Scientists have uncovered a key reason why exercise is so effective at helping older muscles stay strong. A new study from Duke-NUS Medical School shows that physical activity can restore the natural repair systems that weaken with age, helping muscles recover and maintain function later in life.
The research team, working with collaborators from Singapore General Hospital and Cardiff University, found that exercise helps correct an important imbalance that develops inside aging muscle cells. The findings, published in the Proceedings of the National Academy of Sciences (PNAS), provide new insight into the biological mechanisms behind muscle aging and could eventually lead to new approaches for preventing age related muscle loss.
Why Muscle Health Declines With Age
Healthy muscles do far more than support movement. They also play important roles in metabolism, blood sugar regulation, and overall health. Beginning in middle age, muscle strength and function gradually decline, increasing the risk of falls, fractures, and slower recovery after illness or injury.
The consequences extend beyond individual health. As populations age, muscle loss can increase demands on caregivers and healthcare systems. Preserving muscle function is therefore an important part of maintaining independence and quality of life.
One of the key regulators of muscle health is a growth pathway called mTORC1, which helps control protein production and muscle maintenance. In aging muscles, this pathway can become excessively active. When that happens, muscles focus more on building new proteins while becoming less efficient at removing damaged ones.
Over time, these damaged proteins accumulate inside muscle cells, placing them under stress and contributing to the gradual loss of strength associated with aging. Until now, scientists did not fully understand what causes this imbalance.
DEAF1 Emerges as a Key Muscle Aging Gene
The researchers identified a gene called DEAF1 as an important factor behind this process.
According to the study, DEAF1 levels rise in aging 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 aging 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 significantly. 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 and highlights the importance of understanding the underlying biology of muscle aging.
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 aging across different organisms.
Potential Benefits Beyond Aging
The implications of the research may extend beyond normal aging.
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 suggest 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 aging 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 aging populations.”
Duke-NUS is recognized globally for its work in medical education and biomedical research, combining fundamental scientific discoveries with translational research aimed at improving the understanding and treatment of disease in Singapore and around the world.
