Lifespan regulation by the DAF-12 nuclear hormone receptor in C. elegans

描述（由申请人提供）：几年前，凯尼恩实验室发现秀丽隐杆线虫的生殖组织深刻地影响寿命。这很有趣，因为衰老和繁殖之间的联系是生命史的核心。当种系被移除时，寿命延长~60%。因此，生殖系缩短了寿命。相反，体细胞生殖组织可以延长寿命，因为如果在缺乏生殖系的动物身上去除体细胞生殖组织，就不会延长寿命。最近，凯尼恩实验室发现，从生殖系统到肠道（也是动物的脂肪组织）的信号是延长寿命所必需的。亲脂激素信号通路触发DAF-16/FOXO（一种延长寿命的转录因子）在肠道内的核定位。第二种尚未定义的途径是上调肠道中一种新的必需转录因子。凯尼恩实验室已经发现，DAF-16需要体细胞生殖组织来激活一些但不是所有的靶基因，并且已经确定了几个可能需要这种体性腺活性的基因。自噬、microRNA加工、先天免疫和受调节的蛋白质水解，以及其他信号蛋白和转录因子，似乎都在这个延长寿命的系统中发挥作用。在此资助期间，凯尼恩实验室将使用遗传学、激光显微外科和分子方法来研究这些和新的基因如何在分子水平上发挥作用，在生殖细胞被移除时执行和协调延长寿命。当长寿命的胰岛素/IGF-1通路突变体的生殖组织受到干扰时，这些动物保持健康和活力，寿命是正常动物的六倍。这种惊人的寿命延长提供了一个极好的机会，利用遗传学和分子生物学来解决寿命差异是如何产生的问题。在长期存活的胰岛素/ igf -1通路突变体中上调的相同基因是否进一步受到刺激，还是新的基因被激活？自然界中不同的物种是如何进化出惊人的寿命差异的，这是一个深刻而根本的问题。这项研究是在一个单一的、遗传上容易处理的物种中进行的，它为确定导致寿命极端差异的机制提供了一个绝佳的机会

DESCRIPTION (provided by applicant): Several years ago, the Kenyon lab discovered that the reproductive tissues of C. elegans profoundly affect lifespan. This is intriguing, as the link between aging and reproduction is central to life history. When the germline is removed, lifespan is extended ~60%. Thus somehow the germline shortens lifespan. Conversely, the somatic reproductive tissues extend lifespan, because if they are removed in animals lacking a germline, no lifespan extension occurs. Recently, the Kenyon lab discovered that signaling from the reproductive system to the intestine, which is also the animal's adipose tissue, is required for lifespan extension. A lipophilic-hormone signaling pathway triggers the nuclear localization of DAF-16/FOXO, a lifespan-extending transcription factor, within the intestine. A second, yet undefined, pathway up-regulates a new, essential transcription factor in the intestine. The Kenyon lab has found that the somatic reproductive tissues are required for DAF-16 to activate some but not all of its target genes, and it has identified several genes that may be required for this somatic-gonad activity. Autophagy, microRNA processing, innate immunity and regulated proteolysis all appear to play a role in this lifespan-extending system, as do additional signaling proteins and transcription factors. During this funding period, the Kenyon lab will use genetics, laser microsurgery and molecular approaches to investigate how these and new genes act at the molecular level to execute and coordinate an extension in lifespan when the germline is removed. When the reproductive tissues are perturbed in long-lived insulin/IGF-1 -pathway mutants, the animals remain healthy and vigorous and live six times as long as normal. This spectacular lifespan extension provides a wonderful opportunity to address, using genetics and molecular biology, the question of how dramatic differences in lifespan can be produced. Are the same genes that are up-regulated in the long-lived insulin/IGF-1-pathway mutants further stimulated, or are new genes activated? How different species in nature evolved striking differences in lifespan is a profound and fundamental question. This study, which takes place within a single, genetically-tractable, species, provides a fantastic opportunity to identify mechanisms that can produce extreme differences in lifespan