Project Summary With age, dividing cells acquire DNA mutations. A small number of these somatic mutations confer a selective advantage leading to clonal outgrowth. In blood, this process is termed ‘clonal hematopoiesis’ (CH) which includes both point mutations in cancer driver genes (eg. clonal hematopoiesis of indeterminate potential ‘CHIP’) and megabase-scale deletions, duplications and copy-neutral loss-of-heterozygosity (eg, mosaic chromosomal alterations, ‘mCAs’). CH is associated with mortality, infection, cardiovascular disease, cancer and other aging diseases with differential mutations conferring different risk. CH is commonly found in extremely aged individuals implying that a set of individuals have resiliency to CH. Here we seek to identify Clonal Hematopoiesis Aging Resilience Mechanisms (CHARMs). CH clones that expand to make up a larger proportion of the blood confer worse health outcomes. However, we do not know what factors predict the rate of clonal expansion, how rate expansion associates with disease outcomes and whether CH confers differential disease risk across the lifespan. Overall, we hypothesize that CH with higher rates of clonal expansion confer a greater impact on health and that the propensity to expand has genetic and environmental underpinnings. A barrier to addressing this gap is a paucity of large-scale collections of longitudinally-sampled blood. Our team has two recent accomplishments that enable us to address this gap: 1) a survey of CH in >800,000 genomes and 2) development of a novel computational method to estimate the rate of CH expansion from a single timepoint rather than requiring serial samples. The project comprises three key aims: In Aim 1, we will apply a computational method called PACER, which estimates CH expansion rates from a single genome sequenced blood sample to >1.6 Million individuals. This approach allows for the identification of inherited genetic factors that confer resilience to CH expansion. In Aim 2, we will focus on the role of circulating proteins, metabolites, and medications in modulating CH expansion. In vitro and in vivo models will be used to elucidate the mechanisms underlying these CHARMs. In Aim 3, we seek to comprehensively assess the impact of CH on health and disease across the entire human lifespan. By studying two large and diverse cohorts, NIH All of Us (N~750,000) and Vanderbilt BioVU (N~250,000), encompassing individuals that span the entire lifespan from birth to centenarians, the project will analyze the relationship between CH and aging diseases. Our multidisciplinary team with deep expertise in CH, human genomics, experimental hematology, and genetic epidemiology is uniquely poised to accomplish this scientific program. Successful execution of these aims has the potential to improve risk models to stratify individuals with CH for personalized prevention interventions. Additionally, each CHARM we identify would be a potential target for therapeutic development.