1. Can Rapamycin extend our lives? Alexey Bersenev Journal Club Jan. 15, 2010

3. 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?

5. http://en.wikipedia.org/wiki/File:MTOR-pathway-betz.jpg mTOR signaling pathways 

6. 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 

8. 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:

9. The concept:

10. Cancer Cell proliferation Stem cell self-renewal HSC aging Arf Ink4a Bmi-1 Hmga2 Sean Morrison group 2005-2008

11. mTOR activation induces premature aging of hematopoietic stem cells Hypothesis 1:

12. Aging markers, HSC number and function, longevity How did they do that:

13. mTOR in aged HSC

14. p16 (Ink4a) p19 (Arf) p21 aging markers

15. Impaired repopulation with mTOR activation (TSC KO) (1.2%) compared to WT (67.2%) Competitive repopulation HSC transplantation scheme

16. mTOR inhibition rescues hematopoietic stem cell defect and extends life span of mice Hypothesis 2:

17. Rapamycin increases life span of mice! 22 months of age

18. Rescue series of experiments number of HSC aging markers HSC in cell cycle HSC function in transplantation assays

19. Place of mTOR in stem cell aging regulators scheme ? mTOR

23. “ It is not clear whether there is any relationship between stem cell aging and life span” Sean Morrison Open question: