Scientists have discovered an important reason why exercise is so effective at keeping aging muscles strong. A new study from Duke-NUS School of Medicine shows that physical activity restores the natural repair systems that weaken as we age, helping muscles recover and maintain function in old age.
The research team, working with collaborators at Singapore General Hospital and Cardiff University, found that exercise can help correct important imbalances that occur within aging muscle cells. The survey results are Proceedings of the National Academy of Sciences (PNAS) provides new insights into the biological mechanisms behind muscle aging and may ultimately lead to new approaches to prevent age-related muscle loss.
Why muscle health declines with age
Healthy muscles do more than just support movement. It also plays an important role in metabolism, blood sugar regulation, and overall health. After middle age, muscle strength and function gradually decline, increasing the risk of falls and fractures, and slowing recovery after illness or injury.
The impact extends beyond individual health. As the population ages, muscle loss may increase demands on caregivers and healthcare systems. Therefore, maintaining muscle function is important for 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. As muscles age, this pathway can become overactive. Your muscles then focus on building new proteins and become less efficient at removing damaged proteins.
Over time, these damaged proteins accumulate within muscle cells, stressing them and causing them to gradually lose strength as they age. Until now, scientists did not fully understand the cause of this imbalance.
DEAF1 emerges as a major muscle aging gene
Researchers identified a gene called DEAF1 as a key element behind this process.
Research shows that DEAF1 levels increase in aging muscles. Increased DEAF1 increases mTORC1 activity, 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 tightly regulated, its levels rise, and muscles become less able to repair and maintain.
How exercise restores muscle repair
The research team found that exercise can reverse this imbalance, as long as the underlying regulatory systems remain responsive.
“We believe that this is a significant finding,” said Hongwen Tan, assistant professor in the Duke-NUS Cancer and Stem Cell Biology Program, lead author of the study.
“Exercise can reverse this process and correct imbalances. Physical activity activates certain proteins, reduces DEAF1 levels, and rebalances growth pathways. This allows aging muscles to remove damaged proteins, rebuild properly, and remain stronger and more resilient.”
The researchers also found important limitations. Some older muscles have extremely high DEAF1 levels or significantly reduced FOXO activity. In these 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 reap greater benefits from exercise than others and highlights the importance of understanding the biology underlying muscle aging.
Results confirmed in flies and mice
To test their findings, the researchers conducted experiments on both fruit flies and older mice.
The results were consistent for both species. Increasing DEAF1 levels causes muscle weakness to occur more quickly, while lowering DEAF1 restores a healthy protein balance and improves muscle strength. This finding suggests that DEAF1 plays a conserved role in muscle aging across different organisms.
Potential benefits beyond aging
The implications of the research could extend beyond normal aging.
DEAF1 also affects muscle stem cells, which help repair and regenerate muscle tissue. These stem cells naturally become less effective with age, and it appears that recovery becomes even more difficult when DEAF1 is destroyed.
The findings could also prove valuable for people recovering from surgery, illness, or chronic illness such as cancer. Researchers suggest that targeting DEAF1 may be able to reproduce some of the beneficial effects of exercise at a molecular level, potentially helping maintain muscle strength even when physical activity is limited.
Priscilla Choi Se-Moon, research assistant in the Cancer and Stem Cell Biology Program at Duke-NUS and lead author of the study, said:
“Exercise tells your muscles to ‘clean and reset.’ Lowering DEAF1 helps old muscles regain strength and balance, almost as if you hit the rewind button. With millions of older adults at risk for muscle loss, understanding DEAF1 could lead to new ways to protect muscles and improve quality of life.”
Professor Patrick Tan, Duke-NUS Senior Associate Dean for Research, added:
“This study helps explain at a molecular level why aging muscles lose their ability to self-repair, and why exercise can restore that balance in some people. By identifying DEAF1 as a key regulator in this process, these findings could 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 basic scientific discovery and translational research to improve the understanding and treatment of diseases in Singapore and around the world.
This research was supported by the Singapore Ministry of Education (2022-MOET1-0004, FY2025-MOET1-0004), the Diana Koh Innovative Cancer Research Award (Duke-NUS-DKICRA/2024/0001), the National Academy of Medical Sciences (MOH-001189-00), and the National Medical Research Council (NMRC) of MOH Holdings Pte Ltd. Supported by the Singapore Ministry of Health through the Secretariat. NMRC (MOH-001208-00, MOH-001885-00, MOH-001831-00). Authors Qian Gou and Priya D Gopal Krishnan were supported by a Khoo Postdoctoral Fellowship (Duke-NUS-KPFA/2025/0078; Duke-NUS-KPFA/2024/0075).
