Early Stem Cell Aging in the Mature Brain

Abstract

Stem cell dysfunction drives many age-related disorders. Identifying mechanisms that initially compromise stem cell function represent early targets to enhance stem cell behavior later in life. Here, we pinpoint multiple factors that disrupt neural stem cells (NSC) in the adult hippocampus. We find that NSCs exhibit asynchronous maintenance 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 persist for months, but are pushed out of homeostasis by lengthening quiescence. Single cell transcriptome analysis of deep NSC quiescence revealed several hallmarks of biological aging in the mature brain and identified tyrosine-protein kinase Abl1 as an NSC pro-aging factor. Treatment with the Abl-inhibitor Imatinib increased NSC proliferation without impairing NSC maintenance in the middle-aged brain. Further intersectional analysis 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.