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.

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.

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.

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.

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.

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.

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.

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.

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.

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

BACKGROUND: early studies reported controversial findings on association of apolipoprotein E (APOE) polymorphism with disability. OBJECTIVE: to analyse sex-specific associations of APOE genotypes with impairments in (instrumental) activities of daily living [(I)ADL] and mortality. DESIGN: population-based 1999 National Long Term Care Survey (NLTCS) of the US older (65+) individuals. PARTICIPANTS: genetic data are available for 1,805 individuals. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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.

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.

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

OBJECTIVES: 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. DESIGN: Retrospective cross-sectional and longitudinal studies. SETTING: 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. PARTICIPANTS: Approximately 5,000 individuals in each survey. MEASUREMENTS: 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. RESULTS: 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. CONCLUSION: 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.

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.

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.

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.

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.

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.

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.

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.