Scientists have shown that clearing senescent neural precursor cells with the senolytic drug navitoclax reverses the age-related decline in neurogenesis and improves spatial memory in mice [1].
Not to be replaced
The brain is an organ of special concern for geroscientists. It is theorized that we might soon be able to replace many aging organs, such as the kidneys, liver, or heart, but for obvious reasons, it is impossible to replace the brain. Since the brain is prone to age-related decline that leads to dementia, we must find a way to maintain it in working order for as long as possible.
Neurons are very long-lived cells that do not proliferate. All neurons differentiate from multipotent neural precursor cells (NPCs) that are, in turn, a product of differentiation of neural stem cells. Until the 1990s, it had been thought that neurogenesis – that is, the creation of new neurons – does not happen in an adult brain at all. Now we know of two or three regions in the brain, most notably the hippocampus, where adult neurogenesis continues, although its pace slows significantly as we age.
The reasons for this decline are not well known, but research shows that reduced neurogenesis in the hippocampus is firmly linked to the development of Alzheimer’s disease [2]. In this new paper, a group of scientists analyzed the role of cellular senescence in the age-related decline in hippocampal neurogenesis and how it can be mitigated by a popular senolytic Navitoclax.
Senescence slows neurogenesis
First, the researchers confirmed that neurogenesis slows in mice beginning at a young age. In their experiments, between 6 weeks and 3 months of age, the number of immature neurons in the hippocampus decreased by 50%, and by the end of the first year of life, the difference rose to a whopping 90%. That is, by the time mice reach middle age, their hippocampal neurogenesis almost grinds to a halt. Interestingly, the number of neural stem cells did not decline, but these stem cells were much less proliferative than in young age and produced fewer NPCs.
This decline in neurogenesis coincided with the accumulation of senescent cells in the hippocampus, as the researchers showed by analyzing several senescence markers, such as ß-galactosidase (ß-Gal). Most senescent cells happened to be NPCs.
Can an anti-cancer drug help?
Navitoclax is an experimental anti-cancer drug that induces apoptosis (cellular death) in senescent cells. It is one of the most well-researched senolytic compounds. Navitoclax proved to be effective in killing senescent NPCs, both in vitro and in vivo. In mice, navitoclax treatment eliminated 45% of ß-Gal-positive cells in the hippocampus, most of them NPCs. More importantly, the treatment led to an almost 50% increase in the number of immature neurons, indicating strong recovery of neurogenesis.
To confirm that neurogenesis rebounds due to the clearing of senescent cells, the scientists constructed a noteworthy genetic model of cellular senescence. They inserted an artificial gene into the promoter of another gene that produces the protein p16, which is a marker of cellular senescence. This transgene coded for a toxic protein and could be turned on by an introduction of a certain drug. That means that when the scientists introduced the drug into the mice’s hippocampi, it killed off only those cells that were expressing p16 – i.e., senescent cells. This genetic ablation of senescent cells recapitulated the neurogenesis-stimulating effect of navitoclax.
Hippocampus plays a crucial role in our memory function, especially in spatial memory [3]. Consequently, the reinvigoration of hippocampal neurogenesis led to a significant improvement in the spatial memory of 12-month-old mice.
The authors conclude that senescent cells “directly contribute to neurogenic decline in the middle-aged hippocampus, and that clearance of these cells can partially restore hippocampal neurogenesis and function”. Not only do senescent NPCs stop producing neurons themselves, the SASP also seems to adversely affect the differentiation of the neighboring non-senescent cells – not just of NPCs, but of their precursors, neural stem cells, as well.
Conclusion
Cellular senescence is clearly associated with aging, but this relationship is very complex, and scientists continue to elucidate its specific aspects. This new paper shows that eliminating senescent cells from the hippocampal niche can reverse the age-related decline in neurogenesis and can potentially be effective against dementias, such as Alzheimer’s disease. The fact that the drug used was a known anti-cancer medication underscores the systemic impact of cellular senescence.
Literature
[1] Fatt, M. P., Tran, L. M., Vetere, G., Storer, M. A., Simonetta, J. V., Miller, F. D., … & Kaplan, D. R. (2022). Restoration of hippocampal neural precursor function by ablation of senescent cells in the aging stem cell niche. Stem Cell Reports.
[2] Mu, Y., & Gage, F. H. (2011). Adult hippocampal neurogenesis and its role in Alzheimer’s disease. Molecular neurodegeneration, 6(1), 1-9.
[3] Broadbent, N. J., Squire, L. R., & Clark, R. E. (2004). Spatial memory, recognition memory, and the hippocampus. Proceedings of the National Academy of Sciences, 101(40), 14515-14520.
