How exercise fights muscle weakening that comes with age
- A new study published in the Proceedings of the National Academy of Sciences has found that exercise can reverse muscle weakening that comes with age by lowering a gene regulator called DEAF1.
- The study, led by Hong-Wen Tang at Duke-NUS Medical School, suggests that DEAF1 pushes a key muscle-maintenance system into overdrive as we age, leading to muscle cell damage and weakness.
- Exercise was found to lower DEAF1 levels through a well-known set of longevity genes called FOXO, which helps return the mTORC1 pathway to normal function.
- The study highlights a new biological pathway—the FOXO-DEAF1-mTORC1 axis—that explains why muscles weaken with age and why exercise remains an effective way to fight it.
- The findings also point to a promising new therapy, where scientists may be able to design drugs that dampen DEAF1 or boost FOXO to mimic some of the benefits of exercise and potentially treat age-related muscle decline.
A new study in mice is giving scientists fresh clues about why our muscles lose strength as we get older and why exercise remains one of the most reliable ways to fight it.
Researchers at Duke-NUS Medical School (Duke-NUS) say a gene regulator called DEAF1 seems to push a key muscle-maintenance system into overdrive as we age.
When we’re young this system known as mTORC1 helps to build and repair muscle. But later in life, it can get stuck in high gear and begin to damage muscle cells instead.
“The mTORC1 pathway is essential for muscle growth yet becomes chronically overactive in aging—a paradox that has made it challenging to pinpoint what drives this dysregulation,” says the study’s senior author Hong-Wen Tang, an assistant professor in the Cancer and Stem Cell Program at Duke-NUS and Singapore General Hospital.
Until now, scientists didn’t know what caused this shift. The new research in the Proceedings of the National Academy of Sciences points to DEAF1 as a key driver.
“Identifying DEAF1 fills an important gap in understanding how age-related stress signals become hard-wired into a persistent anabolic state that ultimately harms muscle cells,” Tang says.
The study suggests DEAF1 essentially hits the gas on a system already running too fast. By pushing mTORC1 into overdrive, DEAF1 causes muscles to make too many proteins, fail to clear damaged ones, and gradually weaken.
One of the most surprising findings: exercise reverses this process by lowering DEAF1 levels. That means in addition to building muscle, physical activity helps reset the core cellular pathways that keep muscles healthy.
“It was a striking discovery,” says Tang. “It shows that exercise doesn’t just fix damage. It targets the switch that causes muscle aging in the first place.”
Scientists didn’t just look at whether exercise keeps muscles strong—they wanted to know how it does it.
They put aging mice through endurance workouts including an exhausting treadmill run. For comparison, another group of older mice stayed sedentary.
After the workouts, the exercising mice showed big drops in mTORC1, the overactive pathway linked to muscle loss and function known as sarcopenia.
Researchers found that exercise lowers DEAF1 through a well-known set of longevity genes called FOXO. When activated during exercise, FOXO suppresses DEAF1—lifting the foot off the gas pedal—and helps MTORC1 return to normal.
Tang worked with co-lead authors Sze Mun Choy, Kah Yong Goh, and Wen Xing Lee on the study.
Their work highlights a new biological pathway—the FOXO-DEAF1-mTORC1 axis—that helps explain why muscles weaken with age and why exercise remains such a powerful antidote against age-related decline.
“This gives us a clearer way to study how mTORC1 goes off track,” says Tang.
It also points to a promising new therapy. If scientists can design drugs that dampen DEAF1 or boost FOXO, they may be able to mimic some of the benefits of exercise.
Funding for the research came from the Singapore Ministry of Education; Diana Koh Innovative Cancer Research Award; National Academy of Medicine, and National Medical Research Council.
Source: Duke University
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