1. Endogenous hydrogen sulfide production is essential for dietary restriction benefits.
- Author
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Hine C, Harputlugil E, Zhang Y, Ruckenstuhl C, Lee BC, Brace L, Longchamp A, Treviño-Villarreal JH, Mejia P, Ozaki CK, Wang R, Gladyshev VN, Madeo F, Mair WB, and Mitchell JR
- Subjects
- Animals, Biological Evolution, Caenorhabditis elegans physiology, Caloric Restriction, Cystathionine gamma-Lyase metabolism, Cysteine metabolism, Drosophila melanogaster physiology, Female, Kidney blood supply, Kidney injuries, Life Expectancy, Liver blood supply, Liver injuries, Male, Methionine metabolism, Mice, Knockout, NF-E2-Related Factor 2 genetics, NF-E2-Related Factor 2 metabolism, Reperfusion Injury, Signal Transduction, Stress, Physiological, Transcriptome, Yeasts physiology, Diet, Hydrogen Sulfide metabolism
- Abstract
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. PAPERFLICK:, (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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