As we age, cognitive functions like memory and learning often decline. A key contributor to this process is the reduced ability of the brain to generate new neurons, a function reliant on neural stem cells. Now, research published in , suggests a potential pathway to rejuvenate these aging cells, offering a glimmer of hope for slowing or even reversing aspects of brain aging.
Scientists at the Yong Loo Lin School of Medicine at the National University of Singapore have identified a protein, cyclin D-binding myb-like transcription factor 1 (DMTF1), that appears to act as a crucial regulator of neural stem cell activity, particularly as the brain ages. Their findings, published in Science Advances, indicate that DMTF1 plays a role in restoring the regenerative capacity of these cells, even when age-related damage has begun to accumulate.
Transcription factors, like DMTF1, are proteins that control which genes are turned on or off within cells. This control is essential for directing cellular function. Neural stem cells are responsible for creating new neurons, vital for learning and memory. With age, these stem cells lose their ability to renew and proliferate, contributing to cognitive decline. The research team, led by Assistant Professor Ong Sek Tong Derrick, with Dr. Liang Yajing as first author, sought to understand the biological changes that lead to this weakening of neural stem cells, hoping to identify potential therapeutic targets.
The study involved analyzing human neural stem cells and utilizing experimental models designed to mimic the aging process, specifically focusing on conditions where telomeres – protective caps on the ends of DNA – are dysfunctional. Telomere shortening is a well-established marker of cellular aging, as they fray with each cell division, eventually impairing the cell’s ability to grow and divide.
The researchers discovered that levels of DMTF1 were significantly lower in “aged” neural stem cells. Importantly, restoring DMTF1 expression revitalized the stem cells’ ability to proliferate, suggesting a direct link between the protein and cellular regeneration. This finding points to DMTF1 as a potential “switch” to reactivate dormant stem cells.
Further investigation revealed how DMTF1 restores function. The protein appears to influence gene accessibility – essentially, how easily the cell can access and activate specific genes. DMTF1 regulates the expression of Arid2 and Ss18, which are components of the SWI/SNF chromatin remodeling complex. This complex works to loosen the structure of DNA, allowing growth and proliferation-related genes to become active. This process is also linked to the activation of E2F target genes, which are known to be involved in cell cycle regulation and proliferation.
DMTF1 doesn’t just signal stem cells to proliferate; it actively works to make that proliferation possible by opening up access to the necessary genetic machinery. The researchers describe DMTF1 as helping to create an environment where stem cells are “permitted” to grow and divide again.
While these findings are promising, the researchers emphasize that the study was primarily conducted in a laboratory setting. The next steps involve determining whether increasing DMTF1 levels in models of aging – including those with shortened telomeres or undergoing natural aging – can actually increase the number of neural stem cells and, crucially, improve learning and memory function. Safety is also paramount; any strategy that increases cell proliferation in the brain must be carefully evaluated to ensure it doesn’t increase the risk of brain tumors.
Looking ahead, the team suggests exploring small molecule compounds that can safely and effectively activate DMTF1, rather than directly administering the protein. DMTF1 represents a compelling target for future therapies aimed at combating age-related cognitive decline, but significant research remains to validate its efficacy and safety in a clinical setting. The protein has been identified as a potential candidate to restore the “proliferation switch” in aging neural stem cells, but translating these laboratory findings into treatments for human brain aging will require further investigation.
*Reference: DMTF1 up-regulation rescues proliferation defect of telomere dysfunctional neural stem cells via the SWI/SNF-E2F axis. Science Advances, ; 12 (1) DOI: 10.1126/sciadv.ady5905.
