Keywords: Interferon-gamma; Longevity; Inflammation; Centenarians; Immunogenetics

Introduction

Human longevity seems to be directly correlated with optimal functioning of the immune system. It has been reported that the aa repeat microsatellite allele at the first intron of the IFN-y gene is associated with higher levels of in vitro cytokine production (Pravica et al., 1999). More recently, the group has reported an absolute correlation between the CP repeat allele and the presence of the allele at +874 position from the translation start site coinciding with a putative binding site that may be important in the induction of constitutively high IFN-y production (Pravica et al., 1999). 75 NN IE have studied the distribution of +874T - interferon-gamma polymorphisms in a large number of Italian centenarians to evaluate if the two alleles might be differently represented in people selected for longevity. DNAs samples were obtained from 11741 Italian centenarians (8;; cae) years old (DT women and men); and from 248 PN BNI NENT 0 OA/ <60-year-old control subjects (8;/ women and men) matched for geographical distribution. Polymorphisms at +874 were identified using an amplification refractory mutation system methodology. The +874T allele was found less frequently in centenarian women than in centenarian men and control women whereas significant differences were observed in the distribution of the two alleles between males and females. Allele frequencies in centenarian women were not found to be significantly different from male controls. Possession of the +874A allele, known to be associated with low IFN-y production, significantly increases the possibility to achieve extended longevity, suggesting that the pro-inflammatory status characteristic of ageing may be detrimental for successful ageing. The data that the oore allele was significantly increased in female but not in male centenarians strengthens the idea that gender may be a major variable in the biology of ageing. However, the data add another piece of evidence to the complex puzzle of genetic and environmental factors involved in controlling human life span expectancy. Studies on cytokine gene polymorphisms mayCytokines, such as Interferon, are essential for immune system responses and protection from susceptibility to various diseases. Cytokine genes contain single nucleotide polymorphisms (SNPs) or microsatellites in their promoter regions. These changes can have a significant impact on transcription by altering the structure of transcription factor binding sites within gene promoters or enhancers and silencers within introns or more remote sites. It has been hypothesized that these polymorphisms may confer flexibility in the immune response, allowing differential production of cytokines. Cytokine gene polymorphisms have been shown to be involved in susceptibility, severity, and clinical outcome of several diseases. In this study, DNA samples were collected from Italian centenarians and controls matched for geographical origin. The amplified products were monitored by electrophoresis on an agarose gel containing ethidium bromide. The production of Interferon is essential for defense against viruses and intracellular pathogens and in the induction of immune-mediated inflammation and amplification refractory mutation system. Differences were observed in the distribution of two alleles between male and female controls, but no significant difference was observed in the distribution of alleles between centenarian men and male controls. Allele frequencies in centenarian women were significantly different from control women.Peonatural killer 89N: ain't cells play an important role in bringing about the acute inflammatory response. During the subsequent antigen-specific phase of the immune response, IFN-y acts as a regulator of antigen presentation, proliferation, and differentiation of lymphocyte populations. High-level production of IFN-y during this phase of host defence is now classically seen as a hallmark of type I reaction, characterized by activation of macrophages and strong cellular inflammatory reactions (Billiau et al., ,;;(13):5  1$1 Statistical analysis, gene count, and tables were constructed to determine statistical significance (with Yates correction) of differences in allele frequency for the IFN-y in centenarians and controls. 

3.1 Results
Awad et al. ,;;;:(30) described variable length repeat sequence in the first intron of the human IFN-y gene and showed that allele M is associated with a high in vitro IFN-y production. In a consecutive study, allele 7 M was found to be associated with allograft fibrosis in lung transplant patients, confirming its role as a marker of high IFN-y production. In a further study (Pravica et al., 7 .///:(30)), the end 2AM5/-flanking region in the first intron of the human IFN-y gene was described, showing an absolute correlation between the presence of allele 7 and the presence of the high-producing microsatellite allele M. This polymorphism +874T allowed assessment of conformation with the Hardy-Weinberg equilibrium for allele distribution both in centenarian and control population samples, and no significant differences were observed in frequencies of either allele between the two groups of subjects (Table 5). In addition, the frequency of the +874T allele was comparable to that of the so-called allele M (Goris et al., ,;;;:5). When the analysis was performed according to gender, the +874T allele was found less frequently in women (Lio et al. 7).