Role of autophagy and lipid metabolism in organismal aging

描述(由申请人提供)：自噬是细胞成分降解和循环的关键过程，这个过程在几种生物反应中发挥着重要作用，最近的一次是在衰老过程中。例如，我们和其他人已经证明，自噬在几个延长寿命的线虫突变体中上调，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，才能长寿(Melendez等人，Science，2003，Hansen等人，PLoS Genetics，2008)。移除线虫中的生殖系干细胞也可以延长寿命，可能是以一种保守的方式，因为来自生殖系统的信号可以延长苍蝇和老鼠的寿命。线虫生殖系的消融可以通过Notch受体GLP-1的突变在遗传上模拟；因此，GLP-1突变体是长寿的。有趣的是，肠道似乎在调节在无生殖系动物身上观察到的长寿反应方面发挥了关键作用，可能是通过激素信号。虽然已发现一些与激素信号有关的基因是GLP-1突变体长寿所必需的，但GLP-1突变和/或来自性腺的信号延长寿命的细胞机制尚不清楚。我们已经观察到在GLP-1突变体中诱导了自噬，我们的初步数据表明，调节自噬的基因是GLP-1突变体延长寿命所必需的。有趣的是，自噬最近与脂肪新陈代谢有关，而GLP-1突变增加了脂肪水平。此外，据报道，脂肪酶是GLP-1突变体长寿所必需的，这表明在GLP-1动物的营养分配中起着重要作用。重要的是，我们的初步数据表明，在GLP-1突变体中观察到的脂肪增加以及在脂肪酶过度表达的动物中观察到的延长寿命都需要自噬基因，这表明自噬在调节脂肪代谢和脂肪分解对线虫寿命的影响中发挥了新的作用。在这项建议中，我们建议调查自噬的调节机制，以响应生殖细胞系的移除。具体地说，我们假设自噬在调节GLP-1动物寿命方面发挥了作用，至少部分是通过调节脂肪代谢。为此，我们将利用遗传学、细胞学和生化方法在线虫中解决三个特定目标：1)诱导组织自噬并为生殖系介导的长寿所需的检测；2)测试已知的长寿基因，包括那些参与GLP-1突变体中的激素信号的基因是否调节自噬；以及3)确定长寿GLP-1突变体中自噬和脂肪代谢过程是如何协调调节的。自噬与许多疾病有关，包括癌症，而不受控制的脂肪代谢会导致肥胖。了解自噬和脂肪代谢在长寿、无生殖系动物中共同调节的分子机制，可以为生物衰老提供重要的新见解，并促进包括肥胖在内的与年龄相关的疾病的治疗方法的开发。 公共卫生相关性：人类人口正在迅速老龄化，与年龄有关的疾病构成了我们社会的一个主要健康问题；然而，人们对老龄化和与年龄有关的疾病的遗传基础知之甚少。这项研究旨在通过检测自噬、新陈代谢和在没有种系干细胞的线虫中观察到的延长寿命之间的联系来探索自噬在衰老中的作用。自噬是细胞质成分循环的一种细胞途径。这项拟议的研究与公共卫生相关，因为要研究的机制是进化保守的，研究结果可能最终会提供治疗衰老相关疾病的方法。

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. PUBLIC HEALTH RELEVANCE: The human population is rapidly aging and age-related diseases constitute a major health issue in our society; however, the genetic basis of aging and age-related diseases is poorly understood. This study aims to explore the role of autophagy - a cellular pathway by which cytoplasmic components are recycled - in aging by examining links between autophagy, metabolism, and the extended longevity observed in nematodes with no germline stem cells. The proposed research has relevance to public health, because the mechanisms to be investigated are evolutionary conserved and the findings might ultimately provide therapies to treat aging-related diseases.