the attainment of longevity (hemochromatosis, HFE). A possible inference is that environmental factors may be more important in determining the life span of women rather than that of men. This difference should be taken into account when making projections on life span length,43 because changing environmental factors such as diet, lifestyle be- haviors, drugs, and advances in medical science may affect female and male longevity differently. For example, one environmental factor that could specifically influence female longevity in the next decades is modern reproductive be- havior (e.g., birth control, family planning, delayed child- bearing, and spacing birth order), associated with a reduced fertility rate (http://ec.europa.eu/employment_social/social_ situation/docSer/Serec_2007_638_en.pdf/). According to the hypothesis of a trade-off between fertility and longevity, the reduced investment of somatic resources in reproduction might indeed favor a longer life span in women.

In a previous study, the PPARG Pro/Ala genotype was reported to be positively associated with longevity but, again, only in men.15 The opposite action of the PPARG Pro/ Ala genotypes observed in the present study might depend on the different age composition of both the long-lived and the control samples. As observed for other longevity genes,6 the PPARG action could be age-dependent, possibly because of its involvement in susceptibility for age-related diseases such as AD or diabetes, which may have an age-specific prevalence. Conversely, we found that the male gender- specific association of PPARG polymorphism seems to sup- port previous observations.15

In conclusion, the data presented here are in line with the growing body of evidence for the need to take into account the impact of gender on human physiology and pathology. Extending this concept to aging could help us to better un- derstand its gender-related mechanisms and to plan inter- ventions for healthy longevity in men and women alike.

Acknowledgments

The whole data set would indicate that the PPARG gene plays a peculiar role in male longevity and that its action may be age-dependent. Finally, while an overall analysis including FSHR and PPARG together with other relevant variables would undoubtedly have been appropriate, as the complex phenotype longevity is the result of gene–gene/ gene–environment interactions, the size of the study sample was too small to perform an analysis of this magnitude.

This work study was supported by La Sapienza University, Progetti AST 2009, Progetti Universita` 2010 (to R.M.C.). We thank K.A. Britsch for reviewing the manuscript. We are grateful to the anonymous reviewers for their helpful comments.

Author Disclosure Statement

No competing financial interests exist.

Trying to unravel the differential role of the genetic com- ponent in male and female longevity, we collected published data on longevity genes with a gender-specific action (Table 4). Among the associations reported, those of HSP70,35–37 HLA-B8,DR3 ,7 IL-6 ,38 IL-10, 39,40 and PPARG15 have been replicated in independent samples. A greater number of as- sociations are related to male gender. This trend is in line with the emerging picture showing that the genetic background seems to play a more prominent role in longevity attainment in males than in females.6 Looking at the function of male longevity genes, it is evident that the vast majority are part of key processes in life span determination, including immune system regulation, inflammation response, and oxidative damage control. Notably, another large group of genes that seems to regulate male life span comprises those regulating lipid and glucose metabolism, somatic growth, and body weight, all of which are involved in metabolic processes that can be affected by caloric restriction, another basic mechanism modulating the aging process.41,42 PPARG, involved in in- flammation processes as well as lipid and glucose metabolism, would fit well within this emerging framework.

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