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，C。秀丽线虫对寿命有深远的影响。这很有趣，因为衰老和繁殖之间的联系是生命史的核心。当生殖细胞被移除时，寿命延长约60%。因此，生殖细胞以某种方式缩短了寿命。相反，体细胞生殖组织延长寿命，因为如果它们在缺乏生殖系的动物中被移除，寿命不会延长。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。一个亲脂激素信号通路触发了肠道内延长寿命的转录因子α-16/FOXO的核定位。第二个尚未确定的途径上调了肠道中一种新的必需转录因子。凯尼恩实验室发现，体细胞生殖组织是必需的，以激活一些，但不是所有的靶基因，它已经确定了几个基因，可能需要这种体细胞性腺活动。自噬、microRNA加工、先天免疫和受调节的蛋白质水解似乎都在这个延长寿命的系统中发挥作用，其他信号蛋白和转录因子也是如此。在此资助期间，凯尼恩实验室将使用遗传学，激光显微手术和分子方法来研究这些和新基因如何在分子水平上发挥作用，以执行和协调生殖细胞被移除时的寿命延长。当生殖组织在长寿的胰岛素/IGF-1途径突变体中受到干扰时，动物保持健康和活力，寿命是正常的六倍。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如何产生巨大差异的问题。在长寿胰岛素/IGF-1通路突变体中上调的相同基因是否进一步受到刺激，或者新基因是否被激活？自然界中不同的物种是如何进化出寿命上的显著差异的，这是一个深刻而基本的问题。这项研究发生在一个单一的、遗传上易处理的物种中，它提供了一个极好的机会来确定可以产生寿命极端差异的机制。

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