mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells

Age-related declines in hematopoietic stem cell (HSC) function may contribute to anemia, poor response to vaccination, and tumorigenesis. Here, we show that mammalian target of rapamycin (mTOR) activity is increased in HSCs from old mice compared to those from young mice. mTOR activation through con...

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Bibliographic Details
Published in:Science signaling 2009-11, Vol.2 (98), p.ra75-ra75
Main Authors: Chen, Chong, Liu, Yu, Liu, Yang, Zheng, Pan
Format: Article
Language:English
Subjects:
Aging
Animals
Cyclin-Dependent Kinase Inhibitor p16 - metabolism
Cyclin-Dependent Kinase Inhibitor p21 - metabolism
Hematopoiesis
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - metabolism
Male
Mice
Mice, Inbred C57BL
Orthomyxoviridae - metabolism
Protein Kinases - metabolism
Signal Transduction
Sirolimus - pharmacology
Time Factors
TOR Serine-Threonine Kinases
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Summary:Age-related declines in hematopoietic stem cell (HSC) function may contribute to anemia, poor response to vaccination, and tumorigenesis. Here, we show that mammalian target of rapamycin (mTOR) activity is increased in HSCs from old mice compared to those from young mice. mTOR activation through conditional deletion of Tsc1 in the HSCs of young mice mimicked the phenotype of HSCs from aged mice in various ways. These included increased abundance of the messenger RNA encoding the CDK inhibitors p16(Ink4a), p19(Arf), and p21(Cip1); a relative decrease in lymphopoiesis; and impaired capacity to reconstitute the hematopoietic system. In old mice, rapamycin increased life span, restored the self-renewal and hematopoiesis of HSCs, and enabled effective vaccination against a lethal challenge with influenza virus. Together, our data implicate mTOR signaling in HSC aging and show the potential of mTOR inhibitors for restoring hematopoiesis in the elderly.
ISSN:1945-0877
1937-9145
DOI:10.1126/scisignal.2000559