Epigenetic Aging: More Than Just a Clock When It Comes to Cancer

Abstract

The incidence of cancer, adjusted for secular trends, is directly related to age, and advanced chronologic age is one of the most significant risk factors for cancer. Organismal aging is associated with changes at the molecular, cellular, and tissue levels and is affected by both genetic and environmental factors. The specific mechanisms through which these age-associated molecular changes contribute to the increased risk of aging-related disease, such as cancer, are incompletely understood. DNA methylation, a prominent epigenetic mark, also changes over a lifetime as part of an "epigenetic aging" process. Here, we give an update and review of epigenetic aging, in particular, the phenomena of epigenetic drift and epigenetic clock, with regard to its implication in cancer etiology. We discuss the discovery of the DNA methylation-based biomarkers for biological tissue age and the construction of various epigenetic age estimators for human clinical outcomes and health/life span. Recent studies in various types of cancer point to the significance of epigenetic aging in tumorigenesis and its potential use for cancer risk prediction. Future studies are needed to assess the potential clinical impact of strategies focused on lowering cancer risk by preventing premature aging or promoting healthy aging.

Figure 1.

Epigenetic clocks allow comparison of an individual’s chronological age to his or her biological age, as calculated based on DNAm clock CpGs. Different individuals appear to have different epigenetic aging rates, with their biological (or tissue) age accelerated or decelerated compared to their chronological age, which may be secondary to intrinsic individual differences (e.g. due to genetics) and to extrinsic epigenetic modifiers (e.g. lifestyle, microbiome, nutrition, and other exposures).

Figure 2.

Age-related alterations in DNA methylation (DNAm) accumulate in normal tissues and may be used to develop epigenetic clocks to estimate an individual’s age or risk for age-related disease. Epigenetic drift may be linked to a variety of biological processes (cell proliferation, inflammation, oxidative stress and DNA repair, one-carbon (1C) metabolism, among others). and DNA damage repair through imperfect fidelity of DNMT enzymes that copy DNAm patterns during cell division. Extrinsic modifiers of the epigenome include the microbiome, lifestyle and environmental factors. Epigenetic clocks are typically developed using elastic net or other regression methods to link specific CpG dinucleotides on DNA to an individual’s chronological age (Hannum’s 2013 clock with 71CpGs, and Horvath’s 2013 clock with 353 CpGs); to mitotic index in normal tissue and cancers based on DNA methylation of polycomb group target (PCGT) genes (epiTOC using 385 PCGT CpGs); and to life/health span based on clinical markers of disease (Levine’s 2018 PhenoAge clock using 513 CpGs).