Polish researchers publishing in Aging have discovered that the well-known senolytic combination of dasatinib and quercetin improves the cognitive capabilities of older rats.
Understanding neuroplasticity
While new neurons can be formed in the adult hippocampus through neurogenesis [1], learning and behavioral changes caused by changes in the prefrontal cortex are not the result of this process. Instead, neurons in the prefrontal cortex form protrusions called dendritic spines, which then go on to become synapses between other neurons.
Rather than the mass neuronal death seen in Alzheimer’s disease, it is this fundamental ability to form new connections that declines with “normal” aging [2]. The downstream effects of this gradual loss of ability affect practically every aspect of cognitive function, including reasoning, memory, psychomotor abilities, and your ability to remember and understand the contents of this paragraph along with my ability to write it.
As neuroplasticity is directly related to changes in gene expression, it has been shown to be strongly affected by epigenetics, specifically the methylation of histone H3 [3]. The researchers hypothesized that this change in gene expression is linked to the accumulation of senescent cells, specifically due to the senescence-associated secretory phenotype (SASP).
In order to test their hypothesis, the researchers administered the well-known senolytic combination of dasatinib and quercetin (D+Q) to rats.
A series of positive effects
In this experiment, rats were trained to avoid a specific place through small electric shocks. As expected, older rats performed worse on this task than younger rats, which learned to avoid the specific place quickly. However, rats that had performed poorly on this task performed very similarly to younger rats after an administration of D+Q, showing that their short-term memory and skill learning abilities were significantly improved, and they retained this improvement even five weeks after administration of D+Q had ceased. D+Q administration had no apparent effect on younger rats.
The researchers then examined the effects of the SASP on inflammatory cytokine levels. While each individual cytokine was not strongly affected, rats given D+Q had a broad decrease in nearly all of the cytokines tested, including interleukins and interferon-γ. The anti-inflammatory cytokine IL-10, which actually increases with aging, was further increased with D+Q in both young and old animals.
In the next step in this experiment, the researchers carefully examined the dendritic spines of the animals, focusing on the hippocampus. The basal dendrites were unaffected; however, the apical dendritic spines of aged animals given D+Q were shown to be thicker and substantially longer than those of their untreated counterparts, corresponding to their increased ability to retain memory and knowledge.
Finally, the researchers took a look at H3 histone methylation, where the differences were stark and clear. Correlating with cognitive decline, the methlylation of the H3K9me3 site increases with aging, while that of H3K27me3 decreases; D+Q treatment halved H3K9me3 while significantly increasing H3K27me3.
Conclusion
The role of inflammaging and the SASP on cognitive decline has remained an open question, and this study has significantly helped to close it. While senolytics have not been shown to affect diseases such as Alzheimer’s and are unlikely to be the last word in “normal” cognitive decline, this study shows that they have a significant effect on the ability of older animals to perform basic cognitive tasks, right down to the neuronal level.
As always, human trials are required to see whether or not these or any other senolytics have positive effects on the human brain and whether or not targeting inflammaging is a viable method of allowing older people to retain their cognitive abilities.
Literature
[1] Fares, J., Bou Diab, Z., Nabha, S., & Fares, Y. (2019). Neurogenesis in the adult hippocampus: history, regulation, and prospective roles. International Journal of Neuroscience, 129(6), 598-611.
[2] Bloss, E. B., Janssen, W. G., Ohm, D. T., Yuk, F. J., Wadsworth, S., Saardi, K. M., … & Morrison, J. H. (2011). Evidence for reduced experience-dependent dendritic spine plasticity in the aging prefrontal cortex. Journal of Neuroscience, 31(21), 7831-7839.
[3] Parkel, S., Lopez-Atalaya, J. P., & Barco, A. (2013). Histone H3 lysine methylation in cognition and intellectual disability disorders. Learning & Memory, 20(10), 570-579.
