Researchers have uncovered a molecular 'switch' that explains why exercise keeps ageing muscles healthy. By reducing levels of a gene called DEAF1, physical activity allows older muscles to clear out damage, repair themselves, and maintain strength.
Exercise Restores Natural Repair Systems
A new study from Duke-NUS Medical School, in collaboration with Singapore General Hospital and Cardiff University, shows that physical activity can restore the natural repair systems that weaken with age. The findings, published in the Proceedings of the National Academy of Sciences (PNAS), provide new insight into the biological mechanisms behind muscle ageing and could eventually lead to new approaches for preventing age-related muscle loss.
Why Muscle Health Declines With Age
Healthy muscles do much more than enable movement. They are essential for maintaining metabolism, regulating blood sugar levels, and supporting overall health. From middle age onward, muscle strength and function gradually decline, raising the risk of falls, fractures, and delayed recovery from illness or injury. The consequences extend beyond individual health, as muscle loss increases demands on caregivers and healthcare systems.
One of the key regulators of muscle health is the growth pathway mTORC1, which helps control protein production and muscle maintenance. In ageing muscles, this pathway can become excessively active, causing muscles to focus more on building new proteins while becoming less efficient at removing damaged ones. Over time, damaged proteins accumulate inside muscle cells, leading to stress and gradual loss of strength.
DEAF1 Emerges as a Key Muscle Ageing Gene
The researchers identified a gene called DEAF1 as an important factor behind this process. According to the study, DEAF1 levels rise in ageing muscles. As DEAF1 increases, it drives mTORC1 activity higher, disrupting the normal balance between protein production and protein removal. This imbalance accelerates muscle deterioration.
Under normal conditions, DEAF1 is regulated by a group of proteins known as FOXOs. However, FOXO activity naturally declines with age. As a result, DEAF1 is no longer kept under tight control, allowing its levels to increase and pushing muscles further away from repair and maintenance.
How Exercise Restores Muscle Repair
The team discovered that exercise can help reverse this imbalance, provided the underlying regulatory system remains responsive. Assistant Professor Tang Hong-Wen from the Cancer and Stem Cell Biology Program at Duke-NUS, the study's lead author, said: 'Exercise can reverse this process, correcting the imbalance. Physical activity activates certain proteins which lower DEAF1 levels, bringing the growth pathway back into balance. This allows ageing muscles to clear out damaged proteins, rebuild themselves properly, and help them stay stronger and more resilient.'
The researchers also found an important limitation. In some older muscles, DEAF1 levels become extremely high or FOXO activity drops drastically. In those cases, exercise alone may not be enough to fully restore the muscle's repair capacity. This finding may help explain why some older adults experience greater benefits from exercise than others.
Results Confirmed in Flies and Mice
To test their findings, the researchers conducted experiments in both fruit flies and older mice. The results were consistent across both species. Raising DEAF1 levels caused muscles to weaken more rapidly, while lowering DEAF1 restored healthier protein balance and improved muscle strength. The findings suggest that DEAF1 plays a conserved role in muscle ageing across different organisms.
Potential Benefits Beyond Ageing
The implications of the research may extend beyond normal ageing. DEAF1 also influences muscle stem cells, which are responsible for helping muscles repair and regenerate tissue. These stem cells naturally become less effective with age, and disruptions in DEAF1 appear to make recovery even more difficult. The findings could also prove valuable for people recovering from surgery, illness, or chronic diseases such as cancer. Researchers suggested that targeting DEAF1 could potentially reproduce some of the beneficial effects of exercise at the molecular level, helping maintain muscle strength even when physical activity is limited.
Priscillia Choy Sze Mun, a research assistant with the Cancer and Stem Cell Biology Program at Duke-NUS and the study's first author, said: 'Exercise tells muscles to clean up and reset. Lowering DEAF1 helps older muscles regain strength and balance, almost like hitting the rewind button. With millions of older adults at risk of muscle decline, understanding DEAF1 could lead to new ways to protect muscles and improve quality of life.'
Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, added: 'This study helps explain, at a molecular level, why ageing muscles lose their ability to repair themselves and why exercise can restore that balance in some individuals. By identifying DEAF1 as a key regulator in this process, these findings may lead to new ways in which the benefits of exercise can be brought to societies with rapidly ageing populations.'
