Neuroprotective effect of metformin on brain aging and microglial senescence

Aging is the major risk factor for cognitive decline and neurodegenerative diseases, and is associated with progressive alterations in microglial function, among other hallmarks. Microglial senescence, characterized by loss of homeostatic functions and a chronic proinflammatory state, may contribute to age-related brain dysfunction. The antidiabetic drug Metformin (MET) has emerged as a potential repurposing strategy for neurological disorders. Here, we investigated the effects of MET on brain aging and microglial senescence using in vivo and in vitro models. Adult (9-month-old) and aged (17-month-old) male C57BL/6J mice received MET (250 mg/kg, i.p.; 10 doses during the last month) or vehicle. MET did not affect body weight or fasting glycemia. In aged mice, MET reversed anxiety-like behavior assessed by the open field test. In the Barnes Maze, MET improved spatial learning independently of age and enhanced spatial memory in aged animals. Hippocampal Iba1 immunofluorescence showed reduced microglial reactivity following MET treatment. In vitro, FAC-induced senescence in BV2 microglial cells increased nuclear area and p21/p14 expression, while MET attenuated these changes. Overall, MET improved age-associated behavioral alterations and modulated microglial responses in the aging brain, while attenuating senescence-associated phenotype in microglial cells. These findings support microglia as a target of MET and provide a basis for investigating its neuroprotective mechanisms