Early Stem Cell Aging in the Mature Brain

Stem cell dysfunction drives many age-related disorders. Identifying mechanisms that initiate stem cell dysfunction represent early targets to enhance tissue resiliency throughout life. Here, we pinpoint multiple factors that compromise neural stem cell (NSC) behavior in the adult hippocampus. We find that NSCs exhibit asynchronous depletion by identifying short-term (ST-NSC) and intermediate term NSCs (IT-NSCs). ST-NSC divide rapidly to generate neurons and deplete in the young brain. Meanwhile, multipotent IT-NSCs are maintained for months, but are pushed out of homeostasis by lengthening quiescence. Single cell transcriptome analysis of deep NSC quiescence revealed several hallmarks of cellular aging in the mature brain, including changes in tyrosine- protein kinases Abl1 and Abl2. Treatment with Imatinib was sufficient to overcome deep quiescence and restore NSC proliferation in the middle-aged brain. Further examination of mature NSC with old epidermal, hematopoietic, and muscle stem cell transcriptomes identified consensus changes in stem cell aging. Our study elucidates multiple origins of adult neurogenesis decline and reveals that hippocampal NSCs are particularly vulnerable to a shared stem cell aging signature.