Old muscle stem cells can act young again but there’s a catch

A new study from UCLA, conducted in mice, found that aging muscle stem cells build up high levels of a protein that slows their ability to spring into action and repair damaged tissue. At the same time, that protein appears to help the cells endure the challenging conditions found in aging muscle.

The research, published in the journal Science, suggests that some biological changes linked to aging may not simply be signs of decline. Instead, they may serve as protective adaptations that help cells survive.

"This has led us to a new way of thinking about aging," said Dr. Thomas Rando, senior author of the 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."

Protein Linked to Slower Muscle Repair

The researchers, led by postdoctoral scholars Jengmin Kang and Daniel Benjamin, compared muscle stem cells taken from young and old mice. They found that levels of a protein known as NDRG1 rose dramatically with age, reaching concentrations 3.5 times higher in older cells.

NDRG1 functions like a brake inside the cell. It suppresses a signaling pathway called mTOR, which normally helps drive cell activation and growth.

To determine whether NDRG1 was contributing to slower muscle recovery, the scientists studied mice that had aged naturally to roughly the equivalent of 75 human years. When they blocked NDRG1 activity, the older muscle stem cells quickly regained youthful behavior, becoming more active and improving muscle repair after injury.

The improvement, however, came with a drawback. Without the protective effects provided by NDRG1, fewer stem cells remained alive over time. As a result, the tissue became less capable of regenerating after repeated injuries.

Survival Versus Performance

"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."

The researchers confirmed their results using several different methods. They examined muscle stem cells from both young and old mice in laboratory cultures as well as in living tissue.

Across these experiments, the pattern remained consistent. Higher levels of NDRG1 reduced the cells' ability to rapidly activate and repair muscle, while also increasing their resilience and long-term survival.

A Cellular Survivorship Bias

According to the researchers, the rise in NDRG1 may be driven by what they describe as a "cellular survivorship bias" -- stem cells with insufficient NDRG1 gradually disappear over time, leaving behind a population that survives better but functions more slowly.

"Some age-related changes that look detrimental -- like slower tissue repair -- may actually be necessary compromises that prevent something worse: the complete depletion of the stem cell pool," Rando said.

The researchers compare this phenomenon to trade-offs seen throughout nature. During difficult conditions such as drought, famine, or extreme cold, animals often shift resources toward survival mechanisms like hibernation rather than reproduction. Muscle stem cells may be doing something similar as they age, directing resources away from their reproductive role (making more cells) and toward survival.

"Species survive because they reproduce, but in times of deprivation, animals turn on their own resilience programs," Rando said. "There are a lot of examples in nature of allocating resources to survival under times of stress. It's exactly aligned with what we're seeing at the cellular level."

Implications for Future Aging Therapies

The findings could help guide future efforts to develop therapies that improve tissue repair while preserving stem cell survival. However, Rando cautions that enhancing one aspect of stem cell function may come with unintended consequences.

"There's no free lunch. We can improve the function of aged cells for a period of time, for certain tissues, but every time we do this, there's going to be a potential cost and a potential downside."

The team plans to continue studying the molecular mechanisms that determine how stem cells balance survival and performance during aging.

"This gene is almost like our doorway that we've opened into understanding what controls these trade-offs that are so critical, not only for evolution of species but also for the aging of tissues within an individual," Rando said.

Funding for the study came from the National Institutes of Health, the NOMIS Foundation, the Milky Way Research Foundation, the Hevolution Foundation, and the National Research Foundation of Korea.