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.