Aging-related cognitive decline is closely associated with disrupted energy metabolism and impaired autophagic clearance in the brain. Aldometanib, an active ingredient from the traditional formulation Bigujing, exerts systemic metabolic benefits, but its effects on brain aging and the underlying mechanisms remain unclear. This study aims to evaluate the efficacy of Aldometanib in mitigating cognitive decline in D-galactose-induced aging mice, and to elucidate its potential mechanisms involving AMPK-mediated energy metabolism and autophagy regulation. Male C57BL/6 J mice were treated with D-gal for 42 days, with or without 100 μg/mL Aldometanib in drinking water. Cognitive function was evaluated using the novel object recognition test, Y-maze test, and the Morris water maze test. Brain tissues were analyzed for neuronal morphology, the total antioxidant capacity (T-AOC) and the expressions of senescence, AMPK/ACC pathway and autophagy-related proteins (p-mTOR, LC3B-II, P62). In vitro assays validated Aldometanib's mechanistic effects in D-gal-treated C8-D1A astrocytes and Neuro-2a cells. Aldometanib significantly mitigated D-gal-induced weight loss and cognitive deficits and alleviated neuronal atrophy and loss in the hippocampus and cortex. Aldometanib downregulated the expression of senescence markers P53, P21 and P16 and increased T-AOC levels. Mechanistically, Aldometanib specifically activated the AMPK/ACC pathway in neurons and astrocytes, suppressed mTOR phosphorylation and P62 accumulation, and enhanced autophagy both in vivo and in vitro. Aldometanib can effectively ameliorate the cognitive and physiological decline in aged mice by activating AMPK, suppressing mTOR and promoting autophagy, and enhancing antioxidant capacity. It represents a promising therapeutic candidate for age-related neurodegenerative diseases.
