Transcript Diapositiva 1 - SENS Research Foundation

Calogero Caruso
BIOLOGY OF LONGEVITY:
ROLE OF THE IMMUNE SYSTEM
Immunosenescence Group
Dipartment of Pathobiology and Biomedical
Methodologies
University of Palermo
www.unipa.it/immunopatologia
Cambridge, September 8th, 2005
AGEING
Progressive loss of functions
Reduced ability to respond to environmental stimuli
Increased susceptibility to disease
Increased death risk
Immunity, Ageing and Longevity
Relevance of immune system
Both infectious and inflammatory diseases are increased in
frequency and severity in the elderly
Increased frequency
Relative risk of mortality
Cardiovascular diseases
Chronic pulmonary diseases
Acute pulmonary diseases
Cancer
Tuberculosis
100
100
89
43
10
The immune system
CLONOTYPIC
B cells
T cells
(humoral via
antibodies)
(cellular effectors;
cytokines)
antigen-presenting
cells
INNATE
phagocytes
dendritic
cells
NK cells ?
Inflammation
•Antigenic load is
associated with a
loss of early
memory cells, an
increase of highly
differentiated
CD8+ cells, a
gradual reduction
of the
immunological
space and an
immune risk
phenotype (IRP)
predicting
mortality.
•As a consequence,
a peculiar chronic
inflammatory
status characterizes
immunosenescence.
•Lifelong chronic
antigenic load
induces age-related
increase of
activated immune
cells and
hyperproduction of
proinflammatory
cytokines.
IMMUNE SYSTEM IN AGEING
M. De Martinis et al. FEBS
Letters 579 (2005) 2035–2039
HUMAN LONGEVITY APPEARS TO HAVE A
SIGNIFICANT HERITABLE COMPONENT,
CONFIRMING THE OLD ADAGE THAT LONG
LIFE RUNS IN FAMILIES.
Disease
outcome
Centenarian
offspring
N (%)
22 (13)
Controls
N (%)
POR
(95% CI)
p value
45 (27)
.001
8 (5)
27(16)
8 (5)
19 (11)
0 (0)
2 (1)
0.38
(0.21, 0.69)
0.24
(0.13,0.30)
0.37
(0.14, 0.93)
-
10 (6)
14 (8)
46 (26)
86 (52)
7 (4)
19 (11)
32 (18)
27 (16)
4 (2)
7 (4)
0 (0)
14 (8)
1 (1)
16 (10)
Cataracts
52 (30)
32 (19)
Glaucoma
13 (7)
9 (5)
9 (5)
4 (2)
13 (7)
12 (7)
0 (0)
1 (1)
20 (11)
18 (11)
12 (7)
14 (8)
Coronary
heart disease
Coronary
artery disease
Myocardial
infarction
Congestive
heart failure
Arhythmia
Hypertension
Diabetes
Mellitus
Cancer
PREVALENCE
ODDS
ESTIMATES
FOR DISEASE
Stroke
Dementia
Osteoporosis*
Macular
degeneration
Depression
Parkinson’s
disease
Thyroid
condition
COPD
0.65
(0.05, 0.17)
0.33
(0.21, 0.51)
0.32
(0.13, 0.78)
1.14
(0.64, 2.03)
0.51
(0.15, 1.79)
0.80
(0.36, 1.78)
1.47
(0.89, 2.41)
1.35
(0.54, 3.39)
2.13
(0.64, 7.02)
1.0
(0.45, 2.21)
1.02
(0.50, 2.08)
0.77
(0.35, 1.72)
<.001
.035
.358
<.001
.013
.666
.295
.584
.129
.518
.2157
.990
.949
.525
Notes: * Osteoporosis includes Osteoporosis, hip, wrist, and vertebral
fracture. POR= Prevalence Odds Ratio; CI= Confidence Interval; COPD=
Chronic Obstructive Pulmonary Disease
CHEMOKINE
RECEPTORS
ACUTE PHASE PROTEIN
PYRIN
ADHESION MOLECULES
TOLL-LIKE RECEPTORS
CYTOKINES
PROTEASE
INHIBITOR
“So, our hypothesis is
that pro-and anti-inflammatory genes involved
in cardiovascular diseases
may play an opposite role in human longevity”.
Studies performed on the Sicilian population confirm
our suggestion
CHEMOKINE
RECEPTORS
ACUTE PHASE PROTEIN
PYRIN
ADHESION MOLECULES
GAP-JUNCTION
TOLL-LIKE RECEPTORS
CYTOKINES
PROTEASE
INHIBITOR
IL-10 IN AGE RELATED DISEASES
IL-10 GENE POLYMORPHISMS
IL-10R (CA)n
IL-10 G (CA)n
ATG
-6752A/T
-3538A/T
-6208 C/G
-1082 G
-2736A/C
-1354A/G
-819C/T
-1082G/A
Less IL-10 production (from 30 to 50%)
-592C/A
GENOTIPIC FREQUENCIES IN MI
AND LONGEVITY
Lio et al., 2004
IL-10 CONCLUSIONS
 In our study the high producer IL-10 –1082GG
polymorphism showed the highest frequency in
centenarians and the lowest frequency in AMI patients.
 Therefore high IL-10 production seems to be protective
towards cardiovascular diseases and can be seen as a
longevity factor.
CHEMOKINE
RECEPTORS
ACUTE PHASE PROTEIN
PYRIN
ADHESION MOLECULES
GAP-JUNCTION
TOLL-LIKE RECEPTORS
CYTOKINES
PROTEASE
INHIBITOR
THE CCR5 RECEPTOR
Chemokines and their receptors form a regulatory network that
controls the development, recruitment and activation of
leukocytes.
The chemokine CCR5 plays an important role both in
clonotypic and natural immune system, where it is highly
expressed on macrophages, CD4 T cells and endothelial cells.
In inflammation, macrophage inflammatory protein 1α and 1β
(MIP-1α, MIP-1β) latch into CCR5 leading monocytes to the
inflammatory site.
CCR5 gene: 32 bp Deletion
The 32bp (32) deletion causes frame shift mutation at position 185
which is localized by the 2nd extracellular loop of the receptor sequence.
The 185 aa deletion stops the maturation of the protein. (Samson et al.,
Nature, 1996)
CCR5 CONCLUSIONS
The CCR5 32 receptor polymorphism seems to be
associated with a lower risk to develop atherosclerosis and
AMI. The presence of this mutation in CCR5 receptor
abolishes (reduces) the receptor from the cell surface. This
impairs the recruitment of monocytes at the vascular wall.
The mutation might result in an increased chance of
longevity in a modern environment with reduced pathogen
load and improved control of severe infections by
antibiotics.
CHEMOKINE
RECEPTORS
ACUTE PHASE PROTEIN
PYRIN
ADHESION MOLECULES
GAP-JUNCTION
TOLL-LIKE RECEPTORS
CYTOKINES
PROTEASE
INHIBITOR
Toll-like receptors (TLRs) represent a primary line of
defence against invading pathogens in mammals, plants
and insects. Recognition of microbial components by
these receptors triggers the initial innate immune
response that ultimately leads to inflammatory gene
expression and clearance of the infectious agent.
TLR4 Asp299Gly Polymorphism
+896 AG
Aspartic acid Glycin
LPS responsiveness
Pro-inflammatory citokynes production
GENOTYPE DISTRIBUTION OF
+896AG TLR4 GENE
Balistreri CR, Candore G, C, Caruso C.. JAMA 2004.
TLR4 CONCLUSIONS
In our study TLR4 polimorphism seems associated with
reduced risk to develop aterosclerosis and AMI, likely
because it lowers the pro-inflammatory signal in the
monocytes.
The mutation might result in an increased chance of
longevity in a modern environment with reduced pathogen
load and improved control of severe infections by
antibiotics.
What is the meaning
of these data?
Epidemiologic studies suggest that
the pathogenic burden, which every
individual has been exposed, may
be linked to an increased risk of
atherosclerosis.
Inflammatory Exposure and Historical
Changes
in Human Life-Spans
Caleb E. Finch* and Eileen M. Crimmins
17 SEPTEMBER 2004 VOL 305 SCIENCE
Infections, trauma
Inflammatory molecules
Inflammation in early phases of life
can play a relevant role in elderly
morbidity and mortality.
Tissue injury
Disease
Death
The presence of pro-inflammatory gene
polymorphisms may fuel the inflammatory response
promoting
pro-inflammatory
status
and
atheromatous plaque vulnerability.
Conversely, people genetically predisposed to a
weak inflammatory activity, have less chance to
develop CHD and, therefore, more chance to live
longer.
In fact, cardiovascular diseases are a late consequence
of an evolutionary pro-inflammatory response
programmed to resist infections in earlier life.
CONCLUSIONS: Genetics of
inflammation, infections, CVD
and longevity
Longevity
Genetic polymorphisms
responsible for a low
inflammatory response might
result in an increased chance
of long life-span in an
environment with a reduced
pathogen burden, such as a
modern day and health
environment, which also
permit to obtain a lower grade
survivable atherogenic
inflammatory response.
Decreased
life-long
infection
incidence
Socio-oeconomic and
sanitary condition
improvement
IMMUNOSCENESCENCE GROUP
PATHOBIOLOGY AND BIOMEDICAL METHODOLOGY
DEPARTMENT
UNIVERSITY OF PALERMO
Giuseppina Candore
Giuseppina Colonna Romano
Domenico Lio
Florinda Listì
Letizia Scola
Carmela Rita Balistreri
Antonio Crivello
Maria Paola Grimaldi
Domenico Nuzzo
Sonya Vasto
Alessandra Aquino
Matteo Bulati
Valentina Orlando
Mariangela Russo
Antonio Giacalone
Daniele Di Carlo
Vito Ditta
Collaborations
Studies on Centenarians
Dpt. Patologia Sperimentale,
Università di Bologna:
Istituto Nazionale di Riposo e
Cura per Anziani, Ancona:
Claudio Franceschi
Studies on Infarction
Dpt. Patologia Sperimentale,
Università di Bologna:
Istituto di Cardiologia,
Università di Bologna
Federico Licastro
Angelo Branzi
Dipartimento di Medicina Interna,
Malattie Cardiovascolari e Nefrourologiche,
Università di Palermo
Enrico Hoffmann