Epigenetic measures of ageing predict the prevalence and incidence of leading causes of death and disease burden

Abstract

Background: Individuals of the same chronological age display different rates of biological ageing. A number of measures of biological age have been proposed which harness age-related changes in DNA methylation profiles. These measures include five 'epigenetic clocks' which provide an index of how much an individual's biological age differs from their chronological age at the time of measurement. The five clocks encompass methylation-based predictors of chronological age (HorvathAge, HannumAge), all-cause mortality (DNAm PhenoAge, DNAm GrimAge) and telomere length (DNAm Telomere Length). A sixth epigenetic measure of ageing differs from these clocks in that it acts as a speedometer providing a single time-point measurement of the pace of an individual's biological ageing. This measure of ageing is termed DunedinPoAm. In this study, we test the association between these six epigenetic measures of ageing and the prevalence and incidence of the leading causes of disease burden and mortality in high-income countries (n ≤ 9537, Generation Scotland: Scottish Family Health Study). Results: DNAm GrimAge predicted incidence of clinically diagnosed chronic obstructive pulmonary disease (COPD), type 2 diabetes and ischemic heart disease after 13 years of follow-up (hazard ratios = 2.22, 1.52 and 1.41, respectively). DunedinPoAm predicted the incidence of COPD and lung cancer (hazard ratios = 2.02 and 1.45, respectively). DNAm PhenoAge predicted incidence of type 2 diabetes (hazard ratio = 1.54). DNAm Telomere Length associated with the incidence of ischemic heart disease (hazard ratio = 0.80). DNAm GrimAge associated with all-cause mortality, the prevalence of COPD and spirometry measures at the study baseline. These associations were present after adjusting for possible confounding risk factors including alcohol consumption, body mass index, deprivation, education and tobacco smoking and surpassed stringent Bonferroni-corrected significance thresholds. Conclusions: Our data suggest that epigenetic measures of ageing may have utility in clinical settings to complement gold-standard methods for disease assessment and management.

Epigenetic age acceleration is associated with cardiometabolic risk factors and clinical cardiovascular disease risk scores in African Americans

“…Our findings are in line with the literature in cohorts of European ancestry, showing that GrimAA outperforms other measures in its association with CVD incidence [ 21 , 22 ]. The effect size of GrimAA on CVD incidence appears to be remarkably similar across studies in European ancestry, and similar to our estimate in African Americans.…”

“…The effect size of GrimAA on CVD incidence appears to be remarkably similar across studies in European ancestry, and similar to our estimate in African Americans. Comparing the same four measures of epigenetic acceleration that we investigated, Hillary et al found that over thirteen years of follow-up, GrimAA outperforms the other measures in terms of its association with incidence of heart disease (HR: 1.41, 95% CI 1.18–1.68, per 1 SD) [ 21 ]. Wang et al found that a 1 SD increase in GrimAA was associated with elevated risk of myocardial infarction (HR: 1.44, 95% CI 1.16–1.79) and stroke (HR: 1.42, 95% CI 1.06–1.91) in a study of elderly participants from the Normative Ageing Study and the Cooperative Health Research in the Region of Augsburg (KORA) study [ 22 ].…”

“…PhenoAge and GrimAge are more recently developed measures, and so validation of their associations and comparisons to the first-generation measures are in early stages. Two recent studies in participants of European ancestry show that GrimAA outperforms other measures in its association with CVD incidence after adjusting for CVD risk factors [ 21 , 22 ], and additional studies report similar findings with all-cause mortality [ 21 – 24 ]. Yet it is unclear whether epigenetic age acceleration measures could be used to improve CVD prediction in a clinical setting.…”

“…A growing body of literature has examined the association between epigenetic age acceleration and CVD and its risk factors, such as blood pressure and lipids, but the overall evidence remains inconclusive likely due to heterogeneity in study design, the specific outcomes examined, and the epigenetic aging measures used [ 12 – 21 ]. PhenoAge and GrimAge are more recently developed measures, and so validation of their associations and comparisons to the first-generation measures are in early stages.…”

Whole blood DNA methylation aging markers predict colorectal cancer survival: a prospective cohort study

“…Previous studies have shown that Horvath’s and Hannum’s algorithms are statistically significantly associated with all-cause mortality in older general populations [ 20 – 23 ]. Consistent with our findings, DNAmMRsocre, PhenoAge and GrimAge outperformed the first generation of DNAm aging algorithms regarding mortality prediction [ 8 , 9 , 24 – 26 ]. Few studies have focused on the prognostic values of DNAm aging algorithms among cancer patients.…”