Professional Documents
Culture Documents
Disclosure
Jerry W. Shay
The following potential conflict of interest relationships are germane to my
presentation.
Employment: None
Speakers Bureau: None
Stock Shareholder: None
Grant/Research Support: None
Scientific Advisor: Life Length
Neuroendocrine Interventions
AGE Breakers (Advanced Glycation End Products)
Anti-inflammatory Agents
Antioxidant Supplements
Caloric Restriction Mimetics
Mitochondrial Modulators
Stem Cell Therapies
Telomere Extension - Cell Rejuvenation
Neuroendocrine Interventions
AGE Breakers (Advanced Glycation End Products)
Anti-inflammatory Agents
Antioxidant Supplements
Caloric Restriction Mimetics
Mitochondrial Modulators
Stem Cell Therapies
Telomere Extension - Cell Rejuvenation
What is Aging?
Hermann J. Mller
Barbara McClintock
X-ray mutagenesis
experiments in Drosophila
Absence of terminal
deletions or inversions after
irradiation
Telomeres of a young
or quiescent cell
Stop
Hayflick, 1950s
STOP
STOP
STOP
STOP
STOP
STOP
STOP
Harley et al,
Sperm
Placenta
Fetal brain
Fetal kidney
Colon mucosa (30-65 yrs)
Colon mucosa (65-88 yrs)
Blood (20-39 yrs)
Blood (40-59 yrs)
Blood (60-79 yrs)
12
16
20 (kb)
Cancer Incidence
Age
Cancer Rises with Increased Age
Cancer
106
cells
106
cells
106
cells
106
cells
106
cells
106
cells
106
cells
106
cells
cell doublings
Hallmarks of Cancer
Hanahan and Weinberg
Cell 2011
Telomere
hTR
template
hTERT
TRAP
ITAS
Normal
Cancer
GAPDH
Elizabeth Blackburn
Jack Szostak
Carol Greider
Survival
rate (%)
NT
100
Neuroblastoma IVS
9.4
6.6
50
4.4
0
10
(year)
2.3
(Kb)
TRF
hTERC or hTR
RNA Template
Telomerase
A U C C C A A U C UGUU
T AGGG T T AGA C A A
T T AGGG T T
Telomere
GRN163L
Imetelstat
GRN163L (Imetelstat)
13-mer lipidated thio-phosphoramidate
backbone complementary to the
telomerase RNA template with a long
half-life in human tumors
0
H 1703
H 661
H 1299
H 1975
H C C 4006
H 1993
H 1568
H C C 1359
H 1819
H 2882
H 2009
H 1693
H 226
H 838
H 2126
H 2347
H 1355
H O P 62
H 460
H 1155
H 157
H C C 2429
A5 4 9
H 322
H 1395
H 596
H 1792
H 3122
H 1666
H 2122
H 727
H 650
H C C 78
H 2228
H 358
H 2291
H 3255
H 1373
H 441
H C C 1438
H C C 44
H 2073
H 2087
H C C 95
H C C 827
H 522
H 1437
H 1838
H C C 4019
H 23
H C C 2279
H 1650
H 920
H C C 193
H C C 1833
C a lu - 6
H 1648
C a lu - 1
H 1944
H C C 515
H 820
H 2887
C a lu - 3
T e lo m e r e L e n g t h ( k b )
25
20
T o ta l P o p u la tio n D o u b lin g s
15
100
H 460
1 u M Im e te ls ta t
50
0
0
50
100
D ays
T o ta l P o p u la tio n D o u b lin g s
150
200
250
60
C a lu -3
40
C a lu -3
1 u M Im e te ls ta t
20
0
0
20
40
D ays
60
10
5
80
100
Imetelstat
No Imetelstat
Total
Bev
27
13
40
No Bev
50
26
76
Total
77
39
116
0.8
Imetelstat
Control
14.3
11.5
Median
(95% CI)
0.7
0.6
0.5
0.4
0.3
0.2
Control
0.1
Imetelstat
0
0
10
12
14
16
18
20
22
24
114 104 91 84 69 50 41 25 18 11
Control
Imetelstat
0.9
Control
Imetelstat
0.8
0.9
0.7
0.8
Short Telomeres
0.6
0.5
0.4
0.3
0.2
0.1
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
0
10
12
14
16
18
20
10 12 14 16 18 20
Cancer-permissive
PD
Population Doublings
hTERT
30 kb
7.7 kb
ITAS
160
140
hTERT +
120
100
80
hTERT -
60
40
0
50
100
150
200
250
300
Days
TRAP
TRF
Telomeric repeat
amplification protocol
Cancer
hTERT +
present
absent
present
high
low
high
present
absent
present
intact
absent
intact
normal
absent
abnormal
present
normal
absent
finite
indefinite
indefinite
Characteristics
Anchorage dependence
Cell cycle checkpoints
Karyotypic profile
Chronic wounds
Myeloproliferative disorders
Macular degeneration
Arteriosclerosis
Dyskeratosis congenita
Normal
Mutation without IPF
Mutation with IPF
Tsakiri et al, 2007
Telomere
Shortening
Clinical
Disease
Telomere length
Health
Disease risk
30-40
Age (years)
70-80
Telomere length
Health
Disease risk
50-60 70-80
Age (years)
Vitamins
C&E
Vitamins
A&D
Oxidative stress
DNA damage
Inflammation
Telomere
shortening
Telomere Length
Cancer cell
Cell Divisions
2. Anti-inflammatory properties
3. Antioxidant properties
4. Immune stimulating properties
5. Antiviral properties
6. Antibacterial properties
7. Cardiovascular effects
Astragalus membranaceus
Telomere length
Health
Disease risk
70-80 90-100
Age (years)
Lansdorp
Flow cytometry
Multiple
sample
processing
Blackburn
Harley
HT qFISH (blood)
qPCR
Southern Blot
TRF analysis
Dot blot
Blasco
Single
sample
processing
STELA
qFISH Telomapping (tissue)
Lansdorp
Flow cytometry
Multiple
sample
processing
Blackburn
Harley
HT qFISH (blood)
qPCR
Southern Blot
TRF analysis
Dot blot
Blasco
Single
sample
processing
STELA
qFISH Telomapping (tissue)
short telomeres
long telomeres
2) HT Q-FISH
3) Confocal microscopy
6) Data analysis
5) Data processing
4) Capture of individual
telomere signals
Mean TL
60
frequency
% Short telomeres
40
20
0
0
10
15
20
20
15
10
5
0
0
10
20
30
40
Age (years)
50
60
70
10
20
30
40
50
60
70
Age (years)
Normal Prostate
Telomere FISH
Basal
cells
Prostatic
Intraepithelial
Neoplasia (PIN)
Determining average telomere length analysis on this biopsy would not be useful
Science Daily, March 27, 2013. Short telomeres are not only a
marker for higher risk of disease and mortality, but are a likely
underlying cause of several age-related diseasesincluding heart
disease and various cancers. The team measured telomere lengths
in over 48,000 individuals and identified seven genetic variants that
are associated with telomere length, and found that these genetic
variants also affected risk of various diseases.
EurekAlert, March 9, 2013. Scientists at the Intermountain Heart
Institute Salt Lake City, showed that people with longer telomeres
live longer. The study's lead researcher, Dr. John Carlquist, said of
telomere testing "We can already test cholesterol and blood
pressure of a patient to see how treatment is working, but telomere
testing could give us a deeper view into how the treatment is
affecting the body and whether or not the treatment is working.
Conclusions