Deqing Wu

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.

Reproductive potential predicts longevity of female Mediterranean fruitflies.

Reproduction exacts a price in terms of decreased survival. Our analysis of the interplay between age patterns of fecundity and mortality for individual female medflies (Ceratitis capitata) revealed that individual mortality is associated with the time–dynamics of the egg–laying trajectory. In a sample of 531 medflies, we found that each individual has a characteristic rate of decline in egg laying with age. This defines an individuals rate of reproductive exhaustion. This rate was shown to predict subsequent mortality. The larger the remaining reproductive potential, the lower the subsequent mortality. An increased mortality risk was seen in flies for which egg production declined rapidly early on, irrespective of the level of egg production. Thus, reproductive potential and lifetime are coupled in such a way that those flies which are able to profit most from an extended life span in terms of increased egg output are indeed likely to live longer.

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.

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.

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.

Genetic Dissection of Late-Life Fertility in Caenorhabditis elegans

The large post-reproductive life span reported for the free-living hermaphroditic nematode, Caenorhabditis elegans, which lives for about 10 days after its 5-day period of self-reproduction, seems at odds with evolutionary theory. Species with long post-reproductive life spans such as mammals are sometimes explained by a need for parental care or transfer of information. This does not seem a suitable explanation for C elegans. Previous reports have shown that C elegans can regain fertility when mated after the self-fertile period but did not report the functional limits. Here, we report the functional life span of the C elegans germ line when mating with males. We show that C elegans can regain fertility late in life (significantly later than in previous reports) and that the end of this period corresponds quite well to its 3-week total life span. Genetic analysis reveals that late-life fertility is controlled by conserved pathways involved with aging and dietary restriction.

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.

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.

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.

Mortality shifts in Caenorhabditis elegans: remembrance of conditions past

The analysis of age‐specific mortality can yield insights into how anti‐aging interventions operate that cannot be matched by simple assessment of longevity. Mortality, as opposed to longevity, can be used to assess the effects of an anti‐aging intervention on a daily basis, rather than only after most animals have died. Various gerontogene mutations in Caenorhabditis elegans have been shown to increase longevity as much as tenfold and to decrease mortality at some ages even more. Environmental alterations, such as reduced food intake (dietary restriction) and lower temperature also result in reduced mortality soon after the intervention. Here, we ask how soon anti‐aging interventions, applied during adult life, affect age‐specific mortality in nematodes. Using maximum likelihood analysis, we estimated the Gompertz parameters after shifts of temperature, and of food concentration and maintenance conditions. In separate experiments, we altered expression of age‐1 and daf‐16, using RNAi. Using about 44 000 nematodes in total, to examine daily mortality, we find that for both types of environmental shift, mortality responded immediately in the first assessment, while RNAi‐induced changes resulted in a slower response, perhaps due to delayed mechanics of RNAi action. However, under all conditions there is a permanent ‘memory’ of past states, such that the initial mortality component [a] of the Gompertz equation [μ(x) = aebx] bears a permanent ‘imprint’ of that earlier state. However, ‘b’ (the rate of mortality increase with age) is always specified by the current conditions.