Anatomical Society Summer Meeting 2024 From Organ Homeostasis to Healthspan: 25th Anniversary of Aging Cell. 24th—26th July 2024

The prevalence of clonal haematopoiesis of indeterminate potential (CHIP) in healthy individuals increases rapidly from age 60 onwards and has been associated with increased risk for malignancy, heart disease and ischemic stroke.CHIP is driven by somatic mutations in stem cells that are also drivers of myeloid malignancies.We previously set out to quantify the fitness effects of CHIP drivers over a 12-year timespan in older age, using longitudinal error-corrected sequencing data.Two key results support the possibility for individualised clinical monitoring of CHIP: (i) We developed a new filtering method to extract fitness effects from longitudinal data using Bayesian inference, whilst taking into account individual mutational context and co-occurrence of mutations, and thus quantify the growth potential of variants within each individual.This method of CHIP calling outperforms the currently used, arbitrary 2% variant allele frequency cut-off and majorly identifies growing variants.(ii) We show that gene-specific fitness differences can outweigh inter-individual variation and therefore could form the basis for personalised clinical management in the future.We now compare the mutational spectrum and stem cell fitness between participants aged 80 years and above and participants below the age of 75 years in three independent, longitudinal cohorts of aging.We can show differential fitness effects depending on the co-occurrence of mutations and link those effects to outcomes.