Sleep and exercise may dampen genetic drivers of heart disease

Researchers report that lifestyle changes can weaken some genetic effects tied to clonal hematopoiesis—an age-related process in blood cells that raises inflammation and cardiovascular risk. In analysis of more than 91,000 adults, moderate-to-vigorous activity

For people carrying certain inherited-risk mutations, the danger may not be fixed. A new study in Nature points to a more uncomfortable truth—and a more hopeful one: genes associated with heart disease can interact with everyday behavior. and at least some of the damage may be softened by how much you move and how well you sleep.

Clonal hematopoiesis, or CH, begins quietly. Each day, stem cells in our blood divide to generate billions of new immune cells. That routine replenishment keeps the body’s defense system running—but it also produces DNA “glitches.” Most mutations are harmless. but variants of some genes can accumulate disproportionately in blood. a condition known as CH.

In the 2010s, researchers began searching for gene variants associated with CH in DNA from blood drive samples. The idea was that these mutations might be an early step toward cancer. “akin to polyps detected in a colonoscopy. ” as Siddhartha Jaiswal. an immunologist at Stanford University School of Medicine who was not involved in the new study. has described. Jaiswal and colleagues found such mutations in more than 10 percent of people over 70 years old. Those individuals had a higher risk of blood cancer, as expected.

Then came the part that changed how clinicians think about CH. The surprise was that the mutations were also associated with a 30 to 40 percent higher death rate. largely due to fatal strokes and heart attacks. In a large, randomized trial, an anti-inflammatory drug offered modest cardiovascular benefit for high-risk patients.

The biological thread connecting those deaths runs through inflammation inside arteries. Past mouse experiments revealed what can happen next: immune cells called macrophages swarm into clogged arteries to chew up cholesterol deposits. but they also release inflammatory signals. raising the risk of atherosclerosis. Some CH mutations intensify that immune response to plaques collecting in blood vessels, says Mount Sinai neuroimmunologist Cameron McAlpine.

Other studies had already hinted that non-genetic factors—diet and infections, among them—could influence how much these CH mutations accumulate. So McAlpine, Teresa Gerhardt, and colleagues investigated whether lifestyle changes could mitigate the risk of genetically driven cardiovascular disease.

In human data, the signal was modest but real. The researchers evaluated genetic data and physical activity levels from more than 91,000 U.K. and U.S. adults. They found that the proportion of individuals carrying certain CH mutations dropped 13 percent in the subset with moderate to vigorous activity.

The contrast became clearer in mice. The team used genetically engineered animals with CH mutations and fed them a high-cholesterol diet. Some animals were given an exercise wheel. Others experienced sleep disruption from a bar that moved across the cage floor, nudging the animals awake every few minutes.

The exercise wheel made a difference that was easy to see in behavior: many of the running mice voluntarily logged 10 kilometers per day. Those lifestyle changes, the researchers report, influenced the frequency and behavior of mutant macrophages in some mice.

Gerhardt, now in Germany—where she has moved to start her own lab at Goethe University Frankfurt—summed up the pattern in stark terms: “If you exercise, you have smaller plaques and less disease, and if you sleep badly, you have more disease.”

But the story doesn’t fit into a one-size-fits-all rule. The effect of behavior was not universal. The team looked at variants of four different genes implicated in CH, and for each one the degree of benefit—and whether it appeared at all—varied.

Allan Tall. a pulmonologist at Columbia University who studies molecular mechanisms of cardiovascular diseases but wasn’t involved in the work. emphasized the practical implication that comes with that nuance. One of the more harmful mutations is not rare: it is found in 3 to 4 percent of Europeans. The study’s finding that lifestyle factors eased cardiovascular risk in mice with this mutation “could apply to a sizeable segment of the population. ” Tall said.

In human terms, the work lands at the intersection of what clinicians can change quickly and what they can’t. You can stop smoking, but you can’t just get rid of your genes. For people dealing with the legacy of CH mutations. the new study suggests another lever—sleep and movement—may not rewrite risk entirely. but may change how strongly those genetic drivers translate into disease.

clonal hematopoiesis CH heart disease stroke atherosclerosis inflammation sleep exercise macrophages macrophage mutations Nature genetics and behavior