Ketogenic interventions enhance REM sleep in females and support memory in aged rats

Introduction: -hydroxybutyrate ester (KE) supplementation on sleep-wake architecture and novel spatial memory following sleep deprivation in aged rats. Methods: Forty four aged (22-25-month-old) Fischer-344 rats were implanted with frontoparietal EEG and nuchal EMG electrodes for wireless sleep recordings. Following baseline assessment, rats received either KE gavage (2.5 g/kg) or water control or were fed a KD versus control diet for 2 months. Sleep stages were scored using AccuSleep, cognition was assessed using the novel place preference task, and postmortem immunohistochemistry was performed to assess oxidative stress and inflammation. Results: < 0.001). Immunohistochemistry revealed reduced lipid peroxidation (4-HNE) without changes in protein oxidation (3-NT) or NLRP3 expression, while TREM2 was selectively reduced in KD females. This pattern is consistent with altered microglial lipid handling rather than broad suppression of inflammatory signaling. In contrast, aged male rats showed no significant changes in sleep architecture or molecular markers. Discussion: Together, these findings demonstrate that ketone-based interventions selectively enhance REM sleep, reduce lipid-associated oxidative stress in aged female rats and improve novelty preference memory in both sexes. These data highlight a sex-dependent relationship between metabolic flexibility, REM sleep regulation, and cognitive aging, supporting ketone-based strategies as targeted interventions for promoting healthy brain aging.