Association of clonal hematopoiesis driven by mosaic chromosomal alterations with epigenetic age in the PLCO trial.

10556 Background: Mosaic chromosomal alterations (mCAs) are age-associated clonal events detectable in peripheral blood and have been linked to hematologic malignancy risk and adverse clinical outcomes. Whether mCAs are associated with accelerated biological aging, as measured by DNA methylation–based epigenetic clocks, remains poorly understood. Methods: We analyzed peripheral blood DNA methylation data generated using the Illumina EPIC array from 482 participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. mCAs were identified from SNP array data and classified by subtype, including autosomal copy-neutral loss of heterozygosity (CN-LOH), gains, losses, and loss of the sex chromosome . Epigenetic age was estimated using six established DNA methylation clocks: Hannum, Horvath pan-tissue/skin and blood, PhenoAge, GrimAge & DunedinPACE. Associations between mCA presence, mCA subtype, clonal burden, and epigenetic age acceleration were evaluated using multivariable linear regression models adjusted for age, sex, smoking status, body mass index, and genetic ancestry. Results: Among 482 participants, 261 were mCA-free and 221 had at least one detectable mCA. Individuals with any detectable mCA exhibited higher epigenetic age acceleration than mCA-free individuals across multiple clocks, with the most consistent effect sizes across mCA subtypes observed for GrimAge. Although age acceleration was directionally higher among individuals with mCAs across all non–rate-based clocks, statistically significant differences were observed only for the Hannum, PhenoAge, and GrimAge clocks. For GrimAge, estimated effects for mCA-positive individuals were uniformly positive, except for gain-only events, with effect sizes ranging from 1.2 to 1.9 years of age acceleration. Age acceleration increased with clonal burden: participants with multiple mCAs (n = 51) exhibited greater age acceleration than those with a single mCA (n = 170), particularly for GrimAge and PhenoAge. Higher cellular fraction was also associated with increased age acceleration, with significant associations observed for GrimAge (β = 2.97, 95% CI 0.82–5.12, p = 0.007) and Hannum (β = 4.25, 95% CI 1.14–7.37, p = 0.008) clocks. Conclusions: Mosaic chromosomal alterations, particularly CN-LOH and higher clonal burden states, are associated with accelerated biological aging in peripheral blood leukocytes. Epigenetic age acceleration was most consistently observed using GrimAge, a mortality- and healthspan-associated clock, with more variable and less consistent associations observed for chronological age-trained and rate-based clocks. These findings suggest that epigenetic age acceleration may represent a clinically relevant feature of clonal hematopoiesis, warranting further investigation in aging populations. Funded by NCI Contract No. 75N91019D00024.