power point José Viña

 FUNDACION RAMON ARECES. MADRID El ENVEJECIMIENTO A NIVEL
CELULAR Y ORGÁNICO:
ENVEJECER ES NORMAL
JOSE VIÑA
Facultad de Medicina.
UNIVERSIDAD DE VALENCIA
ENVEJECIMIENTO FISIOLOGICO!
¿ENVEJECIMIENTO COMO PROBLEMA? !
!
CARACTERISTICAS DEL ENVEJECIMIENTO: GENE
!
CENTENARIANOS: ENVEJECIMIENTO EXCEPCIONA
!
MODULACION DEL ENVEJECIMIENTO ¿PODEMOS?
!
COROLLARIO : ENVEJECIMIENTO SATISFACTORIO
!
MENSAJE: CUIDESE HOY
1988- 2013
Aging as a problem:THAÏS
Ah ! tais-toi, voix
impitoyable, Voix que
me dis: Thaïs, tu
vieilliras! Un jour,
ainsi,
Thaïs ne serait plus
Thaïs! Non! Non! je
n'y puis croire
Social impact of aging studies
National Geographic!
November 2005!
Scientific American !
March 2006!
Time !
October 2005!
TIME: sept 10, 2013
ENVEJECIMIENTO FISIOLOGICO!
¿ENVEJECIMIENTO COMO PROBLEMA? !
!
CARACTERISTICAS DEL ENVEJECIMIENTO: GENE
!
CENTENARIANOS: ENVEJECIMIENTO EXCEPCIONA
!
MODULACION DEL ENVEJECIMIENTO ¿PODEMOS?
!
COROLLARIO : ENVEJECIMIENTO SATISFACTORIO
!
MENSAJE: CUIDESE HOY
Characteristics of aging
UNIVERSAL
PROGRESSIVE
AGEING
INTRINSIC
DELETERIOUS
Vina et al (2007) IUBMB Life,
according to Strehler, B. L. (1977)
Aging is not a disease: AGE
ASSOCIATED CHANGES
Biological Aging Is No Longer
an Unsolved Problem
LEONARD HAYFLICK
Aging is not a disease: AGE
ASSOCIATED CHANGES
(1) occur in every multicellular animal
that reaches a fixed size at
reproductive maturity
(2) cross virtually all species barriers
(3) occur in all members of a species
only after the age of reproductive
maturation
Aging is not a disease: AGE
ASSOCIATED CHANGES
(4) occur in all animals removed from the wild
and protected by humans even when that
species probably has not experienced aging for
thousands or even millions of years
(5) occur in virtually all animate and inanimate
matter
(6) have the same universal molecular etiology,
that is, thermodynamic instability.
Unlike aging, there is no disease or
pathology that shares these six qualities.
The role of mitochondria
in aging
Role of mitochondria
in aging
LA BUSQUEDA DE GENES DE
LONGEVIDAD
The search for longevity
genes: p53
spontaneous
spontaneous
survival
curve
survival
curve
survival
curve
survival
curve
without
tumors
without
tumors
Logrank
test=
0.010.01
(*) (*)
Logrank
test=
survival (%)
survival (%)
survival (%)
survival (%)
100100
100100
75 75
75 75
50 50
50 50
25 25
Logrank
test=
0.020.02
(*) (*)
Logrank
test=
WTWT
Super/Super
Super/Super
0 0
0 05 5
10 10
15 15
20 20
25 25
30 30
35 35
40 40
time
(months)
time
(months)
25 25
WTWT
Super/Super
Super/Super
0 0
35 35
0 05 10
15 15
20 20
25 25
30 30
40 40
5 10
time
(months)
time
(months)
The search for longevity
genes: telomerase
The search for longevity genes: Ras
AGING : THE PROBLEM
WITH MODELS
CALORIC RESTRICTION
!  MICE (NEJM)
AGING : THE PROBLEM
WITH MODELS
CALORIC RESTRICTION
! M
  ICE (NEJM)
!  MONKEYS (Science vs Nature)
AGING : THE PROBLEM
WITH MODELS
CALORIC RESTRICTION
! M
  ICE (NEJM)
!  MONKEYS (Science vs Nature)
!  HUMANS (JAMA)
Caloric restriction increases life
span in mice
Weindruch and Sohal (1997) N Engl J Med
BMI and mortality
Letter to the Editor JAMA
Title: Overweight is not overweight : comment on “Association of
all-cause mortality with overweight and obesity” .
Authors: Jose Viña, Consuelo Borras, and Mari Carmen GomezCabrera
JAMA13-0598 Decision Letter
Dear Prof. Vina:
We have completed our review of your Letter to the Editor and are pleased to
accept it for publication in JAMA. Your manuscript is accepted with the
understanding that its contents, all or in part, have not been published elsewhere
and will not be published elsewhere in print or electronic format except in
abstract form or by the consent of the editor.
JAMA 2013
. Thus, direct es:mates of total fat mass will provide a more accurate body assessment. It has been shown that, for the general popula:on, in addi:on to BMI, waist circumference and waist to hip ra:o are of importance for assessing mortality risk 7. Consequently, even though it is widely accepted, classifica:ons of obesity based on BMI are inadequate. Indeed, if overweight decreases all-­‐cause mortality, then it is not overweight. Viña et al JAMA, 2013 Overweight and life span
ENVEJECIMIENTO FISIOLOGICO!
¿ENVEJECIMIENTO COMO PROBLEMA? !
!
CARACTERISTICAS DEL ENVEJECIMIENTO: GENE
!
CENTENARIANOS: ENVEJECIMIENTO EXCEPCIONA
!
MODULACION DEL ENVEJECIMIENTO ¿PODEMOS?
!
COROLLARIO : ENVEJECIMIENTO SATISFACTORIO
!
MENSAJE: CUIDESE HOY
The Spanish centenarian study
Which genes are
modulated in extreme
longevity?
Unpublished results
Strategy
Young
Octogenarian
miRNA analysis
Centenarian
mRNA analysis
Genechip Human Gene 1.0ST
Array
CHARACTERISTIC miRNAs AND mRNAs OF CENTENARIANS
Genechip miRNA 2.0 Array
mRNAs regulated by miRNAs
Sub-network analysis
(Software Ariadne Pathway Studio)
miRNAs in centenarians
Young
Octogenarian
Centenarian
miRNAs are
similar in young
and
centenarians!!!!!
Centenarians up-regulate
miRNAs
Downregulate All
d
Pvalue≤0.05
Fold-change|1.8|
Upregulated
C vs Y
7
0
7
O vs Y
1
50
51
C vs O
102
1
103
Functional transcriptomic
analysis
www.nature.com/scientific reports
Strategy
Young
Octogenarian
miRNA analysis
Genechip miRNA 2.0 Array
Centenaria
n
mRNA analysis
Genechip Human Gene
1.0ST Array
mRNAs regulated by miRNAs
Sub-network analysis
(Software Ariadne Pathway Studio)
Functional transcriptomic
analysis
!  Genechip Human Gene 1.0ST Array
!  Estimated number of genes: 28.869
!  200ng de RNAtotal
!  Hibridación a 45oC 60rpm durante 18h
mRNAs in centenarians
Young
Octogenarian
Centenarian
mRNAs are different
between
octogenarians and
centenarians!!!!
Comparison
of mRNAs
C vs Y C vs O The subnetworks...
A “sub-­‐ network” is a group of genes connected structurally or func4onally to one common gene A “sub-­‐ network” is iden4fied when there are known real4onships between the genes involved in the Ariadne data base, Subnetwork
analysis
•  All- 1721 genes that change in centenarians
•  Combine- 51 genes regulated by the 3
miRNAs specific for centenarians (from 1721
genes that change in centenarians)
3
miRNAs
51
mRNA
s
1721
mRNAs
T Cell Receptor
CvsJ OvsJ Arrows indicate genes that are in the “combine” list Subnetworks
: summary
TCR
IFNG
TNF
BCLxL,
FAS,
FASLG,
CCL5
SP1
TGFB
1
CYTO
KINE
The four critical genes
converge in...
Young
Octogenarian
Centenarian
*
2.38
Bcl-xL
Mitochondrial protein!!!!!!
Bcl2 lowers H2O2 levels in cells
H2O2 levels in MCF-7 cells
*
16,0
nmol H2O2/mg de proteínas
14,0
12,0
12,89
10,0
8,0
9,90
6,0
4,0
2,0
0,0
Bcl2+
Bcl2-
Bcl2 lowers protein oxidation in cells
Protein oxidation MCF-7
Proteínas carboniladas (u.a.)
2,50
2,00
2,01
1,50
1,67
1,00
0,50
0,00
Bcl2+
Bcl2-
ENVEJECIMIENTO FISIOLOGICO!
¿ENVEJECIMIENTO COMO PROBLEMA? !
!
CARACTERISTICAS DEL ENVEJECIMIENTO: GENE
!
CENTENARIANOS: ENVEJECIMIENTO EXCEPCIONA
!
MODULACION DEL ENVEJECIMIENTO ¿PODEMOS?
!
COROLLARIO : ENVEJECIMIENTO SATISFACTORIO
!
MENSAJE: CUIDESE HOY
HEALTH SPAN AND LIFESPAN
Elderly people LIFESPAN IS INCREASING
SIGNIFICANTLY
HEALTH SPAN IS NOT
IMPROVING
Increases in life span have led to more age
associated disaseaes
Osteoporosis
Alzheimer
Degeneración macular
Problemas de audición
Accidentes cerebrovasculares
AGING CAN BE MODULATED
! Moderate exercise
! Four helpings of
fruit
! Two wine glasses
!  Do not smoke
Increases life
14 years
Khaw et al Plos
Med (2008)
AGING CAN BE MODULATED
! Moderate exercise
! Four helpings of
fruit
! Two wine glasses
!  Do not smoke
Increases life
14 years
Khaw et al Plos
Med (2008)
AGING CAN BE MODULATED
! Moderate exercise
! Four helpings of
fruit
! Two wine glasses
!  Do not smoke
Increases life
14 years
Khaw et al Plos
Med (2008)
EXERCISE ACTS AS A DRUG (BJP, 2012)
• Exercise is beneficial for your health
• The dosing of exercise
• Exhaustive exercise and longevity
• Systemic adaptations to exercise
• Exercise, a psychoactive drug
• Contraindications of exercise
Participation in the Tour de France
significantly enhances longevity.
Int J Sport Med (2011)
TDF participants
Polynomial regression curve for TDF
participants
General population
Polynomial regression curve for general
population
THE VALENCIA
NUN STUDY
Effect of moderate wine
consumption on longevity
gene expression in humans
Favorable effects of wine…
Effect of wine (moderate) on gene expression
in catholic nuns
Blood sampling:
Before the study
Blood sampling :
after 14 days of
wine
Gene AKT1, CDKN2A, FOXO3, IRS1, FRAP1 TERF1, TERF2, TERT SESN2,CAT, SOD2, P53 SIRT1 IL1A Pathway Insulin Telomerase Oxidative stress Caloric restriction Inflamation Red wine increases catalase expression
Catalase
600 500 %
400 300 200 Before
100 After
-­‐
0
1
2
3
Population 1
n=4
4
5
6
7
8
Population 2
n=5
9
10
Red wine increases Mn-SOD expression
Mn-­‐SOD
350 300 250 % 200 150 Before
100 After
50 -­‐
0
1
2
3
Population 1
n=4
4
5
6
7
8
Population 2
n=5
9
10
Red wine increases p53 expression
%
p53
400 350 300 250 200 150 100 50 -­‐
Before
After
0
1
2
3
Population1
n=4
4
5
6
7
8
Population 2
n=5
9
10
Red wine increases sirtuin expression
%
Sirtuin 1
500 450 400 350 300 250 200 150 100 50 -­‐
Before
After
0
1
2
3
Population1
n=4
4
5
6
7
8
Population 2
n=5
9
10
ENVEJECIMIENTO FISIOLOGICO!
¿ENVEJECIMIENTO COMO PROBLEMA? !
!
CARACTERISTICAS DEL ENVEJECIMIENTO: GENE
!
CENTENARIANOS: ENVEJECIMIENTO EXCEPCIONA
!
MODULACION DEL ENVEJECIMIENTO ¿PODEMOS?
!
COROLLARIO : ENVEJECIMIENTO SATISFACTORIO
!
MENSAJE: CUIDESE HOY
SUCCESSFUL AGING
Aims:
!  Adapt to changes that are going to
occur
!  Compress morbidity
!  Prevent frailty and dependency
!  Feel that you are useful
La respuesta social…..
Comprometidos con el progreso, la investigación, la educación y la cultura
Grandma and granchid
Retired Ferrero people help Foundation
Painting, carving etc late sold in “mercatino”
Successful aging
! People like you and I,
though mortal, of course, do
not grow old no matter how
long we live. What I mean is
that we never cease to
stand like curious children
before the great Mistery into
which we were born
AE. to Otto Juliusberger, close friend and doctor
Successful aging
ENVEJECIMIENTO FISIOLOGICO!
¿ENVEJECIMIENTO COMO PROBLEMA? !
!
CARACTERISTICAS DEL ENVEJECIMIENTO: GENE
!
CENTENARIANOS: ENVEJECIMIENTO EXCEPCIONA
!
MODULACION DEL ENVEJECIMIENTO ¿PODEMOS?
!
COROLLARIO : ENVEJECIMIENTO SATISFACTORIO
!
MENSAJE: CUIDESE HOY
CUÍDESE AHORA
CUIDARSE NO ES SER EGOISTA SINO ALTRUISTA
[www.cuidesehoy.es]
CUIDESE HOY PARA QUE NO
LE CUIDEMOS MAÑANA
Conclusiones (1)
•  Prepararnos para la vejez es una
responsabilidad nuestra
•  La medicina antienvejecimiento es una
especialidad nueva que pretende
aplicar conocimientos actuales al
objetivo de llegar a la vejez de la mejor
manera posible
Conclusiones (2)
Las maniobras antiaging se basan en
•  Moderación dietética (restr. Calórica)
•  Aumentar el aporte de productos vegetales
•  Ejercicio fisico moderado
•  Control del estrés
•  Dejar de fumar
•  PREVENCION de enfermedades degenerativas
(cuanto antes mejor! )
EPILOGO
•  La madurez puede ser un
periodo de gran felicidad
porque las personas
mayores saben su sitio en
el mundo(L. Pauling).
•  Para disfrutar de ese
periodo hace falta cuidarse
para llegar bien al mismo
www.cuidesehoy.es
VIÑA’s LAB
¡GRACIAS!!