Rejuvenation of Aging HSC

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:

Rejuvenation of Aging HSC

by nanog on Jan 18, 2010

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Rejuvenation of Aging HSC — Presentation Transcript