You don't need a weatherman: famines, evolution, and intervention into aging.

Calorie restriction (CR) is the most robust available intervention into biological aging. Efforts are underway to develop pharmaceuticals that would replicate CR's anti-aging effects in humans ("CR mimetics"), on the assumption that the life- and healthspan-extending effects of CR in lower organisms will be proportionally extrapolable to humans (the "proportionality principle" (PP)). A recent argument from evolutionary theory (the "weather hypothesis" (WH)) suggests that CR (or its mimetics) will only provide 2-3 years of extended healthy lifespan in humans. The extension of healthy human lifespan that would be afforded by intervention into aging makes it crucial that resources for therapeutic development be optimally allocated; CR mimetics being the main direction being pursued for interventive biogerontology, this paper evaluates the challenge to the potential efficacy of CR mimetics posed by the WH, on a theoretical level and by reference to the available interspecies data on CR. Rodent data suggest that the anti-aging effects of CR continue to increase in inverse proportion to the degree of energy restriction imposed, well below the level that would be expected to be survivable under the conditions under which the mechanisms of CR evolved and are maintained in the wild. Moreover, the same increase in anti-aging effects continues well below the point at which it interferes with reproductive function. Both of these facts are in accordance with the predictions of evolutionary theory. Granted these facts, the interspecies data-including data available in humans-are consistent with the predictions of PP rather than those of the WH. This suggests that humans will respond to a high degree of CR (or its pharmaceutical simulation) with a proportional deceleration of aging, so that CR mimetics should be as effective in humans as CR itself is in the rodent model. Despite this fact, CR mimetics should not be the focus of biomedical gerontology, as strategies based on the direct targeting of the molecular lesions of aging are likely to lead to more rapidly developable and far more effective anti-aging biomedicines.