Hypothalamic Inflammaging: A Central Driver of Type 2 Diabetes Mellitus and Metabolic Disease in Aging.

Aging is a major risk factor for type 2 diabetes mellitus (T2DM) and is accompanied by chronic, low-grade inflammation known as inflammaging. Emerging evidence indicates that the hypothalamus, a central regulator of energy and glucose homeostasis, undergoes age-associated inflammatory remodeling that contributes to metabolic dysfunction. In particular, glial cells, including microglia, astrocytes, tanycytes, and neural stem cells, acquire senescence-associated phenotypes characterized by impaired homeostatic functions and increased secretion of pro-inflammatory mediators. These changes disrupt hypothalamic neuronal circuits involved in glucose sensing, energy balance, and insulin responsiveness, thereby potentially promoting systemic insulin resistance and T2DM progression. In this review, we summarize current evidence on the cellular and molecular mechanisms of hypothalamic glial inflammaging and discuss how age-related glial dysfunction may contribute to metabolic abnormalities. We also highlight emerging therapeutic strategies targeting neuroinflammation and glial senescence for the prevention and treatment of age-associated T2DM.