Time-Restricted Feeding Orchestrates Astrocytic Metabolic Reprogramming via the Wnt Pathway to Alleviate Sevoflurane-Induced Neural Injury

Perioperative neurocognitive disorders (PND) pose a significant challenge for aging surgical patients, with sevoflurane anesthesia being an identified risk factor. Time-restricted feeding (TRF), a dietary regimen, shows promise in mitigating age-related cognitive decline, but its efficacy and mechanism against sevoflurane-induced PND remain unclear. Using the aging-accelerated mouse model (SAMP8) exposed to sevoflurane, we found that TRF improved cognitive performance and synaptic integrity, as evidenced by increased levels of PSD-95 and synaptophysin. Mechanistically, TRF activated the Wnt/β-catenin pathway, driving a beneficial metabolic reprogramming in hippocampal astrocytes characterized by enhanced ketogenesis and fatty acid oxidation. This was associated with reduced neuroinflammation and oxidative stress. The neuroprotective effects of TRF were abolished by Wnt inhibition and enhanced by Wnt activation. Our study identifies TRF as a non-pharmacological strategy that counteracts PND by linking Wnt-mediated astrocyte metabolic reprogramming to improved neuronal function.