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.
