Modeling of senescent cell dynamics predicts a late-life decrease in cancer incidence.

Current oncogenic theories state that tumors arise from cell lineages that sequentially accumulate (epi)mutations, progressively turning healthy cells into carcinogenic ones. While those models found some empirical support, they are little predictive of intraspecies age-specific cancer incidence and of interspecies cancer prevalence. Notably, in humans and lab rodents, a deceleration (and sometimes decline) of cancer incidence rate has been found at old ages. Additionally, dominant theoretical models of oncogenesis predict that cancer risk should increase in large and/or long-lived species, which is not supported by empirical data. Here, we explore the hypothesis that cellular senescence could explain those incongruent empirical patterns. More precisely, we hypothesize that there is a trade-off between dying of cancer and of (other) ageing-related causes. This trade-off between organismal mortality components would be mediated, at the cellular scale, by the accumulation of senescent cells. In this framework, damaged cells can either undergo apoptosis or enter senescence. Apoptotic cells lead to compensatory proliferation, associated with an excess risk of cancer, whereas senescent cell accumulation leads to ageing-related mortality. To test our framework, we build a deterministic model that first describes how cells get damaged, undergo apoptosis, or enter senescence. We then translate those cellular dynamics into a compound organismal survival metric also integrating life-history traits. We address four different questions linked to our framework: can cellular senescence be adaptive, do the predictions of our model reflect epidemiological patterns observed among mammal species, what is the effect of species sizes on those answers, and what happens when senescent cells are removed? Importantly, we find that cellular senescence can optimize lifetime reproductive success. Moreover, we find that life-history traits play an important role in shaping the cellular trade-offs. Overall, we demonstrate that integrating cellular biology knowledge with eco-evolutionary principles is crucial to solve parts of the cancer puzzle.

Reproductive seasonality in the Baka Pygmies, environmental factors and climatic changes.

Reproductive seasonality is a phenomenon common to human and animal populations and driven by, among others, climatic variables. Given the currently changing climate and its impacts on both the environment and human lives, the question arises of its potential effects on reproductive seasonality. Few studies have specifically explored the seasonality of reproduction among hunter-gatherers and anyone investigated how current climate change might affect this phenomenon. In this study we addressed reproductive seasonality in the Baka Pygmy living in African rain forests. Since reproductive seasonality can be linked to weather patterns, we explore this possibility. However, climatic variables driving weather patterns have changed over the years, so we assessed whether this has influenced the Baka reproductive pattern. Based on 34 years of written birth records and oral questionnaires from 13 years of systematic fieldwork, we observed a bimodal birth pattern with two birth peaks at 6-month intervals. Our results demonstrate that precipitation at conception or at birth potentially has effects, respectively negative and positive on the monthly number of births; and temperature has a role in controlling other variables that do affect the reproductive pattern. Changing weather patterns appear to be affecting the reproductive seasonality in the Baka, suggesting that attention needs to be given to the influence of global climate change on forager societies.

Cancer risk across mammals.

Cancer is a ubiquitous disease of metazoans, predicted to disproportionately affect larger, long-lived organisms owing to their greater number of cell divisions, and thus increased probability of somatic mutations1,2. While elevated cancer risk with larger body size and/or longevity has been documented within species3-5, Peto's paradox indicates the apparent lack of such an association among taxa6. Yet, unequivocal empirical evidence for Peto's paradox is lacking, stemming from the difficulty of estimating cancer risk in non-model species. Here we build and analyse a database on cancer-related mortality using data on adult zoo mammals (110,148 individuals, 191 species) and map age-controlled cancer mortality to the mammalian tree of life. We demonstrate the universality and high frequency of oncogenic phenomena in mammals and reveal substantial differences in cancer mortality across major mammalian orders. We show that the phylogenetic distribution of cancer mortality is associated with diet, with carnivorous mammals (especially mammal-consuming ones) facing the highest cancer-related mortality. Moreover, we provide unequivocal evidence for the body size and longevity components of Peto's paradox by showing that cancer mortality risk is largely independent of both body mass and adult life expectancy across species. These results highlight the key role of life-history evolution in shaping cancer resistance and provide major advancements in the quest for natural anticancer defences.

The kinship matrix: inferring the kinship structure of a population from its demography.

The familial structure of a population and the relatedness of its individuals are determined by its demography. There is, however, no general method to infer kinship directly from the life cycle of a structured population. Yet, this question is central to fields such as ecology, evolution and conservation, especially in contexts where there is a strong interdependence between familial structure and population dynamics. Here, we give a general formula to compute, from any matrix population model, the expected number of arbitrary kin (sisters, nieces, cousins, etc) of a focal individual ego, structured by the class of ego and of its kin. Central to our approach are classic but little-used tools known as genealogical matrices. Our method can be used to obtain both individual-based and population-wide metrics of kinship, as we illustrate. It also makes it possible to analyse the sensitivity of the kinship structure to the traits implemented in the model.

Evolutionary demographic models reveal the strength of purifying selection on susceptibility alleles to late-onset diseases.

Assessing the role played by purifying selection on a susceptibility allele to late-onset disease (SALOD) is crucial to understanding the puzzling allelic spectrum of a disease, because most alleles are recent and rare. This fact is surprising because it suggests that alleles are under purifying selection while those that are involved in post-menopause mortality are often considered neutral in the genetic literature. The aim of this article is to use an evolutionary demography model to assess the magnitude of selection on SALODs while accounting for epidemiological and sociocultural factors. We develop an age-structured population model allowing for the calculation of SALOD selection coefficients (1) for a large and realistic parameter space for disease onset, (2) in a two-sex model in which men can reproduce in old age and (3) for situations in which child survival depends on maternal, paternal and grandmaternal care. The results show that SALODs are under purifying selection for most known age-at-onset distributions of late-onset genetic diseases. Estimates regarding various genes involved in susceptibility to cancer or Huntington's disease demonstrate that negative selection largely overcomes the effects of drift in most human populations. This is also probably true for neurodegenerative or polycystic kidney diseases, although sociocultural factors modulate the effect of selection in these cases. We conclude that neutrality is probably the exception among alleles that have a deleterious effect in old age and that accounting for sociocultural factors is required to understand the full extent of the force of selection shaping senescence in humans.

Survival is reduced when endogenous period deviates from 24 h in a non-human primate, supporting the circadian resonance theory.

Circadian rhythms are ubiquitous attributes across living organisms and allow the coordination of internal biological functions with optimal phases of the environment, suggesting a significant adaptive advantage. The endogenous period called tau lies close to 24 h and is thought to be implicated in individuals' fitness: according to the circadian resonance theory, fitness is reduced when tau gets far from 24 h. In this study, we measured the endogenous period of 142 mouse lemurs (Microcebus murinus), and analyzed how it is related to their survival. We found different effects according to sex and season. No impact of tau on mortality was found in females. However, in males, the deviation of tau from 24 h substantially correlates with an increase in mortality, particularly during the inactive season (winter). These results, comparable to other observations in mice or drosophila, show that captive gray mouse lemurs enjoy better fitness when their circadian period closely matches the environmental periodicity. In addition to their deep implications in health and aging research, these results raise further ecological and evolutionary issues regarding the relationships between fitness and circadian clock.

Flexibility Is Costly: Hidden Physiological Damage From Seasonal Phenotypic Transitions in Heterothermic Species.

Heterothermy allows organisms to cope with fluctuating environmental conditions. The use of regulated hypometabolism allows seasonal heterothermic species to cope with annual resource shortages and thus to maximize survival during the unfavorable season. This comes with deep physiological remodeling at each seasonal transition to allow the organism to adjust to the changing environment. In the wild, this adaptation is highly beneficial and largely overcomes potential costs. However, researchers recently proposed that it might also generate both ecological and physiological costs for the organism. Here, we propose new perspectives to be considered when analyzing adaptation to seasonality, in particular considering these costs. We propose a list of putative costs, including DNA damage, inflammatory response to fat load, brain and cognitive defects, digestive malfunction and immunodeficiency, that should receive more attention in future research on physiological seasonality. These costs may only be marginal at each transition event but accumulate over time and therefore emerge with age. In this context, studies in captivity, where we have access to aging individuals with limited extrinsic mortality (e.g., predation), could be highly valuable to experimentally assess the costs of physiological flexibility. Finally, we offer new perspectives, which should be included in demographic models, on how the adaptive value of physiological flexibility could be altered in the future in the context of global warming.

From matrimonial practices to genetic diversity in Southeast Asian populations: the signature of the matrilineal puzzle.

In matrilineal populations, the descent group affiliation is transmitted by women whereas the socio-political power frequently remains in the hands of men. This situation, named the 'matrilineal puzzle', is expected to promote local endogamy as a coping mechanism allowing men to maintain their decision-making power over their natal descent group. In this paper, we revisit this 'matrilineal puzzle' from a population genetics' point of view. Indeed, such tendency for local endogamy in matrilineal populations is expected to increase their genetic inbreeding and generate isolation-by-distance patterns between villages. To test this hypothesis, we collected ethno-demographic data for 3261 couples and high-density genetic data for 675 individuals from 11 Southeast Asian populations with a wide range of social organizations: matrilineal and matrilocal populations (M), patrilineal and patrilocal populations (P) or cognatic populations with predominant matrilocal residence (C). We observed that M and C populations have higher levels of village endogamy than P populations, and that such higher village endogamy leads to higher genetic inbreeding. M populations also exhibit isolation-by-distance patterns between villages. We interpret such genetic patterns as the signature of the 'matrilineal puzzle'. Notably, our results suggest that any form of matrilocal marriage (whatever the descent rule is) increases village endogamy. These findings suggest that male dominance, when combined with matrilocality, constrains inter-village migrations, and constitutes an underexplored cultural process shaping genetic patterns in human populations. This article is part of the theme issue 'The evolution of female-biased kinship in humans and other mammals'.

Female reproduction bears no survival cost in captivity for gray mouse lemurs.

The survival cost of reproduction has been revealed in many free-ranging vertebrates. However, recent studies on captive populations failed to detect this cost. Theoretically, this lack of survival/reproduction trade-off is expected when resources are not limiting, but these studies may have failed to detect the cost, as they may not have fully accounted for potential confounding effects, in particular interindividual heterogeneity. Here, we investigated the effects of current and past reproductive effort on later survival in captive females of a small primate, the gray mouse lemur. Survival analyses showed no cost of reproduction in females; and the pattern was even in the opposite direction: the higher the reproductive effort, the higher the chances of survival until the next reproductive event. These conclusions hold even while accounting for interindividual heterogeneity. In agreement with aforementioned studies on captive vertebrates, these results remind us that reproduction is expected to be traded against body maintenance and the survival prospect only when resources are so limiting that they induce an allocation trade-off. Thus, the cost of reproduction has a major extrinsic component driven by environmental conditions.

Residence rule flexibility and descent groups dynamics shape uniparental genetic diversities in South East Asia.

OBJECTIVES: Social organization plays a major role in shaping human population genetic diversity. In particular, matrilocal populations tend to exhibit less mitochondrial diversity than patrilocal populations, and the other way around for Y chromosome diversity. However, several studies have not replicated such findings. The objective of this study is to understand the reasons for such inconsistencies and further evaluate the influence of social organization on genetic diversity. MATERIALS AND METHODS: We explored uniparental diversity patterns using mitochondrial HV1 sequences and 17 Y-linked short tandem repeats (STRs) in 12 populations (n = 619) from mainland South-East Asia exhibiting a wide range of social organizations, along with quantitative ethno-demographic information sampled at the individual level. RESULTS: MtDNA diversity was lower in matrilocal than in multilocal and patrilocal populations while Y chromosome diversity was similar among these social organizations. The reasons for such asymmetry at the genetic level were understood by quantifying sex-specific migration rates from our ethno-demographic data: while female migration rates varied between social organizations, male migration rates did not. This unexpected lack of difference in male migrations resulted from a higher flexibility in residence rule in patrilocal than in matrilocal populations. In addition, our data suggested an impact of clan fission process on uniparental genetic patterns. CONCLUSIONS: The observed lack of signature of patrilocality on Y chromosome patterns might be attributed to the higher residence flexibility in the studied patrilocal populations, thus providing a potential explanation for the apparent discrepancies between social and genetic structures. Altogether, this study highlights the need to quantify the actual residence and descent patterns to fit social to genetic structures.

Trait level analysis of multitrait population projection matrices.

In most matrix population projection models, individuals are characterized according to, usually, one or two traits such as age, stage, size or location. A broad theory of multitrait population projection matrices (MPPMs) incorporating larger number of traits was long held back by time and space computational complexity issues. As a consequence, no study has yet focused on the influence of the structure of traits describing a life-cycle on population dynamics and life-history evolution. We present here a novel vector-based MPPM building methodology that allows to computationally-efficiently model populations characterized by numerous traits with large distributions, and extend sensitivity analyses for these models. We then present a new method, the trait level analysis consisting in folding an MPPM on any of its traits to create a matrix with alternative trait structure (the number of traits and their characteristics) but similar asymptotic properties. Adding or removing one or several traits to/from the MPPM and analyzing the resulting changes in spectral properties, allows investigating the influence of the trait structure on the evolution of traits. We illustrate this by modeling a 3-trait (age, parity and fecundity) population designed to investigate the implications of parity-fertilitytrade-offs in a context of fecundity heterogeneity in humans. The trait level analysis, comparing models of the same population differing in trait structures, demonstrates that fertility selection gradients differ between cases with or without parity-fertility trade-offs. Moreover it shows that age-specific fertility has seemingly very different evolutionary significance depending on whether heterogeneity is accounted for. This is because trade-offs can vary strongly in strength and even direction depending on the trait structure used to model the population.

State transitions: a major mortality risk for seasonal species.

Ageing results from the accumulation of multifactorial damage over time. However, the temporal distribution of this damage remains unknown. In seasonal species, transitions between seasons are critical periods of massive physiological remodelling. We hypothesised that these recurrent peaks of physiological remodelling are costly in terms of survival. We tested whether captive small primates exposed to an experimentally increased frequency of seasonal transitions die sooner than individuals living under natural seasonality. The results show that experiencing one additional season per year increases the mortality hazard by a factor of 3 to 4, whereas the expected number of seasons lived is only slightly impacted by the seasonal rhythm. These results demonstrate that physiological transitions between periods of high and low metabolic activity represent a major mortality risk for seasonal organisms, which has been ignored until now.

Actuarial senescence can increase the risk of extinction of mammal populations.

Despite recent acknowledgement that senescence can have negative impact on survival and fertility in natural environments across a wide range of animal species, we still do not know if it can reduce the viability of wild endangered populations. Focusing on actuarial senescence (i.e., the decline of survival probabilities at old ages), we use species-specific demographic information to project the extinction risk of wild populations of 58 species of mammals, accounting (or not) for senescence. Our projections reveal potential negative effects of aging on population viability, with an average decrease of 27% of the time to extinction and a potential deterioration of the population-level projected conservation status in 10% of the species. Senescence is associated with particularly strong increases of the extinction risk in species with low mortality rates and long intervals between litters, independently of their place in the phylogeny, indicating that the pace of life history can be used to forecast the detrimental effects of aging on the viability of species. The aim of the various existing systems of classification of threatened species is to set conservation priorities based on assessments of extinction risk. Our results indicate that the quantitative effects of senescence on extinction are highly heterogeneous, which can affect the ranking of species and populations when setting conservation, priorities. In mammals, based on life history traits of a few species, generic patterns of senescence can be incorporated into projection population models to minimize these biases in viability assessments.

The size-life span trade-off decomposed: why large dogs die young.

Large body size is one of the best predictors of long life span across species of mammals. In marked contrast, there is considerable evidence that, within species, larger individuals are actually shorter lived. This apparent cost of larger size is especially evident in the domestic dog, where artificial selection has led to breeds that vary in body size by almost two orders of magnitude and in average life expectancy by a factor of two. Survival costs of large size might be paid at different stages of the life cycle: a higher early mortality, an early onset of senescence, an elevated baseline mortality, or an increased rate of aging. After fitting different mortality hazard models to death data from 74 breeds of dogs, we describe the relationship between size and several mortality components. We did not find a clear correlation between body size and the onset of senescence. The baseline hazard is slightly higher in large dogs, but the driving force behind the trade-off between size and life span is apparently a strong positive relationship between size and aging rate. We conclude that large dogs die young mainly because they age quickly.

Effect of maternal and grandmaternal care on population dynamics and human life-history evolution: a matrix projection model.

We present a matrix population model for a single-sex human population comprising non-orphan daughters (whose mothers are alive) and orphan daughters (whose mothers are dead). Orphans suffer higher mortality than non-orphans, which simulates the need for daughters to receive maternal care in order to survive. The way that maternal care affects population dynamics and life-history evolution is then analysed for demographic regimes that encompass large ranges of daughter survival, mother survival and fertility. We provide stable age-distributions of orphans and non-orphans for each regime and perform sensitivity analyses on daughter survival, adult survival and fertility. The results show that natural selection will favour (i) faster daughter independence from maternal care, (ii) higher adult survival at all ages, and (iii) early reproduction to the detriment of late reproduction. We then build scenarios concerning the coevolution of daughter survival and maternal care with adult survival and fertility. We also incorporate grandmaternal care into the model. We show that (i) the acute altriciality of human babies, (ii) the increased maternal care resulting from emergence of complex sociality and (iii) the role played by grandmothers in caring for granddaughters may have led to the emergence of specific human life-history traits: a short reproductive period characterised by a reproductive senescence and menopause, as well as an extended lifespan characterised by a post-reproductive life.

Drivers of age-specific survival in a long-lived seabird: contributions of observed and hidden sources of heterogeneity.

1. We assessed the relative influence of variability in recruitment age, dynamic reproductive investment (time-specific reproductive states) and frailty (unobserved differences in survival abilities across individuals) on survival in the black-legged kittiwake. Furthermore, we examined whether observed variability in survival trajectories was best explained by immediate reproductive investment, cumulative investment, or both. 2. Individuals that delayed recruitment (≥ age 7) suffered a higher mortality risk than early recruits (age 3), especially later in life, suggesting that recruitment age may be an indicator of individual quality. Although recruitment age helped explain variation in survival, time-varying reproductive investment had a more substantial influence. 3. The dichotomy of attempting to breed or not explained variability in survival across life better than other parameterizations of reproductive states such as clutch size, brood size or breeding success. In the kittiwake, the sinequanon condition to initiate reproduction is to hold a nest site, which is considered a very competitive activity. This might explain why attempting to breed is the key level of investment that affects survival, independent of the outcome (failure or success). 4. Interestingly, the more individuals cumulate reproductive attempts over life, the lower their mortality risk, indicating that breeding experience may be a good indicator of parental quality as well. In contrast, attempting to breed at time t increased the risk of mortality between t and t + 1. We thus detected an immediate trade-off between attempting to breed and survival in this population; however, the earlier individuals recruited, and the more breeding experience they accumulated, the smaller the cost. 5. Lastly, unobserved heterogeneity across individuals improved model fit more (1·3 times) than fixed and dynamic sources of observed heterogeneity in reproductive investment, demonstrating that it is critical to account for both sources of individual heterogeneity when studying survival trajectories. Only after simultaneously accounting for both sources of heterogeneity were we able to detect the 'cost' of immediate reproductive investment on survival and the 'benefit' of cumulative breeding attempts (experience), a proxy to individual quality.

Can life history trade-offs explain the evolution of short stature in human pygmies? A response to Migliano et al. (2007).

Walker et al. ["Growth rates and life histories in twenty-two small-scale societies," Am. J. Hum. Biol. 18:295-311 (2006)] used life history theory to develop an innovative explanation for human diversity in stature. Short stature could have been selected for in some human populations as a result of the advantage of an earlier growth cessation and earlier reproduction in a context of high mortality. Migliano et al. ["Life history trade-offs explain the evolution of human pygmies," Proc. Natl. Acad. Sci. USA 104:20,216-20,219 (2007)] recently published an important article that tested this hypothesis to explain short stature in human pygmy populations. However innovative this work may be, we believe that some of the data and results presented are controversial if not questionable. As problematic points we note (1) the use of an arbitrary threshold of height (155 cm) to categorize populations into pygmies and nonpygmies; (2) the use of demographic data from Philippine pygmy groups that have experienced dramatic cultural and environmental changes in the last 20 years, and (3) the use of demographic data concerning African pygmy groups because good systematic data on these groups are not available. Finally, we report here mathematical errors and loopholes in the optimization model developed by Migliano and colleagues. In this paper we suggest alternative trade-offs that can be used to explain Migliano's results on more reliable bases.

Senescence of reproduction may explain adaptive menopause in humans: a test of the "mother" hypothesis.

The "mother" hypothesis is one of the main adaptive explanations of human menopause. It postulates that reproductive cessation constitutes a strategy that has been selected for during human evolution because mothers at older ages might maximize their fitness by investing resources in the survival and reproduction of their living children rather than by continuing to reproduce. This study provides a test of this hypothesis. Fertility functions that maximize fitness are built into a model incorporating the fact that the survival of females during the rearing period is a major determinant of their children's survival. Results are given according to different scenarios of increase with mothers' age of maternal mortality risk and risk of stillbirth and birth defects (on the assumption that these females do not experience menopause). Different estimates of the effect of a mother's death on her child's survival were also incorporated. Finally, a population genetics framework allows us to estimate selection on these optimal fertility functions. To determine whether or not these fertility functions show a menopause, three criteria are discussed: the rapidity of fertility decline, if any; the magnitude of selection on menopause compared with a nonmenopausal strategy; and the selection on survival during post-reproductive life. Our results show that menopause and subsequent post-reproductive life are significantly advantageous when two conditions are satisfied: a marked increase in stillbirth and risk of birth defects as well as in maternal mortality with mother's age.

Negative selection on BRCA1 susceptibility alleles sheds light on the population genetics of late-onset diseases and aging theory.

The magnitude of negative selection on alleles involved in age-specific mortality decreases with age. This is the foundation of the evolutionary theory of senescence. Because of this decrease in negative selection with age, and because of the absence of reproduction after menopause, alleles involved in women's late-onset diseases are generally considered evolutionarily neutral. Recently, genetic and epidemiological data on alleles involved in late onset-diseases have become available. It is therefore timely to estimate selection on these alleles. Here, we estimate selection on BRCA1 alleles leading to susceptibility to late-onset breast and ovarian cancer. For this, we integrate estimates of the risk of developing a cancer for BRCA1-carriers into population genetics frameworks, and calculate selection coefficients on BRCA1 alleles for different demographic scenarios varying across the extent of human demography. We then explore the magnitude of negative selection on alleles leading to a diverse range of risk patterns, to capture a variety of late-onset diseases. We show that BRCA1 alleles may have been under significant negative selection during human history. Although the mean age of onset of the disease is long after menopause, variance in age of onset means that there are always enough cases occurring before the end of reproductive life to compromise the selective value of women carrying a susceptibility allele in BRCA1. This seems to be the case for an extended range of risk of onset functions varying both in mean and variance. This finding may explain the distribution of BRCA1 alleles' frequency, and also why alleles for many late-onset diseases, like certain familial forms of cancer, coronary artery diseases and Alzheimer dementia, are typically recent and rare. Finally, we discuss why the two most popular evolutionary theories of aging, mutation accumulation and antagonistic pleiotropy, may underestimate the effect of selection on survival at old ages.