2026-06-10 マウントサイナイ医療システム（MSHS）
Figure: Atherosclerosis in a mouse with clonal hematopoiesis. Atherosclerotic plaques in the aorta of a mouse with immune cells that contain clonal hematopoiesis mutations. Inflammatory proteins are labeled in red and yellow. Credit: Mount Sinai Health System.
＜関連情報＞
- https://www.mountsinai.org/about/newsroom/2026/healthy-sleep-and-regular-exercise-can-mitigate-the-genetic-cardiovascular-risk-of-mutant-white-blood-cells
- https://www.nature.com/articles/s41586-026-10634-0
クローン性造血における睡眠と運動に対する変異依存的な反応 Mutation-dependent responses to sleep and exercise in clonal haematopoiesis
Teresa Gerhardt,Walter Jacob,Lena Gaebel,Merlin Heiser,Christopher Wolfram,Pacific Huynh,Tetsushi Nakao,Bernardo Gindri Dos Santos,Pamela Toh,Aaron Douglas,Niki F. Brisnovali,Emir Radkevich,Md Mesbah Uddin,Abi G. Yates,Annie Khamhoung,Nader Yatim,Matteo Gianeselli,Máté G. Kiss,Sukanya Goswami,Daniella Nelson,Rachel Chen,Darwin D’Souza,Zhihong Chen,Seunghee Kim-Schulze,… Cameron S. McAlpine
Nature Published:10 June 2026
DOI:https://doi.org/10.1038/s41586-026-10634-0
Abstract
Clonal haematopoiesis (CH) activates inflammation and increases the risk of atherosclerosis1,2. 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 Jak2V617F or Tet2 loss of function (LOF), but not Trp53 LOF or Dnmt3aR878H CH, uninterrupted sleep or exercise curtails clone expansion. In CH with the Jak2V617F 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 Jak2V617F-driven, Tet2 LOF-driven and Trp53 LOF-driven, but not Dnmt3aR878H–driven, atherosclerosis by locally reprogramming mutant vascular macrophages, independent of peripheral clone dynamics. In Jak2V617F, 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 Jak2V617F, 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.
