Scientists discover how exercise reverses muscle aging

The research, led by Duke-NUS Medical School in collaboration with Singapore General Hospital and Cardiff University, identified a molecular system that becomes disrupted as muscles grow older. Exercise can help bring this system back into balance, allowing muscle cells to remove damaged proteins and maintain healthy tissue.

Published in the Proceedings of the National Academy of Sciences (PNAS), the findings provide new insight into the biology of muscle aging. They also help explain why exercise may be more effective for some older individuals than others.

Although the experiments were conducted in fruit flies and mice, the researchers believe the underlying mechanism could eventually help scientists develop new approaches to preserving muscle strength and mobility in humans.

Why Muscles Become Weaker With Age

Muscle loss is one of the most significant physical changes associated with aging. Beginning around midlife, muscles gradually lose strength and function, making everyday activities more difficult and increasing the likelihood of falls and broken bones.

Weaker muscles can also complicate recovery from injuries and illnesses and make it harder for the body to regulate blood sugar. Because muscles play an important role in metabolism, their deterioration can affect far more than physical strength.

For aging populations, including Singapore’s, maintaining muscle health is especially important. Preventing muscle decline can help older adults remain independent while reducing the demands placed on caregivers and healthcare systems.

At the cellular level, keeping muscles healthy requires a careful balance between producing new proteins and disposing of old or damaged ones. Proteins form much of the machinery and structure within muscle cells, so this ongoing maintenance is essential for normal function.

One of the main systems responsible for regulating this process is a signaling pathway called mTORC1. It acts as a growth regulator, helping cells determine when to manufacture proteins and support muscle maintenance.

However, this system can become less balanced with age.

When mTORC1 becomes excessively active, muscle cells may devote too much attention to producing proteins while failing to clear away damaged ones. Over time, these defective proteins accumulate, placing stress on cells and interfering with their ability to function properly.

Scientists have long recognized this imbalance as a contributor to muscle deterioration, but the mechanism responsible for pushing the system out of balance remained unclear.

Scientists Discover a Key Gene Behind Muscle Aging

The researchers traced the problem to a gene called DEAF1, which appears to play an important role in controlling how muscles age.

As muscles grow older, DEAF1 levels can increase. The team discovered that this rise drives excessive mTORC1 activity, disrupting the normal cycle of protein production and removal.

The result is a breakdown in muscle maintenance. Instead of efficiently replacing damaged components and preserving healthy tissue, aging muscle cells become increasingly burdened by proteins that should have been cleared away.

Under normal circumstances, DEAF1 is regulated by a family of proteins known as FOXOs.

These proteins help control gene activity and are involved in important cellular maintenance processes. In healthy muscles, they prevent DEAF1 from becoming excessively active.

But FOXO activity tends to decline with age. As this protective regulation weakens, DEAF1 can increase, driving mTORC1 activity higher and further disrupting the processes needed to maintain muscle health.

The researchers found that this chain of events helps explain why aging muscles gradually lose their capacity to repair themselves.

Crucially, they also discovered that exercise can interrupt the process.

How Exercise Helps Aging Muscles Repair Themselves

Exercise does more than stimulate muscles to grow stronger. According to the findings, physical activity can also help restore the cellular maintenance system that becomes disrupted during aging.

The researchers found that exercise activates regulatory proteins that reduce DEAF1 levels. This helps return mTORC1 activity to a healthier balance, allowing muscle cells to remove damaged proteins while continuing to produce the new proteins they need.

In effect, exercise helps muscles perform an important internal cleanup, making it easier for them to maintain healthy tissue and recover from damage.

Assistant Professor Tang Hong-Wen, the study’s lead author from the Cancer and Stem Cell Biology Program at Duke-NUS, explained:

“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.”

However, the researchers discovered an important limitation.

When DEAF1 levels become extremely elevated or FOXO activity falls too low, exercise may no longer be sufficient to fully restore normal muscle repair.

This suggests that the biological condition of muscle cells can influence how effectively they respond to physical activity. It also offers a possible explanation for why some older adults experience greater improvements from exercise than others.

The findings do not suggest that exercise loses its value with age. Rather, they indicate that understanding the biological changes occurring inside aging muscles may be necessary to develop more effective strategies for preventing muscle decline.

Experiments Reveal a Way to Restore Muscle Strength

To investigate the role of DEAF1, the researchers performed experiments using fruit flies and older mice.

These two animal models allowed the team to examine whether the same biological mechanism influences muscle health across very different species.

The results revealed a consistent pattern.

When the researchers increased DEAF1 levels, muscles weakened rapidly. But when they reduced DEAF1, the balance between protein production and removal improved, and muscle strength was restored.

Finding similar effects in both fruit flies and mice suggests that DEAF1 participates in an evolutionarily conserved system, meaning the underlying biological function has been maintained across species over long periods of evolution.

These experiments also provided evidence that DEAF1 is not simply associated with muscle deterioration. Changing its levels directly affected muscle function, strengthening the case that it plays an important role in the aging process.

Whether targeting this system can produce comparable benefits in humans remains to be established.

Could Scientists Mimic the Benefits of Exercise?

The implications of the discovery may extend beyond ordinary muscle aging.

DEAF1 also influences muscle stem cells, which are specialized cells that help repair and regenerate muscle tissue after injury or damage.

As people age, these cells become less effective, and their numbers or activity can decline, making recovery more difficult. Disruptions involving DEAF1 may further impair the body’s ability to regenerate healthy muscle.

By identifying DEAF1 as an important regulator, researchers have uncovered a potential target for therapies designed to improve muscle maintenance and recovery.

Such treatments could eventually benefit people who have difficulty exercising, including those recovering from major surgery, serious illness, or chronic conditions such as cancer.

One possibility is that adjusting DEAF1 activity could reproduce some of the molecular changes normally triggered by physical activity. This might help preserve muscle strength even when a person’s ability to exercise is limited.

However, this remains a potential future application rather than an established treatment. Further research will be needed to determine whether manipulating DEAF1 is both safe and effective in humans.

Priscillia Choy Sze Mun, the study’s first author and a research assistant in the Cancer and Stem Cell Biology Program at Duke-NUS, described the discovery:

“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.”

A New Direction for Fighting Age-Related Muscle Loss

The findings highlight an important distinction between simply stimulating muscle growth and maintaining the cellular systems that keep muscles healthy.

Producing more proteins is not always beneficial if damaged proteins are allowed to accumulate. Effective muscle maintenance requires both processes to work together.

By showing how exercise helps restore this balance, the researchers have identified a potential biological explanation for some of its protective effects against muscle aging.

Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, emphasized the broader significance:

“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.”

The discovery may ultimately help researchers design interventions that complement physical activity, particularly for people whose muscles no longer respond as effectively to exercise.

For now, the research reinforces the importance of exercise while revealing that its benefits depend on an intricate network of molecular processes inside muscle cells.

As populations around the world grow older, understanding these processes could become increasingly valuable for protecting mobility, supporting recovery, and helping people maintain their independence later in life.

Duke-NUS Medical School combines medical education with basic and translational biomedical research. Its work aims to improve understanding of common diseases and translate laboratory discoveries into new approaches to treatment, benefiting patients in Singapore and internationally.

This work was supported by the 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 received support from the Khoo Postdoctoral Fellowship (Duke-NUS-KPFA/2025/0078; Duke-NUS-KPFA/2024/0075).