Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

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).

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons.
E. M. Pietras, R. Lakshminarasimhan, J.-M. Techner, S. Fong, J. Flach, M. Binnewies, and E. Passegue (2014)
J. Exp. Med. 211, 245-262
   Abstract »    Full Text »    PDF »
Rapamycin Extends Life and Health in C57BL/6 Mice.
Y. Zhang, A. Bokov, J. Gelfond, V. Soto, Y. Ikeno, G. Hubbard, V. Diaz, L. Sloane, K. Maslin, S. Treaster, et al. (2014)
J Gerontol A Biol Sci Med Sci 69A, 119-130
   Abstract »    Full Text »    PDF »
Nutrient-sensing pathways and metabolic regulation in stem cells.
J. D. Ochocki and M. C. Simon (2013)
J. Cell Biol. 203, 23-33
   Abstract »    Full Text »    PDF »
Stem cell metabolism in tissue development and aging.
N. Shyh-Chang, G. Q. Daley, and L. C. Cantley (2013)
Development 140, 2535-2547
   Abstract »    Full Text »    PDF »
Sirtuins, Tissue Maintenance, and Tumorigenesis.
M. Mohrin and D. Chen (2013)
Genes & Cancer 4, 76-81
   Abstract »    Full Text »    PDF »
Energy metabolism and energy-sensing pathways in mammalian embryonic and adult stem cell fate.
V. A. Rafalski, E. Mancini, and A. Brunet (2012)
J. Cell Sci. 125, 5597-5608
   Abstract »    Full Text »    PDF »
The sixth sense: hematopoietic stem cells detect danger through purinergic signaling.
L. Rossi, V. Salvestrini, D. Ferrari, F. Di Virgilio, and R. M. Lemoli (2012)
Blood 120, 2365-2375
   Abstract »    Full Text »    PDF »
A Critical Role for Rictor in T Lymphopoiesis.
F. Tang, Q. Wu, T. Ikenoue, K.-L. Guan, Y. Liu, and P. Zheng (2012)
J. Immunol. 189, 1850-1857
   Abstract »    Full Text »    PDF »
Rapamycin Reverses Elevated mTORC1 Signaling in Lamin A/C-Deficient Mice, Rescues Cardiac and Skeletal Muscle Function, and Extends Survival.
F. J. Ramos, S. C. Chen, M. G. Garelick, D.-F. Dai, C.-Y. Liao, K. H. Schreiber, V. L. MacKay, E. H. An, R. Strong, W. C. Ladiges, et al. (2012)
Science Translational Medicine 4, 144ra103
   Abstract »    Full Text »    PDF »
Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity.
D. W. Lamming, L. Ye, P. Katajisto, M. D. Goncalves, M. Saitoh, D. M. Stevens, J. G. Davis, A. B. Salmon, A. Richardson, R. S. Ahima, et al. (2012)
Science 335, 1638-1643
   Abstract »    Full Text »    PDF »
Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing.
A. V. Ergen, N. C. Boles, and M. A. Goodell (2012)
Blood 119, 2500-2509
   Abstract »    Full Text »    PDF »
Empowering Adult Stem Cells for Myocardial Regeneration.
S. Mohsin, S. Siddiqi, B. Collins, and M. A. Sussman (2011)
Circ. Res. 109, 1415-1428
   Abstract »    Full Text »    PDF »
Cell cycle regulation in hematopoietic stem cells.
E. M. Pietras, M. R. Warr, and E. Passegue (2011)
J. Cell Biol. 195, 709-720
   Abstract »    Full Text »    PDF »
An emerging role for TOR signaling in mammalian tissue and stem cell physiology.
R. C. Russell, C. Fang, and K.-L. Guan (2011)
Development 138, 3343-3356
   Abstract »    Full Text »    PDF »
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 »
Mammalian models of extended healthy lifespan.
C. Selman and D. J. Withers (2011)
Phil Trans R Soc B 366, 99-107
   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 »
2009: Signaling Breakthroughs of the Year.
E. M. Adler (2010)
Science Signaling 3, eg1
   Abstract »    Full Text »    PDF »
Science Signaling Podcast: 5 January 2010.
M. B. Yaffe and A. M. VanHook (2010)
Science Signaling 3, pc1
   Abstract »    Full Text »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882