DNA Methylation, Aging, and Cancer

Abstract

Aging and cancer, though distinct biological processes, share overlapping molecular pathways, particularly in epigenetic regulation. Among these, DNA methylation is central to mediating gene expression, maintaining cellular identity, and regulating genome stability. This review explores how age-associated changes in DNA methylation, characterized by both global hypomethylation and focal hypermethylation, contribute to the emergence of cancer. We discuss mechanisms of DNA methylation drift, the development of epigenetic clocks, and the role of entropy and epigenetic mosaicism, in aging and tumorigenesis. Emphasis is placed on how stochastic methylation errors accumulate in aging cells and lead to epiallelic shifts and gene silencing, predisposing tissues to malignant transformation, even despite recently increased cancer incidences at younger ages. We also highlight the translational potential of DNA methylation-based biomarkers, and therapeutic targets, in age-related diseases. By framing cancer as a disease of accelerated epigenetic aging, this review offers a unifying perspective and calls for age-aware approaches to both basic research and clinical oncology.

Keywords: DNA methylation; aging; cancer.

Figure 1

Model of how age-related DNA methylation changes contribute to focal diseases, specifically cancer. In young normal tissues (left), most cells exhibit uniform epigenetic patterns, with occasional outliers showing subtle variation related to genetics or the environment. Age-related DNA methylation changes result in epigenetic mosaicism (middle), as represented by the differently colored cells, showing cell-to-cell epigenetic variation. Further epigenetic changes, combined with DNA mutations or carcinogen exposure, transform the cells into a full-fledged malignancy (right).