Department of Molecular, Cell and Cancer Biology
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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DOI of Published Version
bioRxiv 2020.11.02.364703; doi: https://doi.org/10.1101/2020.11.02.364703. Link to preprint on bioRxiv.
Statzer C, P, Haynes CM, Blackwell TK, Ewald CY. (2020). ATF-4 and hydrogen sulfide signalling mediate longevity from inhibition of translation or mTORC1 [preprint]. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1101/2020.11.02.364703. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1846
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