Endogenous Hydrogen Sulfide Production Is Essential for Dietary Restriction Benefits

Summary 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 (H 2 S) production and protection from hepatic ischemia reperfusion injury. SAA supplementation, mTORC1 activation, or chemical/genetic CGL inhibition reduced H 2 S production and blocked DR-mediated stress resistance. In vitro, the mitochondrial protein SQR was required for H 2 S-mediated protection during nutrient/oxygen deprivation. Finally, TSP-dependent H 2 S 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 H 2 S as a mediator of DR benefits with broad implications for clinical translation. PaperFlick