Scientists have discovered a biological mechanism that helps explain how exercise protects aging muscles and restores their ability to repair themselves. The discovery reveals why physical activity can counteract some of the changes that weaken muscles with age and opens the way to potential new treatments for age-related muscle loss.
The research, led by Duke-NUS Medical School in collaboration with Singapore General Hospital and Cardiff University, identified a molecular system that is disrupted as muscles age. Exercise can help restore balance to this system, allowing muscle cells to break down damaged proteins and maintain healthy tissue.
Published in the Proceedings of the National Academy of Sciences (PNAS), the results provide new information on the biology of muscle aging. They also help explain why exercise may be more effective for some older adults than others.
Although the experiments were conducted on 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 weaken with age
Muscle loss is one of the most significant physical changes associated with aging. Around midlife, muscles gradually lose strength and function, making daily activities more difficult and increasing the risk of falls and fractures.
Weaker muscles can also make it harder to recover from injuries and illnesses and make it harder for the body to regulate blood sugar. Since muscles play an important role in metabolism, muscle deterioration can affect more than just physical strength.
For aging populations, including those in Singapore, maintaining muscle health is particularly important. Preventing muscle decline can help older adults remain independent while reducing demands on caregivers and healthcare systems.
At the cellular level, maintaining healthy muscles requires a careful balance between producing new proteins and eliminating old or damaged ones. Protein makes up much of the machinery and structure of muscle cells, so this continued 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 make proteins and supporting muscle maintenance.
However, this system can become less balanced with age.
When mTORC1 becomes excessively active, muscle cells can devote too much attention to producing proteins without being able to eliminate damaged ones. Over time, these faulty proteins build up, stressing cells and interfering with their ability to function properly.
Scientists have long recognized that this imbalance contributes to muscle deterioration, but the mechanism responsible for the system’s imbalance remains unclear.
Scientists discover key gene behind muscle aging
Researchers attributed the problem to a gene called DEAF1, which appears to play an important role in controlling muscle aging.
As muscles age, DEAF1 levels may increase. The team discovered that this increase leads to excessive mTORC1 activity, disrupting the normal cycle of protein production and disposal.
The result is a breakdown in muscle maintenance. Instead of effectively replacing damaged components and preserving healthy tissue, aging muscle cells become increasingly loaded with proteins that should have been removed.
Under normal circumstances, DEAF1 is regulated by a family of proteins called FOXO.
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 decrease with age. As this protective regulation weakens, DEAF1 may increase, leading to increased mTORC1 activity and further disrupting the processes necessary to maintain muscle health.
Researchers have discovered that this chain of events helps explain why aging muscles gradually lose their ability to repair themselves.
Importantly, they also discovered that exercise can interrupt the process.
How exercise helps aging muscles repair themselves
Exercise does more than stimulate muscles to become stronger. According to the results, physical activity can also help restore the cellular maintenance system that is disrupted during aging.
Researchers have found that exercise activates regulatory proteins that reduce DEAF1 levels. This helps return mTORC1 activity to a healthier balance, allowing muscle cells to eliminate damaged proteins while continuing to produce the new proteins they need.
This is because exercise helps muscles do important internal cleaning, making it easier for them to maintain healthy tissue and recover from damage.
Assistant Professor Tang Hong-Wen, lead author of the study 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 that lower DEAF1 levels, bringing the growth path back into balance. This allows aging muscles to shed damaged proteins, rebuild properly, and help them stay stronger and more resilient.”
However, the researchers discovered an important limitation.
When DEAF1 levels become extremely high or FOXO activity drops too low, exercise may no longer be enough to fully restore normal muscle repair.
This suggests that the biological state of muscle cells may influence how effectively they respond to physical activity. It also offers a possible explanation for why some older adults see greater improvements from exercise than others.
The results do not suggest that exercise loses its value with age. Rather, they indicate that understanding the biological changes occurring in aging muscles may be necessary to develop more effective strategies for preventing muscle decline.
Experiments reveal way to restore muscle strength
To study the role of DEAF1, the researchers performed experiments on fruit flies and older mice.
These two animal models allowed the team to examine whether the same biological mechanism influences muscle health in very different species.
The results revealed a consistent trend.
When researchers increased DEAF1 levels, muscles quickly weakened. But when they reduced DEAF1, the balance between protein production and disposal improved and muscle strength was restored.
The finding of similar effects in fruit flies and mice suggests that DEAF1 participates in an evolutionarily conserved system, meaning that the underlying biological function has been maintained across species over long periods of evolution.
These experiments also proved that DEAF1 is not simply associated with muscle deterioration. Changing its levels directly affects muscle function, strengthening the argument that it plays an important role in the aging process.
It remains to be seen whether targeting this system can produce comparable benefits in humans.
Could scientists imitate the benefits of exercise?
The implications of this finding could 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 efficient and their number or activity may decrease, 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 discovered a potential target for therapies designed to improve muscle maintenance and recovery.
Such treatments could potentially benefit people who have difficulty exercising, including those recovering from major surgery, serious illness, or chronic illnesses such as cancer.
One possibility is that adjusting DEAF1 activity could reproduce some of the molecular changes normally triggered by physical activity. This could 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 manipulation of DEAF1 is both safe and effective in humans.
Priscillia Choy Sze Mun, first author of the study and a research assistant in the Cancer and Stem Cell Biology Program at Duke-NUS, described the discovery:
“Exercise tells muscles to ‘clean 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.”
A new direction to combat age-related muscle loss
The results highlight an important distinction between simply stimulating muscle growth and maintaining the cellular systems that keep muscles healthy.
Producing more protein is not always beneficial if damaged proteins are allowed to build up. Effective muscle maintenance requires both processes to work together.
By showing how exercise helps restore this balance, researchers have identified a potential biological explanation for some of its protective effects against muscle aging.
Professor Patrick Tan, Senior Associate Dean for Research at Duke-NUS, highlighted the broader importance:
“This study helps explain, at the molecular level, why aging muscles lose their ability to repair themselves and why exercise can restore this balance in some individuals. By identifying DEAF1 as a key regulator in this process, these results could lead to new ways to bring the benefits of exercise to societies with rapidly aging populations.”
This discovery could ultimately help researchers design complementary interventions to physical activity, particularly for people whose muscles no longer respond as effectively to…
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