and aging has been well studied, the effect of VDR variability has been evaluated only in relation to diseases; no data exist about its role in aging and longevity. In the present case–control study, we compared allele, genotype and haplotype distribution of five VDR gene variants between healthy-living octogenarians and younger controls to assess VDR as a candidate gene affecting aging and longevity. Our study is the first to provide evidence of an association between VDR gene polymorphisms and longevity, as reflected by the differential distribution of VDR haplotypes that we observed. The positive significant association between longevity and the 30UTR GS and five-marker GGCGS haplotypes was observed in octogenarian males but not in women. Epidemiolog- ical data on long-lived subjects document a clear-cut prevalence of females compared to males, suggesting that sex-specific mortality rates follow different trajectories. Demographic and behavioural risk fac- tors have been considered in the literature, but do not account for the overall sex-related difference in mortality rates (Wingard 1984). In addition, the role of biological factors has been explored with conten- tious results (Austad 2006). Our finding of a sex- specific association was in accordance with previous reports that certain polymorphisms of the interleukin (IL)-6, IL-10 and interferon-gamma genes are male- specific markers for longevity (Bonafe et al. 2001; Di Bona et al. 2009; Giacconi et al. 2004; Lio et al. 2002a, b), supporting a finding that female longevity is less dependent on genetic background than male longevity (Franceschi et al. 2000).

to evaluate differences in VDR variants between young and elderly subjects. The literature contains indirect data on genotype frequencies of VDR mark- ers, but comparison with our data is inappropriate due to differences in the origin of each population and in selection criteria. We acknowledge that our study has a number of potential limitations. Although octogen- arian Caucasian cohorts may have common charac- teristics, such as the limited medical care available until the 1950s, we cannot exclude potential con- founding factors. In particular, two historical events must be taken into account: the Spanish flu epidemic at the beginning of the twentieth century, which depleted the childhood population, and the Civil War (1936–1939) that had an especially important impact on male mortality (Gonza´lez et al. 1996). The first event could have produced biological consequences, while the second had a stochastic effect. Another concern refers to the comparison of different birth cohorts, within which we assumed that initial frequencies are similar (Capri et al. 2008). We cannot exclude this confounding factor in our study. However, our cohorts fit Hardy–Weinberg equilib- rium in all loci analyzed, and neither disturbances on random matting nor selective factors attributable

With respect to the biogerontological significance of the observed association, we can only suggest a

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In conclusion, the well-documented impact of vitamin-D levels on the aging process and on age- related diseases is bolstered by our results. In addition, the study results propose a new scenario in which the variability of the VDR gene is also relevant and emphasize the role of VDR genetic background in determining optimal vitamin-D levels for healthy aging.