Limited Generalizability of Epigenetic Clocks and Scores Across Pediatric Tissues and Age Ranges

Epigenetic clocks and scores have been investigated as potential biomarkers of later-life health outcomes following early-life exposures. In pediatric settings, DNA methylation (DNAm) is often measured in saliva; however, most clocks and scores have been trained in adult blood. Therefore, we assessed the performance, correlation, longitudinal stability, and association with early-life adversity (ELA) for established epigenetic measures in matched pediatric blood and saliva samples. Leveraging the Kids2Health cohort of 291 children (3-12 years, 56% exposed to ELA), we assessed DNAm (Illumina EPICv2) from matched blood and saliva. We calculated 22 commonly used epigenetic measures (chronological and biological clocks, scores for body mass index [BMI], C-reactive protein [CRP], cognition, maternal smoking, telomere length) and compared them with corresponding measured phenotypes (chronological age, BMI, CRP, IQ, telomere length). Overall, performance of epigenetic clocks and scores in children varied widely. Nine epigenetic measures were significantly and equally correlated with their corresponding phenotype across tissues. Six measures were highly correlated between blood and saliva (r[≥]0.7). All age acceleration estimates showed low to moderate cross-tissue correlations (r=0.20-0.68). Epigenetic scores indicating lower cognitive ability and elevated inflammation were associated with ELA and low SES in both tissues. We additionally provide epigenome-wide blood-saliva correlations across 815,069 CpGs. The results indicate limited generalizability of adult-trained epigenetic clocks and scores to pediatric blood and saliva, even when accounting for cell type composition. We advise caution for cross-tissue and cross-age-range applications of epigenetic measures in research and clinical settings and provide a resource to optimize epigenetic biomarkers in children.