DNA Methylation

DNA methylation is an epigenetic mechanism involving the transfer of a methyl group onto the C5 position of cytosine to form 5-methylcytosine. ^[1] The best-characterized DNA modification associated with the modulation of gene activity is methylation of cytosine residues within CpG dinucleotides. ^[2] DNA methylation is a generic, evolutionarily ancient modification that can be incorporated into robust epigenetic codes contributing to development, ageing and disease. ^[3]

DNA methylation regulates gene expression by recruiting proteins involved in gene repression or by inhibiting the binding of transcription factors to DNA. ^[1] The pattern of DNA methylation in the genome is shaped by a dynamic process involving both de novo DNA methylation and demethylation, producing stable tissue-specific patterns that regulate gene transcription. ^[1] CpG dinucleotides are often located near gene promoters, where their methylation associates with gene expression levels. ^[4] Distinct DNA methylation landscapes emerge over the mammalian lifespan and interact with other regulatory layers to support diverse genomic functions. ^[3]

Global levels of DNA methylation increase over the first few years of life and then decrease beginning in late adulthood, while variability of methylation increases with age. ^[4] Age-related DNA methylation changes are driven by two phenomena: epigenetic drift and the epigenetic clock. ^[4] Age-associated changes to the mammalian DNA methylome are well documented and are thought to promote diseases of aging such as cancer. ^[5] Progressive changes to DNA methylation and other epigenetic marks accompany aging in both dividing and nondividing cells and influence the aging process. ^[6]

Biomarkers of aging based on DNA methylation data enable accurate age estimates for any tissue across the entire life course, and these epigenetic clocks link developmental and maintenance processes to biological ageing. ^[7] Classic epigenetic clocks include Horvath's clock, Hannum's clock, DNA PhenoAge, and DNA GrimAge, and they are employed as a practical tool to evaluate the efficacy of age-reversing interventions. ^[8] Epigenetic clocks comprise a set of CpG sites whose DNA methylation levels measure subject age and are being explored to quantify biological aging rates and test longevity or rejuvenating interventions. ^[9] Because DNA methylation and other epigenetic marks are reversible, manipulating them is central to the effectiveness of rejuvenating interventions such as partial reprogramming that aim to delay ageing. ^[10] An expert consensus on biomarkers of aging identified DNA methylation and