rejuvenation of aging hsc
DESCRIPTION
TRANSCRIPT
![Page 1: Rejuvenation of Aging HSC](https://reader035.vdocuments.site/reader035/viewer/2022081412/54559bdbaf7959d2368b779f/html5/thumbnails/1.jpg)
Can RapamycinCan Rapamycin extend our lives? extend our lives?
Alexey Bersenev
Journal Club Jan. 15, 2010
![Page 2: Rejuvenation of Aging HSC](https://reader035.vdocuments.site/reader035/viewer/2022081412/54559bdbaf7959d2368b779f/html5/thumbnails/2.jpg)
![Page 3: Rejuvenation of Aging HSC](https://reader035.vdocuments.site/reader035/viewer/2022081412/54559bdbaf7959d2368b779f/html5/thumbnails/3.jpg)
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?
![Page 4: Rejuvenation of Aging HSC](https://reader035.vdocuments.site/reader035/viewer/2022081412/54559bdbaf7959d2368b779f/html5/thumbnails/4.jpg)
Why did I pick this paper?
• 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
![Page 5: Rejuvenation of Aging HSC](https://reader035.vdocuments.site/reader035/viewer/2022081412/54559bdbaf7959d2368b779f/html5/thumbnails/5.jpg)
http://en.wikipedia.org/wiki/File:MTOR-pathway-betz.jpg
mTOR signaling pathways
![Page 6: Rejuvenation of Aging HSC](https://reader035.vdocuments.site/reader035/viewer/2022081412/54559bdbaf7959d2368b779f/html5/thumbnails/6.jpg)
mTOR
PI3K
AKT
FoxOTSChypoxia
PML
HSC quiescence
PTEN
ROS
Wnt
GSK-3
Adapted from: Ron DePinho, Jian Huang 2009
growth factors
mTOR pathways in HSC
![Page 7: Rejuvenation of Aging HSC](https://reader035.vdocuments.site/reader035/viewer/2022081412/54559bdbaf7959d2368b779f/html5/thumbnails/7.jpg)
Rapamycin (mTOR inhibitor) as a magic bullet:
• 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)
![Page 8: Rejuvenation of Aging HSC](https://reader035.vdocuments.site/reader035/viewer/2022081412/54559bdbaf7959d2368b779f/html5/thumbnails/8.jpg)
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:
![Page 9: Rejuvenation of Aging HSC](https://reader035.vdocuments.site/reader035/viewer/2022081412/54559bdbaf7959d2368b779f/html5/thumbnails/9.jpg)
The concept:
![Page 10: Rejuvenation of Aging HSC](https://reader035.vdocuments.site/reader035/viewer/2022081412/54559bdbaf7959d2368b779f/html5/thumbnails/10.jpg)
Cancer
Cell proliferation
Stem cell
self-renewal
HSC aging
Arf
Ink4a
Bmi-1
Hmga2
Sean Morrison group 2005-2008
![Page 11: Rejuvenation of Aging HSC](https://reader035.vdocuments.site/reader035/viewer/2022081412/54559bdbaf7959d2368b779f/html5/thumbnails/11.jpg)
mTOR activation induces premature aging of hematopoietic stem cells
Hypothesis 1:
![Page 12: Rejuvenation of Aging HSC](https://reader035.vdocuments.site/reader035/viewer/2022081412/54559bdbaf7959d2368b779f/html5/thumbnails/12.jpg)
Aging markers, HSC number and function, longevity
How did they do that:
![Page 13: Rejuvenation of Aging HSC](https://reader035.vdocuments.site/reader035/viewer/2022081412/54559bdbaf7959d2368b779f/html5/thumbnails/13.jpg)
mTOR in aged HSC
![Page 14: Rejuvenation of Aging HSC](https://reader035.vdocuments.site/reader035/viewer/2022081412/54559bdbaf7959d2368b779f/html5/thumbnails/14.jpg)
p16 (Ink4a)p19 (Arf)p21
aging markers
![Page 15: Rejuvenation of Aging HSC](https://reader035.vdocuments.site/reader035/viewer/2022081412/54559bdbaf7959d2368b779f/html5/thumbnails/15.jpg)
Impaired repopulation with mTOR activation (TSC KO) (1.2%) compared to WT (67.2%)
Competitive repopulation HSC transplantation scheme
![Page 16: Rejuvenation of Aging HSC](https://reader035.vdocuments.site/reader035/viewer/2022081412/54559bdbaf7959d2368b779f/html5/thumbnails/16.jpg)
mTOR inhibition rescues hematopoietic stem cell defect and extends life span of
mice
Hypothesis 2:
![Page 17: Rejuvenation of Aging HSC](https://reader035.vdocuments.site/reader035/viewer/2022081412/54559bdbaf7959d2368b779f/html5/thumbnails/17.jpg)
Rapamycin increases life span of mice!
22 months of age
![Page 18: Rejuvenation of Aging HSC](https://reader035.vdocuments.site/reader035/viewer/2022081412/54559bdbaf7959d2368b779f/html5/thumbnails/18.jpg)
Rescue series of experiments
number of HSCaging markers
HSC in cell cycleHSC function in transplantation assays
![Page 19: Rejuvenation of Aging HSC](https://reader035.vdocuments.site/reader035/viewer/2022081412/54559bdbaf7959d2368b779f/html5/thumbnails/19.jpg)
Place of mTOR in stem cell aging regulators scheme
? mTOR
![Page 20: Rejuvenation of Aging HSC](https://reader035.vdocuments.site/reader035/viewer/2022081412/54559bdbaf7959d2368b779f/html5/thumbnails/20.jpg)
Conclusions:
1. mTOR signaling is activated in aged HSC and causes decline in function
2. Inhibition of mTOR by Rapamycin rescued HSC function in aged mice
3. Inhibition of mTOR by Rapamycin increases life span of mice
4. Inhibition of mTOR stimulates immune function in aged mice
![Page 21: Rejuvenation of Aging HSC](https://reader035.vdocuments.site/reader035/viewer/2022081412/54559bdbaf7959d2368b779f/html5/thumbnails/21.jpg)
Things I like:
1. Assays: done on pure HSC (FLSK/CD34/150/48)
2. Transplantation assays
3. Longevity part (bring us closer to understand the relationships between stem cell and aging)
![Page 22: Rejuvenation of Aging HSC](https://reader035.vdocuments.site/reader035/viewer/2022081412/54559bdbaf7959d2368b779f/html5/thumbnails/22.jpg)
Things I don’t like:
1. Cell cycle part is missing (BrdU assay is not enough)
2. HSC self-renewal was not assessed properly
3. Virus – immunity part (not very relevant)
![Page 23: Rejuvenation of Aging HSC](https://reader035.vdocuments.site/reader035/viewer/2022081412/54559bdbaf7959d2368b779f/html5/thumbnails/23.jpg)
“It is not clear whether there is any relationship between stem cell aging and life span”
Sean Morrison
Open question: