Hydrogen Sulfide (H2S) Modulates Metabolic Rewiring in Aging and Type 2 Diabetes, Highlighting Therapeutic Potential

The intersection of aging and type 2 diabetes (T2DM) presents significant health challenges, with metabolic dysregulation being a core component. Current therapeutic strategies often target individual symptoms but struggle to address the underlying age-related metabolic decline. Hydrogen sulfide (H2S), a gaseous signaling molecule, has emerged as a critical player in cellular metabolism, recognized for its antioxidant properties, its role as a substrate for the mitochondrial electron transport chain, and its signaling capabilities via cysteine persulfidation. Understanding H2S's precise mechanisms in these contexts could unlock novel therapeutic avenues for age-related metabolic diseases.

This comprehensive review systematically analyzed existing literature on hydrogen sulfide (H2S) in the context of aging and type 2 diabetes. Researchers synthesized findings from a broad range of studies, including in vitro cell culture experiments, various preclinical animal models, and human observational data. The review focused on elucidating H2S's multifaceted biological actions, particularly its impact on metabolic rewiring, insulin secretion, and insulin sensitivity in target tissues. The authors specifically examined how H2S production and signaling are altered in pathological processes like diabetes and cardiovascular disease.

The review highlights that enhanced intracellular H2S production consistently associates with extended survival across several experimental models of aging. Conversely, decreased H2S levels are strongly linked to various pathological conditions, including diabetes, glioblastoma, and cardiovascular disease. H2S exerts its effects through multiple mechanisms: acting as a potent antioxidant, serving as a vital substrate for the mitochondrial electron transport chain, and functioning as a signaling molecule by promoting cysteine persulfidation in proteins. This persulfidation modifies protein function, influencing key metabolic pathways. The review emphasizes that H2S critically modulates important metabolic processes, including its essential role in controlling both insulin secretion from pancreatic beta cells and insulin sensitivity in peripheral insulin-target tissues. > The therapeutic effects of H2S are highly context-dependent and exhibit a bell-shaped dose-response profile, underscoring the necessity for tight regulation of its production and signaling to achieve beneficial outcomes.