It is well established that TNF-a exerts gender-specific effects; it has been shown that endotoxin (LPS) stimulation of mononu- clear cells from men produced more TNF-a than cells from women [46]. Moreover, estrogen has been reported to suppress the release of TNF from macrophages after trauma-hemorrhage and to de- crease the susceptibility to subsequent sepsis [47], whereas endog- enous testosterone might increase pro-inflammatory cytokines following ischemia/reperfusion injury [48]. Thus, we may specu- late that the different patterns of association with life-expectancy detected in the present study may be related to the effect of TNF-a in influencing Th1/Th2 balance. In this context, the negative selec- tion of ‘‘low TNF-a expression’’ females in comparison 1 could be due to the occurrence of Th2 diseases such as asthma and allergy; it is also noteworthy that the mortality due to asthma among women is higher than men above the age of 65 only [49,50]. The deleterious effect of ‘‘high TNF-a expression’’ in males is sustained by the evidence for an increased TNF-a expression induction by testosterone and by an increased male liability to cardiovascular diseases. Interestingly, the TNF-a (cid:2)308G>A SNP has been sug- gested to play a role in the pathogenesis of cardiac ischemic dam- age, a major causes of death more prevalent in men; in particular, (cid:2)308A⁄ carriers are prone to more severe ischemic damages following myocardial infarction [51].

In conclusion, the present study has shown that a combination of functional SNPs within ADA and TNF-a genes can influence life-expectancy in a gender-specific manner and that males and females follow different pathways to attain longevity. Moreover, our results are supported by the evidence that variability of genetic factors contributes to determine longevity in males much more than in females [25,52–55]. Remarkably, polymorphisms in IGF-1 [56], IL-6 [57,58], and IL-10 [12] genes were found to be associated with longevity in males but not in females.

Lastly, it is worth considering that in a such complex trait as human longevity, gene–gene interactions may play a crucial role. Recognition of the complexity of genetic architecture will be found by embracing the complexity of the genotype-to-phenotype mapping relationship that is likely to be characterized by nonlinear gene–gene interactions and other phenomena such as gene–environment interaction and locus heterogeneity.

Conflict of Interest

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