The Sirt1 activator resveratrol inhibits the mTOR-p70/S6K pathway

Nutrient sensing pathways were found to regulate lifespan in a variety of organisms ranging from yeast to mammals. Two such pathways are Sir2/Sirt1 and mTOR pathways. Sir2/Sirt1 is a NAD dependent protein deacetylase which is active in low energy states. Sirt1 is activated by the polyphenol resveratrol. Mammalian target of rapamycin (mTOR) is a well characterised and highly conserved nutrient sensor. Nutrients, especially amino acids, activate mTOR, while low energy status inhibits mTOR. Treatments with the Sirt1 activator resveratrol for 30min decreased mTOR phosphorylation at Ser2448 and, at a lesser extend, at Ser2481. Furthermore it dephosphorylated the mTOR target p70/S6K at Thr389. One of the primary regulators of mTOR is Akt, which phosphorylates and inactivates the mTOR inhibitors TSC1 and 2. Resveratrol inhibited Akt phosphorylation at Ser473, but not at Thr308 which is the site involved in mTOR activation. Furthermore it did not affect the phosphorylation of PDK1 which is the kinase phosphorylating Akt at Thr308. Akt phosphorylation at Ser473 was recently found to be mediated by the mTOR complex mTORC2. Therefore the inhibitory effect of resveratrol on Akt-Ser473 is more likely the effect and not the cause of mTOR inactivation. Another regulator of mTOR is the nutrient sensor AMPK. AMPK is activated by low energy status and inhibits mTOR activation. Resveratrol was found to increase AMPK phosphorylation, providing a potential mechanism for its inhibitory effect on mTOR. These data suggest that the low energy sensors Sirt1 and AMPK converge to inhibit mTOR and subsequent anabolic processes.