The study reveals how the longevity gene protects brain stem cells from stress

Credit: Image courtesy of Pike Lab.

A new study by Weill Cornell Medical Investigators reports that a gene associated with an unusually long lifespan in humans protects brain stem cells from the harmful effects of stress.

Studies of people living more than 100 years have shown that many share an unusual copy of a gene called Forkhead Box Protein O3 (FOXO3). This discovery led Dr. J. Pike, assistant professor of pathology and laboratory medicine at Weill Cornell Medicine, and her colleagues to investigate how this gene contributes to brain health during aging.

In 2018, Dr. Pike and her team showed that mice lacking the FOXO3 gene in their brain are unable to cope with stressful conditions in the brain, which leads to progressive death of brain cells. Their new study, published January 28 Nature Communications, Reveals that FOXO3 maintains the ability of the brain to regenerate by preventing stem cells from dividing so that the environment supports the survival of new cells.

“Stem cells produce new brain cells, which are essential for learning and memory throughout our adult life,” said Dr. Pike, who is also a member of the Sandra and Edward Mayer Cancer Center at Weill Cornell Medicine. “If stem cells divide uncontrollably, they are depleted. It appears that the FOXO3 gene does its job by stopping the stem cells from dividing until after the pressure has passed.”

Many challenges such as inflammation, radiation, or a lack of adequate nutrients can strain the brain. But Dr. Pike and her colleagues looked specifically at what happens when brain stem cells undergo oxidative stress, which occurs when harmful types of oxygen build up in the body.

“We learned that the FOXO3 protein is directly modified by oxidative stress,” she said. This modification sends the protein to the nucleus of a stem cell where it turns on stress response genes.

The resulting stress response depletes a nutrient called s-adenosylmethionine (SAM). These nutrients are needed to help a protein called lamin form a protective covering around the DNA in the nucleus of a stem cell.

“Without SAM, the lamin cannot form this strong barrier and the DNA starts to leak out,” she said.

The cell mistakes this DNA for a viral infection, which triggers an immune response called a type 1 antiviral response. This causes the stem cells to become dormant and stop producing new nerve cells.

“This response is actually very good for stem cells because the external environment is not ideal for newborn neurons,” said Dr. Pike. If new cells are made under such stressful conditions, they will die. It is best for stem cells to remain dormant and wait for the tension to release neurons. “

The study may help explain why certain versions of FOXO3 are linked to an unusually long and healthy life – it may help people maintain a good reserve of brain stem cells. It may also help explain why regular exercise, which promotes FOXO3, helps maintain mental sharpness. But Dr. Pike cautioned that it was too early to tell whether this new information could be used to devise new treatments for brain disease.

“It could be a double-edged sword,” said Dr. Pike. “Over-activating FOXO3 can be very harmful. We don’t want to keep this around all the time.”

To better understand the processes involved, she and her colleagues will continue to study how FOXO3 is regulated and whether turning it on or off for a brief period is beneficial to health.


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