The evolutionary theory of ageing explains why ageing occurs, giving valuable insight into the mechanisms underlying the complex cellular and molecular changes that contribute to senescence. Such understanding also helps to clarify how the genome shapes the ageing process, thereby aiding the study of the genetic factors that influence longevity and age-associated diseases.

Progressive telomere shortening from cell division (replicative aging) provides a barrier for human tumor progression. This program is not conserved in laboratory mice, which have longer telomeres and constitutive telomerase. Wild species that do / do not use replicative aging have been reported, but the evolution of different phenotypes and a conceptual framework for understanding their uses of telomeres is lacking. We examined telomeres / telomerase in cultured cells from > 60 mammalian species to place different uses of telomeres in a broad mammalian context. Phylogeny-based statistical analysis reconstructed ancestral states. Our analysis suggested that the ancestral mammalian phenotype included short telomeres (< 20 kb, as we now see in humans) and repressed telomerase. We argue that the repressed telomerase was a response to a higher mutation load brought on by the evolution of homeothermy. With telomerase repressed, we then see the evolution of replicative aging. Telomere length inversely correlated with lifespan, while telomerase expression co-evolved with body size. Multiple independent times smaller, shorter-lived species changed to having longer telomeres and expressing telomerase. Trade-offs involving reducing the energetic / cellular costs of specific oxidative protection mechanisms (needed to protect < 20 kb telomeres in the absence of telomerase) could explain this abandonment of replicative aging. These observations provide a conceptual framework for understanding different uses of telomeres in mammals, support a role for human-like telomeres in allowing longer lifespans to evolve, demonstrate the need to include telomere length in the analysis of comparative studies of oxidative protection in the biology of aging, and identify which mammals can be used as appropriate model organisms for the study of the role of telomeres in human cancer and aging.

SUMMARY Sex differences in longevity can provide insights into novel mechanisms of aging, yet they have been little studied. Surprisingly, sex-specific longevity patterns are better known in wild animals. Evolutionary hypotheses accounting for longevity patterns in natural populations include differential vulnerability to environmental hazards, differential intensity of sexual selection and distinct patterns of parental care. Mechanistic hypotheses focus on asymmetric inheritance of sex chromosomes and mitochondria. Virtually all intensively studied species show conditional sex differences in longevity. Humans are the only species in which one sex is known to have a ubiquitous survival advantage. Paradoxically, although women live longer, they suffer greater morbidity particularly late in life. This mortality-morbidity paradox may be a consequence of greater connective tissue responsiveness to sex hormones in women. Human females’ longevity advantage may result from hormonal influences on inflammatory and immunological responses, or greater resistance to oxidative damage; current support for these mechanisms is weak.

Evolutionary theory predicts substantial interspecific and intraspecific differences in the proximal mechanisms of ageing. Our goal here is to seek evidence for common ('public') mechanisms among diverse organisms amenable to genetic analysis. Oxidative damage is a candidate for such a public mechanism of ageing. Long-lived strains are relatively resistant to different environmental stresses. The extent to which these stresses produce oxidative damage remains to be established.

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This study compared trends in body size, life span, metabolic rate, and ecology of bats and marsupials with those from mammals generally, using a 580 species data base. The linear logarithmic relationship between mammalian body mass and maximum longevity, deleting bats and marsupials, is used as a standard against which to measure life spans of particular mammal groups. Bats have maximum life spans a minimum of 3 times those of nonflying eutherians--a trend resulting from neither low basal metabolic rate, the ability to enter torpor, nor large relative brain size. Marsupials live about 80% as long as nonflying eutherians despite averaging lower basal metabolic rates; similarly, there is no effect of heterothermy or relative brain size. These results directly conflict with predictions of both "rate of living" and brain-size mediated theories of aging. However, they are consistent with an evolutionary theory that posits exceptionally long life spans among mammals with reduced environmental vulnerability.

Target of rapamycin inhibition by rapamycin feeding has previously been shown to extend life in genetically heterogeneous mice. To examine whether it similarly affected mouse health, we fed encapsulated rapamycin or a control diet to C57BL/6Nia mice of both sexes starting at 19 months of age. We performed a range of health assessments 6 and 12 months later. Rapamycin feeding significantly reduced mTOR activity in most but not all tissues. It also reduced total and resting metabolic rate during the light (inactive) phase of the light:dark cycle in females only but had no effect on spontaneous activity or metabolism during the dark (active) phase of either sex. Males only had less fragmented sleep when fed rapamycin, whereas stride length and rotarod performance were improved in both sexes. Survival was also improved by this late-life rapamycin feeding, and some pathological lesions were delayed. We found no adverse health consequences associated with rapamycin treatment.