Clonal haematopoiesis of indeterminate potential and epigenetic age acceleration: Systematic review and meta-analysis

Abstract

Clonal haematopoiesis of indeterminate potential (CHIP) represents somatic mutations in haematopoietic stem cells that drive clonal expansion. Epigenetic age acceleration (EAA), estimated from DNA methylation (DNAm) clocks, may capture age-related changes in haematopoiesis. This systematic review and meta-analysis was conducted to synthesise evidence on associations between CHIP and EAA and explore shared biological mechanisms that may underlie this relationship. Six databases were searched from January 1, 2011, to June 6, 2025, adhering to PRISMA 2020. Random-effects meta-analyses were performed. Five studies comprising 7483 individuals (ages 55–79, 67.1% female) assessing associations between CHIP and DNAm clocks were included. Across studies, CHIP individuals had higher EAA than no-CHIP individuals, and larger clones were associated with higher EAA. Meta-analysis of three cross-sectional studies (n = 6946) showed that CHIP had higher EAA versus no-CHIP for Horvath1Age IEAA (mean difference, MD=2.84 years, 95% confidence interval, CI: 1.49–4.19), HannumAge EEAA (MD=2.31 years, 95% CI: 1.14–3.49), PhenoAge (MD=1.84 years, 95% CI: 0.96–2.71), and GrimAge (MD=1.20 years, 95% CI: 0.80–1.61). Both DNMT3A - and TET2 -mutated CHIP were associated with higher EAA with TET2 -mutated CHIP showing larger effect sizes and more consistent associations than DNMT3A -mutated CHIP across DNAm clocks tested. Higher EAA may also act as an effect modifier for morbidity and mortality in CHIP. Larger longitudinal studies are needed to verify a temporal relationship and determine whether EAA provides incremental prognostic value for morbidity and mortality in CHIP.