Dietary restriction (DR) without malnutrition encompasses numerous regimens with overlapping benefits including longevity and stress resistance, but unifying nutritional and molecular mechanisms remain elusive. In a mouse model of DR-mediated stress resistance, we found that sulfur amino acid (SAA) restriction increased expression of the transsulfuration pathway (TSP) enzyme cystathionine γ-lyase (CGL), resulting in increased hydrogen sulfide (H2S) production and protection from hepatic ischemia reperfusion injury. SAA supplementation, mTORC1 activation, or chemical/genetic CGL inhibition reduced H2S production and blocked DR-mediated stress resistance. In vitro, the mitochondrial protein SQR was required for H2S-mediated protection during nutrient/oxygen deprivation. Finally, TSP-dependent H2S production was observed in yeast, worm, fruit fly, and rodent models of DR-mediated longevity. Together, these data are consistent with evolutionary conservation of TSP-mediated H2S as a mediator of DR benefits with broad implications for clinical translation.PaperFlickeyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiI1MGJkYjRmOTM3NDE2M2ZiMTg3ZmNjNmEyMDFhNTc1YiIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc5Mjk4MjMzfQ.V8qXdbtaLAT3ovDBzZSwwxndvK-UQfG2ejlge2oMFM_tYubmoEGGlBAYQsTC7a0ueef3tEtd05gRjhDyicPasVszlXUXyw-wV5ikYC4QBbj_u93mUWcqg9eyXciefhsfNvVvDGqWt2f_Z_0BqK4MybG_CJmg--1MtYcaGM1Z4FbuOg5aEGMTnL-8Eky9McpUsm1jeTPwmdbI3V80zN3J8DUvtueiO-ggVeZUOMbmwZvasuiT5FrLAe_R26rdZIsEjHz36wi6-kgT4otTJPuzJoyUnRRSmp3Uj3SyXoQNrZ7tJCdC69sztBCJ4c2vDD6jDJQFu9eJPNAAoFw4cx_wnA(mp4, (47.93 MB) Download video

Endogenous Hydrogen Sulfide Production Is Essential for Dietary Restriction Benefits