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 Positive studies need confirmation in different Caucasoid populations with different ethnic backgrounds and=or rep- lication in a new cohort of oldest old from the same popu- lation. In Sardinian centenarians, we did not observed the associations demonstrated in the other well-planned and designed studies discussed above.5 One study set out to specifically confirm the previously reported increase in the frequency of AH 8.1 in aged men of the northern Irish population,25 but did not reveal any statistically significant haplotype frequency differences between the aged cohort of individuals compared to the younger controls. However, a striking decrease was observed when the aged women (13.1%) were compared to the control women (17.8%).28

Although, the present study does not support a role for KIR diversity in aging, considerably more research is required to elucidate the precise role that NK cells play in longevity. It is conceivable that epistatic interactions between particular HLA and KIR haplotypes may contribute to the generation of a dynamic immune response that supports successful aging, whereas certain other haplotype combinations may produce suboptimal levels of immunity and reduced life span.

Present and previous findings suggest that HLA=KIR= longevity associations are population specific, being heavily affected by the population-specific genetic and environmen- tal history. On the other hand, our group has performed several studies showing that inflammatory gene variants are associated with longevity.34,35 In our opinion, inflammatory genes are more relevant than immune response genes in the control of successful aging. However, this kind of study is important to better understand aging and longevity, hence enhancing the planning of antiaging strategies.36–38

A pivotal role in the innate immune response is also played by NK cells in successful aging. In particular, some studies have showed 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 im- portance 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 Min- istry of Education, University and Research to C.C. and G.C.

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diversity in immunosenescence and longevity has been in- vestigated only in the Irish population. Although, two KIR genes (2DS3, 2DL5) displayed an initial increased frequency in the aged group, the significance of this association was absent when repeated in a second cohort.16 Both activating and inhibitory KIR genes encode receptors with immune functions that clearly have the potential to optimize NK cell activity in the elderly, thereby contributing to prolonged life span. Hence, the increased prevalence of such a KIR gene in the healthy aged may reflect a role for the activating receptor it encodes in providing an improved level of innate immune protection against virus infection and cancer.

In this study we evaluated the frequencies of genes HLA-DRB1 and KIR in centenarians and controls from Sicily. Our results demonstrate an increase of HLA DRB1*18 allele in male centenarians compared to controls even after Bon- ferroni correction. The frequency of the HLA-B8,DR3 hap- lotype is very low and not significant both in centenarians and in controls as well as in literature data.33 In regard to KIR genes, only a significant decrease of the 2DP1 KIR gene in centenarians was observed, which was no longer