Endogenous hydrogen sulfide production is essential for dietary restriction benefits
Open accessAbstract
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:
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Restriction of individual amino acids upregulates the GCN2 pathway, which stabilizes ATF4, a transcription factor indispensable for the Integrated Stress Response.
“In contrast, the restriction of individual amino acids upregulates the GCN2 pathway, which stabilizes ATF4, a transcription factor indispensable for the Integrated Stress Response (84).”
From Health Benefits of the Mediterranean Diet: Metabolic and Molecular Mechanisms (2018) · cites this paper as [84]
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“Additionally, adult mice subjected to long-term MetR for 4 months in addition to fasting every other day or 20–30%DR for 6 weeks exhibited increased H2S production capacity in liver and kidney extracts compared to control mice fed a complete diet ad libitum (AL) [54].”
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- Authors
- Hine, C., Harputlugil, E., Zhang, Y., Ruckenstuhl, C., Lee, B. C., Brace, L., Longchamp, A., Treviño-Villarreal, J. H., Mejia, P., Ozaki, C. K., Wang, R., Gladyshev, V. N., Madeo, F., Mair, W. B., & Mitchell, J. R.
- Affiliations
- Brigham and Women's Hospital (US)
- University of Graz (AT)
- Lakehead University (CA)
- Corresponding author
- Mitchell, James R.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 160
- Issue
- 1-2
- Pages
- 132-144
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4297538
- OpenAlex
- W2033461907
- Cited by
- 558
- References
- 52
- Citations by year
- 2026: 25 · 2025: 44 · 2024: 37 · 2023: 53 · 2022: 66 · 2021: 66 · 2020: 61 · 2019: 44 · 2018: 56 · 2017: 44 · 2016: 34 · 2015: 27 · 2014: 1
- FWCI
- 15.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association
- Austrian Science Fund
- National Institutes of Health
- Canadian Institutes of Health Research
- National Institute on Aging (R01AG036712, R01AG021518, R01AG044346, R56AG036712)
- National Cancer Institute (T32CA0093823)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK090629)
- National Institute of Environmental Health Sciences (T32ES016645)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Physiology › Dietary Effects on Health
- Keywords
- dietary restriction, hydrogen sulfide, transsulfuration pathway, cystathionine gamma-lyase, stress tolerance, longevity, hepatic ischemia-reperfusion injury, mTORC1, evolutionary conservation
- MeSH terms
- Animals, Cystathionine gamma-Lyase, Cysteine, Diet, Drosophila melanogaster, Biological Evolution, Female, Hydrogen Sulfide, Kidney, Life Expectancy, Liver, Male, Methionine, Stress, Physiological, Yeasts, Signal Transduction, Reperfusion Injury, Caenorhabditis elegans, Mice, Knockout, Caloric Restriction, NF-E2-Related Factor 2, Transcriptome
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