Geneticist Anne Brunet, PhD, thinks a lot about aging. Much of her research focuses on understanding why some people and animals live much longer than their peers. She’s characterized some proteins, including one called FOXO3, that play a role in this process. Today, in a study published in Cell Reports, she and her colleagues outline one of the ways that FOXO3 accomplishes this feat. As Brunet, who recently received a NIH Director’s Pioneer Award to conduct her longevity research, explained to me in an e-mail:
This work is exciting because it reveals for the first time how the pro-longevity factor FOXO3 works in stem cells from the adult brain. FOXO3 belongs to a family of genes that promotes longevity from worms to humans. In fact, humans with variation in the FOXO3 genes have increased chances of becoming centenarians. But how FOXO3 extends lifespan had remained elusive.
Brunet and the study’s lead author, postdoctoral scholar Ashley Webb, PhD, were interested in a previous finding from Brunet’s lab – the ability of FOXO3 to maintain neural stem cells in the adult brain. These cells give rise to neurons that contribute to learning and memory. Preserving these cells, Brunet explains, is likely critical to maintain cognitive function during aging. But until now it wasn’t known exactly how FOXO3 regulated this process.
Webb discovered that FOXO3, which is a transcription factor that binds to DNA and regulates gene expression, latches on to the control regions of genes that are also bound by a protein called ASCL1. According to Brunet:
This was really exciting to us, because ASCL1 has been widely studied, in particular by Marius Wernig, MD, at Stanford, for its ability to convert or ‘reprogram’ cells into neurons. Ashley found that FOXO3 could inhibit the ability of ASCL1 to promote the expression of pro-neuronal genes and the formation of new neurons. This could explain how FOXO3 maintains the pool of adult neural stem cells: by preventing them from undergoing premature differentiation into neurons and by keeping them as “stem cells”.
The researchers are now homing in on the signals that control FOXO3’s activities, and trying to understand how these signals may be affected by aging or age-related brain diseases like Alzheimer’s.