Roles of Lipid Metabolism in Regulation of Longevity

描述（由申请人提供）：脂质代谢在人类健康和寿命中起着关键作用。脂质代谢失调与许多与年龄有关的疾病有关。对无脊椎动物和脊椎动物的遗传研究表明，脂肪组织的内分泌功能与动物寿命的调节有关。然而，它仍然知之甚少脂质代谢是如何耦合到寿命控制。初步研究表明，脂肪酶和脂质伴侣对C.优雅脂肪酶和脂质伴侣在长寿动物中上调，并且是长寿所必需的。它们的功能也是野生型和长寿突变体脂肪动员的关键。脂肪储存组织中脂肪酶K04A8.5的过表达促进脂肪分解以及长寿。这些研究提示了衰老过程中脂质代谢的新机制。本研究拟通过以下几个方面来探讨脂质代谢在长寿调节中的作用：1）研究脂肪酶过表达延长寿命的机制。2)描述脂质伴侣在寿命调节中的作用。3)识别延长寿命的脂质信使。我们将应用遗传技术来探测脂肪酶、脂质伴侣和已知的寿命调节信号之间的遗传相互作用，并筛选上游调节因子。此外，我们将采用生物化学和蛋白质组学方法来研究脂质伴侣复合物和脂质组学方法，目的是确定特定的脂质种类和人类代谢产物作为衰老的关键调节因子。长期目标是探索如何通过调节脂质代谢促进健康衰老。这些研究将深入了解脂质代谢影响衰老过程的机制，并提供新的治疗靶点。这份申请描述了一个综合性的计划，这将有助于我过渡到一个独立的位置在一个学术机构。 公共卫生相关性：这项研究的结果对公共卫生很重要，因为随着年龄的增长，疾病的发病率会增加。这项研究将提供深入了解脂质代谢在调节寿命中的重要作用，以及解决脂质代谢和能量稳态中的许多基本问题。

DESCRIPTION (provided by applicant): Lipid metabolism plays a key role in human health and longevity. Dysregulation of lipid metabolism has been implicated in many age-related diseases. Genetic studies in both invertebrates and vertebrates have implicated the endocrine functions of adipose tissue in regulation of animal lifespan. However, it remains poorly understood how lipid metabolism is coupled to lifespan control. Preliminary studies have suggested that lipases and lipid chaperones exert exquisite control over lipid metabolism and lifespan in C. elegans. Lipases and lipid chaperones are up-regulated in long-lived animals, and are necessary for longevity. Their functions are also pivotal for fat mobilization in wild type and long-lived mutants. Overexpression of the lipase K04A8.5 in fat storage tissue promotes lipolysis as well as longevity. These studies suggest novel mechanisms for lipid metabolism in aging. This proposal seeks to dissect the function of lipid metabolism in regulation of longevity through the following specific aims: 1) Study the mechanisms by which lipase overexpression extends lifespan. 2) Characterize the roles of lipid chaperones in lifespan regulation. 3) Identify lipid messengers that extend lifespan. We will apply genetic techniques to probe genetic interactions among lipases, lipid chaperones and known lifespan regulatory signaling, and also screen for upstream regulatory factors. Additionally, we will employ biochemical and proteomic methodologies to study lipid chaperone complexes and lipidomic approaches with the goal of identifying particular lipid species and human metabolites as key regulators of aging. The long-term goal is to explore how to promote healthy aging via modulating lipid metabolism. These studies will yield insights to mechanisms by which lipid metabolism affects the aging process, and provide novel therapeutic targets. This application describes an integrative plan that will facilitate my transition to an independent position at an academic institution. PUBLIC HEALTH RELEVANCE: Results from this study are important for public health as increased incidence of diseases with age. This study will provide insight into essential roles of lipid metabolism in regulating lifespan as well as address many fundamental issues in lipid metabolism and energy homeostasis.