Sex-specific cognitive and metabolic effects of lifelong caloric restriction and sodium butyrate administration in aging rats

Abstract

Aging is associated with progressive metabolic dysfunction and cognitive decline, which is often accompanied by hippocampal dysfunction and sex-specific vulnerabilities. Caloric restriction (CR) and sodium butyrate (NaBu), a short-chain fatty acid that acts as a histone deacetylase inhibitor, have both been shown to have neuroprotective properties, yet their combined effects on aging remain unexplored. Hence, the impact of lifelong CR and acute NaBu administration on spatial learning, memory and cognitive flexibility was assessed in aged male and female Wistar rats using the Morris water maze (MWM), a paradigm widely employed to study hippocampal‑dependent spatial cognition. Changes to key metabolites like leptin, triglycerides and insulin were also evaluated. MWM performance was significantly compromised in aged rats, with female rats consistently outperforming males even when possible sensorimotor impairments had been ruled out in a cued test. Both CR and NaBu improved cognitive performance in aged rats, effects that were more pronounced when these interventions were combined. Structural equation modeling revealed sex-specific pathways and in females, a CR-associated reduction in triglycerides was associated with better memory and cognitive flexibility, whereas lower insulin levels were linked with improved learning. In males, NaBu was associated with improved spatial learning, while the cognitive benefits of CR were related to lower insulin and leptin levels. NaBu treatment increased hippocampal histone H3 acetylation in both sexes, whereas CR had no significant effect on these modifications. Together, these findings suggest CR and NaBu may influence aging-related cognitive changes through distinct biological mechanisms, while emphasizing the importance of sex as a critical biological variable in such interventions. The data indicate that combined modulation of metabolic and epigenetic pathways may protect against age-related cognitive decline, highlighting the potential of adopting multi-target approaches, although further studies will be needed to clarify the underlying mechanisms and their translational implications.