Aging muscles often struggle to heal after injury, a common frustration among older adults. Now, groundbreaking research from UCLA offers a surprising explanation for this phenomenon, at least in mice. The study reveals that as muscles age, their stem cells accumulate high levels of a protein that slows their ability to repair damaged tissue. Paradoxically, this same protein also helps these cells survive longer in the stressful environment of aging muscles.
The study, published in the journal Science, suggests that some biological changes associated with aging might not simply be detrimental declines. 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.
The Protein That Slows Muscle Repair With Age
The research team, led by postdoctoral scholars Jengmin Kang and Daniel Benjamin, conducted a comparative analysis of muscle stem cells from young and old mice. They discovered that a protein known as NDRG1 increased significantly with age, reaching levels 3.5 times higher in older cells. NDRG1 acts as a brake within the cell, dampening a signaling pathway called mTOR, which typically drives cell activation, growth, and tissue repair.
To test whether NDRG1 was responsible for slower healing, the scientists allowed mice to age naturally to the equivalent of about 75 human years. They then inhibited the activity of NDRG1. Following this intervention, the older muscle stem cells began to behave more like their younger counterparts, activating more quickly and repairing injured muscle faster.
Rejuvenation Comes With a Trade-Off
However, the study also uncovered a downside. When NDRG1 was blocked, fewer muscle stem cells survived over time, which reduced the muscle’s ability to regenerate after repeated injuries. “Think of it like a marathon runner versus a sprinter,” explained 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.”
The team confirmed their findings using various methods, studying muscle stem cells from both young and old mice in lab dishes and within living tissue. Across these experiments, the pattern remained consistent: higher levels of NDRG1 slowed stem cell activation and muscle repair but also enhanced the cells’ long-term survival.
A Cellular Survival Bias in Aging
The researchers propose that the increase in NDRG1 levels reflects a “cellular survivorship bias.” Over time, stem cells that fail to produce enough NDRG1 are more likely to die. Consequently, the remaining population consists of cells that are slower to act but better equipped 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.
Implications for Anti-Aging Therapies
These findings could guide future therapies aimed at boosting muscle regeneration in older adults. However, Rando cautions that enhancing stem cell performance might come with a cost. “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 research team plans to continue studying how the 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 the 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.
