Inhibits the activity of NK cells that it has been reported to play a crucial role in determining successful ageing and longevity []. Of note, ADA deficiency increases thymus apoptosis [44]. Thus, ADA22A carriers may experience increased immunological damage caused by more pronounced thymus involution compared to ADA G/G homozygotes. Finally, it has been demonstrated that ADA inhibition accelerates the process of replicative senescence of CD8+ T lymphocytes, causing a reduction in overall proliferative potential, reduced telomerase activity, and blunted IL-2 gene transcription [45].

Regarding comparison 2, both two-loci and three-loci interactions are significantly associated in males with increased life expectancy over 88 years (Table 3, Fig. 2), with ADA 22G>A/TNF-a 308G>A interaction reporting the highest testing balanced accuracy (TBA = 0.572, Sign Test P = 0.011, CVC = 10/10) and displaying an odds ratio of 2.061 (P = 0.0096). Females do not show any significant gene-gene interaction or attribute association with increased life expectancy (Table 3). Finally, considering the combination of three SNPs studied, we have stratified the subjects studied into three groups based on expected expression of TNF-a, low, normal and high expression respectively (Table 4). Very interestingly, females show a significantly higher frequency of low TNF-a expression gene combinations compared to males in age class 1 (30.9% vs. 15.3%, P = 0.0031), while age classes 2 and 3 do not show any significant gender-specific differences. Moreover, the comparison between age class 1 and age class 2 + 3 displays a significant association of low TNF-a expression with life expectancy, with opposite gender-specific effects (Males, O.R. = 1.704, P = 0.045; Females, O.R. = 0.639, P = 0.031) (Table 4).

Discussion:

The main purpose of the present paper was to further our understanding of the role of ADA and TNF-a genes in the determination of human life expectancy. We report a significant main effect of the ADA 22G>A SNP, especially in males, with a biphasic association with human life expectancy. Given the established evidence for the functional effect of A variant (historically called ADA2, characterized by a 35% lower enzymatic activity compared to allele G, or ADA1), and considering the gender-specific pattern of thymus involution [44], it is reasonable to assume that ADA deficiency may lead to increased immunological damage in males. The majority of studies conducted to date [8,10-15], to our knowledge, this is the first report on the association of TNF-a 238G>A SNP with life expectancy.

Although either single-SNP and haplotype analysis of TNF-a gene did not yield any significant result, we detected an interesting gene-gene interaction between ADA and TNF-a, showing age- and sex-specific effects on life expectancy. Of note, the epistasis between functional SNPs in ADA and TNF-a genes is also supported by established biological evidence that adenosine levels influence TNF-a expression [18-20]. In this respect, the opposite patterns of epistasis detected here between males and females in comparison 1 (Fig. 1) suggest that TNF-a levels exert different effects on longevity in different sexes.

Regarding the TNF-a gene, our study failed to demonstrate an association of TNF-a 308G>A and 238G>A SNPs with human longevity. While for the former our results are in line with polymorphism relevant to the control of human longevity? A review of literature data. Mech Ageing Dev ; : [16], for the latter, our study is the first to report no association with human longevity.

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