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

Abstract Inhibition of the master growth regulator mTORC1 (mechanistic target of mTOR(definition)-inhibiting drug studied for extending healthspan and lifespan." style="text-decoration:underline dotted; text-underline-offset:2px; cursor:help;">rapamycin(definition) 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 (H 2 S) production. This H 2 S boost increases protein persulfidation, a protective modification of redox-reactive cysteines. The ATF-4/CTH-2/H 2 S pathway also mediates longevity and increased stress resistance from mTORC1 suppression. Increasing H 2 S levels, or enhancing mechanisms that H 2 S influences through persulfidation, may represent promising strategies for mobilising therapeutic benefits of the ISR, translation suppression, or mTORC1 inhibition.