6
chance. Very long life, to beyond age 90 years, appears to have an even
stronger genetic basis (Perls TT et al., 2002), which explains why
centenarians and near-centenarians tend to cluster in families. All these data,
suggest the hypothesis that a genetic control of inflammation in ageing
might play a central role to promote longevity.
Accordingly, pro-inflammatory cytokines are believed to play a
pathogenetic role in age-related diseases, and their functional genetic
variations have been shown to influence the susceptibility to age-related
diseases, whereas those individuals who are genetically predisposed to
produce low levels of inflammatory cytokines or high levels of anti-
inflammatory cytokines have an increased capacity to reach the extreme
limits of the human life span (Pawelec G et al., 2002; Candore G et al.,
2003).
In advanced age, several inflammatory markers increase their blood
level, as PCR level, pro-inflammatory cytokines as IL-6, IL-1, IL-18 and
TNF- ∆. Besides, the genetic constitution of the organism interacting with
systemic inflammation may cause defined organ-specific illnesses. In
particular, as discussed below, a considerable body of data indicates that
particular cytokine polymorphisms, especially those involving IL-6 and IL-
10 genes, may influence susceptibility, and in some cases prognosis in age-
related disease. It is intriguing that these two cytokines are involved in
longevity (Bonafé M et al., 2001; Lio D et al., 2002; 2003).
In recent studies genotype high producer of IL-10 was observed
more frequently in centenarian male population respect to young control
group (Lio D et al., 2003), confirming the genetic contribute of anti-
inflammatory response in elderly. It was also confirmed by a study
performed on Italian centenarians reporting that those individuals who are
genetically predisposed to produce high levels of IL-6 during ageing (i.e.,
7
C- men at IL-6 –174 SNP) have a reduced capacity to reach the extreme
limits of human life (Bonafé M et al., 2001).
8
1.2 Age-Related Diseases
1.2.1 Atherosclerosis
Today almost half of all deaths in the developed world and 25% of
all death in the developing world are attributable to cardiovascular disease.
Atherosclerosis, the primary cause of heart disease and stroke, is a very
complex disease of large arteries with multiple genetic and environmental
contributions. It is reported a number of environmental and genetic risk
factors associated with atherosclerosis, broadly summarized by Lusis et al.
(2002).
The clinical manifestations depend on the various region of circulation
affected, taking to angina pectoris and myocardial infarction by involving of
coronary arteries, to stroke by involving of central nervous system arterial,
to claudication and gangrene by involving of peripheral circulation (Ward
MR et al., 2000). It is now clear that favourable conditions, as differences in
blood flow dynamics, may make easier the formation of lesions to
susceptible sites within the arteries.
The early lesions of atherosclerosis consist of sub-endothelial
accumulations of cholesterol-engorged macrophages, called ‘foam cells’.
Primarily, the intake and accumulation of a high-fat, high-cholesterol with
the diet produce aggregates of lipoprotein particles in the intima at sites of
lesion predilection. The monocytes recruited into the intima, proliferate and
differentiate into macrophages that take up these aggregates, forming foam
cells. The more advanced lesions, they are characterized by the
accumulation of lipid-rich necrotic debris, derived by their death, and
smooth muscle cells (SMCs). The evolution of the atherosclerotic plaques
involves a complex balance between cell proliferation and cell death,
9
extracellular matrix production and remodelling and ingress and egress of
lipoproteins and leukocytes. It also involves calcification and neo-
vascularization processes (Ward MR et al., 2000). This process of
remodelling during atheroma formation affect outwardly and inwardly the
arterial wall, ultimately atherosclerotic plaque typically have a ‘fibrous cap’
consisting of SMCs and extracellular matrix that encloses a lipid-rich
‘necrotic core’(Ross R, 1993; Libby P, 1999).
The rupture of the plaque’ fibrous cap exposes the lipid-rich core containing
tissue factor to the coagulation factors in the blood generating immediate
intraluminal thrombus formation, causing acute coronary syndromes (Ward
MR et al., 2000).
It is usually accepted that inflammatory mechanisms couple dyslipidaemia
to atheroma formation. An early event in lesions formation is represented by
modification of trapped LDL, including oxidation, lipolysis, proteolysis and
aggregation, and that such modifications contribute to inflammation as well
as to foam-cell formation. The ‘minimally oxidized’ LDL species have pro-
inflammatory activity (Lusis AJ, 2000). Accumulation of these modified
LDLs stimulates the overlying ECs to produce a number of pro-
inflammatory molecules, including adhesion molecules and growth factors
such as macrophage colony-stimulating factor (M-CSF) and induce the
recruitment of monocytes and lymphocytes, but not neutrophils, to the
artery wall. A number of other factors are likely to modulate inflammation,
including haemodynamic forces, homocysteine levels, sex hormones, and
infection. Diabetes may promote inflammation in part by the formation of
advanced end products of glycation (AGEs) that interact with endothelial
receptors (Hofmann MA et al., 1999).
Biomarkers of inflammation predict outcomes of patients with acute
coronary syndromes, independently of myocardial damage. Levels of CRP
or interleukin-6 (IL-6) have been suggested to be significant predictive risk
10
factors for future development of cardiovascular events (Libby P, 2002;
Ridker PM et al., 2000; Hansson GK et al., 2002). C-reactive protein (CRP)
has been described as an inflammatory marker able to prospectively define
risk of atherosclerotic complications, thus adding to prognostic information
provided by traditional risk factors. Furthermore, increased levels of serum
IL-1 Ε have been associated with high risk of congestive heart failure and
angina pectoris (Di Iorio A et a.,l 2003) and altered levels of IL-1 Ε have
been implicated in chronic inflammation related to high blood pressure
(Barbieri M et al., 2003).
In the early stages of atherosclerosis, endothelial cells undergo activation
producing various molecules involved in the immune response
(Krishnaswamy G et al., 1999; Ross R, 1999). These include adhesion
molecules, chemokines and cytokines, all these molecules have a pivotal
role in regulation of atherogenesis and can lead to atheroma formation
culminating in plaque rupture and coronary thrombotic disease with a fatal
consequence or development of ischemic cardiomyopathy (Kelley JL et al.,
2000; Ross R, 1993; Ross R, 1999). The cytokines, as Macrophage-Colony
Stimulating Factors (M-CSF), tumour necrosis factor- ∆ (TNF- ∆),
interleukin-1 (IL-1) and interferon- ϑ (IFN- ϑ), stimulate the proliferation and
differentiation of monocytes in macrophages, and influences various
macrophage functions such as expression of scavenger receptors (Tontonoz
P et al., 1998). Furthermore, intervention studies in atherosclerotic mouse
models that inhibit major pro- and anti-inflammatory mediators such as
CD40L (Lutgens E et al., 1999; 2000), GM-CSF (Qiao J et al., 1997;
Rajavashisth T et al., 1998), MCP1 (Aiello RJ et al., 1999), IFN- ϑ (Gupta S
et al., 1997) and IL-10 (Pinderski Oslund LJ et al., 1999; Mallat Z et al.,
1999), have a profound effect on lesion initiation, progression, and plaque
composition.
11
A number of data provide in vivo evidence that inhibition of TGF-b
signalling is associated with plaque instability in mouse atherosclerotic
plaques, describing TGF-b as a cytokine with an important role as
immunomodulator and in extracellular matrix biology in atherosclerotic
lesions (Lutgens E & Daemen MJAP, 2001). In vivo and in vitro
experiments showed anti-atherosclerotic effects of IL-10 that is found
within the atheromatous plaque, probably due to local production by the
macrophages. Mallat Z et al., (1999) reported that IL-10 knockout mice,
when grown under conditions that avoid the heavy inflammatory bowel
disease that these animals typically develop, show enhanced formation of
atherosclerotic vascular lesions.
Following the activation leukocytes and intrinsic arterial cells can
release fibrogenic mediators and growth factors that can promote replication
of SMCs and contribute to elaboration by these cells of a dense extracellular
matrix characteristic of the more advanced atherosclerosis lesion (Ross R,
1999). Ultimately, inflammatory mediators can inhibit collagen synthesis
and evoke the expression of collagenases by foam cells within the intimae
lesion. These alterations in extracellular matrix metabolism thin the fibrous
cap, rendering it weak and susceptible to rupture (Libby P et al. 1996; Libby
P, 2001). Macrophages also produce tissue factor, the major procoagulant
and trigger to thrombosis found in plaques. Inflammatory mediators regulate
tissue factor expression by plaque macrophages, demonstrating an essential
link between arterial inflammation and thrombosis (Libby P, 2001; 2002).
12
1.2.2 Alzheimer’s Disease
Alzheimer's disease (AD) is the most common neurodegenerative disease of
aging. AD is an important public health problem and the number of AD
cases is increasing with ageing of the population. There are still no
laboratory tests available for positive AD diagnosis. It is show with
progressive decline in memory and intellectual ability, deteriorating
language and speech skills, and loss of orientation and behavioural abilities
(Kamboh MI, 2004).
The brain tissue of AD-patients is characterised by extracellular Ε-amyloidal
(A Ε) plaques and intracellular neurofibrillary tangles. A Ε has no protective
functions and occurs as a 40 and 42 amino acid peptide (A Ε 40, A Ε 42),
since it is an aggregating, neurotoxin peptide (Pike CJ et al., 1995). Early
aggregations of A Ε 42 are regarded as an initial event in the formation of
senile plaques. Despite have been identified several non genetic risk factors
for AD, including female gender, cerebrovascular disease, smoking, the
most convincing risk factor is established to be increasing age. Only about
1% of all AD cases are represented by people affected before the age of 60
(early-onset AD), the most AD cases occur in old age, then called late-onset
AD. Early-onset AD is usually familial and follows an autosomal dominant
inheritance pattern with a high penetrance. In contrast, most late-onset AD
is sporadic, with no family history of the disease (Kamboh MI, 2004). Early-
onset form have been associated with three genes including amyloidal
precursor protein (APP) gene and presenilin 1 (PSEN1) and presenilin 2
(PSEN2) genes (Tandon A et al., 2000). In contrast, the genetic basis of late-
onset form appears much more complex, with a number of susceptibility
genes implicated to aetiology of AD. The most important gene involved to
increase the risk of AD is APOE gene, in particular the allele ε4 are
13
associated with 3-fold or 15-fold risk, one and two copies respectively
(Kamboh MI, 2004). However, have been reported that APOE genotypes
explain <10% of the variance in late onset form. The scans of genome have
provided evidence for the implication of others genes in sporadic form of
AD. Suggestive investigations are evidenced a role as candidate genes for
HLA loci and in particular A2 allele of the HLA-A locus (Kamboh MI,
2004). However, inconsistent data are shifted the interest to TNF gene
(Collins RG et al., 2000). Analyse of individual polymorphisms revealed no
association with AD, as reported by different findings (Collins RG et al.,
2000; Tarkowski E et al., 2000). However, Collins & colleagues (2000)
have been observed a significant association with haplotype generated by
combination of three polymorphisms of TNF gene.
Microglia and astrocytes, cells crucial for the maintenance of normal
neuronal function, become activated by A Ε deposits in early period to
precede the clinical manifestation of the disease. . Microglial cells activated
show macrophage activity, producing inflammatory cytokines, complement
components, acute phase proteins, enzymes and eicosanoids, as well as
expressing MHC class II and integrins on their surface (McGeer PL &
McGeer EG, 1995). Cytokines, such as IL-1 Ε, IL-3, IL-6 and TNFα have
been reported to occur at high concentrations in the AD brain (McGeer PL
& McGeer EG, 1995) and may interact directly or indirectly with neurons,
influencing their survival. Two contrasting roles, time of exposure
depending, have been suggested for TNFα; in fact this cytokine may protect
rat microglia cells from A Ε -induced cytotoxicity in early phases of
pathogenesis of AD (Barger SW et al., 1995). Nevertheless, if the activation
of glial cells persists and becomes chronic, TNFα may potentiate the ability
of A Ε to induce apoptosis (Blasko I et al., 1997). More recently, the same
group research have been reported a direct involvement of TNFα and IFN ϑ
14
to production of A Ε 40 and A Ε 42 and inhibition of secretion of the N-
terminally truncated soluble APPs, generally regarded as a neuroprotective
protein (Blasko I et al., 1999).
1.2.3 Gastric Carcinoma
Gastric Cancer (GC) is the second most common cause of cancer-related
mortality in the world. To date, this cancer constitutes one of most common
cancer, behind only cancers of the lung, colon, and breast. (Parkin DM et
al., 2002). Affected patients presents between the ages of 65 and 74. In fact,
ageing of the world population contribute to increase the absolute number of
new cases per year. Men appear to show a greater incidence of developing
gastric cancer than women. Gastric cancer is a heterogeneous disease with a
complex pathogenesis that can develop in any part of the stomach. Two
different entities can be finding with at least partly dissimilar pathogenesis,
proximal and distal gastric carcinomas. The vast majority of distal gastric
malignancies are adenocarcinomas that approximately represent the 95% of
all gastric cancers; the remaining 5% comprise non-Hodgkin’s lymphomas
and stromal tumours (Rotterdam H, 1989). Gastric adenocarcinoma, derived
from gastric epithelium is distinct in intestinal and diffuse (undifferentiated)
histological forms (Lauren P, 1965). These types differ in their histology,
epidemiology, pathogenesis, genetic profile, and clinical outcome (Lauren
P, 1965; Nardone G, 2003). The intestinal type is characterized by the
formation of gland-like structures, cellular pleomorphism and
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