Sestrins

Sestrins (SESN1, SESN2, SESN3) are evolutionarily conserved, stress-inducible proteins that suppress mTORC1 (mechanistic target of rapamycin complex 1) and activate AMPK (AMP-activated protein kinase). SESN1 and SESN2 are induced by the tumor suppressor p53 in response to DNA damage, oxidative stress, hypoxia, and ER stress; SESN3 is primarily controlled by FOXO transcription factors. A leucine-binding pocket in SESN2 enables direct leucine sensing: when leucine is scarce, SESN2 sequesters the mTORC1-activating GATOR2 complex, restraining mTORC1 and promoting autophagy — structurally elucidated by Wolfson, Chantranupong et al. (Science, 2016). During aging, chronic mTORC1 hyperactivation and reactive oxygen species accumulation accelerate tissue deterioration; Sestrins attenuate both. In Drosophila, muscle-specific dSestrin overexpression shares features with endurance exercise — TORC2/AKT activation and lysosomal activity — through partially overlapping mechanisms (Sujkowski and Wessells, 2021). In human skeletal muscle, SESN1 and SESN3 protein levels decline with age; Zeng et al. (2018) document altered Sestrin expression in a cross-sectional study of men. Causal evidence remains associational, and no Sestrin-targeted therapeutic has entered clinical trials.