A new study published June 10 in Nature has found that lifestyle factors , sleep quality and physical activity , can suppress the cardiovascular risk associated with certain age-related DNA mutations, but not all of them. The finding provides the first mechanistic explanation for why some people with “bad” genetic signatures remain healthy, while also revealing that the most common mutation of its kind is entirely resistant to lifestyle intervention.
The study, led by Teresa Gerhardt, MD (now at Goethe University Frankfurt, formerly a postdoc at Icahn Mount Sinai) and senior author Cameron S. McAlpine, PhD (Icahn School of Medicine at Mount Sinai), focused on clonal hematopoiesis (CH) , a phenomenon in which blood stem cells carrying somatic mutations expand over time, producing a significant fraction of the body’s blood cells. CH is incredibly common: by age 70, roughly 10-20% of people carry a detectable CH clone. And carrying one of the high-risk mutations , particularly in the genes JAK2 or TET2 , roughly doubles the risk of heart attack and stroke, independent of cholesterol, blood pressure, or any other traditional risk factor.
The central question: can lifestyle change interrupt this pathway?
The four mutations
The team tested four CH driver mutations , JAK2^V617F, TET2 (loss of function), TP53 (loss of function), and DNMT3A^R878H , each engineered into mice fed an atherogenic (high-cholesterol) diet. The mice were then assigned to either voluntary wheel running (many ran ~10 km per day) or sleep fragmentation (a motorized bar swept across the cage floor every few minutes, repeatedly nudging them awake).
The human arm of the study analyzed data from approximately 83,000 UK Biobank participants and 8,400 NIH All of Us participants , roughly 91,000 individuals total , looking at the relationship between self-reported sleep duration, physical activity, CH mutation carriage, and cardiovascular outcomes.
The mutation-specific results
The results were strikingly binary. In mice carrying JAK2^V617F or TET2 loss-of-function mutations, both exercise and normal sleep significantly curtailed the expansion of the mutant clone and reduced atherosclerotic plaque size compared to sedentary or sleep-deprived controls. In the human data, the proportion of individuals carrying non-DNMT3A CH mutations was approximately 13% lower among those reporting moderate-to-vigorous physical activity compared to sedentary individuals.
For TP53 loss-of-function mutations, exercise and sleep reduced atherosclerosis but did not slow the expansion of the mutant clone itself , the benefit was mediated through plaque biology rather than clonal suppression.
For DNMT3A^R878H , the single most common CH mutation in humans , neither exercise nor sleep had any detectable effect on clone expansion or atherosclerosis. The mutation was entirely resistant to lifestyle intervention.
The mechanism
The team traced the molecular pathways underlying the mutation-specific effects. For JAK2^V617F, exercise activated PAC1+ neurons in the locus coeruleus , a brainstem nucleus involved in arousal and stress responses , which increased peripheral noradrenaline. This signaling passed through the ADRB2 adrenergic receptor on mutant macrophages, decreasing inflammation and lesion size. Sleep, meanwhile, repressed CLEC4E signaling and inflammasome activation specifically in JAK2 mutant macrophages, sparing wild-type cells.
The mechanism explains why the effect is mutation-specific: different CH mutations hijack different inflammatory and metabolic pathways, and only some of those pathways are accessible to lifestyle modulation. DNMT3A mutations, it appears, operate through a route that sleep and exercise cannot reach.
What it means
The study has immediate implications for how doctors think about genetic and lifestyle risk. Clonal hematopoiesis is not tested for in routine clinical care, but the growing evidence of its cardiovascular impact has led some researchers to advocate for including CH screening in risk assessment. The new data suggest that such screening would need to be mutation-specific , the lifestyle advice you give to someone with a JAK2 mutation would be different from what you give to someone with DNMT3A.
“The finding that sleep and exercise can mitigate risk from some CH mutations is encouraging, but the resistance of DNMT3A mutations is a sobering counterpoint,” said Siddhartha Jaiswal, MD, PhD, an immunologist at Stanford who pioneered the connection between CH and cardiovascular disease, commenting on the study.
The JAK2^V617F mutation is carried by approximately 3-4% of Europeans, making it one of the more common high-risk CH variants. The study suggests that for these individuals, lifestyle interventions may be particularly beneficial , possibly enough to offset the genetic risk entirely.
Source: Gerhardt, T., McAlpine, C.S. et al. “Mutation-dependent responses to sleep and exercise in clonal haematopoiesis.” Nature (2026). DOI: 10.1038/s41586-026-10634-0. Published 10 June 2026.