PROJECT SUMMARY Cognitive decline is a major feature of aging and neurodegenerative diseases such as Alzheimer’s disease. Neurogenesis, the formation of new neurons, supports learning, memory, mood regulation, and sensory functions in the healthy mammalian brain. During aging, neurogenesis is dramatically reduced due to impairments in neural stem cell (NSC) pools. The mechanisms responsible for dysfunction of the NSC reservoir are not fully understood, but significant evidence implicates changes to the quiescent NSCs, which are the source of the neurogenic lineage. Ths work investigates the mechanisms responsible for failed activation of quiescent NSCs with age. This project is significant because identification of the mechanisms underlying dysfunction of quiescent NSCs with age will reveal strategies to restore new neuron formation in aging and neurodegeneration. Published and preliminary work shows that quiescent NSCs, though relatively dormant, are defective at the chromatin, gene expression, and metabolic levels with age. This study takes an integrated approach to reveal the specific target genes and processes responsible for defects in NSC quiescence with age. Specific Aim 1 will investigate how mitophagy regulates metabolic health of NSCs during aging. Aim 2 employs an integrated multi-omics strategy to fully elucidate the epigenomic and metabolic changes that occur the neurogenic lineage with age. Finally, Aim 3 will address the mechanisms by which NSCs return to quiescence, and the extent to which failure in this process results in depletion of the functional NSC pool with age. Collectively, this work will result in a comprehensive understanding of how dormant NSCs are affected by aging in the mammalian brain. In the long term, these studies have the potential to lead to the development of interventions to improve healthy aging and restore cognition in the context of neurodegeneration.