Review Volume 4, Issue 8 pp 525—534

Caloric restriction: is mammalian life extension linked to p53?


Figure 2. Linking caloric restriction (CR), sirtuins, and mTOR to the p53 pathway. CR and resveratrol activate autophagy through sirtuins, thus extending lifespan. The intracellular mTOR pathway via inputs of PI-3K, AMPK and other sensors integrates nutrient availability and drives cell growth and aging. Rapamycin and resveratrol inhibit the Sirtuin/mTOR network. CR and p53 may also inhibit mTOR activity through upregulation of known negative regulators PTEN, TSC2 and AMPK. The products of two p53 target genes, Sestrin 1 and 2 activate AMPK, which phosphorylates TSC2 and stimulates its GAP activity enabling mTOR inhibition. Glucose starvation inhibits mTOR by promoting TSC1/2 activation.