@article{2f5dad2d390742beaf16a3ac88127ce3,
title = "Early stem cell aging in the mature brain",
abstract = "Stem cell dysfunction drives many age-related disorders. Identifying mechanisms that initially compromise stem cell behavior represent early targets to promote tissue function later in life. Here, we pinpoint multiple factors that disrupt neural stem cell (NSC) behavior in the adult hippocampus. Clonal tracing showed that NSCs exhibit asynchronous depletion by identifying short-term NSCs (ST-NSCs) and long-term NSCs (LT-NSCs). ST-NSCs divide rapidly to generate neurons and deplete in the young brain. Meanwhile, multipotent LT-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 molecular aging in the mature brain and identified tyrosine-protein kinase Abl1 as an NSC aging factor. Treatment with the Abl inhibitor imatinib increased NSC activation without impairing NSC maintenance in the middle-aged brain. Our study indicates that hippocampal NSCs are particularly vulnerable and adaptable to cellular aging.",
keywords = "Abl, Imatinib, adult neurogenesis, aging, bioinformatics, cell fate, clonal analysis, hippocampus, intervention, proliferation, quiescence, single cell RNA-seq, stem cell",
author = "Albina Ibrayeva and Maxwell Bay and Elbert Pu and J{\"o}rg, {David J.} and Lei Peng and Heechul Jun and Naibo Zhang and Daniel Aaron and Congrui Lin and Galen Resler and Axel Hidalgo and Jang, {Mi Hyeon} and Simons, {Benjamin D.} and Bonaguidi, {Michael A.}",
note = "Funding Information: We thank David Cobrinik, Sunhye Lee, and members of the Bonaguidi, Simons, and Jang laboratories for invaluable discussions and comments on the manuscript; Teresa Krieger, Dennisse Jimenez-Cyrus, Avinash Iyer, and Lee McMahon for technical support; and the CHLA FACS Core Facility and Center for Personalized Medicine Sequencing facility for technical assistance. This work was supported by grants to M.A.B. from the NIH ( R00NS080913 and R56AG064077 ), the Donald E. and Delia B. Baxter Foundation , the L. K. Whittier Foundation , the Eli and Edythe Broad Foundation , and the CHLA TSRI pilot program. M.-H.J. was supported by the NIH (grant RO1AG0585560 ). B.D.S. was supported by a Royal Society E P Abraham Professorship ( RP\R1\180165 ) and the Wellcome Trust (grant 098357/Z/12/Z ). A.I. was partially supported by the AFAR Research Scholarship for Research in Biology of Aging and the NIH (fellowship T32HD060549-08 ). M.B. was partially supported by the USC Provost{\textquoteright}s Research Enhancement Fellowship . Funding Information: We thank David Cobrinik, Sunhye Lee, and members of the Bonaguidi, Simons, and Jang laboratories for invaluable discussions and comments on the manuscript; Teresa Krieger, Dennisse Jimenez-Cyrus, Avinash Iyer, and Lee McMahon for technical support; and the CHLA FACS Core Facility and Center for Personalized Medicine Sequencing facility for technical assistance. This work was supported by grants to M.A.B. from the NIH (R00NS080913 and R56AG064077), the Donald E. and Delia B. Baxter Foundation, the L. K. Whittier Foundation, the Eli and Edythe Broad Foundation, and the CHLA TSRI pilot program. M.-H.J. was supported by the NIH (grant RO1AG0585560). B.D.S. was supported by a Royal Society E P Abraham Professorship (RP\R1\180165) and the Wellcome Trust (grant 098357/Z/12/Z). A.I. was partially supported by the AFAR Research Scholarship for Research in Biology of Aging and the NIH (fellowship T32HD060549-08). M.B. was partially supported by the USC Provost's Research Enhancement Fellowship. Conceptualization, A.I. M.B. and M.A.B.; data collection and methodology, A.I. E.P. L.P. N.Z. H.J. M.A.B. C.L. G.R. and A.H. with supervision; data analysis and bioinformatics, A.I. M.B. E.P. D.J.J. L.P. D.A. B.D.S. and M.A.B.; resources, M.-H.J. B.D.S. and M.A.B.; supervision, M.-H.J. B.D.S. and M.A.B.; writing – review & editing, A.I. M.B. D.J.J. M.-H.J. B.D.S. and M.A.B.; project coordination, M.A.B. All authors commented on the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = may,
day = "6",
doi = "10.1016/j.stem.2021.03.018",
language = "English (US)",
volume = "28",
pages = "955--966.e7",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "5",
}