title: Endogenous hydrogen sulfide production is essential for dietary restriction benefits.
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:
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Hine
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Eylul
authors.initials: E
authors.lastname: Harputlugil
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute for Molecular Biosciences, NAWI Graz, University of Graz, Graz 8010, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Ruckenstuhl
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Byung Cheon
authors.initials: BC
authors.lastname: Lee
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lear
authors.initials: L
authors.lastname: Brace
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Surgery and the Heart and Vascular Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alban
authors.initials: A
authors.lastname: Longchamp
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jose H
authors.initials: JH
authors.lastname: Treviño-Villarreal
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Mejia
authors.affiliation: Department of Surgery and the Heart and Vascular Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: C Keith
authors.initials: CK
authors.lastname: Ozaki
authors.affiliation: Department of Biology, Lakehead University, Thunder Bay, ON P7B 5E1, Canada.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Vadim N
authors.initials: VN
authors.lastname: Gladyshev
authors.affiliation: Institute for Molecular Biosciences, NAWI Graz, University of Graz, Graz 8010, Austria; BioTechMed Graz, Humboldtstrasse 50, Graz 8010, Austria.
authors.forename: Frank
authors.initials: F
authors.lastname: Madeo
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Mair
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: jmitchel@hsph.harvard.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D005075:Biological Evolution; D017173:Caenorhabditis elegans / Q000502:physiology; D031204:Caloric Restriction; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D004032:Diet; D004331:Drosophila melanogaster / Q000502:physiology; D005260:Female; D006862:Hydrogen Sulfide / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply / Q000293:injuries; D008017:Life Expectancy; D008099:Liver / Q000098:blood supply / Q000293:injuries; D008297:Male; D008715:Methionine / Q000378:metabolism; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury; D015398:Signal Transduction; D013312:Stress, Physiological; D059467:Transcriptome; D015003:Yeasts / Q000502:physiology
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D008715:Methionine; D003542:Cystathionine gamma-Lyase; D003545:Cysteine; D006862:Hydrogen Sulfide