Grace period of human mortality has declined for over a century.

OBJECTIVES: Human mortality is U-shaped and, therefore, defines an age x * $$ {x}^{\ast } $$ separating lives with an overall negative net change in mortality from lives with an overall positive net change in mortality. How has age x * $$ {x}^{\ast } $$ changed, also relatively to life expectancy, over recent human history? And how does x * $$ {x}^{\ast } $$ compare between humans and other primates, the mortality of which is also U-shaped? METHODS: Modeling data from the Human Mortality Database, the historical change of x * $$ {x}^{\ast } $$ in advanced economies is reported and compared with that of primates in wild and captive conditions the demography of which was already modeled in the literature. RESULTS: In humans, a marked decline in x * $$ {x}^{\ast } $$ for both sexes, also relatively to their life expectancy, is associated with medical and economic progress. Comparing wild with captive conditions in nonhuman primates, magnitude, and direction of the change in x * $$ {x}^{\ast } $$ , both relatively to life expectancy and absolutely, can depend on genus and sex. CONCLUSIONS: With medical and economic progress, human lives have transitioned from a negative to a positive net change in mortality independently of sex. There is no evidence of an analogous transition occurring in other primates when their environment is made more benign.

Understanding and leveraging phenotypic plasticity during metastasis formation.

Cancer metastasis is the process of detrimental systemic spread and the primary cause of cancer-related fatalities. Successful metastasis formation requires tumor cells to be proliferative and invasive; however, cells cannot be effective at both tasks simultaneously. Tumor cells compensate for this trade-off by changing their phenotype during metastasis formation through phenotypic plasticity. Given the changing selection pressures and competitive interactions that tumor cells face, it is poorly understood how plasticity shapes the process of metastasis formation. Here, we develop an ecology-inspired mathematical model with phenotypic plasticity and resource competition between phenotypes to address this knowledge gap. We find that phenotypically plastic tumor cell populations attain a stable phenotype equilibrium that maintains tumor cell heterogeneity. Considering treatment types inspired by chemo- and immunotherapy, we highlight that plasticity can protect tumors against interventions. Turning this strength into a weakness, we corroborate current clinical practices to use plasticity as a target for adjuvant therapy. We present a parsimonious view of tumor plasticity-driven metastasis that is quantitative and experimentally testable, and thus potentially improving the mechanistic understanding of metastasis at the cell population level, and its treatment consequences.

Generation Time in Stage-Structured Populations under Fluctuating Environments.

AbstractA common measure of generation time is the average distance between two recruitment events along a genetic lineage. In populations with stage structure that live in a constant environment, this generation time can be computed from the elasticities of stable population growth to fecundities, and it is equivalent to another common measure of generation time: the average parental age of reproductive-value-weighted offspring. Here, we show three things. First, when the environment fluctuates, the average distance between two recruitment events along a genetic lineage is computed from the elasticities of the stochastic growth rate to fecundities. Second, under environmental stochasticity, this measure of generation time remains equivalent to the average parental age of reproductive-value-weighted offspring. Third, the generation time of a population in a fluctuating environment may deviate from the generation time the population would have in the average environment.

On Citing Dobzhansky about the Significance of Evolution to Biology.

Evolutionary thinking illuminates biology. Dobzhansky advocated this view in two distinct papers. The earliest paper (1964) is a discussion of the relationship between distinct biological disciplines, and one of the key ideas is that evolution is an integrative principle of biology. The later paper (1973) is a long argument to the effect that evolution makes more sense of the living than some creationist doctrines. The first paper should then be the primary reference for those biologists who cite Dobzhansky to champion among their peers the added value of evolutionary thinking in a specific scientific problem. Here, looking at citation data, we find evidence that this expected referencing practice does not coincide with the actual referencing practice in the scientific literature.

Age-specific sensitivity analysis of stable, stochastic and transient growth for stage-classified populations.

Sensitivity analysis in ecology and evolution is a valuable guide to rank demographic parameters depending on their relevance to population growth. Here, we propose a method to make the sensitivity analysis of population growth for matrix models solely classified by stage more fine-grained by considering the effect of age-specific parameters. The method applies to stable population growth, the stochastic growth rate, and transient growth. The method yields expressions for the sensitivity of stable population growth to age-specific survival and fecundity from which general properties are derived about the pattern of age-specific selective forces molding senescence in stage-classified populations.

Selection on age-specific survival: Constant versus fluctuating environment.

According to a classic result in evolutionary biodemography, selection on age-specific survival invariably declines with reproductive age. The result assumes proportional changes in survival and a constant environment. Here, we look at selection on age-specific survival when changes are still proportional but the environment fluctuates. We find that selection may or may not decline with reproductive age depending on how exactly survival is proportionally altered by mutations. However, interpreted in neutral terms, the mathematics behind the classic result capture a general property that the genetics of populations with age structure possess both in a constant and in a fluctuating environment.

The selection force weakens with age because ageing evolves and not vice versa.

According to the classic theory of life history evolution, ageing evolves because selection on traits necessarily weakens throughout reproductive life. But this inexorable decline of the selection force with adult age was shown to crucially depend on specific assumptions that are not necessarily fulfilled. Whether ageing still evolves upon their relaxation remains an open problem. Here, we propose a fully dynamical model of life history evolution that does not presuppose any specific pattern the force of selection should follow. The model shows: (i) ageing can stably evolve, but negative ageing cannot; (ii) when ageing is a stable equilibrium, the associated selection force decreases with reproductive age; (iii) non-decreasing selection is either a transient or an unstable phenomenon. Thus, we generalize the classic theory of the evolution of ageing while overturning its logic: the decline of selection with age evolves dynamically, and is not an implicit consequence of certain assumptions.

Medawar and Hamilton on the selective forces in the evolution of ageing.

Both Medawar and Hamilton contributed key ideas to the modern evolutionary theory of ageing. In particular, they both suggested that, in populations with overlapping generations, the force with which selection acts on traits declines with the age at which traits are expressed. This decline would eventually cause ageing to evolve. However, the biological literature diverges on the relationship between Medawar's analysis of the force of selection and Hamilton's. Some authors appear to believe that Hamilton perfected Medawar's insightful, yet ultimately erroneous analysis of this force, while others see Hamilton's analysis as a coherent development of, or the obvious complement to Medawar's. Here, the relationship between the two analyses is revisited. Two things are argued for. First, most of Medawar's alleged errors that Hamilton would had rectified seem not to be there. The origin of these perceived errors appears to be in a misinterpretation of Medawar's writings. Second, the mathematics of Medawar and that of Hamilton show a significant overlap. However, different meanings are attached to the same mathematical expression. Medawar put forth an expression for the selective force on age-specific fitness. Hamilton proposed a full spectrum of selective forces each operating on age-specific fitness components, i.e. mortality and fertility. One of Hamilton's expressions, possibly his most important, is of the same form as Medawar's expression. But Hamilton's selective forces on age-specific fitness components do not add up to yield Medawar's selective force on age-specific fitness. It is concluded that Hamilton's analysis should be considered neither as a correction to Medawar's analysis nor as its obvious complement.

Memory shapes microbial populations.

Correct decision making is fundamental for all living organisms to thrive under environmental changes. The patterns of environmental variation and the quality of available information define the most favourable strategy among multiple options, from randomly adopting a phenotypic state to sensing and reacting to environmental cues. Cellular memory-the ability to track and condition the time to switch to a different phenotypic state-can help withstand environmental fluctuations. How does memory manifest itself in unicellular organisms? We describe the population-wide consequences of phenotypic memory in microbes through a combination of deterministic modelling and stochastic simulations. Moving beyond binary switching models, our work highlights the need to consider a broader range of switching behaviours when describing microbial adaptive strategies. We show that memory in individual cells generates patterns at the population level coherent with overshoots and non-exponential lag times distributions experimentally observed in phenotypically heterogeneous populations. We emphasise the implications of our work in understanding antibiotic tolerance and, in general, bacterial survival under fluctuating environments.

Sex or cannibalism: Polyphenism and kin recognition control social action strategies in nematodes.

Resource polyphenisms, where single genotypes produce alternative feeding strategies in response to changing environments, are thought to be facilitators of evolutionary novelty. However, understanding the interplay between environment, morphology, and behavior and its significance is complex. We explore a radiation of Pristionchus nematodes with discrete polyphenic mouth forms and associated microbivorous versus cannibalistic traits. Notably, comparing 29 Pristionchus species reveals that reproductive mode strongly correlates with mouth-form plasticity. Male-female species exhibit the microbivorous morph and avoid parent-offspring conflict as indicated by genetic hybrids. In contrast, hermaphroditic species display cannibalistic morphs encouraging competition. Testing predation between 36 co-occurring strains of the hermaphrodite P. pacificus showed that killing inversely correlates with genomic relatedness. These empirical data together with theory reveal that polyphenism (plasticity), kin recognition, and relatedness are three major factors that shape cannibalistic behaviors. Thus, developmental plasticity influences cooperative versus competitive social action strategies in diverse animals.

Generation Time Measures the Trade-Off between Survival and Reproduction in a Life Cycle.

Survival and fertility are the two most basic components of fitness, and they drive the evolution of a life cycle. A trade-off between them is usually present: when survival increases, fertility decreases-and vice versa. Here we show that at an evolutionary optimum, the generation time is a measure of the strength of the trade-off between overall survival and overall fertility in a life cycle. Our result both helps to explain the known fact that the generation time describes the speed of living in the slow-fast continuum of life cycles and may have implications for the extrapolation from model organisms of longevity to humans.

Invasion and effective size of graph-structured populations.

Population structure can strongly affect evolutionary dynamics. The most general way to describe population structures are graphs. An important observable on evolutionary graphs is the probability that a novel mutation spreads through the entire population. But what drives this spread of a mutation towards fixation? Here, we propose a novel way to understand the forces driving fixation by borrowing techniques from evolutionary demography to quantify the invasion fitness and the effective population size for different graphs. Our method is very general and even applies to weighted graphs with node dependent fitness. However, we focus on analytical results for undirected graphs with node independent fitness. The method will allow to conceptually integrate evolutionary graph theory with theoretical genetics of structured populations.

How Life History Can Sway the Fixation Probability of Mutants.

In this work, we study the effects of demographic structure on evolutionary dynamics when selection acts on reproduction, survival, or both. In contrast to the previously discovered pattern that the fixation probability of a neutral mutant decreases while the population becomes younger, we show that a mutant with a constant selective advantage may have a maximum or a minimum of the fixation probability in populations with an intermediate fraction of young individuals. This highlights the importance of life history and demographic structure in studying evolutionary dynamics. We also illustrate the fundamental differences between selection on reproduction and selection on survival when age structure is present. In addition, we evaluate the relative importance of size and structure of the population in determining the fixation probability of the mutant. Our work lays the foundation for also studying density- and frequency-dependent effects in populations when demographic structures cannot be neglected.

The Effect of Post-Reproductive Lifespan on the Fixation Probability of Beneficial Mutations.

Post-reproductive lifespan is a common trait among mammals and is usually considered to be neutral; i.e. with no influence on population dynamics. Here, we explore the role of post-reproductive lifespan in the fixation probability of beneficial genetic variation. We compare two separate, stationary populations living in a constant environment that are equivalent except for the average time their respective members spend in the post-reproductive stage of life. Using a recently derived approximation, we show that fixation of a beneficial mutation is more likely in the population with greater post-reproductive longevity. This finding is surprising, as the population with more prolonged post-reproductive lifespan has smaller effective size and the classic population-genetic model would suggest that decreasing effective size reduces fixation chances of beneficial mutations. Yet, as we explain, in the age-structured case, when effective size gets smaller because of longer post-reproductive lifespan but census size is kept equal, a beneficial mutation has a higher likelihood to get fixed because it finds itself at higher initial frequency.

Modeling evolutionary games in populations with demographic structure.

Classic life history models are often based on optimization algorithms, focusing on the adaptation of survival and reproduction to the environment, while neglecting frequency dependent interactions in the population. Evolutionary game theory, on the other hand, studies frequency dependent strategy interactions, but usually omits life history and the demographic structure of the population. Here we show how an integration of both aspects can substantially alter the underlying evolutionary dynamics. We study the replicator dynamics of strategy interactions in life stage structured populations. Individuals have two basic strategic behaviours, interacting in pairwise games. A player may condition behaviour on the life stage of its own, or that of the opponent, or the matching of life stages between both players. A strategy is thus defined as the set of rules that determines a player׳s life stage dependent behaviours. We show that the diversity of life stage structures and life stage dependent strategies can promote each other, and the stable frequency of basic strategic behaviours can deviate from game equilibrium in populations with life stage structures.

Evolution of aging through reduced demographic stochasticity - an extension of the pleiotropy theory to finite populations.

In finite populations, there is selection against demographic stochasticity. In this study, it is shown that an increase in the rate of aging, here defined as an increase in early-life survival at the expense of later survival, may reduce this form of stochasticity. In particular, a trade-off between juvenile and adult survival is highly efficient in reducing demographic stochasticity. Therefore, aging may evolve as a response to selective pressure for reduced demographic stochasticity.

Are some conventional measures of the rate of ageing consistent with antagonistic pleiotropy?

Several measures of the rate of ageing have been proposed in the literature. But are they all equally good? In this work, three of these measures are considered: ωG and the parameter b for the Gompertz model, and ωW for the Weibull model. It is shown that ωG and ωW may fail to detect genuine changes in the rate of ageing when this rate varies in response to the fixation of antagonistic-pleiotropic mutations with effects on survival, while the parameter b never fails to detect such changes. It is suggested that ωG and ωW are inconsistent with the antagonistic pleiotropy model for the evolution of ageing. Hence, they should not be used to test any prediction that this model is supposed to entail about the evolution of the rate of ageing, notably, Williams' prediction according to which the higher the level of environmental mortality, the higher the evolutionarily favoured rate of ageing.

Is cellular senescence an example of antagonistic pleiotropy?

It is generally accepted that the permanent arrest of cell division known as cellular senescence contributes to aging by an antagonistic pleiotropy mechanism: cellular senescence would act beneficially early in life by suppressing cancer, but detrimentally later on by causing frailty and, paradoxically, cancer. In this review, we show that there is room to rethink this common view. We propose a critical appraisal of the arguments commonly brought in support of it, and we qualitatively analyse published results that are of relevance to understand whether or not cellular senescence-associated genes really act in an antagonistic-pleiotropic manner in humans.