Intermittent Fasting Attenuates Cognitive Decline in D-Galactose-Induced Aging Rats in Association with β-Hydroxybutyrate and PI3K/AKT/GSK-3β Signaling.

Abstract

Age-related cognitive decline is a major public health concern, with few effective interventions available. Intermittent fasting (IF) has emerged as a promising metabolic intervention, potentially enhancing neuroprotection through increased β-hydroxybutyrate (BHB) production. This study aimed to test the hypothesis that IF attenuates cognitive decline in D-galactose (D-gal)-induced aging rats, at least partly in association with BHB elevation and modulation of PI3K/AKT/GSK-3β signaling. Forty-six male Sprague-Dawley rats (2 months old) were assigned to five groups: Control, D-gal-induced aging (D-gal), D-gal + IF, D-gal + IF + LY294002 (a PI3K inhibitor), and D-gal + IF + Solvent. IF was administered for 6 weeks in conjunction with D-gal treatment. Recognition memory and spatial learning/memory were assessed using the novel object recognition and Morris water maze tests, respectively; the open field test was used to evaluate locomotor activity and anxiety-like behavior. Biochemical assays (ELISA, Western blot), histological staining, and RNA-seq transcriptomic analysis were performed. IF improved recognition memory and spatial learning/memory, preserved hippocampal neuronal morphology, increased the proportion of morphologically normal CA1 neurons, elevated serum BHB levels, reduced neuroinflammation and tau phosphorylation, and restored brain-derived neurotrophic factor (BDNF) expression. These improvements were attenuated by LY294002 intervention, supporting the involvement of the PI3K/AKT/GSK-3β pathway. Transcriptomic analysis revealed suppression of senescence-related genes and modulation of neuroprotective pathways. IF attenuated cognitive decline in D-gal-induced aging rats in association with increased BHB levels and modulation of the PI3K/AKT/GSK-3β pathway. These findings suggest that IF may represent a promising non-pharmacological intervention for age-related cognitive dysfunction, although causal roles of ketone metabolism require further validation.