We also performed stepwise regression analysis to determine whether this association was independent from the effect of common cardiovascular risk factors and current treatment. The results showed that RAGE polymorphism remained related to the manifestation of heart disease, even after adjusting for these confounding variables. The correlation analysis, performed to evaluate which clinical-instrumental parameters were correlated to RAGE −374T/A polymorphism, showed that gender significantly correlated with polymorphism.

The number of women is larger among long-living subjects than in the middle-aged group. When categorized by sex, no differences were found about allelic and genotypic frequencies in female subjects. However, the frequency of homozygous AA genotype was higher in male subjects aged ≥90 years than in subjects aged <80 years. In particular, AA genotype was present in 18% of middle-aged individuals and in 43% of long-living subjects (p = 0.028). There was a significant reduction in frequency of heterozygous AT genotype in subjects aged ≥90 years compared to subjects aged <90 (p = 0.023). No differences were found as regards the TT genotype. Concerning allelic frequencies, we observed a greater frequency of A allele in the long-living group and a greater frequencies of T allele in middle-aged individuals, although it did not reach a statistical significance (Table 3).

Table 3. Allelic and genotypic distribution of −374 T/A polymorphisms in middle-aged males and long-living ones.

Middle-aged males Males with ≥90 years RAGE −374T/A p Value (n = 56) (n = 28) Genotype AA 10 (18%) 12 (43%) 0.028 AT 28 (50%) 6 (21%) 0.023 TT 18 (32%) 10 (36%) NS Allele A 48 (43%) 30 (54%) NS T 64 (57%) 26 (46%)

3. Discussion

Demographic and social changes in the past decades have resulted in improvement both in health and in longevity. Centenarians represent excellent models to research biological mechanisms of aging and to study the genetic background. Among the various theories of aging proposed until today, the hypothesis that it is a process dependent on genetic factors is gaining increasing credit. This is based essentially on the fact that the duration of life of children born of long-living individuals is higher than that of children born of not long-living parents [11] and that the co-existence of longevity in identical

Numerous genes would appear to contribute to the determination of longevity and aging; some would appear to increase susceptibility to age-related diseases and early death, while other genes would appear to have a role in slowing the aging process and thus contributing to longer life [13].

would appear to increase susceptibility to age-related diseases and early death, while other genes would appear to have a role in slowing the aging process and thus contributing to longer life [13]. The present study investigated the presence of possible correlation between the −374 T/A polymorphism in the promoter region of the RAGE gene and longevity. We did not find any association between RAGE −374T/A allele and genotype with age in the entire population. However, in the male population, we observed an association between the A allele and genotype homozygous for this allele (AA) with a longer life expectancy. In particular, there was a prevalence of AA genotype and A allele in long-living subjects and a prevalence of the allele T in subjects with middle-age, indicating a possible protective role of the allele A to aging.

Some new studies showing that the aging process in both genders is gender-specific. Recently, Makrantonaki E, et al., documented the gender-independent differences in the expression profiling of aged skin between young and elderly European Caucasian adults when circulating hormones reach their maximum levels in blood and after the onset of hormone decline, accordingly [14]. Previously, Ali SS, et al. explored the association between oxidative stress and gender-specific aging in C57BL6 mice, in which females are the shorter-lived gender. They demonstrated that differences in ROS homeostasis contribute to gender divergence in survival, but also suggest that mitochondrial superoxide production may not be primarily responsible for gender differences in lifespan [15]. Hofmann B, et al. demonstrated that skin autofluorescence and pulse wave velocity as non-invasive parameters significantly correlate with the AGE contained in graft material and therefore are strong

Hofmann B, et al. demonstrated that skin autofluorescence and pulse wave velocity as non-invasive parameters significantly correlate with the AGE contained in graft material and therefore are strong predictors of vessel AGE modifications in patients with coronary heart disease. Whether the analysis