Longevity & Aging

Blood Stem Cell Mutations Accelerate Aortic Valve Calcification via Inflammatory Macrophages

Clonal hematopoiesis (CH) — age-related somatic mutations in blood stem cells — is linked to a significantly elevated risk of aortic valve stenosis (AVS). Analyzing over 886,000 participants across three biobanks, researchers found that CHIP carriers had a 38% higher risk of AVS, with TET2 and ASXL1 mutations conferring the greatest risk. Single-cell RNA sequencing of immune cells from AVS patients revealed that TET2-mutant monocytes display heightened proinflammatory and procalcific gene signatures, most notably overexpressing oncostatin M (OSM). TET2-silenced macrophage secretions drove calcium deposition in mesenchymal cells in vitro, an effect abolished by OSM knockdown. Mouse models receiving TET2-deficient bone marrow transplants showed greater aortic valve calcification, mechanistically linking CH to AVS pathogenesis.