Gender-specific association between 1082 IL-10 promoter polymorphism and longevity

D Lio1, L Scola1, A Crivello1, G Colonna-Romano1, G Candore1, M Bonafe`2, L Cavallone3, C Franceschi2,3 and C Caruso1 1Dipartimento di Biopatologia e Metodologie Biomediche, Universita` di Palermo, Palermo, Italy; 2Dipartimento di Patologia Sperimentale, Universita` di Bologna, Bologna, Italy; 3Istituto Nazionale di Riposo e Cura per Anziani di Ancona, Ancona,

Lio1, L Scola1, A Crivello1, G Colonna-Romano1, G Candore1, M Bonafe`2, L Cavallone3,

1Dipartimento di Biopatologia e Metodologie Biomediche, Universita` di Palermo, Palermo, Italy; 2Dipartimento di Patologia Sperimentale, Universita` di Bologna, Bologna, Italy; 3Istituto Nazionale di Riposo e Cura per Anziani di Ancona, Ancona, Italy

Ageing is characterized by a pro-inflammatory status, which could contribute to the onset of major age-related diseases. Thus, genetic variations in pro- or anti-inflammatory cytokines might influence successful ageing and longevity. IL-10 is an appropriate candidate because it exerts powerful inhibitory effects on pro-inflammatory function. IL-10 production is controlled by several polymorphic elements in the 5(cid:1) flanking region of IL-10 gene on 1q32 locus, involving alleles at two microsatellite regions and several polymorphisms in promoter region. We analysed in 190 Italian centenarians ((cid:2)99 years

Thus, genetic variations in pro- or anti-inflammatory cytokines might influence successful ageing and longevity. IL-10 is appropriate candidate because it exerts powerful inhibitory effects on pro-inflammatory function. IL-10 production is controlled by several polymorphic elements in the 5(cid:1) flanking region of IL-10 gene on 1q32 locus, involving alleles at microsatellite regions and several polymorphisms in promoter region. We analysed in 190 Italian centenarians ((cid:2)99 old, 159 women and 31 men) and in 260 (cid:3)60 years old control subjects (99 women and 161 men), matched for geographical distribution, genotype frequencies for −1082G→A, −819C→T and −592C→A IL-10 proximal promoter biallelic polymorphisms by sequence specific probes. −1082G homozygous genotype was increased in centenarian (P ae 0.025) but not in centenarian women. No difference was found between centenarians and control subjects the other two polymorphisms. The presence of −1082GG genotype, suggested to be associated with high IL-10 production, significantly increases the possibility to reach the extreme limit of human lifespan in men. Together with previous data on other polymorphic loci (Tyrosine Hydroxylase, mitochondrial DNA, IL-6, haemochromatosis, IFN-(cid:4)), finding points out that that gender is a major variable in the genetics of longevity, suggesting that men and women different strategies to reach longevity. Concerning the biological significance of this association, we have not searched functional proves that IL-10 is involved. Thus, we should conclude that our data only suggest that a marker on 1q32 genomic region may be involved in successful ageing in man. However, recent data on IL-6 and IFN-(cid:4) genes suggest longevity is negatively associated with genotypes coding for a pro-inflammatory profile. Thus, it is intriguing that the possession of −1082G genotype, suggested to be associated with IL-10 high production, is significantly increased in centenarians.

geographical distribution, genotype frequencies for −1082G→A, −819C→T and −592C→A IL-10 proximal promoter gene biallelic polymorphisms by sequence specific probes. −1082G homozygous genotype was increased in centenarian men (P ae 0.025) but not in centenarian women. No difference was found between centenarians and control subjects regarding

functional proves that IL-10 is involved. Thus, we should conclude that our data only suggest that a marker on 1q32 genomic region may be involved in successful ageing in man. However, recent data on IL-6 and IFN-(cid:4) genes suggest longevity is negatively associated with genotypes coding for a pro-inflammatory profile. Thus, it is intriguing that the possession of −1082G genotype, suggested to be associated with IL-10 high production, is significantly increased in centenarians.

Keywords: IL-10; longevity; inflammation; centenarians; immunogenetics

Introduction

survival from 80 to more than 100 years of age. Indeed, there is some evidence that extreme longevity clusters in some families,3 and preliminary results from several studies suggest a modest ‘recurrent risk’ for exceptional longevity.4 Therefore, the role of genetics in longevity might be much higher than predicted.5

Current evidence, based primarily on Scandinavian Twin Registries, suggests that about a quarter of the variation in adult lifespan can be attributed to genetic factors, ie the heritability of lifespan is about 25%.1,2 It is not known, however, how important genetic factors are in explaining

A dysregulation of both immune and inflammatory responses occurring with increasing age is believed to substantially contribute to morbidity and mortality in humans.6–8 Conversely, human longevity seems to be directly correlated with optimal functioning of the immune system,9 suggesting that some genetic determi- nants of successful ageing might reside in those poly- morphisms for the immune system genes that regulate immune responses.5,10

Correspondence: Prof. C Caruso, Laboratorio di Immunopatologia, Dipart- imento di Biopatologia e Metodologie Biomediche, Corso Tukory 211,