Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
PLoS One. 2009 Dec 14;4(12):e8210. doi: 10.1371/journal.pone.0008210.
The strong familiality of living to extreme ages suggests that human longevity is genetically regulated. The majority of genes found thus far to be associated with longevity primarily function in lipoprotein metabolism and insulin/IGF-1 signaling. There are likely many more genetic modifiers of human longevity that remain to be discovered.
METHODOLOGY/PRINCIPAL FINDINGS: Here, we first show that 18 single nucleotide polymorphisms (SNPs) in the RNA editing genes ADARB1 and ADARB2 are associated with extreme old age in a U.S. based study of centenarians, the New England Centenarian Study. We describe replications of these findings in three independently conducted centenarian studies with different genetic backgrounds (Italian, Ashkenazi Jewish and Japanese) that collectively support an association of ADARB1 and ADARB2 with longevity. Some SNPs in ADARB2 replicate consistently in the four populations and suggest a strong effect that is independent of the different genetic backgrounds and environments. To evaluate the functional association of these genes with lifespan, we demonstrate that inactivation of their orthologues adr-1 and adr-2 in C. elegans reduces median survival by 50%. We further demonstrate that inactivation of the argonaute gene, rde-1, a critical regulator of RNA interference, completely restores lifespan to normal levels in the context of adr-1 and adr-2 loss of function.
CONCLUSIONS/SIGNIFICANCE: Our results suggest that RNA editors may be an important regulator of aging in humans and that, when evaluated in C. elegans, this pathway may interact with the RNA interference machinery to regulate lifespan.
长寿的强烈家族性表明人类的长寿是受遗传调控的。迄今为止，大多数与长寿相关的基因主要在脂蛋白代谢和胰岛素/IGF-1 信号通路中发挥作用。很可能还有许多其他遗传修饰因子有待发现。
方法/主要发现：首先，我们在美国百岁老人研究——新英格兰百岁老人研究中发现，RNA 编辑基因 ADARB1 和 ADARB2 中的 18 个单核苷酸多态性（SNP）与超高龄有关。我们描述了在具有不同遗传背景（意大利、阿什肯纳兹犹太人和日本人）的三个独立进行的百岁老人研究中对这些发现的复制，这些研究共同支持 ADARB1 和 ADARB2 与长寿有关。ADARB2 中的一些 SNP 在四个群体中一致复制，表明这种强效应独立于不同的遗传背景和环境。为了评估这些基因与寿命的功能关联，我们证明了秀丽隐杆线虫中它们的同源物 adr-1 和 adr-2 的失活使中位生存期缩短了 50%。我们进一步证明，在 adr-1 和 adr-2 功能丧失的情况下，Argonaute 基因 rde-1 的失活可完全将寿命恢复到正常水平，Argonaute 基因 rde-1 是 RNA 干扰的关键调节因子。
结论/意义：我们的结果表明，RNA 编辑可能是人类衰老的一个重要调节因子，并且在秀丽隐杆线虫中进行评估时，该途径可能与 RNA 干扰机制相互作用以调节寿命。
