Prediction of biological age and evaluation of genome-wide dynamic methylomic changes throughout human aging

Abstract

The use of DNA methylation signatures to predict chronological age and aging rate is of interest in many fields, including disease prevention and treatment, forensics, and anti-aging medicine. Although a large number of methylation markers are significantly associated with age, most age-prediction methods use a few markers selected based on either previously published studies or datasets containing methylation information. Here, we implemented reproducing kernel Hilbert spaces (RKHS) regression and a ridge regression model in a Bayesian framework that utilized phenotypic and methylation profiles simultaneously to predict chronological age. We used over 450,000 CpG sites from the whole blood of a large cohort of 4409 human individuals with a range of 10-101 years of age. Models were fitted using adjusted and un-adjusted methylation measurements for cell heterogeneity. Un-adjusted methylation scores delivered a significantly higher prediction accuracy than adjusted methylation data, with a correlation between age and predicted age of 0.98 and a root mean square error (RMSE) of 3.54 years in un-adjusted data, and 0.90 (correlation) and 7.16 (RMSE) years in adjusted data. Reducing the number of predictors (CpG sites) through subset selection improved predictive power with a correlation of 0.98 and an RMSE of 2.98 years in the RKHS model. We found distinct global methylation patterns, with a significant increase in the proportion of methylated cytosines in CpG islands and a decreased proportion in other CpG types, including CpG shore, shelf, and open sea (P < 5e-06). Epigenetic drift seemed to be a widespread phenomenon as more than 97% of the age-associated methylation sites had heteroscedasticity. Apparent methylomic aging rate (AMAR) had a sex-specific pattern, with an increase in AMAR in females with age related to males.