telomeros, envejecimiento y prevencion dr.a.fernandez-cruz - barcelona - april 2014
TRANSCRIPT
Telomerós, Envejecimiento y Prevención
Dr. Arturo Fernández- Cruz
Health demographic change and wellbeing
The economic crisis
Incidencia de IAM en población
de 25 a 74 años por sexos
1200 millones OMS
PREVEND
8074
JIM
Nov 2013
La medicina de las 4 Ps
•PREDICTIVA
•PREVENTIVA
•PERSONALIZADA
•PARTICIPATORIA
La detección temprana 90% de supervivencia
La detección tardía 10% de supervivencia
NEJM Modelo matemático 1980-2000 Reducción de los FRs Nuevos tratamientos Solo el 7% debido CABG o STENTs NEJM enero 2013
Progress in science
depends on new techniques,
new discoveries, and new
ideas probably in that order
Sydney Brenner
Tecnologías que crecen exponencialmente
Test genéticos a bajo coste Test de medición de Telomeros
Computadores-Bio-informática, Historia y archivos electrónicos
Técnicas de imagen TAC, RM (Colonoscopia virtual), “IPad”
Conexión por Internet, medicina on-line (visitas virtuales)
Redes Sociales
Mi tecnología favorita es el iPhone “digital medicine”
NUEVAS TECNOLOGÍAS
“senescent” cells
healthy
cell
50-70 divisions
healthy cells
are MORTAL
cancer
cell
cancer cells are
IMMORTAL unlimited divisions
Henrietta
Lacks
telomere telomere
Chromosome
(parent cell)
Telomeres are lost everytime that a cell divides
“the end-replication problem”
DNA is lost from the ends
Chromosome
(daughter cell #1)
Chromosome
(daughter cell #2)
An embryonary gene known as telomerase is able to elongate
telomeres to compensate excessive telomere loss during embryo
development.
This gene, telomerase, is silenced after birth … however …
Cancer cells manage to reactivate telomerase, thus escaping the mortal
fate of adult cells and becoming immortal.
TTAGGG TTAGGG
AATCCC AATCCC
genes telomeres
TTAGGG TTAGGG
AATCCC AATCCC
TTAGGG TTAGGG
AATCCC AATCCC
cell death
cell senescence
aging
TTAGGG TTAGGG
AATCCC AATCCC
genes telomeres
cancer
TTAGGG TTAGGG
AATCCC AATCCC
TTAGGG TTAGGG
AATCCC AATCCC
TTAGGG TTAGGG
AATCCC AATCCC
TTAGGG TTAGGG
AATCCC AATCCC
TTAGGG TTAGGG
AATCCC AATCCC
Telomere length as a biomarker of biological age & health status
Canela et al., PNAS (2007)
Telomere length predicts age & cognitive impairment Telomere length decreases with age
HT
Q
FIS
H
cancer (> 95% of cancers
activate telomerase)
high
Telo
mere
len
gth
disease
health
age
Telomeres, telomerase and aging
Human pathologies due to telomerase defects
dysqueratosis congenita (DKC1, Terc)
aplastic anemia (Terc, Tert)
idiophatic pulmonary fibrosis (Terc, Tert)
loss of the regenerative capacity of the skin
lungs, bone marrow…
Telomere length=Biomarker of aging?
Lower percentiles of telomere length=
higher risk of diseases (cardiovascular,
neurodegenerative, death by infections)
Telomere length measurements for individuals
Life Length´s partnership with:
Page 20 © 2014 Life Length. All rights reserved. Reproduction of this document or any portion thereof without prior written consent is prohibited.
Telomere Measurements for individuals
Your median telomere length is estimated to be normal compared to Life Length´s database population.
1. Your telomere length
Median Telomere Length: 9.2 Kb
< 7.8 78 – 8.5 8.2 – 13.7 13.7 – 15.3 > 15.3
VERY SHORT SHORT NORMAL LONG VERY LONG
Median Telomere Length (MTL) = 9.2 ± 0.3 Kb
You: 9.2 Kb
The adjacent graph shows a comparative analysis of the median telomere length in your sample compared with the control database.
Each line represents a specific percentage of our database.
For example, falling in the 75th percentile means that 25% of people of your age have a longer median telomere length than you.
It is therefore best if your sample falls into one of the higher bands.
2. Median telomere length – Comparison by age band and percentiles
20 30 40 50 60 70 80 90
Chronological age (years)
Me
dia
n t
elo
me
re
len
gth
(K
b)
16
15
14
13
12
11
9
8
95
90
75
50
25
10
05
%
3. Your estimated biological age
Estimated Biological Age: 55 years old Chronological Age: 50 years old
Value ± SD
Biological age based on chronological age and telomere length
Comparison of MTL per age group
Comparison of MTL against entire database (to find severe outliers)
Extract from actual evaluation
0
50
100
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450
500
0 5 10 15 20 25 30 35 40
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0 5 10 15 20 25 30 35 40
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500
0 5 10 15 20 25 30 35 40
0
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800
0 5 10 15 20 25 30 35 40
0
50
100
150
200
250
300
0 5 10 15 20 25 30 35 40
telo
me
re le
ngth
, kb
telomere length, kb
samples
Subject 49- Male 02/02/78 healthy
Subject 50- Male 22/09/77 medular aplasia, TERC mut
Subject 51- Male 17/05/78 healthy
Subject 52- Male 06/06/78 healthy
frequency
telomere length, kb
telomere length, kb
telomere length, kb
telomere length, kb
frequency
frequency
frequency
frequency
Subject 49
9.49 ± 2.81 kb
n=1951
Subject 50
5.7 ± 2.01 kb
n=1685
Subject 51
10.46 ± 3.28 kb
n=2796
Subject 52
10.06 ± 3.34 kb
n=4811
L5178Y-S
10.06 ± 3.34 kb
n=1408
0
5
10
15
20
subject 49 subject 50 subject 51 subject 52 L5178Y-S
% t
elo
me
res <
8 k
b
samples
n=1951
n=1685
n=2796 n=4811
n=1408
***
0
10
20
30
40
50
60
70
80
90
100
subject 49 subject 50 subject 51 subject 52 L5178Y-S
***
Telomere length as a diagnosis tool
Hospital
Vall d´Hebrón
Canela et al., unpublished
0 10 20 30 40 50 60 700
5
10
15
20
Mea
n t
elo
mer
e le
ngt
h (K
b)
Age (years)
0 10 20 30 40 50 60 700
10
20
30
40
50
60
% s
ho
rt t
elo
me
res
(<3
kb)
Age (years)
Telomere length measurements for individuals
% short telomeres detect more differences between individuals than average length
% short telomeres show higher dispersion as we age
% short telomeres are likely to reflect “way of living” (environment) or biological age
Bioactive food components can influence genetic and epigenetic events
associated with a host of disease processes
Trujillo E et al. J Am Diet Assoc 2006;106:403-413
Trujillo E et al. J Am Diet Assoc 2006;106:403-413
Dietary factors and the regulation of DNA methylation “CpG sites” 28 millones
S Horvad clock-watcher Nature April
2014 Nature 508,22:2014
Methylation
status
353 CpG sites
algorithm
Genetic tests: genes as risk factors for disease
INHERITED
Telomere tests: indication of the degree of aging
INHERITED ENVIRONMENT
MORE POWERFUL PREDICTIONS
OF RISKS AND TIME OF ONSET
# aging is the highest risk factor for all diseases
# telomere length integrates both inheritance & environmental factors EPIGENETICS
DEVELOPMENT OF
NEW TREATMENTS TO
PREVENT DISEASE
A NEW ERA in medicine?: Personalized & preventive medicine
Virus
Inflamación crónica
Factores genéticos
Envejecimiento celular – Estrés oxidativo: Integridad del telómero
Patogenia del cáncer
Inmortalización celular
Fallo en los mecanismos de
control
Telomere length and Cancer
The Association of Telomeres length and Cancer: a Meta-analysis
S A Savage et al Cancer Epidemiology Biomarkers Prev 20:1238,2011
Short Telomeres are associated with excess Cancer Incidence and mortality
A L Kamaroff JAMA 2010 july 7 P Willet JAMA 304:69, 2010
Fifteen year follow up of association between Telomere length and
incidence Cancer and Cancer mortality
JAMA 306:42,2011
Breast cancer: Familial breast cancer
BRCA1/BRCA2
BRCA1
Age (years)
Re
lati
ve
Te
lom
ere
len
gth
BRCA2
Age (years)
Re
lati
ve
Te
lom
ere
len
gth
-0.5
0
0.5
1
1.5
2
2.5
3
3.5
10 20 30 40 50 60 70 80
BRCAX
Age (years)
Re
lati
ve
Te
lom
ere
len
gth
-0.5
0
0.5
1
1.5
2
2.5
3
3.5
10 20 30 40 50 60 70 80
Sporadic BC
Age (years)
Re
lati
ve
Te
lom
ere
len
gth
-0.5
0
0.5
1
1.5
2
2.5
3
3.5
10 20 30 40 50 60 70 80
-0.5
0
0.5
1
1.5
2
2.5
3
3.5
10 20 30 40 50 60 70 80
A C
B D
More powerfull tools to predict risk factors and develop new treatments
Javier Benitez (CNIO)
MEDICINA PREDICTIVA
• BCR Gail mama BCRAs • BRACAPRO mama ovario • BOADICEA mama, ovario,
prostata, melanoma • PREMM colon • PULMON
Cancer genograma
Diabetes FINDRISK SCORE
Cribados
Telomeros
Genes
Can telomerase delay
aging pathologies?
Telomerase as an anti-cancer target (Imetelstat)
Phase II
Clinical trials
(breast, lung, prostate etc)
ratones
K5-mTert
No telomerase
Less
aging
Less
cancer
More cancer Premature aging
La telomerasa se expresa específicamente en células madre
telomerase
Telomere length
Tg telomerase
(epithelia)
Gonzalez-Suarez et al., Oncogene (2004)
Super p53
Super p16
Super p19ARF
Cancer
suppressors
+
SUPER-M
Linear regression:
WT: Slope=-7.03 ± 1.24 kb/year
R2=0.31 (Quadratic: R2=0.34)
p<0.0001
TgTERT: Slope=-7.05 ± 1.60 kb/year
R2=0.22 (Quadratic: R2=0.30)
p<0.0001
0.0 0.5 1.0 1.5 2.0 2.5 0
10
20
30
40
50
60
70
80
Age (years)
Me
an
te
lom
ere
len
gth
(kb)
Vera et al., Cell Reports, 2012
Mouse telomeres shorten 100-times faster than human telomeres
Humans: 70 bps/year
Mice: 7 Kb/year
Incre
ase
in t
he
% o
f
sh
ort
te
lom
ere
s (
pe
r m
on
th)
The increase in the % of short telomeres predicts individual mouse longevity
0 50 100 150 200-0.5
0.0
0.5
1.0
1.5
Lifespan (weeks)
WT: Slope=-0.005022 ± 0.002550
R2=0.2
p=0.06
TgTERT: Slope=-0.01267 ± 0.005604
R2=0.3
p=0.04
WT
TgTERT
WT
TgTERT
telomerase-deficient
wild-type
Blasco et al., Science (1995)
Blasco et al., Cell (1997)
Lee, Blasco, et al., Nature (1998)
González-Suarez et al., Nat Genet (2000)
González-Suarez et al., EMBO J. (2001)
Flores et al., Science (2005)
Telomerase-deficient mice (Terc-/-):
decreased regenerative capacity
due to stem cell dysfunction
less cancer
Super-telomerase mice (K5-Tert):
better tissue fitness
slightly more cancer
The role of telomerase in chromosome stability, cancer & aging
Tomás-Loba et al, Cell (2008)
SUPER Wild-type
Defeating aging with increased telomerase + tumor suppression
Increased “health span” & longevity in SUPER mice
Cancer-free survival Overall survival
0
20
40
60
80
100
0 60 80 100 120 140 160 180
Sp53 (n=25) SUPER (p=0.003; n=6)
su
rviv
al (%
)
age (weeks)
+50%
normales (n=25)
0
20
40
60
80
100
0 60 80 100 120 140 160 180
Sp53 (n=49)
SUPER (p<0.001; n=12)
su
rviv
al (%
)
age (weeks)
+40%
normal (n=49)
0
20
40
60
n=25
n=6
p=0.003
0
20
40
60
n=49
n=12
p<0.001
normal SUPER
Su
rviv
al
at
3 y
ea
rs (
%)
normal SUPER
Su
rviv
al
at
3 y
ea
rs (
%)
Tomás-Loba et al., Cell (2008)
He
alth
sp
an
Improved neuromuscular fitness
25000
30000
35000
40000
45000
glu
co
se
to
lera
nce
(A
UC
)
**
30-76 weeks
Glu
co
se
to
lera
nc
e (
AU
C)
n=5
n=3
wildtype SUPER
p=0.02
Improved glucose tolerance
0
25
50
75
100
125
Su
cc
es
s r
ate
(%
)
n=11
n=9
wildtype
p=0.02
n=8 n=10
SUPER
p=1
young (5-20 weeks) old (116-160 weeks)
Improved health late in life in SUPER mice
Tomás-Loba et al., Cell (2008)
SUPER-M wildtype
young (5-12 weeks)
old (123-165 weeks)
wildtype
Su
bc
uta
ne
ou
s f
at
laye
r (
m)
0
20
40
60
80
100
120
n=19
n=24
SUPER-M
n=11
n=61
Less skin aging in SUPER-M mice
Subcutaneous fat
old (123-165 weeks)
Tomás et al., Cell (2008)
Telomere length and ATHEROSCLEROSIS
Critical values of replicative senescence the “hayflic limit” vascular age
Circ Res 2006
Family History of CHD Heart 2008
European Atherosclerosis Reseach Study II J Mol Med July 2008
White cell telomere lenght and risk of premature AMI Atherosclerosis
Thromb Vasc Biol 2003 Lancet 2001 the WOSCOP study Lancet 2007
Tromboembolism
RY Zee… P Ridker Int J of Clinical Chemistry 2009; 406:148
Telomere length and preclinical ATHEROSCLEROSIS
Framingham Heart Study Arterioesclerosis Thromb Vac Biol May 2011
ASKLEPIOS STUDY European Heart Journal 2009 Obese man
Heart 2008 Carotid Atherosclerosis Hypertension 2004:43;182
Coronary Artery Disease Arterioesclerosis Thromb Vasc Biol 2004:24, 546
Calcium Score Atherosclerosis 2009
Vascular thrombosis RY Zee ..P Ridker 2013
Leukocyte and plaque telomere length in cases and controls.
Huzen J et al. Arterioscler Thromb Vasc Biol. 2011;31:1219-1225
Copyright © American Heart Association, Inc. All rights reserved.
X
LAD
ligation
Aging is not a disease…but there are many aging-associated diseases
preclinical model for cardiovascular disease
Normal heart
Failing heart
Failing heart Normal heart
PET – FDG uptake
Histopathology
AAV9-TERT
AAV9-empty
AAV9-TERT treatment protects 20% of the mice from death by infact
Bruno Bernardes de Jesus
Christian Bär
0 10 20 30 4040
60
80
100
AAV9-empty
AAV9-mTERT:
2x1012vg/m
No virus
Pe
rcen
t su
rviv
al
Hea
rt infa
rct
Days after myocardial infarction
n=35
n=37
n=21
p=0,07
74%
57%
FVB/N
0.0
0.5
1.0
1.5
0.0
0.5
1.0
1.5
Lo
ng
itu
din
al th
ickn
ess
(mm
)
Tra
nsvers
al th
ickn
ess
(mm
)
1 week
p=0.02 p=0.01
p=0.5
n=4
n=13
n=5 n=4
n=13
n=5
p=0.03 p=0.01
p=0.7
1 week
AAV9-empty
AAV9-mTERT:
2x1012vg/m
Sham (no myocardial infarction)
Echocardiography
Myocardial Infaction
AAV9-empty
SHAM
AAV9-mTERT: 2x1012vg/m
An AAV9-TERT treatment reduces scar formation upon infaction
Bruno Bernardes de Jesus
Christian Bär
Masson trichrome
Scar size/LV size, %
Nu
mb
er
of
mic
e
0
5
10
15
20
Mild Severe
Extremely severe
AAV9-
eGFP
AAV9-
mTERT
0
10
20
30
40
% o
f are
a
AAV9-
eGFP
AAV9-
mTERT
n=10
n=7
p=0.14
MI
AAV9-empty
AAV9-mTERT:
2x1012vg/m
0
50
100
150
200
me
an
sp
ot
inte
ns
ity /
nu
cle
us
(a
.u.)
mean 52.33 a.u.
(1850 nuclei) mean 64.98 a.u.
(1968 nuclei)
124% of AAV9 empty
p<0.0001
0
50
100
150
me
an
sp
ot
inte
ns
ity /
nu
cle
us
(a
.u.)
mean 40.08 a.u.
(2455 nuclei) mean 44.85 a.u.
(3096 nuclei)
112% of AAV9 empty
p<0.0001
AAV9-empty (n=4)
AAV9-mTERT (n=4)
(2x1012vg/m)
cardiomyocytes fibroblasts (infarct area)
AAV9-TERT treated mice show longer telomeres in heart after infaction
Bruno Bernardes de Jesus
Christian Bär
Telomere length and Diabetes
Association of Telomere shortening with IGT and DM2 macroangiopathy
Atherosclerosis Nov 2007
Accelerated senescence in the kidneys of patients with DM2 nephropathy
American J of Physiology 2008 DM2
Microalbuminuria Diabetes Care 2007;30:2909 Diabetologia 2006
Leukocyte Telomere shortening in elderly type 2 DM with previous AMI
Atherosclñerosis 2009
Association of Telomere length with type 2 DM oxidative stress and
UCP2 gene variation Atherosclerosis 2010
DNA damage. Diabetes Care 2006
Challenge: Individualized Risk Assessment
in Low- and Intermediate Risk Individuals
Algorithms
Neural
Network
MSCT, MRT, PET
Telomeres
And
Genes of
clinical
relevance
Lp(a) PLA2
CRP, BNP
Apo A-, HDL 2b
ApoB
Phytosterols
Metabolic syndrome
Other
CONFIDENTIAL
Rupture-Prone Plaques may not be Severely Stenosed
but are Inflamed with Thin Fibrous Caps
Early Plaque
with Lipid Pool
Thick Cap with Small
Necrotic Lipid Core
“Stable Plaque”
Thin Cap
“Rupture-Prone”
Plaque
Ruptured Plaque
with Thrombus
in Lumen
Adapted from Kolodgie F, et al. Arterioscler Thromb Vasc Biol 2006.
CARE PATHWAY FOR CARDIOVASCULAR RISK CLINIC
Cardiology REFERRAL
General Practice
05
1015202530
Ave Patient
10
yr
CV
D r
isk
Genetic CRF
CLINIC VISIT
Retest
Genetics
Telomeros
Results
RISK SCORE
Clinical Chem
T-Chol/HDL/TG
Lp(a)? etc?
Results
RISK SCORE + BMI/BP/Smoke
Carotid Coronaries
ACTION PLAN
Blood Pressure
Lowering
Lipid
Lowering
Smoking
Cessation
Weight
Loss
GPs -Specialist
Referral
Cardiology
Referral
Patient Appointment
Saliva sample request + Informed consent
Monitoring other effects than LDL: where do we stand ?
Statin may reduce the rate at which Telomeres shorten
Lancet 2001 2007 Jan 13
Omega-3 fatty acid supplementation reduces Telomere shortening in the cognitively
impaired J of Nutrition October 22 2013
Omega-3 fatty acids, oxidative stress and leukocyte Telomere length- A randomized
controlled trial E, Balackburn et al Brain Behavior Immunity Sept 2012
Longitudinal association of Telomere length and Obesity indices in an Intervention Study
with Mediterranean Diet the PREDIMED-NAVARRA trial S Garcia-Calzon International
Journal of Obesity 2014, 38:177
Paula Martínez, Gonzalo Gómez-López, Fernando García, Evi Mercken, Sarah Mitchell,
Juana M. Flores, Rafael de Cabo, Maria A. Blasco. RAP1 Protects from Obesity through
Its Extratelomeric Role Regulating Gene Expression. Cell Reports, 2013; DOI: 1-
Metabolic Syndrome PREVEND study JIM Nov 2013
The association between Physical Activity in Leisure time and leukocite Telomere
lenght
LF Cherkas Arch Intern Med 2008;168:154. Lancet oncology Sep 2013
Stress can shorten Telomere in chilhood Nature 17 may2011
Telomere length and Aging related to Depression?
Molecular Psychiatry Nov 12 2013 Biol Psychiatry 2012 ;15:294
CORRELATION BETWEEN IMT AND EPC LEVELS IN PATIENTS WITH METABOLIC SYNDROME
0
1
2
3
4
5
6
7
8
9
0,2 0,4 0,6 0,8 1 1,2
GIM
EP
Cs
Ta
rdía
s (
%)
CD
34
+/V
E-c
ad
he
rin
a+
(%
) r = - 0,169
P = 0,017
IMT (mm)
Telomerase activation
(with smal molecules)
Telomerase activation with a nutritional supplement
Infancy/youth/adulthood aging
cancer cardiovascular
diabetes
renal disease
immunosenescence
neurodegeneration
etc…
telomere loss
consequences
Interventions
(ie, TERT)
aging
cancer cardiovascular
diabetes
renal disease
immunosenescence
neurodegeneration
etc…
Infancy/youth/adulthood
Understanding the molecular basis of aging to prevent disease
genetic &
environmental
Everything will be alright in
the end
and if it’s not alright
it’s not the END
Muchas Gracias
Gastamos mas en armamentos que en la Prevención