Rejuvenation of Aging HSC
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Rejuvenation of Aging HSC

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Rejuvenation of Aging HSC Rejuvenation of Aging HSC Presentation Transcript

  • Can Rapamycin extend our lives? Alexey Bersenev Journal Club Jan. 15, 2010
  •  
  • Significance : The first demonstration that mTOR signaling is important in HSC aging The second demonstration that mTOR inhibition can increase life span of mammals Possible impact : Potential of mTOR inhibition for restoring hematopoiesis in elderly?
    • Short
    • Exactly fits my interest
    • Good scientific explanation of commercial drug effects on stem cell and aging
    • Signaling paper without western blots in it
    • Gave me some ideas about my “aging project”
    • Attractive title 
    Why did I pick this paper?
  • http://en.wikipedia.org/wiki/File:MTOR-pathway-betz.jpg mTOR signaling pathways 
  • mTOR PI3K AKT FoxO TSC hypoxia PML HSC quiescence PTEN ROS Wnt GSK-3 Adapted from: Ron DePinho, Jian Huang 2009 growth factors mTOR pathways in HSC 
    • Treatment of rejection in organ transplant (immunosuppression)
    • Used in conjunction with coronary stents to prevent intimal hyperplasia after angioplasty (anti-proliferative effect)
    • Treatment of hematological malignancies (many)
    • Treatment of solid malignant tumors (many)
    • Treatment of Tuberous Sclerosis Complex (TSC) - a congenital disorder
    • Potential treatment of autism
    • Increase life span of mammals (Nature 2009;460:392)
    • Anti-aging effect on adult (skin) stem cells (Cell Stem Cell 2009;5;279)
    Rapamycin (mTOR inhibitor) as a magic bullet:
  • The longevity of s-Arf/p53 mice was significantly extended, with an increase in median lifespan of 16% (Nature 2007;448:375) – almost equal of calories restriction studies Inhibition of mTOR – pathway frequently activated in cancer, Increase life span of mice in median of 9-14% (Nature 2009;460:392) Cancer and longevity:
  • The concept:
  • Cancer Cell proliferation Stem cell self-renewal HSC aging Arf Ink4a Bmi-1 Hmga2 Sean Morrison group 2005-2008
  • mTOR activation induces premature aging of hematopoietic stem cells Hypothesis 1:
  • Aging markers, HSC number and function, longevity How did they do that:
  • mTOR in aged HSC
  • p16 (Ink4a) p19 (Arf) p21 aging markers
  • Impaired repopulation with mTOR activation (TSC KO) (1.2%) compared to WT (67.2%) Competitive repopulation HSC transplantation scheme
  • mTOR inhibition rescues hematopoietic stem cell defect and extends life span of mice Hypothesis 2:
  • Rapamycin increases life span of mice! 22 months of age
  • Rescue series of experiments number of HSC aging markers HSC in cell cycle HSC function in transplantation assays
  • Place of mTOR in stem cell aging regulators scheme ? mTOR
    • mTOR signaling is activated in aged HSC and causes decline in function
    • Inhibition of mTOR by Rapamycin rescued HSC function in aged mice
    • Inhibition of mTOR by Rapamycin increases life span of mice
    • Inhibition of mTOR stimulates immune function in aged mice
    Conclusions:
    • Assays: done on pure HSC (FLSK/CD34/150/48)
    • Transplantation assays
    • Longevity part (bring us closer to understand the relationships between stem cell and aging)
    Things I like:
    • Cell cycle part is missing (BrdU assay is not enough)
    • HSC self-renewal was not assessed properly
    • Virus – immunity part (not very relevant)
    Things I don’t like:
  • “ It is not clear whether there is any relationship between stem cell aging and life span” Sean Morrison Open question: