Scientists at the University of California, Los Angeles, have identified a key reason why muscle repair slows with age.
In older muscle stem cells, a protein called NDRG1 accumulates and acts as a brake on rapid regeneration, according to a study published in the journal Science.
The finding reveals a biological trade-off: while NDRG1 slows activation and repair after injury, it enhances the cells’ long-term survival in the stressful environment of aging tissue. Blocking the protein restored youthful repair speed in aged mice but reduced stem cell numbers over time, impairing recovery from repeated injuries.
Protein Buildup Slows Repair
Researchers led by postdoctoral scholars Jengmin Kang and Daniel Benjamin compared muscle stem cells from young and old mice. They found NDRG1 levels rose dramatically with age, reaching concentrations 3.5 times higher in older cells.
NDRG1 suppresses the mTOR signaling pathway, which normally drives cell activation and growth. In experiments with mice aged to the human equivalent of about 75 years, blocking NDRG1 activity allowed older stem cells to activate more quickly and improve muscle repair after injury.
“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.”
Survival Versus Function
The study, conducted in both lab cultures and living tissue, showed consistent results. Higher NDRG1 reduced rapid repair capacity while increasing resilience.
Rando explained the dynamic with an analogy:
“Think of it like a marathon runner versus a sprinter. 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 attributes the NDRG1 increase to a “cellular survivorship bias,” in which stem cells with lower levels gradually die off, leaving a more resilient but slower population.
“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 added.
He compared the process to evolutionary adaptations in nature, where organisms under stress prioritize survival over reproduction or growth, such as entering hibernation during famine.
“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 Aging Therapies
The research, 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, offers challenges for future therapies.
Rando cautioned that “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 further study of the molecular mechanisms balancing survival and performance.
“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 added.
