Rejuvenation of Aging HSC

Gesundheit & Medizin Technologie

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?

[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],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 

[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],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:

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:

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

[object Object],[object Object],[object Object],[object Object],Conclusions:

[object Object],[object Object],[object Object],Things I like:

[object Object],[object Object],[object Object],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:

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