Mutation-dependent responses to sleep and exercise in clonal haematopoiesis

Clonal haematopoiesis (CH) activates inflammation and increases the risk of atherosclerosis 1 , 2 . Whether lifestyle alters CH clone expansion or the phenotypic programming of CH mutant cells, thereby affecting atherosclerosis, is unknown. Here, in humans and mice and across mutations in Jak2 , Tet2 , Trp53 and Dnmt3a , we demonstrate mutation-dependent responses to sleep and exercise in CH and show that mutant cells are uniquely sensitive to lifestyle. In two human datasets, moderate-to-vigorous physical activity was associated with lower prevalence of non- DNMT3A -driven CH. In atherogenic mice with Jak2 V617F or Tet2 loss of function (LOF), but not Tr p53 LOF or Dnmt3a R878H CH, uninterrupted sleep or exercise curtails clone expansion. In CH with the Jak2 V617F mutation, sleep and exercise reduces clone expansion by selectively reprogramming mutant, but not cohabitant wild type, haematopoietic progenitor cells towards antiproliferative and metabolically healthy phenotypes by tempering bone marrow macrophage–haematopoietic progenitor cell IL-1β signalling. Sleep or exercise also lessens Jak2 V617F -driven, Tet2 LOF-driven and Tr p53 LOF-driven, but not Dnmt3a R878H - driven, atherosclerosis by locally reprogramming mutant vascular macrophages, independent of peripheral clone dynamics. In Jak2 V617F , but not adjacent wild type, aortic macrophages, uninterrupted sleep blunts CLEC4E-dependent inflammasome activation, consequently diminishing lesions. Exercise, meanwhile, activates PAC1 + neurons in the locus coeruleus, raising the levels of peripheral noradrenaline, which signals through adrenergic receptor β2 (ADRβ2) whose expression is preserved by exercise in Jak2 V617F , but not cohabitant wild type, aortic macrophages, selectively repressing their inflammatory programming and atherosclerosis. Our findings establish that healthy lifestyles gene-specifically diminish CH and selectively reprogram mutant haematopoietic progenitor cells and macrophages to maintain cardiovascular health.