With advancing age, the mechanisms for healing and tissue renewal following injuries slow down. This happens in muscles because muscle stem cells cease to operate optimally, impeding muscle tissue growth.
A recent investigation from UCLA has pinpointed the root cause of this age-related impairment. The researchers determined that these cells prioritize self-preservation over full functionality. This “survival bias” ensures the cells persist but drastically curtails their aptitude for muscle repair.
Studies conducted on mice revealed that aging muscle stem cells accumulate elevated concentrations of a specific protein, which diminishes their regenerative capacity and ability to rebuild muscle tissue when needed. Conversely, there is an upside: this same protein acts as a protective agent, helping the cells persist in the harsh environment of older tissues.
When scientists contrasted the muscle stem cells of young and aged mice, they identified a role for the NDRG1 gene. In the muscles of older mice, the levels of the protein coded by this gene were roughly 3.5 times greater compared to those found in younger specimens.
NDRG1 functions as a double-edged sword within aging muscle. On one hand, it safeguards the stem cells, aiding their endurance. On the other hand, it acts as a restraint, dampening the activity of the mTOR signaling pathway, which normally initiates cell growth and repair. This suppression makes it harder for stem cells to engage and mend damaged musculature.
However, when the investigators reduced NDRG1 levels, muscle regeneration showed improvement, confirming this gene’s vital role in the muscle aging process. Yet, this modification carried a drawback. Without NDRG1’s protective effect, only a small portion of the muscle stem cells managed to survive. Consequently, the muscle’s ability to recover from successive injuries diminished, suggesting a tight coupling between survival and restoration in aged tissues.
“Stem cells in younger animals possess hyper-functional traits, excelling at their immediate task—a sprint—but they aren’t geared for long-term survival. They can run the 100-meter dash but won’t finish even half a marathon,” stated experts at the UCLA David Geffen School of Medicine. “Conversely, aged stem cells are like marathon runners: slower to react, but better equipped for sustained effort. But what grants them such endurance over long hauls is precisely what makes them ill-suited for the sprint.”
To validate their findings, the researchers tested muscle stem cells from both young and old mice both in vitro and within living tissue. Across all trials, a clear trend emerged. As NDRG1 levels increased in older muscles, stem cells activated more slowly and repaired damage less rapidly, but they simultaneously exhibited greater resilience and better long-term survival prospects.
Put simply, stem cells failing to accrue sufficient NDRG1 protein eventually perish. What remains is a population of cells that rebuild muscle more slowly but are tougher and more durable, capable of enduring longer under the taxing conditions of aging tissues.
These discoveries could lead to therapeutic interventions that aim to strike a balance between stem cell activation and their endurance, although Rando cautions: “There’s no such thing as a free lunch. We might enhance the function of aging cells temporarily for specific tissues, but every time we do so, it will involve a potential cost and possible adverse outcomes.”
The research team plans to delve deeper into the molecular processes governing the equilibrium between persistence and performance.
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