Nutritional Epigenomics and Age-Related Disease

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.

Keywords: B-vitamins; DNA methylation; aging; diet; epigenetic age; epigenetic age acceleration; epigenetic clock; one-carbon metabolism.

FIGURE 1

Brief summary of 1-carbon metabolism and DNA methylation. BER, base excision repair enzymes; BHMT, betaine-homocysteine S-methyltransferase; DHF, dihydrofolate; DMG, dimethylglycine; DNMT, DNA methyltransferase; MTHFR, methylenetetrahydrofolate reductase; MTR, methionine synthase; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; SHMT, serine hydroxymethyltransferase; TDG, thymine DNA glycosylase; TET, ten-eleven translocation methylcytosine dioxygenase enzymes; THF, tetrahydrofolate.

FIGURE 2

DNA methylation patterns of monozygotic twins diverge during aging. Despite early similarities, stochastic changes occur in the methylome of each twin, A and B during aging. Epigenetic drift results in age-related hypermethylation of CpG-rich sequences such as CGI promoters, typically found in ubiquitously expressed housekeeping genes, which may be switched off as a result of aberrant age-related methylation. In contrast, highly methylated, transcriptionally repressed CpG-poor promoters tend to become hypomethylated during aging, leading to aberrant gene expression. Tandem satellite repeat sequences in the telomere are also heavily methylated which may promote genome stability and inhibit recombination. Hypermethylated interspersed repeats such as LTRs, SINEs, and LINEs tend to undergo generalized hypomethylation during aging. ^⋆A selection of CpGs undergo programed reproducible methylation changes across the population during aging and have been incorporated into epigenetic clock algorithms used to accurately predict epigenetic age. Each lollipop represents an individual CpG, arrows indicate transcription start sites, X indicates transcriptional repression. CGI, CpG island; LINE, long interspersed nuclear element; LTR, long terminal repeat; SINE, short interspersed nuclear element.