Year 3

The adult brain contains pools of stem cells called neural stem cells that are critical for
the formation of new neurons in the adult brain. During aging, the number of neural stem
cells and their ability to give rise to new neurons strikingly decline. This decline could
underlie at least in part memory deterioration that occurs during aging and age-related
neurodegenerative disease such as Alzheimer’s disease. We have been interested over
the years in the importance of genes that regulate overall longevity in the control of the
pool of neural stem cells. We made the important discovery that Foxo3, a gene that has
been implicated in human exceptional longevity, is necessary for preserving the neural
stem cell pool. In the past year, we have made extensive progress in characterizing the
ensemble of genes regulated by Foxo3 in adult neural stem cells, a key step in
unraveling the mechanisms by which neural stem cells are maintained intact. In the past
year, we have observed that in the absence of another gene important for longevity
Sirt1, there is an unexpected increase in oligodendrocyte progenitors, which are cells
that are important for myelination of neurons, which is important for the proper
propagation of the neuronal information. Defects in myelination, which happen for
example in multiple sclerosis, have devastating consequences on the neurological
function. In the past year, we have made progress to understand the cellular and
molecular mechanism of action that enhances the production of oligodendrocytes in the
absence of Sirt1. Finally, we have made progress in initiating a project in human stem
cells that can be reprogrammed from adult cells, to extend our findings from mice to
humans, in particular as it relates to human diseases that have an age-dependent