Scientists have discovered a key reason why exercise is so effective in helping major muscles stay strong. A new study from Duke-NUS Medical School shows that physical activity can restore natural repair systems that weaken with age, helping muscles recover and maintain function well into the future.
The research team, working with collaborators from Singapore General Hospital and Cardiff University, found that exercise helps correct a major imbalance that develops within aging muscle cells. The findings, published in the Proceedings of the National Academy of Sciences (PNAS), provide new insights into the biological mechanisms behind muscle aging and could eventually lead to new approaches to prevent age-related muscle loss.
Why muscle health declines with age
Healthy muscles do much 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, loss of muscle mass can increase demands on caregivers and health systems. Therefore, preserving muscle function is 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 overly active. When that happens, muscles focus more on building new proteins and become less efficient at removing damaged ones.
Over time, these damaged proteins accumulate within muscle cells, subjecting them to 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 gene in muscle aging
The researchers identified a gene called DEAF1 as an important factor behind this process.
According to the study, DEAF1 levels increase in aging muscles. As DEAF1 increases, mTORC1 activity increases, disrupting the normal balance between protein production and disposal. This imbalance accelerates muscle deterioration.
Under normal conditions, DEAF1 is regulated by a group of proteins known as FOXO. However, FOXO activity naturally decreases with age. As a result, DEAF1 is no longer kept under tight control, allowing its levels to increase and distancing muscles from repair and maintenance.
How exercise restores muscle repair
The team found that exercise can help reverse this imbalance, as long as the underlying regulatory system continues to respond.
Assistant Professor Tang Hong-Wen of the Duke-NUS Cancer and Stem Cell Biology Programme, senior author of the study, said:
“Exercise can reverse this process, correcting the imbalance. Physical activity activates certain proteins that reduce DEAF1 levels, returning balance to the growth pathway. This allows aging muscles to eliminate damaged proteins, rebuild 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 ability to repair.
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.
Confirmed results in flies and mice
To test their findings, the researchers conducted experiments on both fruit flies and older mice.
The results were consistent in both species. Increasing DEAF1 levels caused muscles to weaken more quickly, while reducing DEAF1 restored a healthier protein balance and improved muscle strength. The findings suggest that DEAF1 plays a conserved role in muscle aging in 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 alterations in DEAF1 appear to make recovery even more difficult.
The findings could also be valuable to people recovering from surgery, illness or chronic diseases such as cancer. The researchers suggest that targeting DEAF1 could potentially replicate some of the beneficial effects of exercise at the molecular level, helping to maintain muscle strength even when physical activity is limited.
Priscillia Choy Sze Mun, research assistant at the Duke-NUS Cancer and Stem Cell Biology Program and first author of the study, said:
“Exercise tells muscles to ‘cleanse and reset.’ Reducing 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 globally recognized for its work in medical education and biomedical research, combining fundamental scientific discoveries with translational research aimed at improving the understanding and treatment of diseases in Singapore and around the world.
This work was supported by the Ministry of Education of Singapore (2022-MOET1-0004, FY2025-MOET1-0004), the Diana Koh Award for Innovative Cancer Research (Duke-NUS-DKICRA/2024/0001), the National Academy of Medicine (MOH-001189-00) and the Ministry of Health of Singapore through the Office of the National Medical Research Council (NMRC), MOH Holdings Pte Ltd under the NMRC (MOH-001208-00, MOH-001885-00, MOH-001831-00). Authors Qian Gou and Priya D Gopal Krishnan were supported by the Khoo Postdoctoral Fellowship (Duke-NUS-KPFA/2025/0078; Duke-NUS-KPFA/2024/0075).