Epigenetic Clocks Reveal Age Acceleration and Shared Methylation Remodeling Across Cancers

Abstract

DNA methylation-based epigenetic clocks estimate biological age from methylation profiles, and the difference between predicted biological age and chronological age is commonly described as age acceleration (AA). We compared AA across eight cancer types, lung, colorectal, breast, thyroid, bone marrow and blood, kidney, uterus, and head and neck, using seven epigenetic clocks and 5,528 publicly available samples. Across the 56 cancer type clock combinations, tumor tissues showed higher average AA than normal tissues in 44 comparisons. The uterus cohort showed the clearest deviation from this overall trend, with normal samples exhibiting higher AA for six of seven clocks. Analyses of paired normal and tumor samples generally showed higher predicted ages and greater variability in tumor samples. We additionally examined age-associated methylation changes and the ability of clock CpGs to distinguish tumor from normal tissue. Several discriminatory CpGs were shared across cancer types and frequently showed tumor-associated hypermethylation at cancer-related loci. Small subsets of top-ranked CpGs captured substantial discriminatory information. Age-stratified subsampling preserved the main AA patterns, suggesting that chronological-age differences did not explain the observed tumor-normal differences. Overall, these findings highlight broad cancer-associated alterations in epigenetic aging together with substantial cancer type- and clock-specific heterogeneity.