Hydrogen sulfide at the intersection of aging and type 2 diabetes: mechanisms of metabolic rewiring.

Hydrogen sulfide (H2S) is an important molecule in cellular metabolism given its merits as an antioxidant, a substrate for the mitochondrial electron transport chain and as a signaling molecule via promotion of cysteine persulfidation in peptides and proteins. Studies in cell culture, animal models, and humans have supported a central role of H2S in the control of aging and age-related metabolic diseases. Enhanced intracellular H2S production has been associated with extended survival in several experimental models, while decreased H2S production or levels have been linked to pathological processes including diabetes, glioblastoma, and cardiovascular disease. In this review, we describe the latest findings related to the biological actions of H2S and the implications for aging and metabolic diseases, with a special focus on diabetes and its related complications. While aging studies convincingly support that several interventions that enhance H2S generation promote healthy aging and extend life expectancy, the effects are highly context-dependent and reflect a bell-shaped dose-response profile, requiring tight regulation of H2S production and signaling. In this context, H2S modulates important metabolic processes that need to be finely coordinated to promote these benefits, including its essential role in controlling insulin secretion and insulin sensitivity in insulin-target tissues. We support that interventions based on the use of enzymatic and non-enzymatic production of H2S may have therapeutic potential to promote healthy aging and to treat age-related metabolic diseases.