Researchers Discover Biological Mechanism Behind Exercise and Healthier Aging Muscles

Exercise may help aging muscles hit the body's 'reset button,' restoring their natural repair system and keeping them stronger for longer, according to a new study published in the Proceedings of the National Academy of Sciences.

Researchers from Duke-NUS Medical School, together with scientists from Singapore General Hospital and Cardiff University, have identified a key mechanism explaining how exercise helps slow age-related muscle decline and that physical activity restores the balance between muscle growth and repair by regulating a gene called DEAF1.

Healthy muscles support movement, metabolism, blood sugar regulation, and overall health. However, muscle strength naturally declines with age, increasing the risk of falls, fractures, and delayed recovery after illness.

The researchers found that aging muscles develop excessive activity of the mTORC1 growth pathway, which promotes protein production but reduces the removal of damaged proteins, leading to cellular stress and muscle weakness.

The team discovered that rising levels of the DEAF1 gene drive this harmful imbalance. Normally, DEAF1 is controlled by proteins called FOXOs, but FOXO activity decreases with age, allowing DEAF1 levels to increase.

Exercise was found to counter this process by activating proteins that lower DEAF1 levels, restoring the balance between protein production and protein recycling. This enables aging muscles to remove damaged proteins, repair themselves more efficiently, and remain stronger.

However, researchers noted that in some older muscles where DEAF1 levels become extremely high or FOXO activity is severely reduced, exercise alone may not fully reverse the damage.

Experiments in fruit flies and older mice confirmed that reducing DEAF1 improved muscle strength and protein balance, while increasing it accelerated muscle deterioration. Scientists believe targeting DEAF1 could eventually help mimic some benefits of exercise, offering new treatment strategies for age-related muscle loss, recovery after surgery, and chronic diseases where maintaining muscle health is essential.

REFERENCE: Sze Mun Choy, Kah Yong Goh, Wen Xing Lee, Weiyi Jiang, Qian Gou, Priya D. Gopal Krishnan, Shi Chee Ong, Kenon Chua, Nathan Harmston, Hong-Wen Tang. Exercise suppresses DEAF1 to normalize mTORC1 activity and reverse muscle aging. Proceedings of the National Academy of Sciences, 2025; 122 (48) DOI: 10.1073/pnas.2508893122