Signals from the reproductive system that regulate aging in C. elegans

描述（申请人提供）：1999年，我们发现去除C.线虫的生殖细胞延长了整个动物的寿命。这种生命的延长需要体细胞生殖组织的存在，所以，本质上，一个空的性腺延长了生命。这条可能在进化上保守的途径在生物学上是迷人的，因为它似乎协调了两个关键的生命史特征，衰老和繁殖。该系统涉及保守的蛋白质，这些蛋白质在新的、知之甚少的组织间信号传导途径中起作用：生殖信号被发送到肠道（C。elegans的整个内胚层），其反过来处理这些信号以激活延长生命的转录因子。了解这种长寿途径的运作方式最终可能为改善人类健康和长寿提供新的切入点。在这里，我们建立在我们以前的研究结果，以解决有关这一途径的关键未回答的问题。首先，我们的研究表明，生殖系统有两条信号通路。第一个是类固醇激素途径，允许体细胞生殖组织与肠道沟通。然而，我们发现，生殖细胞的损失激活几个基本的生命延长事件独立的体细胞生殖组织。在这项研究中，我们将确定生殖系本身产生了什么信号来影响寿命。其次，我们发现当生殖细胞消失时，肠道中活性氧（ROS）的水平会增加。这种活性氧是延长生命所必需的，至少部分是通过激活SKN-1/Nrf 2抗氧化剂/异生素反应调节剂。在这个项目中，我们将确定当种系消失时刺激ROS产生和SKN-1活性的途径。第三，生殖细胞系丧失所产生的寿命延长需要保守的转录因子fos- 16/FOXO。这种β-16-活化途径不同于在胰岛素/IGF-1途径突变体中活化β-16的途径。在这项研究中，我们将了解新的β-16激活蛋白如何在功能和物理上相互作用。这些研究将为这个迷人的生命延长系统带来机械的洞察力。

DESCRIPTION (provided by applicant): In 1999, we discovered that removing C. elegans' germ cells extends the lifespan of the whole animal. This life extension requires the presence of the somatic reproductive tissues, so, essentially, an empty gonad extends life. This pathway, which may be conserved evolutionarily, is fascinating biologically, as it appears to coordinate two key life-history traits, aging and reproduction. This system involves conserved proteins that act in new, poorly understood, tissue-to-tissue signaling pathways: Reproductive signals are sent to the intestine (C. elegans' entire endoderm), which in turn processes these signals to activate life-extending transcription factors. Learning how this longevity pathway operates could ultimately suggest new entry points for improving human health and longevity. Here, we build upon our previous findings to address key unanswered questions about this pathway. First, our studies have shown that there are two signaling pathways from the reproductive system. The first, a steroid-hormone pathway, allows the somatic reproductive tissues to communicate with the intestine. However, we find that loss of the germ cells activates several essential life-extending events independently of the somatic reproductive tissues. In this study, we will determine what signals are produced by the germ line itself to influence lifespan. Second, we find that when the germ line is gone, the level of reactive oxygen species (ROS) increases in the intestine. This ROS is required for life extension, at least in part by activating the SKN-1/Nrf2 antioxidant/xenobiotic response regulator. In this project, we will identify pathways that stimulat ROS production and SKN-1 activity in the intestine when the germ line is gone. Third, the life extension produced by germ line loss requires the conserved transcription factor DAF- 16/FOXO. This DAF-16-activation pathway is distinct from the pathway that activates DAF-16 in insulin/IGF-1 pathway mutants. In this study, we will learn how new DAF-16-activating proteins interact functionally and physically with one another. Together these studies will bring mechanistic insight to this fascinating life-extension system.