The nuclear hormone receptor DAF-12 has opposing effects on Caenorhabditis elegans lifespan and regulates genes repressed in multiple long-lived worms
The nuclear hormone receptor DAF-12 has opposing effects on Caenorhabditis elegans lifespan and regulates genes repressed in multiple long-lived worms
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DOI：
10.1111/j.1474-9726.2006.00203.x
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发表时间：
2006-04-01
期刊：
影响因子：
7.8
通讯作者：
Lithgow, GJ
中科院分区：
文献类型：
--
作者：
Fisher, AL;Lithgow, GJ
秀丽隐杆线虫中的孤儿核激素受体基因DAF-12在调节成人寿命的发展和确定成人寿命方面起着关键作用。为了了解DAF-12对衰老的影响，我们表征了功能丧失和功能障碍DAF-12等位基因的寿命，这些寿命是根据其对Dauer发育的影响所识别的。我们发现，这些突变对寿命和对氧化和热应激的抗性具有相反的影响，这使DAF-12成为第一个可以延长或缩短寿命的等位基因的基因。我们发现，功能丧失突变的寿命缩短是由于成年时期的加速衰老而不是突变对发育的不利影响。携带两个等位基因的蠕虫的微阵列分析表明，在两种基因型之间表达了相对较少的基因。比较表达曲线与与Dauer形成和长期寿命DAF-2突变体相关的曲线的比较表明，尽管剖面很大不同，但在所有剖面中，基因下调但并非上调的基因之间存在显着的重叠。这些基因中的几个在多个长寿命中下调的基因对寿命具有已知影响，许多基因属于一个特征差的基因家族，这些基因在Dauers，Daf-2突变体和长期存在的基因中强烈下调DAF-12突变体。我们的结果表明，DAF-12通过抑制特定基因来调节衰老和压力反应，并强调了抑制基因在寿命确定中抑制最大寿命的作用。
The orphan nuclear hormone receptor gene daf-12 in Caenorhabditis elegans plays a key role in the regulation of development and determination of adult longevity. To understand the effects of daf-12 on aging we characterized the lifespan of loss-of-function and gain-of-function daf-12 alleles that have been identified on the basis of their effects on dauer development. We find that these mutations have opposing effects on longevity and resistance to oxidative and thermal stress which makes daf-12 the first gene with alleles that can extend or shorten lifespan. We find that the shortened lifespan of the loss-of-function mutation is due to accelerated aging in young adulthood rather than an adverse effect of the mutation on development. Microarray analysis of worms carrying the two alleles revealed a relatively small number of genes differentially expressed between the two genotypes. Comparison of the expression profiles with the profiles associated with dauer formation and long-lived daf-2 mutants revealed that while the profiles are largely different, there is significant overlap among the genes down-regulated, but not up-regulated, in all profiles. Several of these genes down-regulated in multiple long-lived worms have known effects on lifespan, and many of the genes belong to a family of poorly characterized genes that are strongly down-regulated in dauers, daf-2 mutants, and long-lived daf-12 mutants. Our results point to daf-12 modulating aging and stress responses in part through the repression of specific genes, and emphasize the role that the repression of genes that curtail maximal lifespan plays in lifespan determination.