Un gen relacionado con vidas inusualmente largas en humanos protege a las células madre cerebrales de los efectos dañinos del estrés, según un nuevo estudio realizado por investigadores del Centro Médico Weill Cornell de Estados Unidos
Los estudios realizados en personas que viven más de 100 años han demostrado que muchos comparten una versión poco común de un gen llamado Forkhead, o proteína de caja Forkhead O3 (FOXO3). El descubrimiento realizado por el equipo que lidera el doctor Jihye Paik aporta conocimientos al estudio del envejecimiento.
En un estudio anterior, esos mismos investigadores habían comprobado en roedores que la ausencia de ese gen provoca una rápida muerte neuronal porque el cerebro no es capaz de afrontar diferentes situaciones estresantes. Este nuevo estudio muestra, en seres humanos, que la presencia del gen produce el efecto contrario.
Cuando el gen está presente las células madre del cerebro producen nuevas neuronas, que según explican los especialistas son esenciales para procesos como el aprendizaje y la memoria a lo largo de la vida adulta. Si las células madre se dividen sin ningún tipo de control, se agotan y no pueden efectuar esa tarea vital de regeneración del cerebro.
El gran aporte del gen FOXO3 es que logra evitar que las células madre se dividan hasta tanto haya pasado el estrés. De esta forma, permite que puedan esperar el momento ideal para realizar su tarea de reproducción neuronal, incrementando notablemente la efectividad del proceso.
In 2018, Dr. Paik and her team showed that mice who lack the FOXO3 gene in their brain are unable to cope with stressful conditions in the brain, which leads to the progressive death of brain cells. Their new study, published Jan. 28 in Nature Communications, reveals that FOXO3 preserves the brain’s ability to regenerate by preventing stem cells from dividing until the environment will support the new cells’ survival.
“Stem cells produce new brain cells, which are essential for learning and memory throughout our adult lives,” said Dr. Paik, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “If stem cells divide without control, they get depleted. The FOXO3 gene appears to do its job by stopping the stem cells from dividing until after the stress has passed.”
Many challenges like inflammation, radiation or a lack of adequate nutrients can stress the brain. But Dr. Paik and her colleagues looked specifically what happens when brain stem cells are exposed to 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 into the nucleus of the stem cell where it turns on stress response genes.
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 nucleus of the stem cell.
“Without SAM, lamin can’t form this strong barrier and DNA starts leaking out,” she said.
The cell mistakes this DNA for a virus infection, which triggers an immune response called the type-I interferon response. This causes the stem cell to go dormant and stop producing new neurons.
“This response is actually very good for the stem cells because the outside environment is not ideal for newly born neurons,” Dr. Paik explained. “If new cells were made in such stressful conditions they would be killed. It’s better for stem cells to remain dormant and wait until the stress is gone to produce neurons.”
The study may help explain why certain versions of the FOXO3 are linked to extraordinarily long and healthy lives—they may help people keep a good reserve of brain stem cells. It may also help explain why regular exercise, which boosts FOXO3 helps preserve mental sharpness. But Dr. Paik cautioned it is too early to know whether this new information could be used to create new therapies for brain diseases.
“It could be a double-edged sword,” Dr. Paik explained. “Over activating FOXO3 could be very harmful. We don’t want to keep this on all the time.”
To better understand the processes involved, she and her colleagues will continue to study how FOXO3 is regulated and whether briefly turning it on or off would be beneficial for health.
