Performance of cellular senescence measure, p16, and DNA methylation clocks in a clinically relevant model of age acceleration

Cellular senescence and DNA methylation are primary aging mechanisms emerging as a potential means of monitoring human aging and evaluating interventions thought to either accelerate or slow an individual's aging trajectory. However, it is largely unknown whether cellular senescence and signatures of methylation of the specific CpG islands that comprise various epigenetic clocks correlate in humans. We have measured the cellular senescence biomarker, p16 and the five most used epigenetic aging clocks in 251 patients with breast cancer, 49 age-matched non-cancer controls, and 48 patients undergoing cytotoxic chemotherapy treatment. Chemotherapy, a known clinically-relevant inducer of aging, increased expression of p16 but not levels of the most common epigenetic clocks (DNAm-Horvath, PhenoAge, GrimAge, mPoA), with the exception of DNAm-Hannum. Chemotherapy-induced changes in p16 were associated with increased levels of a subset of SASPs, PARC, TNFRII, ICAM1, and TNFa. Cross-sectionally, there was weak to no correlation between p16 expression and epigenetic clocks in cancer patients or non-cancer controls. GrimAge and PhenoAge were the most correlated with p16 (r<0.3), with no correlation between p16 and the pace of aging epigenetic clock. Together, these data show that there is a general discordance between measures of cellular senescence and epigenetic clocks with the senescence marker p16 but not epigenetic clocks of aging responding to a clinically relevant inducer of human aging, cytotoxic chemotherapy.