University of Massachusetts Medical School Faculty Publications

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Department of Molecular, Cell and Cancer Biology

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Article Preprint


Amino Acids, Peptides, and Proteins | Cellular and Molecular Physiology | Enzymes and Coenzymes | Physiological Processes


Inhibition of mTORC1 (mechanistic target of rapamycin 1) slows ageing, but mTORC1 supports fundamental processes that include protein synthesis, making it critical to elucidate how mTORC1 inhibition increases lifespan. Under stress conditions, the integrated stress response (ISR) globally suppresses protein synthesis, resulting in preferential translation of the transcription factor ATF-4. Here we show in C. elegans that the ATF-4 transcription program promotes longevity and that ATF-4 upregulation mediates lifespan extension from mTORC1 inhibition. ATF-4 activates canonical anti-ageing mechanisms but also increases expression of transsulfuration enzymes to promote hydrogen sulfide (H2S) production. ATF-4-induced H2S production mediates longevity and stress resistance from C. elegans mTORC1 suppression, and ATF4 drives H2S production in mammalian dietary restriction. This H2S boost increases protein persulfidation, a protective modification of redox-reactive cysteines. Increasing H2S levels, or enhancing mechanisms that H2S modulates through persulfidation, may represent promising strategies for mobilising therapeutic benefits of the ISR or mTORC1 inhibition.


mRNA translation, cystathionine gamma-lyase, H2S, ageing, mTORC1, Integrated Stress Response, C. elegans, physiology

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bioRxiv 2020.11.02.364703; doi: Link to preprint on bioRxiv.


This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.

Full author list omitted for brevity. For the full list of authors, see article.

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Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.