Refining epigenetic prediction of chronological and biological age

Epigenetic clocks can track both chronological age (cAge) and biological age (bAge). The latter is typically defined by physiological biomarkers and risk of adverse health outcomes, including all-cause mortality. As cohort sample sizes increase, estimates of cAge and bAge become more precise. Here, we aim to refine predictors and improve understanding of the epigenomic architecture of cAge and bAge. First, we perform large-scale (N = 18,413) epigenome-wide association studies (EWAS) of chronological age and all-cause mortality. Next, to improve cAge prediction, we use methylation data from 24,673 participants from the Generation Scotland (GS) study, the Lothian Birth Cohorts (LBC) of 1921 and 1936 and 8 publicly available datasets. Through the inclusion of linear and non-linear age-CpG associations from the EWAS, feature pre-selection/dimensionality reduction in advance of elastic net regression, and a leave-one-cohort-out (LOCO) cross validation framework, we arrive at an improved cAge predictor (median absolute error = 2.3 years across 10 cohorts). In addition, we train a predictor of bAge on 1,214 all-cause mortality events in GS, based on epigenetic surrogates for 109 plasma proteins and the 8 component parts of GrimAge, the current best epigenetic predictor of all-cause mortality. We test this predictor in four external cohorts (LBC1921, LBC1936, the Framingham Heart Study and the Womens Health Initiative study) where it outperforms GrimAge in its association to survival (HRGrimAge = 1.47 [1.40, 1.54] with p = 1.08 x 10-52, and HRbAge = 1.52 [1.44, 1.59] with p = 2.20 x 10-60). Finally, we introduce MethylBrowsR, an online tool to visualize epigenome-wide CpG-age associations.