OR, Odds ratio; CI, confidence interval.

Table Genes with a Potential Gender-Specific Influence on Life Span Determination 4.

Gene Protein function Variant(s) Gender association Ref. ADA Regulation of immune system ADA*1/2 (rs73598374) Males 44,45 ADIPOQ Regulation of energy homeostasis and glucose/ rs7799039 Males 46 lipid metabolism APOA4 Major component of high-density lipoprotein 1033 A/G (rs5104) Males 6 and chylomicrons EXO1 Genomic stability, DNA repair rs1776180 Females 47 FOXO1A Cell cycle regulation, angiogenesis rs2755209, rs2755213 Females 48 FSHR Male and female gonadal function Asn680Ser (rs6166) Females Pres. inv. GH-1 Growth and metabolism rs2665802 Females 49 HFE Regulation of iron absorption in the intestine C282Y (rs1800562) Females 7 HLA Immune system HLA-DR5, Females 7 HLA-B8,DR3 Males 7 HSP70-1 Stress response and immune system functions -110A/C (rs1008438) Females 35–37 HSP70-2 Stress response and immune system functions 1267A/G (rs1061581) Females 37 IFN-G Immune-mediated inflammation response + 874T/A (rs2430561) Females 50 IGF-1R Somatic growth, cell cycle progression, and 3174G/A (rs2229765) Males 51 transformation IL6 Immunoregulatory cytokine -174G/C (rs1800795) Males 38 IL10 Anti-inflammatory cytokine -1082G/A (rs1800896) Males 39,40 LEP Body weight regulation, angiogenesis, immune rs1501299 Males 46 response mtDNA Energy metabolism, oxidative stress J haplogroup Males 52 PPARG Lipid/glucose homeostasis, adipocyte differen- Pro12Ala (rs1801282) Males 15, pres. inv. tiation, inflammation response RANTES Inflammation response rs2107538, rs22807889 Males/females 53 SIRT3 Regulation of energy homeostasis and oxidative VNTR intron 5 Males 54 stress TH Physiology of adrenergic neurons STR intron 1 (TCAT)n Males 55 TNFA Pro-inflammatory cytokine -308A/G (rs1800629) Males 56

subfertility status, as confirmed by some clinical investiga- tions for the Ser/Ser genotype.8,27

Of the two FSHR polymorphisms examined at first and found to be in complete linkage disequilibrium (Thr307Ala and Asn680Ser), only the FSHR Asn680Ser polymorphism, which is the more extensively studied,8 was examined in the total sample. A significant excess of the FSHR 680 Ser/Ser genotype was found in the sample of long-lived women compared to controls, suggesting that the FSHR 680 Ser/Ser genotype may favor survival to more than 90 years of age only in women. From previous observations that the FSHR 680 Ser/Ser genotype seems to have a protective role against AD onset in women,9 it could be speculated that the pre- disposition to longevity associated with the FSHR 680 Ser/ Ser genotype could depend on a protective effect conferred by this genotype against the occurrence of AD, a degenera- tive disease of older age and with a higher prevalence in women.

The finding that the FSHR genotype possibly associated with lower fertility may confer a predisposition to longer life span would be in line with the longevity–fertility trade-off hypothesis. This hypothesis postulates that an antagonistic relationship exists between the two functions because they compete for the same resources.28,29 Hence, increased fertility could come at the expense of a longer life span and vice versa. Despite certain discrepancies,30 the longevity–fertility trade-off mechanism seems to work in humans as well.31,32 The FSHR gene could be part of that set of pleiotropic genes that, in different ways, exert their function across different ages of life in response to different contexts, including dif-

The PPARG Pro/Ala genotype showed a significantly higher frequency in the sample of male subjects who died before 90 years than in the long-lived, suggesting that car- rying the PPARG Pro/Ala genotype may prevent the at- tainment of advanced age, but only in men. This PPARG effect on longevity appears to be independent of the opposite action of the ESR1 PP genotype and fertility level. Here it should be added that the increased reproductive efficiency associated with the PPARG Pro/Ala genotype previously observed in this sample23 did not seem to influence longev- ity, a not unexpected finding because the trade-off phe- nomenon usually concerns only women.30

Taking into account other data showing that the FSHR 680 Ser/Ser genotype confers a lower risk of osteoporosis in postmenopausal women compared to the FSHR 680 Asn/ Asn genotype,26 the more general hypothesis could be ad- vanced that the FSHR Ser/Ser genotype favors survival to older age in women because it appears to predispose to healthy aging. We were unable to find any effect of the FSHR genotype on reproductive efficiency in the present sample of women.22 However, to provide a more complete picture, it should be added that in most studies the FSHR 680 Ser/Ser homozygotes are reported to be associated with significantly higher serum FSH levels.8,18 This property could result in a mild resistance of FSH which, in turn, may lead to a

The negative relationship observed between the PPARG Pro/Ala genotype and longevity is in line with the results of

an epidemiological study that reported that the Ala allele may be a risk factor for AD in octogenarian subjects (male and female subjects).13 Moreover, several studies have re- vealed that PPAR-c, together with PPAR-a, inhibits the ex- pression of inflammatory genes such as cytokines, matrix metalloproteinases (MMPs), and acute-phase proteins.33 And because inflammation is believed to have a major role in aging and aging-related diseases, the anti-inflammatory ac- tion of PPARG could have a beneficial effect on aging pro- cesses. In this context, it could be conjectured that the PPARG Ala allele, which was found to be less active,34 may confer on Pro/Ala heterozygotes a weaker inflammatory inhibitory action, with a lower beneficial effect on aging and longevity compared to Pro/Pro genotypes.