New York, NY- June 13: Healthy sleep and regular exercise can work to counteract genetic mutations in white blood cells that are associated with cardiovascular disease and are most common among elderly people, Mount Sinai researchers have found.
In a study published on June 10 in Nature, the team reported for the first time that sufficient sleep and exercise can help to reduce the cancer-like cell expansion and atherosclerotic risk linked to mutations that spontaneously occur in white blood cells.
These mutations accumulate over our lifetimes and occur most often in hematopoietic stem cells, which are the cells in bone marrow that make the blood cells, including macrophages and monocytes, immune cells that help defend the body. When these cells develop mutations, they start to proliferate, multiplying faster than they should, and become more inflammatory, irritating or damaging tissues in the body.
This condition, known as clonal hematopoiesis (CH), is detectable in a quarter of people over age 70 and half of people over 80, the researchers say, though it is infrequent in young, healthy people.
“We’ve discovered that healthy sleep and exercise can selectively influence immune cells with clonal hematopoiesis mutations, repressing their proliferative programming and expansion, as well as their ability to promote the formation of harmful plaque in the arteries of the heart,” says Cameron McAlpine, PhD, senior author of the study and Associate Professor of Medicine (Cardiology), and Neuroscience at the Icahn School of Medicine at Mount Sinai. “Surprisingly, our findings reveal that CH mutant cells are malleable and selectively responsive to lifestyle behavior in a way that can mitigate atherosclerotic risk.” The large Mount Sinai study led by the Cardiovascular Research Institute at the Icahn School of Medicine of Mount Sinai involved nearly 83,000 participants from the UK Biobank, and 8,404 from All of Us, a diverse dataset managed by the National Institutes of Health. Mouse models were also extensively tested, evaluating the impact of sleep fragmentation and exercise on CH caused by acquired mutations in one of several genes: Jak2, Tet2, p53, and Dnmt3a.
Until now, it has been largely unknown if our daily lifestyles, particularly how much we sleep and exercise, could modify the function and biology of mutant CH cells. Mount Sinai researchers discovered that moderate-to-vigorous physical activity was associated with a reduced incidence of gene-specific CH and fewer mutant cells in the blood. Specifically, they found that sufficient sleep and exercise “turned off” the detrimental effects of rogue Jak2 and Tet2 mutant CH hematopoietic stem cells in the bone marrow, decreasing their ability to proliferate and grow, a precancerous process known as “clonal expansion”.
“Our study showed that healthy sleep and exercise can counteract the harmful effects of certain age-related mutations which occur over time in the hematopoietic stem cells that produce our white blood cells,” notes Teresa Gerhardt, MD, a postdoctoral fellow in the McAlpine Laboratory and lead author of the study. “Significantly, we found that a healthy lifestyle can mitigate CH clonal expansion and the atherosclerotic consequences of CH mutations, making mutant cells behave like healthy, nonmutated cells.”
That pathophysiology was also evident to researchers when examining macrophages—immune cells that live in the tissues and normally seek out and destroy germs and damaged or cancerous cells. However, macrophages with a CH mutation no longer function properly and promote the development of cardiovascular diseases, including atherosclerosis. Indeed, the study found that macrophages carrying a CH mutation, including in the Jak2 gene, can increase atherosclerotic lesions.
Just as important, scientists learned that healthy sleep repressed cell death and inflammatory pathways in Jak2 mutant macrophages (but not in neighboring nonmutant macrophages) by limiting CLEC4E signaling, a pathway that plays a key role in immune responses and inflammation. Exercise had the same effect, inducing sympathetic ADRB2 signaling (also implicated in inflammation) from the brain to Jak2 mutant macrophages in atherosclerotic lesions, thereby decreasing inflammation of those macrophages and lesion size.
The next step for the Mount Sinai team—which drew from resources of the Cardiovascular Research Institute, The Friedman Brain Institute, and The Lipschultz Precision Immunology Institute—is developing therapeutics that can modulate signaling pathways like CLEC4E and ADRB2, in this way targeting mutant cells in people with Jak2 CH. “The malleability of CH mutant cells means we can harness new signaling pathways to shut off the detrimental proliferative and inflammatory functions of those cells, while maintaining the function of healthy neighboring nonmutant cells,” explains Dr. McAlpine.
While healthy sleep and exercise are recommended for everyone, the study emphasized they are especially important for people with Jak2 and Tet2 mutations. “We now have the ability to use genetics to not only develop new therapies,” says Dr. McAlpine, “but to tailor lifestyle management and treatment. We hope to identify people with genetic cardiovascular disease risk factors and then advise them of the steps they can take now to mitigate that risk.”
This work involved collaboration among the following institutions at the Icahn School of Medicine at Mount Sinai: Cardiovascular Research Institute; The Friedman Brain Institute; and The Marc and Jennifer Lipschultz Precision Immunology Institute
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