Syed Ammar Hussain, Majher I. Sarker, Y Liu, Tony Z. Jin
DNA methylation is a central epigenetic mechanism that mediates the interaction between nutritional exposures and gene regulation. Emerging evidence demonstrates that diet, bioactive compounds, genetic background, and lifestyle factors collectively shape the human methylome, influencing metabolic function, disease susceptibility, and biological aging. This review synthesizes current knowledge on the molecular and biochemical mechanisms of DNA methylation, the role of nutrients and dietary patterns in modulating methylation dynamics, and findings from human clinical trials evaluating nutritional interventions. Genotype-specific responses, including polymorphisms in one-carbon metabolism and metabolic pathways, are discussed as key determinants of interindividual variation in methylation outcomes. The review further highlights the advances in epigenetic clocks, systems biology, and multi-omics integration that support the development of precision nutrition frameworks. Ethical considerations and future challenges related to data interpretation, accessibility, and the regulation of epigenetic testing are also examined. Collectively, this review provides an integrative perspective on how DNA methylation serves as a dynamic interface between diet and health and outlines opportunities for implementing personalized nutrition strategies to improve metabolic resilience and promote healthy aging.