of the association with 330T/G IL-2 in a population of centenarians Centre and South Italy

Letizia Scola1, Giuseppina Candore1, Giuseppina Colonna-Romano1, Antonio Crivello1, Giusi I. Giuseppe Paolisso2, Claudio Franceschi3,4, Domenico Lio1 & Calogero Caruso1,5,* 1Gruppo di Studio sull’Immunosenescenza, Dipartimento di Biopatologia e Metodologie Biomediche, Universita` di Palermo, Palermo, Italy; 2Dipartimento di Medicina Geriatria e Malattie Metaboliche, II Universita` di Napoli, Napoli, Italy; 3Dipartimento di Patologia Sperimentale and Centro ‘‘L. Galvani’’, Universita` di Bologna, Bologna , Italy; 4Istituto Nazionale di Riposo e Cura per Anziani, Ancona, Italy; 5Present address: Corso Tukory 211, 90134, Palermo, Italy; *Author for correspondence (e-mail: marcoc@unipa.it; fax: +390916555933)

Received 19 August 2005; accepted in revised form 8 November 2005

Key words: IL-2 immunogenetics, immunosenescence, longevity

Abstract

Immune response in elderly is characterised by a progressive loss of the ability to cope environmental stressors with a characteristic remodelling of cytokine network. One of the data constantly reported in literature is the decrease of IL-2 production. An IL-2 central role in the reconstitution of T cell function in ) vitro is largely documented. Studies on a T fi G polymorphism at 330 nt of IL-2 gene promoter region have demonstrated that T lymphocytes from 330GG homozygous subjects are able to produce in vitro ) ) higher amount of IL-2, than 330TG heterozygous or 330TT homozygous subjects. As a genetic back- ground conditioning the maintaining of an efficient immune response would exert positive effects on healthy ageing, we have typed for 330T/G IL-2 single nucleotide polymorphism (SNP), 168 centenarians and 214 control subjects matched for age and ancestry from Centre and South Italy to check the 330GG genotype association to longevity. The statistical analysis doesn’t show a significant difference of genotypic and allelic ) frequencies at 330 IL-2 T/G SNP among centenarians and controls. Comparing the two cohorts of subjects by extended Mantel Haenszel procedure a marginally significant trend for an increased -330TT genotype frequency was observed. Our data seem to be paradoxical considering the role attributed to a well-conserved T cell function in the successful ageing. On the other hand, in a recent study on a sample of Irish octoge- ) narians a similar distribution of 330T/G genotype even was observed. These data suggest that a genetic background favouring an increased IL-2 production might be detrimental for longevity. On the other hand, an increase of IL-2 and other pro-inflammatory cytokine production characterise the Alzheimer’s disease ) serum profile. All in all our data seem to suggest that reduction of 330G allele frequency might be protective for healthy ageing limiting cell mediated inflammation implied in age associated diseases.

Introduction

some immunological parameters of the immune response are often notably reduced in the elderly (Franceschi et al. 1995; Cossarizza et al. 1997; Globerson and Effros 2000; Pawelec et al. 2002).

In ageing many alterations of both the innate and clonotypic immunity have been described. The modifications of the immune system in the elderly are generally evaluated as a deterioration of the immune system, this is the origin of the term immunosenescence. A good immune system in the elderly is tightly correlated to health, and

An age-related decline in IL-2 production has been recognized since the early work of Gillis et al. (1981) who identified a T cell growth factor, later called IL-2 that was decreased in

Recently, studies on a T fi G polymorphism ) at 330 nt of IL-2 gene (4q26–q27) promoter re- gion have demonstrated that T lymphocytes from ) 330GG homozygous subjects are able to pro- duce in vitro higher amount of IL-2, than ) ) 330TG heterozygous or 330TT homozygous subjects (Hoffmann et al 2001). In addition, it has been demonstrated that IL2 promoter-lucif- erase constructs, transfected in Jurkat cell line, showed twofold higher levels of gene expression ) in the 330 G allele (Matesanz et al. 2004). As a genetic background conditioning the maintaining of an efficient immune response would exert posi- tive effects on healthy ageing, we have typed for ) 330T/G IL-2 SNP, 168 centenarians and 214 control subjects matched for gender and ancestry from Centre and South Italy to check the ) hypothesis that 330GG genotype might be asso- ciated to longevity.

ageing. Subsequent studies showed that IL-2, essential for T cell proliferation and growth and for an efficient effector response, is reduced in aged subjects with associated effects on intracel- lular activation of nuclear transcription pathways (Candore et al. 1992; Caruso et al. 1996; Rea et al. 1996; Pawelec et al. 2002). Moreover hexogen IL-2 was found to reconstitute T cell proliferation and cytokine production in vitro (Candore et al 1996; Lio et al 2000).

On the other hand, individual changes in type and intensity of immune response affecting life span expectancy and health ageing seem to have a genetic component. A well-preserved immune function characterizing the ‘successful ageing’ has been found in long term surviving exceptional individuals that reach the extreme edge of human life. Centenarians, actually, seem to be genetically equipped for overcame the major age- related diseases and polymorphisms of the im- mune system genes regulating immune responses have been found associated to longevity (Caruso et al., 2005; Franceschi et al., 2005).

Materials and methods