SIRT3 deficiency exacerbates cognitive decline by disrupting mitochondrial antioxidant homeostasis in D-galactose-induced aging mice.

BACKGROUND: Age-related cognitive decline poses a growing clinical burden, with mitochondrial oxidative stress recognized as a key mediator. Sirtuin 3 (SIRT3), a mitochondrial deacetylase, is a potential regulator of redox balance, but its role in hippocampal function and cognitive aging, particularly its translational potential, remains unclear. METHODS: We used D-galactose (D-gal)-treated mice (150 mg/kg/day for 8 weeks) to model accelerated aging and neuron-specific SIRT3 knockout (SIRT3(cKO)) mice. Transcriptomic profiling, behavioral tests, electrophysiological recordings, and mitochondrial analyses were performed. Therapeutic potential was assessed via intrahippocampal AAV-SIRT3 overexpression. RESULTS: D-gal induced memory deficits, disrupted hippocampal theta oscillations, and mitochondrial degeneration, with transcriptomics identifying SIRT3 as the sole mitochondrially localized differentially expressed gene. SIRT3(cKO) mice recapitulated these deficits, showing elevated ROS, reduced ATP, aberrant Hif-1α activity, and synaptic/theta rhythm impairments. AAV-SIRT3 overexpression reversed D-gal-induced pathology, which was manifested by the restoration of SOD2 activity, mitochondrial crista density, and theta power, as well as the attenuation of cellular senescence. CONCLUSIONS: SIRT3 is a critical regulator of hippocampal mitochondrial redox homeostasis. Augmenting hippocampal SIRT3 represents a promising therapeutic strategy for age-related cognitive impairment, supporting the translation of these findings to clinical interventions for neurological decline.