mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells
Top Cited Papers
- 24 November 2009
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Signaling
- Vol. 2 (98), ra75
- https://doi.org/10.1126/scisignal.2000559
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.Keywords
This publication has 33 references indexed in Scilit:
- Rapamycin fed late in life extends lifespan in genetically heterogeneous miceNature, 2009
- mTOR regulates memory CD8 T-cell differentiationNature, 2009
- TSC–mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen speciesThe Journal of Experimental Medicine, 2008
- Hematopoiesis: An Evolving Paradigm for Stem Cell BiologyCell, 2008
- Aging Hematopoietic Stem Cells Decline in Function and Exhibit Epigenetic DysregulationPLoS Biology, 2007
- Immunosenescence of ageingThe Journal of Pathology, 2007
- Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4aNature, 2006
- Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageingNature, 2006
- Influence of TOR kinase on lifespan in C. elegansNature, 2003
- Stem Cells: Units of Development, Units of Regeneration, and Units in EvolutionCell, 2000