New research from the University of California, Los Angeles (UCLA) and the National University of Singapore (NUS) has identified distinct cellular mechanisms contributing to age-related decline in stem cell function.
A UCLA study in mice revealed a trade-off between rapid muscle repair and long-term muscle stem cell survival, linked to the protein NDRG1. Separately, the NUS study, using human stem cells and mouse models, identified the protein DMTF1 as crucial for neural stem cell regeneration in the aging brain, potentially offering new avenues for addressing cognitive decline.
Muscle Stem Cell Function and Survival
Researchers at UCLA conducted a study in mice to investigate age-related changes in muscle stem cells. The study found that a protein designated NDRG1 increased significantly with age, becoming 3.5 times more abundant in muscle stem cells from older mice compared to younger mice. NDRG1 functions as a cellular regulator by suppressing the mTOR signaling pathway, which is associated with cell activation and growth. This suppression contributes to a slower activation rate of aged muscle stem cells.
When scientists inhibited NDRG1 activity in aged mice, the muscle stem cells exhibited characteristics similar to those found in young cells, reactivating rapidly and accelerating muscle repair following injury. However, this intervention led to a reduced number of surviving stem cells over time, which subsequently impaired the muscle tissue's capacity for regeneration after repeated injuries.
The findings suggest that some age-related cellular changes, such as slower tissue repair, may represent protective adaptations to prevent the complete depletion of the stem cell population. This concept was described as "cellular survivorship bias," where cells with higher NDRG1 levels may survive longer despite being less efficient at rapid repair.
"Future therapeutic approaches aiming to combat age-related decline would need to balance both the capacity for rapid tissue repair and the long-term survival of cellular populations."
— Dr. Thomas Rando, Senior Author, UCLA Study
This research was published in the journal Science.
Neural Stem Cell Regeneration in the Brain
A separate study conducted by scientists at the National University of Singapore (NUS) focused on the age-related decline in neural stem cell (NSC) production, which can impact cognitive functions such as learning and memory. The research identified cyclin D-binding myb-like transcription factor 1 (DMTF1) as a protein central to NSC regeneration.
Experiments involving human NSC analysis and mouse models demonstrated that DMTF1 is repressed in aged neural stem cells. Conversely, restoring DMTF1 levels encouraged NSCs to grow and divide, potentially facilitating neuron production. DMTF1 was found to activate helper genes, including Arid2 and Ss18, which promote cell growth through chromatin remodeling. This mechanism appeared to rescue the proliferation of neural stem cells impaired by telomere shortening, a known sign of aging, even without restoring telomere length itself.
"Understanding these mechanisms provides a foundation for studying age-related cognitive decline."
— Derrick Sek Tong Ong, Senior Author, NUS Study
While the findings suggest that therapies targeting DMTF1 could potentially reverse age-related decline in brain stem cells, researchers caution that the study is in its early stages. They also noted that manipulating proteins that promote cell growth requires careful study due to potential risks, such as excessive cell duplication that could lead to cancer. This research was published in the journal Science Advances.