FOXO3 – defender of neurons
The main factor of brain longevity has been found
American biologists have found out that the FOXO3 gene protects brain stem cells from aging. The results of the study are published in the journal Nature Communications (Hwang et al., Cellular stress signaling activates type-I IFN response through FOXO3-regulated lamin posttranslational modification).
Scientists know that many super–long–livers - people whose age exceeds 100 years - share an unusual version of the gene responsible for the formation of the protein Forkhead box O3 (FOXO3). Now, researchers from the Cornell University College of Medicine, Weill Cornell Medicine, together with colleagues from Duke University, have described how this gene affects the brain.
In 2018, Dr. Jihe Paik and her team discovered that brain cells of mice that lack the FOXO3 gene cannot cope with oxidative stress and die. In a new study, the authors found that FOXO3 supports the brain's ability to regenerate by suspending the division of stem cells until the environment becomes favorable for the survival of new neurons.
Problems with the viability of brain cells may be associated with inflammation, the effects of radiation or a lack of nutrients. All these conditions cause additional stress on the brain. But the biggest negative impact on brain cells is caused by oxidative stress, in which harmful oxygen compounds accumulate in the body. It is this process that the authors studied.
"Stem cells produce new brain cells that are essential for lifelong learning and memorization. If stem cells divide uncontrollably, they are depleted. The FOXO3 gene does its job by not allowing stem cells to divide until the stress has passed," the researchers note.
Scientists have found out that the FOXO3 protein is directly modified by oxidative stress, and this modification sends the protein to the stem cell nucleus, where it turns on the stress response genes. The resulting reaction leads to the blocking of a nutrient called s-adenosyl methionine (SAM), which is necessary for a protein called lamin to form a protective shell around the DNA in the stem cell nucleus. As a result, the DNA begins to leak out, the cell mistakes it for a viral infection, which causes an immune response called the type I interferon response. One consequence of this response is that stem cells stop producing new neurons.
"In fact, this is very good, because at this time the external environment is not at all ideal for newborn neurons. If the new cells were in such stressful conditions, they would be killed. It is better for stem cells to stay dormant and wait until the stress disappears, then start producing neurons," explains Pike.
The results of the study help explain why certain versions of the FOXO3 gene are associated with an extremely long and healthy life – they help people keep a good supply of brain stem cells. But the authors warn that it is too early to talk about the possibility of creating new methods of rejuvenation and treatment of brain diseases.
"It can be a double-edged sword. Excessive activation of FOXO3, if it happens all the time, can be very harmful," the scientist warns.
Now the authors are investigating how the expression of FOXO3 can be regulated and whether it can be turned on and off for a short time.
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