Endogenous hydrogen sulfide production is essential for dietary restriction benefits

Christopher Hine, Eylul Harputlugil, Yue Zhang, Christoph Ruckenstuhl, Byung Cheon Lee, Lear Brace, Alban Longchamp, Jose H. Treviño-Villarreal, Pedro Mejia, C. Keith Ozaki, Rui Wang, Vadim N. Gladyshev, Frank Madeo, William B. Mair, James R. Mitchell

Research output: Contribution to journalArticlepeer-review

400 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)132-144
Number of pages13
Issue number1-2
Publication statusPublished - 2015 Jan 15
Externally publishedYes

Bibliographical note

Funding Information:
We thank Bruce Kristal and Jaan-Olle Andressoo for critical reading of the manuscript; Silvia Dichtinger, Manmeet Gujral, and Jason Li for technical assistance; and Paul Ney for sharing the NRF2KO mice. This work was supported by grants from NIH (RO1DK090629, R01AG036712) and the Glenn Foundation to J.R.M.; C.H. was supported by T32CA0093823; F.M. was supported by the Austrian Science Fund FWF (LIPOTOX, I1000, P23490-B12, and P24381-B20); W.B.M. was supported by 1R01AG044346; V.N.G. was supported by R01AG021518; C.K.O. was supported by American Heart Association 12GRNT9510001 and 12GRNT1207025; and R.W. was supported by an operating grant from the Canadian Institutes of Health Research.

Publisher Copyright:
© 2015 Elsevier Inc.

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology


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