By Alice McCarthy
A research collaborative led by scientists at the Harvard Stem Cell Institute and Massachusetts General Hospital in Boston discovered that exercise restarts an aged heart’s ability to make new heart cells, a process that usually ends by middle age. The study in older mice, which like humans naturally stop making new heart cells, showed that voluntary exercising prompted the animals to create new cardiac myocytes. The paper describing the results was published in Circulation.
“Because human and mouse heart cell physiology is so similar, this likely means that when you exercise the average age of your heart cells may go down,” says co-senior author and HSCI faculty member Richard Lee, MD, professor in the Department of Stem Cell and Regenerative Biology at Harvard and director of the Brigham Regenerative Medicine Center at Brigham and Women's Hospital. “No matter how old you are, if you start to exercise, we believe that you make your heart younger.”
After birth, the heart makes about 1% to 2% new heart cells per year, a process that continues for the first half of life. In the second half of life, however, the heart cells lose their ability to divide. That means for individuals living to age 50, about half of the heart’s cells have been replaced with new heart muscles since birth. After age 50, humans make few new heart cells, so that number does not change appreciably.
Knowing that heart muscle cell dynamics are highly consistent between humans and mice, Lee has been studying the effects of exercise on the cells in collaboration with Anthony Rosenzweig, MD, Professor of Medicine at Harvard Medical School and Chief of Cardiology at Massachusetts General Hospital. In 2018, the Lee and Rosenzweig laboratories published a study showing that young mice who voluntarily exercised using running wheels turned up their ability to make new heart cells. “The difference was very significant, about a 4.6-fold increase,” says Lee. “But it was unclear whether exercise could activate a similar process in aged animals,” adds Rosenzweig, co-senior author of both the 2018 and current studies.
This study evaluated aged mice (20 months), the equivalent of about 65 years in humans. The team found that these mice will still likely run voluntarily on wheels but not as far as young mice. The mice were evaluated during an 8-week voluntary running protocol.
To decipher new and old heart muscle cells, the team relied on multi-isotope imaging mass spectroscopy (MIMS) to determine when cells were born. In analyses led by Carolin Lerchenmüller, MD, of University Hospital Heidelberg and Ana Vujic, PhD, of the HSCI, co-first authors of the study, 1,793 cardiomyocytes from sedentary aged mice were examined and compared to more than 2,000 matched cardiomyocytes in exercised adult mice. Their findings confirmed that exercise stimulated production of new heart cells in older mice, as it did in younger mice. They calculated an annual rate of 2.3% new cardiomyocytes in exercised older mice. This compares to their earlier findings of an annual new cardiomyocyte production rate of 7.5% in young, exercised mice and 1.63% in young, sedentary mice.
“Since mice and human heart dynamics are so similar, this study tells us that the failure of making new heart muscle cells – or cardiomyocytes – in the second half of life is easily activated and that exercise can do it,” says Lee. “Whether these effects are cumulative with repeated exercise was not tested in this study,” adds Rosenzweig. “But the clinical benefits of habitual exercise are very clear and it seems likely this is one contributor.”
Along with mass spectroscopic imaging, the investigators performed RNA sequencing and bioinformatic analyses to detect any transcriptional changes in the exercised mice. They found that one gene product, RCAN1.4, was exclusively upregulated in the aged, exercised hearts. However, it is unlikely a single gene explains the benefit in full.
By studying the genes that are regulated by exercise in the heart, the researchers found changes in the heart’s circadian rhythm pathway – one that is activated by exercise though the precise mechanism is not clear yet. Similar to the body’s overall circadian rhythm that determines how one sleeps and eats, other peripheral circadian rhythms exist outside of the brain in other tissues, like the heart. “We call these core clocks where genes are coming on and off causing the pathways to cycle,” says Lee. “All of the tissues have clock cycle genes and the heart’s clock cycle seems to be activated by exercise.”
Looking ahead, Lee and Rosenzweig plan on learning more about the molecular mechanisms involved and the implications of myocyte reactivation. “Many forms of heart disease are associated with loss of cardiomyocytes so learning what controls generation of new cardiomyocytes could have important therapeutic implications,” says Lee.
Lerchenmüller C. et al. (2022). Restoration of cardiomyogenesis in aged mouse hearts by voluntary exercise. Circulation. DOI: 10.1161/CIRCULATIONAHA.121.057276