Anatoliy I. Yashin

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.

Novel loci and pathways significantly associated with longevity.

Only two genome-wide significant loci associated with longevity have been identified so far, probably because of insufficient sample sizes of centenarians, whose genomes may harbor genetic variants associated with health and longevity. Here we report a genome-wide association study (GWAS) of Han Chinese with a sample size 2.7 times the largest previously published GWAS on centenarians. We identified 11 independent loci associated with longevity replicated in Southern-Northern regions of China, including two novel loci (rs2069837-IL6; rs2440012-ANKRD20A9P) with genome-wide significance and the rest with suggestive significance (P < 3.65 × 10−5). Eight independent SNPs overlapped across Han Chinese, European and U.S. populations, and APOE and 5q33.3 were replicated as longevity loci. Integrated analysis indicates four pathways (starch, sucrose and xenobiotic metabolism; immune response and inflammation; MAPK; calcium signaling) highly associated with longevity (P ≤ 0.006) in Han Chinese. The association with longevity of three of these four pathways (MAPK; immunity; calcium signaling) is supported by findings in other human cohorts. Our novel finding on the association of starch, sucrose and xenobiotic metabolism pathway with longevity is consistent with the previous results from Drosophilia. This study suggests protective mechanisms including immunity and nutrient metabolism and their interactions with environmental stress play key roles in human longevity.

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

Hypothesizing that members of families enriched for longevity delay morbidity compared to population controls and approximate the health-span of centenarians, we compared the health-spans of older generation subjects of the Long Life Family Study (LLFS) to controls without family history of longevity and to centenarians of the New England Centenarian Study (NECS) using Bayesian parametric survival analysis. We estimated hazard ratios, the ages at which specific percentiles of subjects had onsets of diseases, and the gain of years of disease-free survival in the different cohorts compared to referent controls. Compared to controls, LLFS subjects had lower hazards for cancer, cardiovascular disease, severe dementia, diabetes, hypertension, osteoporosis, and stroke. The age at which 20% of the LLFS siblings and probands had one or more age-related diseases was approximately 10 years later than NECS controls. While female NECS controls generally delayed the onset of age-related diseases compared with males controls, these gender differences became much less in the older generation of the LLFS and disappeared amongst the centenarians of the NECS. The analyses demonstrate extended health-span in the older subjects of the LLFS and suggest that this aging cohort provides an important resource to discover genetic and environmental factors that promote prolonged health-span in addition to longer life-span.

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

Background and Objective: The influence of genes on human lifespan is mediated by biological processes that characterize bodys 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.

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 fathers 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 mothers 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 todays society, studies exploring the LTL association with increased breast cancer risk in daughters of older fathers might be timely and relevant.

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.

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 patients 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 Alzheimers or Parkinsons disease, e.g., decreased lung cancer risk among patients with Alzheimers (HR=0.64) and Parkinsons (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.

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.

Patterns of Aging-Related Changes on the Way to 100: An Approach to Studying Aging, Mortality and Longevity From Longitudinal Data

Abstract 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.

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.