Behind age-related cognitive decline lies a little-known biological phenomenon: our neural stem cells, those neuron factories, don't switch off randomly. Singaporean researchers have just identified a previously ignored mechanism that controls their dormancy. This advance, published in
Science Advances, helps us better understand how our brain loses plasticity over the years.
Brain aging follows an implacable logic. Over time, neural stem cells (NSCs) – those precious cells capable of turning into functional neurons – progressively enter a dormant state. It's as if they are retiring after decades of good and loyal service. This shutdown is inevitably accompanied by a decline in cognitive abilities, with memory and learning becoming less efficient due to a lack of new neurons to renew our brain circuits.
The detector of cellular youth
To understand this phenomenon, one must look at telomeres, those protective caps located at the ends of our chromosomes. With each cell division, they wear down a little more, a process comparable to a shoelace that gradually frays over time. When this wear becomes too significant, neural stem cells lose their ability to divide and eventually die or become senescent. This programmed erosion constitutes one of the fundamental clocks of brain aging.
The team from the National University of Singapore has identified the key player in this process: the protein DMTF1. A true genetic conductor, this molecule acts as a switch capable of turning the expression of certain genes on or off. Analyses revealed its abundant presence in young neural stem cells, while aged cells are dramatically lacking it. This correlation immediately intrigued the researchers.
In the laboratory, scientists artificially increased the amount of DMTF1 in aging neural stem cells, from murine models and human cultures. The result exceeded their expectations: the production of new neurons resumed, as if the biological clock had been rewound. Remarkably, this revival occurs without the length of the telomeres being restored, indicating that DMTF1 uses an alternative pathway to bypass the problem.
The promises and therapeutic limitations
The discovered mechanism proves subtler than a simple repair. DMTF1 activates two auxiliary genes, named Arid2 and Ss18, which in turn stimulate other genes involved in cell growth. It's an activation cascade that allows the restarting of the neuronal production cycle despite DNA wear. This bypass strategy opens up entirely new therapeutic perspectives.
While the enthusiasm is legitimate, the researchers call for the greatest caution. The experiments were conducted in the laboratory on cells and mice, not on humans. The step towards a clinical application remains immense. Derrick Sek Tong Ong, a chemical biologist who participated in the study, insists on the need to first perfectly understand these mechanisms before considering any therapeutic intervention.
A major obstacle stands in the way of future applications: the cancer risk. DMTF1 stimulates cell division, and uncontrolled activation could promote the emergence of tumors. The next steps of research will therefore have to evaluate with extreme rigor the conditions under which this protein could be used safely. The balance between neuronal regeneration and uncontrolled proliferation must be determined with precision.
To go further: What are telomeres and why do they shorten?
Look at your shoelaces. At each end, a small plastic tip prevents the lace from fraying. In our cells, telomeres play exactly that role. They are protective caps located at the ends of our chromosomes, those long filaments that contain our DNA, the precious instruction manual of our body. Without these protections, our genetic material would get damaged with each use.
Every time a cell divides to create a new one, it must copy the entirety of its DNA. But this copying process is imperfect: the very end of the chromosome is not copied. As a result, telomeres shorten slightly with each division, like a candle that burns and diminishes each time it is lit. The longer a cell has lived and divided often, the shorter its telomeres are.
When telomeres become too short, they can no longer effectively protect the DNA. The cell then receives an alarm signal: it stops dividing, enters senescence (a state of forced "retirement"), or dies. This is why cells eventually become exhausted with age: they have reached the limit of their division "counter." This mechanism acts as a biological clock, one of the fundamental causes of the aging of our tissues.
Article author: Cédric DEPOND