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.

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.

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.

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.

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.

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.

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.

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.

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

PURPOSE: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.