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The role of IL-1 gene cluster in longevity: a study in Italian population

a b a a Luca Cavallone , Massimiliano Bonafe` , Fabiola Olivieri , Maurizio Cardelli , a a a a Francesca Marchegiani , Simona Giovagnetti , Grazia Di Stasio , Claudia Giampieri , a a c c Elena Mugianesi , Rosalia Stecconi , Francesca Sciacca , Luigi Maria Grimaldi , d e e a,b, Giovanna De Benedictis , Domenico Lio , Calogero Caruso , Claudio Franceschi *

a Direzione Scientifica, Italian National Research Center on Aging, Villa Gusso, Via S. Margherita, n. 5 Ancona 60121, Italy b Department of Experimental Pathology, University of Bologna, Bologna, Italy c Department of Neuroscience, S. Raffaele Institute, Milan, Italy d Department of Cell Biology, University of Calabria, Rende, Italy

Received 13 August 2002; accepted 20 December 2002

Abstract

In this study, we analysed the polymorphic variants of IL-1a (C(cid:1)T transition at position (cid:2)889), IL-1b (C(cid:1)T transition at / / / position (cid:2)511) and IL-1 receptor antagonist (Ra) (86-bp repeated sequence in intron 2) in 1131 subjects (453 females and 678 males) / from Northern and Central Italy, including 134 centenarians, to evaluate whether IL-1 cluster alleles might be differently represented in people selected for longevity. In addition, IL-1Ra and IL-1b plasma levels were quantified by ELISA in 130 randomly selected subjects. No significant differences in the genotype and allele frequency distributions were observed between young, elderly and centenarian subjects. IL-1Ra plasma levels showed an age-related increase, whereas IL-1b plasma levels did not show any detectable age-related trend. Neither IL-1Ra nor IL-1b plasma levels showed any relationship with genotypes of the three IL-1 genes. These results suggest that no one particular polymorphism in the IL-1 gene cluster yields an advantage for survival in the last decades of life, and that the age-related increase in plasma levels of IL-1Ra seems not to be genetically regulated but a likely safeguard mechanism to buffer the age-associated increased inflammatory state. # 2003 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: IL-1; Longevity; Centenarians; Immunogenetics

1. Introduction

Proinflammatory and regulatory cytokines are be- lieved to play a pathogenetic role in age-related diseases. In several cytokine genes, polymorphisms affecting gene transcription and causing interindividual variations in cytokine production have been described (Bidwell et al., 1999, 2001). In this regard, it has been proposed that genetic variation in pro- or anti-inflammatory cytokines is capable of modulating the susceptibility to age-related diseases (Keen et al., 1998; Francis et al., 1999; Licastro et al., 2000).

Aging is associated with chronic, low-grade systemic inflammation (Franceschi et al., 2000; Bruunsgaard et al., 2001). Inflammatory markers are the predictors of disability and mortality in the elderly (Ferrucci et al., 1999; Harris et al., 1999; Brod, 2000). Indeed, age- related diseases such as Alzheimer’s disease, athero- sclerosis, type 2 diabetes as well as age-related disorders such as sarcopenia and osteoporosis are caused or worsened by systemic inflammation.

Recently, genetic variations in pro- or anti-inflamma- tory cytokines have been shown to affect successful aging and longevity. Indeed, the (cid:3)874T IFN-g allele / involved in high production of the proinflammatory cytokine IFN-g was found less frequently in centenarian

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0047-6374/03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0047-6374(03)00033-2

marriage and of military service for men, age of first and last pregnancy for women, age of children, among others). Information on health status was obtained for all participants. No acute pathological condition was present in the subjects enrolled for the study. All volunteers were informed about the aim of the study and gave consent to it according to Italian laws.

women than in control women (Lio et al., 2002a). Additionally, the proportion of subjects homozygous for the G allele at (cid:2)174 of the IL-6 locus (characterised / by high serum levels of the proinflammatory cytokine IL-6) was significantly decreased in centenarian men (Bonafe` et al., 2001). In contrast, the presence of the  / 1082GG genotype associated with high production of the anti-inflammatory cytokine IL-10 was significantly increased in centenarian men in comparison with younger ones (Lio et al., 2002b). On the whole, these results suggest that the genetic control of the inflamma- tory status and in particular its substantial interaction with gender plays an important role in longevity.

2.2. Genotyping

DNA was extracted from blood lymphocytes by phenol chloroform according to standard procedures

The IL-1 gene cluster is located on the long arm of chromosome 2 (2q13) and contains genes for IL-1a, IL- 1b and IL-1 receptor antagonist (Ra) within a region of 430 kb (Nicklin et al., 1994; Cox et al., 1998; Rosen- wasser, 1998). The agonists, IL-1a and IL-1b, are believed to exert identical actions via binding to a single cell surface receptor (IL-1RI) involved in signal trans- duction. The third member of the IL-1 family, IL-1Ra, is a highly selective, competitive receptor antagonist that binds to IL-1RI, but fails to trigger signal transduction. A number of biallelic and multiallelic markers in the region surrounding the IL-1 genes have been identified and several reports have provided evidence that these polymorphisms play a pathophysiological role by influ- encing the susceptibility to and the severity of a variety of disorders, including age-related diseases (Clay et al., 1994; Crusius et al., 1995; Heresbach et al., 1997; Hurme et al., 1998; Fang et al., 1999; Nemetz et al., 1999; Grimaldi et al., 2000; Iacoviello et al., 2000; Langdahl et