Lifestyle choices such as adequate sleep and regular exercise may play a role in mitigating the risks associated with clonal hematopoiesis (CH), a condition linked to inflammation and an increased risk of atherosclerosis. New research suggests that these habits can gene-specifically impact CH clone expansion and the behavior of mutant cells, thereby influencing the development of cardiovascular disease.
Mutation-Dependent Responses
The study, conducted in both humans and mice, examined mutations in genes including Jak2, Tet2, Trp53, and Dnmt3a. Findings indicate that the responses to sleep and exercise are dependent on the specific mutation present in CH. In human datasets, moderate to vigorous physical activity was associated with a lower prevalence of CH driven by mutations other than in DNMT3A. In mice engineered with specific CH mutations (Jak2V617F or Tet2 loss of function), uninterrupted sleep or exercise was found to curtail clone expansion, although this effect was not observed in mice with Trp53 or Dnmt3aR878H mutations.
Cellular Reprogramming and Atherosclerosis
For CH characterized by the Jak2V617F mutation, both sleep and exercise were shown to reduce clone expansion. This was achieved by selectively reprogramming mutant hematopoietic progenitor cells, not their wild-type counterparts, towards phenotypes that inhibit proliferation and promote metabolic health. This reprogramming appears to be mediated by tempering inflammatory signaling, specifically IL-1β, between bone marrow macrophages and hematopoietic progenitor cells.
Furthermore, sleep or exercise demonstrated an ability to lessen atherosclerosis driven by Jak2V617F, Tet2 loss of function, and Trp53 loss of function mutations, but not by Dnmt3aR878H mutations. This reduction in atherosclerosis occurred through the local reprogramming of mutant vascular macrophages, independent of the overall dynamics of clones in the peripheral blood.
Mechanisms of Action
In the context of Jak2V617F mutations, uninterrupted sleep was found to blunt inflammasome activation in aortic macrophages, a process dependent on CLEC4E. This blunting consequently diminished atherosclerotic lesions. Exercise, on the other hand, was observed to activate specific neurons in the locus coeruleus, leading to increased levels of noradrenaline. This neurotransmitter signals through the beta-2 adrenergic receptor (ADRβ2), whose expression is maintained by exercise in Jak2V617F mutant aortic macrophages but not in adjacent wild-type macrophages. This selective signaling mechanism reportedly represses inflammatory programming and reduces atherosclerosis in these mutant cells.
These findings collectively establish that healthy lifestyle choices can gene-specifically diminish CH and selectively reprogram mutant hematopoietic progenitor cells and macrophages. This targeted cellular reprogramming may be a key mechanism by which lifestyle contributes to maintaining cardiovascular health in individuals with CH.
Steve Lopez is the Editorial Page Editor for News Raise. He covers Health. He has won more than a dozen national journalism awards for his reporting and column writing at seven newspapers and four news magazines.
