SEX-SPECIFIC EFFECTS OF SODIUM BUTYRATE AND CALORIC RESTRICTION ON SYNAPTIC PROTEINS IN AGED RATS

Aging is a biological process accompanied by cognitive decline, largely driven by synaptic dysfunction in brain circuits essential for learning and memory. A key hallmark of aging is epigenetic dysregulation, which disrupts gene expression programs required for synaptic maintenance and function. Notably, epigenetic modifications are reversible, making them attractive targets to promote healthy brain aging. In this study, we measured whether two epigenetic-based interventions - lifelong caloric restriction (CR) and sodium butyrate (NaB) administration - modulate synaptic protein expression in the hippocampus of aged male and female Wistar rats, using Western blot analysis. NaB significantly increased histone H3 acetylation in the hippocampus, confirming effective epigenetic modulation, whereas CR did not alter global acetylation levels. NaB broadly boosted presynaptic proteins, increasing markers of axonal growth/membrane dynamics (GAP-43, BASP-1), the vesicular transporters (VGLUT1 and VGAT), and the active zone scaffolding protein Liprin-α3; with the strongest changes observed in males. In contrast, CR selectively increased SYP levels in female rats, suggesting sex-dependent presynaptic regulation. At the postsynaptic level, Neuroligin, PSD-95, and Homer-1 were mostly increased in male rats, whereas the inhibitory synaptic marker Gephyrin remained unchanged, suggesting specific modulation of excitatory synaptic components. Overall, these results indicate that epigenetic interventions reshape synaptic protein networks in aging in a sex-specific manner, with NaB showing broader effects than CR. Although further research is required, our preliminary findings suggest that epigenetic modifications provide a valuable framework for exploring their relevance in age-related synaptic regulation.