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

Sleep disruption and metabolic decline are key contributors to cognitive aging and dementia risk. While cerebral glucose utilization declines with age, ketone metabolism remains relatively preserved, suggesting that ketogenic interventions may enhance brain energetics, sleep quality, and cognition in older individuals. Therefore, we investigated the effects of a ketogenic diet (KD) and β-hydroxybutyrate ester (KE) supplementation on sleep-wake architecture and novel spatial memory following sleep deprivation in aged rats.

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.

Both KE (p = 0.0152) and KD (p = 0.0385) significantly increased REM sleep in aged female rats, with KE enhancing REM during the light phase and KD during the dark phase. Whereas, KE decreased REM sleep in males during the light phase (p = 0.00165). KD increased the number of REM sleep bouts without altering bout duration in females, consistent with enhanced REM sleep initiation rather than maintenance. EEG spectral analysis revealed no differences in NREM delta power or REM theta power in KD females, suggesting preserved microarchitecture. Sleep deprivation did not change spatial memory in our rats but KD treated rats showed improved novel place recognition in both females and males (p < 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.

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.