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Muscle tissue from aged mice seven days after injury. Left: Aged mice with normal NDRG1 levels show slower regeneration with smaller muscle fibers. Right: Aged mice in which NDRG1 was recently blocked show faster regeneration with larger fibers. Credit: Jengmin Kang, Rando Lab
Aging muscles heal more slowly after injury—a frustrating reality familiar to many older adults. A UCLA study conducted in mice reveals an unexpected cause: Stem cells in aged muscle accumulate higher levels of a protein that slows their ability to activate and repair tissue, but helps the cells survive longer in the harsh environment of aging tissue.
The findings, published today in the journal Science, suggest that some molecular changes associated with getting older may actually be protective adaptations rather than purely detrimental effects.
"This has led us to a new way of thinking about aging," said Dr. Thomas Rando, senior author of the new study and director of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.
"It's counterintuitive, but the stem cells that make it through aging may actually be the least functional ones. They survive not because they're the best at their job, but because they're the best at surviving. That gives us a completely different lens for understanding why tissues decline with age."
The research team, led by postdoctoral scholars Jengmin Kang and Daniel Benjamin, compared muscle stem cells isolated from young and old mice and discovered that a protein called NDRG1 increased dramatically with age—reaching levels 3.5 times higher in old cells than in young cells. NDRG1 acts as a cellular brake, suppressing a key signaling pathway called mTOR that normally promotes cell activation and growth.
To test whether NDRG1 was responsible for the slower muscle repair seen in aging, the researchers allowed mice to age normally to the equivalent of about 75 human years, then blocked NDRG1's activity. The aged muscle stem cells immediately behaved like young cells again, reactivating quickly and accelerating muscle repair after injury.
However, this rejuvenation came at a cost. Without NDRG1's protective effects, fewer muscle stem cells survived over time, limiting the muscle tissue's ability to regenerate after repeated injuries.
"Think of it like a marathon runner versus a sprinter," said Rando, who is also a professor of neurology at the David Geffen School of Medicine at UCLA. "The stem cells in young animals are hyper-functioning—really good at what they do, namely sprinting, but they're not good for the long term. They can make it through the 100-yard dash, but they can't make it even halfway through the marathon. By contrast, aged stem cells are like marathon runners—slower to respond, but better equipped for the long haul. However, what makes them so proficient over long distances is exactly what renders them poor at sprinting."
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