Context Aberrant DNA methylation is linked to various diseases. The supply of methyl groups for methylation reactions is mediated by S-adenosylmethionine, which depends on the availability of folate and related B vitamins. Objectives To investigate the influence of key nutrients involved in 1-carbon metabolism on DNA methylation in adults. Data sources Systematic literature searches were conducted in the Cochrane Library, Medline, Embase, Cumulative Index to Nursing and Allied Health Literature Plus, Scopus, and Web of Science databases. Studies that met the inclusion criteria and were published in English were included. Data extraction The first author, study design, sample size, population characteristics, type and duration of intervention, tissue type or cells analyzed, molecular techniques, and DNA methylation outcomes. Data synthesis A meta-analysis of randomized, controlled trials (RCTs) was conducted to investigate the effect of 1-carbon metabolism nutrients on global DNA methylation. Functional analysis and visualization were performed using BioVenn software. Results From a total of 2620 papers screened by title, 53 studies met the inclusion criteria. Qualitative analysis indicated significant associations between 1-carbon metabolism nutrients and DNA methylation. In meta-analysis of RCTs stratified by method of laboratory analysis, supplementation with folic acid alone or in combination with vitamin B12 significantly increased global DNA methylation in studies using liquid chromatography–mass spectrometry, which had markedly lower heterogeneity (n = 3; Z = 3.31; P = 0.0009; I2 = 0%) in comparison to other methods. Functional analysis highlighted a subset of 12 differentially methylated regions that were significantly related to folate and vitamin B12 biomarkers. Conclusion This study supports significant associations between 1-carbon metabolism nutrients and DNA methylation. However, standardization of DNA methylation techniques is recommended to reduce heterogeneity and facilitate comparison across studies. Systematic Review registration PROSPERO registration number: CRD42018091898.

Abstract Recent advances in epigenetic research have enabled the development of epigenetic clocks, which have greatly enhanced our ability to investigate molecular processes that contribute to aging and age-related disease. These biomarkers offer the potential to measure the effect of environmental exposures linked to dynamic changes in DNA methylation, including nutrients, as factors in age-related disease. They also offer a compelling insight into how imbalances in the supply of nutrients, particularly B-vitamins, or polymorphisms in regulatory enzymes involved in 1-carbon metabolism, the key pathway that supplies methyl groups for epigenetic reactions, may influence epigenetic age and interindividual disease susceptibility. Evidence from recent studies is critically reviewed, focusing on the significant contribution of the epigenetic clock to nutritional epigenomics and its impact on health outcomes and age-related disease. Further longitudinal studies and randomized nutritional interventions are required to advance the field.

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Short running head: DNA methylation of hypertension-related genes in adults screened for the MTHFR C677T polymorphism Declarations of interest: DLM, CPW, SDA, AM, CFH no conflicts of interest. MW, HN,JJS hold an international patent on the use of riboflavin in the treatment of blood pressure.