美国西奈山伊坎医学院Cameron S. McAlpine课题组的最新研究揭示了克隆造血中对睡眠和运动的突变依赖性反应。该项研究成果发表在2026年6月10日出版的《自然》上。

在人类和小鼠中，通过Jak2、Tet2、Trp53和Dnmt3a的突变，研究人员证明了CH对睡眠和运动的突变依赖反应，并表明突变细胞对生活方式非常敏感。在两个人类数据集中，中等至剧烈的身体活动与非Dnmt3a驱动的CH患病率较低相关。在有Jak2^V617F或Tet2功能丧失（LOF），但没有Trp53 LOF或Dnmt3a^R878H CH的动脉粥样硬化小鼠中，不间断的睡眠或运动可抑制克隆扩增。

在Jak2^V617F突变的CH中，睡眠和运动通过选择性地重编程突变而不是共存的野生型造血祖细胞，通过调节骨髓巨噬-造血祖细胞IL-1β信号传导，减少克隆扩增，使造血祖细胞向抗增殖和代谢健康表型转变。睡眠或运动也会减少Jak2^V617F驱动、Tet2 LOF驱动和Trp53 LOF驱动的动脉粥样硬化，但不会减少Dnmt3a^R878H驱动的局部重编程突变血管巨噬细胞，不依赖于外周克隆动力学。

在Jak2^V617F中，而不是邻近的野生型，主动脉巨噬细胞，不间断的睡眠会减弱CLEC4E依赖性炎性体的激活，从而减少病变。同时，运动激活局部的PAC1⁺神经元，提高外周去甲肾上腺素的水平，去甲肾上腺素通过肾上腺素能受体β2 （ADRβ2）发出信号，而ADRβ2的表达在Jak2^V617F中被保留，而不是共存的野生型主动脉巨噬细胞，选择性地抑制其炎症程序和动脉粥样硬化。他们的研究结果表明，健康的生活方式基因特异性地减少CH，并选择性地对突变的造血祖细胞和巨噬细胞进行重编程，以维持心血管健康。

据悉，克隆造血（CH）激活炎症，增加动脉粥样硬化的风险。生活方式是否会改变CH克隆扩增或CH突变细胞的表型编程，从而影响动脉粥样硬化，目前尚不清楚。

附：英文原文

Title: Mutation-dependent responses to sleep and exercise in clonal haematopoiesis

Author: Gerhardt, Teresa, Jacob, Walter, Gaebel, Lena, Heiser, Merlin, Wolfram, Christopher, Huynh, Pacific, Nakao, Tetsushi, Gindri Dos Santos, Bernardo, Toh, Pamela, Douglas, Aaron, Brisnovali, Niki F., Radkevich, Emir, Uddin, Md Mesbah, Yates, Abi G., Khamhoung, Annie, Yatim, Nader, Gianeselli, Matteo, Kiss, Mt G., Goswami, Sukanya, Nelson, Daniella, Chen, Rachel, DSouza, Darwin, Chen, Zhihong, Kim-Schulze, Seunghee, Fidler, Trevor, Ezzat, Daniel, Khurshid, Shaan, Bick, Alexander G., Natarajan, Pradeep, Ellinor, Patrick T., Rajbhandari, Abha K., Merad, Miriam, Swirski, Filip K., Cohen, Oren, Goedeke, Leigh, Honigberg, Michael C.

Issue&Volume: 2026-06-10

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.

DOI: 10.1038/s41586-026-10634-0

Source: https://www.nature.com/articles/s41586-026-10634-0