Lio D, Scola L, Crivello A, Colonna-Romano G, Candore G, Bonafè M, Cavallone L, Franceschi C, Caruso C
Dipartimento di Biopatologia e Metodologie Biomediche, Università di Palermo, Palermo, Italy.
Genes Immun. 2002 Feb;3(1):30-3. doi: 10.1038/sj.gene.6363827.
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' 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 (>99 years old, 159 women and 31 men) and in 260 <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 gene biallelic polymorphisms by sequence specific probes. -1082G homozygous genotype was increased in centenarian men (P < 0.025) but not in centenarian women. No difference was found between centenarians and control subjects regarding 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-gamma), this finding points out that that gender is a major variable in the genetics of longevity, suggesting that men and women follow different strategies to reach longevity. Concerning the biological significance of this association, we have not searched for 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-gamma genes suggest that 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.
衰老的特征是促炎状态,这可能导致主要的年龄相关性疾病的发生。因此,促炎或抗炎细胞因子的基因变异可能会影响成功衰老和长寿。白细胞介素-10(IL-10)是一个合适的候选因子,因为它对促炎功能具有强大的抑制作用。IL-10的产生受位于1q32位点的IL-10基因5'侧翼区域的几个多态性元件控制,涉及两个微卫星区域的等位基因以及启动子区域的几个多态性。我们对190名意大利百岁老人(>99岁,159名女性和31名男性)和260名<60岁的对照受试者(99名女性和161名男性)进行了分析,这些受试者在地理分布上相匹配,通过序列特异性探针分析了IL-10近端启动子基因双等位基因多态性-1082G→A、-819C→T和-592C→A的基因型频率。百岁男性中-1082G纯合基因型增加(P<0.025),但百岁女性中没有增加。在百岁老人和对照受试者之间,关于其他两个多态性未发现差异。-1082GG基因型的存在被认为与IL-10的高产生有关,它显著增加了男性达到人类寿命极限的可能性。连同先前关于其他多态性位点(酪氨酸羟化酶、线粒体DNA、IL-6、血色素沉着症、干扰素-γ)的数据,这一发现指出性别是长寿遗传学中的一个主要变量,表明男性和女性遵循不同的策略来实现长寿。关于这种关联的生物学意义,我们尚未寻找IL-10参与的功能证据。因此,我们应该得出结论,我们的数据仅表明1q32基因组区域上的一个标记可能参与人类的成功衰老。然而,最近关于IL-6和干扰素-γ基因的数据表明,长寿与编码促炎特征的基因型呈负相关。因此,有趣的是,被认为与IL-10高产生有关的-1082G基因型在百岁老人中的比例显著增加。