Abstract Alzheimer’s disease (AD) is characterized by cognitive decline and impaired brain energy metabolism. Time-restricted feeding (TRF) is a dietary regimen that confines daily food intake to a limited window without caloric reduction, aligning feeding with circadian rhythms and inducing intermittent ketosis. In this study, an 8-hour TRF regimen was compared with a ketogenic diet (KD) in an Aβ-injected AD mouse model to evaluate their effects on cognition and underlying mechanisms. After one month of intervention, TRF significantly improved spatial learning, memory, and recognition in AD mice, with outcomes comparable to or better than KD group. TRF preserved hippocampal neuron morphology, reduced amyloid-β deposition and neuroinflammation, elevated blood and brain β-hydroxybutyrate levels, restored brain ATP levels, and partially rescued mitochondrial respiratory complex activities. Mechanistically, TRF activated the NAD⁺-dependent deacetylase SIRT2 in the hippocampus and cortex. SIRT2 activation upregulated PGC-1α and TFAM expression and activated PINK1/Parkin-mediated mitophagy, thereby improving mitochondrial function and energy metabolism. Notably, unlike KD, TRF did not raise blood lipid levels, indicating a superior safety profile. In conclusion, TRF alleviates Aβ-induced cognitive impairment in AD model mice by enhancing SIRT2-mediated mitochondrial homeostasis, supporting TRF as a promising and metabolically balanced intervention for AD.
Rong et al. (2026) studied this question.