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

描述(申请人提供)：衰老和生殖是生活史的中心方面。我们发现，在线虫体内，生殖系统发出的信号调节寿命。当生殖细胞被移除时，寿命增加了大约60%。这种调节在进化上可能是保守的，因为去除果蝇生殖系干细胞也可以延长寿命。生殖组织对衰老的控制可能为动物提供了一种协调其衰老速度和生殖时机的方法。在线虫中，来自生殖系统的信号通过控制FOXO家族转录因子DAF-16来影响寿命。已知当胰岛素/胰岛素样生长因子-1信号水平降低时，依赖于DAF-16/FOXO的转录被刺激，但当胰岛素/胰岛素样生长因子-1信号水平降低时，不需要在去除生殖系时刺激DAF-16‘S活性所需的基因来刺激DAF-16。因此，从本质上说，我们正在研究一种新的信号通路，它将生殖状态的信息传递给进化保守的核心长寿机制。我们已经了解到，生殖细胞的丢失在另一种组织，即肠道中触发了一种分子反应，包括DAF-16/FOXO的核定位和编码另一种转录因子的GOS-1的表达增加。(在线虫中，肠道的作用类似于整个内胚层，包括脂肪组织。)DAF-16和GOS-1都是延长寿命所必需的，也是缺乏生殖细胞的动物新的基因表达模式所必需的。我们已经确定了几个基因，包括Wnt信号通路的组成部分，允许生殖系统控制DAF-16和GOS-1，并开发了强大的工具来分析它们。使用这些工具，我们将询问Wnt信号是否将有关生殖系统的信息传递到肠道，我们还将询问肠道中发生了什么事件，导致DAF-16和GOS-1刺激新的基因表达模式。这是令人兴奋的，因为在分子水平上很好地理解这个系统可能会提出人为激活人类保守的长寿机制的方法，从而带来巨大的健康和长寿好处。与公共卫生相关：延长寿命的突变也使人对与年龄有关的疾病产生抵抗力。我们已经发现，线虫的生殖系统是一种简单的蛔虫，通过向进化保守的核心长寿途径发出信号来影响寿命。我们已经确定了将信息从生殖组织传递到这些保守途径的新基因。我们打算了解生殖系统的信号如何影响寿命，希望找到新的方法来增加人类的年轻和健康，并与年龄相关的疾病作斗争。

DESCRIPTION (provided by applicant): Aging and reproduction are central aspects of life history. We have found that in C. elegans, signals from the reproductive system regulate lifespan. When the germ cells are removed, lifespan is increased approximately sixty percent. This regulation may be evolutionarily conserved, as germline-stem cell removal in flies also extends lifespan. It is possible that the control of aging by reproductive tissues provides a way for the animal to coordinate its rate of aging with its timing of reproduction. In C. elegans, signals from the reproductive system affect lifespan by controlling the FOXO-family transcription factor DAF-16. DAF-16/FOXO-dependent transcription is known to be stimulated when the level of insulin/IGF-1 hormone signaling is reduced, but the genes needed to stimulate DAF-16's activity when the germline is removed are not needed to stimulate DAF-16 when insulin/IGF-1 signaling is reduced. Therefore, in essence, we are studying a new signaling pathway that conveys information about reproductive status to evolutionarily-conserved, core longevity mechanisms. We have learned that germ-cell loss triggers a molecular response in another tissue, the intestine, which includes the nuclear localization of DAF-16/FOXO and increased expression of gos-1, which encodes another transcription factor. (In C. elegans, the intestine behaves as the entire endoderm, including the adipose tissue.). Both DAF-16 and GOS-1 are required for lifespan extension, and both are required for new patterns of gene expression in animals that lack germ cells. We have identified several genes, including components of a Wnt signaling pathway, that allow the reproductive system to control DAF-16 and GOS-1, and we have developed powerful tools for their analysis. Using these tools, we will ask whether a Wnt signal conveys information about the reproductive system to the intestine, and we will ask what events occur in the intestine to cause DAF-16 and GOS-1 to stimulate new patterns of gene expression. This is exciting, because understanding this system well at the molecular level may suggest ways to artificially activate conserved longevity mechanisms in humans, with great health and longevity benefits. PUBLIC HEALTH RELEVANCE: Mutations that increase lifespan also confer resistance to age-related disease. We have found that the reproductive system of C. elegans, a simple roundworm, influences lifespan by signaling to core, evolutionarily-conserved longevity pathways. We have identified new genes that convey information from the reproductive tissues to these conserved pathways. We propose to learn how signals from the reproductive system influence lifespan, in hopes of finding new ways to increase youthfulness and health, and to combat age-related disease, in humans.