A unified framework for evolutionary genetic and physiological theories of aging.

Why and how we age are 2 intertwined questions that have fascinated scientists for many decades. However, attempts to answer these questions remain compartmentalized, preventing a comprehensive understanding of the aging process. We argue that the current lack of knowledge about the evolution of aging mechanisms is due to a lack of clarity regarding evolutionary theories of aging that explicitly involve physiological processes: the disposable soma theory (DST) and the developmental theory of aging (DTA). In this Essay, we propose a new hierarchical model linking genes to vital rates, enabling us to critically reevaluate the DST and DTA in terms of their relationship to evolutionary genetic theories of aging (mutation accumulation (MA) and antagonistic pleiotropy (AP)). We also demonstrate how these 2 theories can be incorporated in a unified hierarchical framework. The new framework will help to generate testable hypotheses of how the hallmarks of aging are shaped by natural selection.

The transition to modernity and chronic disease: mismatch and natural selection.

The Industrial Revolution and the accompanying nutritional, epidemiological and demographic transitions have profoundly changed human ecology and biology, leading to major shifts in life history traits, which include age and size at maturity, age-specific fertility and lifespan. Mismatch between past adaptations and the current environment means that gene variants linked to higher fitness in the past may now, through antagonistic pleiotropic effects, predispose post-transition populations to non-communicable diseases, such as Alzheimer disease, cancer and coronary artery disease. Increasing evidence suggests that the transition to modernity has also altered the direction and intensity of natural selection acting on many traits, with important implications for public and global health.

Natural Selection and the Evolution of Asynchronous Aging.

AbstractUnderstanding within-population variation in aging rates across different phenotypic traits is a central focus of biogerontological studies. Early evolutionary models predict that natural selection acts to cause all traits to deteriorate simultaneously. However, observations of aging rates provide evidence for widespread patterns of asynchronous aging in laboratory and natural populations. Recent verbal models put forth to explain such observations argue that because senescence is costly to fitness, selection should cause phenotypic traits that are most important to fitness to senesce slower than traits that are less related to fitness. Here, we show that formal evolutionary theory supports neither prediction. Instead, we find that selection will favor the evolution of the most rapid rates of aging in those traits that are under the strongest selection at early ages because selection for these traits erodes the fastest. This reinforces the expectation that natural selection should play a role in the evolution of among-trait variation in aging, but in a contradictory way to that suggested previously. We demonstrate how to quantify age-specific sources of selection for age-specific traits and how these estimates can be used to understand how well patterns of age-related changes in selection can explain observed patterns of among-trait variation in aging rates.

The diversity of maternal-age effects upon pre-adult survival across animal species.

Maternal senescence is the detrimental effect of increased maternal age on offspring performance. Despite much recent interest given to describing this phenomenon, its distribution across animal species is poorly understood. A review of the published literature finds that maternal age affects pre-adult survival in 252 of 272 populations (93%) representing 97 animal species. Age effects tended to be deleterious in invertebrates and mammals, including humans, confirming the presence of senescence. However, bird species were a conspicuous exception, as pre-adult survival tended to increase with maternal age in surveyed populations. In all groups, maternal-age effects became more negative in older mothers. Invertebrates senesced faster than vertebrates, and humans aged faster than non-human mammals. Within invertebrates, lepidopterans demonstrated the most extreme rates of maternal-effect senescence. Among the surveyed studies, phylogeny, life history and environment (e.g. laboratory versus wild populations) were tightly associated; this made it difficult to make confident inferences regarding the causes of diversity for the phenomenon. However, we provide some testable suggestions, and we observe that some differences appear to be consistent with predictions from evolutionary theory. We discuss how future work may help clarify ultimate and proximate causes for this diversity.

Effects of inbreeding on behavioural plasticity of parent-offspring interactions in a burying beetle.

Inbreeding depression is defined as a fitness decline in progeny resulting from mating between related individuals, the severity of which may vary across environmental conditions. Such inbreeding-by-environment interactions might reflect that inbred individuals have a lower capacity for adjusting their phenotype to match different environmental conditions better, as shown in prior studies on developmental plasticity. Behavioural plasticity is more flexible than developmental plasticity because it is reversible and relatively quick, but little is known about its sensitivity to inbreeding. Here, we investigate effects of inbreeding on behavioural plasticity in the context of parent-offspring interactions in the burying beetle Nicrophorus vespilloides. Larvae increase begging with the level of hunger, and parents increase their level of care when brood sizes increase. Here, we find that inbreeding increased behavioural plasticity in larvae: inbred larvae reduced their time spent associating with a parent in response to the length of food deprivation more than outbred larvae. However, inbreeding had no effect on the behavioural plasticity of offspring begging or any parental behaviour. Overall, our results show that inbreeding can increase behavioural plasticity. We suggest that inbreeding-by-environment interactions might arise when inbreeding is associated with too little or too much plasticity in response to changing environmental conditions.

Evolution of maternal effect senescence.

Increased maternal age at reproduction is often associated with decreased offspring performance in numerous species of plants and animals (including humans). Current evolutionary theory considers such maternal effect senescence as part of a unified process of reproductive senescence, which is under identical age-specific selective pressures to fertility. We offer a novel theoretical perspective by combining William Hamilton's evolutionary model for aging with a quantitative genetic model of indirect genetic effects. We demonstrate that fertility and maternal effect senescence are likely to experience different patterns of age-specific selection and thus can evolve to take divergent forms. Applied to neonatal survival, we find that selection for maternal effects is the product of age-specific fertility and Hamilton's age-specific force of selection for fertility. Population genetic models show that senescence for these maternal effects can evolve in the absence of reproductive or actuarial senescence; this implies that maternal effect aging is a fundamentally distinct demographic manifestation of the evolution of aging. However, brief periods of increasingly beneficial maternal effects can evolve when fertility increases with age faster than cumulative survival declines. This is most likely to occur early in life. Our integration of theory provides a general framework with which to model, measure, and compare the evolutionary determinants of the social manifestations of aging. Extension of our maternal effects model to other ecological and social contexts could provide important insights into the drivers of the astonishing diversity of lifespans and aging patterns observed among species.

Disentangling Pre- and Postnatal Maternal Age Effects on Offspring Performance in an Insect with Elaborate Maternal Care.

Maternal effect senescence has attracted much recent scientific interest. However, the age-related effects of pre- and postnatal maternal age are often conflated, as these naturally originate from the same individual. Additionally, many maternal effect senescence studies fail to account for potential biases associated with selective disappearance. Here we use a cross-fostered laboratory population of a burying beetle, Nicrophorus vespilloides, to examine both the effects of female pre- and postnatal maternal age on offspring life-history traits and the postcare outcomes of mothers while accounting for selective disappearance of postnatal caregivers. Neither pre- nor postnatal maternal age affected offspring longevity or larval weight at hatching, and postnatal age had no effect on postcare maternal outcomes except to confirm the presence of actuarial senescence. There was weak evidence for concave relationships between two larval traits (dispersal weight and survival) and the age of egg producers. Selective disappearance of caregivers had no clear effect on any of the measured offspring traits. Contrary to predictions from evolutionary theory, maternal effect senescence and reproductive effort increases do not always manifest, and current theory may be insufficient to account for the true diversity of aging patterns relating to maternal care.

Parental care buffers against inbreeding depression in burying beetles.

When relatives mate, their inbred offspring often suffer a reduction in fitness-related traits known as "inbreeding depression." There is mounting evidence that inbreeding depression can be exacerbated by environmental stresses such as starvation, predation, parasitism, and competition. Parental care may play an important role as a buffer against inbreeding depression in the offspring by alleviating these environmental stresses. Here, we examine the effect of parental care on the fitness costs of inbreeding in the burying beetle Nicrophorus vespilloides, an insect with facultative parental care. We used a 2 × 2 factorial design with the following factors: (i) the presence or absence of a caring female parent during larval development and (ii) inbred or outbred offspring. We examined the joint influence of maternal care and inbreeding status on fitness-related offspring traits to test the hypothesis that maternal care improves the performance of inbred offspring more than that of outbred offspring. Indeed, the female's presence led to a higher increase in larval survival in inbred than in outbred broods. Receiving care at the larval stage also increased the lifespan of inbred but not outbred adults, suggesting that the beneficial buffering effects of maternal care can persist long after the offspring have become independent. Our results show that parental care has the potential to moderate the severity of inbreeding depression, which in turn may favor inbreeding tolerance and influence the evolution of mating systems and other inbreeding-avoidance mechanisms.

Individual fitness and phenotypic selection in age-structured populations with constant growth rates.

Powerful multiple regression-based approaches are commonly used to measure the strength of phenotypic selection, which is the statistical association between individual fitness and trait values. Age structure and overlapping generations complicate determinations of individual fitness, contributing to the popularity of alternative methods for measuring natural selection that do not depend upon such measures. The application of regression-based techniques for measuring selection in these situations requires a demographically appropriate, conceptually sound, and observable measure of individual fitness. It has been suggested that Fisher's reproductive value applied to an individual at its birth is such a definition. Here I offer support for this assertion by showing that multiple regression applied to this measure and vital rates (age-specific survival and fertility rates) yields the same selection gradients for vital rates as those inferred from Hamilton's classical results. I discuss how multiple regressions, applied to individual reproductive value at birth, can be used efficiently to estimate measures of phenotypic selection that are problematic for sensitivity analyses. These include nonlinear selection, components of the opportunity for selection, and multilevel selection.

Selection gradients, the opportunity for selection, and the coefficient of determination.

Abstract We derive the relationship between R(2) (the coefficient of determination), selection gradients, and the opportunity for selection for univariate and multivariate cases. Our main result is to show that the portion of the opportunity for selection that is caused by variation for any trait is equal to the product of its selection gradient and its selection differential. This relationship is a corollary of the first and second fundamental theorems of natural selection, and it permits one to investigate the portions of the total opportunity for selection that are involved in directional selection, stabilizing (and diversifying) selection, and correlational selection, which is important to morphological integration. It also allows one to determine the fraction of fitness variation not explained by variation in measured phenotypes and therefore attributable to random (or, at least, unknown) influences. We apply our methods to a human data set to show how sex-specific mating success as a component of fitness variance can be decoupled from that owing to prereproductive mortality. By quantifying linear sources of sexual selection and quadratic sources of sexual selection, we illustrate that the former is stronger in males, while the latter is stronger in females.

The distribution of the Lansing Effect across animal species.

Maternal senescence is the reduction in individual performance associated with increased maternal age at conception. When manifested on adult lifespan, this phenomenon is known as the "Lansing Effect." Single-species studies report both maternal age-related increases and decreases in adult lifespan, but no comprehensive review of the literature has yet been undertaken to determine if the Lansing Effect is a widespread phenomenon. To address this knowledge gap, we performed a meta-analysis of maternal aging rates taken from all available published studies. We recovered 78 estimates from 22 studies representing 15 species. All studies taken together suggest a propensity for a Lansing Effect, with an estimated average effect of maternal age on offspring's adult lifespan of between -17% and -22%, depending upon our specific choice of model. We failed to find a significant effect of animal class or insect order but given the oversampling of insect species in the published literature and the paucity of vertebrate studies, we infer that only rotifers and insects yet demonstrate a tendency toward expressing the phenomenon.

Genetic variance and indirect genetic effects for affiliative social behavior in a wild primate.

Affiliative social behaviors are linked to fitness components in multiple species. However, the role of genetic variance in shaping such behaviors remains largely unknown, limiting our understanding of how affiliative behaviors can respond to natural selection. Here, we employed the "animal model" to estimate environmental and genetic sources of variance and covariance in grooming behavior in the well-studied Amboseli wild baboon population. We found that the tendency for a female baboon to groom others ("grooming given") is heritable (h2 = 0.22 ± 0.048), and that several environmental variables-including dominance rank and the availability of kin as grooming partners-contribute to variance in this grooming behavior. We also detected small but measurable variance due to the indirect genetic effect of partner identity on the amount of grooming given within dyadic grooming partnerships. The indirect and direct genetic effects for grooming given were positively correlated (r = 0.74 ± 0.09). Our results provide insight into the evolvability of affiliative behavior in wild animals, including the possibility for correlations between direct and indirect genetic effects to accelerate the response to selection. As such they provide novel information about the genetic architecture of social behavior in nature, with important implications for the evolution of cooperation and reciprocity.

Triparental ageing in a laboratory population of an insect with maternal care.

Parental age at reproduction influences offspring size and survival by affecting prenatal and postnatal conditions in a wide variety of species, including humans. However, most investigations into this manifestation of ageing focus upon maternal age effects; the effects of paternal age and interactions between maternal and paternal age are often neglected. Furthermore, even when maternal age effects are studied, pre- and post-natal effects are often confounded. Using a cross-fostered experimental design, we investigated the joint effects of pre-natal paternal and maternal and post-natal maternal ages on five traits related to offspring outcomes in a laboratory population of a species of burying beetle, Nicrophorus vespilloides. We found a significant positive effect of the age of the egg producer on larval survival to dispersal. We found more statistical evidence for interaction effects, which acted on larval survival and egg length. Both interaction effects were negative and involved the age of the egg-producer, indicating that age-related pre-natal maternal improvements were mitigated by increasing age in fathers and foster mothers. These results agree with an early study that found little evidence for maternal senescence, but it emphasizes that parental age interactions may be an important contributor to ageing patterns. We discuss how the peculiar life history of this species may promote selection to resist the evolution of parental age effects, and how this might have influenced our ability to detect senescence.

Evolutionary demography and quantitative genetics: age-specific survival as a threshold trait.

Researchers must understand how mutations affect survival at various ages to understand how ageing evolves. Many models linking mutation to age-specific survival have been proposed but there is little evidence to indicate which model is most appropriate. This is a serious problem because the predicted evolutionary endpoints of ageing depend upon the details of the specific model. We apply an explicitly quantitative genetic perspective to the problem. To determine the inheritance of dichotomous traits (such as survival), quantitative genetics has long employed a threshold model. Beginning from first principles, we show how this is the most defensible mutational model for age-specific survival and how this, relative to the standard model, predicts delayed senescence and mortality deceleration at late age. These are commonly observed patterns of ageing that heretofore have required more complicated survival models. We also show how this model can be developed further to unify quantitative genetics and evolutionary demography into a more complete conceptual framework for understanding the evolution of ageing.

Mating system change reduces the strength of sexual selection in an American frontier population of the 19th century.

Sexual selection, or competition among members of one sex for reproductive access to the other, is one of the strongest and fastest evolutionary processes. Comparative studies support the prediction that sexual selection is stronger in polygamous than in monogamous species. We report the first study of the effect on sexual selection of a change in mating system, from polygyny to monogamy, within a historical human population. Here we show that over the reproductive lifetimes of Utahns born between 1830 and 1894, socially induced reductions in the rate and degree of polygamy correspond to a 58% reduction in the strength of sexual selection. Polygyny conferred a strong advantage to male fitness as well as a weak disadvantage to female fitness. In contrast, mating with multiple males provided little benefit to females in this population. Polygamy benefitted males by increasing reproductive rates and by lengthening reproductive tenure. Each advantage contributed to roughly half of the increased total lifetime reproductive success. This study illustrates both the potency of sexual selection in polygynous human populations and the dramatic influence that short-term societal changes can have on evolutionary processes.

What can genetic variation tell us about the evolution of senescence?

Quantitative genetic approaches have been developed that allow researchers to determine which of two mechanisms, mutation accumulation (MA) or antagonistic pleiotropy (AP), best explain observed variation in patterns of senescence using classical quantitative genetic techniques. These include the creation of mutation accumulation lines, artificial selection experiments and the partitioning of genetic variances across age classes. This last strategy has received the lion's share of empirical attention. Models predict that inbreeding depression (ID), dominance variance and the variance among inbred line means will all increase with age under MA but not under those forms of AP that generate marginal overdominance. Here, we show that these measures are not, in fact, diagnostic of MA versus AP. In particular, the assumptions about the value of genetic parameters in existing AP models may be rather narrow, and often violated in reality. We argue that whenever ageing-related AP loci contribute to segregating genetic variation, polymorphism at these loci will be enhanced by genetic effects that will also cause ID and dominance variance to increase with age, effects also expected under the MA model of senescence. We suggest that the tests that seek to identify the relative contributions of AP and MA to the evolution of ageing by partitioning genetic variance components are likely to be too conservative to be of general value.

Levels of selection on threshold characters.

Threshold models are useful for understanding the evolution of dimorphic traits with polygenic bases. Selection for threshold characters on individuals is expected to be frequency dependent because of the peculiar way that selection views underlying genetic and environmental factors. Selection among individuals is inefficient because individual phenotypes fall into only two discrete categories that map imperfectly to the underlying genes. Incidence, however, can be continuously distributed among groups, making among-group selection relatively more efficient. Differently put, the group-mean phenotype can be a better predictor of an individual's genotype than that individual's own phenotype. Because evolution in group-structured populations is governed by the balance of selection within and between groups, we can expect threshold traits to evolve in fundamentally different ways when group mean fitness is a function of morph frequency. We extend the theory of selection on threshold traits to include group selection using contextual analysis. For the simple case of linear group-fitness functions, we show that the group-level component of selection, like the individual-level component, is frequency dependent. However, the conditions that determine which component dominates when levels of selection are in conflict (as described by Hamilton's rule) are not frequency dependent. Thus, enhanced group selection is not an inherent property of threshold characters. Nevertheless, we show that predicting the effects of multiple levels of selection on dimorphic traits requires special considerations of the threshold model.

A theory of age-dependent mutation and senescence.

Laboratory experiments show us that the deleterious character of accumulated novel age-specific mutations is reduced and made less variable with increased age. While theories of aging predict that the frequency of deleterious mutations at mutation-selection equilibrium will increase with the mutation's age of effect, they do not account for these age-related changes in the distribution of de novo mutational effects. Furthermore, no model predicts why this dependence of mutational effects upon age exists. Because the nature of mutational distributions plays a critical role in shaping patterns of senescence, we need to develop aging theory that explains and incorporates these effects. Here we propose a model that explains the age dependency of mutational effects by extending Fisher's geometrical model of adaptation to include a temporal dimension. Using a combination of simple analytical arguments and simulations, we show that our model predicts age-specific mutational distributions that are consistent with observations from mutation-accumulation experiments. Simulations show us that these age-specific mutational effects may generate patterns of senescence at mutation-selection equilibrium that are consistent with observed demographic patterns that are otherwise difficult to explain.

Evolutionary Ecology of Senescence and a Reassessment of Williams' 'Extrinsic Mortality' Hypothesis.

The evolutionary theory of senescence underpins research in life history evolution and the biology of aging. In 1957 G.C. Williams predicted that higher adult death rates select for earlier senescence and shorter length of life, but preadult mortality does not matter to the evolution of senescence. This was subsequently interpreted as predicting that senescence should be caused by 'extrinsic' sources of mortality. This idea still motivates empirical studies, although formal, mathematical theory shows it is wrong. It has nonetheless prospered because it offers an intuitive explanation for patterns observed in nature. We review the flaws in Williams' model, explore alternative explanations for comparative patterns that are consistent with the evolutionary theory of senescence, and discuss how hypotheses based on it can be tested. We argue that focusing on how sources of mortality affect ages differently offers greater insight into evolutionary processes.

Measuring selection for genes that promote long life in a historical human population.

The unusually long lifespans of humans and the persistence of post-reproductive lifespans in women represent evolutionary puzzles because natural selection cannot directly favour continued living in post-menopausal women or elderly men. Suggested sources of indirect selection require genetic correlations between fitness and survival or reproduction at younger ages, reproduction in the opposite sex, or late-life contributions to offspring or grandoffspring fitness. Here we apply quantitative genetic analyses to data from a historical human population to explicitly test these evolutionary genetic hypotheses. Total genetic selection increased the male post-50 lifespans by 0.138 years per generation; 94% of this arose from indirect selection acting to favour early-life fitness in both sexes. These results argue strongly against life-history models of ageing that depend on trade-offs between reproduction and late-life survival. No source of indirect selection for female post-50 lifespan was detected, deepening the mystery of why female post-reproductive survival persists. This result is probably due to recent changes in the genetic architecture of female lifespan, and it highlights the need for similar quantitative genetic analyses of human populations at other points along demographic transitions.