The positive significant association between 1082 IL- 10 polymorphism and longevity was observed in centen- arian men but not in women, in accord with previous observations on polymorphisms in Tyrosine Hydroxylase gene38 and mtDNA haplogroups.39 On the other hand,  haemochromatosis40 and interferon(IFN)- 41 gene polymorphisms have been shown to be associated with longevity in women, but not in men. Altogether, these findings point out that gender is a major variable in the genetics of longevity, and suggest as a working hypoth- esis that men and women follow different strategies to reach longevity.42

The clean effect of a given gene is a function of the gene pair combination received from parents and for − 1082 SNP a gene dosage dependent effect on the IL-10 production has been suggested.23 Thus, we have evalu- ated the homo- and heterozygous frequency for the three SNPs under study in the two groups of subjects (Table − 1). The number of centenarians homozygous for 1082G genotype was increased in comparison with younger con- trol subjects, but this increase attained significance only 8 in men (P 0.025). Turner et al23 showed not only that − 1082G allele is correlated with a high capability to pro- duce IL-10 but also that this characteristic is independent − − on the polymorphisms at positions 819 and 592. How- − → ever, in our samples, genotype frequencies for 819C T − → and 592C A homozygous and heterozygous SNPs were not different between centenarians and control sub-

Concerning the biological significance of this associ- ation, we have not searched for functional proves that IL- 10 is involved. Thus, we should conclude that our data only suggest that a marker on 1q32 genomic region may be involved in successful ageing in man. That might due to IL-10 or other gene sequences associated with the pres- − ence of 1082G allele.

However, ageing is associated with increased inflam- matory activity reflected by increased circulating levels of pro-inflammatory cytokines, and acute phase proteins in vivo,7,8 in turn related to higher risk of morbidity and mortality in the elderly.8,15–19,43 Moreover, recent data on “ae IL-620 and IFN- 41 genes suggest that longevity is negatively associated with genotypes coding for a pro- inflammatory profile. Thus, it is intriguing that the

− → − → − → Table 1 Genotype frequencies for 1082G A, 819C T and 592C A IL-10 promoter gene SNPs among Italian centenarians and

− − − Genotypes 1082 819 592 GG GA AA CC CT TT CC CA AA All the subjects (P = NS)a (P = NS)a (P = NS)a Centenarians 87 81 22 142 45 3 142 45 3 = (n 190) (46%) (43%) (11%) (75%) (23%) (2%) (75%) (23%) (2%) Controls 97 137 26 177 80 3 177 80 3 = (n 260) (37%) (53%) (10%) (68%) (31%) (1%) (68%) (31%) (1%) << = = Men (P 0.025)* (P NS)* (P NS)* Centenarians 18 9 4 24 6 1 24 6 1 = (n 31) (58%) (29%) (13%) (78%) (19%) (3%) (78%) (19%) (3%) Controls 55 88 18 110 49 2 24 6 1 = (n 161) (34%) (55%) (11%) (68%) (30%) (1%) (77%) (19%) (3%)

aChi-square test (3 × 2 tables) was performed to calculate significant different genotype distribution between centenarians and controls.

possession of 1082G genotype, suggested to be associa- ted with IL-10 high production, is significantly increased in centenarians.

population pairwise differentiation test (Arlequin × Software). 3 2 tables were constructed to determine stat- Ae istical significance ( 2 analysis) of differences in percent- ages of homo and heterozygous individuals for the single IL-10 nucleotide polymorphisms in centenarians and con- trol groups.

Furthermore, studies on cytokine gene polymorphisms may help in identifying genetic factors, which impinge upon survival and longevity in humans.

Materials and methods

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