Calorie restriction (CR) promotes healthy aging in diverse species. Recently, it has been shown that fasting for a portion of each day has metabolic benefits and promotes lifespan. These findings complicate the interpretation of rodent CR studies, in which animals typically eat only once per day and rapidly consume their food, which collaterally imposes fasting. Here, we show that a prolonged fast is necessary for key metabolic, molecular and geroprotective effects of a CR diet. Using a series of feeding regimens, we dissect the effects of calories and fasting, and proceed to demonstrate that fasting alone recapitulates many of the physiological and molecular effects of CR. Our results shed new light on how both when and how much we eat regulate metabolic health and longevity, and demonstrate that daily prolonged fasting, and not solely reduced calorie intake, is likely responsible for the metabolic and geroprotective benefits of a CR diet.

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Inhibition of mTORC1 (mechanistic Target Of Rapamycin Complex 1) with the pharmaceutical rapamycin prolongs the lifespan and healthspan of model organisms including rodents, with evidence now emerging that rapamycin and its analogs may also have rejuvenative effects in dogs and humans. However, the side effects associated with long-term rapamycin treatment, many of which are due to inhibition of a second mTOR complex, mTORC2, have seemed to preclude the routine use of rapamycin as a therapy for age-related diseases. Here, we discuss recent findings suggesting that strong, chronic inhibition of both mTOR complexes may not be necessary to realize the geroprotective effects of rapamycin. Instead, modestly but specifically inhibiting mTORC1 via a variety of emerging techniques, including intermittent or transient treatment with rapamycin derivatives, or specific dietary regimens, may be sufficient to promote health and longevity with reduced side effects. We will also discuss prospects for the development of new molecules that, by harnessing the detailed molecular understanding of mTORC1 signaling developed over the last decade, will provide new routes to the selective inhibition of mTORC1. We conclude that therapies based on the selective inhibition of mTORC1 may soon permit the safer treatment of diseases of aging.