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再循环的关键过程，这一过程在几种生物体反应中起着重要作用，最近在衰老中起作用。例如，我们和其他人已经证明，在一些长寿的秀丽隐杆线虫突变体中，自噬被上调，包括胰岛素/IGF-1受体daf-2突变体。有趣的是，这些突变体需要自噬基因，如beclin -1/beclin -1才能存活（Melendez等人，Science, 2003； Hansen等人，PLoS Genetics, 2008）。去除秀丽隐杆线虫的生殖系干细胞也可以延长寿命，可能是一种保守的方式，因为来自生殖系统的信号可以延长苍蝇和老鼠的寿命。秀丽隐杆线虫可以通过Notch受体glp-1的突变来模拟种系消融；因此，glp-1突变体寿命较长。有趣的是，肠道似乎在无生殖系动物的长寿反应中发挥了关键作用，可能是通过激素信号传导。虽然已经发现glp-1突变体长寿需要几个参与激素信号传导的基因，但glp-1突变和/或性腺信号延长寿命的细胞机制尚不清楚。我们观察到glp-1突变体诱导自噬，我们的初步数据表明，调节自噬的基因是延长glp-1突变体寿命所必需的。有趣的是，自噬最近与脂肪代谢有关，glp-1突变体增加了脂肪水平。此外，据报道，glp-1突变体长寿需要一种脂肪酶，这表明glp-1动物的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突变体中发现的脂肪增加以及在脂酶过表达动物中观察到的寿命延长都需要自噬基因，这表明自噬在调节脂肪代谢和脂肪分解对秀丽隐杆线虫寿命的影响中发挥了新的作用。在这一建议中，我们建议研究自噬在种系去除反应中受到调节的机制。具体来说，我们假设自噬在调节glp-1动物的寿命延长中发挥作用，至少部分是通过调节脂肪代谢。为此，我们将利用遗传学、细胞学和生化方法来解决线虫的三个具体目标：1)测定组织自噬是如何诱导的，并且是种系介导的长寿所必需的；2)测试已知的长寿基因（包括glp-1突变体中涉及激素信号的基因）是否调节自噬；3)确定长寿命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，而脂肪代谢失调导致肥胖。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，可以为生物体衰老提供重要的新见解，并促进治疗年龄相关疾病（包括肥胖）的开发。

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.