Sleep and exercise selectively rein in mutant blood stem cells and protect arteries
Uninterrupted sleep and exercise curbed expansion of Jak2 and Tet2 mutant blood clones and reduced atherosclerosis in mice, while Dnmt3a clones did not respond.
Résumé
Clonal haematopoiesis (CH) is an age-related condition in which blood stem cells acquire mutations, expand, and raise atherosclerosis risk. This study asked whether lifestyle changes the course of CH. In two large human cohorts (UK Biobank and All of Us), more daily moderate-to-vigorous activity was linked to lower prevalence of non-DNMT3A CH, but not DNMT3A CH. In atherogenic mice, uninterrupted sleep and exercise slowed expansion of Jak2V617F and Tet2-deficient clones, while sleep fragmentation sped it up. Trp53 and Dnmt3aR878H clones did not respond in terms of expansion. Lifestyle selectively reprogrammed mutant cells, not neighbouring normal cells, through IL-1β signalling, CLEC4E inflammasome activity and noradrenaline-ADRβ2 signalling in vascular macrophages. The mouse findings are mechanistic, and the human data are associational.
Résumé détaillé
Clonal haematopoiesis arises when ageing blood stem cells acquire somatic mutations that give them a growth advantage. The resulting mutant immune cells are more inflammatory and raise atherosclerosis risk. Whether lifestyle can change how these clones expand, or how mutant cells behave, was unknown, and this paper addresses that gap.
The researchers first analysed UK Biobank and All of Us participants with accelerometer-measured activity and sequencing-based CH calls. Each additional hour per day of moderate-to-vigorous activity was associated with lower prevalence of non-DNMT3A CH (meta-analysed OR 0.86, 95% CI 0.78–0.95), with no association for DNMT3A CH. Results held after adjusting for BMI and in both sexes. In mice, the team built mixed bone marrow chimeras on an atherogenic Ldlr−/− background, with 10% mutant (Jak2V617F, Tet2 loss, Trp53 loss or Dnmt3aR878H) and 90% wild-type cells. Mice ate a high-cholesterol diet for 12 weeks and were sedentary, exercised on running wheels, or subjected to tactile sleep fragmentation.
Sleep fragmentation accelerated, and exercise abolished, expansion of Jak2V617F and Tet2-deficient clones. Trp53 and Dnmt3aR878H clones were unaffected. The effects were specific to mutant cells. Single-cell RNA sequencing showed that fragmentation raised proliferation genes in Jak2V617F progenitors, while exercise boosted oxidative metabolism genes and lowered proliferative ones. Neighbouring wild-type progenitors barely changed. Bone marrow macrophage IL-1β drove the effect, because Jak2V617F progenitors were hypersensitive to it and IL-1β blockade removed the fragmentation-induced expansion.
Lifestyle also altered atherosclerosis. Fragmentation enlarged lesions in Jak2V617F, Tet2 and Trp53 mice, and exercise reduced them in Jak2V617F and Tet2 mice. Exercise restored Jak2V617F lesion size to the level of mice without CH. Dnmt3aR878H lesions did not respond. In aortic Jak2V617F macrophages, fragmentation induced CLEC4E, inflammasome activation and cell death. Anti-CLEC4E antibody blocked the fragmentation-accelerated atherosclerosis without changing blood clone expansion. The abstract further reports that exercise activates PAC1+ locus coeruleus neurons, raising noradrenaline that signals through macrophage ADRβ2, though the supplied text ends before these data.
Together, the findings suggest that healthy lifestyles act gene-specifically on CH and may buffer cardiovascular risk in carriers of certain mutations. Caveats include the observational human data, the artificial chimeric mouse models and the 12-week intervention. The tactile sleep fragmentation model may also not reflect human sleep disruption, and no human intervention trial exists yet.
Principales conclusions
- Each extra hour/day of moderate-to-vigorous activity was linked to 14% lower odds of non-DNMT3A CH (meta-analysed OR 0.86), but not DNMT3A CH.
- In mice, exercise abolished Jak2V617F clone expansion, while sleep fragmentation accelerated it; Tet2-loss clones responded similarly.
- Trp53-loss and Dnmt3aR878H clones did not change their expansion with sleep fragmentation or exercise, showing mutation-specific lifestyle effects.
- Lifestyle reprogrammed only mutant progenitors and macrophages, and blocking IL-1β or CLEC4E removed the harm of sleep fragmentation.
- Exercise restored Jak2V617F atherosclerotic lesion size to the level of mice without CH.
Méthodologie
Human analyses used actigraphy-measured activity and CH calls from the UK Biobank (exome) and All of Us (genome), with adjusted logistic regression and meta-analysis. Mechanistic work used Ldlr−/− mixed bone marrow chimeras (10% mutant, 90% wild-type) on a high-cholesterol diet for 12 weeks, with exercise, sleep fragmentation or sedentary conditions. Methods included flow cytometry, scRNA-seq with CD45.1/CD45.2 oligo-tagging, antibody blockade (IL-1β, CLEC4E, Ly6G) and BMDM assays.
Limites de l'étude
Human findings are cross-sectional and associational, so causality and residual confounding remain open, and the All of Us result was borderline (P = 0.052). The mouse models use irradiation chimeras, inducible mutations, a Ldlr−/− high-cholesterol background and tactile sleep fragmentation, which limit translation to human sleep and exercise. The supplied text is truncated before the exercise-noradrenaline-ADRβ2 data, so that mechanism rests on the abstract.
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