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

描述(申请人提供)：1999年，我们发现去除线虫的生殖细胞可以延长整个动物的寿命。这种寿命的延长需要体细胞生殖组织的存在，因此，从本质上讲，一个空的性腺可以延长寿命。这条可能在进化上保守的途径，在生物学上是令人着迷的，因为它似乎协调了两个关键的生活史特征，即衰老和繁殖。这个系统涉及保守的蛋白质，这些蛋白质作用于新的、鲜为人知的组织到组织的信号通路：生殖信号被发送到肠道(线虫的整个内胚层)，肠道反过来处理这些信号以激活延长生命的转录因子。了解这条长寿途径是如何运作的，最终可能会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发现的基础上，解决关于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。第一个途径是类固醇-荷尔蒙途径，它允许躯体生殖组织与肠道进行交流。然而，我们发现生殖细胞的丧失激活了几个基本的延长生命的事件，而不是依赖于体细胞生殖组织。在这项研究中，我们将确定由生殖系本身产生的影响寿命的信号。其次，我们发现，当胚系消失时，肠道中的活性氧物种(ROS)水平会增加。这种ROS是延长生命所必需的，至少部分是通过激活SKN-1/Nrf2抗氧化剂/异种生物反应调节因子来实现的。在这个项目中，我们将确定当生殖系消失时，刺激肠道中ROS产生和SKN-1活性的途径。第三，生殖系丧失所产生的寿命延长需要保守的转录因子DAF-16/FOXO。这种DAF-16激活途径不同于胰岛素/IGF-1途径突变体中激活DAF-16的途径。在这项研究中，我们将了解新的DAF-16激活蛋白如何在功能和物理上相互作用。总之，这些研究将为这一迷人的寿命延长系统带来机械性的洞察力。

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.