Longevity gene could help maintain cognitive function during aging

WASHINGTON - A gene known for its link with longevity in roundworms and humans could affect the function of stem cells that generate new neurons in the adult brain, according to researchers at Stanford University School of Medicine.

The rodent study indicated that the gene might play an important role in maintaining cognitive function during aging.

“It’s intriguing to think that genes that regulate life span in invertebrates may have evolved to control stem cell pools in mammals,” said Dr. Anne Brunet, senior author of the research.

Adult brain maintains two small caches of neural stem cells, which can both self-renew and give rise to neurons and other cells known as oligodendrocytes and astrocytes.

Properly balancing these functions allows you to generate new nerve cells as needed while also maintaining a robust neural stem cell pool.

The researchers studied a family of transcription factors called FoxO known to be involved in proliferation, differentiation and programmed cell death.

FoxO genes are required for the extreme longevity seen in some strains of laboratory roundworms, and a single mutation in the FoxO3 gene has recently been associated with long life in Japanese, German, American and Italian populations.

“We wanted to know if FoxO3 could be involved in regulating the pool of neural stem cells,” said Brunet.

For this, they examined laboratory mice in which the FoxO3 gene was knocked out.

They used mice of three different ages, both with and without the gene: 1-day-old (newborns), 3-month-old (young adult) and 1-year-old (middle age).

They found that, overall, adult and middle-aged mice without FoxO3 had fewer neural stem cells than did age-matched mice with this regulatory protein.

There were no significant differences between the newborn mice with and without FoxO3, suggesting that FoxO3 loss only affects adults.

The researchers also discovered that the few stem cells found in the adult mice without FoxO3 more rapidly churned out neural cell precursors - those cells destined to become new neurons - than did the mice with normal FoxO3 levels.

In fact, the brains of the mice that lacked FoxO3 were heavier than the control group, perhaps because they were burning through their pool of neural stem cells by making too many new nerve cells.

After looking at the neural stem cell in a laboratory dish, they found that those from young and middle-aged adult mice lacking FoxO3 - but not those from newborn mice - seemed to be compromised in their ability to self-renew and to generate the three types of nerve cells.

They also discovered that the FoxO3 protein regulates the expression of genes involved in quiescence and differentiation in cells.

The researchers concluded that FoxO3 may be needed for the stem cells to re-enter a waiting state called quiescence that normally occurs after dividing.

Cells that are unable to enter quiescence are less able to self-renew and may lose their ability to become any of the three nerve cell types.

Together, the research results suggest that FoxO3 is important to regulate the pool of neural stem cells in the adult brain.

The study will be published Nov. 6 in Cell Stem Cell. (ANI)