Quantitative genetic tests of recent senescence theory: age-specific mortality and male fertility in Drosophila melanogaster

Quantitative genetic models of aging predict that additive genetic variance for fitness components should increase with age. However, recent studies have found that at very late ages, the genetic variance components decline. This decline may be due to an age-related drop in reproductive effort. If genetic variance in reproductive effort affects the genetic variance in mortality, the decline in reproductive effort at late ages should lead to a decrease in the genetic variance in mortality. To test this, we carried out a large-scale quantitative genetic analysis of age-specific mortality and fertility in virgin male Drosophila melanogaster. As in earlier studies, we found that the additive variance for age-specific mortality and fertility declined at late ages. Also, recent theoretical developments provide new predictions to distinguish between the mutation accumulation (MA) and antagonistic pleiotropy (AP) models of senescence. The deleterious effects of inbreeding are expected to increase with age under MA, but not under AP. This prediction was supported for both age-specific mortality and male fertility. Under AP, the ratio of dominance to additive variance is expected to decline with age. This predicition, too, was supported by the data analyzed here. Taken together, these analyses provide support for both the models playing a role in the aging process. We argue that the time has come to move beyond a simple comparison of these genetic models, and to think more deeply about the evolutionary causes and consequences of senescence.     

Why men matter: mating patterns drive evolution of human lifespan

Evolutionary theory predicts that senescence, a decline in survival rates with age, is the consequence of stronger selection on alleles that affect fertility or mortality earlier rather than later in life. Hamilton quantified this argument by showing that a rare mutation reducing survival is opposed by a selective force that declines with age over reproductive life. He used a female-only demographic model, predicting that female menopause at age ca. 50 yrs should be followed by a sharp increase in mortality, a "wall of death." Human lives obviously do not display such a wall. Explanations of the evolution of lifespan beyond the age of female menopause have proven difficult to describe as explicit genetic models. Here we argue that the inclusion of males and mating patterns extends Hamilton's theory and predicts the pattern of human senescence. We analyze a general two-sex model to show that selection favors survival for as long as men reproduce. Male fertility can only result from matings with fertile females, and we present a range of data showing that males much older than 50 yrs have substantial realized fertility through matings with younger females, a pattern that was likely typical among early humans. Thus old-age male fertility provides a selective force against autosomal deleterious mutations at ages far past female menopause with no sharp upper age limit, eliminating the wall of death. Our findings illustrate the evolutionary importance of males and mating preferences, and show that one-sex demographic models are insufficient to describe the forces that shape human senescence.     

A comparative analysis of senescence in adult damselflies and dragonflies (Odonata)

Any population whose members are subject to extrinsic mortality should exhibit an increase in mortality with age. Nevertheless, the prevailing opinion is that populations of adult damselflies and dragonflies do not exhibit such senescence. Here, we challenge this contention by fitting a range of demographic models to the data on which these earlier conclusions were based. We show that a model with an exponential increase in age-related mortality (Gompertz) generally provides a more parsimonious fit than alternative models including age-independent mortality, indicating that many odonates do indeed senesce. Controlling for phylogeny, a comparison of the daily mortality of 35 odonate species indicates that although male and female mortalities are positively correlated, mortality tends to be higher in males of those species that exhibit territoriality. Hence, we show for the first time that territoriality may impose a survivorship cost on males, once the underlying phylogenetic relationships are accounted for.     

An explanation for negligible senescence in animals

Negligible or negative senescence occurs when mortality risk is stable or decreases with age, and has been observed in some wild animals. Age‐independent mortality in animals may lead to an abnormally long maximum individual lifespans and be incompatible with evolutionary theories of senescence. The reason why there is no evidence of senescence in these animals has not been fully understood. Recovery rates are usually very low for wild animals with high dispersal ability and/or small body size (e.g., bats, rodents, and most birds). The only information concerning senescence for most of these species is the reported lifespan when individuals are last seen or caught. We deduced the probability density function of the reported lifespan based on the assumption that the real lifespan corresponding to Weibull or Gompertz distribution. We show that the magnitude of the increase in mortality risk is largely underestimated based on the reported lifespans with low recovery probability. The risk of mortality can aberrantly appear to have a negative correlation with age when it actually increases with increasing lifespan. We demonstrated that the underestimated aging rate for wild animals with low recovery probability can be generalizable to any aging models. Our work provides an explanation for the appearance of negligible senescence in many wild animals. Humans attempt to obtain insights from other creatures to better understand our own biology and its gain insight into how to enhance and extended human health. Our advice is to take a second glance before admiring the negligible senescence in other animals. This ability to escape from senescence is possibly only as beautiful illusion in animals.     

Density dependence triggers runaway selection of reduced senescence

In the presence of exogenous mortality risks, future reproduction by an individual is worth less than present reproduction to its fitness. Senescent aging thus results inevitably from transferring net fertility into younger ages. Some long-lived organisms appear to defy theory, however, presenting negligible senescence (e.g., hydra) and extended lifespans (e.g., Bristlecone Pine). Here, we investigate the possibility that the onset of vitality loss can be delayed indefinitely, even accepting the abundant evidence that reproduction is intrinsically costly to survival. For an environment with constant hazard, we establish that natural selection itself contributes to increasing density-dependent recruitment losses. We then develop a generalized model of accelerating vitality loss for analyzing fitness optima as a tradeoff between compression and spread in the age profile of net fertility. Across a realistic spectrum of senescent age profiles, density regulation of recruitment can trigger runaway selection for ever-reducing senescence. This novel prediction applies without requirement for special life-history characteristics such as indeterminate somatic growth or increasing fecundity with age. The evolution of nonsenescence from senescence is robust to the presence of exogenous adult mortality, which tends instead to increase the age-independent component of vitality loss. We simulate examples of runaway selection leading to negligible senescence and even intrinsic immortality.     

When can a clonal organism escape senescence?

Abstract Some clonal organisms may live for thousands of years and show no signs of senescence, while others consistently die after finite life spans. Using two models, we examined how stage-specific life-history rates of a clone's modules determine whether a genetic individual escapes senescence by replacing old modules with new ones. When the rates of clonal or sexual reproduction and survival of individual modules decline with age, clones are more likely to experience senescence. In addition, the models predict that there is a greater tendency to find senescence in terms of a decline in the rate of sexual reproduction with clone age than in terms of an increase in the probability of clone mortality, unless rates of sexual reproduction increase dramatically with module stage. Using a matrix model modified to represent the clonal lifestyle, we show how a trade-off between sexual and clonal reproduction could result in selection for or against clonal senescence. We also show that, in contrast to unitary organisms, the strength of selection on life-history traits can increase with the age of a clone even in a growing population, countering the evolution of senescence.     

DOES INCREASED MORTALITY FAVOR THE EVOLUTION OF MORE RAPID SENESCENCE?

It is widely believed (following the 1957 hypothesis of G. C. Williams) that greater rates of “extrinsic” (age- and condition-independent) mortality favor more rapid senescence. However, a recent analysis of mammalian life tables failed to find a significant correlation between minimum adult mortality rate and the rate of senescence. This article presents a simple theoretical analysis of how extrinsic mortality should affect the rate of senescence (i.e., the rate at which probability of mortality increases with age) under different evolutionary and population dynamical assumptions. If population dynamics are density independent, extrinsic mortality should not alter the senescence rate favored by natural selection. If population growth is density dependent and populations are stable, the effect of extrinsic mortality depends on the age specificity of the density dependence and on whether survival or reproduction (or both) are functions of density. It is possible that higher extrinsic mortality will increase the rate of senescence at all ages, decrease the rate at all ages, or increase it at some ages while decreasing it at others. Williams's hypothesis is most likely to be supported when density dependence acts primarily on fertility and does not differentially decrease the fertilities of older individuals. Patterns contrary to Williams's prediction are possible when density dependence acts primarily on the survival or fertility of later ages or when most variation in mortality rates is due to variation in nonextrinsic mortality.     

OPTIMALITY THEORY,GOMPERTZ' LAW,AND THE DISPOSABLE SOMA THEORY OF SENESCENCE

The “disposable soma” theory for the evolution of senescence suggests that senescence arises from an optimal balancing of resources between reproduction and somatic repair. Dynamic programming models are constructed and analyzed to determine the optimal relationship between reproduction, diversion of resources from repair, and added senescent mortality. Of particular interest is the relationship between the repair-reproduction trade-off and the form of the mortality-rate-versus-age curve predicted. The models analyzed in the greatest detail assume that the relationship between reproduction and added senescent mortality does not change with age. These suggest that mortality should increase at an increasing rate with age, but may approach a linear rate as mortality becomes very high. General results are derived for the shape of the mortality curves early and late in the senescing part of the life span, and mortality curves for specific trade-off functions are illustrated. An exponential increase in death rate with age (Gompertz' Law) corresponds to only one of many possible relationships between reproduction and aging. The “Law” is unlikely to hold generally if the disposable soma theory accounts for a large fraction of the observed senescent increase in mortality with age. However, support for the generality of Gompertz' Law is weak, and other theories have not produced an evolutionary explanation for the law. The disposable soma theory is consistent with some of the exceptions to Gompertz' Law that have been observed.     

Two stochastic processes shape diverse senescence patterns in a single‐cell organism

Despite advances in aging research, a multitude of aging models, and empirical evidence for diverse senescence patterns, understanding of the biological processes that shape senescence is lacking. We show that senescence of an isogenic Escherichia coli bacterial population results from two stochastic processes. The first process is a random deterioration process within the cell, such as generated by random accumulation of damage. This primary process leads to an exponential increase in mortality early in life followed by a late age mortality plateau. The second process relates to the stochastic asymmetric transmission at cell fission of an unknown factor that influences mortality. This secondary process explains the difference between the classical mortality plateaus detected for young mothers’ offspring and the near nonsenescence of old mothers’ offspring as well as the lack of a mother–offspring correlation in age at death. We observed that lifespan is predominantly determined by underlying stochastic stage dynamics. Surprisingly, our findings support models developed for metazoans that base their arguments on stage‐specific actions of alleles to understand the evolution of senescence. We call for exploration of similar stochastic influences that shape aging patterns beyond simple organisms.     

The Rarity of Survival to Old Age Does Not Drive the Evolution of Senescence

The evolution of senescence is often explained by arguing that, in nature, few individuals survive to be old and hence it is evolutionarily unimportant what happens to organisms when they are old. A corollary to this idea is that extrinsically imposed mortality, because it reduces the chance of surviving to be old, favors the evolution of senescence. We show that these ideas, although widespread, are incorrect. Selection leading to senescence does not depend directly on survival to old age, but on the shape of the stable age distribution, and we discuss the implications of this important distinction. We show that the selection gradient on mortality declines with age even in the hypothetical case of zero mortality, when survivorship does not decline. Changing the survivorship function by imposing age independent mortality has no affect on the selection gradients. A similar result exists for optimization models: age independent mortality does not change the optimal result. We propose an alternative, brief explanation for the decline of selection gradients, and hence the evolution of senescence.     

Comparative studies of senescence in natural populations of guppies

Investigators have rarely sought evidence for senescence in natural populations because it is assumed that relatively few individuals will survive long enough in the wild to exhibit the intrinsic increase in mortality with age expected from senescent individuals. Nevertheless, senescence has been documented in some natural populations, mostly in birds and mammals. Here we report on a comparative study of senescence in two natural populations of guppies (Poecilia reticulata). We document senescence as an age-specific increase in mortality rate, with use of mark-recapture studies and implementation of program MARK for analysis of such observations. Extrinsic mortality was controlled for by choosing populations that experience low rates of predation because they coexist with only a single piscine predator (Rivulus hartii). These populations differ in their evolutionary history because one was native to such a site whereas the other was introduced to a site that previously contained no guppies. The source of the introduced guppies was a high-predation population downstream below a barrier waterfall. Theory predicts that the guppies derived from a high-predation locality should experience senescence at an earlier age than the native low-predation population; however, the historical differences among these populations are also confounded with everything else that differs among the two localities. We found that females from a natural low-predation population have delayed senescence compared with the recently established population and hence that the differences among localities in senescence conform to theoretical predictions. The males from natural low-predation environments also had lower overall mortality rates, but contrary to predictions, the pattern of senescence for males did not differ between populations. The difference between the sexes is potentially attributable to two factors that lower the statistical power for distinguishing differences in the age-specific acceleration of mortality in males. One factor is that males have higher mortality rates, so fewer survive to advanced ages. A second is that we had a greater ability to discriminate among older age classes in females. We also found that the introduced population sustained a higher rate of disease than the native low-predation population. Such disease may represent a confounding factor in our comparison, but it may also reflect one of the trade-offs inherent in the life-history differences of these populations.     

Toward reconciling inferences concerning genetic variation in senescence in Drosophila melanogaster.

Standard models for senescence predict an increase in the additive genetic variance for log mortality rate late in the life cycle. Variance component analysis of age-specific mortality rates of related cohorts is problematic. The actual mortality rates are not observable and can be estimated only crudely at early ages when few individuals are dying and at late ages when most are dead. Therefore, standard quantitative genetic analysis techniques cannot be applied with confidence. We present a novel and rigorous analysis that treats the mortality rates as missing data following two different parametric senescence models. Two recent studies of Drosophila melanogaster, the original analyses of which reached different conclusions, are reanalyzed here. The two-parameter Gompertz model assumes that mortality rates increase exponentially with age. A related but more complex three-parameter logistic model allows for subsequent leveling off in mortality rates at late ages. We find that while additive variance for mortality rates increases for late ages under the Gompertz model, it declines under the logistic model. The results from the two studies are similar, with differences attributable to differences between the experiments.     

Parallel lines: nothing has changed?

The exponential increase in mortality rate with age is a universal feature of aging and is described mathematically by the Gompertz equation. When this equation is transformed semilogarithmically, it conforms to a straight line, the slope of which is generally used to reflect the rate of senescence. Historical and contemporary data of human and nonhuman populations show that adverse environmental conditions do not always change the slope of the log mortality rate over age. From these latter observations it is sometimes mistakenly inferred that the rate of senescence is unaffected by environmental conditions. Current biological inference emphasizes that gene action is dependent on the environment in which it is expressed. Here, we propose using the tangent line of the Gompertz equation to assess whether the rate of senescence has altered. Such an approach unmasks different rates of senescence when parameter G has remained constant, an observation that is in line with the notion that a plastic life history trait such as the rate of senescence results from the interplay of both genes and environment.     

When being alive implies being safe: variation in mortality rates can cause oviposition selectivity to increase with age

Optimal behavioural decisions are expected to depend on various state variables, such as physiological condition or age. In insects, empirical evidence of the effect of adult age on oviposition selectivity is mixed. Consistently, optimality models – which primarily incorporate the effects of egg load and senescence – fail to provide universal predictions. Here we propose that spatial variation in mortality rates creates an additional mechanism able to select for an increase in selectivity with age. Females can be selected to use the fact of having reached an advanced age as a cue of low mortality rates in their environment. Older females may thus be less time-limited, and can afford for more careful host selection. This is because variation in mortality rates can cause a positive correlation between individual age, and expected residual life span. We present a simulation model that formalises the verbal argument presented above, and discuss the findings in the more general context of the dependence of reproductive output on age.     

The life-history trade-off between fertility and child survival

Evolutionary models of human reproduction argue that variation in fertility can be understood as the local optimization of a life-history trade-off between offspring quantity and ‘quality’. Child survival is a fundamental dimension of quality in these models as early-life mortality represents a crucial selective bottleneck in human evolution. This perspective is well-rehearsed, but current literature presents mixed evidence for a trade-off between fertility and child survival, and little empirical ground to evaluate how socioecological and individual characteristics influence the benefits of fertility limitation. By compiling demographic survey data, we demonstrate robust negative relationships between fertility and child survival across 27 sub-Saharan African countries. Our analyses suggest this relationship is primarily accounted for by offspring competition for parental investment, rather than by reverse causal mechanisms. We also find that the trade-off increases in relative magnitude as national mortality declines and maternal somatic (height) and extrasomatic (education) capital increase. This supports the idea that socioeconomic development, and associated reductions in extrinsic child mortality, favour reduced fertility by increasing the relative returns to parental investment. Observed fertility, however, falls considerably short of predicted optima for maximizing total offspring survivorship, strongly suggesting that additional unmeasured costs of reproduction ultimately constrain the evolution of human family size.     

Age‐specific mortality analysis of the dry forest kissing bug,Rhodnius neglectus

Age‐specific mortality patterns can be very different across insects with different life histories. Some holometabolous insects (like mosquitoes, fruit flies) show a pattern where mortality rate decelerates at older ages, whereas other holometabolous insects (bruchid beetles) and hemimetabolous insects (cotton stainers, milkweed bugs, and kissing bugs) show an age‐specific mortality pattern that increases through all ages. Kissing bugs are strictly hematophagous and are vectors of Trypanosoma cruzi Chagas, the etiologic agent of Chagas disease. Here, we tested whether cohort data from the dry forest kissing bug, Rhodnius neglectus Lent (Hemiptera: Reduviidae), supports an increase of mortality rate that decelerates with age. We analyzed the age‐specific mortality pattern of a cohort of 250 individuals of R. neglectus. We used a suite of seven models with different degrees of complexity, to model age‐dependent forms of change in mortality rate increase in R. neglectus in the laboratory. We used the Akaike model selection criterion to choose between models that consider absence or presence of mortality deceleration. Five of the seven models (logistic, Gavrilovs, Gompertz, DeMoivre, and exponential) showed a statistically significant fit to the mortality rate. Weak late‐age mortality deceleration in R. neglectus was supported by the best fit (logistic model), and this result is consistent with predictions of the disposable soma theory of senescence.     

Age specificity of inbreeding load in Drosophila melanogaster and implications for the evolution of late-life mortality plateaus

Current evolutionary theories explain the origin of aging as a byproduct of the decline in the force of natural selection with age. These theories seem inconsistent with the well-documented occurrence of late-life mortality plateaus, since under traditional evolutionary models mortality rates should increase monotonically after sexual maturity. However, the equilibrium frequencies of deleterious alleles affecting late life are lower than predicted under traditional models, and thus evolutionary models can accommodate mortality plateaus if deleterious alleles are allowed to have effects spanning a range of neighboring age classes. Here we test the degree of age specificity of segregating alleles affecting fitness in Drosophila melanogaster. We assessed age specificity by measuring the homozygous fitness effects of segregating alleles across the adult life span and calculated genetic correlations of these effects across age classes. For both males and females, we found that allelic effects are age specific with effects extending over 1-2 weeks across all age classes, consistent with modified mutation-accumulation theory. These results indicate that a modified mutation-accumulation theory can both explain the origin of senescence and predict late-life mortality plateaus.     

Stage dynamics, period survival, and mortality plateaus

Mortality plateaus at advanced ages have been found in many species, but their biological causes remain unclear. Here, we exploit age-from-stage methods for organisms with stage-structured demography to study cohort dynamics, obtaining age patterns of mortality by weighting one-period stage-specific survivals by expected age-specific stage structure. Cohort dynamics behave as a killed Markov process. Using as examples two African grasses, one pine tree, a temperate forest perennial herb, and a subtropical shrub in a hurricane-driven forest, we illustrate diverse patterns that may emerge. Age-specific mortality always reaches a plateau at advanced ages, but the plateau may be reached rapidly or slowly, and the trajectory may follow positive or negative senescence along the way. In variable environments, birth state influences mortality at early but not late ages, although its effect on the level of survivorship persists. A new parameter micro omega summarizes the risk of mortality averaged over the entire lifetime in a variable environment. Recent aging models for humans that employ nonobservable abstract states of "vitality" are also known to produce diverse trajectories and similar asymptotic behavior. We discuss connections, contrasts, and implications of our results to these models for the study of aging.     

Evolutionary mechanisms of senescence

This paper reviews theories of the evolution of senescence. The population genetic basis for the decline with age in sensitivity of fitness to changes in survival and fecundity is discussed. It is shown that this creates a presure of selection that disproportionately favors performance early in life. The extent of this bias is greater when there is a high level of extrinsic mortality; this accounts for much the diversity in life-history patterns among different taxa. The implications of quantitative genetic theory for experimental tests of alternative population genetic models of senescence are discussed. In particular, the negative genetic correlations between traits predicted by the antagonistic pleiotropy model may be obscured by positive correlations that are inevitable in a multivariate system, or by the effects of variation due to deleterious mutations. The status of the genetic evidence relevant to these theories is discussed.     

HUMAN ACTUARIAL AGING INCREASES FASTER WHEN BACKGROUND DEATH RATES ARE LOWER: A CONSEQUENCE OF DIFFERENTIAL HETEROGENEITY?

Many analyses of human populations have found that age-specific mortality rates increase faster across most of adulthood when overall mortality levels decline. This contradicts the relationship often expected from Williams' classic hypothesis about the effects of natural selection on the evolution of senescence. More likely, much of the within-species difference in actuarial aging is not due to variation in senescence, but to the strength of filters on the heterogeneity of frailty in older survivors. A challenge to this differential frailty hypothesis was recently posed by an analysis of life tables from historical European populations and traditional societies that reported variation in actuarial aging consistent with Williams' hypothesis after all. To investigate the challenge, we reconsidered those cases and aging measures. Here we show that the discrepancy depends on Ricklefs' aging rate measure, ω, which decreases as mortality levels drop because it is an index of mortality level itself, not the rate of increase in mortality with age. We also show unappreciated correspondence among the parameters of Gompertz-Makeham and Weibull survival models. Finally, we compare the relationships among mortality parameters of the traditional societies and the historical series, providing further suggestive evidence that differential heterogeneity has strong effects on actuarial aging.