How Exercise Reverses Muscle Aging

Exercise can help aging muscles remove damaged proteins and retain strength by lowering the activity of DEAF1, according to research led by Duke-NUS Medical School. In fruit flies and older mice, physical activity reduced DEAF1 and brought the mTORC1 growth pathway back toward a more balanced state, although the study did not test the mechanism in people.

The study was published in the Proceedings of the National Academy of Sciences in 2025. Researchers from Duke-NUS Medical School worked with Singapore General Hospital and Cardiff University on the project, which examined why aging muscle becomes less able to repair itself.

What did scientists learn about muscle aging?

Muscle function declines with age. The source article says muscle loss can begin around midlife, making daily activities harder and increasing the likelihood of falls and broken bones. Reduced muscle function can also complicate recovery from injuries and illnesses and make blood-sugar regulation more difficult.

At the cellular level, muscle health depends on matching two jobs: making the proteins that support muscle structure and clearing proteins that are old or damaged. The mTORC1 signaling pathway helps regulate both processes. During aging, mTORC1 can become chronically overactive, pushing muscle cells toward protein production while suppressing autophagy, the process that breaks down and recycles damaged cellular components.

The PNAS study identified DEAF1, a transcription factor regulated by FOXO proteins, as an upstream driver of that shift. Higher DEAF1 expression increased mTOR transcription, leading to excessive mTORC1 activity, impaired protein balance and muscle decline. Weak FOXO regulation can allow DEAF1 to rise, while exercise activates FOXO and suppresses DEAF1.

How does exercise help aging muscles?

The experiments found that exercise reduced DEAF1 levels and restored a healthier balance between protein production and protein removal. In older mice, endurance workouts, including an exhausting treadmill run, produced large drops in mTORC1 activity compared with sedentary older mice, according to Duke-NUS Medical School’s report on the mouse study.

That cellular effect matters because producing more protein is useful only if damaged proteins are also removed. The researchers found that blocking FOXO or increasing DEAF1 prevented exercise from providing its muscle-health benefits in the animal models.

Hong-Wen Tang, the study’s senior author and an assistant professor in the Cancer and Stem Cell Biology Program at Duke-NUS and Singapore General Hospital, described the result as more than a way to build muscle. In the Duke-NUS report, he said physical activity can reset a cellular pathway involved in muscle aging.

The researchers also identified a limit. Exercise may not fully restore muscle repair when DEAF1 activity is extremely high or FOXO activity is very low. The source article presents this as a possible reason why some older adults gain more from physical activity than others, not as a reason to avoid exercise.

What did the animal experiments show?

The team used fruit flies and older mice to test whether the same mechanism appeared in different species. Raising DEAF1 caused rapid muscle weakening in both models. Lowering DEAF1 improved the balance between protein production and removal and restored muscle strength.

The similar results support the idea that DEAF1 belongs to an evolutionarily conserved system. Because researchers changed DEAF1 levels and observed changes in muscle function, the experiments provide evidence that it contributes to the aging mechanism rather than merely occurring alongside muscle deterioration.

These findings do not show that lowering DEAF1 through a drug would safely or effectively treat muscle loss in humans. The researchers said that targeting the FOXO-DEAF1-mTORC1 pathway is a possible future approach for people who cannot exercise, including those recovering from major surgery, serious illness or cancer.

What does the research mean for older adults?

A separate study of 51 healthy adults provides human evidence for a benefit from resistance training, but it does not test DEAF1. In the 2007 PLOS One study, researchers compared muscle biopsies from 25 older adults with 26 younger adults. Before training, the older group was 59% weaker than the younger group. After a six-month resistance exercise program, the older participants’ strength improved significantly, leaving them 38% weaker than the younger comparison group. Gene-expression measurements also showed that much of the age-related molecular pattern was reversed after training.

That study involved human muscle biopsies and a defined resistance training program, so it adds context to the animal findings. It cannot confirm that DEAF1 caused the observed improvement, however, because the researchers did not test that pathway in the human trial.

What to do now

Use the study as additional support for regular physical activity, while recognizing that the DEAF1 experiments involved fruit flies and older mice rather than a human exercise program.
Choose activity that is safe and sustainable for your current health. Ask a healthcare professional for guidance if injury, illness, surgery, cancer or another chronic condition limits your movement.
Do not look for a DEAF1-targeting treatment on the basis of this study. The source says researchers still need to establish whether manipulating DEAF1 is safe and effective in humans.
Track changes in strength and daily function over time, and report persistent weakness or difficulty with normal activities to a healthcare professional.

FAQ

How can exercise reverse muscle aging?

In fruit flies and older mice, exercise reduced DEAF1 levels and helped rebalance mTORC1 activity. That allowed muscle cells to remove damaged proteins while continuing to produce the proteins they need. The mechanism has not been confirmed in humans.

What is the role of DEAF1 in muscle aging?

DEAF1 levels can rise as muscles age. The increase can drive excessive mTORC1 activity, disrupt protein production and removal and weaken the muscle’s ability to repair itself.

Has a treatment based on DEAF1 been established for humans?

No. Targeting DEAF1 remains a possible future application. The study was conducted in fruit flies and mice, and further research is needed to determine whether manipulating DEAF1 is safe and effective in humans.

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