As we age, recovery from muscle damage often slows, and scientists may have discovered an important reason why.
A new UCLA study conducted in mice found that aging muscle stem cells accumulate high levels of proteins that slow their ability to activate and repair damaged tissue. At the same time, the protein appears to help cells withstand the difficult conditions found in aging muscle.
Research published in journals sciencesuggests that some biological changes associated with aging may be more than just signs of decline. Rather, they may function as a protective adaptation that helps cells survive.
“This leads us to a new way of thinking about aging,” said Thomas Rand, Ph.D., senior author of the study and director of UCLA’s Eli Edith Broad Center for Regenerative Medicine and Stem Cell Research.
“Counterintuitively, the stem cells that survive aging may actually be the least functional cells. Stem cells survive not because they are the best at their job, but because they are best able to survive. This gives us a completely different perspective on understanding why tissues decline with age.”
Relationship between delayed muscle repair and protein
The researchers, led by postdoctoral fellows Zhenming Kang and Daniel Benjamin, compared muscle stem cells taken from young and old mice. They found that levels of a protein known as NDRG1 rise dramatically with age, reaching 3.5-fold higher concentrations in older cells.
NDRG1 acts like a brake within cells. It suppresses a signaling pathway called mTOR, which normally helps activate cells and promote proliferation.
To determine whether NDRG1 contributed to delayed muscle recovery, the scientists studied naturally aged mice to the equivalent of 75 years in humans. When NDRG1 activity was inhibited, old muscle stem cells quickly regained youthful behavior, became more active, and improved muscle repair after injury.
However, this improvement also had its drawbacks. Without the protective effects of NDRG1, fewer stem cells survive over time. As a result, repeated injuries reduced the tissue’s ability to regenerate.
survival and performance
“Think of it like marathon runners and sprinters,” says Rand, who is also a professor of neurology at the David Geffen School of Medicine at the University of California, Los Angeles. “Stem cells in young animals are very functional and very good at what they do, which is sprinting, but they’re bad in the long run. They can break the 100-yard dash, but they can’t even get through half a marathon. In contrast, aging stem cells are like marathon runners: slower to react, but better equipped for long distance running. But what makes them good at long distance is exactly what makes them bad 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 and in living tissue.
The pattern remained consistent across these experiments. Higher levels of NDRG1 reduce the ability of cells to quickly activate and repair muscle, while also increasing cell resilience and long-term survival.
cell survival bias
According to the researchers, the increase in NDRG1 may be caused by what they call “cell survival bias.” That is, NDRG1-deficient stem cells gradually disappear over time, leaving a population that survives better but functions more slowly.
“Age-related changes that appear detrimental, such as delayed tissue repair, may actually be something worse: a necessary compromise to prevent complete depletion of the stem cell pool,” Rand said.
Researchers compare this phenomenon to trade-offs seen throughout nature. Under difficult conditions such as drought, famine, or extreme cold, animals often shift resources to survival mechanisms such as hibernation rather than reproduction. Muscle stem cells may be doing something similar as we age, directing resources away from their reproductive role (making more cells) and toward survival.
“Species survive because they reproduce, but in times of poverty animals turn on their resilience programs,” Rand said. “There are many examples in nature of allocating resources for survival under stress. This matches exactly what we see at the cellular level.”
Implications for future aging treatments
The findings could guide future efforts to develop treatments that improve tissue repair while preserving stem cell survival. But Rand cautions that enhancing one aspect of stem cell function can have unintended consequences.
“There is no such thing as a free lunch. For certain tissues, we can improve the function of aging cells over a period of time, but every time we do this, we incur potential costs and potential downsides.”
The research team plans to continue studying the molecular mechanisms that determine how stem cells balance survival and performance during aging.
“This gene is kind of the gateway we have opened for understanding what controls tradeoffs that are so important not only to the evolution of species but also to the aging of tissues within individuals,” Rand said.
Funding for this study was provided by the National Institutes of Health, NOMIS Foundation, Milky Way Research Foundation, Evolution Foundation, and the Korea National Research Foundation.
