between populations can affect genetic diversity, we selected a homogeneous population from western Sicily. We used polymerase chain reaction-sequence-specific primers (PCR-SSP) to assess the frequencies of HLA-DRB1 and KIR receptors=HLA ligands in our study population of centenarians and controls.

Previous studies have suggested that longevity is associated with optimal immune system functioning, which may be influenced by specific genetic determinants. These determinants may include loci that regulate the immune response, such as HLA and KIR genes. Positive selection of certain alleles or haplotypes has been linked to resistance to infectious diseases, while the cytolytic activity of NK cells is controlled by activating and inhibitory cell-surface receptors, including KIR.

We found an increase in the HLA DRB1*18 allele frequency in male centenarians, but no significant difference was observed for KIR after Bonferroni correction. Our findings suggest that associations between HLA=KIR=longevity are population-specific and influenced by genetic and environmental history.

To validate gender-related associations between HLA-DRB1 genes and longevity observed in other Caucasoid populations, and to determine whether a particular repertoire of KIR receptors is associated with successful aging, we genotyped centenarians and controls from a homogeneous population in western Sicily.

We used statistical analysis to evaluate allele frequencies by gene count and construct 2x2 tables to determine statistical significance. The data were tested for goodness of fit between observed and expected genotype values, as well as their fit to Hardy-Weinberg equilibrium.

Our study is important for enhancing the understanding of aging and longevity, which may help in planning anti-aging strategies. However, association studies are subjected to possible confounding factors like population homogeneity in terms of geographic origin.study was played by the HLA and KIR genes, which regulate immune responses. The study was conducted on individuals of Sicilian ethnicity, with all four grandparents born in western Sicily. The University Hospital Ethics Committee approved the study, and all participants provided written informed consent. The investigation found that the HLA-DRB1* allele frequencies in 299 controls and 77 centenarians were consistent with those predicted by the Hardy-Weinberg equilibrium (HWE). Table 1 shows that there was a significant increase of HLA DRB1*18 allele in male centenarians (p=0.0019), which remained significant even after Bonferroni correction (p=0.0266). No significant differences were observed between centenarians and controls for other alleles, including HLA-B8,DR3 phenotype, as shown in a sample of 38 healthy controls and 44 centenarians. Table 2 shows that the only significant difference observed for KIR genes was a decrease of the 2DP1 KIR gene in centenarians (p=0.03), but it was no longer significant after Bonferroni correction. No significant difference was obtained when stratifying the subjects by gender. Table 3 shows no significant difference between centenarians and controls for HLA ligands frequency.

The DNA was extracted using the salting-out method following the standard protocol.18 The distributions of A haplotype, B haplotype, and A=B haplotype were analyzed, but there were no significant differences. The AH 8.1 haplotype seems to be associated with longevity in elderly men but not women, while immune dysfunctions of AH 8.1 may contribute to early morbidity and mortality in elderly women, as well as more susceptibility to autoimmune diseases than men.

The study suggests that only an HLA allele (DRB1*18) is associated with longevity, but further studies are needed to confirm this association in a new cohort of centenarians and controls. Moreover, the study does not support a role for KIR diversity in aging, but more research is required to elucidate the precise role that NK cells play in longevity. The study highlights that HLA=KIR=longevity associations are population-specific and affected by the population-specific genetic and environmental history. Inflammatory gene variants are more relevant than immune response genes in the control of successful aging, according to previous and present findings. However, this kind of study is important to better understand aging and longevity, hence enhancing the planning of anti-aging strategies.The innate immune response is also played by NK cells in successful aging. In particular, some studies have shown that decreased NK cell function is associated with an increased incidence of infectious diseases both in aged humans (29) and in mice (30), highlighting the importance of a well-preserved NK cell function in old age. The elderly (>85 years) with low numbers of NK cells were reported to have three times the mortality risk in the first 2 years of follow-up than those with high NK cell numbers (31). In addition, high NK cytotoxicity in aged people is related both to a low incidence of respiratory tract infections and to good development of protective antibody titers in response to influenza vaccination (32). Hence, preserved NK cytotoxicity should be considered a biomarker of healthy aging and longevity, whereas low NK cytotoxicity is a predictor of morbidity and mortality due to infections.

Acknowledgments: This work was supported by grants from the Italian Ministry of Education, University and Research to C.C. and G.C.

References: 

Candore G, Colonna-Romano G, Lio D, Caruso C. Immunological and immunogenetic markers of successful and unsuccessful aging. In: Pawelec G, ed. Advances in Cell Aging and Gerontology Basic Biology and Clinical Impact of Immunosenescence, Elsevier Science, Amsterdam.

Caruso C, Candore G, Colonna-Romano G, Lio D, Bonafe M, Valesin F, Franceschi C. HLA, aging and longevity: A critical reappraisal. Human Immunol ; :