Duke-NUS scientists uncover how exercise helps ageing muscles repair themselves

Scientists at Duke-NUS Medical School have uncovered how exercise helps ageing muscles regain their ability to repair themselves, shedding light on why physical activity remains one of the most effective ways to preserve strength and mobility later in life.

Working with collaborators from Singapore General Hospital and Cardiff University, the team found that exercise helps restore a critical balance in muscle cells that is disrupted with age. Their findings, published in the Proceedings of the National Academy of Sciences (PNAS), offer new insight into the biological processes that drive muscle ageing and may guide future strategies to prevent age-related muscle loss.

Strong, healthy muscles are essential for movement, metabolism, and overall vitality. From mid-life onwards, muscle function gradually declines, increasing the risk of falls and fractures, slowing recovery from illness or injury, and making blood sugar harder to regulate. The effects extend beyond individuals, increasing the burden on caregivers and raising healthcare costs. In ageing societies such as Singapore, maintaining muscle health is key to preserving independence and quality of life.

At the centre of muscle health is a growth pathway known as mTORC1, which regulates protein production and muscle tissue maintenance. As muscles age, this pathway can become overactive, prioritising new proteins building, while slowing the removal of damaged proteins. The accumulation of these damaged proteins places stress on muscle cells, contributing to gradual weakening. Until now, what triggered this imbalance was unclear.

The researchers identified a gene called DEAF1 as a key driver of the protein imbalance in ageing muscles. They found that rising DEAF1 levels in ageing muscles push the growth regulator mTORC1 into overdrive, disrupting normal protein turnover and accelerating muscle decline.

DEAF1 is usually kept in check by a group of regulatory proteins called FOXOs. However, FOXO activity declines with age, allowing DEAF1 to rise unchecked. This loss of control appears to tip the balance away from muscle repair and towards deterioration.

Importantly, the study showed that exercise can reverse this imbalance but only when this regulatory system remains responsive.

Assistant Professor Tang Hong-Wen from the Cancer and Stem Cell Biology Programme 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.”

However, researchers also found that when DEAF1 levels remain too high or FOXO activity is severely reduced—as can happen in older muscles—exercise alone may not fully restore muscle repair. This helps explain why some older adults may not see the full benefits of exercise as compared to others, and underscores the importance of understanding muscle biology alongside lifestyle interventions.

To validate their findings, the team conducted experiments in both fruit flies and older mice. In both models, increasing DEAF1 levels led to rapid muscle weakness, while lowering DEAF1 restored protein balance and muscle strength, highlighting its conserved role across species.

The findings also have implications beyond ageing. DEAF1 is also known to influence muscle stem cells, which play a crucial role in tissue repair and regeneration. These stem cells naturally decline with age, and when DEAF1 is out of balance, muscle recovery slows even further[1]. The findings also have potential benefits for people recovering from illness, surgery, or chronic conditions such as cancer. Adjusting DEAF1 levels may allow researchers to mimic some of exercise’s effects at the molecular level, helping muscles stay strong even with limited physical activity.

Priscillia Choy Sze Mun, a research assistant with the Cancer and Stem Cell Biology Programme 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.”

Duke-NUS is a global leader in medical education and a biomedical research powerhouse, combining basic scientific research with translational know-how to bring a better understanding to common diseases and develop new treatment approaches to improve the lives of people in Singapore and beyond.

This work was supported by Singapore Ministry of Education (2022-MOET1-0004, FY2025-MOET1-0004), Diana Koh Innovative Cancer Research Award (Duke-NUS-DKICRA/2024/0001), National Academy of Medicine (MOH-001189-00), and the Singapore Ministry of Health through the National Medical Research Council (NMRC) Office, 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).

[1] Duke-NUS Medical School. (2025, December 8). Duke-NUS discovery advances quest for treatment for age- and cancer-related muscle degeneration. Duke-NUS. [Duke-NUS discovery advances quest for treatment for age- and cancer-related muscle degeneration]