Browsing by Author "Ukraintseva, Svetlana V"

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Open Access
Age trajectories of physiological indices in relation to healthy life course.
(Mech Ageing Dev, 2011-03) Arbeev, Konstantin G; Ukraintseva, Svetlana V; Akushevich, Igor; Kulminski, Alexander M; Arbeeva, Liubov S; Akushevich, Lucy; Culminskaya, Irina V; Yashin, Anatoliy I
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.
Open Access
Age, gender, and cancer but not neurodegenerative and cardiovascular diseases strongly modulate systemic effect of the Apolipoprotein E4 allele on lifespan.
(PLoS Genet, 2014-01) Kulminski, Alexander M; Arbeev, Konstantin G; Culminskaya, Irina; Arbeeva, Liubov; Ukraintseva, Svetlana V; Stallard, Eric; Christensen, Kaare; Schupf, Nicole; Province, Michael A; Yashin, Anatoli I
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.
Open Access
Beta2-adrenergic receptor gene polymorphisms as systemic determinants of healthy aging in an evolutionary context.
(Mech Ageing Dev, 2010-05) Kulminski, Alexander M; Culminskaya, Irina; Ukraintseva, Svetlana V; Arbeev, Konstantin G; Land, Kenneth C; Yashin, Anatoli I
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.
Open Access
Biodemographic Analyses of Longitudinal Data on Aging, Health, and Longevity: Recent Advances and Future Perspectives.
(Adv Geriatr, 2017-06-02) Arbeev, Konstantin G; Akushevich, Igor; Kulminski, Alexander M; Ukraintseva, Svetlana V; Yashin, Anatoliy I
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.
Open Access
Birth Cohort, Age, and Sex Strongly Modulate Effects of Lipid Risk Alleles Identified in Genome-Wide Association Studies.
(PLoS One, 2015) Kulminski, Alexander M; Culminskaya, Irina; Arbeev, Konstantin G; Arbeeva, Liubov; Ukraintseva, Svetlana V; Stallard, Eric; Wu, Deqing; Yashin, Anatoliy I
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.
Open Access
Dynamics of biomarkers in relation to aging and mortality.
(Mech Ageing Dev, 2016-06) Arbeev, Konstantin G; Ukraintseva, Svetlana V; Yashin, Anatoliy I
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.
Open Access
Early hematopoiesis inhibition under chronic radiation exposure in humans.
(Radiat Environ Biophys, 2010-05) Akleyev, Alexander V; Akushevich, Igor V; Dimov, Georgy P; Veremeyeva, Galina A; Varfolomeyeva, Tatyana A; Ukraintseva, Svetlana V; Yashin, Anatoly I
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.
Open Access
Early hematopoietic effects of chronic radiation exposure in humans.
(Health Phys, 2010-09) Akleyev, Alexander V; Akushevich, Igor V; Dimov, Georgy P; Veremeyeva, Galina A; Varfolomeyeva, Tatyana A; Ukraintseva, Svetlana V; Yashin, Anatoly I
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.
Open Access
Effect of the APOE Polymorphism and Age Trajectories of Physiological Variables on Mortality: Application of Genetic Stochastic Process Model of Aging.
(Scientifica (Cairo), 2012) Arbeev, Konstantin G; Ukraintseva, Svetlana V; Kulminski, Alexander M; Akushevich, Igor; Arbeeva, Liubov S; Culminskaya, Irina V; Wu, Deqing; Yashin, Anatoliy I
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.
Open Access
Evaluation of genotype-specific survival using joint analysis of genetic and non-genetic subsamples of longitudinal data.
(Biogerontology, 2011-04) Arbeev, Konstantin G; Ukraintseva, Svetlana V; Arbeeva, Liubov S; Akushevich, Igor; Kulminski, Alexander M; Yashin, Anatoliy I
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.
Open Access
Explicating heterogeneity of complex traits has strong potential for improving GWAS efficiency.
(Sci Rep, 2016-10-14) Kulminski, Alexander M; Loika, Yury; Culminskaya, Irina; Arbeev, Konstantin G; Ukraintseva, Svetlana V; Stallard, Eric; Yashin, Anatoliy I
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.
Open Access
Genetic Structures of Population Cohorts Change with Increasing Age: Implications for Genetic Analyses of Human aging and Life Span.
(Ann Gerontol Geriatr Res, 2017-06-02) Yashin, Anatoliy I; Wu, Deqing; Arbeev, Konstantin G; Arbeeva, Liubov S; Akushevich, Igor; Kulminski, Alexander; Culminskaya, Irina; Stallard, Eric; Ukraintseva, Svetlana V
BACKGROUND: 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. PROBLEM: 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. DATA AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Open Access
Genetics of aging, health, and survival: dynamic regulation of human longevity related traits.
(Front Genet, 2015) Yashin, Anatoliy I; Wu, Deqing; Arbeeva, Liubov S; Arbeev, Konstantin G; Kulminski, Alexander M; Akushevich, Igor; Kovtun, Mikhail; Culminskaya, Irina; Stallard, Eric; Li, Miaozhu; Ukraintseva, Svetlana V
BACKGROUND: 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. DATA AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Open Access
How genes influence life span: the biodemography of human survival.
(Rejuvenation Res, 2012-08) Yashin, Anatoliy I; Wu, Deqing; Arbeev, Konstantin G; Stallard, Eric; Land, Kenneth C; Ukraintseva, Svetlana V
BACKGROUND: 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. DATA AND METHOD: 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. RESULTS: 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. CONCLUSION: Biodemographic analyses could provide important information about the properties of genes affecting phenotypic traits.
Open Access
How Genes Modulate Patterns of Aging-Related Changes on the Way to 100: Biodemographic Models and Methods in Genetic Analyses of Longitudinal Data.
(N Am Actuar J, 2016) Yashin, Anatoliy I; Arbeev, Konstantin G; Wu, Deqing; Arbeeva, Liubov; Kulminski, Alexander; Kulminskaya, Irina; Akushevich, Igor; Ukraintseva, Svetlana V
BACKGROUND AND OBJECTIVE: 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. DATA AND METHODS: 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. RESULTS: 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. CONCLUSIONS: . 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.
Open Access
How lifespan associated genes modulate aging changes: lessons from analysis of longitudinal data.
(Front Genet, 2013) Yashin, Anatoliy I; Arbeev, Konstantin G; Wu, Deqing; Arbeeva, Liubov S; Kulminski, Alexander; Akushevich, Igor; Culminskaya, Irina; Stallard, Eric; Ukraintseva, Svetlana V
BACKGROUND AND OBJECTIVE: 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. DATA AND METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.
Open Access
How the effects of aging and stresses of life are integrated in mortality rates: insights for genetic studies of human health and longevity.
(Biogerontology, 2016-02) Yashin, Anatoliy I; Arbeev, Konstantin G; Arbeeva, Liubov S; Wu, Deqing; Akushevich, Igor; Kovtun, Mikhail; Yashkin, Arseniy; Kulminski, Alexander; Culminskaya, Irina; Stallard, Eric; Li, Miaozhu; Ukraintseva, Svetlana V
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.
Open Access
How the quality of GWAS of human lifespan and health span can be improved.
(Front Genet, 2013) Yashin, Anatoliy I; Arbeev, Konstantin G; Wu, Deqing; Arbeeva, Liubov S; Kulminski, Alexander M; Akushevich, Igor; Culminskaya, Irina; Stallard, Eric; Ukraintseva, Svetlana V
Open Access
Joint Analyses of Longitudinal and Time-to-Event Data in Research on Aging: Implications for Predicting Health and Survival.
(Front Public Health, 2014) Arbeev, Konstantin G; Akushevich, Igor; Kulminski, Alexander M; Ukraintseva, Svetlana V; Yashin, Anatoliy I
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.
Open Access
Joint influence of small-effect genetic variants on human longevity.
(Aging (Albany NY), 2010-09) Yashin, Anatoliy I; Wu, Deqing; Arbeev, Konstantin G; Ukraintseva, Svetlana V
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.

Browsing by Author "Ukraintseva, Svetlana V"

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