from cardiovascular disease has to be further tested [16]. In our previous study, we found that the AA genotype seemed to correlate with the age of onset of myocardial infarction: patients with this genotype showed a 5 years higher mean age of onset than patients with at least one T allele, indicating that homozygosis for the A allele could play a protective role in the pathogenesis of the disease [17]. Our research group has also shown the beneficial influence of the homozygous genotype AA with respect to the development and progression/restenosis after percutaneous myocardial revascularization (PTCA) of advanced atherosclerotic lesions [18–20]. Women live longer than men and make up a large proportion of the older population. Whether genetic factors play more or less of a role in men or in women is a matter open to debate. Estrogens and phyto-estrogens up-regulate expression of antioxidant enzymes through estrogen receptor and MAPK activation, which activate the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling pathway, resulting in the up-regulation of expression of longevity-related genes [21]. The association of A allele and longevity, found in the present study, seem to confirm the role of AGE-RAGE interaction in human age-related endothelial dysfunction.

In our previous study, we found that the AA genotype seemed to correlate with the age of onset of myocardial infarction: patients with this genotype showed a 5 years higher mean age of onset than patients with at least one T allele, indicating that homozygosis for the A allele could play a protective role in the pathogenesis of the disease [17]. Our research group has also shown the beneficial influence of the homozygous genotype AA with respect to the development and progression/restenosis after percutaneous myocardial revascularization (PTCA) of advanced atherosclerotic lesions [18–20].

Women live longer than men and make up a large proportion of the older population. genetic factors play more or less of a role in men or in women is a matter open to debate. and phyto-estrogens up-regulate expression of antioxidant enzymes through estrogen receptor MAPK activation, which activate the NF-κB (nuclear factor kappa-light-chain-enhancer of activated cells) signaling pathway, resulting in the up-regulation of expression of longevity-related genes [21]. association of A allele and longevity, found in the present study, seem to confirm the role AGE-RAGE interaction in human age-related endothelial dysfunction.

The current study is a candidate-gene association study that compared long-living subjects with middle-aged subjects with no possible prediction of their future longevity. The mechanisms underlying the association between the studied polymorphism and longevity cannot be directly inferred from the present study but it can be assumed that the reduction of transcription of RAGE gene associated with AA genotype generate a decreased expression of the receptor on the cell surface and consequently a decrease in the pro-inflammatory signal in male subjects. The correct trigger axis RAGE-ligand results in a cell phenotype in which the activation of transcriptional factor NF-κB leads to the overproduction of pro-inflammatory mediators [22]. Cytokines, for example, have a key role in maintaining homeostasis of lymphocytes, in fact, alterations in the sequence of several genes coding for cytokines are associated with longevity [23–25]. A recent study by Balistreri et al. [26] found that male centenarians are characterized by the presence of allelic variants that suppress inflammation, so they seem better equipped in the defense of the major age-related disorders.

The aging process is a universal, intrinsic, progressive accumulation of deleterious changes in cells and tissues that increases morbidity and leads to death. The immune system seems to be involved in the chronic oxidative and inflammatory stress conditions of aging, according to the recent theory of oxidation-inflammation to explain the aging process [27]. Thus, human ageing can be explained at least in part by the concept of “inflamm-ageing” according to which ageing can be driven by the pro-inflammatory cytokines and other inflammatory mediators produced by the innate immune system [28]. In longevity, a higher frequency of genetic markers associated with a reduced proinflammatory ability seems to counteract the onset of the main age-related inflammatory disorders. It was demonstrated that Centenarians are enriched in “good” genotypes and show opposite frequencies of “bad” genotypes in comparison with patients affected by major age-related pathologies [29].

4. Methods

The population in this study consists of 254 Caucasian subjects (170 women and 84 men). Subject aged 18 to <80 years, no personal history of coronary artery disease, no diabetes mellitus, no high alcohol consumption, professional athleticism and any chronic disease were used as control group (middle-aged group, n = 135). Subject aged ≥90 years who had MMSE (Mini Mental State Examination) score in the top 75th percentile [30] were included in the long-living group (n = 119). This MMSE cut-off has previously been used to characterize individuals as having “intact cognition” [31]. Patients with chronic inflammatory or autoimmune diseases and with known malignancies and renal or hepatic impairment were excluded from the study.