Project

Aging is accompanied by a range of alterations of the immune system, collectively termed immunosenescence, which contribute significantly to the development of age-associated diseases. However, the mechanisms by which aging modulates immune function remain poorly understood. One hallmark of aging is the accumulation of somatic mutations in human cells, leading to the expansion of clonal populations across various tissues. Despite this, the impact of age-related clonal hematopoiesis on immune responses has not been thoroughly investigated. In this study, we aim to determine the prevalence and immunological consequences of clonal hematopoiesis of indeterminate potential (CHIP) within the Milieu Intérieur longitudinal cohort. To identify rare somatic events, we will perform targeted deep sequencing (1000× coverage) of 91 genes known to be associated with CHIP, in 415 participants aged 30 to 80 years—sampled at two time points a decade apart, allowing to distinguish somatic from germline mutations. We will assess associations between somatic mutation load and key immune parameters, including blood cell composition, transcriptional responses to pathogen stimulation, and chromatin accessibility, leveraging single-cell transcriptomic and epigenomic data from the same individuals. This project aims to elucidate how DNA replication errors contribute to the progressive decline of immune function with age, providing insights into the molecular underpinnings of immunosenescence.