SIRT1 Negatively Regulates The Mammalian Target Of Rapamycin

Research Summary

An experimental study testing whether SIRT1 – a NAD-dependent deacetylase linked to calorie restriction and lifespan in model organisms – regulates mTOR signalling. The authors report that SIRT1 restrains mTOR and locate the effect upstream of mTORC1.

Who Or What Was Studied?

Cultured cells and mouse tissue: mouse embryonic fibroblasts from normal and SIRT1-knockout mice, human HeLa cells with SIRT1 depleted by shRNA, and TSC2-knockout fibroblasts, examined under normal conditions and under stress such as leucine starvation, glucose or serum withdrawal, and tunicamycin.

What Did The Research Show?

• SIRT1-deficient mouse fibroblasts and SIRT1-depleted HeLa cells showed higher phosphorylation of mTOR and of its downstream targets S6K1, 4E-BP1 and S6.
• In SIRT1-null cells the elevated mTOR signalling persisted under leucine starvation, unlike in normal cells.
• Tissue from SIRT1-knockout mice also showed higher phospho-S6 and phospho-4E-BP1, and the SIRT1-deficient cells were larger with more protein per cell.
• The SIRT1 activator resveratrol reduced, and the SIRT1 inhibitor nicotinamide increased, mTOR activity in a SIRT1-dependent manner.
• SIRT1 was found to interact with TSC2, and the effect on mTOR signalling depended on TSC2: in TSC2-null cells resveratrol no longer suppressed mTOR.

Limitations And Interpretation

• This is cell-culture and knockout-mouse-tissue work; it describes a mechanism, not a health or lifespan outcome.
• The exact way SIRT1 acts on the TSC1/TSC2 complex is not established – the authors note that further study is needed.
• Resveratrol acted through both SIRT1-dependent and SIRT1-independent routes, so resveratrol results alone do not prove the SIRT1 mechanism.