Researchers at Duke-NUS Medical School, working in collaboration with Singapore General Hospital and Cardiff University, have discovered a molecular mechanism that explains how exercise protects aging muscles and restores their ability to repair themselves. The findings, published in the Proceedings of the National Academy of Sciences (PNAS), show that physical activity can counteract the biological processes that weaken muscles over time by helping cells clear out damaged proteins.
Gene DEAF1 Disrupts Cellular Maintenance in Aging Muscles
Muscle loss gradually weakens strength and function beginning around midlife, increasing the likelihood of falls, broken bones, and complications in recovering from injuries. At the cellular level, this decline occurs when a signaling pathway called mTORC1 becomes excessively active, causing cells to focus on producing new proteins while failing to clear away defective ones. The research team traced this imbalance to a gene named DEAF1, which increases in activity as muscles grow older and drives excessive mTORC1 function.
Under normal circumstances, DEAF1 is regulated by a family of protective proteins known as FOXOs, which keep cellular maintenance in check. However, FOXO activity diminishes over time, enabling DEAF1 levels to increase and disrupt the standard cycle of protein production and removal. “Exercise can reverse this process, correcting the imbalance,” said Assistant Professor Tang Hong-Wen, the study’s lead author from the Cancer and Stem Cell Biology Program at Duke-NUS. Physical activity activates regulatory proteins that lower DEAF1 levels, bringing the mTORC1 growth pathway back into equilibrium.
Animal Experiments Confirm Exercise Restores Muscle Strength
To test how DEAF1 influences muscle health across species, the researchers conducted experiments using both fruit flies and older mice. When the team artificially increased DEAF1 levels in these animal models, the subjects’ muscles weakened rapidly. Conversely, reducing DEAF1 restored the balance between protein production and removal, which successfully brought back muscle strength.
The research also revealed an important biological limitation regarding physical activity. When DEAF1 levels are significantly heightened or FOXO activity is markedly reduced, exercise might not be adequate to completely reinstate normal muscle repair. This finding offers a possible explanation for why some older individuals experience greater physical improvements from exercise than others, depending on the baseline biological condition of their muscle cells.
Targeting DEAF1 to Treat Age-Related Muscle Loss
The implications of the discovery extend to muscle stem cells, which help regenerate tissue after injury and become less effective as people age. Priscillia Choy Sze Mun, a research assistant and the study’s first author at Duke-NUS, described the mechanism by noting that exercise tells muscles to clean up and reset. Lowering DEAF1 helps older muscles regain strength and balance, acting almost like hitting a rewind button.
By identifying DEAF1 as a key regulator, scientists have uncovered a potential therapeutic target for people who have difficulty exercising, such as those recovering from major surgery, serious illness, or cancer. Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, emphasized that the findings may lead to new ways to bring the benefits of exercise to societies with rapidly aging populations.
Duke-NUS Medical School Leads Aging Muscle Research
Which institutions led the research on muscle aging?
The study was led by Duke-NUS Medical School in collaboration with Singapore General Hospital and Cardiff University, with findings published in the Proceedings of the National Academy of Sciences.
What specific gene drives the imbalance in aging muscles?
A gene called DEAF1 increases in aging muscles and drives excessive mTORC1 activity, which stops cells from clearing away damaged proteins.
Can exercise completely reverse muscle aging in all cases?
The researchers found a limitation where exercise may not fully restore muscle repair if DEAF1 levels are extremely elevated or FOXO activity has dropped too low.
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