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 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.

SKN-1 regulates stress resistance downstream of amino catabolism pathways

“…Moreover the gcn-2 inhibitor, impt-1, extends the lifespan of C. elegans and requires SKN-1, highlighting potential interactions between gcn-2 , the ISR and SKN-1. However, we do not see a significant expression change of the ATF4 homolog, atf-5 , or its putative targets in amdh-1 mutants ( Table S1 ) ( Statzer et al., 2022 ). Further studies are needed to determine the entirety of the signaling cascade that culminates in the activation of SKN-1 upon metabolic perturbations, as the partial dependence of gcn-2 suggests other factors are involved.…”

Longevity-Promoting Pathways and Transcription Factors Respond to and Control Extracellular Matrix Dynamics During Aging and Disease

“…Activated mTORC1 signaling inhibits the insulin–PI3K–AKT pathway, and this negative feedback loop has an essential role in insulin-resistant diabetes and cancer ( Easton et al, 2006 ; Um et al, 2006 ; Ma and Blenis, 2009 ). By contrast, reducing mTOR signaling promotes autophagy, mRNA splicing fidelity, hydrogens sulfide signaling, and other mechanisms promoting lifespan increase across species ( Harrison et al, 2009 ; Blackwell et al, 2019 ; Liu and Sabatini, 2020 ; Statzer et al, 2022a ).…”

“…Activated mTORC1 signaling inhibits the insulin-PI3K-AKT pathway, and this negative feedback loop has an essential role in insulin-resistant diabetes and cancer (Easton et al, 2006;Um et al, 2006;Ma and Blenis, 2009). By contrast, reducing mTOR signaling promotes autophagy, mRNA splicing fidelity, hydrogens sulfide signaling, and other mechanisms promoting lifespan increase across species (Harrison et al, 2009;Blackwell et al, 2019;Liu and Sabatini, 2020;Statzer et al, 2022a). Mechanical stretching can activate the Akt/mTOR pathway via β1 integrin (Figure 1), leading to phosphorylation of 4E-BP and ribosomal S6 and causing an increase in the synthesis of collagen, a major structural component of ECM (Mousavizadeh et al, 2020).…”

Methionine restriction - Association with redox homeostasis and implications on aging and diseases

“…Although ATF4 is not required for many responses to MR, including body weight reduction and body composition shift (towards leanness), it is required for maintenance of redox homeostasis through the transsulfuration pathway leading to production of endogenous H 2 S [ 126 ]. In C. elegans , the ATF4/CTH2/H 2 S pathway also increases stress resistance by suppressing mTORC1 [ 127 ]. Furthermore plasma H 2 S levels are negatively correlated with adiposity [ 128 ] and H 2 S modulates Sirt1, which in turn is able to interact with mTOR to suppress oxidative stress [ 129 ].…”