Table Allele Frequencies in Controls Women and Men 1. HLA-DRB1* 299 (171 128 ) and in Centenarians Women and Men from Sicily 77 (51 26 )

Controls Centenarians HLA All Women Men All Women Men DRB1*01 43 (14.4%) 25 (14.5%) 18 (14%) 9 (12%) 7 (13.7%) 2 (8.7%) DRB1*15 74 (24.7%) 39 (22.6%) 35 (27.3%) 12 (16.2%) 7 (13.7%) 5 (21.7%) DRB1*16 20 (6.6%) 8 (4.6%) 12 (9.3%) 3 (4%) 1 (2%) 2 (8.7%) DRB1*17 70 (23.4%) 40 (23.2%) 30 (23.4%) 15 (20%) 12 (23.5%) 3 (13%) DRB1*18 2 (0.6%) 2 (1.1%) 0 6 (8.1%) 3 (5.8%) 3 (13%)a DRB1*4 62 (20.7%) 32 (18.6%) 30 (23.4%) 15 (20%) 11 (21.5%) 4 (17.4%) DRB1*10 12 (4%) 6 (3.4%) 6 (4.6%) 3 (2.7%) 3 (5.9%) 0 DRB1*11 117 (39.1%) 73 (42.4%) 44 (34.3%) 27 (36.5%) 19 (37.2%) 8 (34.8%) DRB1*12 10 (3.3%) 10 (5.8%) 0 3 (4%) 2 (4%) 1 (4.3%) DRB1*13 43 (14.4%) 26 (15.1%) 17 (13.3%) 17 (23%) 13 (25.5%) 4 (17.4%) DRB1*14 21 (7%) 13 (7.5%) 8 (6.2%) 7 (9%) 4 (7.9%) 3 (13%) DRB1*7 37 (16.1%) 24 (11.6%) 13 (10.1%) 9 (12%) 5 (9.8%) 4 (17.4%) DRB1*08 4 (1.3%) 2 (1.1%) 2 (1.5%) 1 (1.3%) 1 (1.9%) 0 DRB1*09 1 (0.3%) 1 (0.5%) 0 2 (2.7%) 1 (1.9) 1 (4.3)

ap¼0.0019 by chi-squared Yates correction, p¼0.0266 after Bonferroni’s correction. HLA, Human leukocyte antigen.

in the polymorphisms for genes that regulate immune re- sponses as HLA and KIR.1 HLA polymorphisms have been the focus of a vast number of aging association studies, in contrast to only two studies of KIR genes.16 Conflicting results have been obtained regarding HLA, suggesting that the ob- served age-related differences in the frequency of HLA anti- gens are due to bias. The studies performed on the association between longevity and HLA are generally difficult to inter- pret, owing to major methodological problems. However, as reported Caruso et al.,2,3 some that were well designed and performed suggest an HLA effect on longevity. In studies performed in Caucasoids, an increase in HLA-DRB1*11 in Dutch women over 85 years was observed.20 The same laboratory performed a further study and, by using a ‘‘birth- place-restricted comparison’’ in which the origin of all the subjects was ascertained, the authors were able to confirm that aging in women was positively associated with HLA- DR5.21 Two French studies confirmed the relevance of HLA- DR11 to longevity in aged populations.22,23 This increase is consistent with the protective effects of this allele in viral diseases, as HLA-DR5, or its subtype HLA-DR11, frequencies have been shown to be decreased in some viral diseases.2,3

Analyzing the distributions of ‘‘A’’ haplotype, ‘‘B’’ haplotype, and ‘‘A=B’’ haplotype, there are not significant differences (data not shown). However, the A haplotype predominates in the Sicilian population (26% vs. 0% in healthy controls).

Discussion

Longevity is the result of several interacting factors, in- cluding genetic, environmental, and behavioral compo- nents.19 Several studies suggest that human longevity is inextricably linked to the optimal function of the immune system. Hence, genetic determinants of longevity might reside

2. KIR in Healthy Controls and Centenarians 57 44

Controls Centenarians KIR genes (n ¼57) (n ¼44) p value 2DL1 56 (98.2%) 42 (95.5%) 2DL2 40 (70%) 28 (63.6%) 2DL3 39 (68.4%) 30 (68%) 2DL4 56 (98.2%) 43 (97.7%) 2DL5A 10 (17.5%) 10 (22.7%) 2DL5B 18 (31.5%) 10 (22.7%) 2DS1 28 (49.1%) 19 (43.2%) 2DS2 36 (63.1%) 29 (66%) 2DS3 30 (52.6%) 24 (54.5%) 2DS4001=002 10 (17.5%) 8 (18%) 2DS4003=007 43 (75.4%) 32 (72.7%) 2DS5 24 (42.1%) 16 (36.3%) 3DL1 51 (89.5%) 39 (88.6%) 3DL2 54 (94.7%) 42 (95.5%) 3DL3 56 (98.2%) 44 (100%) 3DS1 25 (43.8%) 21 (47.7%) 2DP1 55 (96.5%) 37 (84%) 0.03a 3DP1001=004 2 (3.5%) 4 (9%) 3DP1003 53 (93%) 37 (84%)

An association between longevity and the haplotype AH 8.1 seems to emerge. An excess of this AH in the oldest old men has been reported in French and in North Ireland populations.24,25 This association appears to be gender spe- cific. In fact, a Greek study showed a significant decrease of

Table 3. The HLA Ligands Frequencies Observed in 57 Healthy Controls and 44 Centenarians

Controls Centenarians Group (n¼ 57) (n ¼44) p value C1 16 (28%) 19 (43%) N.S. C2 17 (30%) 11 (25%) N.S. C1,C2 24 (42%) 14 (32%) N.S.

aUncorrected p value by chi-squares Yates correction. KIR, Killer cell immunoglobulin-like receptor.

HLA, Human leukocyte antigen; N.S., not significant.

AH 8.1 in aged women.26 Thus, immune dysfunctions of AH 8.1 should contribute to early morbidity and mortality in elderly women, to more susceptibility to autoimmune dis- eases than men, and to longevity in elderly men.2–4

significant after Bonferroni correction. As in other Caucasian populations, the A haplotype was found to be prevalent in Sicilian population. Thus, results obtained show that only an HLA allele (DRB1*18) is associated with longevity. To con- firm this association, a further study in a new cohort of centenarians and controls is needed. On the other hand, no significant association between successful aging and KIR gene content was observed in this Sicilian population.

pected on the basis of available data on the genetics of lon- gevity, showing that the association of longevity with particular alleles may be found only in one gender.27 How- ever, in a longitudinal study, in which a total of 919 subjects aged 85 and older were HLA-typed and followed up for at least 5 years, no HLA association with mortality was found. 21