Intermittent Fasting Enhances Genome Integrity and Cytoprotective Pathways via (BHB) β-Hydroxybutyrate Signaling and Chromatin Remodeling

DNA damage and oxidative stress are key drivers of cellular aging and brain dysfunction, and enhancing cytoprotective pathways is therefore a promising strategy to preserve neuronal genome integrity. Intermittent fasting (IF) elevates the ketone body β-hydroxybutyrate (BHB), a signaling metabolite implicated in cytoprotective pathways and, more recently, in chromatin regulation. Yet the mechanisms by which repeated fasting reshapes hippocampal epigenetic programs and influences genome maintenance remain poorly defined. Here, we compared a single 24-h fast versus a month-long IF regimen in adult female mice, focusing on oxidative stress defense and DNA repair pathways, and tested whether protective states persist after refeeding. During a single 24-h fast, hippocampal nuclear BHB increased modestly and coincided with elevated HDAC2 activity, consistent with a transient metabolic stress response. In parallel, acetyl-CoA levels remained unchanged, potentially limiting broader EP300-driven acetylation. Under these conditions, we observed a brief enrichment of H3K9bhb at promoters of cytoprotective genes, suggesting an early priming phase. In contrast, recurrent IF was associated with robust nuclear BHB accumulation and reduced HDAC2 activity. Together with increased hippocampal acetyl-CoA availability and enhanced EP300 interaction with chromatin, recurrent IF shifted promoter regulation toward sustained H3K27 acetylation and robust induction of cytoprotective transcriptional programs. Functionally, IF and IF-refed mice exhibited reduced nuclear 8-oxo-dG accumulation and accelerated resolution of γH2AX foci following hippocampal activation by contextual fear conditioning, indicating enhanced genome stability and improved DNA repair capacity. Collectively, these findings support a model in which IF drives a coordinated metabolic–epigenetic transition from an early, transient priming state to a more sustained cytoprotective program that promotes genome maintenance in the hippocampus.