Loading...
Thumbnail Image
Publication

ATF-4 and hydrogen sulfide signalling mediate longevity from inhibition of translation or mTORC1 [preprint]

Statzer, Cyril
Haynes, Cole M
Blackwell, T. Keith
Ewald, Collin Y.
Liu, Pengpeng
Embargo Expiration Date
Link to Full Text
Abstract

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.

Source

bioRxiv 2020.11.02.364703; doi: https://doi.org/10.1101/2020.11.02.364703. Link to preprint on bioRxiv.

Year of Medical School at Time of Visit
Sponsors
Dates of Travel
DOI
10.1101/2020.11.02.364703
PubMed ID
Other Identifiers
Notes

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 Preprints are preliminary reports of work that have not been certified by peer review.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.

Funding and Acknowledgements
Corresponding Author
Related Resources

Now published in Nature Communications, doi: https://doi.org/10.1038/s41467-022-28599-9

Related Resources
Repository Citation
Rights
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.