FOXO IN AGING AND LONGEVITY
Defining the biological functions of FOXOs in neural cells:
The mammalian brain maintains the ability to generate new neurons in the face of advancing age and injury. This regenerative capacity derives from neural stem cells. Identifying the genes and pathways governing neural stem cell reserves and restorative functions will enhance understanding and treatment of age-dependent cognitive decline and neurodegenerative diseases. We continue to evaluate important biological functions of FOXO transcription factors in maintenance of adult neural stem cell reserves. We demonstrated that FOXO-dependent maintenance of neural stem cell quiescence is necessary for lifelong neurogenesis in the mammalian brain (Cell Stem Cell 2009). We further determined the molecular basis of FOXO-dependent neural stem cell homeostasis by unbiased metabolomic and gene expression analysis, which demonstrated that FOXO1-dependent Notch activity and FOXO3-dependent regulation of glucose and glutamine catabolism is essential for cell fate decision (EMBO J 2013, Cell Death Diff 2015). This work was initially supported by Ellison Medical Foundation and is currently supported by NIH/NIA. We will continue this line of investigation in coming years. In addition, we investigate the role of neuronal FOXO in preventing age-progressive neurodegeneration.