How does the body know how old it is? Introducing the epigenetic clock hypothesis.

Animals and plants have biological clocks that help to regulate circadian cycles, seasonal rhythms, growth, development and sexual maturity. If aging is not a stochastic process of attrition but is centrally orchestrated, it is reasonable to suspect that the timing of senescence is also influenced by one or more biological clocks. Evolutionary reasoning first articulated by G. Williams suggests that multiple, redundant clocks might influence organismal aging. Some aging clocks that have been proposed include the suprachiasmatic nucleus, the hypothalamus, involution of the thymus, and cellular senescence. Cellular senescence, mediated by telomere attrition, is in a class by itself, having recently been validated as a primary regulator of aging. Gene expression is known to change in characteristic ways with age, and in particular DNA methylation changes in age-related ways. Herein, I propose a new candidate for an aging clock, based on epigenetics and the state of chromosome methylation, particularly in stem cells. If validated, this mechanism would present a challenging but not impossible target for medical intervention.

Programmed life span in the context of evolvability.

Population turnover is necessary for progressive evolution. In the context of a niche with fixed carrying capacity, aging contributes to the rate of population turnover. Theoretically, a population in which death is programmed on a fixed schedule can evolve more rapidly than one in which population turnover is left to a random death rate. Could aging evolve on this basis? Quantitative realization of this idea is problematic, since the short-term individual fitness cost is likely to eliminate any hypothetical gene for programmed death before the long-term benefit can be realized. In 2011, one of us proposed the first quantitative model based on this mechanism that robustly evolves a finite, programmed life span. That model was based on a viscous population in a rapidly changing environment. Here, we strip this model to its essence and eliminate the assumption of environmental change. We conclude that there is no obvious way in which this model is unrealistic, and that it may indeed capture an important principle of nature's workings. We suggest aging may be understood within the context of the emerging science of evolvability.

Evolutionary orthodoxy: how and why the evolutionary theory of aging went astray.

Prevailing ideas of how aging evolved are a poor fit with the picture of aging that is developing from genetics labs and breeding experiments. Nevertheless, the community of theorists is reluctant to consider alternate approaches because the differences are profound, calling into question much of the standard methodology of Population Genetics. (At stake is not the legacy of Darwin, but the particular model of Darwinian selection that has dominated the field of research since the middle of the 20th Century). This model may be a historic artifact, arising from a time before computers, when a premium was placed on equations that could be solved analytically. The standard Population Genetic model gained credibility through agreement with laboratory experiments that were designed to realize the assumptions of the model, rather than to mirror conditions in the natural world. Models of evolution based on pure individual selection or inclusive fitness cannot explain the basic phenomenology of aging. Aging is not the only area of conflict, however. Other areas which present difficulties for the standard model include the origin of sex, the maintenance of diversity, the basis of evolvability (including hierarchical structure of the genome), occasional persistence of eusociality without close relatedness, and many examples of strong altruism. From many corners of the field, creative and visionary biologists are calling for a re-thinking of the fundamental mechanisms of natural selection.

Female fertility and longevity.

Does bearing children shorten a woman's life expectancy? Pleiotropic theories of aging predict that it should, and in particular, the Disposable Soma theory predicts unequivocally that this effect should be inescapable. But many demographic studies, historic and current, have found no such effect. In this context,the Caerphilly cohort study stands apart as the sole test that corroborates the theory. Why has this study found an effect that others fail to see? Their analysis is based on Poisson regression, a statistical technique that is accurate only if the underlying data are Poisson distributed.But the distribution of the number of children born to women in the Caerphilly data based departs strongly from Poisson at the high end. This makes the result overly sensitive to a handful of women with 15 children or more who lived before 1700. When these five women are removed from a database of more than 2,900, the Poisson regression no longer shows a significant result. Bilinear regression relating life span to fertility and date of birth results in a small positive coefficient for fertility, in agreement with the main trend of reported results.

How can evolutionary theory accommodate recent empirical results on organismal senescence?

According to a prominent recent report, guppies collected from sites lacking predators are inferior in every aspect of their life history profile to those evolved in other, nearby sites with predators present. This is an exception to two classical predictions of evolutionary theory: that low extrinsic mortality should be associated with longer life span, and that higher fertility should be associated with shorter life span. Some theorists have tried to accommodate this and other anomalous results within the standard framework, but we argue that the exceptions they carve out do not explain the results at hand. In fact, the findings suggest that population regulation has been selected at the group level, though this is a mechanism that most theorists regard with suspicion. We conclude by relating the present result to other experiments that seem to point in the same direction.

Programmed and altruistic ageing.

Ageing is widely believed to be a non-adaptive process that results from a decline in the force of natural selection. However, recent studies in Saccharomyces cerevisiae are consistent with the existence of a programme of altruistic ageing and death. We suggest that the similarities between the molecular pathways that regulate ageing in yeast, worms, flies and mice, together with evidence that is consistent with programmed death in salmon and other organisms, raise the possibility that programmed ageing or death can also occur in higher eukaryotes.