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