A Systematic Review of Food-derived DNA Methyltransferase Modulators: Mechanistic Insights and Perspectives for Healthy Aging

: DNA methylation represents a crucial epigenetic mechanism orchestrating gene expression, cellular homeostasis, and the aging trajectory. Dysregulation of DNA methyltransferases (DNMTs)-the enzymes catalyzing this process-has been implicated in a wide spectrum of chronic conditions, including cancer, cardiovascular and metabolic disorders, and neurodegenerative diseases. Emerging evidence suggests that food-derived bioactive compounds can act as DNMT inhibitors, reshaping epigenetic landscapes. This systematic review, registered in PROSPERO (CRD42022320316), critically evaluated in vitro, in vivo animal, and ex vivo studies investigating the effects of dietary bioactives on DNMT expression and activity. A thorough search of PubMed up to May 23, 2025, yielded 103 studies, of which 76 met the inclusion criteria. Eligible publications were original, peer-reviewed, and provided evidence from in vitro, in vivo animal, or ex vivo models. Frequent candidates included epigallocatechin-3-gallate, curcumin, genistein, resveratrol, sulforaphane, and folate. Notably, nearly 90% of studies reported DNMT inhibition-often dose- and time-dependent. Approximately 21% defined minimal effective concentrations, predominantly for isolated compounds. Several studies described synergistic interactions between bioactives, and emerging data highlighted the gut microbiota's mediating role in epigenetic modulation. Despite promising outcomes, the predominance of preclinical evidence and variability in experimental protocols and dosing limit immediate translational impact. Nonetheless, current findings underscore the promise of dietary DNMT modulators as foundational elements for precision nutrition strategies aimed at promoting healthy aging and mitigating age-associated disease risk. The potential application of DNA methylation age (DNAmAge) as a biomarker of biological aging has been increasingly supported by recent literature, reinforcing its relevance in future nutritional epigenetics research. Further well-designed clinical trials are warranted to assess long-term efficacy, safety, and bioavailability of these compounds, and to validate their use in personalized epigenetic interventions, using biological aging markers. This review was funded by the European Union-Next Generation EU, PNRR Project Age-It (DM 1557 11.10.2022), and the University of Padua SID Grant (2024DCTV1SIDPROGETTI-00194).