Background: Clonal hematopoiesis (CH), the age-related expansion of mutated hematopoietic stem cells, is a newly recognized and potent risk factor for atherosclerosis and a major determinant of cardiovascular mortality. Mutations in JAK2, TET2, and TP53 are among the most pro-atherogenic, yet no preventive strategy currently targets this genetic cardiovascular risk. Lifestyle factors such as sleep and exercise profoundly influence cardiometabolic health, but whether they modulate CH clone dynamics and their inflammatory programming remains unknown.
Aim: To determine how sleep and exercise modulate CH clone dynamics and CH-driven atherosclerosis via neuroimmune and systemic pathways.
Methods: We analyzed two independent population cohorts, UK Biobank (n > 400,000) and All of Us (n > 90,000), to test associations between lifestyle behaviors, CH prevalence, and cardiovascular events. In mechanistic studies, we used Ldlr–/–mice reconstituted with 10% mutant (Jak2V617F, Tet2–/–, or p53–/–) or wild-type (control) bone marrow and exposed them to voluntary exercise, tactile sleep fragmentation (SF), or sedentary housing for 12 weeks. Complementary in vivo perturbation experiments targeting inflammatory, immune, and adrenergic pathways, together with bulk and single-cell RNA sequencing, metabolic profiling, and neural activation mapping, defined causal mechanisms linking lifestyle to CH and vascular inflammation.
Results: Across both human cohorts, exercise was associated with lower CH prevalence and mitigated CH-related cardiovascular risk. In mice, SF accelerated, whereas exercise constrained, Jak2 and Tet2 clone expansion by reprogramming HSC proliferation and metabolism, selectively affecting mutant but not wild-type hematopoiesis. SF amplified CLEC4E-dependent inflammasome activation and IL-1β release in Jak2V617F aortic macrophages, promoting plaque growth and necrosis. Conversely, exercise activated PAC1⁺ neurons in the locus coeruleus, increased norepinephrine, and reprogrammed Jak2V617F macrophages via β₂-adrenergic signaling toward a reparative phenotype. Genetic and pharmacologic pathway inhibition confirmed these causal links. p53 CH remained unresponsive to either intervention.
Conclusions: Sleep and exercise differentially shape CH clone behavior and atherogenesis through brain–body neuroimmune circuits. These effects are not universal but depend on the underlying CH mutation. Our findings reveal a mechanistic basis through which lifestyle modifies genetic cardiovascular risk and open new avenues for personalized prevention.
