Association of DNA Methylation-Based Biological Age With Health Risk Factors and Overall and Cause-Specific Mortality

Abstract

Measures of biological age based on blood DNA methylation, referred to as age acceleration (AA), have been developed. We examined whether AA was associated with health risk factors and overall and cause-specific mortality. At baseline (1990-1994), blood samples were drawn from 2,818 participants in the Melbourne Collaborative Cohort Study (Melbourne, Victoria, Australia). DNA methylation was determined using the Infinium HumanMethylation450 BeadChip array (Illumina Inc., San Diego, California). Mixed-effects models were used to examine the association of AA with health risk factors. Cox models were used to assess the association of AA with mortality. A total of 831 deaths were observed during a median 10.7 years of follow-up. Associations of AA were observed with male sex, Greek nationality (country of birth), smoking, obesity, diabetes, lower education, and meat intake. AA measures were associated with increased mortality, and this was only partly accounted for by known determinants of health (hazard ratios were attenuated by 20%-40%). Weak evidence of heterogeneity in the association was observed by sex (P = 0.06) and cause of death (P = 0.07) but not by other factors. DNA-methylation-based AA measures are associated with several major health risk factors, but these do not fully explain the association between AA and mortality. Future research should investigate what genetic and environmental factors determine AA.

DNA methylation‐based biological aging and cancer risk and survival: Pooled analysis of seven prospective studies

“…As in previous studies, we observed consistently stronger associations with both cancer risk and survival for measures derived from the Hannum predictor, which was validated using blood samples. Therefore, although measures derived from the Horvath predictor may be more generalizable because they have been validated across multiple tissue types, our findings indicate that a predictor validated on the tissue on which it is used might be preferable.…”

“…While several studies have assessed the association of age acceleration with mortality, there have been fewer analyses of cancer incidence and cancer survival. Levine et al .…”

“…The difference between predicted age and chronological age has been named “age acceleration” and interpreted in recent epidemiological and clinical studies as a marker of biological aging. Several studies have assessed the association between age acceleration and mortality . Few studies have examined whether the epigenetic clock is associated with the risk of cancer.…”

“…We previously found that age acceleration was associated with all‐cause mortality independently of major health risk factors . In this study, we aimed to assess associations of age acceleration with cancer risk and survival.…”

Age-dependent methylation in epigenetic clock CpGs is associated with G-quadruplex, co-transcriptionally formed RNA structures and tentative splice sites

“…Identification of the critical elements responsible for the loss of epigenetic surveillance is important for understanding the impact of CpG mutations, polymorphisms, and changes in their surrounding sequences and for designing appropriate diagnostic tools. A better understanding of the mechanisms underlying these processes will also help us identify the environmental factors that play a regulatory role in formulating our epigenome [11,47,48] and their effects on epigenetic heredity [49]. Moreover, it improves our understanding of the splicing and alternative splicing processes, which are still poorly understood [50–52].…”