A surprising discovery made by scientists from UCLA, published in Science, reveals that aging muscles heal more slowly due to the protein NDRG1 building up to act like a brake in older muscle stem cells, which slows the ability for the cells to go into repair mode after an injury. However, the surprise is that this protein also helps the cells survive the stresses of aging to allow them to last longer.
This new study, conducted in mice, suggests that some biological changes that are linked to aging may not be simply signs of decline, but rather, they may also serve as protective adaptations that help stem cells survive.
“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.”
Slower Muscle Repair
Muscle stem cells from old and young mice were compared for this study. The analysis revealed that the levels of protein NDRG1 increased rather dramatically with age to reach concentration levels that were 3.5 times higher in older stem cells.
The protein functions like a brake within the cells, suppressing the mTOR signaling pathway, which typically helps to drive cell growth and activation.
To determine if the protein was contributing to slower muscle recovery, NDRG1 activity was blocked within the mice, which revealed that when blocked, the older muscle stem cells quickly regained youthful behaviors and improved muscle repair after injury.
However, this improvement was paired with a drawback, as without the protective effects of the protein, fewer stem cells were observed to remain alive over time. This decline resulted in the tissues becoming less capable of regenerating after repeated injuries.
| Credit: Jengmin Kang, Rando Lab
Stem Cell Performance vs Survival
“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.”
These results were confirmed using several different methods, and the patterns were found to remain consistent. Higher levels of the protein reduced cells’ ability to rapidly activate and repair muscle, while increasing resilience and long-term survival.
Survivorship Bias
“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.
“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
“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.”
“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.
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https://stemcell.ucla.edu/news/muscle-stem-cells-build-resilience-lose-regenerative-power-age
