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Sci. Signal., 24 November 2009
Vol. 2, Issue 98, p. ra75
[DOI: 10.1126/scisignal.2000559]
RESEARCH ARTICLES
mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells
Chong Chen1,
Yu Liu1,
Yang Liu1,2*, and
Pan Zheng1,3*
1 Division of Immunotherapy, Department of Surgery, University of Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, MI 48109, USA. 2 Department of Internal Medicine, University of Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, MI 48109, USA. 3 Department of Pathology, University of Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, MI 48109, USA.
Abstract:
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 p16Ink4a, p19Arf, and p21Cip1; 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.
* To whom correspondence should be addressed. E-mail: panz{at}umich.edu (P.Z.) and yangl{at}umich.edu (Y.L.)
Citation: C. Chen, Y. Liu, Y. Liu, P. Zheng, mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells. Sci. Signal.2, ra75 (2009).
The Tuberous Sclerosis Complex-Mammalian Target of Rapamycin Pathway Maintains the Quiescence and Survival of Naive T Cells.
Q. Wu, Y. Liu, C. Chen, T. Ikenoue, Y. Qiao, C.-S. Li, W. Li, K.-L. Guan, Y. Liu, and P. Zheng (2011)
J. Immunol.
187, 1106-1112
|Abstract »|Full Text »|PDF »
Rapamycin, But Not Resveratrol or Simvastatin, Extends Life Span of Genetically Heterogeneous Mice.
R. A. Miller, D. E. Harrison, C. M. Astle, J. A. Baur, A. R. Boyd, R. de Cabo, E. Fernandez, K. Flurkey, M. A. Javors, J. F. Nelson, et al. (2011)
J Gerontol A Biol Sci Med Sci
66A, 191-201
|Abstract »|Full Text »|PDF »
Targeting the CXCR4-CXCL12 Axis Mobilizes Autologous Hematopoietic Stem Cells and Prolongs Islet Allograft Survival via Programmed Death Ligand 1.
P. Fiorina, M. Jurewicz, A. Vergani, A. Petrelli, M. Carvello, F. D'Addio, J. G. Godwin, K. Law, E. Wu, Z. Tian, et al. (2011)
J. Immunol.
186, 121-131
|Abstract »|Full Text »|PDF »
