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

来自调节线虫衰老的生殖系统信号

• 批准号: 8049042
• 负责人: CYNTHIA J. KENYON
• 金额: $ 29.23万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049042
• 关键词: Adaptor Signaling Protein; Adipose tissue; Adult; Affect; Aging; Animals; Biochemical; Caenorhabditis elegans; Candidate Disease Gene; Cell Nucleus; Complex; Disease; Endoderm; Event; Excision; Family; Gastrointestinal tract structure; Gene Expression; Genes; Genetic Transcription; Germ Cells; Germ Lines; Goals; Gonadal structure; Grant; Health; Hormones; Human; Insulin; Insulin-Like Growth Factor I; Intestines; Laboratories; Lasers; Learning; Life; Longevity; Longevity Pathway; Mediating; Molecular; Molecular Genetics; Mutation; Nematoda; Nuclear; Pathway interactions; Pattern; Play; Proteins; Regulation; Reproduction; Reproductive system; Resistance; Role; Signal Pathway; Signal Transduction; Stem cells; System; Testing; Time; Tissues; Up-Regulation; age related; combat; fascinate; fly; hatching; life history; precursor cell; protein complex; reproductive; response; tool; transcription factor

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.

描述（由申请人提供）：衰老和繁殖是生命史的中心方面。我们发现秀丽隐杆线虫是由生殖系统发出的信号来调节寿命的。当生殖细胞被移除时，寿命增加了大约60%。这种调节可能是进化保守的，因为生殖系干细胞的移除也延长了果蝇的寿命。生殖组织对衰老的控制可能为动物提供了一种使其衰老速度与繁殖时间相协调的方法。在秀丽隐杆线虫中，来自生殖系统的信号通过控制foxo家族转录因子DAF-16影响寿命。众所周知，当胰岛素/IGF-1激素信号水平降低时，DAF-16/ foxo依赖性转录受到刺激，但当胰岛素/IGF-1信号水平降低时，刺激DAF-16活性所需的基因并不需要刺激DAF-16。因此，从本质上讲，我们正在研究一种新的信号通路，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，生殖细胞的丢失会引发另一种组织的分子反应，即肠道，其中包括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。（在秀丽隐杆线虫中，肠道表现为包括脂肪组织在内的整个内胚层。）DAF-16和GOS-1都是延长寿命所必需的，在缺乏生殖细胞的动物中，它们都是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，这些基因允许生殖系统控制DAF-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信号是否将生殖系统的信息传递到肠道，我们将询问肠道中发生什么事件导致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，可能会提出人工激活人类保守的长寿机制的方法，对健康和长寿有很大的好处。公共卫生相关性：延长寿命的突变也赋予对年龄相关疾病的抵抗力。我们发现秀丽隐杆线虫（一种简单的蛔虫）的生殖系统通过向核心的、进化保守的长寿途径发送信号来影响寿命。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。我们建议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，并对抗与年龄有关的疾病。