ATF-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mTORC1

Cyril Statzer, Jin Meng, Richard Venz, Monet Bland, Stacey Robida-Stubbs, Krina Patel, Dunja Petrovic, Raffaella Emsley, Pengpeng Liu, Ianessa Morantte, Cole Haynes, William B. Mair, Alban Longchamp, Milos R. Filipovic, T. Keith Blackwell () and Collin Y. Ewald ()
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Cyril Statzer: Eidgenössische Technische Hochschule Zürich, Department of Health Sciences and Technology, Institute of Translational Medicine
Jin Meng: Harvard Medical School
Richard Venz: Eidgenössische Technische Hochschule Zürich, Department of Health Sciences and Technology, Institute of Translational Medicine
Monet Bland: Harvard Medical School
Stacey Robida-Stubbs: Harvard Medical School
Krina Patel: Harvard Medical School
Dunja Petrovic: Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V.
Raffaella Emsley: Centre Hospitalier Universitaire Vaudois and University of Lausanne
Pengpeng Liu: Cell and Cancer Biology, University of Massachusetts Medical School
Ianessa Morantte: Harvard School of Public Health
Cole Haynes: Cell and Cancer Biology, University of Massachusetts Medical School
William B. Mair: Harvard School of Public Health
Alban Longchamp: Centre Hospitalier Universitaire Vaudois and University of Lausanne
Milos R. Filipovic: Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V.
T. Keith Blackwell: Harvard Medical School
Collin Y. Ewald: Eidgenössische Technische Hochschule Zürich, Department of Health Sciences and Technology, Institute of Translational Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Inhibition of the master growth regulator mTORC1 (mechanistic target of rapamycin complex 1) slows ageing across phyla, in part by reducing protein synthesis. Various stresses globally suppress protein synthesis through the integrated stress response (ISR), resulting in preferential translation of the transcription factor ATF-4. Here we show in C. elegans that inhibition of translation or mTORC1 increases ATF-4 expression, and that ATF-4 mediates longevity under these conditions independently of ISR signalling. ATF-4 promotes longevity by activating canonical anti-ageing mechanisms, but also by elevating expression of the transsulfuration enzyme CTH-2 to increase hydrogen sulfide (H2S) production. This H2S boost increases protein persulfidation, a protective modification of redox-reactive cysteines. The ATF-4/CTH-2/H2S pathway also mediates longevity and increased stress resistance from mTORC1 suppression. Increasing H2S levels, or enhancing mechanisms that H2S influences through persulfidation, may represent promising strategies for mobilising therapeutic benefits of the ISR, translation suppression, or mTORC1 inhibition.

Date: 2022
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DOI: 10.1038/s41467-022-28599-9

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