Age-related dynamics of DNA co-methylation modules in humans

Age-related changes in the mean or variance of DNA methylation (DNAm) at individual CpG sites are well established. However, CpGs that share biological functions often exhibit coordinated regulation. Here, we analysed whole-blood DNAm data from over 7,500 individuals and identified modules of co-methylated CpGs that either maintain consistent correlations with age (age-stable modules) or undergo age-related remodelling (age-variable modules). We show that co-methylation modules are largely preserved during healthy aging, with only a small subset (~15%) showing substantial age-related reorganisation. Age-stable modules are enriched for CpG loci within promoters, transcription start sites, and CpG islands, whereas age-variable modules harbour loci that are depleted in these genomic domains and enriched for repressive chromatin marks. Age-stable co-methylation modules are also associated with long-range genetic regulation (trans-meQTLs), promoter-associated chromatin states, and higher-order chromatin interactions. While both age-stable and age-variable modules are enriched for developmental pathways, immune-related processes are distinctly associated with age-stable modules. Overall, our findings suggest that epigenetic aging is characterised by a spectrum of co-methylation network trajectories, ranging from stability to disruption, shaped by underlying genomic regulatory architecture.