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.     

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.     

Heterogeneity in Individual Mortality Risk and Its Importance for Evolutionary Studies of Senescence

Mortality was simulated under the assumption of heterogeneity in individual age-specific mortality risk. Heterogeneity was modeled by assigning each individual its own Gompertz mortality function. Means and variances of the Gompertz intercept and slope parameters were based on published data for Drosophila melanogaster. Simulations of large cohorts reproduced mortality plateaus similar to those observed for actual cohorts of flies. Catastrophic late-age mortality was not observed except when heterogeneity was very low and rates of senescence were very high. A second set of simulations was designed to mimic experiments that have investigated age-specific patterns of genetic variance in mortality rates. Within-genotype heterogeneity in mortality risk resulted in a decline in genetic variance of mortality rates at old ages. That result suggests that the decline in genetic variance at old ages that has been observed in some experiments is an artifact of heterogeneity. Mortality rate plateaus, decrease in genetic variance of mortality rates at old ages, and absence of catastrophic late-age mortality all appear to contradict predictions of the evolutionary theory of senescence. Heterogeneity in mortality risk may explain those contradictions.     

The Effects of Spontaneous Mutation on Quantitative Traits. I. Variances and Covariances of Life History Traits

We have accumulated spontaneous mutations in the absence of natural selection in Drosophila melanogaster by backcrossing 200 heterozygous replicates of a single high fitness second chromosome to a balancer stock for 44 generations. At generations 33 and 44 of accumulation, we extracted samples of chromosomes and assayed their homozygous performance for female fecundity early and late in adult life, male and female longevity, male mating ability early and late in adult life, productivity (a measure of fecundity times viability) and body weight. The variance among lines increased significantly for all traits except male mating ability and weight. The rate of increase in variance was similar to that found in previous studies of egg-to-adult viability, when calculated relative to trait means. The mutational correlations among traits were all strongly positive. Many correlations were significantly different from 0, while none was significantly different from 1. These data suggest that the mutation-accumulation hypothesis is not a sufficient explanation for the evolution of senescence in D. melanogaster. Mutation-selection balance does seem adequate to explain a substantial proportion of the additive genetic variance for fecundity and longevity.     

Quantitative trait loci with age-specific effects on fecundity in Drosophila melanogaster

Life-history theory and evolutionary theories of aging assume the existence of alleles with age-specific effects on fitness. While various studies have documented age-related changes in the genetic contribution to variation in fitness components, we know very little about the underlying genetic architecture of such changes. We used a set of recombinant inbred lines to map and characterize the effects of quantitative trait loci (QTL) affecting fecundity of Drosophila melanogaster females at 1 and 4 weeks of age. We identified one QTL on the second chromosome and one or two QTL affecting fecundity on the third chromosome, but these QTL affected fecundity only at 1 week of age. There was more genetic variation for fecundity at 4 weeks of age than at 1 week of age and there was no genetic correlation between early and late-age fecundity. These results suggest that different loci contribute to the variation in fecundity as the organism ages. Our data provide support for the mutation accumulation theory of aging as applied to reproductive senescence. Comparing the results from this study with our previous work on life-span QTL, we also find evidence that antagonistic pleiotropy may contribute to the genetic basis of senescence in these lines as well.     

Age-specific changes in epistatic effects on mortality rate in Drosophila melanogaster

Models for the evolution of senescence assume that genes with age-specific effects act independently of one another. Although recent empirical data show that longevity is influenced in part by interactions between genes, there are currently few data on whether epistasis influences age-specific components of mortality. To gauge if and how interactions affect age-specific traits, we incorporated the Drosophila visible marker mutations ebony, forked, and purple into seven wild-caught strains of D. melanogaster to examine gene x genetic background interactions. We found significant natural genetic variation for longevity and baseline mortality rates. Gene x genetic background interactions were prevalent not only for longevity but also for baseline mortality rates and age-specific mortality rates. We conclude that gene x genetic background epistasis is prevalent for aging-related traits and could play a significant role in the evolution of aging. These results suggest that future genetic models for the evolution of aging should incorporate the effects of epistasis.     

Evolutionary genetics of lifespan and mortality rates in two populations of the seed beetle, Callosobruchus maculatus

The age at which individuals die varies substantially within and between species, but we still have little understanding of why there is such variation in life expectancy. We examined sex-specific and genetic variation in adult lifespan and the shape of mortality curves both within and between two populations of the seed beetle, Callosobruchus maculatus, that differ in a suite of life history characters associated with adaptation to different host species. Mean adult lifespan and the shape of the logistic mortality curves differed substantially between males and females (males had lower initial mortality rates, but a faster increase in the rate of mortality with increasing age) and between populations (they differed in the rate of increase in mortality with age). Larger individuals lived longer than smaller individuals, both because they had lower initial mortality rates and a slower increase in the rate of mortality with increasing age. However, differences in body size were not adequate to explain the differences in mortality between the sexes or populations. Both lifespan and mortality rates were genetically variable within populations and genetic variance/covariance matrices for lifespan differed between the populations and sexes. This study thus demonstrated substantial genetic variation in lifespan and mortality rates within and between populations of C. maculatus.     

The influence of environmentally induced heterogeneity on age-specific genetic variance for mortality rates

Using parametric models that describe the increase in mortality rates with age, we demonstrate that environmentally induced heterogeneity among genetically identical individuals is sufficient to generate biased estimates of age-specific genetic variance. Although the magnitude of the bias may change with age, one general trend emerges: the true genetic variance at the oldest ages is likely to be dramatically underestimated. Our results are robust to different manifestations of heterogeneity and suggest that such a bias is a general feature of these models. We note that age-dependent estimates of genetic variance for characters that are correlated with mortality (either genetically or environmentally) can be expected to be similarly affected. The results are independent of sample size and suggest that the bias may be more widespread in the literature than is currently appreciated. Our results are discussed with reference to existing data on mortality variance in Drosophila melanogaster.     

When individuals senesce: the 'Florida effect' on stable populations of territorial, long-lived birds

Senescence can be defined as the entire set of age-related changes that affect both vitality and function, one of which is within-individual age-related decline in reproduction. This factor is crucial for population persistence, because the senescence of individuals of a population can increase the likelihood of local extinction. Using simulations based on long-term information on a small metapopulation of a long-lived bird species, we highlight two mechanisms able to engender senescence in both breeders and floaters (i.e. non-breeding individuals) of the same population. We define 'floater shortage senescence' as breeder senescence due to low juvenile replacement rates because of high floater mortality during dispersal. Less obviously, senescence can also occur with very low floater mortality rates, and when breeding populations are remarkably free from factors that could cause catastrophic population decimation. In this scenario, low mortality in reproductive areas results in territory owners in breeding populations being characterised by progressively older breeding individuals, and old individuals waiting for a breeding opportunity: a phenomenon we refer to as the 'Florida effect'. Consistent with current views that adaptive death plays a crucial role in population dynamics, it seems reasonable to suppose that, under stable environmental conditions, the evolution of some mating mechanisms could limit the senescence of breeding individuals in a population, allowing the pool of breeding individuals to be refreshed by selection of younger breeders.     

Age-specific properties of spontaneous mutations affecting mortality in Drosophila melanogaster.

An analysis of the effects of spontaneous mutations affecting age-specific mortality was conducted using 29 lines of Drosophila melanogaster that had accumulated spontaneous mutations for 19 generations. Divergence among the lines was used to estimate the mutational variance for weekly mortality rates and the covariance between weekly mortality rates at different ages. Significant mutational variance was observed in both males and females early in life (up to approximately 30 days of age). Mutational variance was not significantly different from zero for mortality rates at older ages. Mutational correlations between ages separated by 1 or 2 wk were generally positive, but they declined monotonically with increasing separation such that mutational effects on early-age mortality were uncorrelated with effects at later ages. Analyses of individual lines revealed several instances of mutation-induced changes in mortality over a limited range of ages. Significant age-specific effects of mutations were identified in early and middle ages, but surprisingly, mortality rates at older ages were essentially unaffected by the accumulation procedure. Our results provide strong evidence for the existence of a class of polygenic mutations that affect mortality rates on an age-specific basis. The patterns of mutational effects measured here relate directly to recently published estimates of standing genetic variance for mortality in Drosophila, and they support mutation accumulation as a viable mechanism for the evolution 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.     

Seasonal fluctuation in susceptibility to insecticides within natural populations of Drosophila melanogaster. II. Features of genetic variation in susceptibility to organophosphate insecticides within natural populations of D. melanogaster

To elucidate genetic variation in susceptibility to organophosphate insecticides within natural populations of Drosophila melanogaster, we conducted an analysis of variance for mortality data sets of isofemale lines (10-286 lines) used in the previous studies. Susceptibility of isofemale lines to the three organophosphate insecticides was continuously distributed within each natural population, ranging from susceptible to resistant. Analysis of variance showed highly significant variation among isofemale lines in susceptibility to each insecticide for each natural population. Significant genetic variances in susceptibility to the three chemicals were estimated for the Katsunuma population; 0.0529-0.2722 for malathion, 0.0492-0.1603 for prothiophos, and 0.0469-0.1696 for fenitrothion. Contrary to the consistent seasonal tendency towards an increase in mean susceptibility in the fall, reported in the previous study, genetic variances in susceptibility to the three organophosphates did not change significantly in 1997 but tended to increase by 2- to 5-times in 1998. We tested whether both the observed situations, maintenance and increase in genetic variance in organophosphate resistance, can be generated under circumstances in which the levels of resistance to the three organophosphates tended to decrease, by conducting a simulation analysis, based on the hypothesis that resistant genotypes have lower fitnesses than susceptible ones under the density-independent condition. The simulation analysis generally explained the pattern in the mean susceptibility and genetic variances in susceptibility to the three organophosphates, observed in the Katsunuma population of D. melanogaster. It was suggested that the differences in the frequencies of resistance genes in the summer population could affect the patterns in genetic variance in organophosphate resistance in the fall population.     

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.     

Complex genetic architecture of population differences in adult lifespan of a beetle: nonadditive inheritance, gender differences, body size and a large maternal effect

Evolutionary responses to selection can be complicated when there is substantial nonadditivity, which limits our ability to extrapolate from simple models of selection to population differentiation and speciation. Studies of Drosophila melanogaster indicate that lifespan and the rate of senescence are influenced by many genes that have environment- and sex-specific effects. These studies also demonstrate that interactions among alleles (dominance) and loci (epistasis) are common, with the degree of interaction differing between the sexes and among environments. However, little is known about the genetic architecture of lifespan or mortality rates for organisms other than D. melanogaster. We studied genetic architecture of differences in lifespan and shapes of mortality curves between two populations of the seed beetle, Callosobruchus maculatus (South India and Burkina Faso populations). These two populations differ in various traits (such as body size and adult lifespan) that have likely evolved via host-specific selection. We found that the genetic architecture of lifespan differences between populations differs substantially between males and females; there was a large maternal effect on male lifespan (but not on female lifespan), and substantial dominance of long-life alleles in females (but not males). The large maternal effect in males was genetically based (there was no significant cytoplasmic effect) likely due to population differences in maternal effects genes that influence lifespan of progeny. Rearing host did not affect the genetic architecture of lifespan, and there was no evidence that genes on the Y-chromosome influence the population differences in lifespan. Epistatic interactions among loci were detectable for the mortality rate of both males and females, but were detectable for lifespan only after controlling for body size variation among lines. The detection of epistasis, dominance, and sex-specific genetic effects on C. maculatus lifespan is consistent with results from line cross and quantitative trait locus studies of D. melanogaster.     

Actuarial senescence in laboratory and field populations of Lepidoptera

1. Recent observations of actuarial senescence – an increase in mortality rate with age – have challenged the assertion that the brevity of adult insect life spans precludes ageing. 2. Here the rate of senescence in 22 species of Lepidoptera was quantified by fitting demographic models to adult survivorship data drawn from a range of field and laboratory studies. 3. Senescence was evident in all 22 species investigated, with a model of age‐related mortality consistently fitting the survivorship curves significantly better than an alternative model which assumes constant mortality. 4. The rates of senescence varied significantly among species. The rates of senescence also differed significantly between sexes for all species tested, but not in a consistent way.     

The evolution of age-specific mortality rates in Drosophila melanogaster: genetic divergence among unselected lines.

Age-specific effects of spontaneous mutations on mortality rates in Drosophila are inferred from three large demographic experiments. Data were collected from inbred lines that were allowed to accumulate spontaneous mutations for 10, 19, and 47 generations. Estimates of age-specific mutational variance for mortality were based on data from all three experiments, totalling approximately 225,000 flies, using a model developed for genetic analysis of age-dependent traits (the character process model). Both within- and among-generation analyses suggest that the input of genetic variance is greater for early life mortality rates than for mortality at older ages. In females, age-specific mutational variances ranged over an order of magnitude from 5.96 x 10(-3) at 2 wk posteclosion to 0.02 x 10(-3) at 7 wk. The male data show a similar pattern. Age-specific genetic variances were substantially less at generation 47 than at generation 19-an unexplained observation that is likely due to block effects. Mutational correlations among mortality rates at different ages tend to increase with the accumulation of new mutations. Comparison of the mutation-accumulation lines at generations 19 and 47 with their respective control lines suggests little age-specific mutational bias.     

A Model for Antagonistic Pleiotropic Gene Action for Mortality and Advanced Age

Association or linkage studies involving control and long-lived populations provide information on genes that influence longevity. However, the relationship between allele-specific differences in survival and the genetic structure of aging cohorts remains unclear. We model a heterogeneous cohort comprising several genotypes differing in age-specific mortality. In its most general form, without any specific assumption regarding the shape of mortality curves, the model permits derivation of a fundamental property underlying abrupt age-related changes in the composition of a cohort. The model is applied to sex-specific survival curves taken from period life tables, and Gompertz-Makeham mortality coefficients are calculated for the French population. Then, adjustments are performed under Gompertz-Makeham mortality functions for three genotypes composing a heterogeneous cohort, under the constraint of fitting the resultant mortality to the real French population mortality obtained from life tables. Multimodal curves and divergence after the 8th decade appear as recurrent features of the frequency trajectories. Finally, a fit to data previously obtained at the angiotensin-converting-enzyme locus is realized, explaining what had seemed to be paradoxical results-namely, that the frequency of a genotype known as a cardiovascular risk factor was increased in centenarians. Our results help explain the well-documented departure from Gompertz-Makeham mortality kinetics at older ages. The implications of our model are discussed in the context of known genetic effects on human longevity and age-related pathologies. Since antagonistic pleiotropy between early and late survival emerges as a general rule, extrapolating the effects measured for a gene in a particular age class to other ages could be misleading.     

Patterns of age-specific means and genetic variances of mortality rates predicted by the mutation-accumulation theory of ageing

A general quantitative genetic model of mutations with age-specific deleterious effects is developed. It is shown that, for the simplest case of a species with age-independent reproductive rates and extrinsic adult mortality rates, and no pleiotropic effects of age-specific mutations, exponential increases with age of both the mean and additive genetic variance of age-specific mortality rates are expected. Models where age-specific mutations have pleiotropic effects on mortality that extend either throughout adult life, or are confined to juvenile stages, produce equilibria with exponential increases in the mean and additive variance of mortality rates during much of adult life. However, the rates of increase diminish late in life, and can even become zero. Predictions concerning the additive genetic correlations in mortality rates between different ages are also developed. The predictions of the models are compared with data on humans and Drosophila.     

EXPERIMENTAL EVOLUTION OF SENESCENCE: AN ANALYSIS USING A “HETEROGENEITY” MORTALITY MODEL

A long-term laboratory selection experiment has produced replicated populations of fruit flies that differ in mean life span by more than twofold. An analysis of age-specific mortality rates indicated that differences in mean life span have been achieved principally by evolution of patterns of senescence. These results provide empirical confirmation that senescence can be modified within species by appropriate forms of natural selection, which is a fundamental prediction of theories regarding the genetic basis and evolution of senescence. Mortality data were fit to a model that accounts for the leveling off of cohort mortality rates at older ages, but that does not necessarily imply that very old individuals cease to senesce.     

Reproductive diapause and life-history clines in North American populations of Drosophila melanogaster

Latitudinal clines are widespread in Drosophila melanogaster, and many have been interpreted as adaptive responses to climatic variation. However, the selective mechanisms generating many such patterns remain unresolved, and there is relatively little information regarding how basic life-history components such as fecundity, life span and mortality rates vary across environmental gradients. Here, it is shown that four life-history traits vary predictably with geographic origin of populations sampled along the latitudinal gradient in the eastern United States. Although such patterns are indicative of selection, they cannot distinguish between the direct action of selection on the traits in question or indirect selection by means of underlying genetic correlations. When independent suites of traits covary with geography, it is therefore critical to separate the widespread effects of population source from variation specifically for the traits under investigation. One trait that is associated with variation in life histories and also varies with latitude is the propensity to express reproductive diapause; diapause expression has been hypothesized as a mechanism by which D. melanogaster adults overwinter, and as such may be subject to strong selection in temperate habitats. In this study, recently derived isofemale lines were used to assess the relative contributions of population source and diapause genotype in generating the observed variance for life histories. It is shown that although life span, fecundity and mortality rates varied predictably with geography, diapause genotype explained the majority of the variance for these traits in the sampled populations. Both heat and cold shock resistance were also observed to vary predictably with latitude for the sampled populations. Cold shock tolerance varied between diapause genotypes and the magnitude of this difference varied with geography, whereas heat shock tolerance was affected solely by geographic origin of the populations. These data suggest that a subset of life-history parameters is significantly influenced by the genetic variance for diapause expression in natural populations, and that the observed variance for longevity and fecundity profiles may reflect indirect action of selection on diapause and other correlated traits.