frequencies per group are reported in parentheses). 

Allele Centenarians (n=168) Controls (n=214) 
T 212 (63.1%) 248 (57.9%) 
G 124 (36.9%) 180 (42.1%) 

The statistical analysis did not show a significant difference in allelic frequencies at -330 IL-2 T/G SNP among centenarians and controls. The absence of statistical difference among centenarians and controls was also confirmed by studying allele frequencies stratified according to gender.

Discussion

The immune response in the elderly is characterized by a progressive loss of the ability to cope with environmental stressors, which leads to a characteristic remodeling of the cytokine network. One of the most commonly reported data in the literature is the decrease in IL-2 production. IL-2 plays a central role in the reconstitution of T cell function in vitro and studies on a T/G polymorphism at 330 nt of IL-2 gene promoter region have demonstrated that T lymphocytes from 330GG homozygous subjects are able to produce higher amounts of IL-2 than 330TG heterozygous or 330TT homozygous subjects.

As a genetic background conditioning the maintaining of an efficient immune response would exert positive effects on healthy aging, this study aimed to investigate the association between 330T/G IL-2 single nucleotide polymorphism (SNP) and longevity in a population of centenarians and controls matched for age and ancestry from Centre and South Italy.

The statistical analysis did not show a significant difference in genotypic and allelic frequencies at -330 IL-2 T/G SNP among centenarians and controls, except for a marginally significant trend for an increased -330TT genotype frequency observed through extended Mantel Haenszel procedure. These findings seem paradoxical considering the role attributed to well-conserved T cell function in successful aging, but a similar distribution of 330T/G genotype was also observed in a recent study on a sample of Irish octogenarians. These data suggest that a genetic background favoring an increased IL-2 production might be detrimental for longevity.

In addition, an increase in IL-2 and other pro-inflammatory cytokine production characterizes the Alzheimer's disease serum profile. All in all, these data suggest that a reduction of 330G allele frequency might be protective for healthy aging, limiting cell-mediated inflammation implied in age-associated diseases.

Conclusion

This study investigated the association between 330T/G IL-2 SNP and longevity in a population of centenarians and controls matched for age and ancestry from Centre and South Italy. The statistical analysis did not show a significant difference in genotypic and allelic frequencies at -330 IL-2 T/G SNP among centenarians and controls, except for a marginally significant trend for an increased -330TT genotype frequency observed through extended Mantel Haenszel procedure. These findings suggest that a genetic background favoring an increased IL-2 production might be detrimental for longevity.Frequencies per group are reported in parentheses. Ageing data are accumulating on the role that high IL-2 production might play in immune-inflammatory mediated diseases. In humans, as reported by Solerte et al. (2000), high IL-2, as well as interferon-c and tumor necrosis factor-a, serum levels characterize subjects affected by Alzheimer's disease. Furthermore, IL-2 increase has been associated with evolving atherosclerosis and coronary events in stable and unstable angina patients (Elkind et al. 2005; Methe et al. 2005). So the role of IL-2 in ageing might be more complex than that postulated as adaptive response rescue factor in immunosenescence (Lio et al. 2000; Candore et al. 2002; Pawelec et al. 2002). Immunosenescence may actually be considered an attempt to adapt response to the stressors of an aged immune system (Franceschi et al. 2005). A beneficial mechanism (i.e., genetically determined IL-2 high production), devoted to the neutralization of dangerous/harmful agents early in life and in adulthood, turns out to be detrimental late in life, in a period largely not foreseen by evolutionary strengths, and the reduction of IL-2 production, at least in part favored by genetic background, or modification of cellular machinery of signal transduction might be a protective adaptation against age-related diseases that are the price we pay for a lifelong active immune system (Caruso et al. 2005; Licastro et al. 2005).

IL-2 )330 Alleles Centenarians Controls 336 (%) 428 (%) T 212 (63.1) 248 (57.9) G 124 (36.9) 180 (42.1)

No significant different distributions of IL-2 )330T/G alleles were observed among control and centenarian subjects.

Discussion mediated immune response and defects in IL-2-mediated activation (e.g., for a deficit of c chain of Il-2 receptor) induce severe immune deficiency (Demoulin and Renauld 1998). An age-related decline in IL-2 production with associated effects on intracellular activation of nuclear transcription pathways involving a reduction of ERK2 activity (Douziech et al. 2002) is considered a marker for immune senescence (Candore et al. 1992; Caruso et al. 1996; Rea et al. 1996; Pawelec et al. 2002). Recently, a polymorphism (T/G), reported in the promoter region of IL-2 at the nucleotide position 330, (John et al. 1998), has been shown to influence IL-2 production and in vitro cytokine production in anti-D3/CD28-stimulated peripheral blood lymphocytes (Hoffman et al. 2001). G allele frequencies of IL-2 330 polymorphism in smaller samples of Caucasian populations across Europe have been documented as 30-40% in Germany, in Ireland, and in North Italy (John et al. 1998; Reynard et al. 2000; Ross et al. 2003; Uboldi de Capei et al. 2003), and about 35% was observed in our control population.