Linking calorie restriction to longevity through sirtuins and autophagy: any role for TOR

In this issue of Cell Death & Disease, Morselli et al. described that calorie restriction (CR) and resveratrol activate autophagy through sirtuin-1 and, most importantly, autophagy is required for the life extending effect of CR (Figure 1a). This paper touches upon three hot topics, entering into three debated fields. Let us discuss this in a broader context. In almost all species from yeast to primates, CR increases both median and maximal lifespan. Still the topic remains highly controversial. Why? As I recently analyzed, the antiaging effect of CR rules out the most intuitive theory of aging (see for reference, Blagosklonny1). According to the current dogma, aging is caused by lifelong accumulation of molecular damage. This damage is not repaired completely because energetic resources are limited in the wild.2 This must predict that the fewer the resources (CR), the less resources could be spend for repair (and the faster aging). Yet we know that CR slows down aging. To reconcile this fact with the theory, it was suggested that an organism allocates more resources to fight aging during famine or CR, in order to live longer and to reproduce later,2 even though aging does not limit lifespan in the wild. This suggestion leads to unfathomable paradoxes, forcing us to reconsider the origin of aging.1 In fact, recent discoveries reveal that aging is genetically regulated.3 For example, inhibition of TOR (target of rapamyin) or activation of sirtuins prolongs lifespan. And CR both deactivates TOR and activates sirtuins. But here is a second debate: which is indispensable for prolonged lifespan by CR, inhibiting TOR or activating sirtuins?