As people grow older, the brain gradually loses its ability to repair and renew itself. This decline is linked to reduced activity of neural stem cells, which play a crucial role in memory, learning and overall brain health. New research suggests that a single gene may help reverse some of this damage, offering fresh hope for tackling brain ageing and cognitive decline. The findings were published in Science Advances.
The study focused on neural stem cells affected by telomere dysfunction, a hallmark of ageing. Telomeres are protective caps at the ends of chromosomes that shorten over time, especially in cells with low levels of telomerase. When telomeres become critically short, cells enter a stressed state and stop dividing properly, contributing to impaired neurogenesis.
Using a mouse model with telomerase deficiency, researchers found that a gene known as DMTF1 was significantly reduced in neural stem cells with dysfunctional telomeres. This drop in DMTF1 was also observed in human neural progenitor cells lacking telomerase activity. The finding was unexpected, as DMTF1 has often been studied in the context of cancer biology rather than brain ageing.
When scientists increased DMTF1 levels in these telomere dysfunctional cells, the results were striking. Proliferation markers such as MCM2 rose, DNA damage signals fell, and the cells regained much of their capacity to divide. Importantly, this rescue effect did not lengthen the damaged telomeres themselves, suggesting that DMTF1 works through a different pathway to restore neural stem cell growth.
Further experiments showed that removing DMTF1 had the opposite effect. In both mouse and human neural stem cells, silencing DMTF1 reduced cell division, increased cell death and impaired the formation of neurospheres, which are clusters that reflect stem cell activity. Human cortical organoids lacking DMTF1 were smaller and contained fewer proliferating stem cells, reinforcing its importance in early brain development and maintenance.
At a molecular level, DMTF1 appears to regulate two key genes, Arid2 and Ss18, which are components of the SWI/SNF chromatin remodelling complexes . These complexes help control which genes are switched on or off by modifying chromatin structure. When DMTF1 levels fell, Arid2 and Ss18 expression dropped, leading to reduced activity of genes involved in the cell cycle and DNA replication.
The researchers found that this effect converged on the E2F pathway, a central driver of cell cycle progression . Without sufficient DMTF1, there was less activation of E2F target genes and more repressive chromatin marks at their promoters. In simple terms, the machinery that allows neural stem cells to enter and progress through the cell cycle became less efficient.
Interestingly, DMTF1 has previously been described as a tumour suppressor in certain cancers. In neural stem cells, however, it appears to promote healthy proliferation. The authors suggest that DMTF1 may act in a cell type specific manner, suppressing uncontrolled growth in some tissues while supporting regenerative capacity in others.