Limitations

No adjustment for inflation of type I error due to multiple comparisons was made as a result of their relatively low number.

between 90 and 111 years (median + interquartile range: 93 + 4 years); 12 individuals were centenarians (from 100 to 111 years). The median age of the control group (18-80 years) was 60 + 21 years.

Discussion

We studied 3 SNPs in 4 candidate genes in pathways related to lipoprotein metabolism, hypertension, and stress response, as these are closely related to aging.18-20 We found that the I car- riers of ACE gene were fewer in nonagenarians compared to centenarians and more frequent in centenarians compared to controls.

Nonagenarian and Centenarian groups

The I carriers of ACE I/D gene were fewer in nonagenarians compared to centenarians (37.6% vs 62.5%, P ¼ .016; Tables 2 and 3).

There are many controversial studies reporting that various CETP polymorphisms may be involved in longevity and ather- osclerosis.21 In the West of Scotland Coronary Prevention Study (WOSCOPS) the B2 homozygous had a 30% reduced risk of a cardiovascular event compared to B1 homozygotes.22 Few years ago, our group23 reported a positive association between B1 genotype and postprandial lipemia which normally

Centenarian and Control groups

The I carriers of ACE gene were more frequent in centenarians compared to controls (62% vs 41%, P ¼ .045; Tables 2 and 3).

frequency of NFkB gene polymorphism between the groups. To our knowledge, until now, no other study had evaluated NFkB gene polymorphism and longevity.

Table 3. ACE I/D Allele Frequency in Control, Nonagenarian, and Centenarian Groups.a

ACE I/D Alleles I D Total Age <80 Count 82 118 200 % within age 41.0% 59.0% 100.0% % within ACE I/D allele 34.6% 32.9% 33.6% (cid:2)90 Count 140 232 372 % within age 37.6% 62.4% 100.0% % within ACE I/D allele 59.1% 64.6% 62.4% (cid:2)99 Count 15 9 24 % within age 62.5% 37.5% 100.0% % within ACE I/D allele 6.3% 2.5% 4.0% Total Count 237 359 596 % within age 39.8% 60.2% 100.0% % within ACE I/D allele 100.0% 100.0% 100.0%

in some cohorts of European centenarians, including France,36 United Kingdom,37 and Italy38 compared to their younger ethnically matched referents. Recently, Petranovic´ et al39 reported that the DD genotype was twice as frequent in 80þ cohort compared to the general population of Croatia. However, Fiuza-Luces et al40 reported no differences in the allelic or genotypic frequencies between controls and centenarians in a Spanish population. This is in agreement with Han Chinese centenarians,41 a French population,42 and Asian centenarians.43

more frequent in centenarians compared to nonagenarians and controls. The finding that D allele is correlated to longevity is paradoxical and difficult to explain especially as many studies reported that the D allele is associated with increased risk of myocardial infarction and coronary heart disease.44 In contrast, the I allele was found to correlate with a lower presence of heart failure (which normally increases with age) compared to the D allele.45 Also, Abchee et al46 reported a protective role of the ACE I allele in individuals who may be at risk of devel- oping coronary artery disease. However, Yang et al47 did not find any association of ACE gene polymorphism and longevity in a Han Chinese population. Similarly, Blanche´ et al48 in a French centenarian cohort did not confirm the ACE gene asso- ciation with longevity and discussed the risk of reporting false positive associations.

Abbreviations: ACE, angiotensin-converting enzyme; ACE I/D, ACE Ins(I)/ Del(D) alleles. a P ¼ .045 centenarian versus control groups; P ¼ .016 nonagenarian versus centenarian groups.

a P ¼ .045 centenarian versus control groups; P ¼ .016 nonagenarian versus centenarian groups.

increases with age; the definition, assessment, and clinical implications of postprandial lipemia were recently discussed by an expert panel.24-26 Barzilai et al27 suggested that excep- tional longevity was associated with approximately a 3-fold increased frequency of homozygosityV of CETP I405 V gene. Also, Soerensen et al28 found that CETP gene polymorphism is associated with longevity in oldest-old (ages 92-93) Danes population.

Females live longer than males. Vina et al49 reported that estrogens and phytoestrogens can upregulate the expression of antioxidant enzymes via the estrogen receptor and mitogen-activated protein kinases activation, which in turn activate the NFkB signaling pathway, resulting in the upregu- lation of the expression of longevity-related genes. When cate- gorized by gender, no significant associations between genotypic or allele frequencies and age groups were observed.

In this study, we have not found any differences in geno- types/allele frequency of both (TaqB1 and I405 V) CETP gene polymorphisms between groups. Similarly, Cellini et al29 did not confirm the association between the CETPI405 V variation and the healthy aging phenotype described in the Ashkenazi Jewish population and suggested that other gene environment interactions contribute to longevity. Also, Novelli et al30 except for APOE gene did not find any association with longevity and gene polymorphisms (including CETP I405 V) in a large cohort of long-living individuals and their controls, pointing to the need of larger populations for case-control studies in extreme longevity.