Correlating Cancer Risk with Epigenetic Age

Epigenetic clocks measure changes in epigenetic marks on the genome that correlate with age. Greater epigenetic change at a given chronological age indicates a greater burden of biological aging, more damage and dysfunction. It remains to be determined with any great rigor as to exactly which damage and dysfunction causes any given set of epigenetic changes, which makes it challenging to use epigenetic age as a measure of success in the development of rejuvenation therapies. Development continues apace, however. For example, researchers here show that second generation epigenetic clocks show a greater correlation with risk of cancer than is the case for first generation clocks.

DNA methylation is one of the key mechanisms thought to underlie the association between aging and cancer. Biological aging measures derived from blood DNA methylation - taking advantage of varying rates of aging-associated methylation changes between individuals - have gained considerable popularity as tools to better understand and predict disease. We previously investigated the association between 5 "first-generation" measures of epigenetic aging and the risk of 7 cancer types using data from the Melbourne Collaborative Cohort Study (MCCS). The observed associations were relatively weak compared with those obtained for all-cause mortality; cancer risk overall was increased by 4%-9% per 5-year increase in methylation "age acceleration," although these estimates varied by cancer type.

Two novel methylation-based measures of biological aging, called PhenoAge and GrimAge, have been developed based on associations of DNA methylation with, for PhenoAge, age, mortality, and clinical biomarkers; and for GrimAge, smoking pack-years and plasma concentrations of adrenomedullin, beta-2 microglobulin, cystatin C, growth differentiation factor 15, leptin, plasminogen activation inhibitor 1, and tissue inhibitor metalloproteinase 1. These new measures have proved to be more strongly associated with mortality than the first-generation measures. This study assessed cancer risk associations for 3 recently developed methylation-based biomarkers of aging: PhenoAge, GrimAge, and predicted telomere length.

We observed relatively strong associations of age-adjusted PhenoAge with risk of colorectal, kidney, lung, mature B-cell, and urothelial cancers. Similar findings were obtained for age-adjusted GrimAge, but the association with lung cancer risk was much larger, after adjustment for smoking status, pack-years, starting age, time since quitting, and other cancer risk factors. Most associations appeared linear, larger than for the first-generation measures, and were virtually unchanged after adjustment for a large set of sociodemographic, lifestyle, and anthropometric variables.



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