Sestrins

Sestrins (SESN1, SESN2, SESN3) are stress-triggered proteins, conserved across evolution. They turn down mTORC1 (a master growth switch) and turn up AMPK (an energy sensor), the same one your cells use when fuel runs low. SESN1 and SESN2 are switched on by the tumor suppressor p53, in response to DNA damage, oxidative stress, low oxygen, and ER stress. SESN3 is mainly controlled by FOXO transcription factors. SESN2 has a pocket that binds leucine, letting it sense that amino acid directly. When leucine is scarce, SESN2 grabs the mTORC1-activating GATOR2 complex, which restrains mTORC1 and promotes autophagy (cellular self-cleanup). Wolfson, Chantranupong et al. worked out that structure (Science, 2016). During aging, constant mTORC1 over-activity and a build-up of reactive oxygen species speed tissue decline. Sestrins push back on both. In fruit flies, boosting dSestrin only in muscle shares features with endurance exercise, like TORC2/AKT activation and lysosomal activity (Sujkowski and Wessells, 2021). In human skeletal muscle, SESN1 and SESN3 protein levels fall with age; Zeng et al. (2018) document altered Sestrin levels in a cross-sectional study of men. The causal evidence is still associational, and no Sestrin-targeted drug has entered clinical trials.

Last reviewed: June 22, 2026

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