The epigenome, consisting of chemical modifications that influence chromatin structure and gene activity without altering DNA sequences, undergoes substantial age-related remodelling. DNA methylation (DNAm), one of the most widely studied epigenetic marks, predominantly occurs at cytosine-guanine (CpG) sites and is known to change across the lifespan. Although previous studies have explored the aging methylome, including linear changes, variability (VMPs), and entropy (distribution of methylation), the extent of these changes across different human tissues remains to be fully characterized.
This study presents a comprehensive, multi-tissue analysis of age-related DNAm changes in seventeen human tissues by constructing a dataset of >80,000 methylomes from >150 publicly available datasets. A rigorous statistical pipeline facilitated a large-scale, tissue-specific Epigenome-Wide Association Study (EWAS) meta-analysis, allowing for precise quantification of differentially methylated positions (DMPs), VMPs, and entropy across tissues.
In blood, 47% of CpGs analysed were DMPs, with two-thirds (66%) showing age-related hypomethylation, alongside a marked increase in entropy driven by DMPs. While age-related DMPs were observed in all tissues, only blood, brain, saliva, and skin displayed VMPs, with VMPs undetectable in muscle and adipose tissues. These findings suggest that tissue-specific age-related DNAm changes may correlate with the proliferative capacity of each tissue. Notably, patterns of hyper- versus hypomethylation differed among tissues, underscoring the complexity of the aging methylome.
This multi-tissue approach provides the most extensive map of DNAm aging to date, offering key insights into the global and tissue-specific dynamics of epigenetic aging in humans. The findings contribute to a deeper understanding of how DNAm remodelling varies by tissue, with implications for age-related biological processes and potential clinical applications.