ABL1 Inhibition Increases Neural Stem Cell Activity in the Aging Brain

Putting stem cells back to work is the theme of a great of the research that takes place in the regenerative medicine community. Stem cells are responsible for producing a supply of daughter somatic cells, required to replace losses and maintain functional tissue. Stem cell activity throughout the body declines with age, however. Much of this decline is not caused by intrinsic cell and tissue damage that would prevent activity, but is rather an evolved reaction to the presence of that damage.

Suppressing stem cell activity likely serves to reduce cancer risk in later life. The more cell activity there is in a damaged environment, the greater the odds that cancerous cells will arise. Unfortunately, the consequence of a reduced rate of rapid death by cancer is the certainty of a slow and drawn out decline due to organ failure. Thus, there are projects such as the one noted here, in which scientists search for ways to force stem cells into greater activity, despite the presence of damage.

By tracing individual neural stem cells (NSCs) in mice over the course of several months, researchers identified "short-term NSCs" that quickly differentiate into more specialized neurons, and "long-term NSCs" that continually divide and replicate themselves to maintain an ongoing reserve of stem cells with the ability to generate many different cell types in the brain. This key population of long-term NSCs divided less often and failed to maintain their numbers as the mice aged.

The scientists next examined thousands of genes in the long-term NSCs, which were dividing less often and had slipped into an inactive state known as quiescence. The gene activity of the quiescent NSCs varied greatly in young versus middle-aged animals. As expected, there were changes in genes that control how long-term NSCs divide, as well as generate new neurons and other brain cells. Remarkably, there were many important changes in gene activity related to biological aging at younger ages than anticipated. These pro-aging genes make it more difficult for cells to repair damage to their DNA, regulate their genetic activity, control inflammation, and handle other stresses. Among the pro-aging genes, the scientists were most intrigued by Abl1, which formed the hub of a network of interrelated genes.

Using an existing, FDA-approved chemotherapy drug called Imatinib, scientists could easily inhibit the activity of the gene Abl1. The scientists gave older mice doses of Imatinib for six days. After the drug blocked the activity of the gene Abl1, the NSCs began to divide more and proliferate in the hippocampus, the part of the brain responsible for learning and memory. We've succeeded in getting neural stem cells to divide more without depleting, and that's step one. Step two will be to induce these stem cells to make more neurons. Step three will be to demonstrate that these additional neurons actually improve learning and memory."

Link: https://www.genengnews.com/news/neural-stem-cells-decline-during-aging/

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