Epigenetic modification of neurotransmitter pathways during fasting: a systematic review

Background Dietary restriction, encompassing intermittent fasting and caloric restriction, represents a prominent non-pharmacological approach to modulating brain aging and neuronal resilience. Emerging evidence links metabolism to long-term neural plasticity through epigenetic mechanisms, yet findings remain fragmented. This review integrates preclinical evidence on how dietary restriction alters brain epigenetic regulation and links these changes to neurocognitive outcomes. Methods The review followed PRISMA 2020 and the Synthesis Without Meta-analysis (SWiM) reporting guideline. PubMed and SciSpace were searched from inception to December 2025. Eligible studies assessed DNA methylation, histone modifications, non-coding RNA, or epigenetic regulators in brain tissue of animal or human subjects undergoing dietary restriction. Risk of bias was appraised with the SYRCLE tool, and a qualitative narrative synthesis was undertaken given methodological heterogeneity. Results Nine preclinical animal studies met the inclusion criteria; no human study qualified. Dietary restriction significantly affected DNA methylation, histone modifications, and non-coding RNA expression, exerting a recalibrating influence that attenuated age-associated epigenetic drift and restored homeostatic regulation. Sirtuin-1/CREB signalling, BDNF/TrkB signalling, metabolic signalling (mTOR, AMPK, FOXO), and neuroinflammatory modulation were the principal pathways implicated. Intermittent fasting and caloric restriction showed overlapping and distinct mechanisms, with ketone-induced histone deacetylase inhibition linked to fasting. Cognitive benefit, particularly in hippocampal-dependent memory, accompanied the epigenetic changes, although persistent epigenetic memory of dietary restriction was less clear. Risk of bias was high in seven studies and moderate in two, reflecting incomplete reporting of randomisation, blinding, and protocols. Conclusion Dietary restriction alters brain epigenetics through multiple interconnected pathways that strengthen neural circuits and improve cognitive function. The preclinical evidence is consistent across several layers of epigenetic regulation, but the absence of human studies, small sample sizes, and limited causal evidence constrain translation. Multi-omics approaches and epigenome editing are required to establish causality and the therapeutic potential of dietary restriction. Systematic review registration https://www.crd.york.ac.uk/prospero/ , identifier CRD420251035303.