High Glucose Triggers Macrophage Senescence Through Mitochondrial Dysfunction and Mitophagy Impairment

ABSTRACT Chronic hyperglycemia accelerates immune aging and contributes to diabetic complications, yet the mitochondrial mechanisms responsible for macrophage senescence remain unclear. In this study, both cultured and primary macrophages were treated with high glucose to model hyperglycemic conditions. High glucose significantly increased markers of macrophage senescence, including SA‐β‐Gal staining, expression of p16 and p21, and secretion of pro‐inflammatory cytokines. Mitochondrial dysfunction was evident, as shown by loss of mitochondrial membrane potential (ΔΨm) and elevated mitochondrial reactive oxygen species (mtROS). In addition, mitophagy was impaired, with PINK1 accumulation and reduced Parkin recruitment. Rescue experiments demonstrated that treatment with the mitochondria‐targeted antioxidant MitoTempo, the general antioxidant N‐acetylcysteine, or the anti‐diabetic drug metformin effectively restored mitochondrial function and alleviated senescence. These findings indicate that mitochondrial dysfunction and impaired mitophagy are central to high glucose‐induced macrophage senescence, and that targeting mitochondrial oxidative stress with antioxidants or metformin may offer a promising strategy to mitigate immune aging and inflammation associated with metabolic disorders.