Aging muscles heal more slowly after injury, a frustrating reality familiar to many older adults.
New research from UCLA, conducted in mice, points to a surprising explanation. As muscles age, their stem cells build up high levels of a protein that makes them slower to switch on and repair damaged tissue. At the same time, that same protein helps the cells survive longer in the more stressful environment of older muscle.
The study, published in the journal Science, suggests that some biological changes linked to aging may not simply be harmful decline. Instead, they may represent built in survival strategies. “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.”
The Protein That Slows Muscle Repair With Age
The research team, led by postdoctoral scholars Jengmin Kang and Daniel Benjamin, compared muscle stem cells from young and old mice. They found that a protein called NDRG1 increased sharply with age, reaching levels 3.5 times higher in older cells than in younger ones. NDRG1 acts like a brake inside the cell. It dampens a signaling pathway known as mTOR, which normally drives cells to activate, grow, and repair tissue.
To determine whether NDRG1 was responsible for slower healing, the scientists allowed mice to age naturally to the equivalent of about 75 human years. They then blocked the activity of NDRG1. Once this protein was inhibited, the older muscle stem cells began behaving more like young ones. They activated more quickly and repaired injured muscle faster.
Rejuvenation Comes With a Trade Off
There was a downside. When NDRG1 was blocked, fewer muscle stem cells survived over time. As a result, the muscle’s ability to regenerate after repeated injuries was reduced.
“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 team confirmed their results using several different methods. They studied muscle stem cells from both young and old mice in lab dishes and inside living tissue. Across experiments, the pattern was consistent. Higher levels of NDRG1 slowed stem cell activation and muscle repair, but also strengthened the cells’ long term survival.
A Cellular Survival Bias in Aging
The researchers propose that rising NDRG1 levels reflect what they call a “cellular survivorship bias.” Over time, stem cells that fail to produce enough NDRG1 are more likely to die. The remaining population is made up of cells that are slower to act but better able to withstand the stresses of aging.
“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.
Rando compares this shift to survival trade offs seen in nature. In extreme conditions such as droughts, famines or freezing temperatures, animals activate resilience programs like hibernation instead of investing energy in reproduction. Similarly, aging stem cells appear to divert resources away from producing new cells and toward survival programs as they cope with stress.
“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 Anti Aging Therapies
These findings may guide future therapies designed to boost muscle regeneration in older adults. However, Rando cautions that increasing stem cell performance may come at a price. “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 how this balance between survival and regeneration is controlled at the molecular level.
“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.
The study was funded by the National Institutes of Health, the NOMIS Foundation, the Milky Way Research Foundation, the Hevolution Foundation and the National Research Foundation of Korea.
