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

项目摘要 衰老和繁殖是生命史的核心方面。我们发现，在C。elegans，信号来自 生殖系统调节寿命。当生殖细胞被移除时， 大约百分之六十。这种调节可能是进化上保守的，因为生殖干细胞去除 也能延长寿命。生殖组织对衰老的控制可能为人类提供了一种途径， 使动物的衰老速度与繁殖时间相协调。 In C.在线虫中，来自生殖系统的信号通过控制FOXO家族影响寿命 转录因子Ⅶ-16。已知当水平升高时，β-16/FOXO依赖性转录被刺激。 胰岛素/IGF-1激素信号的减少，但当胰岛素分泌时，刺激β-16活性所需的基因 当胰岛素/IGF-1信号传导减少时，不需要去除生殖细胞来刺激β-16。因此，我们认为， 从本质上讲，我们正在研究一种新的信号通路，它将有关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，生殖细胞的损失会引发另一种组织（肠道）的分子反应， 包括GOS-16/FOXO的核定位和gos-1表达的增加，gos-1编码 另一个转录因子(In C.在线虫中，肠表现为整个内胚层，包括 脂肪组织）。延长寿命需要GOS-16和GOS-1， 缺乏生殖细胞的动物的基因表达模式。我们已经确定了几个基因，包括 Wnt信号通路的组分，其允许生殖系统控制β-16和GOS-1， 我们已经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，我们将询问在肠道中发生了什么事件。 肠导致EST-16和GOS-1刺激新的基因表达模式。太令人兴奋了， 因为在分子水平上充分了解这个系统可能会提出人工激活的方法 在人类中保存的长寿机制，具有巨大的健康和长寿益处。

Project Summary 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.