# Role of Endogenous hydrogen sulfide production in Longevity and Stress Resistance

> **NIH NIH P01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2022 · $316,869

## Abstract

PROJECT SUMMARY/ABSTRACT 
Increased multi-factorial stress resistance is a property widely shared by models of extended longevity 
across evolutionary boundaries. Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) receptor 
deficiencies, for example, which extend lifespan in experimental rodents, also increase resistance to acute 
oxidative stressors such as paraquat. Dietary restriction, in addition to extending longevity in a wide range 
of experimental organisms, confers protection against numerous clinically relevant acute stressors, 
including ischemia reperfusion injury to brain, kidney and liver as well as protection against the toxic side- 
effects of chemotherapy. 
Using diet-induced protection from ischemic injury as a model system, we recently identified a novel role for 
endogenous hydrogen sulfide (H2S) produced by the transsulfuration pathway (TSP) in stress resistance 
and longevity regulation by dietary restriction. H2S is a gas produced by TSP enzymes CBS and CGL, 
whose primary role is to convert the essential amino acid methionine to cysteine. Exogenously added H2S 
can confer numerous benefits ranging from resistance to ischemic injury and suspended animation in 
experimental mammals, to extended longevity in flies and worms. However, endogenous H2S had not been 
previously linked to the benefits of dietary restriction. 
Here, we propose to test the hypothesis that increased endogenous H2S production by TSP enzymes 
underlies stress resistance and longevity benefits shared by long-lived models. In support of this 
hypothesis, TSP activity and H2S production are increased in a number of dietary restriction regimens 
across evolutionary boundaries including in yeast, worms and flies, and in multiple organs in mice upon 
fasting or dietary protein restriction. Our preliminary data indicate that H2S production by TSP enzymes is 
repressed by GH and mTOR signaling, two other pathways highly involved in regulation of longevity and 
stress resistance. Finally, pharmacological or genetic inhibition of CGL and H2S production prevented the 
benefits of short-term protein restriction against hepatic ischemic injury and protection of bone marrow stem 
cells from ionizing radiation. 
Together, these data warrant an investigation into the triggers of endogenous H2S production, the 
mechanisms by which it promotes oxidative stress resistance and stem cell regeneration, and its interaction 
with other longevity regulators such as the mitochondrial peptide humanin.

## Key facts

- **NIH application ID:** 10374751
- **Project number:** 5P01AG055369-05
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Sarah Jayne Mitchell
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $316,869
- **Award type:** 5
- **Project period:** 2018-02-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10374751

## Citation

> US National Institutes of Health, RePORTER application 10374751, Role of Endogenous hydrogen sulfide production in Longevity and Stress Resistance (5P01AG055369-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10374751. Licensed CC0.

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