The results are unexpected as previous studies have found sex-dependent effects of these polymorphisms on other phenotypical traits. For example, the genotypes of the angiotensinogen gene were found to be significantly associated with variation in systolic resting and exercise blood pressure but only in males. The results indicate that genetic variation in the locus modifies the responsiveness of blood pressure to endurance training, but the functional impact is related to differences in sex. The gender-related effect in the genetic modulation of blood pressure is related to differences in sex.FVII plasma levels have been studied by Tan et al. Experimental studies in gerontology showed a stronger effect of FVIII plasma levels in male AMPs than in female Italians. Castelnuovo et al. showed that the clotting activity of plasma FVII has been suggested as a risk marker of cardiac death and Meade et al. suggest that FVII polymorphisms are predictive of risk in Italian studies. However, the putative relation between FVII polymorphisms and risk (i.e. -613T>A and -323Ins10) has been turned down in other studies (Lane et al., Feng et al.), and it may be speculated that this discrepancy is at least partly caused by an effect of gender. In women, FVII levels are increased by 1 year after menopause (Scarabin et al., Cushman et al.), and elderly women have higher plasma FVII levels than men of the same age (Scarabin et al., Ishikawa et al.). Also, women with coronary artery disease have higher FVII levels than men with the same disease (Kalaria et al., Ssei-Gerning et al.). Perhaps the effect of hormones and lifestyle factors drown out the effect of genotype on risk in women. Although there have been many studies on disease association, the present study reveals, for the first time, the sex-dependent association of the -603A>G and -323Ins10 polymorphisms with longevity. Genetic remodulation of human span has been studied in other studies as well, such as studies of the APOE alleles (Franceschi et al., Ivanova et al.), the ADRB2 alleles (Proust et al.), and the large norepinephrine allele group at the tyrosine hydroxylase locus (Benedictis et al., Martin). The sex-dependent influence indicates that the effect of a certain gene on survival could vary between the sexes. The existence of gene-sex interaction shows not only the complexity of the aging process, but also indicates that the two sexes follow different trajectories toward extreme longevity. The polygenic feature of life makes it imperative to take into account the unobserved heterogeneity or hidden heterogeneity in individual frailty for two reasons. First, there is unobserved heterogeneity in individuals' genetic makeup, which accounts for about 70% of the variation in life span according to previous studies (Herskind et al., Yashin and Jachine). Regarding the number of genetic variations that contribute to life span, Martin estimated that there could be up to about 150. In such a highly polygenic situation, it is advisable to consider the influences from other unobserved genes when making an inference from observed ones. Second, there are also non-genetic factors that have a predominant influence on life span, and these constitute another layer of heterogeneity in individual frailty. The existence of genetic and non-genetic heterogeneity in individual factors affecting span can influence an inference from an observed genetic polymorphism. In our analysis, we also tried to apply a simple model that does not take unobserved frailty into account. The estimated relative risks of gene-sex interaction for the three significant alleles were systematically weaker than they were in the heterogeneity model with risk parameters F71 for angiotensinogen, F7J for FVII (-603A>G), and F1 for 9p21.3. Differences in parameter inference present a good example of the difficult situation facing studies of longevity and multifactorial diseases. Individual heterogeneity in unobserved attributes is an obstacle that prevents us from unraveling the genetic component. We thank Oeppen from Cambridge University for useful discussions. The authors also want to thank the anonymous reviewers for their valuable suggestions that helped in improving the text. Alvarez, Alvarez, Lahoz, C.H., Martinez, Pena, Guisasola, L.M., Salas-Puig, J, Moris, Uria, Menes, BB., Ribacoba, Vidal, Sanchez, JM and Coto.EEE ALONE MILES Association between alpha-2 macroglobulin and H. polymorphism and late-onset Alzheimer's disease. Biochem. Biophys. Res. DF Apotech Yay, Teo System, EEE Mathematical and Statistical System. Vol. System and Graphics NNN AIO Apotech System, Maple Valley, WA. 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