rejuvenation of aging hsc
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Can RapamycinCan Rapamycin extend our lives? 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?
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
http://en.wikipedia.org/wiki/File:MTOR-pathway-betz.jpg
mTOR signaling pathways
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
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)
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 HSCaging markers
HSC in cell cycleHSC function in transplantation assays
Place of mTOR in stem cell aging regulators scheme
? mTOR
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
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)
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)
“It is not clear whether there is any relationship between stem cell aging and life span”
Sean Morrison
Open question: