Getting older often means recovering more slowly from muscle injuries, but scientists may have discovered an important reason.
A new UCLA study, conducted in mice, found that aging muscle stem cells accumulate 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 cells withstand the challenging conditions found in aging muscles.
The research, published in the journal Sciencesuggests that some biological changes related to aging may not simply be signs of deterioration. 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, lead author of the study and director of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at UCLA.
“It’s counterintuitive, but the stem cells that survive aging may actually be the least functional. They survive not because they are the best at their job, but because they are the best at surviving. That gives us a completely different perspective for understanding why tissues decline with age.”
Protein linked to slower muscle repair
The researchers, led by postdoctoral researchers 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 increased dramatically with age, reaching 3.5 times higher concentrations in older cells.
NDRG1 functions as a brake within the cell. It suppresses a signaling pathway called mTOR, which normally helps drive cell activation and growth.
To determine whether NDRG1 contributed to slower muscle recovery, the scientists studied mice that had naturally aged to about the equivalent of 75 human years. When they blocked NDRG1 activity, older muscle stem cells quickly regained their youthful behavior, becoming more active and improving muscle repair after injury.
The improvement, however, had a drawback. Without the protective effects provided by NDRG1, fewer stem cells remained alive over time. As a result, the tissue became less able to regenerate after repeated injuries.
Survival versus performance
“Think of it as a marathon runner versus a sprinter,” said Rando, who is also a professor of neurology at the David Geffen School of Medicine at UCLA. “Stem cells in young animals are hyperfunctioning: they are very good at what they do, that is, running, but they are not good in the long run. They can go over 100 yards, but they can’t even make it to the half-marathon. In contrast, aged stem cells are like marathon runners: they respond more slowly, but are better equipped for the long run. However, what makes them so competent at long distances is exactly what makes them poor at running.”
The researchers confirmed their results using several different methods. They examined muscle stem cells from young and old mice in laboratory cultures as well as in living tissue.
In all these experiments, the pattern remained constant. Higher levels of NDRG1 reduced the cells’ ability to rapidly activate and repair muscles, while increasing their long-term endurance and survival.
A cell survival bias
According to the researchers, the increase in NDRG1 may be due to what they describe as a “cell survival 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 seem detrimental (such as slower tissue repair) may actually be necessary compromises that prevent something worse: complete depletion of the stem cell pool,” Rando said.
Researchers compare this phenomenon to trade-offs seen in nature. During difficult conditions such as drought, famine, or extreme cold, animals often divert resources toward survival mechanisms such as hibernation instead of reproduction. Muscle stem cells may be doing something similar as they age, diverting resources from their reproductive function (producing more cells) toward survival.
“Species survive because they reproduce, but in times of deprivation, animals activate their own resilience programs,” Rando said. “There are many examples in nature of resource allocation to survive in times of stress. It is exactly aligned with what we are seeing at the cellular level.”
Implications for future anti-aging therapies
The findings could help guide future efforts to develop therapies that enhance tissue repair while preserving stem cell survival. However, Rando cautions that improving one aspect of stem cell function can have unintended consequences.
“There is nothing free. We can improve the function of aged cells over a period of time, for certain tissues, but every time we do this, there will be a potential cost and a possible disadvantage.”
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 door that we have opened to understand what controls these compensations that are so critical, not only for the evolution of the 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.