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

Area of Science:

• Neuroscience
• Epigenetics
• Metabolism

Background:

• DNA damage and oxidative stress contribute to brain aging and dysfunction.
• Intermittent fasting (IF) increases β-hydroxybutyrate (BHB), a metabolite influencing cytoprotective and epigenetic pathways.
• Mechanisms linking IF, hippocampal epigenetics, and genome maintenance require clarification.

Purpose of the Study:

• To investigate how single fasting versus recurrent IF impacts hippocampal epigenetic programs and genome maintenance in mice.
• To determine if IF-induced protective states endure after refeeding.
• To elucidate the role of BHB, histone acetylation, and DNA repair pathways in IF's effects.

Main Methods:

• Comparison of a single 24-h fast with a month-long IF regimen in adult female mice.
• Analysis of nuclear BHB levels, acetyl-CoA, histone modifications (H3K9bhb, H3K27ac), and enzyme activity (HDAC2, EP300).
• Assessment of DNA damage markers (8-oxo-dG, γH2AX foci) and repair capacity following contextual fear conditioning.

Main Results:

• A single fast induced transient nuclear BHB increase and HDAC2 activity, with limited histone acetylation.
• Recurrent IF led to sustained nuclear BHB, reduced HDAC2 activity, increased acetyl-CoA, and enhanced EP300-chromatin interaction.
• Recurrent IF promoted sustained H3K27 acetylation and robust cytoprotective gene expression.
• IF and IF-refed mice showed reduced DNA damage (8-oxo-dG) and faster DNA repair (γH2AX resolution).

Conclusions:

• IF induces a metabolic-epigenetic shift, transitioning from transient priming to sustained cytoprotective programs.
• Recurrent IF enhances hippocampal genome maintenance and DNA repair capacity.
• These findings highlight IF as a strategy to promote neuronal genome integrity and potentially mitigate brain aging.