confer an advantage in reaching a far advanced age. The 71377 polymorphism is situated in the binding site for SP- 1 transcription factor, and the presence of A in both alleles could significantly modify the transcription of Fas, with important consequences for the equilibrium of Fas/FasL apoptotic pathway. We are tempted to speculate that presence of the homozygous form of this mutation could be harmful, and so the occurrence of A/A genotype in 71377 position is strongly negatively selected. However, young controls who have this genotype apparently do not show any disorder that can be associated to impaired expression of Fas. This point needs further investigation, and can be at least in part clarified by the direct quantitation of Fas mRNA in lymphocytes or other cells obtained from these subjects, as well as by in vitro analysis of Fas promoter activity with A or G in position 71377. Electro-mobility shift assays could further elucidate the eventual modifications occurring in SP-1 binding, when A allele is present in both copies of Fas gene. Finally, it will be crucial to investigate these polymorphisms in subjects of other age-groups.

expression of Fas on lymphocytes from elderly donors, which could be due to age-related changes in the susceptibility of these cells to undergo apoptosis.18–21 However, few and controversial data are present in literature. Some investigators have reported a decrease of Fas/FasL-induced apoptosis in aged animals,36 as well as in human CD8+ T cells reaching replicative senescence.37 Accordingly, we have recently reported that an inverse correlation exists between human age and the propensity of lymphocytes to undergo apoptosis induced by oxidative stress.38 On the other hand, other authors reported increased apoptosis in lymphocytes from elderly people following activation with anti-CD3, phytohemagglutinin, concanavalin A,19,39 or activation with polyclonal mitogens plus anti Fas treatment.22,40

play a role in regulating the expression of a given gene. Thus, we explored whether genetic polymorphisms of apoptotic genes such as Fas and FasL exist that could help in explaining the aforementioned phenomena, taking into account that no data exist on their distribution and role in human aging and longevity. In this study we have analyzed the presence of new genetic markers, i.e. 7670 and 71377 polymorphisms in Fas promoter, and IVS2nt- 124 and IVS3nt169 in FasL gene, in a group of 50 Italian centenarians and 86 young donors. No significant differ- ences were found in the genotype and allele frequency between centenarians and controls for all polymorphisms; these data suggest that these polymorphisms likely do not confer any genetic advantage to reach the extreme limit of human life. Moreover, considering the entire group of individuals we have analyzed, our data on Fas gene are in agreement with data reported by Huang et al. for normal Caucasian population.23,24 Indeed, the frequencies of the alleles we have analyzed are very similar to those previously reported.

and found no major differences between centenarians and young donors. The only differences concerned the frequencies of the Fas (71377A/7670A) and (71377A/ 7670G) haplotypes (Table 3A and B), but they could be explained considering the low frequency of A/A genotype at position 71377. The presence of even one centenarian with this genotype could greatly influence the haplotype estimation, and completely change the analysis. A similar observation was made as far as FasL haplotypes is concerned. Indeed, the only difference regards the fact that among centenarians the haplotype with G in position IVS2nt-124 and delT in position IVSnt169 is represented. Indeed, there is one centenarian with genotype A/G in the position IVS2nt-124 and delT/delT in the position IVS3nt169. However – even if fascinating – we do not think that such a phenomenon has any biological relevance, since the presence of just one young individual with the same genotype would cancel any difference between the groups.

higher than males,41 and our population well represents this distribution. Thus, we examined the frequencies of Fas and FasL polymorphisms in female subgroups to analyze any possible association with sex. Even if there was a difference in 7670 Fas polymorphism, as a higher number of centenarians were homozygous for allele A (36% vs 19%), such difference was not statistically significant likely because of the low number of donors we could analyze. Studies are in course to verify this possibility.

Recently, different authors have analyzed the role of Fas in immunosenescence, and several studies have shown an increased expression of Fas in the elderly, due to an increased number of Fas+ lymphocytes,18,19,21 or increased expression of the gene.20 It is well known that Fas is expressed during T cell activation, and that during a typical immune response Fas-induced apoptosis prevents an excessive clonal expansion. As defects in the Fas gene are related to development of autoimmune diseases (reviewed in14), the increased expression of Fas antigen on lymphocytes might suggest an enhanced proneness to undergo apoptosis. From this point of view, it can be hypothesized that although there is a large amount of ‘memory-preactivated’ lymphocytes in the elderly,19 the inability to evoke a strong secondary response may be attributable to enhanced apoptosis of these ‘old’ T cells, in respect to those from young people. A different transcrip- tion caused by genetic differences in the promoter of Fas