Check Against Delivery. Embargoed until 3:45 PM, 6 November 2010 Targeting endogenous stem and somatic cell by Karl Lenhard Rudolph Ulm University, Germany Session 10, Workshop 10.2 „Emerging Therapies“ Our Common Future, Essen, November 6th, 2010 Our Common Future, Hannover/Essen, 2-6 November 2010 (www.ourcommonfuture.de))
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Check Against Delivery.Embargoed until 3:45 PM, 6 November 2010
Targeting endogenous stem and somatic cell
by Karl Lenhard RudolphUlm University, Germany
Session 10, Workshop 10.2 „Emerging Therapies“Our Common Future, Essen, November 6th, 2010
Our Common Future, Hannover/Essen, 2-6 November 2010 (www.ourcommonfuture.de))
Targeting endogenous stem and somatic cells
Human life expectancy
Africa50.000 b.c.
Europe15.000 b.c.
19001980
Trauma
10 20 30 40 50 60 70 80 90 100
Age (years)
Sur
viva
l (%
)
100
50
44
Decrease inorgan function
T Rando, Nature 2006
Mechanisms of stem cell aging
Miller, Richard A.'Accelerated aging': a primrose path to insight?.Aging Cell 3 (2), 47-51.
Rothmund-Thomson Syndrome:near normal ifespan, cataracts, osteoporosis, hairgreying, alopeciaMutation in a DNA-helicase of unknown functionWerner Syndrom:- average lifespan: 50 years, alopecia, hair greying,osteoporosis, arteriosclerosis, diabetes, cataract, skinatrophy, teleangiektaisas mutation of WRN gene: DNA-helicase involved in DNA-repair by NHEJAtaxia teleangiectasia:skin atrophy, immunodeficiency, hair greying, neuronalcell lossATM-gene is involved in DNA damage signallingHutchinson-Gilford-Progeria:average lifespan 13 years, alopecia, wrinkling of skin,cachexia, arteriosklerosislamin A mutation: nuclear structure protein
Reviewed in Lieber et al., Nature Reviews 2004
DNA damage: a molecular mechanism of aging
Eliizabeth Blackburn
End replication problem of DNA-Polymerase:Telomeres shorten with each round of cell division
- simple repeat elements (TTAGGG)- no coding sequence- main function: chromosomal capping
Hayflick 1968, Allsopp et al. 1990, Wright and Shay, 1992, Vaziri et al. 1994, Bodnar et al. 1998Hayflick 1968, Allsopp et al. 1990, Wright and Shay, 1992, Vaziri et al. 1994, Bodnar et al. 1998
p53p53stem cells
?
9
Telomere shortening in human tissues and stem cells
Affected organs:
Accelerated in chronic diseases:Anemia, arteriosklerosis, hepatitis, colitis ulcerosa, HIV, etc.
Blood cells, arteries, epithelia of the GI tract, kidney, liver, spleen, among others
Stem cells:CD34+ hematopoietic cells (Vaziri et al. PNAS 1994)
Telomerase mutations are linked to stem cell and organ failure:Dyskertaosis congenita, aplastic anemia, idiopathic lung fibrosis(Dokal, Besser, Collins, Amanios, Garcia and others)
Peptidomics (CE-TOF-MS) : biomarker oftelomere dysfunction and DNA damage
1
1
2
2
mTE
RC
-m
Terc
-/-m
Terc
+/+
jung alt
0 20 40 60 80 10020
40
60
80
100
Age
Co
mb
inati
on
sco
re
rho=0.5328 P<0.0001
0 20 40 60 80 1002
4
6
8
10
Age
Telo
mere
len
gth
(kb
)
rho=-0.318 P=0.0001
11
0.51-Specificity
1Young30±3.8
Old85±8.1
Old patients73±8.5
1
2
3
Mar
ker-
Com
bina
tion
P<0.001
P<0.001P<0.001
1
0.5 0.99720.98940.8863
Proteins from telomere dysfunctional cells arebiomarkers of human aging & disease
P<0.001
P<0.001P<0.001
12
G3 mTERC-/- (18 months)
mTERC+/+(22 months)
Impaired Wound Healing
Crypt Atrophy
Premature Aging
M1
mTERC+M1
G4 mTERC-
Impaired Stem CellMaintenance & Function
G4TERC-/-TERC+/+
mTERC+
G4mTERC-
mTERC+/+ G3 mTERC-/-
Impaired Liver Regeneration
Telomere dysfunctional mice
Rudolph et al. Cell 1999
surv
ival
(%)
20
40
60
80
100
3 9 15 21 27Age (months)
mTERC+/+ G1 G2-3 G4-5 G6
Reduced lifespan of telomere dysfunctional miceReduced lifespan of telomere dysfunctional mice
Cirrhosis- high regenerative reserve of hepatocytes- cirrhosis evolves after long latencies: 20-40 years- cirrhosis is characterized by an impaired regenerative capacity
Telomere shortening & organ regeneration
RNRN
FS
FSRN
100
200
300
controlsHC SC
p<0.0001 p<0.0001
TFI
HCcirrhosis
20%
60%
100%
cirrhosiscontrols
27/31
1/11
p=0.002S
enes
cent
HC
(%)
Wiemann et al. FASEB J. 2002
Hepatocellular telomere shortening and senescencecharacterize human cirrhosis
- Increases lifespan of yeast- increases lifespan (30%) and reduces tumor risk in mice- Delays aging in primates
Aging telomere dysfunctional mice exhibit weight loss andCR-induced metabolic changes
High glucose diet increases lifespan of telomeredysfunctional mice
Glucose re-feeding reverts CR-profile of telomeredysfunctional mice
Group I HealthyGroup II MalnourishedGroup III Malnourished fed with high protein/calorie diet
Beaumont et al.
Glucose re-feeding ameloriates DNA damage signalling andimproves cell proliferation and organ maintenance
Calorie restriction may delay tissue aging by improving the clearance ofdamaged cells but this response could turn out to be deleterious at advancedage when tissues accumulate high rates of damaged cells.
- cell intrinsic checkpoints limit the function of adult stem cells in response toDNA damage and telomere dysfunction
- the abrogation of checkpoints can improve stem cell function and organmaintenance
- cell extrinsic checkpoints can limit the function of adult stem cells and theengraftment of transplanted cells possibly limiting cell transplantation therapies
- deficiencies in energy supply limit lifespan in the context of telomeredysfunction by amplifying checkpoint responses
Conclusions
Max-Planck-Partner Group atILAS, CAMS, Beijing, China:
Zhenyu Ju
Karin KleinhansAndré Lechel Hye-Min LeePallavi Mahaddalkar Pavlos MissiosKodandaramireddy NalapareddySatyavani RavipatiSundaram ReddyTao Si Zhangfa SongTobias SperkaHelen Qian SunStefan TümpelJianwei WangGuido von FiguraYuan Zhou
Cooperation:
Wolf-Georg Forssmann, Medical School Hannover – Serum FractionsDr. Thomas Illig, HZM - MetabolomicsChristoph Klein, Regensburg – Stem cell gene expression analysisMichael Manns, MHH, Hannover – human cirrhosis & HCCHarald Mischak, Mosaiques Diagnostics - PeptidomicsMichael Speicher, Austria – ArrayCGHRudi Westendorp, Leyden – human agingLars Zender, HZI – Deep Sequencing