mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells

Sci Signal. 2009 Nov 24;2(98):ra75. doi: 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 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.

MeSH terms

  • 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
  • TOR Serine-Threonine Kinases
  • Time Factors

Substances

  • Cdkn1a protein, mouse
  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p21
  • Protein Kinases
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Sirolimus