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

描述（由申请人提供）：1999年，我们发现去除秀丽隐杆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，所以，从本质上讲，一个空的性腺可以延长寿命。这条途径可能在进化上是保守的，但在生物学上是迷人的，因为它似乎协调了两个关键的生活史特征，衰老和繁殖。这个系统涉及保守的蛋白质，这些蛋白质在新的、尚不清楚的、组织到组织的信号传导途径中起作用：生殖信号被发送到肠道（秀丽隐杆线虫的整个内胚层），后者反过来处理这些信号以激活延长生命的转录因子。了解这种长寿途径是如何运作的，最终可以为改善人类健康和长寿提供新的切入点。在这里，我们建立在我们之前的研究结果的基础上，以解决关于这一途径的关键未解问题。首先，我们的研究表明生殖系统有两条信号通路。第一种是类固醇激素通路，它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丧失激活了几个独立于体细胞生殖组织的基本生命延长事件。在这项研究中，我们将确定生殖系本身产生的哪些信号会影响寿命。其次，我们发现当种系消失时，肠道中的活性氧（ROS）水平增加。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/异种反应调节因子来实现的。在这个项目中，我们将确定当种系消失时，肠道中刺激ROS产生和SKN-1活性的途径。第三，生殖系丧失产生的生命延长需要保守转录因子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.