Cellular senescence and metabolic aging in type 2 diabetes: mechanistic insights and translational implications

Type 2 diabetes mellitus (T2DM) is traditionally conceptualized as a disorder of insulin resistance and β-cell dysfunction driven by metabolic overload. Increasing evidence now implicates cellular senescence-a stress-induced state of durable cell-cycle arrest accompanied by a pro-inflammatory senescence-associated secretory phenotype (SASP)-as a biologically distinct contributor to metabolic dysfunction. Senolytic therapies, which selectively eliminate senescent cells by targeting senescent cell anti-apoptotic pathways (SCAPs), have therefore emerged as potential disease-modifying interventions.

We conducted a structured narrative review of preclinical and human studies published between 2010 and 2025, identified through PubMed, Scopus, and Embase. Evidence was synthesized qualitatively, with emphasis on mechanistic plausibility, tissue specificity, translational readiness, and safety considerations relevant to T2DM and its complications.

Preclinical studies consistently demonstrate that clearance of senescent cells in adipose tissue, liver, and pancreatic islets improves insulin sensitivity, attenuates SASP-mediated inflammation, and preserves β-cell function across multiple diabetic models. Human evidence remains limited to small, short-duration pilot studies primarily designed to assess biological target engagement and short-term safety. These studies report reductions in senescence markers and inflammatory mediators following intermittent senolytic exposure, but lack standardized metabolic endpoints and long-term follow-up.

Senolytic therapy represents a biologically compelling yet still experimental strategy for addressing the intersection of metabolic dysfunction and biological aging in T2DM. By reframing T2DM as a disease of metabolic aging, this review positions cellular senescence as an upstream therapeutic target and provides a conceptual framework to guide future precision-based clinical trials, rather than advocating near-term clinical adoption. By integrating geroscience with diabetology, this review positions cellular senescence as a biologically upstream framework that may inform future precision-based and disease-modifying strategies in type 2 diabetes.