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.

Keywords: Biological ageing; DNA methylation; Epidemiology; Epigenetic age acceleration.

Fig. 1

The associations between epigenetic measures of ageing and disease prevalence, continuous traits and all-cause mortality in Generation Scotland. Only associations present in discovery and replication sets are shown, and replication test statistics are presented. Continuous: Age-adjusted DNAm GrimAge was associated with greater deprivation (lower SIMD rank), reduced forced expiratory flow and forced expiratory volume. Age-adjusted DNAm GrimAge was positively associated with serum creatinine levels and average heart rate. Age-adjusted DNAm PhenoAge was positively associated with body mass index, average heart rate and smoking pack years. Age-adjusted DNAm Telomere Length was negatively associated with smoking pack years. Higher values for DunedinPoAm were associated with greater deprivation (lower SIMD rank), a higher average heart rate and smoking pack years. Age-adjusted Hannum Age was positively associated with serum creatinine levels. Disease: Age-adjusted DNAm GrimAge alone was associated with the prevalence of COPD in both discovery and replication sub-cohorts after correction for multiple testing. All-Cause Mortality: Age-adjusted DNAm GrimAge alone was associated with all-cause mortality in both sets after multiple testing correction. Associations represent a one standard deviation increase in the respective measure of biological ageing. Models were adjusted for age, sex, alcohol consumption, body mass index, deprivation, education and smoking. Models involving lung function tests were also corrected for height. COPD (chronic obstructive pulmonary disease), SIMD (Scottish Index of Multiple Deprivation)

Fig. 2

The associations between epigenetic measures of ageing and incidence of common disease states in Generation Scotland. Age-adjusted DNAm GrimAge was associated with the incidence of COPD, type 2 diabetes and ischemic heart disease after 13 years of follow-up. Age-adjusted DNAm PhenoAge associated with the incidence of type 2 diabetes. Age-adjusted measures of DNAm Telomere Length associated with the incidence of ischemic heart disease. Higher DunedinPoAm values, indicating a faster pace of ageing, were associated with the incidence of COPD and lung cancer. Associations represent a one standard deviation increase in the respective epigenetic measure of ageing. Models were adjusted for age, sex, alcohol consumption, body mass index, deprivation, education and smoking. COPD (chronic obstructive pulmonary disease)