Clearing Old Brain Progenitor Cells Paves the Way For New Neurons
Our brains decay with age partly because cells become senescent, a phenomenon of growth and replicative arrest. But which brain cells shut down into senescent silence and drive the withering away of cognition remains to be fully understood.
New research from the Hospital for Sick Children in Toronto demonstrates that senescent neural progenitor cells (NPCs), hubs of cells that generate new neurons (neurogenesis) well into adulthood, accumulate in the brain with age. As mice reach middle age, a substantive proportion of NPCs become senescent, thereby making them unavailable to generate new neurons while also adversely affecting neurogenesis from their non-senescent neighbors. Published in Stem Cell Reports, this study showed that eliminating these senescent NPCs caused a rapid increase in the non-senescent NPC-based generation of new neurons and had long-term effects in middle-aged mice, such as improvements to cognitive functions like memory and learning.
“Our results provide further support for the notion that excessive senescence is a driving factor behind aging, and even late-life reduction of these cells can rejuvenate and restore the function of the stem cell niche,” says senior author David Kaplan of The Hospital for Sick Children (SickKids) in Toronto, Canada. “Moreover, they identify stem cells as a key cellular target, potentially explaining the widespread effects of senescent cells on tissue decline.”
The adult mammalian brain generates new neurons…until it doesn’t
The adult human brain contains billions of cells made of an ever growing list of cell types. At the core of this diversification are neural stem and precursor cells that generate new neurons. These cells are not only important for the growth of the brain during development but are critical for sustaining several cognitive functions well into life.
NPCs reside in two main regions deep inside of the mammalian brain, the hippocampus and lateral ventricles. The NPCs in the hippocampus make neurons necessary for memory formation and consolidation. In contrast, the ventricular NPCs make olfactory bulb neurons that contribute to scent discrimination and olfactory learning.
But the ability for NPCs to contribute to neurogenesis appears to wane with age. For example, hippocampal neurogenesis declines rapidly with age, coincident with reduced stem cell activity and decreased hippocampus-dependent cognitive functions like learning and memory. While several mechanisms have been implicated in this age-associated decline in neurogenesis, the underlying causes are unclear.
Senescent neural precursor cells accumulate with age
In this study, Dr. Kaplan and his colleagues showed that aging has two distinct effects on hippocampal NPCs in mice. First, the proliferation of NPCs decreases, in part likely due to increased senescence. Second, the non-senescent NPCs that remained at one year of age were defective in their ability to replicate and make neurons. Further, by blocking neurogenesis, these senescent NPCs appear to disrupt cognition related to learning and memory.
“Stem cells last throughout life and, like us, are subjected to the ravages of aging, environmental stressors, and deterioration of the machinery that enables them to function optimally,” Kaplan explains. “To survive, many stem cells revert to a dormant, unresponsive, and inactive state. Our goal was to wake up these dormant cells and, in doing so, enable them to carry out their biological functions that facilitate learning, memory, and brain repair.”
But what the Toronto-based researchers found was that in order to wake some of the NPCs up, they had to wipe the senescent ones out. When the research team from the Hospital for Sick Children used a drug called ABT-263 that specifically targets senescent cells for elimination, they observed a rapid increase in NPC replication and neurogenesis. With just one application of ABT-263, Kaplan and colleagues were able to stimulate NPC proliferation after 5 days.
This sharp burst of neurogenesis had long-term effects in middle-aged mice, leading to improvements in cognition. Specifically, one month after ABT-263 treatment, adult-born hippocampal neuron numbers increased, and hippocampus-dependent spatial memory was enhanced.
“When we improve the neighborhood by getting rid of deleterious cells in the stem cell niche, we begin to mobilize and wake up the dormant stem cells, enabling them to generate new neurons for spatial learning and memory,” Kaplan says. “We think that it is the senescent stem cells we removed that were responsible for improving the function of the normal non-senescent stem cells in the niche.”
A remaining question is whether reducing the number of senescent stem cells alone will improve normal stem cell function and cognition or if removing other senescent cell types is also important. While these conditions are more specific for removing senescent stem cells, it is likely that treatments that reduce the amounts of all deleterious senescent cells in the brain will produce the best outcomes.
References:
Fatt MP, Tran LM, Vetere G, et al. Stem Cell Reports. 2021;S2213-6711(21)00649-4.