Abstract A016: DNA methylation variability in aging and Clonal Hematopoiesis

Abstract DNA methylation (DNAm) reflects regions of the genome that are transcriptionally repressed or active depending on the methylation level. Multitudes of DNAm “clocks” have been created to predict biological age and health outcomes. Deviations in biological age from chronological age reflect an alteration in the normal biological aging process. Clonal hematopoiesis of indeterminate potential (CHIP) arises in hematopoietic stem cells that have accumulated somatic mutations in key driver genes which provide a selective advantage for clonal expansion. Subjects with CHIP mutations are more prone to negative clinical outcomes such as coronary heart disease. While DNAm and CHIP have been studied for the past decade, the associations between the two are only now starting to become apparent. In this study we propose an improved measurement of aging based on the Jenson-Shannon distance (JSD) and associate this measurement with CHIP and adverse clinical outcomes. Bisulfite amplicon sequencing of 20 CpG-rich targets that change in methylation with age was performed on an initial cohort of 155 individuals from the National Institute of Neurological Disorders and Stroke (NINDS). JSD was used to construct a DNA methylation chaos clock (DMC) on these targets. DMC provided better predictions of chronological age than DNAm alone (r=0.9; p<0.0001). We validated our findings in 286 individuals from Cooper University Hospital for Management of Trauma where the accuracy of the DMC was confirmed in correlations of predicted vs actual age (r=0.86; p<0.0001). We next examined the association between DMC age acceleration and clinical outcomes. It was found that in individuals over the age of 50, DMC acceleration was associated with smoking and disease incidence (e.g. congestive heart failure and chronic obstructive pulmonary disease) independent of chronological age. The incidence of CHIP mutations in three key driver genes (DNMT3A, TET2, and ASXL1) was assayed in a subset of 345 individuals from both cohorts. Individuals with CHIP mutations in key driver genes had greater deviations in their predicted age than individuals without CHIP mutations (p<0.001). This study demonstrates that the DMC assay is a candidate for improvements in our measurements of biological age and it reflects important changes in an individual’s biological aging process. Citation Format: Anthony J Pompetti, Woonbok Chung, Jaroslav Jelinek, Tanya Egodage, Jean-Pierre Issa. DNA methylation variability in aging and Clonal Hematopoiesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr A016.