rejuvenation of aging hsc

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

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Page 1: Rejuvenation of Aging HSC

Can RapamycinCan Rapamycin extend our lives? extend our lives?

Alexey Bersenev

Journal Club Jan. 15, 2010

Page 2: Rejuvenation of Aging HSC
Page 3: Rejuvenation of Aging HSC

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?

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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

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http://en.wikipedia.org/wiki/File:MTOR-pathway-betz.jpg

mTOR signaling pathways

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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

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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)

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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:

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The concept:

Page 10: Rejuvenation of Aging HSC

Cancer

Cell proliferation

Stem cell

self-renewal

HSC aging

Arf

Ink4a

Bmi-1

Hmga2

Sean Morrison group 2005-2008

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mTOR activation induces premature aging of hematopoietic stem cells

Hypothesis 1:

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Aging markers, HSC number and function, longevity

How did they do that:

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mTOR in aged HSC

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p16 (Ink4a)p19 (Arf)p21

aging markers

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Impaired repopulation with mTOR activation (TSC KO) (1.2%) compared to WT (67.2%)

Competitive repopulation HSC transplantation scheme

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mTOR inhibition rescues hematopoietic stem cell defect and extends life span of

mice

Hypothesis 2:

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Rapamycin increases life span of mice!

22 months of age

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Rescue series of experiments

number of HSCaging markers

HSC in cell cycleHSC function in transplantation assays

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Place of mTOR in stem cell aging regulators scheme

? mTOR

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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

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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)

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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)

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“It is not clear whether there is any relationship between stem cell aging and life span”

Sean Morrison

Open question: