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Calogero CarusoCalogero Caruso
Immunosenescence GroupDipartment of Pathobiology and Biomedical
MethodologiesUniversity of Palermo
www.unipa.it/immunopatologia
Cambridge, September 8th, 2005
BIOLOGY OF LONGEVITY: ROLE OF THE IMMUNE SYSTEM
AGEING
Progressive loss of functions
Increased death risk
Reduced ability to respond to environmental stimuli
Increased susceptibility to disease
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 100 Chronic pulmonary diseases 100 Acute pulmonary diseases 89 Cancer 43 Tuberculosis 10
Inflammation
The immune systemThe immune system
CLONOTYPIC INNATE
B cells(humoral viaantibodies)
T cells(cellular effectors;
cytokines)
antigen-presentingcells
dendritic cells
phagocytes
NK cells ?
M. De Martinis et al. FEBS Letters 579 (2005) 2035–2039
•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 andhyperproduction of proinflammatory cytokines.
IMMUNE SYSTEM IN AGEING
HUMAN LONGEVITY APPEARS TO HAVE A SIGNIFICANT HERITABLE COMPONENT,
CONFIRMING THE OLD ADAGE THAT LONG LIFE RUNS IN FAMILIES.
Disease outcome
Centenarian offspring
N (%)
Controls N (%)
POR (95% CI)
p value
Coronary heart disease
22 (13) 45 (27) 0.38 (0.21, 0.69)
.001
Coronary artery disease
8 (5) 27(16) 0.24 (0.13,0.30)
<.001
Myocardial infarction
8 (5) 19 (11) 0.37 (0.14, 0.93)
.035
Congestive heart failure
0 (0) 2 (1) - -
Arhythmia 10 (6) 14 (8) 0.65 (0.05, 0.17)
.358
Hypertension 46 (26) 86 (52) 0.33 (0.21, 0.51)
<.001
Diabetes Mellitus
7 (4) 19 (11) 0.32 (0.13, 0.78)
.013
Cancer 32 (18) 27 (16) 1.14 (0.64, 2.03)
.666
Stroke 4 (2) 7 (4) 0.51 (0.15, 1.79)
.295
Dementia 0 (0) 1 (1) - - Osteoporosis* 14 (8) 16 (10) 0.80
(0.36, 1.78) .584
Cataracts 52 (30) 32 (19) 1.47 (0.89, 2.41)
.129
Glaucoma 13 (7) 9 (5) 1.35 (0.54, 3.39)
.518
Macular degeneration
9 (5) 4 (2) 2.13 (0.64, 7.02)
.2157
Depression 13 (7) 12 (7) 1.0 (0.45, 2.21)
.990
Parkinson’s disease
0 (0) 1 (1) - -
Thyroid condition
20 (11) 18 (11) 1.02 (0.50, 2.08)
.949
COPD 12 (7) 14 (8) 0.77 (0.35, 1.72)
.525
Notes: * Osteoporosis includes Osteoporosis, hip, wrist, and vertebral fracture. POR= Prevalence Odds Ratio; CI= Confidence Interval; COPD= Chronic Obstructive Pulmonary Disease
PREVALENCE ODDS
ESTIMATES FOR DISEASE
CYTOKINES
ADHESION MOLECULES
TOLL-LIKE RECEPTORS
PYRIN
ACUTE PHASE PROTEIN
CHEMOKINE RECEPTORS
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
GAP-JUNCTION
ADHESION MOLECULES
TOLL-LIKE RECEPTORS
PYRIN
ACUTE PHASE PROTEIN
CHEMOKINE RECEPTORS
PROTEASE
INHIBITOR
CYTOKINES
IL-10 IN AGE RELATED DISEASES
IL-10 GENE POLYMORPHISMS
-3538A/T-6752A/T -819C/T
-6208 C/G -2736A/C
IL-10R (CA)n IL-10 G (CA)n ATG
-1354A/G
-1082G/A -592C/A
-1082 G Less IL-10 production (from 30 to 50%)
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.
GAP-JUNCTION
ADHESION MOLECULES
TOLL-LIKE RECEPTORS
PYRIN
ACUTE PHASE PROTEIN
CHEMOKINE RECEPTORS
PROTEASE
INHIBITOR
CYTOKINES
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.
GAP-JUNCTION
ADHESION MOLECULES
TOLL-LIKE RECEPTORS
PYRIN
ACUTE PHASE PROTEIN
CHEMOKINE RECEPTORS
PROTEASE
INHIBITOR
CYTOKINES
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.
+896 AG
Aspartic acid Glycin
LPS responsiveness
Pro-inflammatory citokynes production
TLR4 Asp299Gly Polymorphism
GENOTYPE DISTRIBUTION OF +896AG 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.
Inflammation in early phases of life can play a relevant role in elderly
morbidity and mortality.
Inflammatory moleculesInfections, trauma
Tissue injury
Disease
Death
Inflammatory Exposure and Historical Changesin Human Life-SpansCaleb E. Finch* and Eileen M. Crimmins17 SEPTEMBER 2004 VOL 305 SCIENCE
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
Decreased life-long infection incidence
Socio-oeconomic and sanitary condition
improvement
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.
IMMUNOSCENESCENCE GROUPPATHOBIOLOGY AND BIOMEDICAL METHODOLOGY
DEPARTMENT UNIVERSITY OF PALERMO
Giuseppina Candore Giuseppina Colonna Romano Domenico Lio
Florinda Listì Letizia Scola
Carmela Rita BalistreriAntonio Crivello
Maria Paola Grimaldi Domenico Nuzzo
Sonya Vasto
Alessandra Aquino Antonio Giacalone
Matteo Bulati Daniele Di Carlo Valentina Orlando Vito Ditta Mariangela Russo
Collaborations
Studies on CentenariansDpt. 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: Federico LicastroIstituto di Cardiologia, Università di Bologna
Angelo BranziDipartimento di Medicina Interna, Malattie Cardiovascolari e Nefrourologiche,Università di Palermo
Enrico Hoffmann