Endogenous hydrogen sulfide production is essential for dietary restriction benefits

Cell. 2015 Jan 15;160(1-2):132-44. doi: 10.1016/j.cell.2014.11.048. Epub 2014 Dec 23.

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:

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Evolution
  • Caenorhabditis elegans / physiology
  • Caloric Restriction
  • Cystathionine gamma-Lyase / metabolism
  • Cysteine / metabolism
  • Diet*
  • Drosophila melanogaster / physiology
  • Female
  • Hydrogen Sulfide / metabolism*
  • 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

Substances

  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Methionine
  • Cystathionine gamma-Lyase
  • Cysteine
  • Hydrogen Sulfide