disorders. Conversely, other inhibitory KIR genes may offer a protective effect against self-reactivity and autoimmunity.

In recent years, it has been postulated that gender is a variable concerning the genetics of ageing (Franceschi et al., 2000b) and studies have shown that men and women may follow different pathways to extreme longevity. The most notable of these have examined possible gender-specific markers of longevity within loci that regulate the immune response, namely the polymorphic HLA and cytokine networks (Rea and Middleton, 1994; Bonafe et al., 2001; Lio et al., 2002; Olivieri et al., 2002). To highlight possible gender-specific markers of longevity within the KIR gene network, KIR genotype and gene frequencies were analysed with respect to gender. Interestingly, two KIR genotypes (1 and 3/9) and two KIR genes (KIR2DS2, KIR2DL2) displayed gender-specific variations in frequency between aged subjects of a particular sex and young controls of the same gender. The two KIR genotypes displayed a gender- associated decrease in frequency relative to controls, with genotype 1 decreased in aged females and genotype 3/9 decreased in aged males. This suggests that certain combinations of KIR genes may exert subtle gender- dependent effects during the ageing process. Conversely, the KIR2DS2 and KIR2DL2 genes displayed an increased prevalence in aged females relative to young female controls, suggesting these genes may have beneficial effects that extend the lifespan of members of this sex.

Although, the present study does not support a role for KIR diversity in ageing, considerably more research is required to elucidate the precise role that NK cells play in longevity. Further studies, based on larger pooled sample groups, aimed at investigating whether the polymorphic nature of the genes encoded within the LRC is important in ageing, are also required. This initial study will allow more focussed attention on this region and will aid in the analysis by permitting meta-analysis with future studies, helping to overcome the problem of sample numbers that hinder studies in successful ageing. In addition, the formation of immunogenetic profiles for healthy elderly individuals incorporating parameters such as cytokine gene polymorph- ism profiles with HLA and KIR haplotypes, will aid our understanding of the molecular mechanisms that underlie immunosenescence and longevity.

Acknowledgements

With respect to NK cell activity, both cytokines and HLA class I molecules mediate important immunomodulatory functions—for example, certain cytokines including IL-2, IL-15 and IL-18 are capable of inducing NK cell activity (Perussia, 1996), while HLA class I molecules are the ligands for certain activating and inhibitory KIRs. In parallel with the KIR gene network, both the HLA and cytokine systems display considerable levels of poly- morphic variation (Ross et al., 2003a,b). Hence, it is plausible that the polymorphic nature of each of these gene systems manifests itself in the existence of a myriad of cytokine, HLA, and KIR haplotypes that circulate within the human population. With respect to the ageing process, it is certainly conceivable that epistatic interactions between particular cytokine, HLA, and KIR haplotypes may contribute to the generation of a dynamic immune response that supports successful ageing, whereas certain other haplotype combinations may produce sub-optimal levels of immunity and reduced lifespan.

We are grateful to the following organisations for their support of this work: The R&D Office of the Health and Personal Social Services (Northern Ireland) and the Department of Employment and Learning (Northern Ireland). L.D. Maxwell is a recipient of the Dunville Scholarship awarded by Queens University Belfast. We are grateful to all the participants of the study for their time and patience.

References

Arm, J.P., Nwankwo, C., Austen, K.F.,

Molecular identification of a novel family of human Ig superfamily members that possess immunoreceptor tyrosine based inhibition motifs and homology to the mouse gp

B

inhibitory receptor. J. Immunol.

,

–

Biassoni, R., Cantoni, C., Falco, M., Pende, D., Millo, R., Moretta, L., Bottino, C., Moretta, A.,

Human natural killer cell activating receptors. Mol. Immunol.

,

–

Biron, C.A., Nguyen, K.B., Pien, G.C., Cousens, L.P., Salazar-Mather, T.P.,

Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu. Rev. Immunol.

,

–

Bonafe, M., Olivieri, F., Cavallone, L., Giovagnetti, S., Marchegiani, F., Cardelli, M., Pieri, C., Marra, M., Antonicelli, R., Lisa, R., Rizzo, M.R., Paolisso, G., Monti, D., Franceschi, C.,

A gender-dependent genetic predisposition to produce high levels of IL-

is detrimental for longevity. Eur. J. Immunol.

,

–

Bruhns, P., Marchetti, P., Fridman, W.H., Vivier, E., Daeron, M.,

Differential roles of N- and C-terminal ITIMs during inhibition of cell activation by killer cell inhibitory receptors. J. Immunol.

,

–

The present study aimed to investigate the potential role that KIR diversity may play in immunosenescence and longevity within the Irish population. However, no significant association between successful ageing and KIR gene content was observed. A number of reasons could help explain this lack of association; sample numbers are always a concern when examining regions of extreme genetic diversity and the use of two independent aged sampling cohorts was employed to try and minimise any false- positive findings of association. In the context of the present

L.D. Maxwell et al. / Experimental Gerontology 39 (2004) 1223–1232

Lio, D., Scola, L., Crivello, A., Colonna-Romano, G., Candore, G., Bonafe, M., Cavallone, L., Franceschi, C., Caruso, C.,

Gender-specific association between—

IL-

promoter polymorphism and long- evity. Genes Immun.

(

),

–

Ljunggren, H.G., Karre, K.,

In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunol. Today

,