ATF-4 Upregulation is Downstream of mTORC1 Inhibition in Effects on Aging

mTORC1 inhibition slows aging modestly, albeit to a greater degree in short-lived species. It is an open question as to whether the benefits in humans are large enough to be worth chasing versus other programs of research and development. Early trials of mTORC1 inhibitor drugs have produced results that were interesting but mixed. mTORC1 inhibition is, considered at the high level, a form of calorie restriction mimetic approach, thought to act on life span primarily through upregulation of stress response mechanisms such as autophagy. Researchers here follow the trail of connections to investigate the role of ATF-4 in the signaling changes produced by mTORC1 inhibition, linking this research to other lines of inquiry related to the role of hydrogen sulfide in metabolism relevant to aging.

Inhibition of the master growth regulator mTORC1 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.


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