Inhibition of Sirtuin 2 enhances autophagy and restores neuronal function in aged hippocampal neurons

Age-related cognitive decline is linked to impaired autophagy and hippocampal dysfunction. This study investigates the role of Sirtuin 2 (SIRT2) in age-related cognitive decline, focusing on its impact on autophagy and hippocampal function. Quantitative proteomic analysis revealed 67 significantly dysregulated proteins in the hippocampus of naturally aged male mice, including upregulated SIRT2 and impaired autophagy. To explore the role of SIRT2 in brain aging and its association with autophagy, naturally aged male mice received AK7, a SIRT2-specific inhibitor, for four consecutive weeks, followed by behavioral assessment using the Morris water maze. Western blot and immunofluorescence analyses were applied to assess mTOR phosphorylation, LC3B-II turnover, and SQSTM1/p62 degradation, complemented by in vitro validation in a D-galactose-induced HT-22 cellular senescence model. The results indicated that AK7 administration improved cognitive performance in aged mice, while simultaneously reducing mTOR phosphorylation and enhancing autophagy markers. In vitro, SIRT2 genetic knockdown restored the mTOR phosphorylation, LC3B-II/LC3I ratio, and SQSTM1/p62 accumulation, while also reducing senescence markers (including TNF-α, P21,Trp53) in D-galactose-induced HT-22 cells. These effects were abolished by mTOR activation, confirming mTOR as a downstream mediator of SIRT2. Our findings highlight SIRT2 inhibition as a promising therapeutic strategy to counteract age-related cognitive decline through the modulation of mTOR-dependent autophagy in the hippocampus.