Role of autophagy and lipid metabolism in organismal aging

自噬和脂质代谢在机体衰老中的作用

• 批准号: 8446999
• 负责人: Malene Hansen
• 金额: $ 35.9万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8446999
• 关键词: Ablation; Address; Adult; Affect; Age; Aging; Animals; Autophagocytosis; Biochemical; Biological Assay; Biological Process; Caenorhabditis elegans; Data; Defect; Deposition; Disease; Excision; Fatty acid glycerol esters; Fluorescence; Gene Silencing; Genes; Genetic; Germ Lines; Gonadal structure; Health; Hormonal; Human; Insulin; Insulin-Like Growth Factor I; Intestines; Knowledge; Laboratories; Life; Link; Lipase; Lipids; Lipolysis; Longevity; Malignant Neoplasms; Mammals; Measures; Mediating; Metabolism; Modeling; Molecular; Mus; Mutation; Nematoda; Nuclear Hormone Receptors; Nutrient; Obesity; Oocytes; Organism; Pathway interactions; Play; Population; Positioning Attribute; Process; Public Health; RNA Interference; Recycling; Regulation; Reporter; Reporter Genes; Reporting; Reproductive system; Research; Role; Science; Signal Transduction; Societies; Stem cells; Stress; Subcutaneous Tissue; Testing; Time; Tissues; Transgenic Organisms; Transmission Electron Microscopy; Work; age related; base; fly; gene function; glucagon-like peptide 1; innovation; insight; lipid metabolism; longevity gene; mutant; notch protein; novel; overexpression; public health relevance; receptor; response; therapy development; tissue processing; transcription factor; young adult

DESCRIPTION (provided by applicant): Autophagy is a key process by which cellular components are degraded and recycled, and this process plays important roles in several organismal responses, most recently in aging. For example, we and others have shown that autophagy is upregulated in several C. elegans mutants with extended longevity, including insulin/IGF-1 receptor daf-2 mutants. Intriguingly, such mutants require autophagy genes, e.g. bec-1/beclin 1, to live long (Melendez et al., Science, 2003, Hansen et al., PLoS Genetics, 2008). Removal of germline stem cells in C. elegans also extends lifespan, potentially in a conserved fashion as signals from the reproductive system can extend the lifespan of flies and mice. Germ line ablation can be mimicked genetically in C. elegans by mutation of the Notch receptor glp-1; accordingly, glp-1 mutants are long-lived. Interestingly, the intestine appears to play a key role in mediating the longevity response observed in germ line-less animals, possibly via hormonal signaling. While several genes with roles in hormonal signaling have been found to be required for glp-1 mutants to live long, the cellular mechanisms by which glp-1 mutations and/or signals from the gonad extend lifespan remains unclear. We have observed that autophagy is induced in glp-1 mutants, and our preliminary data indicate that genes that regulate autophagy are required for the extended longevity of glp-1 mutants. Interestingly, autophagy was recently linked to fat metabolism, and glp-1 mutants have increased fat levels. Moreover, a lipase has been reported to be required for glp-1 mutants to live long, suggesting an important role for nutrient partitioning in glp-1 animals. Importantly, our preliminary data indicate that autophagy genes are required for both the increase in fat seen in glp-1 mutants as well as the extended longevity observed in lipase-overexpressing animals, suggesting a novel role for autophagy in regulating fat metabolism and for the effects of lipolysis on C. elegans longevity. In this proposal, we propose to investigate the mechanisms by which autophagy is regulated in response to germ line removal. Specifically, we hypothesize that autophagy plays a role in mediating lifespan extension of glp-1 animals, at least in part by regulating fat metabolism. To this end, we will address three specific aims using genetic, cytological, and biochemical approaches in C. elegans: 1) assay in which tissues autophagy is induced and required for germline-mediated longevity, 2) test whether known longevity genes, including those involved in hormonal signaling in glp-1 mutants, regulate autophagy, and 3) determine how the processes of autophagy and fat metabolism are coordinately regulated in long-lived glp-1 mutants. Autophagy has been implicated in many disorders, including cancer, whereas deregulated fat metabolism results in obesity. Understanding the molecular mechanisms by which autophagy and fat metabolism are co- regulated in long-lived, germ line-less animals could provide important new insights into organismal aging and facilitate development of therapies for age-related diseases, including obesity.

描述（由申请人提供）：自噬是一个关键过程，通过将细胞成分降解和回收利用，并且该过程在几种有机体反应中起着重要作用，最近一次是在衰老中。例如，我们和其他人表明，自噬在具有延长寿命的几个秀丽隐杆线虫突变体中被上调，包括胰岛素/IGF-1受体DAF-2突变体。有趣的是，这种突变体需要自噬基因，例如BEC-1/BECLIN 1，长寿（Melendez等，Science，2003； Hansen等，PLOS Genetics，2008）。秀丽隐杆线虫中的种系干细胞的去除也可以延长寿命，可能以保守的方式延长寿命，因为生殖系统的信号可以延长苍蝇和小鼠的寿命。通过Notch受体GLP-1突变，可以在秀丽隐杆线虫中模仿遗传的生殖线消融。因此，GLP-1突变体是长寿的。有趣的是，肠道似乎在介导在无线动物中观察到的寿命反应（可能是通过激素信号传导）中起着关键作用。虽然已经发现几种在激素信号传导中具有作用的基因是GLP-1突变体长寿所必需的，但GONAD延伸寿命的GLP-1突变和/或信号的细胞机制仍不清楚。我们已经观察到自噬在GLP-1突变体中诱导，我们的初步数据表明，调节自噬的基因是GLP-1突变体的延长寿命所必需的。有趣的是，自噬最近与脂肪代谢有关，而GLP-1突变体的脂肪水平升高。此外，据报道，GLP-1突变体的寿命需要长时间，这表明在GLP-1动物中营养分配起着重要作用。重要的是，我们的初步数据表明，在GLP-1突变体中看到的脂肪增加以及在过表达脂肪酶的动物中观察到的延长寿命，这是必需的，这表明自噬在调节脂肪代谢中的新作用以及对脂肪分解对Elemans Longevity的影响的新作用。在此提案中，我们建议研究根据响应生殖系的去除来调节自噬的机制。具体而言，我们假设自噬在介导GLP-1动物的寿命延长中起作用，至少部分通过调节脂肪代谢。为此，我们将使用秀丽隐杆线虫中使用遗传，细胞学和生化方法来解决三个特定目标：1）诱导组织自噬的组织自动介导的寿命，2）测试已知的寿命基因是否参与GLP-1中的激素信号，以及调节自动化的过程，并确定如何调节自动化的效果。在长寿命的GLP-1突变体中协调调节。自噬已与许多疾病有关，包括癌症，而放松调节的脂肪代谢会导致肥胖。了解自噬和脂肪代谢在长期生存的无线动物中共同调节的分子机制可以为有机体衰老提供重要的新见解，并促进与年龄相关疾病（包括肥胖）的疗法开发。