SAGE-DM—Senescence-Associated Gluco-Endocrinopathy Diabetes Mellitus: comprehensive review

Diabetes mellitus encompasses a spectrum of disorders unified by hyperglycaemia but diverse in aetiology, pathophysiology and clinical expression. Despite repeated efforts at refinement, current classification systems—most recently defined by the WHO—fail to fully capture the heterogeneity of diabetes, particularly in elderly. Recent cluster analyses reveal that diabetes is not a binary entity but a continuum of overlapping subtypes with distinct molecular and physiological signatures. Here, we propose SAGE-DM (Senescence-Associated Gluco-Endocrinopathy Diabetes Mellitus), a novel conceptual framework that extends the definition of so-called “type 4 diabetes.” SAGE-DM is characterised by insulin resistance and glucose dysregulation in lean or olders with sarcopenic obesity individuals, arising from endocrine senescence, chronic low-grade inflammation, and immune–metabolic crosstalk. Distinct from classical type 2 diabetes, SAGE-DM involves impaired beta-cells and alfa-cells function, altered insulin clearance, visceral fat redistribution, and immune alterations, such as adipose accumulation of regulatory T cells. Emerging data also implicate FGF-1 signalling and age-related hormonal declines—including adrenopause, andropause and somatopause—as contributors to its pathogenesis. Recognising SAGE-DM underscores the need for precision diagnosis in diabetes care, moving beyond the one-size-fits-all paradigm. Future research should focus on validating this construct, identifying specific biomarkers, and testing targeted interventions such as immune modulation and senotherapeutic strategies. By reframing diabetes through the lens of aging biology, SAGE-DM offers a new avenue for understanding and managing metabolic disease in the growing elderly population. This manuscript highlights a newly recognized form of diabetes called SAGE-DM, which develops in older or lean individuals due to age-related changes in hormones, immune function, and fat tissue, rather than obesity. Unlike classic type 2 diabetes, SAGE-DM involves altered insulin regulation, immune cell changes, and metabolic shifts linked to aging. Recognizing SAGE-DM emphasizes the need for personalized diagnosis and treatment strategies tailored to the unique biology of aging.