Issue
3
Publish Date
2008
Start Page
288
End Page
293
DOI
10.1093/ageing/afn003

What age trajectories of cumulative deficits and medical costs tell us about individual aging and mortality risk: Findings from the NLTCS-Medicare data.

An important feature of aging-related deterioration in human health is the decline in organisms' resistance to stresses, which contributes to an increase in morbidity and mortality risks. In human longitudinal studies of aging, such a decline is not measured directly, so indirect methods of statistical modeling have to be used for evaluating this characteristic. Since medical interventions reflect severity of occurring health disorders, data from Medicare service use files can be used for such modeling. In this paper, we use the National Long Term Care Survey (NLTCS) data merged with the Medicare service use files to investigate dynamics of stress resistance in the U.S. elderly. We constructed individual indices of cumulative deficits and medical costs and investigated their separate and joint effects on dynamics of mortality risks using the quadratic hazard model (QHM). We found that males show a faster decline in stress resistance with age than females.

Authors
Yashin, AI; Arbeev, KG; Kulminski, A; Akushevich, I; Akushevich, L; Ukraintseva, SV
MLA Citation
Yashin, AI, Arbeev, KG, Kulminski, A, Akushevich, I, Akushevich, L, and Ukraintseva, SV. "What age trajectories of cumulative deficits and medical costs tell us about individual aging and mortality risk: Findings from the NLTCS-Medicare data." Mechanisms of ageing and development 129.4 (April 2008): 191-200.
PMID
18242665
Source
epmc
Published In
Mechanisms of Ageing and Development
Volume
129
Issue
4
Publish Date
2008
Start Page
191
End Page
200
DOI
10.1016/j.mad.2007.12.005

Health-protective and adverse effects of the apolipoprotein E epsilon2 allele in older men.

To reexamine a health-protective role of the common apolipoprotein E (APOE) polymorphism focusing on connections between the APOE epsilon2-containing genotypes and impairments in instrumental activities of daily living (IADLs) in older (> or = 65) men and women and to examine how diagnosed coronary heart disease (CHD), Alzheimer's disease, colorectal cancer, macular degeneration, and atherosclerosis may mediate these connections.Retrospective cross-sectional study.The unique disability-focused data from a genetic subsample of the 1999 National Long Term Care Survey linked with Medicare service use files.One thousand seven hundred thirty-three genotyped individuals interviewed regarding IADL disabilities.Indicators of IADL impairments, five geriatric disorders, and epsilon2-containing genotypes.The epsilon2/3 genotype is a major contributor to adverse associations between the epsilon2 allele and IADL disability in men (odds ratio (OR)=3.09, 95% confidence interval (CI)=1.53-6.26), although it provides significant protective effects for CHD (OR=0.55, 95% CI=0.33-0.92), whereas CHD is adversely associated with IADL disability (OR=2.18, 95% CI=1.28-3.72). Adjustment for five diseases does not significantly alter the adverse association between epsilon2-containing genotypes and disability. Protective effects of the epsilon2/3 genotype for CHD (OR=0.52, 95% CI=0.27-0.99) and deleterious effects for IADLs (OR=3.50, 95% CI=1.71-7.14) for men hold in multivariate models with both these factors included. No significant associations between the epsilon2-containing genotypes and IADL are found in women.The epsilon2 allele can play a dual role in men, protecting them against some health disorders, while promoting others. Strong adverse relationships with disability suggest that epsilon2-containing genotypes can be unfavorable factors for the health and well-being of aging men.

Authors
Kulminski, AM; Ukraintseva, SV; Arbeev, KG; Manton, KG; Oshima, J; Martin, GM; Il'yasova, D; Yashin, AI
MLA Citation
Kulminski, AM, Ukraintseva, SV, Arbeev, KG, Manton, KG, Oshima, J, Martin, GM, Il'yasova, D, and Yashin, AI. "Health-protective and adverse effects of the apolipoprotein E epsilon2 allele in older men." Journal of the American Geriatrics Society 56.3 (March 2008): 478-483.
PMID
18179501
Source
epmc
Published In
Journal of American Geriatrics Society
Volume
56
Issue
3
Publish Date
2008
Start Page
478
End Page
483
DOI
10.1111/j.1532-5415.2007.01574.x

An inverse association between self-reported arthritis and mortality in the elderly: findings from the national long-term care survey.

Major musculoskeletal conditions including arthritis represent an increasing burden on individuals and societies. We analyzed the association between self-reported arthritis and mortality in the U.S. elderly disabled and non-disabled individuals using unique disability-focused data from the large-scale population-based National Long Term Care Survey. It was found that males and females who reported arthritis/rheumatism have, generally, smaller risks of death than those who did not report those conditions. This inverse relationship is more pronounced in disabled individuals. This finding holds for both short-term (relative risk [RR] = 0.81; 95% confidence interval [CI] = 0.75-0.88 for males and RR = 0.76; CI = 0.71-0.82 for females) and long-term follow-ups (RR = 0.82; CI = 0.78-0.87 for males and RR = 0.83; CI = 0.79-0.87 for females). For females, this effect is age insensitive, while for males it is limited to ages below 85. Demographic and 19 major self-reported geriatric conditions have trivial effect on these risks, supporting the view that a better survival of diseased individuals can be attributed to the effects of medical treatment. Given the widespread prevalence of arthritis/rheumatism and disability in elderly populations and the increasing population of the elderly, these findings call for comprehensive analyses of factors driving better survival and medical costs associated with extended lives.

Authors
Kulminski, AM; Kulminskaya, IV; Ukraintseva, SV; Land, K; Yashin, AI
MLA Citation
Kulminski, AM, Kulminskaya, IV, Ukraintseva, SV, Land, K, and Yashin, AI. "An inverse association between self-reported arthritis and mortality in the elderly: findings from the national long-term care survey." Rejuvenation research 11.1 (February 2008): 251-257.
PMID
18240974
Source
epmc
Published In
Rejuvenation Research
Volume
11
Issue
1
Publish Date
2008
Start Page
251
End Page
257
DOI
10.1089/rej.2007.0611

Model of hidden heterogeneity in longitudinal data.

Variables measured in longitudinal studies of aging and longevity do not exhaust the list of all factors affecting health and mortality transitions. Unobserved factors generate hidden variability in susceptibility to diseases and death in populations and in age trajectories of longitudinally measured indices. Effects of such heterogeneity can be manifested not only in observed hazard rates but also in average trajectories of measured indices. Although effects of hidden heterogeneity on observed mortality rates are widely discussed, their role in forming age patterns of other aging-related characteristics (average trajectories of physiological state, stress resistance, etc.) is less clear. We propose a model of hidden heterogeneity to analyze its effects in longitudinal data. The approach takes the presence of hidden heterogeneity into account and incorporates several major concepts currently developing in aging research (allostatic load, aging-associated decline in adaptive capacity and stress-resistance, age-dependent physiological norms). Simulation experiments confirm identifiability of model's parameters.

Authors
Yashin, AI; Arbeev, KG; Akushevich, I; Kulminski, A; Akushevich, L; Ukraintseva, SV
MLA Citation
Yashin, AI, Arbeev, KG, Akushevich, I, Kulminski, A, Akushevich, L, and Ukraintseva, SV. "Model of hidden heterogeneity in longitudinal data." Theoretical population biology 73.1 (February 2008): 1-10.
PMID
17977568
Source
epmc
Published In
Theoretical Population Biology
Volume
73
Issue
1
Publish Date
2008
Start Page
1
End Page
10
DOI
10.1016/j.tpb.2007.09.001

Body mass index and nine-year mortality in disabled and nondisabled older U.S. individuals.

OBJECTIVES: To investigate the relationship between body mass index (BMI) and 9-year mortality in older (> or = 65) Americans with and without disability. DESIGN: Cohort study. SETTING: The unique disability-focused National Long Term Care Survey (NLTCS) data that assessed the health and well-being of older individuals in 1994 were analyzed. PARTICIPANTS: Four thousand seven hundred ninety-one individuals in the 1994 survey. MEASUREMENTS: BMI (kg/m2) was calculated from self- or proxy reports of height and weight. The analysis was adjusted for 1-year change in BMI and demographic and health-related factors, as well as reports by proxies, and death occurring during the first 2 years after the interview. RESULTS: The relative risk of death as a function of BMI formed a nonsymmetric U-shaped pattern, with larger risks associated with lower BMI (< 22.0) and minimal risks for BMI of 25.0 to 34.9. (BMI 22.0-24.9 was the reference.) Adjustments for demographic and health-related factors had little effect on this pattern. Nondisabled individuals exhibited a similar U-shaped pattern but with lower risks associated with lower BMI. For disabled individuals, the mortality-risk pattern was higher for lower BMI (< 22.0) and flat for higher BMI, thus exhibiting an inverse J shape. BMI patterns were age sensitive, with disability status affecting sensitivity. CONCLUSION: Overweight or mild (grade 1) obesity was not a risk factor for 9-year mortality in older Americans participating in the 1994 NLTCS. A flatter BMI pattern of the relative risk of death for disabled than for nondisabled individuals suggests that optimal body weight can be sensitive to age and health and well-being.

Authors
Kulminski, AM; Arbeev, KG; Kulminskaya, IV; Ukraintseva, SV; Land, K; Akushevich, I; Yashin, AI
MLA Citation
Kulminski, AM, Arbeev, KG, Kulminskaya, IV, Ukraintseva, SV, Land, K, Akushevich, I, and Yashin, AI. "Body mass index and nine-year mortality in disabled and nondisabled older U.S. individuals." Journal of the American Geriatrics Society 56.1 (January 2008): 105-110.
PMID
18005352
Source
epmc
Published In
Journal of American Geriatrics Society
Volume
56
Issue
1
Publish Date
2008
Start Page
105
End Page
110
DOI
10.1111/j.1532-5415.2007.01494.x

Epidemiology of hormone-associated cancers as a reflection of age.

In this chapter we review the epidemiology of hormone-associated cancers (prostate, breast, endometrial, ovarian, pancreatic and thyroid) paying special attention to the variability in the age patterns of cancer incidence rate over populations and time periods. We emphasize the comparative analysis of the age specific incidence rate curves as a valuable source of hypotheses about factors influencing cancer risks in populations in addition to the analysis of the age-adjusted rates.

Authors
Ukraintseva, SV; Arbeev, KG; Yashin, AI
MLA Citation
Ukraintseva, SV, Arbeev, KG, and Yashin, AI. "Epidemiology of hormone-associated cancers as a reflection of age." Advances in experimental medicine and biology 630 (January 2008): 57-71. (Review)
PMID
18637485
Source
epmc
Published In
Advances in experimental medicine and biology
Volume
630
Publish Date
2008
Start Page
57
End Page
71

Nonpathological senescence arises from unsuitable external influences.

One of the most exciting events in current biogerontology is the elucidation of environmental control over the rate of aging. Many observations suggest that appropriate external stimuli can ameliorate the state of various biological entities and even rejuvenate them. Recent findings support the possibility that nonpathological aging of cells may be caused solely by external signals and moreover that this aging might be reversible. We have extended this principle to the level of the whole organism. We have suggested that a range of natural environmental conditions exists that corresponds to adequate vital activity within which an organism can maintain optimal functioning, renew itself, and remain ageless. But the environmental mortality of such organisms in natural niches is rather high. To reduce this mortality, the organism requires a milder but less stimulating environment in the presence of which (below some threshold level), the organism's renewal process becomes incomplete and the organism starts to age. Nevertheless, an age-dependent increase in the mortality rate due to senescence can be compensated for by a significant initial reduction in mortality due to environmental causes. The moderate present-day increase of life expectancy is the result of just such an initial mortality reduction. Living in a safe environment along with simulation of natural external positive influences or adequate responses to negative influences can decelerate, stop, and even reverse aging as well as considerably extend mean and extreme life span.

Authors
Khalyavkin, AV; Yashin, AI
MLA Citation
Khalyavkin, AV, and Yashin, AI. "Nonpathological senescence arises from unsuitable external influences." Ann N Y Acad Sci 1119 (November 2007): 306-309. (Review)
PMID
18056977
Source
pubmed
Published In
Annals of the New York Academy of Sciences
Volume
1119
Publish Date
2007
Start Page
306
End Page
309
DOI
10.1196/annals.1404.022

Accelerated accumulation of health deficits as a characteristic of aging.

Cross-sectional analyses show that an index of aging-associated health/well-being deficits, called the "frailty index", can characterize the aging process in humans. This study provides support for such characterization from a longitudinal analysis of the frailty index properties. The data are from the National Long Term Care Survey assessed longitudinally health and functioning of the U.S. elderly in the period 1982-1999. In cross-sectional analysis, the frailty index exhibits accelerated increase with age till oldest-old ages (95+), with possible deceleration thereafter. Longitudinal analysis confirms the accelerated accumulation of deficits in aging individuals. The time-dynamics of the frailty index is affected by two sex-sensitive processes: (i) selection of robust individuals, resulting in a decline of the mean frailty index with age and (ii) accumulation of deficits associated with physiological aging and its interaction with environment, which results in an accelerated increase of individual frailty index prior to death irrespective of chronological age. Current frailty index levels in individuals are more predictive of death than the index past values. Longitudinal analysis provides strong evidence that the cumulative index of health/well-being deficits can characterize aging-associated processes in humans and predict death better than chronological age during short-term periods.

Authors
Kulminski, A; Ukraintseva, SV; Akushevich, I; Arbeev, KG; Land, K; Yashin, AI
MLA Citation
Kulminski, A, Ukraintseva, SV, Akushevich, I, Arbeev, KG, Land, K, and Yashin, AI. "Accelerated accumulation of health deficits as a characteristic of aging." Experimental gerontology 42.10 (October 2007): 963-970.
PMID
17601693
Source
epmc
Published In
Experimental Gerontology
Volume
42
Issue
10
Publish Date
2007
Start Page
963
End Page
970
DOI
10.1016/j.exger.2007.05.009

A correlated frailty model with long-term survivors for estimating the heritability of breast cancer.

The aim of this study is to investigate the role of genetics and environment in susceptibility to breast cancer (frailty). An interdisciplinary approach was adopted, combining a correlated frailty-mixture model with genetic equations, allowing for decomposition of the frailty variance into genetic and environmental components. In addition, the possibility that a fraction of the population under study is 'immune' to the disease is evaluated, and changes in heritability estimates introducing a fraction of non-susceptible individuals are determined. The methodology is applied to breast cancer data from the Swedish Twin Registry, including information about all female monozygotic and dizygotic twin pairs born in Sweden between 1886 and 1967. The inferential problem is solved in a Bayesian framework and the numerical work is carried out using Markov chain Monte Carlo (MCMC) methods.

Authors
Locatelli, I; Rosina, A; Lichtenstein, P; Yashin, AI
MLA Citation
Locatelli, I, Rosina, A, Lichtenstein, P, and Yashin, AI. "A correlated frailty model with long-term survivors for estimating the heritability of breast cancer." Stat Med 26.20 (September 10, 2007): 3722-3734.
PMID
17139701
Source
pubmed
Published In
Statistics in Medicine
Volume
26
Issue
20
Publish Date
2007
Start Page
3722
End Page
3734
DOI
10.1002/sim.2761

The apolipoprotein E epsilon2 allele and aging-associated health deterioration in older males.

Authors
Kulminski, AM; Ukraintseva, SV; Yashin, AI
MLA Citation
Kulminski, AM, Ukraintseva, SV, and Yashin, AI. "The apolipoprotein E epsilon2 allele and aging-associated health deterioration in older males." Journal of the American Geriatrics Society 55.9 (September 2007): 1479-1480. (Letter)
PMID
17767697
Source
epmc
Published In
Journal of American Geriatrics Society
Volume
55
Issue
9
Publish Date
2007
Start Page
1479
End Page
1480
DOI
10.1111/j.1532-5415.2007.01311.x

Stochastic model for analysis of longitudinal data on aging and mortality.

Aging-related changes in a human organism follow dynamic regularities, which contribute to the observed age patterns of incidence and mortality curves. An organism's 'optimal' (normal) physiological state changes with age, affecting the values of risks of disease and death. The resistance to stresses, as well as adaptive capacity, declines with age. An exposure to improper environment results in persisting deviation of individuals' physiological (and biological) indices from their normal state (due to allostatic adaptation), which, in turn, increases chances of disease and death. Despite numerous studies investigating these effects, there is no conceptual framework, which would allow for putting all these findings together, and analyze longitudinal data taking all these dynamic connections into account. In this paper we suggest such a framework, using a new version of stochastic process model of aging and mortality. Using this model, we elaborated a statistical method for analyses of longitudinal data on aging, health and longevity and tested it using different simulated data sets. The results show that the model may characterize complicated interplay among different components of aging-related changes in humans and that the model parameters are identifiable from the data.

Authors
Yashin, AI; Arbeev, KG; Akushevich, I; Kulminski, A; Akushevich, L; Ukraintseva, SV
MLA Citation
Yashin, AI, Arbeev, KG, Akushevich, I, Kulminski, A, Akushevich, L, and Ukraintseva, SV. "Stochastic model for analysis of longitudinal data on aging and mortality." Mathematical biosciences 208.2 (August 2007): 538-551.
PMID
17300818
Source
epmc
Published In
Mathematical Biosciences
Volume
208
Issue
2
Publish Date
2007
Start Page
538
End Page
551
DOI
10.1016/j.mbs.2006.11.006

Cumulative index of health deficiencies as a characteristic of long life.

To describe the accumulation of aging-associated health disorders using a cumulative measure known as a frailty index (FI) and to evaluate its ability to differentiate long- and short-life phenotypes as well as the FI's connection to aging-associated processes in older people.Retrospective cross-sectional and longitudinal studies.The National Long-Term Care Survey (NLTCS) data that assessed health and functioning of U.S. older individuals (> or =65) in 1982, 1984, 1989, 1994, and 1999 were analyzed. The NLTCS sample in each survey represents a mixture of longitudinal and cross-sectional components.Approximately 5,000 individuals in each survey.A cumulative index of health and well-being deficiencies (disabilities, signs, diseases) was calculated as a count of deficits observed in an individual divided by the total number of all considered deficits.Men and women who died before the age of 75 and those who died after the age of 85 exhibited remarkably similar FI frequency patterns despite the 10-year age difference between age profiles in these samples. Long life is consistently characterized in longitudinal analyses by lower FIs. FI dynamics are found to be strongly sex sensitive.The FI appears to be a sensitive age-independent indicator of sex-specific physiological decline in aging individuals and a sex-specific discriminator of survival chances. The FI is a promising characteristic suitable for improving sex-sensitive forecasts of risks of adverse health outcomes in older people.

Authors
Kulminski, AM; Ukraintseva, SV; Akushevich, IV; Arbeev, KG; Yashin, AI
MLA Citation
Kulminski, AM, Ukraintseva, SV, Akushevich, IV, Arbeev, KG, and Yashin, AI. "Cumulative index of health deficiencies as a characteristic of long life." Journal of the American Geriatrics Society 55.6 (June 2007): 935-940.
PMID
17537097
Source
epmc
Published In
Journal of American Geriatrics Society
Volume
55
Issue
6
Publish Date
2007
Start Page
935
End Page
940
DOI
10.1111/j.1532-5415.2007.01155.x

The accuracy of statistical estimates in genetic studies of aging can be significantly improved.

The sample size of the data used in genetic studies is often a factor limiting the accuracy of statistical estimates. In this paper we suggest a new approach to evaluation of genetic influence on risk of development of aging-related health disorders. The approach results in substantial improvement of the accuracy of statistical estimates without an increase in the size of the genetic sample. The approach is based on the joint analysis of data from the genetic samples and easily accessible non-genetic data, such as data collected in epidemiological, demographic, and longitudinal studies of human aging and aging-related pathologies.

Authors
Yashin, AI; Arbeev, KG; Ukraintseva, SV
MLA Citation
Yashin, AI, Arbeev, KG, and Ukraintseva, SV. "The accuracy of statistical estimates in genetic studies of aging can be significantly improved." Biogerontology 8.3 (June 2007): 243-255.
PMID
17160500
Source
epmc
Published In
Biogerontology
Volume
8
Issue
3
Publish Date
2007
Start Page
243
End Page
255
DOI
10.1007/s10522-006-9072-4

Health decline, aging and mortality: how are they related?

The deterioration of human health with age is manifested in changes of thousands of physiological and biological variables. The contribution of some of such changes to the mortality risk may be small and cannot be reliably detected by existing statistical methods. A cumulative index of health/well-being disorders, which counts changes in observed variables on the way of losing health, may be an appropriate way to take the effects of such variables into account. In this paper we investigate regularities of the aging-related changes in human health/well-being/survival status described by such an index using the new version of the quadratic hazard model of human aging and mortality. We found that the shape and the location of the mortality risk, considered as a function of the introduced health-related index, changes with age reflecting the decline in stress resistance and the age-dependence of the "optimal" health/well-being status. Comparison of these results with findings from early studies using the Cox's-like model of risk function indicates that the results are likely to describe regularities of deterioration in human health during the aging process.

Authors
Yashin, AI; Arbeev, KG; Kulminski, A; Akushevich, I; Akushevich, L; Ukraintseva, SV
MLA Citation
Yashin, AI, Arbeev, KG, Kulminski, A, Akushevich, I, Akushevich, L, and Ukraintseva, SV. "Health decline, aging and mortality: how are they related?." Biogerontology 8.3 (June 2007): 291-302.
PMID
17242962
Source
epmc
Published In
Biogerontology
Volume
8
Issue
3
Publish Date
2007
Start Page
291
End Page
302
DOI
10.1007/s10522-006-9073-3

Cumulative index of health disorders as an indicator of aging-associated processes in the elderly: results from analyses of the National Long Term Care Survey.

We employ an approach based on the elaborated frailty index (FI), which is capable of taking into account variables with mild effect on the aging, health and survival outcomes, and investigate the connections between the FI, chronological age and the aging-associated outcomes in the elderly.Cross-sectional analysis of pooled data from the National Long Term Care Survey (NLTCS) assessing health and functioning of the U.S. elderly in 1982, 1984, 1989, 1994, and 1999.Distributions of frequency, residual life span, mortality rate, and relative risk of death are remarkably similar over age and FI. Coefficients of correlation between FI and age are low both for males (0.127, p<.01) and females (0.221, p<.01). The FI-specific age patterns show deceleration at advanced ages. The FI can provide order of magnitude better resolution in estimating mean remaining life span compared to age. Males have smaller FI than females while males' mortality risks are higher. For short-time horizons, the FI and age are largely independently associated with mortality risks.The FI: (i) can be considered as an adequate sex-specific indicator of the aging-associated processes in the elderly, (ii) can characterize these processes independently of age, and (iii) is a better characteristic of the aging phenotype than chronological age.

Authors
Kulminski, A; Yashin, A; Arbeev, K; Akushevich, I; Ukraintseva, S; Land, K; Manton, K
MLA Citation
Kulminski, A, Yashin, A, Arbeev, K, Akushevich, I, Ukraintseva, S, Land, K, and Manton, K. "Cumulative index of health disorders as an indicator of aging-associated processes in the elderly: results from analyses of the National Long Term Care Survey." Mechanisms of ageing and development 128.3 (March 2007): 250-258.
PMID
17223183
Source
epmc
Published In
Mechanisms of Ageing and Development
Volume
128
Issue
3
Publish Date
2007
Start Page
250
End Page
258
DOI
10.1016/j.mad.2006.12.004

Cumulative index of elderly disorders and its dynamic contribution to mortality and longevity.

The composite index constructed from longitudinal survey data as the level of deficits accumulated by an individual (frailty index) captures important systemic aspects of deterioration in a human organism, and is an attractive candidate for studying determinants of aging and longevity. The objective of this paper was to investigate the ability of this index to characterize human aging, mortality, and longevity. We use 32 variables from the National Long Term Care Survey data characterizing health and daily activities deficits to construct the cumulative frailty index. We use the Cox's proportional hazard model to describe its contribution to mortality. The risk of death considered as the function of the frailty index has asymmetric U-shaped form. The asymmetric U-function of the absolute risk is getting steeper (narrower) with age. The asymmetric U-function describing the relative risk exhibits the opposite tendency with age. The narrowing of the absolute risk functions with age reflects the age-related decline in stress resistance. The widening of the relative risk function with age indicates an increase in the relative contribution of other, unobserved, risk factors (including senescence) to the risk of death. This suggests increasing the role of senescence per se in the increasing risk of death with age compared to the role of specific pathology.

Authors
Yashin, AI; Arbeev, KG; Kulminski, A; Akushevich, I; Akushevich, L; Ukraintseva, SV
MLA Citation
Yashin, AI, Arbeev, KG, Kulminski, A, Akushevich, I, Akushevich, L, and Ukraintseva, SV. "Cumulative index of elderly disorders and its dynamic contribution to mortality and longevity." Rejuvenation research 10.1 (March 2007): 75-86.
PMID
17378754
Source
epmc
Published In
Rejuvenation Research
Volume
10
Issue
1
Publish Date
2007
Start Page
75
End Page
86
DOI
10.1089/rej.2006.0500

New models and methods for survival analysis of experimental data

Authors
Semenchenko, GV; Yashin, AI; Johnson, TE; Cypser, JW
MLA Citation
Semenchenko, GV, Yashin, AI, Johnson, TE, and Cypser, JW. "New models and methods for survival analysis of experimental data." 2007.
Source
wos-lite
Published In
ADVANCES IN STATISTICAL METHODS FOR THE HEALTH SCIENCES: APPLICATIONS TO CANCER AND AIDS STUDIES, GENOME SEQUENCE ANALYSIS, AND SURVIVAL ANALYSIS
Publish Date
2007
Start Page
179
End Page
+
DOI
10.1007/978-0-8176-4542-7_12

The role of correlated frailty models in studies of human health, ageing, and longevity

Authors
Wienke, A; Lichtenstein, P; Czene, K; Yashin, AI
MLA Citation
Wienke, A, Lichtenstein, P, Czene, K, and Yashin, AI. "The role of correlated frailty models in studies of human health, ageing, and longevity." 2007.
Source
wos-lite
Published In
ADVANCES IN STATISTICAL METHODS FOR THE HEALTH SCIENCES: APPLICATIONS TO CANCER AND AIDS STUDIES, GENOME SEQUENCE ANALYSIS, AND SURVIVAL ANALYSIS
Publish Date
2007
Start Page
151
End Page
+
DOI
10.1007/978-0-8176-4542-7_10

Insights on aging and exceptional longevity from longitudinal data: novel findings from the Framingham Heart Study.

Age trajectories of physiological indices contain important information about aging-related changes in the human organism and therefore may help us understand human longevity. The goal of this study is to investigate whether shapes of such trajectories earlier in life affect the residual life span distribution. We used longitudinal limited access data from seven physiological indices and life spans of respective individuals collected in the Framingham Heart Study (FHS). These include: diastolic blood pressure (DBP), pulse pressure (PP), body mass index (BMI), serum cholesterol (SCH), blood glucose (BG), hematocrit (HC), and pulse rate (PR). We developed a method for assigning individuals to groups of potentially long-lived (PLL) and potentially medium-lived (PML) groups using age trajectories of physiological indices at the age interval between 40 and 60 years. The analysis shows that the longevity of individuals who survived to age of 65 depends on the behavior of the physiological indices between 40 and 60 years of age.

Authors
Yashin, AI; Akushevich, IV; Arbeev, KG; Akushevich, L; Ukraintseva, SV; Kulminski, A
MLA Citation
Yashin, AI, Akushevich, IV, Arbeev, KG, Akushevich, L, Ukraintseva, SV, and Kulminski, A. "Insights on aging and exceptional longevity from longitudinal data: novel findings from the Framingham Heart Study." Age (Dordrecht, Netherlands) 28.4 (December 2006): 363-374.
PMID
17895962
Source
epmc
Published In
AGE
Volume
28
Issue
4
Publish Date
2006
Start Page
363
End Page
374
DOI
10.1007/s11357-006-9023-7

Accumulation of health disorders as a systemic measure of aging: Findings from the NLTCS data.

An index of age-associated health/well-being disorders (deficits), called the "frailty index" (FI), appears to be a promising characteristic to capture dynamic variability in aging manifestations among age-peers. In this study we provide further support toward this view focusing on the analysis of the FI age patterns in the participants of the National Long Term Care Survey (NLTCS).The NLTCS assessed health and functioning of the U.S. elderly in 1982, 1984, 1989, 1994, and 1999. Detailed information for our sample was assessed from about 26,700 interviews. The individual FI is defined as a proportion of health deficits for a given person.The FI in the NLTCS exhibits accelerated age patterns. The acceleration is larger for elderly who, at younger ages, had a lower FI (low FI group) than for those who showed a higher FI at younger ages (high FI group). Age-patterns for low and high FI groups tend to converge at advanced ages. The rate of deficit accumulation is sex-sensitive.The accelerated FI age patterns suggest that FI can be considered as a systemic measure of aging process. Convergence of the (sex-specific) FI age patterns for low and high FI groups by extreme ages might reflect the limit of the FI-specific (or systemic) age as well as the limit of adaptation capacity in aging individuals.

Authors
Kulminski, A; Yashin, A; Ukraintseva, S; Akushevich, I; Arbeev, K; Land, K; Manton, K
MLA Citation
Kulminski, A, Yashin, A, Ukraintseva, S, Akushevich, I, Arbeev, K, Land, K, and Manton, K. "Accumulation of health disorders as a systemic measure of aging: Findings from the NLTCS data." Mechanisms of ageing and development 127.11 (November 2006): 840-848.
PMID
16978683
Source
epmc
Published In
Mechanisms of Ageing and Development
Volume
127
Issue
11
Publish Date
2006
Start Page
840
End Page
848
DOI
10.1016/j.mad.2006.08.005

Population models for the health effects of ionizing radiation.

In this paper we review recently-developed extension frailty, quadratic hazard, stochastic process, microsimulation, and linear latent structure models, which have the potential to describe the health effects of human populations exposed to ionizing radiation. We discuss the most common situations for which such models are appropriate. We also provide examples of how to estimate the parameters of these models from datasets of various designs. Carcinogenesis models are reviewed in context of application to epidemiologic data of population exposed to ionizing radiation. We also discuss the ways of how to generalize stochastic process and correlated frailty models for longitudinal and family analyses in radiation epidemiology.

Authors
Akushevich, I; Manton, KG; Kulminski, A; Kovtun, M; Kravchenko, J; Yashin, A
MLA Citation
Akushevich, I, Manton, KG, Kulminski, A, Kovtun, M, Kravchenko, J, and Yashin, A. "Population models for the health effects of ionizing radiation." Radiatsionnaia biologiia, radioecologiia 46.6 (November 2006): 663-674. (Review)
PMID
17323694
Source
epmc
Published In
Radiatsionnaya Biologiya Radioekologiya
Volume
46
Issue
6
Publish Date
2006
Start Page
663
End Page
674

Decrease in the lgl tumor suppressor dose in Drosophila increases survival and longevity in stress conditions.

Recent studies suggest that downregulation of tumor suppressor genes might not only favor cancer development but also postpone organisms' aging and increase longevity. However, there is lack of population-based studies directly supporting this idea. We studied the lgl lethal alleles which are widespread in natural Drosophila populations. We demonstrate, for the first time, that animals heterozygous on the loss-of-function lgl tumor suppressor gene display a clear pre-adult viability advantage under stressful conditions (high 29 degrees C and low 16 degrees C temperatures). We found also the survival and longevity advantage effect of the lgl loss-of-function in the temperature stress conditions. The main features of this longevity influence are following. First, the lgl-dependent life span increase is sex-dependent; in all experimental combinations males are more sensitive than females of relevant genotypes. Second, the effect is stronger under the life-shortening temperature stress, 29 degrees C, where the hormesis was demonstrated. Third, the favoring effect of reduced dosage of tumor suppressor displays clearly in old but not young animals, delaying aging. Forth, the maternal or epigenetic inheritance of thermotolerance from mother to offspring appears to strengthen the observed longevity effects. One possible explanation of this stress-adaptive effect of reduced tumor suppressor dose might be a better resistance of Drosophila post-mitotic cells to a stress-associated apoptosis at old ages.

Authors
Golubovsky, MD; Weisman, NY; Arbeev, KG; Ukraintseva, SV; Yashin, AI
MLA Citation
Golubovsky, MD, Weisman, NY, Arbeev, KG, Ukraintseva, SV, and Yashin, AI. "Decrease in the lgl tumor suppressor dose in Drosophila increases survival and longevity in stress conditions." Experimental gerontology 41.9 (September 2006): 819-827.
PMID
16905287
Source
epmc
Published In
Experimental Gerontology
Volume
41
Issue
9
Publish Date
2006
Start Page
819
End Page
827
DOI
10.1016/j.exger.2006.06.035

Inadequate intensity of various components of total environmental signals can lead to natural aging.

We suppose that natural aging derives from an inevitable shift in certain parameters of physiological control systems under the influence of inadequate environmental conditions, which are not able to fully induce an organism's "optimal" existence in the self-maintenance mode. In this case the rate of aging is proportional to the multidimensional difference between the cues from evolutionarily designed adequate habitat and signals from the real environment. The negative correlation between parameters of Gompertzian mortality (and some other published findings) is compatible with this view. Here we discuss examples from intracellular to organism level in order to show that adequate patterns of outer signals can reverse some aging manifestations.

Authors
Khalyavkin, AV; Yashin, AI
MLA Citation
Khalyavkin, AV, and Yashin, AI. "Inadequate intensity of various components of total environmental signals can lead to natural aging." Ann N Y Acad Sci 1067 (May 2006): 45-46. (Review)
PMID
16803969
Source
pubmed
Published In
Annals of the New York Academy of Sciences
Volume
1067
Publish Date
2006
Start Page
45
End Page
46
DOI
10.1196/annals.1354.007

Visualizing hidden heterogeneity in isogenic populations of C. elegans.

Age-specific mortality levels off at advanced ages in many species; one explanation for this phenomenon is provided by the population heterogeneity theory. Although mortality at advanced ages can be well fit by heterogeneity models, population heterogeneity remains theoretical, lacking much direct evidence to support the existence of unobserved heterogeneity. Here, we provide direct evidence to support the heterogeneity theory by using isogenic population of worms of Caenorhabditis elegans. We measure the ability of individual worms to respond to a heat stress using an HSP-16.2 promoter that has been attached to GFP, a fluorescent marker that can be assessed in living animals. Worms differ substantially in their response; worms with high response have a long lifespan, and worms with low response to stress have a short life. Each of these classes results from a mix of two distinct, heterogeneous classes of worms and the addition of more classes does not result in a better fit.

Authors
Wu, D; Rea, SL; Yashin, AI; Johnson, TE
MLA Citation
Wu, D, Rea, SL, Yashin, AI, and Johnson, TE. "Visualizing hidden heterogeneity in isogenic populations of C. elegans." Experimental gerontology 41.3 (March 2006): 261-270.
PMID
16480844
Source
epmc
Published In
Experimental Gerontology
Volume
41
Issue
3
Publish Date
2006
Start Page
261
End Page
270
DOI
10.1016/j.exger.2006.01.003

Increasing rates of dementia at time of declining mortality from stroke

Background and Purpose - Stroke is associated with increased risk of dementia. There has been a decline in mortality from stroke among persons 65 and over in recent decades in the US. It is not clear, however, how this process has affected incidence of various dementias. Methods - We evaluated over time changes in stroke admission rates and survival, and in rates of newly diagnosed dementias (Alzheimer disease, senile, and cerebrovascular disease-related dementia) in persons with and without stroke aged 65 and over, using Medicare inpatient records, 1984 to 2001, linked to the National Long-Term Care Survey (about 380 000 person-years totally). Results - Age-adjusted stroke rate increased from 0.0066 to 0.008 (P=0.08) from 1984-1990 to 1991-2001. One-year survival after stroke improved from 53% in 1984 to 1990 to 65% in 1991 to 1996 (P<0.0001). Age-standardized rate of diagnosed dementias increased from 0.0062 in 1984 to 1990 to 0.0095 in 1991 to 2000 (P=0.001). Among stroke patients the rate rose from 0.043 to 0.080. The relative increase in risk was largest for cerebrovascular disease-related dementia (3.68). For senile dementia, the increase was small and not significant. Rates of dementia among persons without stroke rose mainly attributable to Alzheimer disease. Conclusions - Mortality from stroke declined mainly because of declining stroke case-fatality. In parallel, the rate of diagnosed dementia increased. The increase was larger for persons with stroke compared with stroke-free population. Improved survival from stroke may contribute to this trend. Other contributing factors may include better diagnostics, an increased propensity to make the diagnosis, and increasing dementia risk attributable to factors other than stroke. © 2006 American Heart Association, Inc.

Authors
Ukraintseva, S; Sloan, F; Arbeev, K; Yashin, A
MLA Citation
Ukraintseva, S, Sloan, F, Arbeev, K, and Yashin, A. "Increasing rates of dementia at time of declining mortality from stroke." Stroke 37.5 (2006): 1155-1159.
PMID
16601210
Source
scival
Published In
Stroke
Volume
37
Issue
5
Publish Date
2006
Start Page
1155
End Page
1159
DOI
10.1161/01.STR.0000217971.88034.e9

Two proofs of a recent formula by Griffith Feeney

This reflexion provides two mathematical proofs for Equation (1) in Feeney (2006), published in this journal as 14-2. © 2006 Max-Planck-Gesellschaft.

Authors
Gampe, J; Yashin, A
MLA Citation
Gampe, J, and Yashin, A. "Two proofs of a recent formula by Griffith Feeney." Demographic Research 14 (2006): 47-50.
Source
scival
Published In
Demographic research
Volume
14
Publish Date
2006
Start Page
47
End Page
50
DOI
10.4054/DemRes.2006.14.3

Difference between male and female cancer incidence rates: How can it be explained

Authors
Arbeev, KG; Ukraintseva, SV; Arbeeva, LS; Yashin, AI
MLA Citation
Arbeev, KG, Ukraintseva, SV, Arbeeva, LS, and Yashin, AI. "Difference between male and female cancer incidence rates: How can it be explained." 2006.
Source
wos-lite
Published In
PROBABILITY, STATISTICS AND MODELLING IN PUBLIC HEALTH
Publish Date
2006
Start Page
12
End Page
+
DOI
10.1007/0-387-26023-4_2

Central and peripheral effects of insulin/IGF-1 signaling in aging and cancer: antidiabetic drugs as geroprotectors and anticarcinogens.

Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors both in aging and in the development of cancer. Insulin/insulin-like growth factor 1 (IGF-1) signaling molecules linked to longevity include DAF-2 and insulin receptor (InR) and their homologues in mammals and to inactivation of the corresponding genes followed by increased life span in nematodes, fruit flies, and mice. It is possible that the life-prolonging effect of caloric restriction are due to decreasing IGF-1 levels. A search of pharmacological modulators of life span-extending mutations in the insulin/IGF-1 signaling pathway and mimetics of effects of caloric restriction could be a direction in the regulation of longevity. Some literature and our own observations suggest that antidiabetic drugs could be promising candidates for both life span extension and prevention of cancer.

Authors
Anisimov, VN; Berstein, LM; Popovich, IG; Zabezhinski, MA; Egormin, PA; Tyndyk, ML; Anikin, IV; Semenchenko, AV; Yashin, AI
MLA Citation
Anisimov, VN, Berstein, LM, Popovich, IG, Zabezhinski, MA, Egormin, PA, Tyndyk, ML, Anikin, IV, Semenchenko, AV, and Yashin, AI. "Central and peripheral effects of insulin/IGF-1 signaling in aging and cancer: antidiabetic drugs as geroprotectors and anticarcinogens." Ann N Y Acad Sci 1057 (December 2005): 220-234.
PMID
16399897
Source
pubmed
Published In
Annals of the New York Academy of Sciences
Volume
1057
Publish Date
2005
Start Page
220
End Page
234
DOI
10.1196/annals.1356.017

A comparison of different bivariate correlated frailty models and estimation strategies.

Frailty models are becoming increasingly popular in multivariate survival analysis. Shared frailty models in particular are often used despite their limitations. To overcome their disadvantages numerous correlated frailty models were established during the last decade. In the present study, we examine bivariate correlated frailty models, and especially the behavior of the parameter estimates when using different estimation strategies. We consider three different bivariate frailty models: the gamma model and two versions of the log-normal model. The traditional maximum likelihood procedure of parameter estimation in the gamma case with an explicit available likelihood function is compared with maximum likelihood methods based on numerical integration and a Bayesian approach using MCMC methods with the help of a comprehensive simulation study. We detected a strong dependence between the two parameter estimates (variance and correlation of frailties) in the bivariate correlated frailty model and analyzed this dependence in detail.

Authors
Wienke, A; Arbeev, KG; Locatelli, I; Yashin, AI
MLA Citation
Wienke, A, Arbeev, KG, Locatelli, I, and Yashin, AI. "A comparison of different bivariate correlated frailty models and estimation strategies." Mathematical biosciences 198.1 (November 2005): 1-13.
PMID
16185720
Source
epmc
Published In
Mathematical Biosciences
Volume
198
Issue
1
Publish Date
2005
Start Page
1
End Page
13
DOI
10.1016/j.mbs.2004.11.010

Cancer in rodents: does it tell us about cancer in humans?

Information obtained from animal models (mostly mice and rats) has contributed substantially to the development of treatments for human cancers. However, important interspecies differences have to be taken into account when considering the mechanisms of cancer development and extrapolating the results from mice to humans. Comparative studies of cancer in humans and animal models mostly focus on genetic factors. This review discusses the bio-epidemiological aspects of cancer manifestation in humans and rodents that have been underrepresented in the literature.

Authors
Anisimov, VN; Ukraintseva, SV; Yashin, AI
MLA Citation
Anisimov, VN, Ukraintseva, SV, and Yashin, AI. "Cancer in rodents: does it tell us about cancer in humans?." Nat Rev Cancer 5.10 (October 2005): 807-819. (Review)
PMID
16195752
Source
pubmed
Published In
Nature Reviews Cancer
Volume
5
Issue
10
Publish Date
2005
Start Page
807
End Page
819
DOI
10.1038/nrc1715

Individual fecundity and senescence in Drosophila and medfly.

Evolutionary theory postulates that there should be a robust relationship between fecundity and longevity. Prior work has generally supported this concept, but has not shed much light on the mechanisms at play. In preceding work, we have developed and verified a mathematical model of Drosophila melanogaster female fecundity based on the analysis of empirical studies independently done by several different laboratories. Then we applied this technique to Mediterranean fruit fly (medfly) populations. In this article we analyze associations between individual longevity and the parameters of individual fecundity pattern in Drosophila and medfly. We cluster both Drosophila and medfly individuals by life span and discuss the differences. It allows us to demonstrate that only one fecundity-related parameter is associated with longevity in Drosophila, whereas two such parameters can be found in medflies. This difference demonstrates different ways of aging in various Diptera species. Finally, we discuss the possible implications of this finding.

Authors
Novoseltsev, VN; Arking, R; Carey, JR; Novoseltseva, JA; Yashin, AI
MLA Citation
Novoseltsev, VN, Arking, R, Carey, JR, Novoseltseva, JA, and Yashin, AI. "Individual fecundity and senescence in Drosophila and medfly." J Gerontol A Biol Sci Med Sci 60.8 (August 2005): 953-962.
PMID
16127096
Source
pubmed
Published In
Journals of Gerontology: Series A
Volume
60
Issue
8
Publish Date
2005
Start Page
953
End Page
962

Decline in human cancer incidence rates at old ages: Age-period-cohort considerations

Analysis of age-specific trajectories of cancer incidence rates for all sites combined (data source: International Agency for Research on Cancer) reveals a leveling-off and decline of the rates at old ages in different countries and time periods. We apply a nonlinear age-period-cohort model (James and Segal 1982) to obtain declining cancer incidence rates at old ages. The age effects are represented by a power function of age in accordance with a multistage model of carcinogenesis (Armitage and Doll 1954). Applications to cancer incidence in England and Wales, Japan (Miyagi prefecture) and the USA (New York State and San Francisco) illustrate the approach. Further topics of research are discussed. © 2005 Max-Planck-Gesellschaft.

Authors
Arbeev, KG; Ukraintseva, SV; Arbeeva, LS; Yashin, AI
MLA Citation
Arbeev, KG, Ukraintseva, SV, Arbeeva, LS, and Yashin, AI. "Decline in human cancer incidence rates at old ages: Age-period-cohort considerations." Demographic Research 12 (May 13, 2005): 273-300.
Source
scopus
Published In
Demographic research
Volume
12
Publish Date
2005
Start Page
273
End Page
300

Mathematical models for human cancer incidence rates

The overall cancer incidence rate declines at old ages. Possible causes of this decline include the effects of cross-sectional data that transform cohort dynamics into age patterns, population heterogeneity that selects individuals susceptible to cancer, a decline in some carcinogenic exposures in older individuals, underdiagnostics, and the effects of individual aging that slow down major physiological processes in an organism. We discuss several mathematical models contributing to the explanation of this phenomenon. We extend the Strehler and Mildvan model of aging and mortality and apply it to the analysis of data on cancer incidence at old ages (data source: International Agency for Research on Cancer). The model explains the observed time trends and age patterns of cancer incidence rates. © 2005 Max-Planck-Gesellschaft.

Authors
Arbeev, KG; Ukraintseva, SV; Arbeeva, LS; Yashin, AI
MLA Citation
Arbeev, KG, Ukraintseva, SV, Arbeeva, LS, and Yashin, AI. "Mathematical models for human cancer incidence rates." Demographic Research 12 (May 7, 2005): 237-272.
Source
scopus
Published In
Demographic research
Volume
12
Publish Date
2005
Start Page
237
End Page
272

Insulin in aging and cancer: antidiabetic drug Diabenol as geroprotector and anticarcinogen.

The effects of new antidiabetic drug Diabenol (9-beta-diethylaminoethyl-2,3-dihydroimidazo-(1,2-alpha)benzimidazol dihydrochloride) on life span and spontaneous tumor incidence in NMRI and transgenic HER-2/neu mice as well as on colon carcinogenesis induced by 1,2-dimethylhydrazine in rats are studied. It is shown that treatment with the drug failed influence body weight gain dynamics, food and water consumption and the body temperature, slowed down age-related disturbances in estrous function and increased life span of all and 10% most long-living NMRI mice. The treatment with Diabenol inhibited spontaneous tumor incidence and increased the mammary tumor latency in these mice. Diabenol treatment slowed down age-related changes in estrous function in HER-2/neu mice, failed influence survival of these mice and slightly inhibited the incidence and decreased the size of mammary adenocarcinoma metastases into the lung. In rats exposed to 1,2-dimethylhydrazine, treatment with Diabenol significantly inhibited multiplicity of all colon tumors, decreased by 2.2 times the incidence of carcinomas in ascending colon and by 3.1 times their multiplicity. Treatment with Diabenol was followed by higher incidence of exophytic and well-differentiated colon tumors as compared with the control rats exposed to the carcinogen alone (76.3% and 50%, and 47.4% and 14.7%, respectively). Thus, the drug increases survival and inhibits spontaneous carcinogenesis in mice and inhibits colon carcinogenesis in rats.

Authors
Popovich, IG; Zabezhinski, MA; Egormin, PA; Tyndyk, ML; Anikin, IV; Spasov, AA; Semenchenko, AV; Yashin, AI; Anisimov, VN
MLA Citation
Popovich, IG, Zabezhinski, MA, Egormin, PA, Tyndyk, ML, Anikin, IV, Spasov, AA, Semenchenko, AV, Yashin, AI, and Anisimov, VN. "Insulin in aging and cancer: antidiabetic drug Diabenol as geroprotector and anticarcinogen." Int J Biochem Cell Biol 37.5 (May 2005): 1117-1129.
PMID
15743682
Source
pubmed
Published In
The International Journal of Biochemistry & Cell Biology
Volume
37
Issue
5
Publish Date
2005
Start Page
1117
End Page
1129
DOI
10.1016/j.biocel.2004.08.002

What evidence is there for the existence of individual genes with antagonistic pleiotropic effects?

Classical evolutionary theory predicts the existence of genes with antagonistic effects on longevity and various components of early-life fitness. Quantitative genetic studies have provided convincing evidence that such genes exist. However, antagonistic pleiotropic effects have rarely been attributed to individual loci. We examine several classes of longevity-assurance genes: those involved in regulation of the gonad; the insulin-like growth factor pathway; free-radical scavenging; heat shock proteins and apoptosis. We find initial evidence that antagonistic pleiotropic effects are pervasive in each of these classes of genes and in various model systems--although most studies lack explicit studies of fitness components. This is particularly true of human studies. Very little is known about the early-life fitness effects of longevity loci. Given the possible medical importance of such effects we urge their future study.

Authors
Leroi, AM; Bartke, A; De Benedictis, G; Franceschi, C; Gartner, A; Gonos, ES; Fedei, ME; Kivisild, T; Lee, S; Kartaf-Ozer, N; Schumacher, M; Sikora, E; Slagboom, E; Tatar, M; Yashin, AI; Vijg, J; Zwaan, B
MLA Citation
Leroi, AM, Bartke, A, De Benedictis, G, Franceschi, C, Gartner, A, Gonos, ES, Fedei, ME, Kivisild, T, Lee, S, Kartaf-Ozer, N, Schumacher, M, Sikora, E, Slagboom, E, Tatar, M, Yashin, AI, Vijg, J, and Zwaan, B. "What evidence is there for the existence of individual genes with antagonistic pleiotropic effects?." Mech Ageing Dev 126.3 (March 2005): 421-429. (Review)
PMID
15664630
Source
pubmed
Published In
Mechanisms of Ageing and Development
Volume
126
Issue
3
Publish Date
2005
Start Page
421
End Page
429
DOI
10.1016/j.mad.2004.07.012

The heritability of CHD mortality in danish twins after controlling for smoking and BMI.

Cause-specific mortality data on Danish monozygotic and dizygotic twins are used to analyze heritability estimates of susceptibility to coronary heart disease (CHD) after controlling for smoking and Body Mass Index (BMI). The sample includes 1209 like-sexed twin pairs born between 1890 and 1920, where both individuals were still alive in 1966. The participants completed a questionnaire in 1966 which included questions on smoking, height and weight. The analysis was conducted with both sexes pooled due to the relatively small number of twin pairs. Follow-up was conducted from January 1, 1966 to December 31, 1993. The correlated gammafrailty model with observed covariates was used for the genetic analysis of frailty to account for censoring and truncation in the lifetime data. During the follow-up, 1437 deaths occurred, including 435 deaths due to CHD. Proportions of variance of frailty attributable to genetic and environmental factors were analyzed using the structural equation model approach. Different standard biometric models are fitted to the data to evaluate the magnitude and nature of genetic and environmental factors on mortality. Using the best-fitting model without covariates, heritability of frailty to CHD was found to be 0.45 (0.11). This result changes only slightly to 0.55 (0.13) in a DE model after controlling for smoking and BMI. This analysis underlines the existence of a substantial genetic influence on individual frailty associated with mortality caused by CHD.

Authors
Wienke, A; Herskind, AM; Christensen, K; Skytthe, A; Yashin, AI
MLA Citation
Wienke, A, Herskind, AM, Christensen, K, Skytthe, A, and Yashin, AI. "The heritability of CHD mortality in danish twins after controlling for smoking and BMI." Twin Res Hum Genet 8.1 (February 2005): 53-59.
PMID
15836811
Source
pubmed
Published In
Twin Research & Human Genetics
Volume
8
Issue
1
Publish Date
2005
Start Page
53
End Page
59
DOI
10.1375/1832427053435328

Genetic markers data in survival studies of twins: the results of a simulation study.

Previous longevity studies of related individuals such as twins or siblings based on the major gene model have shown that the frequency and the relative risk of mortality of a beneficial allele in the population could be estimated. If, in addition to survival data for related individuals, the genetic markers data are available, one could try to locate the longevity allele in the genome. In the case where the phenotypic trait is life span or age at onset of disease, a two-step procedure can be used. First, the parameters of bivariate survival functions must be estimated from bivariate survival data for twins without markers. The second step is focused on determining the position of longevity genes between respective markers. To calculate the joint distribution of inheritance vector and genetic markers, the hidden Markov chain technique is used. This approach is illustrated with a simulation example for one longevity gene.

Authors
Begun, AZ; Yashin, AI
MLA Citation
Begun, AZ, and Yashin, AI. "Genetic markers data in survival studies of twins: the results of a simulation study." Twin Res Hum Genet 8.1 (February 2005): 34-38.
PMID
15836808
Source
pubmed
Published In
Twin Research & Human Genetics
Volume
8
Issue
1
Publish Date
2005
Start Page
34
End Page
38
DOI
10.1375/1832427053435355

The heritability of CHD mortality in Danish twins after controlling for smoking and BMI

Authors
Wienke, A; Herskind, AM; Christensen, K; Skytthe, A; Yashin, AI
MLA Citation
Wienke, A, Herskind, AM, Christensen, K, Skytthe, A, and Yashin, AI. "The heritability of CHD mortality in Danish twins after controlling for smoking and BMI." TWIN RESEARCH AND HUMAN GENETICS 8.1 (February 2005): 53-59.
Source
wos-lite
Published In
Twin Research & Human Genetics
Volume
8
Issue
1
Publish Date
2005
Start Page
53
End Page
59
DOI
10.1375/twin.8.1.53

Genetic markers data in survival studies of twins: The results of a simulation study

Authors
Begun, AZ; Yashin, AI
MLA Citation
Begun, AZ, and Yashin, AI. "Genetic markers data in survival studies of twins: The results of a simulation study." TWIN RESEARCH AND HUMAN GENETICS 8.1 (February 2005): 34-38.
Source
wos-lite
Published In
Twin Research & Human Genetics
Volume
8
Issue
1
Publish Date
2005
Start Page
34
End Page
38

Treating cancer with embryonic stem cells: rationale comes from aging studies.

In an earlier poster paper (1) we proposed that cancer can be viewed not only as a fatal disease but also as a local aberrant, rejuvenation, in an organism, and this fact can be useful for developing new anti-aging and anti-cancer treatments. In this paper we provide additional evidence from human and experimental animal studies in support of this view. First, we discuss cancer genes as candidate targets for anti-aging interventions. We review examples in which the life of experimental animals has been prolonged in situations of increased activity of proto-oncogenes - or decreased activity of tumor suppressors - in normal (non-cancerous) cells in vivo. Studies of genetic polymorphisms revealed similar effects on longevity in humans. Second, we discuss the possibility of treating cancer with embryonic stem cells. The fact that cancer cells do not, age, means that these cells overcome aging host cells. However, cancer cells can be suppressed by young and quickly proliferating non-cancer cells, such as embryonic stem cells. The grafting of these cells in the tumor environment could be a prospective non-toxic anti-cancer treatment. We discuss recent evidence in support of this view.

Authors
Ukraintseva, SV; Yashin, AI
MLA Citation
Ukraintseva, SV, and Yashin, AI. "Treating cancer with embryonic stem cells: rationale comes from aging studies. (Published online)" Front Biosci 10 (January 1, 2005): 588-595. (Review)
PMID
15569600
Source
pubmed
Published In
Frontiers in bioscience : a journal and virtual library
Volume
10
Publish Date
2005
Start Page
588
End Page
595

Estimating haplotype relative risks on human survival in population-based association studies.

Association-based linkage disequilibrium (LD) mapping is an increasingly important tool for localizing genes that show potential influence on human aging and longevity. As haplotypes contain more LD information than single markers, a haplotype-based LD approach can have increased power in detecting associations as well as increased robustness in statistical testing. In this paper, we develop a new statistical model to estimate haplotype relative risks (HRRs) on human survival using unphased multilocus genotype data from unrelated individuals in cross-sectional studies. Based on the proportional hazard assumption, the model can estimate haplotype risk and frequency parameters, incorporate observed covariates, assess interactions between haplotypes and the covariates, and investigate the modes of gene function. By introducing population survival information available from population statistics, we are able to develop a procedure that carries out the parameter estimation using a nonparametric baseline hazard function and estimates sex-specific HRRs to infer gene-sex interaction. We also evaluate the haplotype effects on human survival while taking into account individual heterogeneity in the unobserved genetic and nongenetic factors or frailty by introducing the gamma-distributed frailty into the survival function. After model validation by computer simulation, we apply our method to an empirical data set to measure haplotype effects on human survival and to estimate haplotype frequencies at birth and over the observed ages. Results from both simulation and model application indicate that our survival analysis model is an efficient method for inferring haplotype effects on human survival in population-based association studies.

Authors
Tan, Q; Christiansen, L; Bathum, L; Zhao, JH; Yashin, AI; Vaupel, JW; Christensen, K; Kruse, TA
MLA Citation
Tan, Q, Christiansen, L, Bathum, L, Zhao, JH, Yashin, AI, Vaupel, JW, Christensen, K, and Kruse, TA. "Estimating haplotype relative risks on human survival in population-based association studies." Hum Hered 59.2 (2005): 88-97.
PMID
15838178
Source
pubmed
Published In
Human heredity
Volume
59
Issue
2
Publish Date
2005
Start Page
88
End Page
97
DOI
10.1159/000085223

Erratum: What evidence is there for the existence of individual genes with antagonistic pleiotropic effects? (Mechanisms of Ageing and Development (2005) 126 (421-429) PII: S0047637404001897 and DOI: 10.1016/j.mad.2004.07.012)

Authors
Leroi, AM; Bartke, A; Benedictis, GD; Franceschi, C; Gartner, A; Gonos, ES; Fedei, ME; Kivisild, T; Lee, S; Kartaf-Ozer, N; Schumacher, M; Sikora, E; Slagboom, E; Tatar, M; Yashin, AI; Vijg, J; Zwaan, B
MLA Citation
Leroi, AM, Bartke, A, Benedictis, GD, Franceschi, C, Gartner, A, Gonos, ES, Fedei, ME, Kivisild, T, Lee, S, Kartaf-Ozer, N, Schumacher, M, Sikora, E, Slagboom, E, Tatar, M, Yashin, AI, Vijg, J, and Zwaan, B. "Erratum: What evidence is there for the existence of individual genes with antagonistic pleiotropic effects? (Mechanisms of Ageing and Development (2005) 126 (421-429) PII: S0047637404001897 and DOI: 10.1016/j.mad.2004.07.012)." Mechanisms of Ageing and Development 126.8 (2005): 906--.
Source
scival
Published In
Mechanisms of Ageing and Development
Volume
126
Issue
8
Publish Date
2005
Start Page
906-
DOI
10.1016/j.mad.2005.03.001

Effect of epitalon and melatonin on life span and spontaneous carcinogenesis in Senescence Accelerated Mice (SAM)

Female senescence accelerated mice SAMP-1 (prone) and SAMR-1 (resistant) were exposed 5 times a week monthly to melatonin (with drinking water 20mg/ml during the night hours) or to s.c. injections of epitalon (Ala-Glu-Asp-Gly) at a single dose 1mkg/mouse. Control mice were intact or exposed to injection of 0.1 ml normal saline. The body weight and temperature, food consumption, estrous function were monitored regularly. The life span and tumor incidence were evaluated as well. As age advanced, the weight increased whereas food consumption and body temperature did not change. There was no significant substrain difference in these parameters. Exposure to melatonin or epitalon also failed to influence those indices. As age advanced, the incidence of irregular estrous cycles increased both in SAMP-1 and SAMR-1, whereas the treatment with both melatonin and epitalon prevented such disturbances. SAMP-1 revealed some features of accelerated aging as compared to SAMR-1. The mean life span of the 10% of the last survivors among treated SAMP-1 was shorter than that of SAMR-1, aging rate increased and mortality doubling time decreased. There was a direct correlation between body mass of the two substrains at the age of 3 and 12 months matched by body mass increase and longer life span. Melatonin or epitalon treatment was followed by longer mean and maximum survival in the 10% of the last survivors among SAMP-1. Melatonin involved decreased aging rate and increased mortality doubling time. Malignant lymphomas predominated in SAM without any significant difference in frequency between the substrains. While melatonin failed to influence tumor incidence or term of detection in SAMP-1, neither did epitalon affect frequency. However, it was followed by longer survival in tumor-free animals. No link between melatonin or epitalon treatment, on the one hand, and carcinogenesis, on the other, was reported in SAMR-1.

Authors
Anisimov, VN; Popovich, IG; Zabezhinsky, MA; Rosenfeld, SV; Khavinson, VK; Semenchenko, AV; Yashin, AI
MLA Citation
Anisimov, VN, Popovich, IG, Zabezhinsky, MA, Rosenfeld, SV, Khavinson, VK, Semenchenko, AV, and Yashin, AI. "Effect of epitalon and melatonin on life span and spontaneous carcinogenesis in Senescence Accelerated Mice (SAM)." Voprosy Onkologii 51.1 (2005): 93-98.
PMID
15909815
Source
scival
Published In
Voprosy onkologii
Volume
51
Issue
1
Publish Date
2005
Start Page
93
End Page
98

THE EFFECT OF THE ORGANISMS' BODY SIZE AND ENERGY RESERVES IN MODELS FOR POPULATION DYNAMICS

Authors
KULMINSKI, A; MANTON, K; AKUSHEVICH, I; YASHIN, A
MLA Citation
KULMINSKI, A, MANTON, K, AKUSHEVICH, I, and YASHIN, A. "THE EFFECT OF THE ORGANISMS' BODY SIZE AND ENERGY RESERVES IN MODELS FOR POPULATION DYNAMICS." Journal of Biological Systems 12.04 (December 2004): 419-437.
Source
crossref
Published In
Journal of Biological Systems
Volume
12
Issue
04
Publish Date
2004
Start Page
419
End Page
437
DOI
10.1142/S0218339004001336

Genetic influences on CHD-death and the impact of known risk factors: comparison of two frailty models.

The importance of some recognized risk factors on genetic influences for coronary heart disease (CHD) needs further clarification. The aim of the present study was therefore to study the impact of known risk factors on genetic influences for CHD-death. Both twin (correlated gamma-frailty) and non-twin models (univariate gamma-frailty) were utilized and compared regarding their suitability for genetic analyses. The study population consisted of twins born in Sweden between 1886 and 1925. As expected, our findings indicate that genetic influences are important for CHD-death. Inclusion of risk factors in the twin-model increased heritability estimates, primarily due to a substantial reduction in non-shared environmental variances. The genetic influences for CHD-death are only marginally mediated through the risk factors among males, but more so among females. Although the outcome phenotype used in the present study is not behavioral, the analyses demonstrate the potential of frailty models for quantitative genetic analyses of categorical phenotypes.

Authors
Zdravkovic, S; Wienke, A; Pedersen, NL; Marenberg, ME; Yashin, AI; de Faire, U
MLA Citation
Zdravkovic, S, Wienke, A, Pedersen, NL, Marenberg, ME, Yashin, AI, and de Faire, U. "Genetic influences on CHD-death and the impact of known risk factors: comparison of two frailty models." Behav Genet 34.6 (November 2004): 585-592.
PMID
15520515
Source
pubmed
Published In
Behavior Genetics
Volume
34
Issue
6
Publish Date
2004
Start Page
585
End Page
592
DOI
10.1007/s10519-004-5586-1

Stressors and antistressors: how do they influence life span in HER-2/neu transgenic mice?

The purpose of this study is to investigate possible influences of different stressors (saline injections, light deprivation and constant light regimen) and geroprotectors (Epitalon and melatonin) on survivals of female HER-2/neu transgenic mice. We propose a semi-parametric model of heterogeneous mortality (frailty model) for the analysis of the experimental data. In this model, we assume that treatment influences parameters of both frailty distribution and baseline hazard. The unique design of the experiments makes it possible to compare the effects on survival produced by different treatments in terms of changes in population heterogeneity and underlying hazard. Parameters of the model help to describe the possible influences of various stressors, geroprotectors, and their dosage on the life span of laboratory animals. The proposed model helps to advance our understanding of the effects--such as debilitation, longevity hormesis and incomplete hormesis--which occur in the population as a result of different treatments.

Authors
Semenchenko, GV; Anisimov, VN; Yashin, AI
MLA Citation
Semenchenko, GV, Anisimov, VN, and Yashin, AI. "Stressors and antistressors: how do they influence life span in HER-2/neu transgenic mice?." Exp Gerontol 39.10 (October 2004): 1499-1511.
PMID
15501020
Source
pubmed
Published In
Experimental Gerontology
Volume
39
Issue
10
Publish Date
2004
Start Page
1499
End Page
1511
DOI
10.1016/j.exger.2004.08.007

Effect of exposure to light-at-night on life span and spontaneous carcinogenesis in female CBA mice.

The effect of constant illumination on the development of spontaneous tumors in female CBA mice was investigated. Fifty female CBA mice starting from the age of 2 months were kept under standard light/dark regimen (12 hr light:12 hr dark; LD) and 50 CBA mice of similar age were kept under constant illumination (24 hr a day, 2,500 Lux, LL). Exposure to the LL regimen decreased food consumption but did not influence body weight, significantly accelerated age-related disturbances in estrous function, and was followed by a significant increase in spontaneous tumor incidence in female CBA mice. Tumor incidence as well as the number of total or malignant tumors was significantly increased in the LL group compared to the LD group (p < 0.001). The incidence of lung adenocarcinomas, leukemias and hepatocarcinomas was 7/50; 6/50 and 4/50 in the LL group and 1/50; 0/50 and 0/50 in the LD group. Mice from the LL groups had shorter life spans then those from the LD group. The data demonstrate, for the first time, that exposure to constant illumination was followed by increases in the incidence of spontaneous lung carcinoma, leukemias and hepatocarcinoma in female CBA mice.

Authors
Anisimov, VN; Baturin, DA; Popovich, IG; Zabezhinski, MA; Manton, KG; Semenchenko, AV; Yashin, AI
MLA Citation
Anisimov, VN, Baturin, DA, Popovich, IG, Zabezhinski, MA, Manton, KG, Semenchenko, AV, and Yashin, AI. "Effect of exposure to light-at-night on life span and spontaneous carcinogenesis in female CBA mice." Int J Cancer 111.4 (September 10, 2004): 475-479.
PMID
15239122
Source
pubmed
Published In
International Journal of Cancer
Volume
111
Issue
4
Publish Date
2004
Start Page
475
End Page
479
DOI
10.1002/ijc.20298

Effect of exposure to light-at-night on life span and spontaneous carcinogenesis in female CBA mice

Authors
Anisimov, VN; Baturin, DA; Popovich, IG; Zabezhinski, MA; Manton, KG; Semenchenko, AV; Yashin, AI
MLA Citation
Anisimov, VN, Baturin, DA, Popovich, IG, Zabezhinski, MA, Manton, KG, Semenchenko, AV, and Yashin, AI. "Effect of exposure to light-at-night on life span and spontaneous carcinogenesis in female CBA mice." INTERNATIONAL JOURNAL OF CANCER 111.4 (September 10, 2004): 475-479.
Source
wos-lite
Published In
International Journal of Cancer
Volume
111
Issue
4
Publish Date
2004
Start Page
475
End Page
479
DOI
10.1002/jc.20298

[A model of resource reallocation during physiological adaptation in Mediterranean fruit fly females].

Analysis of experimental data on longevity and fertility of females of Mediterranean fruit fly Ceratitis capitata demonstrates that flies lay fewer eggs on the average as the average life-span increases. At the same time, the values of individual life-span and the number of eggs laid are positively correlated. To explain these results, a resource model describing the allocation and reallocation of resources between two basic functions, reproduction and maintenance, was proposed. The reallocation of resources, is triggered by changes in environmental conditions such as diet changes, and the parameters of reallocation depend on the current environmental conditions. Modeling demonstrated that the results of experiments are greatly influenced by population selection and heterogeneity.

Authors
Romaniukha, AA; Carey, JR; Karkach, AS; Yashin, AI
MLA Citation
Romaniukha, AA, Carey, JR, Karkach, AS, and Yashin, AI. "[A model of resource reallocation during physiological adaptation in Mediterranean fruit fly females]." Biofizika 49.5 (September 2004): 897-903.
PMID
15526477
Source
pubmed
Published In
Biofizika
Volume
49
Issue
5
Publish Date
2004
Start Page
897
End Page
903

The impact of diet switching on resource allocation to reproduction and longevity in Mediterranean fruitflies.

Understanding the factors that determine the allocation and utilization of organism resources may provide an insight into the mechanisms of adaptation, ageing and reproduction. Resource allocation, which is regarded as a method of adaptation, increases fitness and is genetically controlled. Experiments with variable diet feeding of female Mediterranean fruitflies (Ceratitis capitata) demonstrated that the feeding regime dramatically influences lifespan, mortality and the reproduction of flies. An analysis of experimental data and numerical experiments reveals that resource allocation could explain lifespan increase when females are switched from a sugar-only to a protein-containing diet. The heterogeneity of the initial female cohort in terms of the total amount of resources and its allocation to the processes of maintenance and reproduction plays a significant role in this.

Authors
Romanyukha, AA; Carey, JR; Karkach, AS; Yashin, AI
MLA Citation
Romanyukha, AA, Carey, JR, Karkach, AS, and Yashin, AI. "The impact of diet switching on resource allocation to reproduction and longevity in Mediterranean fruitflies." Proc Biol Sci 271.1545 (June 22, 2004): 1319-1324.
PMID
15306357
Source
pubmed
Published In
Proceedings of the Royal Society of London: Biological Sciences
Volume
271
Issue
1545
Publish Date
2004
Start Page
1319
End Page
1324
DOI
10.1098/rspb.2004.2719

The impact of diet switching reproduction and longevity in on resource allocation to Mediterranean fruitflies

Authors
Romanyukha, AA; Carey, JR; Karkach, AS; Yashin, AI
MLA Citation
Romanyukha, AA, Carey, JR, Karkach, AS, and Yashin, AI. "The impact of diet switching reproduction and longevity in on resource allocation to Mediterranean fruitflies." PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES 271.1545 (June 22, 2004): 1319-1324.
Source
wos-lite
Published In
Proceedings of the Royal Society of London: Biological Sciences
Volume
271
Issue
1545
Publish Date
2004
Start Page
1319
End Page
1324
DOI
10.1016/rspb.2004.2719

How an individual fecundity pattern looks in Drosophila and medflies.

Reproduction usually is characterized by a mean-population fecundity pattern. Such a pattern has a maximum at earlier ages and a subsequent gradual decline in egg production. It is shown that individual fecundity trajectories do not follow such a pattern. In particular, the regular individual fecundity pattern has no maximum so that experimentally observed maximums are average-related artifacts. The three-stage description of individual fecundity, which includes maturation, maturity, and reproductive senescence, is more appropriate. Data are presented for Drosophila and Mediterranean fruitfly females that clearly confirm this hypothesis. A systematic error between egg-laying scores and the regular individual pattern allows for evaluation of how close the random scores are to the pattern. The first finding of the analysis of the systematic errors is that they are consistent with the three-stage hypothesis and do not contradict the absence of the maximum in the regular individual pattern. The other finding is the existence of obvious dynamic properties of the systematic error. The slow decrease in egg-laying at the maturity stage might be the result of a cost of mating. It can also be a consequence of "structural" senescence, that is, a slow rate accumulation of oxidative damage in the gonads.

Authors
Novoseltsev, VN; Arking, R; Carey, JR; Novoseltseva, JA; Yashin, AI
MLA Citation
Novoseltsev, VN, Arking, R, Carey, JR, Novoseltseva, JA, and Yashin, AI. "How an individual fecundity pattern looks in Drosophila and medflies." Ann N Y Acad Sci 1019 (June 2004): 577-580.
PMID
15247090
Source
pubmed
Published In
Annals of the New York Academy of Sciences
Volume
1019
Publish Date
2004
Start Page
577
End Page
580
DOI
10.1196/annals.1297.108

Antiaging treatments have been legally prescribed for approximately thirty years.

There is an interesting divergence between the achievements of geriatrics and gerontology. On the one hand, during the last 30 years physicians in many developed countries have successfully prescribed several medicines to cure various symptoms of senescence. On the other hand, the influence of such medicines on human life span practically has not been studied. The most common of the relevant medicines are nootropic piracetam, gamma-aminobutyric acid (GABA), selegiline, Ginkgo biloba, pentoxifylline, cerebrolysin, solcoseryl, ergoloid, vinpocetin, sertraline, and estrogens, among others. Available data from human clinical practices and experimental animal studies indicate that treatments with these drugs improve learning, memory, brain metabolism, and capacity. Some of these drugs increase tolerance to various stresses such as oxygen deficit and exercise, stimulate the regeneration of neurons in the old brain, and speed up the performance of mental and physical tasks. This means that modern medicine already has "antiaging" treatments at its disposal. However, the influence of such treatments on the mean and maximal life span of humans, and on the age trajectory of a human survival curve has been poorly studied. The increase in human life expectancy at birth in the second half of the last century was mostly caused by the better survival at the old and oldest old rather than at the young ages. In parallel, the consumption of brain protective and regenerative drugs has been expanding in the elderly population. We provide evidence in support of the idea that the consumption of medicines exerting antiaging properties may contribute to the increase in human longevity.

Authors
Ukraintseva, SV; Arbeev, KG; Michalsky, AI; Yashin, AI
MLA Citation
Ukraintseva, SV, Arbeev, KG, Michalsky, AI, and Yashin, AI. "Antiaging treatments have been legally prescribed for approximately thirty years." Annals of the New York Academy of Sciences 1019 (June 2004): 64-69. (Review)
PMID
15246996
Source
epmc
Published In
Annals of the New York Academy of Sciences
Volume
1019
Publish Date
2004
Start Page
64
End Page
69
DOI
10.1196/annals.1297.014

Is early life body weight a predictor of longevity and tumor risk in rats?

Heavy body weight (BW) is thought to be associated with reduced longevity and age-associated diseases, including cancer, both in laboratory rodents and humans. To further investigate the interactions between BW, longevity and spontaneous tumor development, we measured the correlations between BW in early life, BW in middle life, and parameters of life span and tumorigenesis in male and female outbred rats. The data show that BW at the ages of both 3 and 12 months are significant predictors of longevity in rats. Heavier female rats tend to live longer than the lighter female rats, while in male those who were light at 3 months but heavy at 12 month had the best longevity. BW at the age 3 months was not predictive of tumor growth but being heavier at the age of 1 year did confer an increased risk of tumor development for both male and female rats.

Authors
Anisimov, VN; Arbeev, KG; Popovich, IG; Zabezhinksi, MA; Arbeeva, LS; Yashin, AI
MLA Citation
Anisimov, VN, Arbeev, KG, Popovich, IG, Zabezhinksi, MA, Arbeeva, LS, and Yashin, AI. "Is early life body weight a predictor of longevity and tumor risk in rats?." Experimental gerontology 39.5 (May 2004): 807-816.
PMID
15130675
Source
epmc
Published In
Experimental Gerontology
Volume
39
Issue
5
Publish Date
2004
Start Page
807
End Page
816
DOI
10.1016/j.exger.2004.02.004

The heritability of breast cancer: a Bayesian correlated frailty model applied to Swedish twins data.

The aim of this study was to investigate the role of genes and environment in susceptibility to breast cancer and to give an estimate of heritability in the propensity to develop the disease. To do this we applied an interdisciplinary approach, merging models developed in the field of demography and survival analysis - so-called frailty models - and models coming from quantitative genetics and epidemiology, namely genetic models. In our study, the inferential problem was solved in a Bayesian framework and the numerical work was carried out using MCMC methods. We used the special information coming from twin data, particularly breast cancer data, from the Swedish Twin Register. The application of a correlated log-normal frailty model leads to a very large estimate of the population heterogeneity (sigma = 6.7), and relatively small correlations between co-twins' frailties - around 0.3 for monozygotic and 0.1 for dizygotic twins. Comparing three different genetic models (an ACE, an AE and an ADE model), we furthermore concluded that genetic effects would explain globally almost 30% of the total variability of propensity to breast cancer. Environmental effects would be predominant in determining breast cancer susceptibility and these effects would be primarily individual-specific, that is, non-shared effects. Finally, a model which includes dominance genetic effects (ADE model) is preferred for genetic and statistical reasons.

Authors
Locatelli, I; Lichtenstein, P; Yashin, AI
MLA Citation
Locatelli, I, Lichtenstein, P, and Yashin, AI. "The heritability of breast cancer: a Bayesian correlated frailty model applied to Swedish twins data." Twin Res 7.2 (April 2004): 182-191.
PMID
15169603
Source
pubmed
Published In
Twin research : the official journal of the International Society for Twin Studies
Volume
7
Issue
2
Publish Date
2004
Start Page
182
End Page
191
DOI
10.1375/136905204323016168

Body weight is not always a good predictor of longevity in mice.

There have been some observations that low body weight and a low level of some hormones (e.g. IGF-1) during the first half of life are predictors of longer life in mice. However, contradictions in the available data on the biomarkers of aging and predictors of longevity have shown that the research in these fields has become a controversial pursuit. In our study we addressed the following questions: (i) Can particular physiological parameters (body weight, food intake, estrus function, body temperature, incidence of chromosome aberrations in bone marrow cells) measured at the age of 3 and 12 months be a predictor of longevity and the rate of tumor development in five strains of mice? (ii) Can a heavy body weight at the age of 3 and 12 months be a predictor of longevity and high tumor risk in five strains of mice? Mice of five strains-CBA, SHR, SAMR, SAMP and transgenic HER-2/neu (FVB/N)-were under observation from the age of 2-3 months until natural death. Body weight and temperature, food consumption, and estrous cycle were longitudinally studied in all animals. Tumors discovered at autopsy were studied morphologically. We calculated the life span's parameters (mean, maximum, mortality rate, mortality rate doubling time) as well as their correlation with other parameters studied. The longest living CBA mice have the lowest body weight at the ages of 3 and 12 months, the lowest food consumption, body temperature, incidence of chromosome aberrations and spontaneous tumor incidence. In comparison with all other mouse strains they also have the latest disturbances in estrus function and highest body weight gain. The shortest living transgenic HER-2/neu mice have the lowest weight at the ages of 12 months, the lowest body weight gain, maximal body temperature, the most rapid disturbances in estrus function and the highest incidence of chromosome aberrations and tumor incidence in comparison to all other mouse strains. Our findings have shown that heavier body weight at the age of 12 months is a predictor of longevity in female CBA and SAMP mice but not in SHR, SAMR and HER-2/neu mice. Excessive body weight at the ages of 3 or 12 months is not a predictor of increased tumor risk in the strains studied. In general, the existence and direction of a significant correlation between body weight and life span depends upon the animals' age and genotype.

Authors
Anisimov, VN; Arbeev, KG; Popovich, IG; Zabezhinksi, MA; Rosenfeld, SV; Piskunova, TS; Arbeeva, LS; Semenchenko, AV; Yashin, AI
MLA Citation
Anisimov, VN, Arbeev, KG, Popovich, IG, Zabezhinksi, MA, Rosenfeld, SV, Piskunova, TS, Arbeeva, LS, Semenchenko, AV, and Yashin, AI. "Body weight is not always a good predictor of longevity in mice." Experimental gerontology 39.3 (March 2004): 305-319.
PMID
15036390
Source
epmc
Published In
Experimental Gerontology
Volume
39
Issue
3
Publish Date
2004
Start Page
305
End Page
319
DOI
10.1016/j.exger.2003.12.007

Disability trends in gender and race groups of early retirement ages in the USA.

OBJECTIVES: To analyse disability trends over the 1980s-1990s in gender and race groups of early retirement ages in USA. METHODS: Disability trends for white and black males and females aged 65-69 and 70+ are analysed using the 1982-1999 NLTCS. Disability is analysed at three levels (instrumental activities of daily living (IADL), activities of daily living (ADL), and institutionalisation). RESULTS: 1) A larger increase in proportions of non-disabled blacks aged 65-69 compared with whites and males compared with females. 2) Differences in disability trends among gender and race groups. 3) A faster absolute decline in non-institutionalised disabled aged 65-69. 4) A larger absolute decline and a smaller relative decline in proportions of disabled aged 70+ compared with 65-69. 5) A significant decrease in the proportion of ADL disabled blacks and an increase of ADL disabled white females in the age group 70+. CONCLUSIONS: Americans aged 65-69 years manifest a significant improvement in health over the 1980s-1990s but the dynamics differs in gender and race groups. Possible reasons for these differences are discussed.

Authors
Arbeev, KG; Butov, AA; Manton, KG; Sannikov, IA; Yashin, AI
MLA Citation
Arbeev, KG, Butov, AA, Manton, KG, Sannikov, IA, and Yashin, AI. "Disability trends in gender and race groups of early retirement ages in the USA." Sozial- und Praventivmedizin 49.2 (January 2004): 142-151.
PMID
15150866
Source
epmc
Published In
Sozial- und Praventivmedizin
Volume
49
Issue
2
Publish Date
2004
Start Page
142
End Page
151
DOI
10.1007/s00038-004-3041-y

Systemic mechanisms of individual reproductive life history in female Medflies.

This paper is the second one in a series of two papers hypothesizing and testing systemic grounds of reproductive life history in the female fruit fly. In the first paper, we analyzed mechanisms of individual fecundity scheduling and have drawn the following conclusions. Individual fecundity in female flies is endowed as a flat pattern with a steady-state period of a constant rate of egg-laying. An individual female reveals three stages in her adult life history: maturation, maturity, and senescence. The first stage is a transient period of achieving a steady state at maturity, which can be maintained until the senescence stage. Thus, an individual fecundity pattern has no maximum. The maximums observed experimentally are averaging-caused artifacts. Two natural causes of deaths exist in flies, senescence-caused ones and premature deaths, probably due to a reproductive overload. In this paper, to confirm these findings, we use individual daily scores of egg-laying in four populations of Mediterranean fruit flies. Based on fecundity scores, we divide each Medfly population into four classes, namely zero-egg, short-, medium- and long-lived egg-layers. We demonstrate that, indeed, the three above findings definitely exist in Medflies. Our procedure allows the efficient storage of individual fecundity in parametric form, with only five numbers for each fly. Finally, this protocol will allow a more precise analysis of fecundity-energy trade-offs in flies carrying appropriate longevity mutations.

Authors
Novoseltsev, VN; Carey, RJ; Novoseltseva, JA; Papadopoulos, NT; Blay, S; Yashin, AI
MLA Citation
Novoseltsev, VN, Carey, RJ, Novoseltseva, JA, Papadopoulos, NT, Blay, S, and Yashin, AI. "Systemic mechanisms of individual reproductive life history in female Medflies." Mech Ageing Dev 125.1 (January 2004): 77-87.
PMID
14706240
Source
pubmed
Published In
Mechanisms of Ageing and Development
Volume
125
Issue
1
Publish Date
2004
Start Page
77
End Page
87

Multidisciplinary approaches in genetic studies of human aging and longevity

The amount of research on human aging and longevity has been growing rapidly in recent years. Multidisciplinary approaches, which integrate classic population genetics methods with the principles of epidemiological and demographic investigation, are emerging as powerful tools for disentangling the complex gene network which modulates human lifespan. We try to summarize the different approaches and discuss the various aspects concerning their applications in studies of human aging and longevity. We also discuss the significance of the newly emerging DNA chip technology and its implications by highlighting new research topics. In fact, with the entering of the post-genomic era, hints given by observational studies, and thus founded on statistical evidence, can be exploited to cast light upon biological pathways crucial in aging and longevity. © 2004 Bentham Science Publishers Ltd.

Authors
Tan, Q; Yashin, AI; Christensen, K; Jeune, B; Benedictis, GD; Kruse, TA; Vaupel, JW
MLA Citation
Tan, Q, Yashin, AI, Christensen, K, Jeune, B, Benedictis, GD, Kruse, TA, and Vaupel, JW. "Multidisciplinary approaches in genetic studies of human aging and longevity." Current Genomics 5.5 (2004): 409-416.
Source
scival
Published In
Current Genomics
Volume
5
Issue
5
Publish Date
2004
Start Page
409
End Page
416
DOI
10.2174/1389202043349101

Assessing genetic association with human survival at multi-allelic loci.

Genetic variation plays an important role in natural selection and population evolution. However, it also presents geneticists interested in aging research with problems in data analysis because of the large number of alleles and their various modes of action. Recently, a new statistical method based on survival analysis (the relative risk model or the RR model) has been introduced to assess gene-longevity associations [Yashin et al. (1999) Am J Hum Genet 65: 1178-1193] which outperforms the traditional gene frequency method. Here we extend the model to deal with polymorphic genes or gene markers. Assuming the Hardy-Weinberg equilibrium at birth, we first introduce an allele-based parameterization on gene frequency which helps to cut down the number of frequency parameters to be estimated. We then propose both the genotype and allele-based parameterizations on risk parameters to estimate genotype and allelic relative risks (the GRR and ARR models). While the GRR model allows us to investigate whether the alleles are recessive, dominant or codominant, the ARR model further minimizes the number of parameters to be estimated. As an example, we apply the methods to empirical data on Renin gene polymorphism and longevity. We show that our models can serve as useful tools in searching for important genetic variations implicated in human aging and longevity.

Authors
Tan, Q; De Benedictis, G; Yashin, AI; Bathum, L; Christiansen, L; Dahlgaard, J; Frizner, N; Vach, W; Vaupel, JW; Christensen, K; Kruse, TA
MLA Citation
Tan, Q, De Benedictis, G, Yashin, AI, Bathum, L, Christiansen, L, Dahlgaard, J, Frizner, N, Vach, W, Vaupel, JW, Christensen, K, and Kruse, TA. "Assessing genetic association with human survival at multi-allelic loci." Biogerontology 5.2 (2004): 89-97.
PMID
15105583
Source
pubmed
Published In
Biogerontology
Volume
5
Issue
2
Publish Date
2004
Start Page
89
End Page
97
DOI
10.1023/B:BGEN.0000025072.30441.1c

Effect of light deprivation on homeostasis, life span and development of spontaneous tumors in her-2/neu transgenic mice

Twenty five female HER-2/neu transgenic mice (FVB/N), aged 2 months, were surgically deprived of lighting; 30 intact transgenic mice, kept under standard conditions, were in control. Light deprivation was followed by inhibited intake of feed, decreased body mass and delayed age-associated estral disorders, as compared with control. Mean survival rate among experimental mice was higher by 13.5% than in control (p(0.001). Mean life span among the last surviving 10% of the experimental mice was longer than in control by 21.5 % while maximum life span - by 21%. Although the number of tumor bearers under 7 months in the study group was twice that in control (p<0.05). they had almost equalized by the end of the experiment. The number of multiple malignancies and the size of tumor and metastases to the lung increased too.

Authors
Baturin, DA; Alimova, IN; Popovich, IG; Zabezhinsky, MA; Semenchenko, AV; Yashin, AI; Anisimov, VN
MLA Citation
Baturin, DA, Alimova, IN, Popovich, IG, Zabezhinsky, MA, Semenchenko, AV, Yashin, AI, and Anisimov, VN. "Effect of light deprivation on homeostasis, life span and development of spontaneous tumors in her-2/neu transgenic mice." Voprosy Onkologii 50.3 (2004): 332-338.
PMID
15318708
Source
scival
Published In
Voprosy Onkologii
Volume
50
Issue
3
Publish Date
2004
Start Page
332
End Page
338

Serotonin transporter gene polymorphism and factors influencing mental and physical health in aging

Genetic predisposition is thought to exert a certain influence on the indices related to longevity and quality of life. Many of the indices, namely cognitive functioning, stress resistance, metabolism control, may be related to serotonin activity. To study polymorphic serotonin transporter gene variants and their association with features relevant for survival and longevity prognosis, a sample of elderly Russians from Moscow community recruited in the project "Stress-related mechanisms in Russia", comprising 196 subjects, mean age 76, 2±5, 3 years, 155 men, 41 women, has been genotyped. Allele and genotype frequencies have been estimated in 3 groups, aged 60-69, 70-79 and 80-87 years, respectively. A trend (χ2=4, 1; p=0, 12) to the prevalence of individuals with SS genotype (21, 8%), as compared to expected level (14, 6%), was found in the group of octogenarians (n=55, mean age 82, 8±1, 9 years). An association analysis between genotype and physiological traits revealed a genotype contribution to past smoking on tendency level (p=0, 069), waist to hip ratio (WHR) (p=0, 012) and plasma insulin concentration (p=0, 02), with a higher frequency of SS genotype among non-smokers and subjects with lower WHR and insulin concentration. Genotype effect on the traits was stronger, being considered in interaction with the age above 80 years. Genotype was not associated with cognitive functioning (MMSE), but proved to be a significant predictor of MMSE performance (p=0, 03) in octogenarians. The results obtained are in line with current concepts of serotonin role in smoking, obesity and cognitive functioning.

Authors
Golimbet, VE; Ukraintseva, SV; Yashin, AI; Korovaitseva, GI; Shalnova, SA; Deev, AD; Shkolnikova, MA
MLA Citation
Golimbet, VE, Ukraintseva, SV, Yashin, AI, Korovaitseva, GI, Shalnova, SA, Deev, AD, and Shkolnikova, MA. "Serotonin transporter gene polymorphism and factors influencing mental and physical health in aging." Zhurnal Nevrologii i Psihiatrii imeni S.S. Korsakova 104.5 (2004): 46-49.
PMID
15272632
Source
scival
Published In
Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova / Ministerstvo zdravookhraneniia i meditsinskoi promyshlennosti Rossiiskoi Federatsii, Vserossiiskoe obshchestvo nevrologov [i] Vserossiiskoe obshchestvo psikhiatrov
Volume
104
Issue
5
Publish Date
2004
Start Page
46
End Page
49

Model of resource reallocation during physiological adaptation of females of the Mediterranean fruit fly Ceratitis capitata

The results of studying the life span and fertility of females of the Mediterranean fruit fly Ceratitis capitata suggest that an increase in the mean life span is accompanied by a proportional decrease in the mean number of eggs laid. At the same time, the data on the individual life span and number of eggs laid are indicative of a positive correlation between these indices. To explain these and other relationships exhibited during adaptation, a mathematical model is proposed. The model describes resource reallocation between the two main functions of the organism: reproduction and self-maintenance. A signal for reallocation is a change in the environmental conditions (diet), and the parameters of the new allocation are determined by the state of the individual. The calculations reveal a significant role of selection and intrapopulation heterogeneity in the the balance between fertility and life span. Copyright © 2004 by MAIK "Nauka/Interperiodica".

Authors
Romanyukha, AA; Carey, JR; Karkach, AS; Yashin, AI
MLA Citation
Romanyukha, AA, Carey, JR, Karkach, AS, and Yashin, AI. "Model of resource reallocation during physiological adaptation of females of the Mediterranean fruit fly Ceratitis capitata." Biophysics 49.5 (2004): 822-827.
Source
scival
Published In
Biophysics
Volume
49
Issue
5
Publish Date
2004
Start Page
822
End Page
827

Immune system aging may be affected by HIV infection: The mathematical model of immunosenescence

In this paper, we analyse the structure of equations in the earlier proposed mathematical model of the dynamics of age-related changes in population of peripheral T lymphocytes. To investigate behaviour of the model solutions in a wide range of values of variables we introduce a linear relation between the rate constants of T lymphocytes proliferation and the values of the mean length of telomeric chromosome fragments spent by naive and memory cells in the course of immune response, as well as the dependence of these parameters on the value of the cell replicative potential. We obtain sufficient conditions for existence, uniqueness, and positiveness of solutions over the whole time interval. The results of numerical calculations illustrate the capabilities of the model for describing accelerated aging mechanisms of the immune system using the example of HIV infection.

Authors
Sannikova, TE; Rudnev, SG; Romanyukha, AA; Yashin, AI
MLA Citation
Sannikova, TE, Rudnev, SG, Romanyukha, AA, and Yashin, AI. "Immune system aging may be affected by HIV infection: The mathematical model of immunosenescence." Russian Journal of Numerical Analysis and Mathematical Modelling 19.4 (2004): 315-329.
Source
scival
Published In
Russian Journal of Numerical Analysis and Mathematical Modelling
Volume
19
Issue
4
Publish Date
2004
Start Page
315
End Page
329
DOI
10.1163/1569398041974897

Cancer as "rejuvenescence"

Comparative analysis of malignant and senescent cells shows that their phenotypic features are in many instances contrary. Cancer cells do not "age"; their metabolic and growth characteristics are opposite to those observed with cellular aging (both replicative and functional). In many such characteristics, cancer cells resemble embryonic cells. One can say that cancer manifests itself as a local uncontrolled "rejuvenation" in an organism. Available evidence from human and animal studies suggests that the opposite phenotypic features of aging and cancer arise from the opposite regulation of common genes, such as those participating in apoptosis/growth arrest or in growth signal transduction pathways in the cell. For instance, in aging cells and organisms, proto-oncogenes are often downregulated, while tumor suppressors are permanently expressed. In cancer cells the situation is just the opposite: the proto-oncogenes are commonly overexpressed, while tumor suppressors are downregulated. This fact may have various applications for the development of new antiaging and anticancer treatments. First, genes that are oppositely regulated in cancer and aging could be candidate targets for antiaging interventions. Their "cancerlike" regulation, if strictly controlled, might help to rejuvenate the aging organism. Recent evidence from human and animal studies in support of this view is discussed. Second, the fact that cancer cells do not "age" implies that these cells may have a survival advantage in the surrounding of senescent cells. This could be a partial reason for an increase in the risk of cancer with age, because the proportion of senescent cells increases in an organism with age, too. In such a situation, the rejuvenation of normal cells surrounding the tumor might be a perspective anticancer treatment. For instance, a controlled activation of oncogenes in normal host cells or the grafting of young proliferating cells (such as embryonic stem cells) in the area near a malignant tumor might help to supplant cancer cells rather than to MH them.

Authors
Ukraintseva, SV; Yashin, AI
MLA Citation
Ukraintseva, SV, and Yashin, AI. "Cancer as "rejuvenescence"." Annals of the New York Academy of Sciences 1019 (2004): 200-205.
PMID
15247014
Source
scival
Published In
Annals of the New York Academy of Sciences
Volume
1019
Publish Date
2004
Start Page
200
End Page
205
DOI
10.1196/annals.1297.032

Stress resistance declines with age: analysis of data from a survival experiment with Drosophila melanogaster.

An approach towards analyzing survivorship data is proposed for the study of changes in stress resistance with age in the population of Drosophila melanogaster. This is based on the model of heterogeneous mortality (frailty model). Results of the data analysis show that observed populations of flies are heterogeneous and the accelerated selection, debilitative effect and changes in individual frailties are the aftermath of stress. These results also reveal that debilitative effect and accelerated selection are much better pronounced in survivals of flies that are stressed at an older age. Mild stress, when applied at both ages, produced a reduction in frailty variance. Stress of greater magnitude produced higher frailty variance in the young-treated flies. Among the old-treated insects, stress of longer duration led to a reduction of both the mean and the variance of frailty distribution. Population of young-treated flies became more heterogeneous, population of old-treated flies became less heterogeneous, and both populations became more robust in average after stress.

Authors
Semenchenko, GV; Khazaeli, AA; Curtsinger, JW; Yashin, AI
MLA Citation
Semenchenko, GV, Khazaeli, AA, Curtsinger, JW, and Yashin, AI. "Stress resistance declines with age: analysis of data from a survival experiment with Drosophila melanogaster." Biogerontology 5.1 (2004): 17-30.
PMID
15138378
Source
pubmed
Published In
Biogerontology
Volume
5
Issue
1
Publish Date
2004
Start Page
17
End Page
30

The heritability of cause-specific mortality: a correlated gamma-frailty model applied to mortality due to respiratory diseases in Danish twins born 1870-1930.

The genetic influence on susceptibility to diseases of the respiratory system and all-cause mortality was studied using data for identical (MZ) and fraternal (DZ) twins. Data from the Danish Twin Register include 1344 MZ and 2411 DZ male twin pairs and 1470 MZ and 2730 DZ female twin pairs born between 1870 and 1930, where both individuals were alive on 1 011943. We used the correlated gamma-frailty model. Proportions of variance in frailty attributable to genetic and environmental factors were assessed using the structural equation model approach. For all-cause mortality the correlation coefficients of frailty for MZ twins tend to be higher than for DZ twins. For mortality with respect to respiratory diseases this effect was only seen in females, whereas males showed the opposite effect. Five standard biometric models are fitted to the data to evaluate the magnitude and nature of genetic and environmental factors on mortality. Using the best fitting biometric model heritability for cause of death was found to be 0.58 (0.07) for all-cause mortality (AE-model) and zero for diseases of the respiratory system for males. Heritability was 0.63 (0.11) for all-cause mortality (DE-model) and 0.18 (0.09) for diseases of the respiratory system (DE-model) for females. The analysis confirms the presence of a strong genetic influence on individual frailty associated with all-cause mortality. For respiratory diseases, no genetic influence was found in males and only weak genetic influence in females. The nature of genetic influences on frailty with respect to all-cause mortality is probably additive in males and dominant in females, whereas for frailty with respect to deaths caused by respiratory diseases in females, there are genetic factors present which are caused by dominance. Environmental influences are non-shared with exception of frailty with respect to respiratory diseases in males, where the shared environment plays an important role.

Authors
Wienke, A; Holm, NV; Christensen, K; Skytthe, A; Vaupel, JW; Yashin, AI
MLA Citation
Wienke, A, Holm, NV, Christensen, K, Skytthe, A, Vaupel, JW, and Yashin, AI. "The heritability of cause-specific mortality: a correlated gamma-frailty model applied to mortality due to respiratory diseases in Danish twins born 1870-1930." Stat Med 22.24 (December 30, 2003): 3873-3887.
PMID
14673944
Source
pubmed
Published In
Statistics in Medicine
Volume
22
Issue
24
Publish Date
2003
Start Page
3873
End Page
3887
DOI
10.1002/sim.1669

A bivariate frailty model with a cure fraction for modeling familial correlations in diseases.

We suggest a cure-mixture model to analyze bivariate time-to-event data, as motivated by the article of Chatterjee and Shih (2001, Biometrics 57, 779-786), but with a simpler estimation procedure and the correlated gamma-frailty model instead of the shared gamma-frailty model. This approach allows us to deal with left-truncated and right-censored lifetime data, and accounts for heterogeneity, as well as for an insusceptible (cure) fraction in the study population. We perform a simulation study to evaluate the properties of the estimates in the proposed model and apply it to breast cancer incidence data for 5857 Swedish female monozygotic and dizygotic twin pairs from the so-called old cohort of the Swedish Twin Registry. This model is used to estimate the size of the susceptible fraction and the correlation between the frailties of the twin partners. Possible extensions, advantages, and limitations of the proposed method are discussed.

Authors
Wienke, A; Lichtenstein, P; Yashin, AI
MLA Citation
Wienke, A, Lichtenstein, P, and Yashin, AI. "A bivariate frailty model with a cure fraction for modeling familial correlations in diseases." Biometrics 59.4 (December 2003): 1178-1183.
PMID
14969499
Source
pubmed
Published In
Biometrics
Volume
59
Issue
4
Publish Date
2003
Start Page
1178
End Page
1183

Effect of neuronol on lifespan and development of spontaneous tumors in SAMP-1 mice with genetically accelerated aging.

Treatment of female SAMP-1 mice with Neuronol (drug containing succinic acid) given with drinking water starting from the age of 2 months during the whole life prolonged the lifespan and markedly reduced mortality of animals aged 1.5-2 years. Neuronol inhibited the development of spontaneous tumors, primarily lymphomas, and significantly prolonged lifespan in mice with tumors. Long-term treatment with Neuronol had no pathological side effects. Our experiments demonstrated geroprotective and anticarcinogenic activity of Neuronol and safety of its long-term use.

Authors
Popovich, IG; Zabezhinskii, MA; Anisimov, VN; Kovalenko, AL; Petrov, AY; Semenchenko, AV; Yashin, AI
MLA Citation
Popovich, IG, Zabezhinskii, MA, Anisimov, VN, Kovalenko, AL, Petrov, AY, Semenchenko, AV, and Yashin, AI. "Effect of neuronol on lifespan and development of spontaneous tumors in SAMP-1 mice with genetically accelerated aging." Bull Exp Biol Med 136.6 (December 2003): 595-598.
PMID
15500082
Source
pubmed
Published In
Bulletin of Experimental Biology and Medicine
Volume
136
Issue
6
Publish Date
2003
Start Page
595
End Page
598

Opposite phenotypes of cancer and aging arise from alternative regulation of common signaling pathways.

Phenotypic features of malignant and senescent cells are in many instances opposite. Cancer cells do not "age"; their metabolic, proliferative, and growth characteristics are opposite to those observed with cellular aging (both replicative and functional). In many such characteristics cancer cells resemble embryonic cells. One can say that cancer manifests itself as a local, uncontrolled "rejuvenation" in an organism. Available evidence from human and animal studies suggests that the opposite phenotypic features of aging and cancer arise from the opposite regulation of genes participating in apoptosis/growth arrest or growth signal transduction pathways in cells. This fact may be applicable in the development of new anti-aging treatments. Genes that are contrarily regulated in cancer and aging cells (e.g., proto-oncogenes or tumor suppressors) could be candidate targets for anti-aging interventions. Their "cancer-like" regulation, if strictly controlled, might help to rejuvenate the human organism.

Authors
Ukraintseva, SV; Yashin, AI
MLA Citation
Ukraintseva, SV, and Yashin, AI. "Opposite phenotypes of cancer and aging arise from alternative regulation of common signaling pathways." Ann N Y Acad Sci 1010 (December 2003): 489-492. (Review)
PMID
15033776
Source
pubmed
Published In
Annals of the New York Academy of Sciences
Volume
1010
Publish Date
2003
Start Page
489
End Page
492

Variability of the SIRT3 gene, human silent information regulator Sir2 homologue, and survivorship in the elderly.

The human sirtuin 3 (SIRT3) gene encodes a putative mitochondrial NAD-dependent deacetylase (SIRT3) which belongs to the evolutionary conserved family of sirtuin 2 proteins. Studies in model organisms have demonstrated that SIR2 genes control lifespan, while no data are available regarding a possible role of SIRT3 in human longevity. By analysing the genotype-specific survival function relevant to the G477T marker of SIRT3, we found that in males the TT genotype increases (p=0.0272), while the GT genotype decreases (p=0.0391) survival in the elderly. Since SIRT3 lies in a chromosomal region (11p15.5) where four genes potentially associated with longevity are located (HRAS1, Insulin-like Growth Factor 2, Proinsulin, and Tyrosine Hydroxylase) we tested for linkage-disequilibrium between G477T alleles and alleles of the above genes. The disequilibrium was not significant in any case, thus suggesting that SIRT3 itself, or a gene strictly linked to SIRT3, may have a role in human longevity.

Authors
Rose, G; Dato, S; Altomare, K; Bellizzi, D; Garasto, S; Greco, V; Passarino, G; Feraco, E; Mari, V; Barbi, C; BonaFe, M; Franceschi, C; Tan, Q; Boiko, S; Yashin, AI; De Benedictis, G
MLA Citation
Rose, G, Dato, S, Altomare, K, Bellizzi, D, Garasto, S, Greco, V, Passarino, G, Feraco, E, Mari, V, Barbi, C, BonaFe, M, Franceschi, C, Tan, Q, Boiko, S, Yashin, AI, and De Benedictis, G. "Variability of the SIRT3 gene, human silent information regulator Sir2 homologue, and survivorship in the elderly." Exp Gerontol 38.10 (October 2003): 1065-1070.
PMID
14580859
Source
pubmed
Published In
Experimental Gerontology
Volume
38
Issue
10
Publish Date
2003
Start Page
1065
End Page
1070

Effect of delta-sleep inducing peptide-containing preparation Deltaran on biomarkers of aging, life span and spontaneous tumor incidence in female SHR mice.

From the age of 3 months until their natural deaths, female Swiss-derived SHR mice were subcutaneously injected 5 consecutive days every month with 0.1 ml of normal saline (control) or with 2.5 microg/mouse (approximately 100 microg/kg) of delta-sleep inducing peptide (DSIP, Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu) as the preparation Deltaran solved in 0.1 ml of saline. There were 54 mice in each group. The results of this study show that the treatment with Deltaran did not influence food consumption, but decreased the body weight of mice; it slowed down the age-related switching-off of estrous function; it decreased by 22.6% the frequency of chromosome aberrations in bone marrow cells; it did not influence mean life span; and it increased by 17.1% life span of the last 10% of the survivors and by 24.1% maximum life span in comparison with the control group. We also found that treatment with Deltaran significantly decreased total spontaneous tumor incidence (by 2.6-fold), mainly mammary carcinomas and leukemias in mice as compared with the control group. This is the first report on geroprotector and anticarcinogenic effect of DSIP-containing preparation Deltaran.

Authors
Popovich, IG; Voitenkov, BO; Anisimov, VN; Ivanov, VT; Mikhaleva, II; Zabezhinski, MA; Alimova, IN; Baturin, DA; Zavarzina, NY; Rosenfeld, SV; Semenchenko, AV; Yashin, AI
MLA Citation
Popovich, IG, Voitenkov, BO, Anisimov, VN, Ivanov, VT, Mikhaleva, II, Zabezhinski, MA, Alimova, IN, Baturin, DA, Zavarzina, NY, Rosenfeld, SV, Semenchenko, AV, and Yashin, AI. "Effect of delta-sleep inducing peptide-containing preparation Deltaran on biomarkers of aging, life span and spontaneous tumor incidence in female SHR mice." Mech Ageing Dev 124.6 (June 2003): 721-731.
PMID
12782416
Source
pubmed
Published In
Mechanisms of Ageing and Development
Volume
124
Issue
6
Publish Date
2003
Start Page
721
End Page
731

What fecundity patterns indicate about aging and longevity: insights from Drosophila studies.

The age pattern of fecundity is represented as a result of a superposition of two processes: the genetic fecundity program encoded in the organism's reproductive machinery and senescence of the reproductive system. Accumulation of oxidative damage produces the energy decline, which could potentially be used in reproduction. As a result, the age-declining process arises in the reproductive machinery at a critical age. We show that this mechanism is common for different species. It establishes a connection between the decline of organism vitality and reproductive senescence. We suggest a parametric description of a fecundity pattern that allows for prediction of reproductive longevity. We apply the approach to Drosophila studies to analyze the relation between fecundity and survival. We show that fecundity patterns may predict a mean life span in Drosophila under specified environmental conditions.

Authors
Novoseltsev, VN; Novoseltseva, JA; Boyko, SI; Yashin, AI
MLA Citation
Novoseltsev, VN, Novoseltseva, JA, Boyko, SI, and Yashin, AI. "What fecundity patterns indicate about aging and longevity: insights from Drosophila studies." J Gerontol A Biol Sci Med Sci 58.6 (June 2003): 484-494.
PMID
12807919
Source
pubmed
Published In
Journals of Gerontology: Series A
Volume
58
Issue
6
Publish Date
2003
Start Page
484
End Page
494

What does a fly's individual fecundity pattern look like? The dynamics of resource allocation in reproduction and ageing.

Reproduction is usually characterised by an average fecundity pattern having a maximum at earlier ages and a subsequent gradual decline later on. An individual fecundity trajectory does not follow such a pattern and has no maximum. A three-stage pattern, which includes maturation, maturity and reproductive senescence, is a more appropriate description. An analysis of the power balance of an adult female fly during its life course allows us to predict two critical periods in an individual life history. The first crisis occurs at early ages when the increasing power demand becomes greater than the power supply. It often results in premature death. The surviving flies enjoy maturity and lay eggs at a presumably constant rate. The second critical period at advanced ages ends up in a senescence-caused death. Our approach predicts that there will be a bimodal death time distribution for a population of flies.

Authors
Novoseltsev, VN; Novoseltseva, JA; Yashin, AI
MLA Citation
Novoseltsev, VN, Novoseltseva, JA, and Yashin, AI. "What does a fly's individual fecundity pattern look like? The dynamics of resource allocation in reproduction and ageing." Mech Ageing Dev 124.5 (May 2003): 605-617.
PMID
12735901
Source
pubmed
Published In
Mechanisms of Ageing and Development
Volume
124
Issue
5
Publish Date
2003
Start Page
605
End Page
617

Number of pregnancies and ovariectomy modify mammary carcinoma development in transgenic HER-2/neu female mice.

We studied effect of pregnancy and ovariectomy on the development of mammary tumors in homozygous female HER-2/neutransgenic mice. The mean life span of uniparous mice was decreased by 16% in comparison to the control (P<0.05) and of mice which have two pregnancies decreased by 11% (P<0.05). Ovariectomy at the age of 2 months was followed by 32.7% increase in mean life span of mice. The incidence or multiplicity of mammary adenocarcinomas did not change in uniparous mice, whereas the size of the tumors and metastatic potential were decreased as compared to the virgins. When mice have two full-time pregnancies, there was an increase in multiplicity of mammary carcinomas and significant (2.1-fold) decrease in the survival time of tumor-bearing mice. Ovariectomy significantly decreased the total incidence of mammary carcinomas, the number of tumors per tumor-bearing animal, and inhibited metastasizing into lungs. Our results indicate that pregnancy accelerated the development of mammary adenocarcinomas in transgenic HER-2/neu mice whereas ovariectomy inhibits their development.

Authors
Anisimov, VN; Popovich, IG; Alimova, IN; Zabezhinski, MA; Semenchenko, AV; Yashin, AI
MLA Citation
Anisimov, VN, Popovich, IG, Alimova, IN, Zabezhinski, MA, Semenchenko, AV, and Yashin, AI. "Number of pregnancies and ovariectomy modify mammary carcinoma development in transgenic HER-2/neu female mice." Cancer Lett 193.1 (April 10, 2003): 49-55.
PMID
12691823
Source
pubmed
Published In
Cancer Letters
Volume
193
Issue
1
Publish Date
2003
Start Page
49
End Page
55

Age related changes in population of peripheral T cells: towards a model of immunosenescence.

In this paper, we presented the results of analysis of experimental evidence for the decline of the human immune system functioning with age using mathematical model of immunosenescence. The most prominent changes in this system are related to the decline in the T-cellular immunity. These include the decline in the nai;ve T cells generation rate, shrinkage of the volume of the peripheral lymphoid tissue, decline of absolute and relative concentrations of nai;ve T cells in the blood, shortening of the average telomere length of T cells. These alterations in the immune system are responsible for sharp increase of morbidity and mortality caused by infectious agents at old ages. Analysis shows that concentrations of memory and nai;ve T cells in peripheral lymphoid tissue are the key variables in this process. Simulation experiments with our model show that the average life span of memory T cells must grow with age, and that decreasing of antigenic load led to considerable increase in organism's resistance in middle ages, but only to slight increase in old ages. Restriction in the rate of thymus involution resulted in an increase of organism's resistance to infections in old ages. However, this growth is accompanied by the decline of concentration of memory T cells and shortening of their life span. The proposed model describes the trade-off between concentrations of nai;ve and memory T cells and their potential to proliferate in human organism.

Authors
Romanyukha, AA; Yashin, AI
MLA Citation
Romanyukha, AA, and Yashin, AI. "Age related changes in population of peripheral T cells: towards a model of immunosenescence." Mech Ageing Dev 124.4 (April 2003): 433-443.
PMID
12714250
Source
pubmed
Published In
Mechanisms of Ageing and Development
Volume
124
Issue
4
Publish Date
2003
Start Page
433
End Page
443

Dose-dependent effect of melatonin on life span and spontaneous tumor incidence in female SHR mice.

From the age of 3 months until their natural death, female Swiss-derived SHR mice were given melatonin with their drinking water (2 or 20mg/l) for 5 consecutive days every month. Intact mice served as controls. There were 54 mice in each group. The results of this study show that the treatment of melatonin did not significantly influence food consumption, but its administration at lower doses did decrease the body weight of mice; it slowed down the age-related switching-off of estrous function; it did not influence the frequency of chromosome aberrations in bone marrow cells; it did not influence mean life span; and it increased life span of the last 10% of the survivors in comparison to controls. We also found that treatment with low dose melatonin (2mg/l) significantly decreased spontaneous tumor incidence (by 1,9-fold), mainly mammary carcinomas, in mice whereas higher doses (20mg/l) failed to influence tumor incidence as compared to controls. For this reason, we conclude that the effect of melatonin as a geroprotector is dose-dependent.

Authors
Anisimov, VN; Alimova, IN; Baturin, DA; Popovich, IG; Zabezhinski, MA; Rosenfeld, SV; Manton, KG; Semenchenko, AV; Yashin, AI
MLA Citation
Anisimov, VN, Alimova, IN, Baturin, DA, Popovich, IG, Zabezhinski, MA, Rosenfeld, SV, Manton, KG, Semenchenko, AV, and Yashin, AI. "Dose-dependent effect of melatonin on life span and spontaneous tumor incidence in female SHR mice." Exp Gerontol 38.4 (April 2003): 449-461.
PMID
12670632
Source
pubmed
Published In
Experimental Gerontology
Volume
38
Issue
4
Publish Date
2003
Start Page
449
End Page
461

The effect of melatonin treatment regimen on mammary adenocarcinoma development in HER-2/neu transgenic mice.

The effect of various regimens of treatment with melatonin on the development of mammary tumors in HER2/neu transgenic mice was investigated. Female HER-2/neu mice starting from the age of 2 months were kept under standard light/dark regimen and as given melatonin with tap water (20 mg/l) during the night time 5 times monthly (interrupted treatments) or constantly to natural death. Intact mice served as controls. Treatment with melatonin slowed down age-related disturbances in estrous function most in the group exposed to interrupted treatment with the hormone. Constant treatment with melatonin decreased incidence and size of mammary adenocarcinomas, and incidence of lung metastases, compared to controls. The number of mice bearing 4 and more tumors was reduced in the group with constant melatonin treatment. Interrupted treatment with melatonin promote mammary carcinogenesis in HER-2/neu transgenic mice. The data demonstrate the regimen-dependent inhibitory effect of melatonin on the development of spontaneous mammary tumors in HER-2/neu mice but not on overall survival with implication about the likely cause of the effect. Polycystic kidney disease is common in this transgenic line. Adverse effect of melatonin on the life span in our study may be unique to the transgenic model used and may not be relevant to the suppressive effect of melatonin in delay of mammary cancer.

Authors
Anisimov, VN; Alimova, IN; Baturin, DA; Popovich, IG; Zabezhinski, MA; Manton, KG; Semenchenko, AV; Yashin, AI
MLA Citation
Anisimov, VN, Alimova, IN, Baturin, DA, Popovich, IG, Zabezhinski, MA, Manton, KG, Semenchenko, AV, and Yashin, AI. "The effect of melatonin treatment regimen on mammary adenocarcinoma development in HER-2/neu transgenic mice." Int J Cancer 103.3 (January 20, 2003): 300-305.
PMID
12471612
Source
pubmed
Published In
International Journal of Cancer
Volume
103
Issue
3
Publish Date
2003
Start Page
300
End Page
305
DOI
10.1002/ijc.10827

How the analysis of genetic mutations can help us to solve basic problems in gerontology? I. Life extending genetic modifications in round worm C. elegans.

The results of recent molecular biological studies of aging and longevity confirmed substantial genetic contribution to the life span. The analysis of these findings showed substantial role of specific mutations in genes involved in regulatory processes on both the extra- and intracellular levels. We suggest that difference in responses of intact and mutant animals to the same set of environmental signals may be useful to clarify contribution of organism-environment interactions into the rate of aging, mortality and longevity of respective organisms. In our opinion such clarification is important for better understanding the origin of natural senescence and its dependence on external conditions.

Authors
Khalyavkin, AV; Yashin, AI
MLA Citation
Khalyavkin, AV, and Yashin, AI. "How the analysis of genetic mutations can help us to solve basic problems in gerontology? I. Life extending genetic modifications in round worm C. elegans." Adv Gerontol 11 (2003): 34-42.
PMID
12820519
Source
pubmed
Published In
Advances in Gerontology
Volume
11
Publish Date
2003
Start Page
34
End Page
42

Effect of Epitalon on biomarkers of aging, life span and spontaneous tumor incidence in female Swiss-derived SHR mice.

From the age of 3 months until their natural deaths, female outbred Swiss-derived SHR mice were subcutaneously injected on 5 consecutive days every month with 0.1 ml of normal saline (control) or with 1.0 microg/mouse (approximately 30-40 microg/kg) of tetrapeptide Epitalon (Ala-Glu-Asp-Gly) dissolved in 0.1 ml saline. There were 54 mice in each group. The results of this study show that treatment with Epitalon did not influence food consumption, body weight or mean life span of mice. However, it slowed down the age-related switching-off of estrous function and decreased the frequency of chromosome aberrations in bone marrow cells (by 17.1%, P<0.05). It also increased by 13.3% the life span of the last 10% of the survivors (P<0.01) and by 12.3% the maximum life span in comparison with the control group. We also found that treatment with Epitalon did not influence total spontaneous tumor incidence, but inhibited the development of leukemia (6.0-fold), as compared with the control group. The data obtained suggest a geroprotector activity of Epitalon and the safety of its long-term administration in mice.

Authors
Anisimov, VN; Khavinson, VK; Popovich, IG; Zabezhinski, MA; Alimova, IN; Rosenfeld, SV; Zavarzina, NY; Semenchenko, AV; Yashin, AI
MLA Citation
Anisimov, VN, Khavinson, VK, Popovich, IG, Zabezhinski, MA, Alimova, IN, Rosenfeld, SV, Zavarzina, NY, Semenchenko, AV, and Yashin, AI. "Effect of Epitalon on biomarkers of aging, life span and spontaneous tumor incidence in female Swiss-derived SHR mice." Biogerontology 4.4 (2003): 193-202.
PMID
14501183
Source
pubmed
Published In
Biogerontology
Volume
4
Issue
4
Publish Date
2003
Start Page
193
End Page
202

Logistic regression models for polymorphic and antagonistic pleiotropic gene action on human aging and longevity

In this paper, we apply logistic regression models to measure genetic association with human survival for highly polymorphic and pleiotropic genes. By modelling genotype frequency as a function of age, we introduce a logistic regression model with polytomous responses to handle the polymorphic situation. Genotype and allele-based parameterization can be used to investigate the modes of gene action and to reduce the number of parameters, so that the power is increased while the amount of multiple testing minimized. A binomial logistic regression model with fractional polynomials is used to capture the age-dependent or antagonistic pleiotropic effects. The models are applied to HFE genotype data to assess the effects on human longevity by different alleles and to detect if an age-dependent effect exists. Application has shown that these methods can serve as useful tools in searching for important gene variations that contribute to human aging and longevity.

Authors
Tan, Q; Bathum, L; Christiansen, L; Benedicts, GD; Dahlgaard, J; Frizner, N; Vach, W; Vaupel, JW; Yashin, AI; al, E
MLA Citation
Tan, Q, Bathum, L, Christiansen, L, Benedicts, GD, Dahlgaard, J, Frizner, N, Vach, W, Vaupel, JW, Yashin, AI, and al, E. "Logistic regression models for polymorphic and antagonistic pleiotropic gene action on human aging and longevity." Annals of Human Genetics 67.6 (2003): 598-607.
PMID
14641247
Source
scival
Published In
Annals of Human Genetics
Volume
67
Issue
6
Publish Date
2003
Start Page
598
End Page
607
DOI
10.1046/j.1529-8817.2003.00051.x

Individual aging and cancer risk: How are they related?

When individuals get older, the risk of many chronic diseases increases. This increase is in agreement with common theories of aging, such as mutation accumulation, wear and tear, antagonistic pleiotropy, etc. Surprisingly, however, the risk of some chronic conditions (e.g. asthma, arterial hypertension) declines in the old. The cancer incidence rate also declines at old ages after a steep increase during adult life. It contrasts with the continuing increase in total mortality that is often referred to as the aging process. Which forces contribute to a decline in cancer risk in the old? In this paper we review evidence from experimental biology, illustrating the ambivalent role of individual aging in cancer risk, in particular in forming non-monotonic age-patterns of cancer incidence rate. We show that age-associated changes in the organism may contribute not only to the rise, but also to the deceleration and the decline in cancer risk at old ages. © 2003 Max-Planck-Gesellshaft.

Authors
Ukraintseva, SV; Yashin, AI
MLA Citation
Ukraintseva, SV, and Yashin, AI. "Individual aging and cancer risk: How are they related?." Demographic Research 9 (2003): 163-195.
Source
scival
Published In
Demographic Research
Volume
9
Publish Date
2003
Start Page
163
End Page
195

How the analysis of genetic mutations can help us to solve basic problems in gerontology? II. Life extending genetic modifications in budding yeast S. cereviseae, fruit fly D. melanogaster and laboratory mice M. musculus.

Most studies of aging are conducted in humans and domestic or laboratory animals, i.e. in conditions where artificial environment protection is applied, This yields changes in physiology and behavior, which set up organism's state unobserved in wild life. This state may be less adequate to the evolutionary adjusted genetic construction of an organism, which generates a hypothesis that in natural niches the aging rate can be lower and stress resistance can be higher than in captivity despite the fact that life expectancy in habitat is essentially lower than that in laboratory conditions due to high external mortality. Direct test of this hypothesis is difficult because of problems related to reconstruction of natural environment conditions in the laboratory. Substantial life-extending effect of some mutated genes can serve as indirect test of the hypothesis. We propose that in some cases genetic mutations can distort reaction of an organism on environmental cues and change control parameters of its life cycle. As a result such mutants in laboratory may partly demonstrate life traits similar to those observed in natural environment, e.g. associated with high stress resistance and low rate of aging. These features combined with low external mortality in laboratory conditions may lead to significant extension in the life span of mutants. Recently we considered 56 life-extending gene modifications in nematode C. elegans (Adv. Gerontol., 2003, Vol. 11), scattered in many publications. In this paper we consider pertinent life-extending gene modifications corresponded to the budding yeast S. cerevisease (29 genes), fruit fly D. melanogaster (22 genes) and laboratory mice M. musculus (8 genes).

Authors
Khalyavkin, AV; Yashin, AI
MLA Citation
Khalyavkin, AV, and Yashin, AI. "How the analysis of genetic mutations can help us to solve basic problems in gerontology? II. Life extending genetic modifications in budding yeast S. cereviseae, fruit fly D. melanogaster and laboratory mice M. musculus." Adv Gerontol 12 (2003): 46-56. (Review)
PMID
14743601
Source
pubmed
Published In
Advances in Gerontology
Volume
12
Publish Date
2003
Start Page
46
End Page
56

Reproduction and survival in Mediterranean fruit flies: a "protein and energy" free radical model of aging.

We propose a "protein and energy" free radical model of aging that predicts patterns of survival and fertility curves for Mediterranean fruit flies. Mathematical and simulation models of individual physiological processes were constructed in terms of stochastic differential equations. The free radical theory of aging was used as a basis for construction of the model and was extended to describe the dynamics of the protein and energy balance in the functioning organism, including the concept of a maximum capacity for energy production. We fit the model to observed patterns of survival and fertility in flies given the basic diet schemes used in respective experiments. Age patterns of fertility and survival were predicted under various diet scenarios using the model, revealing that the predictions of the model are in good agreement with experimental data.

Authors
Butov, AA; Carey, JR; Volkov, MA; Sehl, ME; Yashin, AI
MLA Citation
Butov, AA, Carey, JR, Volkov, MA, Sehl, ME, and Yashin, AI. "Reproduction and survival in Mediterranean fruit flies: a "protein and energy" free radical model of aging." Biogerontology 4.6 (2003): 387-395.
PMID
14739710
Source
pubmed
Published In
Biogerontology
Volume
4
Issue
6
Publish Date
2003
Start Page
387
End Page
395
DOI
10.1023/B:BGEN.0000006559.59110.10

Insulin and longevity: antidiabetic biguanides as geroprotectors.

The results of previous experimental studies of effects of antidiabetic biguanides (phenformin and buformin) on life span and spontaneous tumor incidence in mice and rats were recalculated and reanalyzed using standard demographic models of mortality. The chronic treatment of female C3H/Sn mice with phenformin prolonged the mean life span by 21.1% (P < 0.05), the mean life span of the last 10% survivors by 28.4% and the maximum life span by 5.5 months (by 26%) in comparison with the control. The demographic aging rate represented by the estimate of respective Gompertz's parameter decreased by 31.2% and MRDT increased 1.45-fold. The treatment significantly inhibited (4.0-fold, P < 0.01) the incidence of mammary adenocarcinomas in mice. Administration of phenformin to female LIO rats failed to influence the mean life span. At the same time, the mean life span of the last 10% survivors increased by 10.1% (P < 0.05), and maximum life span increased by 3 months (+9.8%). Phenformin attenuated the development of spontaneous tumors in comparison to the control. The treatment of female rats with another antidiabetic biguanide, buformin, slightly increased their mean life span (by 7.3%; P > 0.05). The mean life span of the last 10% survivors increased by 12% (P < 0.05) and the maximum life span increased by 2 months (+5.5%) as compared with controls. The population aging rate decreased by 18.1% (P < 0.05) and MRDT increased 1.22-fold under the influence of buformin (P < 0.05). The total tumor incidence decreased by 49.5% in buformin-treated rats. Both antidiabetic biguanides slightly decreased the body weight, slowed down the age-related decline of the reproductive function in female rats. The results of our experiments provide evidence that antidiabetic biguanides are promising geroprotectors as well as drugs which can be used in the prevention of cancer.

Authors
Anisimov, VN; Semenchenko, AV; Yashin, AI
MLA Citation
Anisimov, VN, Semenchenko, AV, and Yashin, AI. "Insulin and longevity: antidiabetic biguanides as geroprotectors." Biogerontology 4.5 (2003): 297-307.
PMID
14618027
Source
pubmed
Published In
Biogerontology
Volume
4
Issue
5
Publish Date
2003
Start Page
297
End Page
307

Male/female ratio in centenarians: a possible role played by population genetic structure.

All the demographic surveys on the centenarians have highlighted that females outnumber males. The centenarians' male/female (M/F) ratio reported by most studies ranges between 1:4 and 1:7. A puzzling 1:2 ratio was observed in Calabria, a Southern Italian region. To our knowledge only in Sardinia a similar phenomenon had been previously observed. We have therefore used the data of the Italian Institute of Statistics to figure out the centenarians' M/F ratio in the Italian regions. We found that this ratio gradually decreases from South to North. Such a result is certainly due to many factors. Thus, we have explored the possibility, it is also influenced by the genetic structure of the Italian population. In fact, the distribution of the centenarians' M/F ratio turned out to be significantly correlated with the genetic structure of the Italian population as outlined by the principal component analysis.

Authors
Passarino, G; Calignano, C; Vallone, A; Franceschi, C; Jeune, B; Robine, JM; Yashin, AI; Cavalli Sforza, LL; De Benedictis, G
MLA Citation
Passarino, G, Calignano, C, Vallone, A, Franceschi, C, Jeune, B, Robine, JM, Yashin, AI, Cavalli Sforza, LL, and De Benedictis, G. "Male/female ratio in centenarians: a possible role played by population genetic structure." Exp Gerontol 37.10-11 (October 2002): 1283-1289.
PMID
12470842
Source
pubmed
Published In
Experimental Gerontology
Volume
37
Issue
10-11
Publish Date
2002
Start Page
1283
End Page
1289

A multistate model for the genetic analysis of the ageing process.

In this paper a multivariate frailty model is suggested that can be used in the genetic analysis of the ageing process as a whole, simplified to consisting of the states 'healthy', 'disabled' and 'deceased'. The model allows us to evaluate simultaneously the relative magnitude of genetic and environmental influences on frailty variables corresponding to the period of good health and to the life span. The frailty variables can be interpreted as susceptibility to illness or death. The model can be applied to data on groups of related individuals (twins, siblings, a litter). One of the major advantages of this model is that it allows one to include groups of individuals where some or all members of the group are already deceased at the time of observation. The current health status of the living individuals and the exact life span of individuals who are already deceased is the only information necessary for the application of the model. Questions concerning the identifiability of the model based on current health status data and estimation strategies are discussed in the context of specifying the model for twins. Finally, the results of a sample analysis of twin data on prostate cancer are presented.

Authors
Giard, N; Lichtenstein, P; Yashin, AI
MLA Citation
Giard, N, Lichtenstein, P, and Yashin, AI. "A multistate model for the genetic analysis of the ageing process." Stat Med 21.17 (September 15, 2002): 2511-2526.
PMID
12205696
Source
pubmed
Published In
Statistics in Medicine
Volume
21
Issue
17
Publish Date
2002
Start Page
2511
End Page
2526
DOI
10.1002/sim.1197

Individual aging and mortality rate: how are they related?

Many researchers working in the area of aging and longevity base their conclusions on the behavior of empirical age trajectories of mortality rates. In such analyses, changes in the slope of the logarithm of the mortality curve are often associated with changes in the rate of individual aging. We show that such interpretation may be incorrect: the changes in the slope of this curve do not necessarily correspond to the changes in the rate of individual aging. We use three models of mortality and aging to illustrate this statement. The first one is based on the idea of frailty. We show that changes in frailty distribution alone may be responsible for changes in the slope. The second model exploits the idea of saving lives. It evaluates changes in mortality rate after elimination of lethal stressful events. The third model uses the idea of Strehler and Mildvan (1960). It shows that changes in the rate of individual aging may take place without changes in the slope of the logarithm of the mortality curve.

Authors
Yashin, AI; Ukraintseva, SV; Boiko, SI; Arbeev, KG
MLA Citation
Yashin, AI, Ukraintseva, SV, Boiko, SI, and Arbeev, KG. "Individual aging and mortality rate: how are they related?." Social biology 49.3-4 (September 2002): 206-217.
PMID
14652918
Source
epmc
Published In
Social biology
Volume
49
Issue
3-4
Publish Date
2002
Start Page
206
End Page
217

Heritability of death from coronary heart disease: a 36-year follow-up of 20 966 Swedish twins.

OBJECTIVE: The aim of the present study was to evaluate and distinguish between environmental and genetic effects for death from coronary heart disease (CHD) as well as to determine whether the importance of genetic influences is changing with age. DESIGN: A cohort study with a follow-up time of 36 years. SUBJECTS: The cohort drawn for the present study includes 20 966 twins born in Sweden between 1886 and 1925 where both twins within a pair still lived within the country in 1961. METHODS: Concordances and correlated gamma-frailty model were used to assess and distinguish between genetic and environmental influences as well as to evaluate age-related changes in genetic influences. RESULTS: A total number of 4007 CHD-deaths (2208 males, and 1799 females) was observed. The probability of dying from CHD given that one's twin partner already has died from CHD decreased with increasing age, particularly amongst males. The genetic variation in susceptibility to death from CHD was moderately large, and decreased slightly across time, particularly amongst males. The heritability was 0.57 (95% CI, 0.45-0.69) amongst male twins, and 0.38 (0.26-0.50) amongst female twins. CONCLUSIONS: The genetic contribution to the variation in CHD-mortality was moderate both in females and males. Furthermore, although genetic effects appeared to be greater at younger ages of death, our findings clearly suggest that genetic factors are in operation throughout the entire life span.

Authors
Zdravkovic, S; Wienke, A; Pedersen, NL; Marenberg, ME; Yashin, AI; De Faire, U
MLA Citation
Zdravkovic, S, Wienke, A, Pedersen, NL, Marenberg, ME, Yashin, AI, and De Faire, U. "Heritability of death from coronary heart disease: a 36-year follow-up of 20 966 Swedish twins." J Intern Med 252.3 (September 2002): 247-254.
PMID
12270005
Source
pubmed
Published In
Journal of Internal Medicine
Volume
252
Issue
3
Publish Date
2002
Start Page
247
End Page
254

Epithalon decelerates aging and suppresses development of breast adenocarcinomas in transgenic her-2/neu mice.

Female transgenic FVB/N mice carrying the breast cancer gene HER-2/neu received epithalon (Ala-Glu-Asp-Gly) in a dose of 1 mg subcutaneously 5 times a week to from the 2nd month of life to death. Epithalon prolonged the average and maximum lifetimes of mice by 13.5 (p<0.05) and 13.9%, respectively. The peptide prolonged the average lifetime of animals without neoplasms (by 34.2%, p<0.05). Epithalon decelerated the development of age-related disturbances in reproductive activity and suppressed the formation of neoplasms. The peptide decreased the incidence of breast adenocarcinomas, lungs metastases (by 1.6 times, p<0.05), and multiple tumors (by 2 times). Epithalon 3.7-fold increased the number of mice without breast tumors (p<0.05), while the number of animals with 6 or more breast tumors decreased by 3 times (p<0.05). Epithalon prolonged the lifetime of mice with breast tumors by 1.4 times (p<0.05). These results indicate that Epithalon possesses geroprotective activity and inhibits breast carcinogenesis in transgenic mice, which is probably related to suppression of HER-2/neu expression.

Authors
Anisimov, VN; Khavinson, VK; Alimova, IN; Semchenko, AV; Yashin, AI
MLA Citation
Anisimov, VN, Khavinson, VK, Alimova, IN, Semchenko, AV, and Yashin, AI. "Epithalon decelerates aging and suppresses development of breast adenocarcinomas in transgenic her-2/neu mice." Bull Exp Biol Med 134.2 (August 2002): 187-190.
PMID
12459848
Source
pubmed
Published In
Bulletin of Experimental Biology and Medicine
Volume
134
Issue
2
Publish Date
2002
Start Page
187
End Page
190

Genetic analysis of cause of death in a mixture model of bivariate lifetime data

Authors
Wienke, A; Christensen, K; Skytthe, A; Yashin, AI
MLA Citation
Wienke, A, Christensen, K, Skytthe, A, and Yashin, AI. "Genetic analysis of cause of death in a mixture model of bivariate lifetime data." Statistical Modelling: An International Journal 2.2 (July 2002): 89-102.
Source
crossref
Published In
Statistical Modeling
Volume
2
Issue
2
Publish Date
2002
Start Page
89
End Page
102
DOI
10.1191/1471082x02st030oa

The influences on human longevity by HUMTHO1.STR polymorphism (Tyrosine Hydroxylase gene). A relative risk approach.

A new method based on the recently developed relative risk approach is introduced, and applied to data from Italian centenarian study (965 subjects aged from 13 to 109 years old) for investigating influences on longevity by Tyrosine Hydroxylase (TH) gene variability. The strategic parameterization enables the model to disentangle the various ways by which HUMTHO1.STR alleles (alleles 6, 7, 8, 9, 10*, 10, as defined according to the number of repeats) may contribute in reducing or increasing the hazard of death with different patterns of influences. Among all the alleles, we have found that allele 10* (10 imperfect repeats) shows a remarkable dominant and beneficial effect that reduces the log hazard of death in an additive manner. The results confirm that HUMTHO1.STR polymorphism is involved in the modulation of human longevity.

Authors
Tan, Q; Bellizzi, D; Rose, G; Garasto, S; Franceschi, C; Kruse, T; Vaupel, JW; De Benedictis, G; Yashin, AI
MLA Citation
Tan, Q, Bellizzi, D, Rose, G, Garasto, S, Franceschi, C, Kruse, T, Vaupel, JW, De Benedictis, G, and Yashin, AI. "The influences on human longevity by HUMTHO1.STR polymorphism (Tyrosine Hydroxylase gene). A relative risk approach." Mech Ageing Dev 123.10 (July 2002): 1403-1410.
PMID
12297342
Source
pubmed
Published In
Mechanisms of Ageing and Development
Volume
123
Issue
10
Publish Date
2002
Start Page
1403
End Page
1410

Evolutionary optimality applied to Drosophila experiments: hypothesis of constrained reproductive efficiency.

The general purpose of the paper is to test evolutionary optimality theories with experimental data on reproduction, energy consumption, and longevity in a particular Drosophila genotype. We describe the resource allocation in Drosophila females in terms of the oxygen consumption rates devoted to reproduction and to maintenance. The maximum ratio of the component spent on reproduction to the total rate of oxygen consumption, which can be realized by the female reproductive machinery, is called metabolic reproductive efficiency (MRE). We regard MRE as an evolutionary constraint. We demonstrate that MRE may be evaluated for a particular Drosophila phenotype given the fecundity pattern, the age-related pattern of oxygen consumption rate, and the longevity. We use a homeostatic model of aging to simulate a life history of a representative female fly, which describes the control strain in the long-term experiments with the Wayne State Drosophila genotype. We evaluate the theoretically optimal trade-offs in this genotype. Then we apply the Van Noordwijk-de Jong resource acquisition and allocation model, Kirkwood's disposable soma theory. and the Partridge-Barton optimality approach to test if the experimentally observed trade-offs may be regarded as close to the theoretically optimal ones. We demonstrate that the two approaches by Partridge-Barton and Kirkwood allow a positive answer to the question, whereas the Van Noordwijk-de Jong approach may be used to illustrate the optimality. We discuss the prospects of applying the proposed technique to various Drosophila experiments, in particular those including manipulations affecting fecundity.

Authors
Novoseltsev, VN; Arking, R; Novoseltseva, JA; Yashin, AI
MLA Citation
Novoseltsev, VN, Arking, R, Novoseltseva, JA, and Yashin, AI. "Evolutionary optimality applied to Drosophila experiments: hypothesis of constrained reproductive efficiency." Evolution 56.6 (June 2002): 1136-1149.
PMID
12144015
Source
pubmed
Published In
Evolution
Volume
56
Issue
6
Publish Date
2002
Start Page
1136
End Page
1149

A case-only approach for assessing gene by sex interaction in human longevity.

As one aspect of the complex feature of longevity, gene by sex interaction plays an important role in influencing human life span. With advances in molecular genetics, more studies aimed at assessing gene by sex interaction are expected. New and valid statistical methods are needed. In this article, we introduce a nontraditional approach, the case-only design, which was originally proposed for assessing gene and disease associations, to detect gene by sex interaction in human longevity. Applications of this method to data collected from centenarian studies show that it can produce consistent results as compared with results obtained from case-control and other approaches. The method cannot be used as a substitute for traditional case-control studies since it is limited to the detection of interactions only. However, the easily applicable case-only approach can be an important tool for screening many potential genes that contribute to human longevity.

Authors
Tan, Q; Yashin, AI; Bladbjerg, EM; de Maat, MPM; Andersen-Ranberg, K; Jeune, B; Christensen, K; Vaupel, JW
MLA Citation
Tan, Q, Yashin, AI, Bladbjerg, EM, de Maat, MPM, Andersen-Ranberg, K, Jeune, B, Christensen, K, and Vaupel, JW. "A case-only approach for assessing gene by sex interaction in human longevity." J Gerontol A Biol Sci Med Sci 57.4 (April 2002): B129-B133.
PMID
11909876
Source
pubmed
Published In
Journals of Gerontology: Series A
Volume
57
Issue
4
Publish Date
2002
Start Page
B129
End Page
B133

New age patterns of survival improvement in Sweden: do they characterize changes in individual aging?

The parameters of the Gompertz approximation to the mortality curve are negatively correlated. Strehler and Mildvan [Science 132 (1960) 14] predicted this property of the mortality curve using a mathematical model of mortality and aging and then confirmed it in empirical studies. Despite the fact that their theory was based on the cohort model of mortality the SM correlation was also revealed in the analysis of period mortality data. In fact, most applications of the SM model to human data use Gompertz's approximation to the period mortality rate. Many researchers studying SM correlation consider it a universal demographic law. Such correlation prescribes a certain regularity in mortality changes. All mortality curves must intersect at one point. Mortality decline must produce the rectangularization of survival curves. In this paper we investigated the changes in the patterns of mortality decline in Sweden between 1861 and 1999. We found a difference in patterns of SM correlation for cohort and period mortality data. We investigated trends in survival improvement and found that the tendency to rectangularization of the survival curve existed for only a limited period of time. Then it was gradually replaced by near parallel shift of the survival curve to the right. We found that the pattern of SM correlation was relatively stable only at certain phases of the survival history of male and female populations. We analyzed past and recent patterns of survival changes and discussed possible causes for instability of SM correlation both in cohort and in period mortality data.

Authors
Yashin, AI; Begun, AS; Boiko, SI; Ukraintseva, SV; Oeppen, J
MLA Citation
Yashin, AI, Begun, AS, Boiko, SI, Ukraintseva, SV, and Oeppen, J. "New age patterns of survival improvement in Sweden: do they characterize changes in individual aging?." Mech Ageing Dev 123.6 (March 31, 2002): 637-647.
PMID
11850027
Source
pubmed
Published In
Mechanisms of Ageing and Development
Volume
123
Issue
6
Publish Date
2002
Start Page
637
End Page
647

An allele of HRAS1 3'variable number of tandem repeats is a frailty allele: implication for an evolutionarily-conserved pathway involved in longevity.

The human HRAS1 belongs to an evolutionarily-conserved family of genes which enrolls among its members the yeast RAS2, a gene which regulates stress response and longevity in the Saccharomyces cerevisiae. In this paper we report that the frequency of the a3 allele of HRAS1 3'variable number tandem repeat (HRAS1 3'VNTR) decreases in centenarians in respect to young people, and we estimate that during aging a3 carriers have a relative mortality risk of 1.126 (95% CI=1.044-1.213). We propose that the germ-line variability at the HRAS1 locus impacts on the individual's capacity to reach the extreme limits of human life-span. Furthermore, we provide suggestive evidence that a3 HRAS1 3'VNTR allele and inherited variants of the mitochondrial genome (mtDNA haplogroups) do not affect independently human longevity, thus recalling the nucleus-mitochondrion interaction which regulates stress response and life-span in the yeast.

Authors
Bonafè, M; Barbi, C; Olivieri, F; Yashin, A; Andreev, KF; Vaupel, JW; De Benedictis, G; Rose, G; Carrieri, G; Jazwinski, SM; Franceschi, C
MLA Citation
Bonafè, M, Barbi, C, Olivieri, F, Yashin, A, Andreev, KF, Vaupel, JW, De Benedictis, G, Rose, G, Carrieri, G, Jazwinski, SM, and Franceschi, C. "An allele of HRAS1 3'variable number of tandem repeats is a frailty allele: implication for an evolutionarily-conserved pathway involved in longevity." Gene 286.1 (March 6, 2002): 121-126.
PMID
11943467
Source
pubmed
Published In
Gene
Volume
286
Issue
1
Publish Date
2002
Start Page
121
End Page
126

Heat shock changes the heterogeneity distribution in populations of Caenorhabditis elegans: does it tell us anything about the biological mechanism of stress response?

In this paper we analyze survival data of populations of sterilized nematodes, Caenorhabditis elegans, exposed to heat shocks of different duration at the beginning of their adult lives. There are clear hormesis effects after short exposure to heat and clear debilitation effects after long exposure. Intermediate durations result in a mixture of these two effects. In this latter case, the survival curves for the control and experimental populations intersect. We show that observed effects may be explained by using a model of discrete heterogeneity. According to this model, each population of worms in the experiment is a mixture of subcohorts of frail, normal, and robust individuals; exposure to heat changes the initial proportion of worms in the subcohorts (heterogeneity distribution); and these changes depend on the duration of exposure. In other words, exposure to heat does not influence mortality rates (survival functions) in the subcohorts but does cause individuals to move from one subcohort to another. In a biological interpretation of this finding we hypothesize that, when coping with stress, the organisms of worms use several lines of defense. Switching these lines on and off in response to stress in individual organisms generates the spectrum of observed survival effects at the population level. We discuss possible molecular biological mechanisms of stress response and directions for further research.

Authors
Yashin, AI; Cypser, JW; Johnson, TE; Michalski, AI; Boyko, SI; Novoseltsev, VN
MLA Citation
Yashin, AI, Cypser, JW, Johnson, TE, Michalski, AI, Boyko, SI, and Novoseltsev, VN. "Heat shock changes the heterogeneity distribution in populations of Caenorhabditis elegans: does it tell us anything about the biological mechanism of stress response?." J Gerontol A Biol Sci Med Sci 57.3 (March 2002): B83-B92.
PMID
11867644
Source
pubmed
Published In
Journals of Gerontology: Series A
Volume
57
Issue
3
Publish Date
2002
Start Page
B83
End Page
B92

User interface design patterns for interactive modeling in demography and biostatistics

© Springer-Verlag Berlin Heidelberg 2002. The paper is focused on the interface design patterns for interactive modeling and it is an effort to systematically describe the usage of UID patterns in this area. Main objectives were to develop the UID patterns to increase the usability of the software for numerical computing and to make the process of numerical simulation highly interactive. On the basis of these UID patterns authors developed reusable software components in several programming languages: Java, Python, C++ and Matlab. The patterns described in the paper were verified in the development of practical software tools for demographers and biostatisticians, but can be readily applicable to other domains of numerical computing.

Authors
Boyko, S; Forbrig, P; Yashin, A
MLA Citation
Boyko, S, Forbrig, P, and Yashin, A. "User interface design patterns for interactive modeling in demography and biostatistics." January 1, 2002.
Source
scopus
Published In
Lecture notes in computer science
Volume
2545
Publish Date
2002
Start Page
148
End Page
158
DOI
10.1007/3-540-36235-5_11

Detection of hormesis effect in longevity: simulation approach for heterogeneous population.

Manifestation of hormesis in longevity was modelled by modification of the mortality rate during and after the period of a stress factor action. In heterogeneous population this can lead to observation of unchanged mortality during action of the stress and decrease in mortality after stress period. Stochastic simulations were made to investigate the possibility of detecting the hormesis effect on the basis of the stress-control longitudinal data. The goal of the stochastic simulation was to investigate the role in the hormesis detection of control and stressed group size, of population heterogeneity variance value, of stress and hormesis attributable risks as well as the role of a prior information about the survival in the control group. It was demonstrated that if the attributable risks for stress and hormesis effects are approximately equal, then in both 'high' and 'low' heterogeneous populations the hormesis phenomenon is detected with probability higher than 75% even in relatively 'small' groups of 50 subjects. In case of 'weak' effect the hormesis phenomenon is not detected in a 'highly heterogeneous' population even in a group composed of 1000 subjects. In a 'low heterogeneous' population the hormesis phenomenon is detected with probability higher than 70% when the group size is not less than 200 subjects. Information about the survival in control group did not play a critical role in all experiments and exact survival curve may be replaced by the traditional Kaplan-Meier estimate.

Authors
Michalski, AI; Yashin, AI
MLA Citation
Michalski, AI, and Yashin, AI. "Detection of hormesis effect in longevity: simulation approach for heterogeneous population." Math Biosci 175.1 (January 2002): 57-66.
PMID
11779627
Source
pubmed
Published In
Mathematical Biosciences
Volume
175
Issue
1
Publish Date
2002
Start Page
57
End Page
66

A centenarian-only approach for assessing gene - Gene interaction in human longevity

In this study, we introduce a centenarian-only approach to the assessment of gene-gene interaction that contributes to human longevity. This approach corresponds to the non-traditional case-only method in the genetic study of gene and disease associations. We first describe how the method can be implemented to screen for gene-gene interaction in human longevity. Then we apply the method to centenarian data collected from an Italian centenarian study in order to detect the interactions between the REN gene and the mitochondrial haplotypes. A significant interaction between REN gene allele 10 and the mitochondrial H haplotype, which may favour longevity, was found. Important features of the application in human longevity studies are highlighted and discussed. Since centenarians constitute a special population representing successful ageing, the centenarian-only approach will be an important tool in the search for major genes that contribute to human longevity.

Authors
Tan, Q; Benedictis, GD; Ukraintseva, SV; Franceschi, C; Vaupel, JW; Yashin, AI
MLA Citation
Tan, Q, Benedictis, GD, Ukraintseva, SV, Franceschi, C, Vaupel, JW, and Yashin, AI. "A centenarian-only approach for assessing gene - Gene interaction in human longevity." European Journal of Human Genetics 10.2 (2002): 119-124.
PMID
11938442
Source
scival
Published In
European Journal of Human Genetics
Volume
10
Issue
2
Publish Date
2002
Start Page
119
End Page
124
DOI
10.1038/sj/ejhg/5200770

A model of accelerated aging induced by 5-bromodeoxyuridine.

We consider a scheme of aging with two possible mechanisms of senescence processes: aging with apoptosis and necrosis for differentiated cells and a multistage process of malignant transformation. Our model describes the multistage phenomena of aging and carcinogenesis by a set of stochastic equations using multivariate and diffusion processes. This model fits experimental data on the acceleration of aging processes from postnatal exposure to 5-bromodeoxyuridine (BrdU), and the induction of genome instability. The methods of stochastic modeling and computer simulation of the processes of aging and carcinogenesis have been used for the verification of the biological suggestions.

Authors
Butov, AA; Volkov, MA; Anisimov, VN; Sehl, ME; Yashin, AI
MLA Citation
Butov, AA, Volkov, MA, Anisimov, VN, Sehl, ME, and Yashin, AI. "A model of accelerated aging induced by 5-bromodeoxyuridine." Biogerontology 3.3 (2002): 175-182.
PMID
12075136
Source
pubmed
Published In
Biogerontology
Volume
3
Issue
3
Publish Date
2002
Start Page
175
End Page
182

A logistic regression model for measuring gene-longevity associations.

The logistic regression model is a popular model for data analysis in epidemiological research. In this paper, we use this model to analyze genetic data collected from gene-longevity association studies. This new approach models the probability of observing one genotype as a function of the age of investigated individuals. Applying the model to genotype data on the TH and 3'ApoB-VNTR loci collected from an Italian centenarian study, we show how it can be used to model the different ways that genes affect survival, including sex- and age-specific influences. We highlight the advantages of this application over other available models. The application of the model to empirical data indicates that it is an efficient and easily applicable approach for determining the influences of genes on human longevity.

Authors
Tan, Q; Yashin, AI; De Benedictis, G; Cintolesi, F; Rose, G; Bonafe, M; Franceschi, C; Vach, W; Vaupel, JW
MLA Citation
Tan, Q, Yashin, AI, De Benedictis, G, Cintolesi, F, Rose, G, Bonafe, M, Franceschi, C, Vach, W, and Vaupel, JW. "A logistic regression model for measuring gene-longevity associations." Clin Genet 60.6 (December 2001): 463-469.
PMID
11846740
Source
pubmed
Published In
Clinical Genetics
Volume
60
Issue
6
Publish Date
2001
Start Page
463
End Page
469

The new trends in survival improvement require a revision of traditional gerontological concepts.

In 1960, Strehler and Mildvan (SM) theoretically predicted that the parameters of the Gompertz approximation to a mortality curve are negatively correlated. This means that the changes in the human mortality rate resulting from improvement in living standards, progress in health care or the influence of other factors must follow certain regularities prescribed by dependence between the Gompertz parameters. Such dependence, called SM correlation, was then confirmed in a number of empirical studies using period data on human mortality. Since the SM theory was based on the cohort model of mortality, it was tacitly assumed that period and cohort SM correlation patterns are similar. The remarkable stability of the SM correlation pattern revealed in these studies was often regarded as manifestation of a universal demographic law regulating changes in the age pattern of mortality rates. In this paper, we investigated trends in mortality decline in France, Japan, Sweden and the United States. In contrast with traditional expectations, we found that the SM correlation pattern was relatively stable only in certain periods of a population's survival history. Recently, several new correlation patterns emerged and, despite some differences in the timing of the changes, the new patterns are remarkably similar in all four countries. Contrary to traditional expectations, the patterns are not the same for cohort and period mortality data when SM correlations are calculated for France, Sweden and the United States. We show that some changes in the patterns of SM correlation admit interpretation in terms of a biological mechanism of individual adaptation (survival trade off). Some other patterns, however, contradict basic postulates of the SM theory. This indicates the need for revision of traditional concepts establishing the relationship between physiological and demographic patterns of aging.

Authors
Yashin, AI; Begun, AS; Boiko, SI; Ukraintseva, SV; Oeppen, J
MLA Citation
Yashin, AI, Begun, AS, Boiko, SI, Ukraintseva, SV, and Oeppen, J. "The new trends in survival improvement require a revision of traditional gerontological concepts." Exp Gerontol 37.1 (December 2001): 157-167.
PMID
11738156
Source
pubmed
Published In
Experimental Gerontology
Volume
37
Issue
1
Publish Date
2001
Start Page
157
End Page
167

Have the oldest old adults ever been frail in the past? A hypothesis that explains modern trends in survival.

Three important results concerning the shape and the trends of the human mortality rate were discussed recently in demographic and epidemiological literature. These are the deceleration of the mortality rate at old ages, the tendency to rectangularization of the survival curve, and the decline of the old age mortality observed in the second part of the 20th century. In this paper we show that all these results can be explained by using a model with a new type of heterogeneity associated with individual differences in adaptive capacity. We first illustrate the idea of such a model by considering survival in a mixture of two subpopulations of individuals (called "labile" and "stable"). These subpopulations are characterized by different Gompertz mortality patterns, such that their mortality rates cross over. The survival chances of individuals in these subpopulations have different sensitivities to changes in environmental conditions. Then we develop a more comprehensive model in which the mortality rate is related to the adaptive capacity of an organism. We show that the trends in survival patterns experienced by a mixture of such individuals resemble those obtained in an analysis of empirical data on survival in developed countries. Lastly, we present evidence of the existence of subpopulations of phenotypes in both humans and experimental organisms, which were used as prototypes in our models. The existence of such phenotypes provides the possibility that at least part of today's centenarians originated from an initially frail part of the cohort.

Authors
Yashin, AI; Ukraintseva, SV; De Benedictis, G; Anisimov, VN; Butov, AA; Arbeev, K; Jdanov, DA; Boiko, SI; Begun, AS; Bonafe, M; Franceschi, C
MLA Citation
Yashin, AI, Ukraintseva, SV, De Benedictis, G, Anisimov, VN, Butov, AA, Arbeev, K, Jdanov, DA, Boiko, SI, Begun, AS, Bonafe, M, and Franceschi, C. "Have the oldest old adults ever been frail in the past? A hypothesis that explains modern trends in survival." The journals of gerontology. Series A, Biological sciences and medical sciences 56.10 (October 2001): B432-B442. (Review)
PMID
11584028
Source
epmc
Published In
Journals of Gerontology: Series A
Volume
56
Issue
10
Publish Date
2001
Start Page
B432
End Page
B442
DOI
10.1093/gerona/56.10.b432

Cardiovascular mortality in twins and the fetal origins hypothesis.

The intrauterine growth patterns for twins are characterized by normal development during the first two trimesters and reduced growth during the third trimester. According to the fetal origins hypothesis this growth pattern is associated with risk factors for cardiovascular morbidity and mortality. We studied cause-specific mortality of 19,986 Danish twin individuals from the birth cohorts 1870-1930 followed from 1952 through 1993. Despite the large sample size and follow-up period we were not able to detect any difference between twins and the general population with regard to all-cause mortality or cardiovascular mortality. Hence, the intrauterine growth retardation experienced by twins does not result in any "fetal programming" of cardiovascular diseases. There is still an important role for twins (and other sibs) to play in the testing of the fetal origins hypothesis, namely in studies of intra-pair differences, which can assess the role of genetic confounding in the association between fetal growth and later health outcome.

Authors
Christensen, K; Wienke, A; Skytthe, A; Holm, NV; Vaupel, JW; Yashin, AI
MLA Citation
Christensen, K, Wienke, A, Skytthe, A, Holm, NV, Vaupel, JW, and Yashin, AI. "Cardiovascular mortality in twins and the fetal origins hypothesis." Twin Res 4.5 (October 2001): 344-349.
PMID
11869487
Source
pubmed
Published In
Twin research : the official journal of the International Society for Twin Studies
Volume
4
Issue
5
Publish Date
2001
Start Page
344
End Page
349
DOI
10.1375/1369052012506

Ageing and survival after different doses of heat shock: the results of analysis of data from stress experiments with the nematode worm Caenorhabditis elegans.

Stress experiments performed on a population of sterilised nematode worms (Caenorhabditis elegans) show a clear hormesis effect after short exposure and clear debilitation effects after long exposure to heat shock. An intermediate duration of exposure results in a mixture of these two effects. In this latter case the survival curves for populations in the stress and control groups intersect. In this paper we develop an adaptation model of stress and apply it to the analysis of survival data from three such stress experiments. We show that the model can be used to explain empirical age-patterns of mortality and survival observed in these experiments. We discuss possible biological mechanisms involved in stress response and directions for further research.

Authors
Yashin, AI; Cypser, JR; Johnson, TE; Michalski, AI; Boyko, SI; Novoseltsev, VN
MLA Citation
Yashin, AI, Cypser, JR, Johnson, TE, Michalski, AI, Boyko, SI, and Novoseltsev, VN. "Ageing and survival after different doses of heat shock: the results of analysis of data from stress experiments with the nematode worm Caenorhabditis elegans." Mech Ageing Dev 122.13 (September 15, 2001): 1477-1495.
PMID
11470134
Source
pubmed
Published In
Mechanisms of Ageing and Development
Volume
122
Issue
13
Publish Date
2001
Start Page
1477
End Page
1495

How individual age-associated changes may influence human morbidity and mortality patterns.

Patterns of human mortality share common traits in different populations. They include higher mortality in early childhood, lower mortality during the reproductive period, an accelerated increase of mortality near the end of the reproductive period, and deceleration in the mortality increase at oldest old ages. The deceleration of mortality rate is one of the most intriguing recent findings in longevity research. The role of differential selection in this phenomenon has been well studied. Possible contribution of individual aging in the shape of mortality curve is also recognized. However, this contribution has not been studied in details. In this paper, we specify most common patterns of age-associated changes in an individual organism and discuss their possible influence on morbidity and mortality in population. We subdivide individual age-associated changes into three components, having different influence on morbidity and mortality: (1) basal, (2) ontogenetic, and (3) time-dependent. Basal changes are connected with the universal decrease in the rate of living during an individual life. As a result, some phenotypic effects of aging may accumulate in an organism at a slower rate with age. Basal changes are likely to contribute to a plateau of morbidity often observed at old ages, and may partially be responsible for mortality deceleration at oldest old ages. Ontogenetic component is connected with change of the stages of ontogenesis (e.g., the growth, the reproductive period and the climacteric) during an individual life. The ontogenesis-related changes contribute to wave-like patterns of morbidity in population and may partially be responsible for mortality increase at middle ages and its deceleration at old ages. Time-dependent changes are connected with long-time exposure of an organism to different harmful factors. They are most likely to contribute to morbidity and mortality acceleration. We discuss how all three components of individual age-associated changes may interact in human organism and influence patterns of morbidity and mortality in population.

Authors
Ukraintseva, SV; Yashin, AI
MLA Citation
Ukraintseva, SV, and Yashin, AI. "How individual age-associated changes may influence human morbidity and mortality patterns." Mech Ageing Dev 122.13 (September 15, 2001): 1447-1460.
PMID
11470132
Source
pubmed
Published In
Mechanisms of Ageing and Development
Volume
122
Issue
13
Publish Date
2001
Start Page
1447
End Page
1460

Variations of cardiovascular disease associated genes exhibit sex-dependent influence on human longevity.

This article investigates the relationship between the polymorphic variations in genes associated with cardiovascular disease and longevity in the Danish population. A new procedure that combines both demographic and the individual genetic information in determining the relative risks of the observed genetic variations is applied. The sex-dependent influences can be found by introducing sex-specific population survival and incorporating the risk of gene-sex interaction. Three genetic polymorphisms, angiotensinogen M/T235, blood coagulation factor VII (FVII) R/Q353 and FVII-323ins10, manifest significant influences on survival in males, with reduced hazards of death for carriers of the angiotensinogen M235 allele, the F VII Q353 allele, and the FVII-323P10 allele. The results show that some of these genotypes associated with lower risk of CVD could also reduce the carrier's death rate and contribute to longevity. However, the presence of sex-dependent effects and the fact that major CVD-associated genes failed to impose detrimental influence on longevity lead us to concur that the aging process is highly complicated.

Authors
Tan, Q; Yashin, AI; Bladbjerg, EM; de Maat, MP; Andersen-Ranberg, K; Jeune, B; Christensen, K; Vaupel, JW
MLA Citation
Tan, Q, Yashin, AI, Bladbjerg, EM, de Maat, MP, Andersen-Ranberg, K, Jeune, B, Christensen, K, and Vaupel, JW. "Variations of cardiovascular disease associated genes exhibit sex-dependent influence on human longevity." Exp Gerontol 36.8 (August 2001): 1303-1315.
PMID
11602206
Source
pubmed
Published In
Experimental Gerontology
Volume
36
Issue
8
Publish Date
2001
Start Page
1303
End Page
1315

The heritability of mortality due to heart diseases: a correlated frailty model applied to Danish twins.

Data of the Danish Twin Registry on monozygotic and dizygotic twins are used to analyse genetic and environmental influences on susceptibility to heart diseases for males and females, respectively. The sample includes 7955 like-sexed twin pairs born between 1870 and 1930. Follow-up was from 1 January 1943 to 31 December 1993 which results in truncation (twin pairs were included in the study if both individuals were still alive at the beginning of the follow-up) and censoring (nearly 40% of the study population was still alive at the end of the follow-up). We use the correlated gamma-frailty model for the genetic analysis of frailty to account for this censoring and truncation. During the follow-up 9370 deaths occurred, 3393 deaths were due to heart diseases in general, including 2476 deaths due to coronary heart disease (CHD). Proportions of variance of frailty attributable to genetic and environmental factors were analyzed using the structural equation model approach. Different standard biometric models are fitted to the data to evaluate the magnitude and nature of genetic and environmental factors on mortality. Using the best fitting model heritability of frailty (liability to death) was found to be 0.55 (0.07) and 0.53 (0.11) with respect to heart diseases and CHD, respectively, for males and 0.52 (0.10) and 0.58 (0.14) for females in a parametric analysis. A semi-parametric analysis shows very similar results. These analyses may indicate the existence of a strong genetic influence on individual frailty associated with mortality caused by heart diseases and CHD in both, males and females. The nature of genetic influences on frailty with respect to heart diseases and CHD is probably additive. No evidence for dominance and shared environment was found.

Authors
Wienke, A; Holm, NV; Skytthe, A; Yashin, AI
MLA Citation
Wienke, A, Holm, NV, Skytthe, A, and Yashin, AI. "The heritability of mortality due to heart diseases: a correlated frailty model applied to Danish twins." Twin Res 4.4 (August 2001): 266-274.
PMID
11665307
Source
pubmed
Published In
Twin research : the official journal of the International Society for Twin Studies
Volume
4
Issue
4
Publish Date
2001
Start Page
266
End Page
274

Recent advances in human gene-longevity association studies.

This paper reviews the recent literature on genes and longevity. The influence of genes on human life span has been confirmed in studies of life span correlation between related individuals based on family and twin data. Results from major twin studies indicate that approximately 25% of the variation in life span is genetically determined. Taking advantage of recent developments in molecular biology, researchers are now searching for candidate genes that might have an influence on life span. The data on unrelated individuals emerging from an ever-increasing number of centenarian studies makes this possible. This paper summarizes the rich literature dealing with the various aspects of the influence of genes on individual survival. Common phenomena affecting the development of disease and longevity are discussed. The major methodological difficulty one is confronted with when studying the epidemiology of longevity involves the complexity of the phenomenon, which arises from the polygenic nature of life span and historical mortality change. We discuss this issue and suggest new methodological approaches.

Authors
De Benedictis, G; Tan, Q; Jeune, B; Christensen, K; Ukraintseva, SV; Bonafè, M; Franceschi, C; Vaupel, JW; Yashin, AI
MLA Citation
De Benedictis, G, Tan, Q, Jeune, B, Christensen, K, Ukraintseva, SV, Bonafè, M, Franceschi, C, Vaupel, JW, and Yashin, AI. "Recent advances in human gene-longevity association studies." Mech Ageing Dev 122.9 (July 15, 2001): 909-920. (Review)
PMID
11348658
Source
pubmed
Published In
Mechanisms of Ageing and Development
Volume
122
Issue
9
Publish Date
2001
Start Page
909
End Page
920

Melatonin increases both life span and tumor incidence in female CBA mice.

From the age of 6 months until their natural deaths, female CBA mice were given melatonin with their drinking water (20 mg/l) for 5 consecutive days every month. Intact mice served as controls. The results of this study show that the consumption of melatonin did not significantly influence food consumption, but it did increase the body weight of older mice; it did not influence physical strength or the presence of fatigue; it decreased locomotor activity and body temperature; it inhibited free radical processes in serum, brain, and liver; it slowed down the age-related switching-off of estrous function; and it increased life span. However, we also found that treatment with the used dose of melatonin increased spontaneous tumor incidence in mice. For this reason, we concluded that it would be premature to recommend melatonin as a geroprotector for long-term use.

Authors
Anisimov, VN; Zavarzina, NY; Zabezhinski, MA; Popovich, IG; Zimina, OA; Shtylick, AV; Arutjunyan, AV; Oparina, TI; Prokopenko, VM; Mikhalski, AI; Yashin, AI
MLA Citation
Anisimov, VN, Zavarzina, NY, Zabezhinski, MA, Popovich, IG, Zimina, OA, Shtylick, AV, Arutjunyan, AV, Oparina, TI, Prokopenko, VM, Mikhalski, AI, and Yashin, AI. "Melatonin increases both life span and tumor incidence in female CBA mice." J Gerontol A Biol Sci Med Sci 56.7 (July 2001): B311-B323.
PMID
11445596
Source
pubmed
Published In
Journals of Gerontology: Series A
Volume
56
Issue
7
Publish Date
2001
Start Page
B311
End Page
B323

Replication studies in longevity: puzzling findings in Danish centenarians at the 3'APOB-VNTR locus.

In Danes we replicated the 3'APOB-VNTR gene/longevity association study previously carried out in Italians, by which the Small alleles (less than 35 repeats) had been identified as frailty alleles for longevity. In Danes, neither genotype nor allele frequencies differed between centenarians and 20-64-year-old subjects. However, when Danish and Italian data were compared, a significant difference (p = 0.0004) was found between the frequencies of Small alleles in youths, which disappeared in centenarians (p = 0.290). Furthermore, the demographic-genetic approach revealed in Danes a significant gene-sex interaction relevant to Long alleles (more than 37 repeats). The different findings in Denmark and Italy suggest that gene/longevity associations are population-specific, and heavily affected by the population-specific genetic and environmental history.

Authors
Varcasia, O; Garasto, S; Rizza, T; Andersen-Ranberg, K; Jeune, B; Bathum, L; Andreev, K; Tan, Q; Yashin, AI; Bonafè, M; Franceschi, C; De Benedictis, G
MLA Citation
Varcasia, O, Garasto, S, Rizza, T, Andersen-Ranberg, K, Jeune, B, Bathum, L, Andreev, K, Tan, Q, Yashin, AI, Bonafè, M, Franceschi, C, and De Benedictis, G. "Replication studies in longevity: puzzling findings in Danish centenarians at the 3'APOB-VNTR locus." Ann Hum Genet 65.Pt 4 (July 2001): 371-376.
PMID
11592926
Source
pubmed
Published In
Annals of Human Genetics
Volume
65
Issue
Pt 4
Publish Date
2001
Start Page
371
End Page
376
DOI
10.1017/S0003480001008715

Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer's disease.

Allele epsilon4 of the nuclear APOE gene is a leading genetic risk factor for sporadic Alzheimer's disease (AD). Moreover, an allele-specific effect of APOE isoforms on neuronal cell oxidative death is known. Because of the role of the mitochondrial genome (mtDNA) in oxidative phosphorylation and oxidative stress, an interaction between APOE polymorphism and mtDNA inherited variability in the genetic susceptibility to sporadic AD can be hypothesized. We have explored this hypothesis by analyzing mtDNA germline variants (mtDNA haplogroups) in a sample of AD patients (213 subjects) genotyped for APOE and classified as APOE epsilon4 carriers and non-carriers. We found that the frequency distribution of mtDNA haplogroups is different between epsilon4 carriers and non-carriers (P=0.018), thus showing non-random association between APOE and mtDNA polymorphisms. The same analysis, carried out in two samples of healthy subjects (179 age-matched and 210 individuals aged more than 100 years), showed independence between epsilon4 allele and mtDNA haplogroups. Therefore, the APOE/mtDNA interaction is restricted to AD and may affect susceptibility to the disease. In particular, some mtDNA haplogroups (K and U) seem to neutralize the harmful effect of the APOE epsilon4 allele, lowering the epsilon4 odds ratio from statistically significant to non-significant values.

Authors
Carrieri, G; Bonafè, M; De Luca, M; Rose, G; Varcasia, O; Bruni, A; Maletta, R; Nacmias, B; Sorbi, S; Corsonello, F; Feraco, E; Andreev, KF; Yashin, AI; Franceschi, C; De Benedictis, G
MLA Citation
Carrieri, G, Bonafè, M, De Luca, M, Rose, G, Varcasia, O, Bruni, A, Maletta, R, Nacmias, B, Sorbi, S, Corsonello, F, Feraco, E, Andreev, KF, Yashin, AI, Franceschi, C, and De Benedictis, G. "Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer's disease." Hum Genet 108.3 (March 2001): 194-198.
PMID
11354629
Source
pubmed
Published In
Human Genetics
Volume
108
Issue
3
Publish Date
2001
Start Page
194
End Page
198

Effect of synthetic thymic and pineal peptides on biomarkers of ageing, survival and spontaneous tumour incidence in female CBA mice.

Fifty female CBA mice were injected s.c. either with 0.1 ml saline, or with synthetic thymic dipeptide Lys-Glu or with synthetic pineal tetrapeptide Ala-Glu-Asp-Gly both in a single dose of 0.1 microg/animal monthly for five consecutive days from the age of 6 months until natural death. Lys-Glu did not significantly influence the body weight and food consumption, free radical processes and estrus function in mice and did increase their physical activity with the subsequent decrease in spontaneous lung adenomas incidence. The pineal peptide treatment was failed to modify the food consumption and physical strength of mice, and was followed by the increase in the body weight, mean survival (by 5.3%, P<0.05) and maximum (by 10 months), by slow down of the ageing of estrus function, by the decrease in body temperature, physical activity, free radical processes and spontaneous tumor incidence (mainly, lung adenomas) in mice. These data suggest the geroprotector potential of the pineal peptide.

Authors
Anisimov, VN; Khavinson, VK; Mikhalski, AI; Yashin, AI
MLA Citation
Anisimov, VN, Khavinson, VK, Mikhalski, AI, and Yashin, AI. "Effect of synthetic thymic and pineal peptides on biomarkers of ageing, survival and spontaneous tumour incidence in female CBA mice." Mech Ageing Dev 122.1 (January 2001): 41-68.
PMID
11163623
Source
pubmed
Published In
Mechanisms of Ageing and Development
Volume
122
Issue
1
Publish Date
2001
Start Page
41
End Page
68

Measuring the genetic influence in modulating the human life span: gene-environment interaction and the sex-specific genetic effect.

New approaches are needed to explore the different ways in which genes affect the human life span. One needs to assess the genetic effects themselves, as well as gene-environment interactions and sex dependency. In this paper, we present a new model that combines both genotypic and demographic information in the estimation of the genetic influence on life spans. Based on Cox's proportional hazard assumption, the model measures the risks for each gene as well as for gene-environment and gene-sex interactions, while controlling for confounding factors. A two-step MLE is introduced to obtain a non-parametric form of the baseline hazard function. The model is applied to genotypic data from Italian centenarian studies to estimate relative risks of candidate genes, risks due to interactions and initial frequencies of different genes in the population. Results from models that either do or do not take into consideration individual heterogeneity are compared. It is shown that ignoring the existence of heterogeneity can lead to a systematic underestimation of genetic effects and effects due to interactions.

Authors
Tan, Q; De Benedictis, G; Yashi, AI; Bonafe, M; DeLuca, M; Valensin, S; Vaupel, JW; Franceschi, C
MLA Citation
Tan, Q, De Benedictis, G, Yashi, AI, Bonafe, M, DeLuca, M, Valensin, S, Vaupel, JW, and Franceschi, C. "Measuring the genetic influence in modulating the human life span: gene-environment interaction and the sex-specific genetic effect." Biogerontology 2.3 (2001): 141-153.
PMID
11708716
Source
pubmed
Published In
Biogerontology
Volume
2
Issue
3
Publish Date
2001
Start Page
141
End Page
153

Hormesis and debilitation effects in stress experiments using the nematode worm Caenorhabditis elegans: The model of balance between cell damage and HSP levels

In this article, we discuss mechanisms responsible for the effects of heat treatment on increasing subsequent survival in the nematode worm Caenorhabditis elegans. We assume that the balance between damage associated with exposure to thermal stress and the level of heat shock proteins produced plays a key role in forming the age-pattern of mortality and survival in stress experiments. We propose a stochastic model of stress, which describes the accumulation of damage in the cells of the worm as the worm ages. The model replicates the age trajectories of experimental survival curves in three experiments in which worms were heat-treated for 0, 1, 2, 4, 6, or 8 h. We also discuss analytical results and directions of further research. The proposed method of stochastic modelling of survival data provides a new approach that can be used to model, analyse and extrapolate experimental results. © 2001 Elsevier Science Inc. All rights reserved.

Authors
Butov, A; Johnson, T; Cypser, J; Sannikov, I; Volkov, M; Sehl, M; Yashin, A
MLA Citation
Butov, A, Johnson, T, Cypser, J, Sannikov, I, Volkov, M, Sehl, M, and Yashin, A. "Hormesis and debilitation effects in stress experiments using the nematode worm Caenorhabditis elegans: The model of balance between cell damage and HSP levels." Experimental Gerontology 37.1 (2001): 57-66.
PMID
11738147
Source
scival
Published In
Experimental Gerontology
Volume
37
Issue
1
Publish Date
2001
Start Page
57
End Page
66
DOI
10.1016/S0531-5565(01)00161-9

A homeostatic model of oxidative damage explains paradoxes observed in earlier aging experiments: a fusion and extension of older theories of aging.

The Rate of Living and the Threshold Theories of Aging are two contradicting approaches used to explain experimental facts about aging in fruit flies. In this paper we suggest an approach that unifies these theories and removes the contradiction. The approach involves quantitative description of the oxidative stress theory of aging, which is presented in the form of a mathematical homeostatic model. The crucial variable in the model is called 'homeostatic capacity', which is analogous to the classical notion of vitality. We model the process of aging as the age-related accumulation of damage produced by oxidative stress, which reduces the homeostatic capacity of the organism. The model is tested with the experimental data obtained in the classical experiments by Maynard Smith in 1958-1963. Our homeostatic model explains the well-known results of these experiments more accurate than any one of the early theories of aging. We form an hypothesis about the mechanisms underlying the results observed in the experiments and analyze a possible interplay of these mechanisms. Our virtual replication of Maynard Smith's classical experiments demonstrates that mathematical modeling can be a powerful tool to reveal and investigate the inherent genetic and physiological processes underlying the data observed in complicated insect experiments.

Authors
Novoseltsev, VN; Novoseltseva, J; Yashin, AI
MLA Citation
Novoseltsev, VN, Novoseltseva, J, and Yashin, AI. "A homeostatic model of oxidative damage explains paradoxes observed in earlier aging experiments: a fusion and extension of older theories of aging." Biogerontology 2.2 (2001): 127-138. (Review)
PMID
11708379
Source
pubmed
Published In
Biogerontology
Volume
2
Issue
2
Publish Date
2001
Start Page
127
End Page
138

Heating stress patterns in Caenorhabditis elegans longevity and survivorship.

Survival data from Caenorhabditis elegans strain TJ1060 (spe-9; fer-15) following brief exposure to 35 degrees C have been investigated. Three experiments with 3-day-old worms were conducted with heat duration ranging between 0 and 12 hours. A statistically significant increase in life expectancy was observed in the groups heated for less than 2 hours, as compared to the unheated control groups. In different experiments P-values for the observed life spans under the hypothesis that heating has no influence on longevity were P < 0.004 after 0.5 hour heat, P < 0.012 after 1 hour heat and P < 0.055 after 2 hours of heating. A biphasic survival model with Gamma distributed frailty has been constructed to describe the survival of worms after heating. The increase in the remaining life expectancy is determined by more effective protection by heat-induced substances in the ages yanger than 27 days. The unheated control group demonstrated acquired heterogeneity of frailty with chronological age while the heat-induced substances defend the worms in a universal way and protect against the development of frailty.

Authors
Michalski, AI; Johnson, TE; Cypser, JR; Yashin, AI
MLA Citation
Michalski, AI, Johnson, TE, Cypser, JR, and Yashin, AI. "Heating stress patterns in Caenorhabditis elegans longevity and survivorship." Biogerontology 2.1 (2001): 35-44.
PMID
11708615
Source
pubmed
Published In
Biogerontology
Volume
2
Issue
1
Publish Date
2001
Start Page
35
End Page
44

Anticipation of oxidative damage decelerates aging in virgin female medflies: hypothesis tested by statistical modeling.

Empirical analysis of survival data obtained from large samples of Mediterranean fruit flies shows that the trajectory of the mortality rate for virgin females departs from that for females maintained in mixed sex cages. It increases, decelerates, reaches its maximum, declines and then increases again within the reproductive interval. Non-virgin females, however, display an early-age plateau instead of this dip. We assume that these deviations are produced by the interplay between changes in oxygen consumption associated with reproductive behavior and the antioxidant defense that acts against anticipated oxidative damage caused by reproduction. Since there are no data on antioxidant mechanisms in medflies available that explain the observed patterns of mortality, we develop a model of physiological aging based on oxidative stress theory, which describes age-related changes in oxygen consumption and in antioxidative capacity during the reproductive period. Using this model, we simulate virtual populations of 25,000 virgin and non-virgin flies, calculate the respective mortality rates and show that they practically coincide with those of experimental populations. We show that the hypothesis about the biological support of reproduction used in our model does not contradict experimental data. The model explains how the early-age dip and plateau might arise in the mortality rates of female medflies and why the male mortality pattern does not exhibit such deviations.

Authors
Novoseltsev, VN; Carey, J; Liedo, P; Novoseltseva, J; Yashin, AI
MLA Citation
Novoseltsev, VN, Carey, J, Liedo, P, Novoseltseva, J, and Yashin, AI. "Anticipation of oxidative damage decelerates aging in virgin female medflies: hypothesis tested by statistical modeling." Exp Gerontol 35.8 (October 2000): 971-987.
PMID
11121684
Source
pubmed
Published In
Experimental Gerontology
Volume
35
Issue
8
Publish Date
2000
Start Page
971
End Page
987

The network and the remodeling theories of aging: historical background and new perspectives.

Two general theories, i.e. "the network theory of aging" (1989) and "the remodeling theory of aging" (1995), as well as their implications, new developments, and perspectives are reviewed and discussed. Particular attention has been paid to illustrate: (i) how the network theory of aging fits with recent data on aging and longevity in unicellular organisms (yeast), multicellular organisms (worms), and mammals (mice and humans); (ii) the evolutionary and experimental basis of the remodeling theory of aging (immunological, genetic, and metabolic data in healthy centenarians, and studies on the evolution of the immune response, stress and inflammation) and its recent development (the concepts of "immunological space" and "inflamm-aging"); (iii) the profound relationship between these two theories and the data which suggest that aging and longevity are related, in a complex way, to the capability to cope with a variety of stressors.

Authors
Franceschi, C; Valensin, S; Bonafè, M; Paolisso, G; Yashin, AI; Monti, D; De Benedictis, G
MLA Citation
Franceschi, C, Valensin, S, Bonafè, M, Paolisso, G, Yashin, AI, Monti, D, and De Benedictis, G. "The network and the remodeling theories of aging: historical background and new perspectives." Exp Gerontol 35.6-7 (September 2000): 879-896. (Review)
PMID
11053678
Source
pubmed
Published In
Experimental Gerontology
Volume
35
Issue
6-7
Publish Date
2000
Start Page
879
End Page
896

Genetic marker data in survival studies of siblings: The results of simulation study

Authors
Yashin, AI; Iachine, IA; Begun, AZ
MLA Citation
Yashin, AI, Iachine, IA, and Begun, AZ. "Genetic marker data in survival studies of siblings: The results of simulation study." September 2000.
Source
wos-lite
Published In
Behavior Genetics
Volume
30
Issue
5
Publish Date
2000
Start Page
422
End Page
423

Genetic and environmental influences on functional abilities in Danish twins aged 75 years and older.

BACKGROUND: Functional abilities vary widely among elderly persons. The determinants of this variation are probably multiple and include normal aging processes as well as disease expression. This study estimates the relative importance of genetic and environmental factors to variation in functional abilities in elderly persons. METHODS: We conducted a survey among all Danish twins aged 75 years and older who were identified in the population-based Danish Twin Registry. Interviews were conducted with 77% (7% by proxy responders) of the 3099 individuals in the study population. Functional abilities were assessed by validated Danish survey instruments and were scored on three scales. Heritability (proportion of the population variance attributable to genetic variation) was estimated using structural equation analyses. RESULTS: Structural equation analyses revealed a substantial heritability (34%-47%) for the three functional ability scores among the women aged 80 years and older compared with a more modest heritability (15%-34%) among the women aged 75-79 years. The remaining variation could be attributed to individuals' nonfamilial environments. Comparisons of the functional abilities of twins with living versus deceased co-twins also suggested a difference in the genetic influence for the two age groups. Although heritability estimates were uniformly low in the male participant sample, the size of the sample was not sufficiently large to allow for precise estimates of heritability. CONCLUSION: For women we found that the effect of genetic factors on functional abilities increases with age and accounts for one third to one half of the variation among individuals aged 80 years and older. An understanding of the genetic mechanisms underlying functional abilities in the oldest individuals may enhance the possibilities for improving health in the elderly population by modifying environmental factors.

Authors
Christensen, K; McGue, M; Yashin, A; Iachine, I; Holm, NV; Vaupel, JW
MLA Citation
Christensen, K, McGue, M, Yashin, A, Iachine, I, Holm, NV, and Vaupel, JW. "Genetic and environmental influences on functional abilities in Danish twins aged 75 years and older." J Gerontol A Biol Sci Med Sci 55.8 (August 2000): M446-M452.
PMID
10952367
Source
pubmed
Published In
Journals of Gerontology: Series A
Volume
55
Issue
8
Publish Date
2000
Start Page
M446
End Page
M452

Genes and longevity: lessons from studies of centenarians.

In population studies of aging, the data on genetic markers are often collected for individuals from different age groups. The idea of such studies is to identify "longevity" or "frailty" genes by comparing the frequencies of genotypes in the oldest and in the younger groups of individuals. In this paper we discuss a new approach to the analysis of such data. This approach, based on the maximum likelihood method, combines data on genetic markers with survival information obtained from standard demographic life tables. This method allows us to evaluate survival characteristics for individuals carrying respective candidate genes. It can also be used in the estimation of the effects of allele-area and allele-allele interaction, either in the presence or absence of hidden heterogeneity. We apply this method to the analysis of Italian data on genetic markers for five autosomal loci and mitochondrial genomes. Then we discuss basic assumptions used in this analysis and directions of further research.

Authors
Yashin, AI; De Benedictis, G; Vaupel, JW; Tan, Q; Andreev, KF; Iachine, IA; Bonafe, M; Valensin, S; De Luca, M; Carotenuto, L; Franceschi, C
MLA Citation
Yashin, AI, De Benedictis, G, Vaupel, JW, Tan, Q, Andreev, KF, Iachine, IA, Bonafe, M, Valensin, S, De Luca, M, Carotenuto, L, and Franceschi, C. "Genes and longevity: lessons from studies of centenarians." J Gerontol A Biol Sci Med Sci 55.7 (July 2000): B319-B328.
PMID
10898245
Source
pubmed
Published In
Journals of Gerontology: Series A
Volume
55
Issue
7
Publish Date
2000
Start Page
B319
End Page
B328

Genetic nature of individual frailty: comparison of two approaches.

The traditional frailty models used in genetic analysis of bivariate survival data assume that individual frailty (and longevity) is influenced by thousands of genes, and that the contribution of each separate gene is small. This assumption, however, does not have a solid biological basis. It may just happen that one or a small number of genes makes a major contribution to determining the human life span. To answer the questions about the nature of the genetic influence on life span using survival data, models are needed that specify the influence of major genes on individual frailty and longevity. The goal of this paper is to test the nature of genetic influences on individual frailty and longevity using survival data on Danish twins. We use a new bivariate survival model with one major gene influencing life span to analyse survival data on MZ (monozygotic) and DZ (dizygotic) twins. The analysis shows that two radically different classes of model provide an equally good fit to the data. However, the asymptotic behaviour of some conditional statistics is different in models from different classes. Because of the limited sample size of bivariate survival data we cannot draw reliable conclusions about the nature of genetic effects on life span. Additional information about tails of bivariate distribution or risk factors may help to solve this problem.

Authors
Begun, AZ; Iachine, IA; Yashin, AI
MLA Citation
Begun, AZ, Iachine, IA, and Yashin, AI. "Genetic nature of individual frailty: comparison of two approaches." Twin Res 3.1 (March 2000): 51-57.
PMID
10808241
Source
pubmed
Published In
Twin research : the official journal of the International Society for Twin Studies
Volume
3
Issue
1
Publish Date
2000
Start Page
51
End Page
57

Vitality index in survival modeling: how physiological aging influences mortality.

We investigated the relation of the age trajectory of physiological indicators of the average metabolic activity of organisms in a population to the age-specific population mortality rate. We show that a metabolic rate indicator (MRI) can be estimated using traditional physiological measures, such as homeostatic serum glucose concentration, vital capacity, and such. Estimates of the MRI were made from data collected in the Multiple Risk Factor Intervention Trial (MRFIT) study. The relation of the empirical mortality rate and MRI was also tested using MRFIT data. The age trajectory of MRI was evaluated using Swedish mortality data. The mortality results reproduce the "Strehler and Mildvan effect." The average rate of decline of MRI with age coincides with estimates predicted by Strehler using other methods. Possible extensions of the method are discussed.

Authors
Zuev, SM; Yashin, AI; Manton, KG; Dowd, E; Pogojev, IB; Usmanov, RN
MLA Citation
Zuev, SM, Yashin, AI, Manton, KG, Dowd, E, Pogojev, IB, and Usmanov, RN. "Vitality index in survival modeling: how physiological aging influences mortality." J Gerontol A Biol Sci Med Sci 55.1 (January 2000): B10-B19.
PMID
10719758
Source
pubmed
Published In
Journals of Gerontology: Series A
Volume
55
Issue
1
Publish Date
2000
Start Page
B10
End Page
B19

Multivariate frailty model with a major gene: Application to genealogical data

Multivariate survival models are shown to be appropriate for the analysis of the genetic and the environmental nature of a human life-span. Models which involve continuously distributed individual frailty, play an important role in the genetic analysis of an individual's susceptibility to disease and death. These models, however, are not appropriate for the detection of the effects of separate genes on survival. For this purpose we developed a 'major gene' frailty model of multivariate survival and applied it to simulated and real pedigree data. The analysis shows that this model can be used for the detection of the presence of major genes in the population and for the evaluation of the effects of such genes on survival.

Authors
Begun, A; Desjardins, B; Iachine, I; Yashin, A
MLA Citation
Begun, A, Desjardins, B, Iachine, I, and Yashin, A. "Multivariate frailty model with a major gene: Application to genealogical data." Studies in Health Technology and Informatics 77 (2000): 412-416.
Source
scival
Published In
Studies in health technology and informatics
Volume
77
Publish Date
2000
Start Page
412
End Page
416
DOI
10.3233/978-1-60750-921-9-412

Mortality modeling: A review

Looking at survival in terms of biological indicators of aging has given rise to various models of mortality, some of which we review here. The most notable models are that of Strehler and Mildvan, which relates the force of mortality to the ability of organisms to compensate for stress, and that of Sacher and Trucco, which describes the role played by homeostatic forces in shaping the age-specific pattern of mortality. The analysis of longitudinal data in aging studies now incorporates the notions of heterogeneity and frailty, as well as that of changes in the "repair capacity" of organisms. Furthermore, attention is now being paid to evolutionary theory and to models of senescence. These models and directions for further research are discussed.

Authors
Yashin, AI; Iachine, IA; Begun, AS
MLA Citation
Yashin, AI, Iachine, IA, and Begun, AS. "Mortality modeling: A review." Mathematical Population Studies 8.4 (2000): 305-332.
Source
scival
Published In
Mathematical Population Studies
Volume
8
Issue
4
Publish Date
2000
Start Page
305
End Page
332

Heritability of death from respiratory diseases: an analysis of Danish twin survival data using a correlated frailty model.

Authors
Wienke, A; Christensen, K; Holm, NV; Yashin, AI
MLA Citation
Wienke, A, Christensen, K, Holm, NV, and Yashin, AI. "Heritability of death from respiratory diseases: an analysis of Danish twin survival data using a correlated frailty model." Stud Health Technol Inform 77 (2000): 407-411.
PMID
11187584
Source
pubmed
Published In
Studies in health technology and informatics
Volume
77
Publish Date
2000
Start Page
407
End Page
411

Genes, demography, and life span: the contribution of demographic data in genetic studies on aging and longevity.

In population studies on aging, the data on genetic markers are often collected for individuals from different age groups. The purpose of such studies is to identify, by comparison of the frequencies of selected genotypes, "longevity" or "frailty" genes in the oldest and in younger groups of individuals. To address questions about more-complicated aspects of genetic influence on longevity, additional information must be used. In this article, we show that the use of demographic information, together with data on genetic markers, allows us to calculate hazard rates, relative risks, and survival functions for respective genes or genotypes. New methods of combining genetic and demographic information are discussed. These methods are tested on simulated data and then are applied to the analysis of data on genetic markers for two haplogroups of human mtDNA. The approaches suggested in this article provide a powerful tool for analyzing the influence of candidate genes on longevity and survival. We also show how factors such as changes in the initial frequencies of candidate genes in subsequent cohorts, or secular trends in cohort mortality, may influence the results of an analysis.

Authors
Yashin, AI; De Benedictis, G; Vaupel, JW; Tan, Q; Andreev, KF; Iachine, IA; Bonafe, M; DeLuca, M; Valensin, S; Carotenuto, L; Franceschi, C
MLA Citation
Yashin, AI, De Benedictis, G, Vaupel, JW, Tan, Q, Andreev, KF, Iachine, IA, Bonafe, M, DeLuca, M, Valensin, S, Carotenuto, L, and Franceschi, C. "Genes, demography, and life span: the contribution of demographic data in genetic studies on aging and longevity." Am J Hum Genet 65.4 (October 1999): 1178-1193.
PMID
10486337
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
65
Issue
4
Publish Date
1999
Start Page
1178
End Page
1193
DOI
10.1086/302572

Half of the variation in susceptibility to mortality is genetic: findings from Swedish twin survival data.

Molecular epidemiological studies confirm tremendous variability in genetic and environmental susceptibility to disease and death for humans. This variability as well as the roles of genetic and environmental factors in susceptibility to death can be estimated in the analysis of survival data on related individuals (e.g., twins). In this paper, correlated gamma-frailty models are applied to survival data on Swedish twins to estimate genetic parameters in six models of susceptibility. It is shown that the frailty model with additive genetic and nonshared environmental components fits the data best. The estimate of narrow-sense heritability in gamma frailty is about 50%. The results of genetic analysis confirm our earlier findings from the studies of Danish twins that about 50% of individual susceptibility approximated by gamma-distributed frailty is heritable.

Authors
Yashin, AI; Iachine, IA; Harris, JR
MLA Citation
Yashin, AI, Iachine, IA, and Harris, JR. "Half of the variation in susceptibility to mortality is genetic: findings from Swedish twin survival data." Behav Genet 29.1 (January 1999): 11-19.
PMID
10371754
Source
pubmed
Published In
Behavior Genetics
Volume
29
Issue
1
Publish Date
1999
Start Page
11
End Page
19

Dependent Hazards in Multivariate Survival Problems

A new class of bivariate survival distributions is constructed from a given family of survival distributions. The properties of these distributions are analyzed. It is shown that the same bivariate survival function can be derived using two radically different concepts: one involves transformation of the well-known bivariate survival function; the other involves correlated stochastic hazards. The new conditions that guarantee negative associations of life spans are derived. An exponential representation of the survival function for two related individuals is derived in terms of the conditional distribution of the stochastic hazards among survivors. Versions of the multivariate correlated gamma-frailty model are investigated. © 1999 Academic Press.

Authors
Yashin, AI; Iachine, IA
MLA Citation
Yashin, AI, and Iachine, IA. "Dependent Hazards in Multivariate Survival Problems." Journal of Multivariate Analysis 71.2 (1999): 241-261.
Source
scival
Published In
Journal of Multivariate Analysis
Volume
71
Issue
2
Publish Date
1999
Start Page
241
End Page
261
DOI
10.1006/jmva.1999.1848

On the possibility of immune response control based on parameterization and a mathematical model of molecular cellular kinetics

In this paper we attempt to show that it is possible to study an 'age-immune system-mortality' chain, using mathematical models of disease. We also give the results of parameterization of models of this type and formulate a problem of optimal control over disease treatment. © VSP 1999.

Authors
Belykh, LN; Usmanov, RN; Yashin, AI; Zuev, SM
MLA Citation
Belykh, LN, Usmanov, RN, Yashin, AI, and Zuev, SM. "On the possibility of immune response control based on parameterization and a mathematical model of molecular cellular kinetics." Russian Journal of Numerical Analysis and Mathematical Modelling 14.6 (1999): 469-478.
Source
scival
Published In
Russian Journal of Numerical Analysis and Mathematical Modelling
Volume
14
Issue
6
Publish Date
1999
Start Page
469
End Page
478

Genetic factors in susceptibility to death: a comparative analysis of bivariate survival models.

BACKGROUND: Molecular epidemiological studies of aging and longevity are focused on evaluating the effects of single genes on susceptibility to disease and death. The effects of all genetic factors on susceptibility can be evaluated from the analysis of survival data on related individuals. METHOD: The analyses of survival data on Danish monozygotic (MZ) and dizygotic (DZ) twins are performed using gamma, inverse Gaussian and three-parameter correlated frailty models. The semiparametric representations of the respective models are used to obtain maximum likelihood estimates of model parameters. The results are compared using the likelihood ratio test. RESULTS: The survival of Danish MZ and DZ twins can be characterised by the same marginal hazards and identical univariate frailty distributions for any of the three frailty models. In all three cases the genetic influence on frailty is statistically significant. CONCLUSION: All three models can be used to study genetic effects on susceptibility. The gamma and inverse Gaussian frailty models fit the Danish twin data equally well. Our analyses show that for the Danish twin data these two models are preferable to the three-parameter model.

Authors
Yashin, AI; Begun, AZ; Iachine, IA
MLA Citation
Yashin, AI, Begun, AZ, and Iachine, IA. "Genetic factors in susceptibility to death: a comparative analysis of bivariate survival models." J Epidemiol Biostat 4.1 (1999): 53-60.
PMID
10613717
Source
pubmed
Published In
Journal of Epidemiology and Biostatistics
Volume
4
Issue
1
Publish Date
1999
Start Page
53
End Page
60

What difference does the dependence between durations make? Insights for population studies of aging.

The interpretation of age-specific changes in hazards, relative risks, genetic parameters and other indicators of aging calculated from data on related individuals should take into account the regularities of bivariate selection. Due to such selection the hazard rate calculated for twins who have survived to a certain age may be lower than for singletons, even if marginal chances of survival for all individuals are the same. In a mixed population of relatives the proportion of pairs with closer family links increases with age, even if all marginal individual chances of survival are the same. The proportion of chronic conditions for MZ twins observed in a cross-sectional study may be different from that of DZ twins. The age-dependence of relative risks calculated in genetic-epidemiological studies of twins does not necessarily reflect changes in genetic influence on individual susceptibility to disease and death during the aging process. The age-related changes in heritability of susceptibility estimated in twin studies may have nothing to do with changes in the genetic determination of diseases with age. These issues are illustrated by empirical graphs together with the results of modeling and statistical analysis.

Authors
Yashin, AI; Iachine, IA
MLA Citation
Yashin, AI, and Iachine, IA. "What difference does the dependence between durations make? Insights for population studies of aging." Lifetime Data Anal 5.1 (1999): 5-22.
PMID
10213999
Source
pubmed
Published In
Lifetime Data Analysis
Volume
5
Issue
1
Publish Date
1999
Start Page
5
End Page
22

How heritable is individual susceptibility to death? The results of an analysis of survival data on Danish, Swedish and Finnish twins.

Molecular epidemiological studies confirm a substantial contribution of individual genes to variability in susceptibility to disease and death for humans. To evaluate the contribution of all genes to susceptibility and to estimate individual survival characteristics, survival data on related individuals (eg twins or other relatives) are needed. Correlated gamma-frailty models of bivariate survival are used in a joint analysis of survival data on more than 31,000 pairs of Danish, Swedish and Finnish male and female twins using the maximum likelihood method. Additive decomposition of frailty into genetic and environmental components is used to estimate heritability in frailty. The estimate of the standard deviation of frailty from the pooled data is about 1.5. The hypothesis that variance in frailty and correlations of frailty for twins are similar in the data from all three countries is accepted. The estimate of narrow-sense heritability in frailty is about 0.5. The age trajectories of individual hazards are evaluated for all three populations of twins and both sexes. The results of our analysis confirm the presence of genetic influences on individual frailty and longevity. They also suggest that the mechanism of these genetic influences may be similar for the three Scandinavian countries. Furthermore, results indicate that the increase in individual hazard with age is more rapid than predicted by traditional demographic life tables.

Authors
Iachine, IA; Holm, NV; Harris, JR; Begun, AZ; Iachina, MK; Laitinen, M; Kaprio, J; Yashin, AI
MLA Citation
Iachine, IA, Holm, NV, Harris, JR, Begun, AZ, Iachina, MK, Laitinen, M, Kaprio, J, and Yashin, AI. "How heritable is individual susceptibility to death? The results of an analysis of survival data on Danish, Swedish and Finnish twins." Twin Res 1.4 (December 1998): 196-205.
PMID
10100811
Source
pubmed
Published In
Twin research : the official journal of the International Society for Twin Studies
Volume
1
Issue
4
Publish Date
1998
Start Page
196
End Page
205

Gene/longevity association studies at four autosomal loci (REN, THO, PARP, SOD2).

The possibility that four loci (REN, THO, PARP, SOD2) are associated with longevity was explored by comparing the genotypic pools of subjects older than 100 years with those of younger subjects matched for sex and geographic area (northern and southern Italy). The markers (all located within the respective gene) were HUMREN4; HUMTHO1; HUMPARP (gt)845nt; SOD2(C/T)401nt. In order to reduce the number of genotypes, multiallelic polymorphisms were recoded as diallelic according to allele size and frequency patterns (small: S, and large: L, alleles). A significant loss of LL homozygous genotypes was found at the THO locus in male but not in female centenarians with respect to matched controls. On the other hand no significant difference was found between case/control genotypic frequencies at REN, PARP, SOD2 loci. The latter loci therefore do not affect inter-individual variability in life expectancy (at least in terms of qualitative variants associated with the tested markers). However, the data is consistent with an association between the THO locus and longevity.

Authors
De Benedictis, G; Carotenuto, L; Carrieri, G; De Luca, M; Falcone, E; Rose, G; Cavalcanti, S; Corsonello, F; Feraco, E; Baggio, G; Bertolini, S; Mari, D; Mattace, R; Yashin, AI; Bonafè, M; Franceschi, C
MLA Citation
De Benedictis, G, Carotenuto, L, Carrieri, G, De Luca, M, Falcone, E, Rose, G, Cavalcanti, S, Corsonello, F, Feraco, E, Baggio, G, Bertolini, S, Mari, D, Mattace, R, Yashin, AI, Bonafè, M, and Franceschi, C. "Gene/longevity association studies at four autosomal loci (REN, THO, PARP, SOD2)." Eur J Hum Genet 6.6 (November 1998): 534-541.
PMID
9887369
Source
pubmed
Published In
European Journal of Human Genetics
Volume
6
Issue
6
Publish Date
1998
Start Page
534
End Page
541
DOI
10.1038/sj.ejhg.5200222

Biodemographic trajectories of longevity.

Old-age survival has increased substantially since 1950. Death rates decelerate with age for insects, worms, and yeast, as well as humans. This evidence of extended postreproductive survival is puzzling. Three biodemographic insights--concerning the correlation of death rates across age, individual differences in survival chances, and induced alterations in age patterns of fertility and mortality--offer clues and suggest research on the failure of complicated systems, on new demographic equations for evolutionary theory, and on fertility-longevity interactions. Nongenetic changes account for increases in human life-spans to date. Explication of these causes and the genetic license for extended survival, as well as discovery of genes and other survival attributes affecting longevity, will lead to even longer lives.

Authors
Vaupel, JW; Carey, JR; Christensen, K; Johnson, TE; Yashin, AI; Holm, NV; Iachine, IA; Kannisto, V; Khazaeli, AA; Liedo, P; Longo, VD; Zeng, Y; Manton, KG; Curtsinger, JW
MLA Citation
Vaupel, JW, Carey, JR, Christensen, K, Johnson, TE, Yashin, AI, Holm, NV, Iachine, IA, Kannisto, V, Khazaeli, AA, Liedo, P, Longo, VD, Zeng, Y, Manton, KG, and Curtsinger, JW. "Biodemographic trajectories of longevity." Science 280.5365 (May 8, 1998): 855-860. (Review)
PMID
9599158
Source
pubmed
Published In
Science
Volume
280
Issue
5365
Publish Date
1998
Start Page
855
End Page
860

The genetic component of discrete disability traits: an analysis using liability models with age-dependent thresholds.

The presence of familial and genetic effects in the Activities-of-Daily-Life (ADL) data collected in the first wave of the 1995 Longitudinal Study of Aging of Danish Twins (LSADT) older than 75 is tested using multithreshold liability models of disability with age-dependent thresholds. These models are developed for discrete scores represented by five disability scales of male and female Danish twins. The presence of familial effects is revealed in all five scales of disability data for females and in three scales of data for males. Genetic effects are found to be significant in all four levels of aggregation of the Upper Limb-T (T = tiredness) disability scale for females and in the PADL-H (H = need for help) scale for males. Genetic effects are also pronounced in the Mobility-T scale for females and in the Lower Limb-T scale for males and females. For females, the genetic effects in the T-scale seem to be more pronounced than in the H-scale. For males, genetic effects are more pronounced in the H-scale. The estimates for MZ correlations in liability tend to be higher than the estimates for DZ correlations in almost all cases, which suggests that additional genetic effects may be revealed should the sample size of the ADL data be increased.

Authors
Yashin, AI; Iachine, IA; Christensen, K; Holm, NV; Vaupel, JW
MLA Citation
Yashin, AI, Iachine, IA, Christensen, K, Holm, NV, and Vaupel, JW. "The genetic component of discrete disability traits: an analysis using liability models with age-dependent thresholds." Behav Genet 28.3 (May 1998): 207-214.
PMID
9670596
Source
pubmed
Published In
Behavior Genetics
Volume
28
Issue
3
Publish Date
1998
Start Page
207
End Page
214

Age-related changes of the 3'APOB-VNTR genotype pool in ageing cohorts

The analysis of seven different age cohorts (697 individuals from 10 to 109 years old) revealed age-related changes in the 3'APOB-VNTR genotype pool. By recoding the 3'APOB-VNTR alleles into three size-classes (small, S, 26-34 repeats; medium, M, 35-39 repeats; large, L, 41-55 repeats), an age-related convex trajectory of the frequency of SS homozygotes was found. The frequency of SS in the genotype pool increased from the group aged 10-19 years (3.06 ± 1.74%) to that aged 40-49 years (8.51 ± 4.07%). Then it declined reaching the minimum value in centenarians (1.58 ± 0.90%). The observed trajectory is in agreement with that expected by assuming crossing of mortality curves relevant to subgroups of individuals having different genotypes.

Authors
Benedictis, GD; Carotenuto, L; Carrieri, G; Luca, MD; Falcone, E; Rose, G; Yashin, AI; Bonafè, M; Franceschi, C
MLA Citation
Benedictis, GD, Carotenuto, L, Carrieri, G, Luca, MD, Falcone, E, Rose, G, Yashin, AI, Bonafè, M, and Franceschi, C. "Age-related changes of the 3'APOB-VNTR genotype pool in ageing cohorts." Annals of Human Genetics 62.2 (1998): 115-122.
PMID
9759473
Source
scival
Published In
Annals of Human Genetics
Volume
62
Issue
2
Publish Date
1998
Start Page
115
End Page
122
DOI
10.1017/S0003480098006757

Multistate models of postpartum infecundity, fecundability and sterility by age and parity: Methodological issues

How do hidden physiological processes influence estimates of fecundability and sterility? Does unobserved heterogeneity play a role in these estimates? To address these questions mathematical models of the reproductive process are needed. It is not well known how to evaluate characteristics of reproductive models based on observed reproductive history data, and such models may not be identifiable without ancillary information. However, little is known about how to introduce ancillary information into reproductive models. Furthermore, even if such information was involved, the use of standard software packages for maximization of the likelihood function is often not feasible, because the function cannot be represented in an explicit parametric form. In this paper we propose an approach which represents the likelihood function in a form useful for further analysis. This approach is based on multistate models of the basic physiological processes that influence reproductive outcomes, and it is suitable in applications where ancillary information is given in the form of hazard rates. As an alternative, a competing risks model with incomplete information is discussed. © 1993 OPA (Overseas Publishers Association) Amsterdam B.V. Published under license under the Gordon and Breach Publishers imprint.

Authors
Yashin, AI; Iachine, IA; Andreev, KF; Larsen, U
MLA Citation
Yashin, AI, Iachine, IA, Andreev, KF, and Larsen, U. "Multistate models of postpartum infecundity, fecundability and sterility by age and parity: Methodological issues." Mathematical Population Studies 7.1 (1998): 51-78.
Source
scival
Published In
Mathematical Population Studies
Volume
7
Issue
1
Publish Date
1998
Start Page
51
End Page
78

How frailty models can be used for evaluating longevity limits: taking advantage of an interdisciplinary approach.

In this paper we discuss an approach to the analysis of mortality and longevity limits when survival data on related individuals with and without observed covariates are available. The approach combines the ideas of demography and survival analysis with methods of quantitative genetics and genetic epidemiology. It allows us to analyze the genetic structure of frailty in the Cox-type hazard model with random effects. We demonstrate the implementation of this strategy to survival data on Danish twins. We then evaluate the resulting lower bounds for biological limits of human longevity. Finally, we discuss the limitations of this approach and directions of further research.

Authors
Yashin, AI; Iachine, IA
MLA Citation
Yashin, AI, and Iachine, IA. "How frailty models can be used for evaluating longevity limits: taking advantage of an interdisciplinary approach." Demography 34.1 (February 1997): 31-48. (Review)
PMID
9074830
Source
pubmed
Published In
Demography
Volume
34
Issue
1
Publish Date
1997
Start Page
31
End Page
48

Analyses of cohort mortality incorporating observed and unobserved risk factors

Interventions to prevent disease and increase life expectancy are most effectively developed from data on pathways to disease and death. Unfortunately, most national data sets separate end-state information-i.e., cause-specific mortality-from pathway data describing how specific diseases result from environmental and behavioral processes. Thus, a coherent empirical picture of routes to death from a diversity of causes requires a data combining and modelling strategy that, of necessity, incorporates theory and prior-knowledge-based assumptions together with sensitivity analyses to assess the stability of conclusions. In this paper, a general data combining statistical strategy is presented and illustrated for smoking behavior and lung cancer mortality. Specifically, National Health Interview Survey data on smoking is combined with U.S. vital statistics data 1950 to 1987 to analyze the joint distribution of total and lung cancer mortality. Parameters were estimated for mortality, smoking cessation processes, and for individual risk heterogeneity for nine U.S. white male and female cohorts aged 30 to 70 in 1950 and followed until 1987.

Authors
Manton, KG; Lowrimore, G; Yashin, A; Tolley, HD
MLA Citation
Manton, KG, Lowrimore, G, Yashin, A, and Tolley, HD. "Analyses of cohort mortality incorporating observed and unobserved risk factors." Mathematical and Computer Modelling 25.7 (1997): 89-107.
Source
scival
Published In
Mathematical and Computer Modelling
Volume
25
Issue
7
Publish Date
1997
Start Page
89
End Page
107
DOI
10.1016/S0895-7177(97)00051-4

Evaluating partially observed survival histories: Retrospective projection of covariate trajectories

The use of maximum likelihood methods in analysing times to failure in the presence of unobserved randomly changing covariates requires constrained optimization procedures. An alternative approach using a generalized version of the EM-algorithm requires smoothed estimates of covariate values. Similar estimates are needed in evaluating past exposures to hazardous chemicals, radiation or other toxic materials when health effects only become evident long after their use. In this paper, two kinds of equation for smoothing estimates of unobserved covariates in survival problems are derived. The first shows how new information may be used to update past estimates of the covariates' values. The second can be used to project the covariates' trajectory from the present to the past. If the hazard function is quadratic in form, both types of smoothing equation can be derived in a closed analytical form. Examples of both types of equation are presented. Use of these equations in the extended EM-algorithm, and in estimating past exposures to hazardous materials, are discussed. © 1997 by John Wiley & Sons, Ltd.

Authors
Yashin, AI; Manton, KG; Lowrimore, GR
MLA Citation
Yashin, AI, Manton, KG, and Lowrimore, GR. "Evaluating partially observed survival histories: Retrospective projection of covariate trajectories." Applied Stochastic Models and Data Analysis 13.1 (1997): 1-13.
Source
scival
Published In
Applied Stochastic Models and Data Analysis
Volume
13
Issue
1
Publish Date
1997
Start Page
1
End Page
13

Effects of Unobserved and Partially Observed Covariate Processes on System Failure: A Review of Models and Estimation Strategies

Stochastically changing covariates may influence survival. They may be observed, unobserved or partly observed. We review the properties of hazard models explicitly representing the effects of unobserved, and partially observed, stochastic covariates. Such models will increase in importance as new longitudinal population studies, and longitudinal surveys of high dimensional failure processes in humans, become available - many are now in progress. It is shown that marginal survival distributions and likelihoods generated in analytically closed form make such parametrically detailed models computationally tractable. Several ways of defining the marginal distribution of the data for constructing a likelihood function are considered. The most complete models can handle both continuously and discretely evolving covariates. Parameters can be estimated from multiple data sets to retrospectively and prospectively evaluate covariate trajectories. Such methods will both extract more information from a longitudinal study and use it in a parametric structure that is logically consistent with the behavior of the underlying processes of substantive interest.

Authors
Yashin, AI; Manton, KG
MLA Citation
Yashin, AI, and Manton, KG. "Effects of Unobserved and Partially Observed Covariate Processes on System Failure: A Review of Models and Estimation Strategies." Statistical Science 12.1 (1997): 20-34.
Source
scival
Published In
Statistical Science
Volume
12
Issue
1
Publish Date
1997
Start Page
20
End Page
34

Mortality amongst twins after the age of six

According to the foetal-origins hypothesis the risk of adult morbidity and mortality is heightened by intrauterine growth retardation. Twins, and in particular monozygotic twins, experience growth retardation in utero. A total of 8495 twin individuals born 1870-1900 in Denmark were followed through 1991 and death rates were calculated on a cohort basis. Deaths rates for twins and the general population were not significantly different except for females aged 60-89: mortality for female twins in this age group was 1.14 times (SE 0.03) higher than the general population. Female dizygotic twins experienced death rates 1.77 times (SE 0.18) higher than monozygotic twins at ages 30-59. Otherwise, mortality for monozygotic and dizygotic twins did not consistently differ after age six. The findings in the present study suggest that the foetal-origins hypothesis is not true for the intrauterine growth retardation experienced by twins.

Authors
Christensen, K; Vaupel, JW; Holm, NV; Yashin, AI
MLA Citation
Christensen, K, Vaupel, JW, Holm, NV, and Yashin, AI. "Mortality amongst twins after the age of six." Ugeskrift for Laeger 158.51 (1996): 7415-7419.
PMID
9012061
Source
scival
Published In
Ugeskrift for Laeger
Volume
158
Issue
51
Publish Date
1996
Start Page
7415
End Page
7419

How long can humans live? Lower bound for biological limit of human longevity calculated from Danish twin data using correlated frailty model.

How long can people live? Opinions of the researchers diverge and debates continue. Is there any systematic way to address this question? In this paper, we suggest an approach to the estimation of the biological limit of human longevity using survival data for twins from different zygocity groups. The approach is based on the genetic model of individual frailty. It combines ideas used in demography and survival analysis with methods of quantitative genetics and genetic epidemiology. The association between the life-spans of related individuals is described by the correlated frailty model of bivariate survival. A version of this model is used in order to estimate heritability of the individual frailty and to calculate the lower bound of human longevity. The limitations of this approach and directions of further research are discussed.

Authors
Yashin, AI; Iachine, I
MLA Citation
Yashin, AI, and Iachine, I. "How long can humans live? Lower bound for biological limit of human longevity calculated from Danish twin data using correlated frailty model." Mech Ageing Dev 80.3 (June 9, 1995): 147-169.
PMID
7564568
Source
pubmed
Published In
Mechanisms of Ageing and Development
Volume
80
Issue
3
Publish Date
1995
Start Page
147
End Page
169

A NEW APPROACH TO GENETIC-ANALYSIS OF DURATION DATA

Authors
YASHIN, AI; IACHINE, IA
MLA Citation
YASHIN, AI, and IACHINE, IA. "A NEW APPROACH TO GENETIC-ANALYSIS OF DURATION DATA." May 1995.
Source
wos-lite
Published In
Behavior Genetics
Volume
25
Issue
3
Publish Date
1995
Start Page
294
End Page
294

Mortality among twins after age 6: fetal origins hypothesis versus twin method.

OBJECTIVE: To test the validity of the fetal origins hypothesis and the classic twin method. DESIGN: Follow up study of pairs of same sex twins in which both twins survived to age 6. SETTING: Denmark. SUBJECTS: 8495 twin individuals born 1870-1900, followed through to 31 December 1991. MAIN OUTCOME MEASURES: Mortality calculated on a cohort basis. RESULTS: Mortality among twins and the general population was not significantly different except among females aged 60-89, in whom mortality among twins was 1.14 times (SE 0.03) higher than in the general population. Mortality among female dizygotic twins was 1.77 times (0.18) higher than among monozygotic twins at age 30-59. Otherwise, mortality for monozygotic and dizygotic twins did not consistently differ after age 6. CONCLUSION: According to the fetal origins hypothesis the risk of adult morbidity and mortality is heightened by retardation in intrauterine growth. Twins, and in particular monozygotic twins, experience growth retardation in utero. The findings in the present study suggest that the fetal origins hypothesis is not true for the retardation in intrauterine growth experienced by twins. Furthermore, the data are inconsistent with the underlying assumption of a recent claim that the classic twin method is invalid for studies of adult diseases. The present study is, however, based on the one third of all pairs of twins in which both twins survived to age 6. The possible impact of this selection can be evaluated in future studies of cohorts of younger twins with lower perinatal and infant mortality.

Authors
Christensen, K; Vaupel, JW; Holm, NV; Yashin, AI
MLA Citation
Christensen, K, Vaupel, JW, Holm, NV, and Yashin, AI. "Mortality among twins after age 6: fetal origins hypothesis versus twin method." BMJ 310.6977 (February 18, 1995): 432-436.
PMID
7873948
Source
pubmed
Published In
BMJ (Clinical research ed.)
Volume
310
Issue
6977
Publish Date
1995
Start Page
432
End Page
436

The effects of health histories on stochastic process models of aging and mortality.

A model of human health history and aging, based on a multivariate stochastic process with both continuous diffusion and discrete jump components, is presented. Discrete changes generate non-Gaussian diffusion with time varying continuous state distributions. An approach to calculating transition rates in dynamically heterogeneous populations, which generalizes the conditional averaging of hazard rates done in "fixed frailty" population models, is presented to describe health processes with multiple jumps. Conditional semi-invariants are used to approximate the conditional p.d.f. of the unobserved health history components. This is useful in analyzing the age dependence of mortality and health changes at advanced age (e.g., 95+) where homeostatic controls weaken, and physiological dynamics and survival manifest nonlinear behavior.

Authors
Yashin, AI; Manton, KG; Woodbury, MA; Stallard, E
MLA Citation
Yashin, AI, Manton, KG, Woodbury, MA, and Stallard, E. "The effects of health histories on stochastic process models of aging and mortality." J Math Biol 34.1 (1995): 1-16.
PMID
8568421
Source
pubmed
Published In
Journal of Mathematical Biology
Volume
34
Issue
1
Publish Date
1995
Start Page
1
End Page
16

Correlated individual frailty: an advantageous approach to survival analysis of bivariate data.

"We develop a new model of bivariate survival based on the notion of correlated individual frailty. We analyze the properties of this model and suggest a new approach to the analysis of bivariate data that does not require a parametric specification--but permits estimation--of the form of the hazard function for individuals. We empirically demonstrate the advantages of the model in the statistical analysis of bivariate data." (SUMMARY IN FRE)

Authors
Yashin, AI; Vaupel, JW; Iachine, IA
MLA Citation
Yashin, AI, Vaupel, JW, and Iachine, IA. "Correlated individual frailty: an advantageous approach to survival analysis of bivariate data." Math Popul Stud 5.2 (1995): 145-183.
PMID
12290053
Source
pubmed
Published In
Mathematical Population Studies
Volume
5
Issue
2
Publish Date
1995
Start Page
145
End Page
183
DOI
10.1080/08898489509525394

Survival of related individuals: an extension of some fundamental results of heterogeneity analysis.

"Many ideas in the analysis of heterogeneous mortality are based on the relationship between individual and observed hazard rates. This connection is established with the help of conditional averaging procedure: The observed risk of death at age x is calculated among those who survive this age. The analogy of this result for bivariate survival model with correlated individual hazards is derived. In the case of correlated frailty model the parametric specification of the mean, variance and correlation coefficient of the bivariate frailty distribution among survivors is obtained. The relationship between local association measure and the characteristics of the bivariate frailty distribution among survivors is established." (SUMMARY IN FRE)

Authors
Yashin, AI; Iachine, IA
MLA Citation
Yashin, AI, and Iachine, IA. "Survival of related individuals: an extension of some fundamental results of heterogeneity analysis." Math Popul Stud 5.4 (1995): 321-377.
PMID
12347230
Source
pubmed
Published In
Mathematical Population Studies
Volume
5
Issue
4
Publish Date
1995
Start Page
321
End Page
377
DOI
10.1080/08898489509525410

Genetic analysis of durations: correlated frailty model applied to survival of Danish twins.

Population studies of changes in human morbidity and mortality require models which take into account the influence of genetic and environmental factors on life-related durations, such as age at onset of the disease or disability, age at death, etc. In this paper we show how a bivariate survival model based on the concept of correlated individual frailty can be used for the genetic analysis of durations. Six genetic models of frailty are considered and applied to Danish twin survival data. The results of statistical analysis allow us to conclude that at least 50% of variability in individual frailty is determined by environmental factors. The approach suggests a method of estimation of the lower bound for the biological limit of human longevity. Directions for further research are discussed.

Authors
Yashin, AI; Iachine, IA
MLA Citation
Yashin, AI, and Iachine, IA. "Genetic analysis of durations: correlated frailty model applied to survival of Danish twins." Genet Epidemiol 12.5 (1995): 529-538.
PMID
8557185
Source
pubmed
Published In
Genetic Epidemiology
Volume
12
Issue
5
Publish Date
1995
Start Page
529
End Page
538
DOI
10.1002/gepi.1370120510

A multistate model of fecundability and sterility.

This paper develops a multistate hazards model for estimating fecundability and sterility from data on waiting times to conception. Important features of the model include separate sterile and nonsterile states, a distinction between preexisting sterility and sterility that begins after initiation of exposure, and log-normally distributed fecundability among nonsterile couples. Application of the model to data on first birth intervals from Taiwan, Sri Lanka, and the Amish shows that heterogeneity in fecundability is statistically significant at most ages, but that preexisting sterility and new sterility are unimportant before age 40. These results suggest that sterility may not be an important determinant of natural fertility until later reproductive ages.

Authors
Wood, JW; Holman, DJ; Yashin, AI; Peterson, RJ; Weinstein, M; Chang, MC
MLA Citation
Wood, JW, Holman, DJ, Yashin, AI, Peterson, RJ, Weinstein, M, and Chang, MC. "A multistate model of fecundability and sterility." Demography 31.3 (August 1994): 403-426.
PMID
7828764
Source
pubmed
Published In
Demography
Volume
31
Issue
3
Publish Date
1994
Start Page
403
End Page
426

A duality in aging: the equivalence of mortality models based on radically different concepts.

Several alternative mortality models fit Swedish old-age mortality data equally well. The models build on two different concepts of the heterogeneity of individuals in a population. The first concept concerns fixed, genetic differences among individuals in their risk of death. The second concept involves acquired susceptibility to death due to physiological changes and environmental influences. We show that alternative mortality models based on either of these two concepts or some mix of them lead to the same parametric form of observed age-specific death rates. We discuss this duality property of mortality processes and show that even when a mortality model fits the data, the concepts used to construct the model may not be correct.

Authors
Yashin, AI; Vaupel, JW; Iachine, IA
MLA Citation
Yashin, AI, Vaupel, JW, and Iachine, IA. "A duality in aging: the equivalence of mortality models based on radically different concepts." Mech Ageing Dev 74.1-2 (May 1994): 1-14.
PMID
7934200
Source
pubmed
Published In
Mechanisms of Ageing and Development
Volume
74
Issue
1-2
Publish Date
1994
Start Page
1
End Page
14

Modifications of the EM algorithm for survival influenced by an unobserved stochastic process

Let Y=(Yt)t≥0) be an unobserved random process which influences the distribution of a random variable T which can be interpreted as the time to failure. When a conditional hazard rate corresponding to T is a quadratic function of covariates, Y, the marginal survival function may be represented by the first two moments of the conditional distribution of Y among survivors. Such a representation may not have an explicit parametric form. This makes it difficult to use standard maximum likelihood procedures to estimate parameters - especially for censored survival data. In this paper a generalization of the EM algorithm for survival problems with unobserved, stochastically changing covariates is suggested. It is shown that, for a general model of the stochastic failure model, the smoothing estimates of the first two moments of Y are of a specific form which facilitates the EM type calculations. Properties of the algorithm are discussed. © 1994.

Authors
Yashin, AI; Manton, KG
MLA Citation
Yashin, AI, and Manton, KG. "Modifications of the EM algorithm for survival influenced by an unobserved stochastic process." Stochastic Processes and their Applications 54.2 (1994): 257-274.
Source
scival
Published In
Stochastic Processes and their Applications
Volume
54
Issue
2
Publish Date
1994
Start Page
257
End Page
274

HAZARD RATE AND OBSERVED COVARIATES - A NATURAL WAY OF PARAMETRIZATION

Authors
YASHIN, AI
MLA Citation
YASHIN, AI. "HAZARD RATE AND OBSERVED COVARIATES - A NATURAL WAY OF PARAMETRIZATION." STOCHASTIC ANALYSIS AND APPLICATIONS 12.3 (1994): 379-397.
Source
wos-lite
Published In
Stochastic Analysis and Applications
Volume
12
Issue
3
Publish Date
1994
Start Page
379
End Page
397
DOI
10.1080/07362999408809358

Methods for combining ancillary data in stochastic compartment models of cancer mortality: generalization of heterogeneity models.

"We present a mortality model where nationally representative survey data on risk factor distributions are combined with data on cohort mortality rates to increase information, i.e., a fixed marginal risk factor distribution is combined with a cohort model representing unobserved individual risk heterogeneity. The model is applied to lung cancer mortality in nine U.S. white male cohorts aged 30 to 70 in 1950 and followed 38 years. Estimates of the cohort specific proportions of smokers were made from the National Health Interview Survey. Comparisons are made for models with different patterns of changes with age of individual heterogeneity." (SUMMARY IN FRE)

Authors
Manton, KG; Lowrimore, G; Yashin, A
MLA Citation
Manton, KG, Lowrimore, G, and Yashin, A. "Methods for combining ancillary data in stochastic compartment models of cancer mortality: generalization of heterogeneity models." Math Popul Stud 4.2 (1993): 133-149.
PMID
12286785
Source
pubmed
Published In
Mathematical Population Studies
Volume
4
Issue
2
Publish Date
1993
Start Page
133
End Page
149
DOI
10.1080/08898489309525365

The propagation of uncertainty in human mortality processes operating in stochastic environments.

This paper presents a model describing how the uncertainty due to influential exogenous processes combines with stochasticity intrinsic to physiological aging processes and propagates through time to generate uncertainty about the future physiological state of the population. Variance expressions are derived for (a) the future values of the physiological variables under the assumption that external factors evolve under a linear stochastic diffusion process, and (b) the cohort survival functions and cohort life expectancies which reflect the uncertainty in the future values of the physiological variables. The model implies that a major component of uncertainty in forecasts of the physiological characteristics of a closed cohort is due to differential rates of survival associated with different realizations of the external process. This suggests that the limits to forecasting may be different in physiological systems subject to systematic mortality than in physical systems such as weather where the concepts of closed cohorts and of mortality selection have no simple analog.

Authors
Yashin, AI; Manton, KG; Stallard, E
MLA Citation
Yashin, AI, Manton, KG, and Stallard, E. "The propagation of uncertainty in human mortality processes operating in stochastic environments." Theor Popul Biol 35.2 (April 1989): 119-141.
PMID
2727949
Source
pubmed
Published In
Theoretical Population Biology
Volume
35
Issue
2
Publish Date
1989
Start Page
119
End Page
141

Applications of Martingale methods

A range of applications that can be effectively handled by Martingale methods are described here. The applications discussed include price determination, life insurance, adaptive filtering, sequential hypothesis testing, gaussian diffusion approximation in queueing models, consistent least squares estimation, and software reliability.

Authors
Liptser, RS; Yashin, AI
MLA Citation
Liptser, RS, and Yashin, AI. "Applications of Martingale methods." Automation and Remote Control 49.11 pt 2 (1989): 1526-1532.
Source
scival
Published In
Automation and Remote Control
Volume
49
Issue
11 pt 2
Publish Date
1989
Start Page
1526
End Page
1532

Estimating hidden morbidity via its effect on mortality and disability.

The applicability of the theory of partially observed finite-state Markov processes to the study of disease, morbidity, and disability is explored. A method is developed for the continuous updating of parameter estimates over time in longitudinal studies analogous to Kalman filtering in continuous valued continuous time stochastic processes. It builds on a model of filtering of incompletely observed finite-state Markov processes subject to mortality due to Yashin et al. The method of estimation is based on maximum likelihood theory and the incompleteness in the observation of the process is dealt with by applying missing information principles in maximum likelihood estimation.

Authors
Woodbury, MA; Manton, KG; Yashin, AI
MLA Citation
Woodbury, MA, Manton, KG, and Yashin, AI. "Estimating hidden morbidity via its effect on mortality and disability." Stat Med 7.1-2 (January 1988): 325-336.
PMID
3353611
Source
pubmed
Published In
Statistics in Medicine
Volume
7
Issue
1-2
Publish Date
1988
Start Page
325
End Page
336

Age-specific mortality trends in France and Italy since 1900: period and cohort effects.

Authors
Caselli, G; Vallin, J; Vaupel, JW; Yashin, A
MLA Citation
Caselli, G, Vallin, J, Vaupel, JW, and Yashin, A. "Age-specific mortality trends in France and Italy since 1900: period and cohort effects." Eur J Popul 3.1 (November 1987): 33-60.
PMID
12158949
Source
pubmed
Published In
European Journal of Population / Revue européenne de Démographie
Volume
3
Issue
1
Publish Date
1987
Start Page
33
End Page
60

Repeated resuscitation: how lifesaving alters life tables.

Authors
Vaupel, JW; Yashin, AI
MLA Citation
Vaupel, JW, and Yashin, AI. "Repeated resuscitation: how lifesaving alters life tables." Demography 24.1 (February 1987): 123-135.
PMID
3556687
Source
pubmed
Published In
Demography
Volume
24
Issue
1
Publish Date
1987
Start Page
123
End Page
135

Debilitation's aftermath: stochastic process models of mortality.

A stochastic differential equation model is developed to clarify the interaction of debilitation, recuperation, selection, and aging. The model yields various insights about the lingering mortality consequences of disasters such as wars, famines, and epidemics that may weaken the survivors. A key result is that debilitation and selection are interdependent: debilitation that increases population heterogeneity will result in subsequent selection; selection, by altering the distribution of population heterogeneity, will influence the impact of debilitating events.

Authors
Vaupel, JW; Yashin, AI; Manton, KG
MLA Citation
Vaupel, JW, Yashin, AI, and Manton, KG. "Debilitation's aftermath: stochastic process models of mortality." Math Popul Stud 1.1 (1987): 21-48.
PMID
12315003
Source
pubmed
Published In
Mathematical Population Studies
Volume
1
Issue
1
Publish Date
1987
Start Page
21
End Page
48

Targeting lifesaving: Demographic linkages between population structure and life expectancy

Life expectancy in a heterogeneous population can be increased by lowering mortality rates or by averting deaths at different ages, from different causes, or for different groups, as well as by changing the proportions of individuals in various risk groups, perhaps by altering the transition rates between groups. Understanding how such changes in population structure affect life expectancy is useful in evaluating alternative lifesaving policies. © 1986 Elsevier Science Publishers B.V.

Authors
Vaupel, JW; Yashin, AI
MLA Citation
Vaupel, JW, and Yashin, AI. "Targeting lifesaving: Demographic linkages between population structure and life expectancy." European Journal of Population 2.3-4 (1987): 335-360.
PMID
12158947
Source
scival
Published In
European Journal of Population / Revue européenne de Démographie
Volume
2
Issue
3-4
Publish Date
1987
Start Page
335
End Page
360
DOI
10.1007/BF01796596

A note on the conditioning of the survival probability on random information

Authors
Arjas, E; Yashin, A
MLA Citation
Arjas, E, and Yashin, A. "A note on the conditioning of the survival probability on random information." Stochastic Processes and their Applications 26.C (1987): 231--.
Source
scival
Published In
Stochastic Processes and their Applications
Volume
26
Issue
C
Publish Date
1987
Start Page
231-

Continuous-time adaptive filtering

Authors
Yashin, A
MLA Citation
Yashin, A. "Continuous-time adaptive filtering." IEEE Transactions on Automatic Control 31.8 (August 1986): 776-779.
Source
crossref
Published In
IEEE Transactions on Automatic Control
Volume
31
Issue
8
Publish Date
1986
Start Page
776
End Page
779
DOI
10.1109/TAC.1986.1104380

Applications of the grade of membership technique to event history analysis: Extensions to multivariate unobserved heterogeneity

Analyses of the event histories of social and service utilization processes are often difficult because of a lack of adequate theory to specify the distributional form of any latent heterogeneity [J. Heckman and B. Singer, The identifiability of the proportional hazards model. Rev. Econ. Studies 51, 231-241 (1984); ibid., A method for minimizing the impact of distributional assumptions in econometric models for duration data. Econometrics 52, 271-320 (1984).] or the form of the basic hazard rate [J. Trussel and C. Hammerslough, A hazards-model analysis of the covariates of infant and child mortality in Sri Lanka. Demography 20, 1-26 (1983).]. In this study we present an analytic strategy that deals with both questions nonparametrically using a conditional likelihood approach. The model is illustrated using 24 months of follow-up data on Supplemental Security Income beneficiaries in Type D (Nursing Home) living arrangements. The parameter estimates can be used in standard life table computations to determine the amount of time expected to be spent in different residential and payment statuses for different analytically identified classes of beneficiaries. © 1986.

Authors
Manton, KG; Stallard, E; Woodbury, MA; Yashin, AI
MLA Citation
Manton, KG, Stallard, E, Woodbury, MA, and Yashin, AI. "Applications of the grade of membership technique to event history analysis: Extensions to multivariate unobserved heterogeneity." Mathematical Modelling 7.9-12 (1986): 1375-1391.
Source
scival
Published In
Mathematical modelling
Volume
7
Issue
9-12
Publish Date
1986
Start Page
1375
End Page
1391

Evaluating the effects of observed and unobserved diffusion processes in survival analysis of longitudinal data

In biostatistical, epidemiological and demographic studies of human survival it is often necessary to consider the dynamics of physiological processes and their influences on observed mortality rates. The parameters of a stochastic covariate process can be estimated using a conditional Gaussian strategy based on the mortality model presented in M.A. Woodbury and K.G. Manton, A random walk model of human mortality and aging. Theor. Popul. Biol. 11, 37-48 (1977) and A.I. Yashin, K.G. Manton, and J.W. Vaupel, Mortality and aging in a heterogeneous population: A stochastic process model with observed and unobserved variables. Theor. Popul. Biol., in press. (1985). The utility of this approach for modeling survival in a longitudinally followed population is discussed-especially in the context of conducing coordinated analyses of multiple similarly constituted databases. Furthermore, the conditional Gaussian approach offers several substantive and computational advantages over the Cameron- Martin approach R.H. Cameron and W.T. Martin, The Wiener measure of Hilbert neighborhoods in the space of real continuous functions. J. Math. Phys. 23, 195-209. © 1986.

Authors
Yashin, AI; Manton, KG; Stallard, E
MLA Citation
Yashin, AI, Manton, KG, and Stallard, E. "Evaluating the effects of observed and unobserved diffusion processes in survival analysis of longitudinal data." Mathematical Modelling 7.9-12 (1986): 1353-1363.
Source
scival
Published In
Mathematical modelling
Volume
7
Issue
9-12
Publish Date
1986
Start Page
1353
End Page
1363

Dependent competing risks: a stochastic process model.

Analyses of human mortality data classified according to cause of death frequently are based on competing risk theory. In particular, the times to death for different causes often are assumed to be independent. In this paper, a competing risk model with a weaker assumption of conditional independence of the times to death, given an assumed stochastic covariate process, is developed and applied to cause specific mortality data from the Framingham Heart Study. The results generated under this conditional independence model are compared with analogous results under the standard marginal independence model. Under the assumption that this conditional independence model is valid, the comparison suggests that the standard model overestimates by 4% the effect on life expectancy at age 30 due to the hypothetical elimination of cancer and by 7% the effect for cardiovascular/cerebrovascular disease. By age 80 the overestimates were 11% for cancer and 16% for heart disease. These results suggest the importance of avoiding the marginal independence assumption when appropriate data are available--especially when focusing on mortality at advanced ages.

Authors
Yashin, AI; Manton, KG; Stallard, E
MLA Citation
Yashin, AI, Manton, KG, and Stallard, E. "Dependent competing risks: a stochastic process model." J Math Biol 24.2 (1986): 119-140.
PMID
3746135
Source
pubmed
Published In
Journal of Mathematical Biology
Volume
24
Issue
2
Publish Date
1986
Start Page
119
End Page
140

CONTINUOUS-TIME ADAPTIVE FILTERING.

Necessary and sufficient conditions are established for convergence of Bayesian parameter estimators in a continuous-time adaptive Kalman filter with a denumerable or finite set of parameter values.

Authors
Yashin, AI
MLA Citation
Yashin, AI. "CONTINUOUS-TIME ADAPTIVE FILTERING." IEEE Transactions on Automatic Control AC-31.8 (1986): 776-779.
Source
scival
Published In
IEEE Transactions on Automatic Control
Volume
AC-31
Issue
8
Publish Date
1986
Start Page
776
End Page
779

APPLICATION OF THE GRADE OF MEMBERSHIP TECHNIQUE TO EVENT HISTORY ANALYSIS - EXTENSIONS TO MULTIVARIATE UNOBSERVED HETEROGENEITY

Authors
MANTON, KG; STALLARD, E; WOODBURY, MA; YASHIN, AI
MLA Citation
MANTON, KG, STALLARD, E, WOODBURY, MA, and YASHIN, AI. "APPLICATION OF THE GRADE OF MEMBERSHIP TECHNIQUE TO EVENT HISTORY ANALYSIS - EXTENSIONS TO MULTIVARIATE UNOBSERVED HETEROGENEITY." 1986.
Source
wos-lite
Published In
Population index
Volume
52
Issue
3
Publish Date
1986
Start Page
423
End Page
423

Heterogeneity's ruses: some surprising effects of selection on population dynamics.

"As a cohort of people, animals, or machines ages, the individuals at highest risk tend to die or exit first. This differential selection can produce patterns of mortality for the population as a whole that are surprisingly different from the patterns for subpopulations or individuals. Naive acceptance of observed population patterns may lead to erroneous policy recommendations if an intervention depends on the response of individuals. Furthermore, because patterns at the individual level may be simpler than composite population patterns, both theoretical and empirical research may be unnecessarily complicated by failure to recognize the effects of heterogeneity."

Authors
Vaupel, JW; Yashin, AI
MLA Citation
Vaupel, JW, and Yashin, AI. "Heterogeneity's ruses: some surprising effects of selection on population dynamics." Am Stat 39.3 (August 1985): 176-185.
PMID
12267300
Source
pubmed
Published In
The American statistician
Volume
39
Issue
3
Publish Date
1985
Start Page
176
End Page
185

Mortality and aging in a heterogeneous population: a stochastic process model with observed and unobserved variables.

Various multivariate stochastic process models have been developed to represent human physiological aging and mortality. These efforts are extended by considering the effects of observed and unobserved state variables on the age trajectory of physiological parameters. This is done by deriving the Kolmogorov-Fokker-Planck equations describing the distribution of the unobserved state variables conditional on the history of the observed state variables. Given some assumptions, it is proved that the distribution is Gaussian. Strategies for estimating the parameters of the distribution are suggested based on an extension of the theory of Kalman filters to include systematic mortality selection. Various empirical applications of the model to studies of human aging and mortality as well as to other types of "failure" processes in heterogeneous populations are discussed.

Authors
Yashin, AI; Manton, KG; Vaupel, JW
MLA Citation
Yashin, AI, Manton, KG, and Vaupel, JW. "Mortality and aging in a heterogeneous population: a stochastic process model with observed and unobserved variables." Theor Popul Biol 27.2 (April 1985): 154-175.
PMID
4023952
Source
pubmed
Published In
Theoretical Population Biology
Volume
27
Issue
2
Publish Date
1985
Start Page
154
End Page
175

Mortality in Italy: contours of a century of evolution.

The authors construct contour maps of Italian male and female mortality rates for ages 0-79 for the years 1870-1979 using life table data from published sources. The maps "display persistent global and prominent local patterns of mortality, simultaneously over age, by period, and for cohorts." Previously documented aspects of the evolution of Italian mortality are highlighted graphically, and new areas for study are indicated. (summary in FRE, ITA)

Authors
Caselli, G; Vaupel, JW; Yashin, AI
MLA Citation
Caselli, G, Vaupel, JW, and Yashin, AI. "Mortality in Italy: contours of a century of evolution." Genus 41.1-2 (January 1985): 39-55.
PMID
12267538
Source
pubmed
Published In
Genus
Volume
41
Issue
1-2
Publish Date
1985
Start Page
39
End Page
55

Marriage and fertility in China: a graphical analysis.

Data from China's 1982 one-in-a-thousand fertility survey are used to construct contour maps of Chinese marriage and fertility. They offer a panoramic view of the interaction of age, period, and cohort variations. The maps display long-term trends over the last three decades: an upward shift of about four years in age at marriage and dramatic fertility declines, especially before age 20 and after age 30. They also reveal the substantial impact of disruptions such as that associated with the Great Leap Forward. Two striking regularities persist: marriage remains virtually universal by age 35 and fertility among married women under age 26 remains as high as it has been over the last 30 to 40 years.-from Authors

Authors
Yi, Z; Vaupel, JW; Yashin, AI
MLA Citation
Yi, Z, Vaupel, JW, and Yashin, AI. "Marriage and fertility in China: a graphical analysis." Population & Development Review 11.4 (1985): 721-736.
Source
scival
Published In
Population & Development Review
Volume
11
Issue
4
Publish Date
1985
Start Page
721
End Page
736

THE DEVIANT DYNAMICS OF DEATH IN HETEROGENEOUS POPULATIONS

Authors
VAUPEL, JW; YASHIN, AI
MLA Citation
VAUPEL, JW, and YASHIN, AI. "THE DEVIANT DYNAMICS OF DEATH IN HETEROGENEOUS POPULATIONS." SOCIOLOGICAL METHODOLOGY (1985): 179-211.
Source
wos-lite
Published In
Sociological Methodology
Publish Date
1985
Start Page
179
End Page
211

INFORMATION-THEORETIC ASPECTS OF PARAMETER ESTIMATION.

Authors
Yashin, AI
MLA Citation
Yashin, AI. "INFORMATION-THEORETIC ASPECTS OF PARAMETER ESTIMATION." (1984): 99-102.
Source
scival
Publish Date
1984
Start Page
99
End Page
102

EFFICIENT SOLUTION OF THE INTERPOLATION PROBLEM ON THE BASIS OF OBSERVATIONS OF JUMP PROCESSES.

The authors investigate the problem of interpolating a process with piecewise-continuous trajectories on the basis of observations of a multivariate point process. Equations are derived for the estimates and errors of direct and inverse interpolation in the case of a conditionally Gaussian observation scheme.

Authors
Khametov, VM; Yashin, AI
MLA Citation
Khametov, VM, and Yashin, AI. "EFFICIENT SOLUTION OF THE INTERPOLATION PROBLEM ON THE BASIS OF OBSERVATIONS OF JUMP PROCESSES." Problems of information transmission 19.2 (1983): 119-131.
Source
scival
Published In
Problems of information transmission
Volume
19
Issue
2
Publish Date
1983
Start Page
119
End Page
131

The deviant dynamics of death in heterogeneous populations.

The members of most populations gradually die off or drop out: people die, machines wear out, residents move out, etc. In many such aging populations, some members are more likely to die than others. Standard analytical methods largely ignore this heterogeneity; the methods assume that all members of a population cohort at a given age face the same probability of death. This paper presents some mathematical methods for studying how the behavior over time of a heterogeneous cohort deviates from the behaviour of the individuals that make up the cohort. The methods yield some startling results: individuals age faster than cohorts, eliminating a cause of death can decrease life expectancy, a cohort can suffer a higher death rate than another cohort even though its members have lower death rates, and cohort death rates can be increasing even though its members' death rates are decreasing.-Authors

Authors
Vaupel, JW; Yashin, AI
MLA Citation
Vaupel, JW, and Yashin, AI. "The deviant dynamics of death in heterogeneous populations." International Institute for Applied Systems Analysis, Research Report RR-83-1 (1983).
Source
scival
Published In
International Institute for Applied Systems Analysis, Research Report
Issue
RR-83-1
Publish Date
1983

CONVERGENCE OF BAYESIAN ESTIMATIONS IN ADAPTIVE CONTROL SCHEMES.

This paper is devoted to the problem of finding strong consistency conditions for denumerable and uncountable sets of parameter values in the continuous time stochastic observation process. It turns out that the consistency property is often equivalent to the property of absolute continuity and singularity for some special family of probabilistic measures. The case of the uncountable set of parameter values yields more restraints on the links between unknown parameters and the observation process.

Authors
Yashin, A
MLA Citation
Yashin, A. "CONVERGENCE OF BAYESIAN ESTIMATIONS IN ADAPTIVE CONTROL SCHEMES." Ricerche di Automatica 13.1 (1982): 6-19.
Source
scival
Published In
Ricerche di Automatica
Volume
13
Issue
1
Publish Date
1982
Start Page
6
End Page
19

GENERALIZED OBSERVATIONS CONTROL IN PROBLEMS OF STOCHASTICAL OPTIMIZATION.

Authors
Butov, AA; Kuznetsov, NA; Liptser, RS; Miller, BM; Rubinovich, EY; Serebrovskii, AP; Yashin, AI
MLA Citation
Butov, AA, Kuznetsov, NA, Liptser, RS, Miller, BM, Rubinovich, EY, Serebrovskii, AP, and Yashin, AI. "GENERALIZED OBSERVATIONS CONTROL IN PROBLEMS OF STOCHASTICAL OPTIMIZATION." (1982): 851-856.
Source
scival
Publish Date
1982
Start Page
851
End Page
856

Extrapolation of Conditionally-gaussian Processes from the Observations of Jump-type Processes.

Two types of extrapolation are considered: the direct and inverse. Mesh equations are obtained for the first and second conditional moments assuming the observability of a multivariable process with gaussian compensators and the non-observability of a continuous gaussian Markov process.

Authors
Khametov, VM; Yashin, AI
MLA Citation
Khametov, VM, and Yashin, AI. "Extrapolation of Conditionally-gaussian Processes from the Observations of Jump-type Processes." Izvestia vyssih ucebnyh zavedenij. Priborostroenie 25.7 (1982): 6-10.
Source
scival
Published In
Izvestia vyssih ucebnyh zavedenij. Priborostroenie
Volume
25
Issue
7
Publish Date
1982
Start Page
6
End Page
10

ON CONSISTENT PARAMETER ESTIMATION IN ADAPTIVE FILTERING.

The paper investigates the necessary and sufficient conditions for consistency of parameter estimates in adaptive Kalman filtering. The unknown parameter is assumed to dictate the evolution of both the observed and unobserved processes and to take on values from a certain numerical set.

Authors
Kuznetsov, NA; Yashin, AI
MLA Citation
Kuznetsov, NA, and Yashin, AI. "ON CONSISTENT PARAMETER ESTIMATION IN ADAPTIVE FILTERING." Problems of control and information theory 10.5 (1981): 317-327.
Source
scival
Published In
Problems of control and information theory
Volume
10
Issue
5
Publish Date
1981
Start Page
317
End Page
327

CONSISTENCY OF BAYESIAN PARAMETER ESTIMATES IN ADAPTIVE KALMAN FILTERING.

The properties of Bayesian estimates of the parameters of linear systems whose characteristics are observed on a random noise background are studied. It is assumed that with known parameter values it is possible to estimate the unobservable variables with the aid of a Kalman filter. In the case of an unknown parameter that takes a countable set of values, it is possible to use an adaptive filter for estimating the parameters and the variables of the system. The necessary and sufficient conditions of consistency are formulated for parameter estimates expressed in terms of the coefficients of the original system and the characteristics of the corresponding Kalman filters. An example is also presented.

Authors
Kuznetsov, NA; Lubkov, AV; Yashin, AI
MLA Citation
Kuznetsov, NA, Lubkov, AV, and Yashin, AI. "CONSISTENCY OF BAYESIAN PARAMETER ESTIMATES IN ADAPTIVE KALMAN FILTERING." Automation and Remote Control 42.4 pt 1 (1981): 446-454.
Source
scival
Published In
Automation and Remote Control
Volume
42
Issue
4 pt 1
Publish Date
1981
Start Page
446
End Page
454

CONSISTENCY OF BAYESIAN PARAMETER ESTIMATION.

The consistency problem is investigated for estimates of the conditional expectation types for random variables with a countable set of values acording to observations of random processes in discrete time. Necessary and sufficient conditions for strong consistency are obtained in terms of the characteristics of the likelihood ratio of certain special probability measures. It is shown that the more detailed characterization of observed random processes makes it possible to obtain the consistency condition in terms of their probability characteristics. Consistency conditions are given for parameter estimates obtained from observations of the paths of a Markov chain and a Gausian process.

Authors
Yashin, AI
MLA Citation
Yashin, AI. "CONSISTENCY OF BAYESIAN PARAMETER ESTIMATION." Problems of information transmission 17.1 (1981): 42-49.
Source
scival
Published In
Problems of information transmission
Volume
17
Issue
1
Publish Date
1981
Start Page
42
End Page
49

CONDITIONAL GAUSSIAN ESTIMATION OF DYNAMIC SYSTEM RESPONSE ON THE BASIS OF JERKY OBSERVATIONS.

Practical cases of filtering on the basis of jerky observations are examined, and conditions are presented under which the a posteriori distribution of the observed process characteristics is Gaussian with probability one. Formulas for the optimal estimates are also presented.

Authors
Yashin, AI
MLA Citation
Yashin, AI. "CONDITIONAL GAUSSIAN ESTIMATION OF DYNAMIC SYSTEM RESPONSE ON THE BASIS OF JERKY OBSERVATIONS." Automation and Remote Control 41.5 pt 1 (1980): 618-626.
Source
scival
Published In
Automation and Remote Control
Volume
41
Issue
5 pt 1
Publish Date
1980
Start Page
618
End Page
626

MANAGEMENT PROBLEMS IN PUBLIC HEALTH.

The methodological aspects of making managerial decisions in a public-health system are discussed. A functional block diagram for a public-health system and approaches to the development of dialog decision-making procedures are described.

Authors
Borodkin, LI; Klement'ev, AA; Petrovskii, AM; Yashin, AI
MLA Citation
Borodkin, LI, Klement'ev, AA, Petrovskii, AM, and Yashin, AI. "MANAGEMENT PROBLEMS IN PUBLIC HEALTH." Automation and Remote Control 40.6 pt 2 (1979): 897-903.
Source
scival
Published In
Automation and Remote Control
Volume
40
Issue
6 pt 2
Publish Date
1979
Start Page
897
End Page
903

Synthesis of oligomeric π-allylic complexes on the basis of reactions of triisobutylaluminum with nickel and cobalt halides

1. The reaction of NiCl2 and CoCl2 with Al(i-Bu)3 in the presence of small amounts of dienes has been studied. 2. The reaction of NiCl2 with Al(i-Bu)3 in the presence of a diene results in the formation of π-alkylnickel chlorides, in which the alkenyl ligand contains an oligomer of the diene and an H atom or an isobutyl group, with yields of ∼ 100%. The compounds synthesized are fairly stable with respect to deoxygenated water and aqueous solutions of HCl and H2SO4 and do not undergo disproportionation reactions. 3. The reaction of CoCl2 with Al(i-Bu)3 in the presence of 1,3-pentadiene results in the predominant formation of organocobalt compounds which do not contain chlorine and which are less stable with respect to deoxygenated water and aqueous solutions of acids. © 1979 Plenum Publishing Corporation.

Authors
Yashin, AI; Tinyakova, EI; Bryantseva, YV; Miesserov, KG; Makhdi, V; Dolgoplosk, BA
MLA Citation
Yashin, AI, Tinyakova, EI, Bryantseva, YV, Miesserov, KG, Makhdi, V, and Dolgoplosk, BA. "Synthesis of oligomeric π-allylic complexes on the basis of reactions of triisobutylaluminum with nickel and cobalt halides." Bulletin of the Academy of Sciences of the USSR Division of Chemical Science 27.7 (1978): 1404-1410.
Source
scival
Published In
Bulletin of the Academy of Sciences of the USSR Division of Chemical Science
Volume
27
Issue
7
Publish Date
1978
Start Page
1404
End Page
1410
DOI
10.1007/BF00946881

ESTIMATION OF THE CHARACTERISTICS OF RANDOM DISCONTINUOUS PROCESSES.

The scope of application of the estimation theory based on intermittent observations is considered. The basic estimation algorithms are given. The validity conditions for estimates of discontinuous process parameters are formulated.

Authors
Yashin, AI
MLA Citation
Yashin, AI. "ESTIMATION OF THE CHARACTERISTICS OF RANDOM DISCONTINUOUS PROCESSES." Automation and Remote Control 37.4 pt 1 (1976): 521-526.
Source
scival
Published In
Automation and Remote Control
Volume
37
Issue
4 pt 1
Publish Date
1976
Start Page
521
End Page
526

ON CONSTRUCTIVE ALGORITHMS OF OPTIMAL NONLINEAR FILTERING - 2.

Consideration of the construction of estimates in the case of logic interaction between a signal and noise. Nonlinear equations are obtained for optimum signal estimates.

Authors
Yashin, AI
MLA Citation
Yashin, AI. "ON CONSTRUCTIVE ALGORITHMS OF OPTIMAL NONLINEAR FILTERING - 2." Automation and Remote Control 36.12 pt 2 (1975): 2027-2033.
Source
scival
Published In
Automation and Remote Control
Volume
36
Issue
12 pt 2
Publish Date
1975
Start Page
2027
End Page
2033

CONSTRUCTIVE ALGORITHMS OF OPTIMAL NONLINEAR FILTERING - 1.

Optimal nonlinear filtering of discontinuous processes is investigated, and constructive algorithms are described that make it possible to obtain rms optimal estimates on the basis of discontinuous observation results.

Authors
Yashin, AI
MLA Citation
Yashin, AI. "CONSTRUCTIVE ALGORITHMS OF OPTIMAL NONLINEAR FILTERING - 1." Automation and Remote Control 36.11 pt 1 (1975): 1775-1781.
Source
scival
Published In
Automation and Remote Control
Volume
36
Issue
11 pt 1
Publish Date
1975
Start Page
1775
End Page
1781

Markov-process filtering when the observation noise varies spasmodically

Authors
Yashin, AI
MLA Citation
Yashin, AI. "Markov-process filtering when the observation noise varies spasmodically." Radiophysics and Quantum Electronics 12.7 (1972): 788-791.
Source
scival
Published In
Radiophysics and Quantum Electronics
Volume
12
Issue
7
Publish Date
1972
Start Page
788
End Page
791
DOI
10.1007/BF01031075

CORRECTION PROBLEM IN THE PRESENCE OF COST OF OBSERVATIONS

Optimal control of a Markovian step process is considered in the presence of observation cost. It is shown that the optimization procedure can be carried out by a method analogous to that described in Dynamic Programming and Markovian Processes by G. A. Howard.

Authors
YASHIN, A
MLA Citation
YASHIN, A. "CORRECTION PROBLEM IN THE PRESENCE OF COST OF OBSERVATIONS." Avtomat i Telemekh 9 (1970): 170-172.
Source
scival
Published In
Avtomat i Telemekh
Issue
9
Publish Date
1970
Start Page
170
End Page
172

Filtering of jump processes

Formulas are derived for the a posteriori probabilities of a studied process. The methods developed may be considered a generalization of the methods based on the theory of conditional Markovian processes and developed for observing processes with continuous trajectories. See also English translation in Automat Remote Contr n 5 May 1970 p 725-30

Authors
YASHIN, A
MLA Citation
YASHIN, A. "Filtering of jump processes." Avtomat i Telemekh 5 (1970): 52-8.
Source
scival
Published In
Avtomat i Telemekh
Issue
5
Publish Date
1970
Start Page
52
End Page
8.

RELATIVE SEMI-INVARIANTS IN THE FILTERING OF PROCESSES WITH STEP COMPONENTS

Algorithms for approximate determination of the optimum estimates are devised. Examples are given.

Authors
YASHIN, A
MLA Citation
YASHIN, A. "RELATIVE SEMI-INVARIANTS IN THE FILTERING OF PROCESSES WITH STEP COMPONENTS." Avtomat i Telemekh 2 (1970): 20-26.
Source
scival
Published In
Avtomat i Telemekh
Issue
2
Publish Date
1970
Start Page
20
End Page
26

DETECTING STEP-VARYING PARAMETERS OF MULTIDIMENSIONAL PROCESSES

Optimal methods of filtering step-function processes are investigated. It is shown that an optimal filter must be nonlinear. A system of equations is derived which permits the detection of current values of step-varying components of multidimensional processes.

Authors
YASHIN, A
MLA Citation
YASHIN, A. "DETECTING STEP-VARYING PARAMETERS OF MULTIDIMENSIONAL PROCESSES." Avtomat i Telemekh 10 (1969): 60-67.
Source
scival
Published In
Avtomat i Telemekh
Issue
10
Publish Date
1969
Start Page
60
End Page
67

ON THE CHOICE OF OPTIMAL OBSERVATION PROCESS

The choice of optimal observation process in a certain ensemble is investigated. It is shown that the solution of this problem reduces to the application of the maximum principle and subsequent solution of a boundary-value problem.

Authors
YASHIN, A
MLA Citation
YASHIN, A. "ON THE CHOICE OF OPTIMAL OBSERVATION PROCESS." Akademiya Nauk, Izvestiya, Tekhnicheskaya Kibernetika 2 (1969): 121-123.
Source
scival
Published In
Akademiya Nauk, Izvestiya, Tekhnicheskaya Kibernetika
Issue
2
Publish Date
1969
Start Page
121
End Page
123

FILTERING OF NONSTATIONARY PROCESSES TAKING OBSERVATIONAL COSTS INTO ACCOUNT

Paper considers optimal control of observation; it is shown that this problem leads to use of usual methods of optimization for controls and functionals which depend on a posteriori characteristics.

Authors
YASHIN, A
MLA Citation
YASHIN, A. "FILTERING OF NONSTATIONARY PROCESSES TAKING OBSERVATIONAL COSTS INTO ACCOUNT." Avtomatika i Telemekhanika 2 (1969): 40-42.
Source
scival
Published In
Avtomatika i Telemekhanika
Issue
2
Publish Date
1969
Start Page
40
End Page
42
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