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

Luca Cavallone, Massimiliano Bonafe', Fabiola Olivieri, Maurizio Cardelli, Francesca Marchegiani, Simona Giovagnetti, Grazia Di Stasio, Claudia Giampieri, Elena Mugianesi, Rosalia Stecconi, Francesca Sciacca, Luigi Maria Grimaldi, 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 analyzed the polymorphic variants of IL-1a (C>T transition at position 889), IL-1b (C>T transition at position 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. We aimed to evaluate whether IL-1 cluster alleles might be differently represented in people selected for longevity. In addition, we quantified IL-1Ra and IL-1b plasma levels by ELISA in 130 randomly selected subjects. No significant differences in genotype and allele frequency distributions were observed between young and elderly subjects or centenarians. 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 particular polymorphism in the IL-1 gene cluster yields an advantage for survival in the last decades of life. Furthermore, 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.

Keywords: IL-1; Longevity; Centenarians; Immunogenetics

Introduction

Proinflammatory and regulatory cytokines are believed to play a pathogenetic role in age-related diseases. Polymorphisms affecting gene transcription and causing interindividual variations in cytokine production have been described in several cytokine genes (Bidwell et al., 1999, 2001). 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 predictors of disability and mortality in the elderly (Ferrucci et al., 1999; Harris et al., 1999; Brod, 2000). Age-related diseases such as Alzheimer's disease, atherosclerosis, 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-inflammatory cytokines have been shown to affect successful aging and longevity. The (874T) IFN-g allele involved in high production of the proinflammatory cytokine IFN-g was found less frequently in centenarian women than in control women (Lio et al., 2002a). Additionally, the proportion of subjects homozygous for the G allele at position 174 of the IL-6 locus (characterized 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 inflammatory status and its interaction with gender plays an important role in longevity.

Materials and methods

Subjects

1131 unrelated individuals (453 females and 678 males) born and resident in Northern and Central Italy, ranging from 20 to 102 years, were enrolled for the study. The sample included 134 centenarians (94 females and 40pg/ml. IL-1b plasma levels were quantified by human IL-1b-specific ELISA kits (Biosource International, Inc., Camarillo, USA) according to the manufacturer's instructions. The detection limit was 0.12 pg/ml. When the analysis was performed separately in each gender, the regression analysis showed a significant increase in the age range from 60 to 100 in both women and men. In the same group of 130 unrelated individuals, the IL-1b plasma levels were assessed. In 27 subjects, the IL-1b plasma levels were below the sensitivity of the assay (less than 0.12 pg/ml), so only 103 subjects (64 females and 39 males) had detectable IL-1b levels. IL-1b plasma levels did not show any detectable age-related trend (P>0.796). No detectable age-related trend was found when the analysis was performed separately in each gender.

2.4. Statistical analysis

Allele and genotype frequency distributions were compared by Monte-Carlo x2 implemented in Statistical Product and Service Solution Package (SPSS, Chicago, IL). Hardy-Weinberg equilibrium (HWE) was checked by Monte-Carlo Markov Chain (Guo and Thompson, 1992). Since IL-1b and IL-1Ra plasma levels were not normally distributed, values were ln-transformed (Ferrucci et al., 1999). Linear regression was employed to assess the age effects on plasma levels. General linear model (implemented in SPSS Package) was employed to test the age-adjusted effects of genetic factors on cytokine production.