Genes associated with abnormally long lifespan in humans protect brain stem cells from the harmful effects of stress, according to a new study by researchers at Weil Cornell Medicine.
Studies of humans living for over 100 years have shown that many share a rare version of a gene called the forkheadbox protein O3 (FOXO3). With that discovery, Dr. Jihye Paik, an associate professor of pathology and laboratory medicine at Weill Cornell Medicine, and her colleagues investigated how this gene contributes to brain health during aging.
In 2018, Dr. Pike and her team showed that mice lacking the FOXO3 gene in the brain could not cope with stress conditions in the brain, leading to progressive death in the brain. cell..Their new study was published on January 28th Nature CommunicationsReveals that FOXO3 maintains the ability of the brain to regenerate by preventing Stem cells From division to the environment supporting the survival of new cells.
“Stem cells produce new brain cells, which are essential for our learning and memory as a whole. Adult life“When stem cells divide uncontrolled, they are depleted. The FOXO3 gene appears to play its role by stopping stem cell division,” said Dr. Pike, a member of the Sandra and Edward Meyer Cancer Center at Weil Cornell Medicine. is. stress It has passed. “
Many challenges, such as inflammation, radiation, and lack of proper nutrients, can stress the brain.However, Dr. Pike and her colleagues specifically investigated what happens when brain stem cells are exposed. Oxidative stressIt occurs when harmful types of oxygen accumulate in the body.
“I learned that the FOXO3 protein is directly modified by oxidative stress,” she said.This modification sends the protein to the nucleus of the stem cell, where it turns on the stress response. gene..
The resulting stress response leads to the depletion of a nutrient called s-adenosylmethionine (SAM). This nutrient is needed to help a protein called lamin form a protective envelope around the DNA in the stem cell’s nucleus.
“Without SAM, Lamin would not be able to form this strong barrier and DNA would begin to leak,” she said.
Cells mistake this DNA for a viral infection and trigger an immune response called the type I interferon response. This puts the stem cells in a dormant state and stops the production of new neurons.
“This response is actually very good for stem cells, as the external environment is not ideal for newly born neurons,” explained Dr. Pike. “When new cells are created under these stressful conditions, they are killed. It is better to keep the stem cells dormant and wait until the stress is gone to generate neurons.”
This study may help explain why certain versions of FOXO3 are associated with a very long and healthy life-they may help people maintain adequate reserves. There is Brain stem cells.. It may also help explain why regular exercise that boosts FOXO3 helps maintain mental sharpness. However, Dr. Pike warned that it was too early to know if this new information could be used to create new treatments. brain sick.
“It may be a double-edged sword,” explained Dr. Pike. “Excessive activation of FOXO3 can be very harmful. We don’t want to keep this all the time.”
To better understand the processes involved, she and her colleagues discuss how FOXO3 is regulated and whether it is beneficial to health to turn it on or off for a short period of time. I will continue to study.
Inaphan and other cell stress signaling activates type I IFN responses through post-translational modification of lamin regulated by FOXO3. Nature Communications (2021). DOI: 10.1038 / s41467-020-20839-0
Weil Cornell Medical College
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