LIPID SIGNALING IN REGULATION OF LONGEVITY

描述(申请人提供)：脂类代谢对人类健康和长寿起着关键作用。在衰老过程中，脂质代谢发生了根本性的变化，这导致了许多与年龄相关的疾病的发展，如糖尿病、神经退行性疾病和癌症。脂肪组织作为脂肪代谢的主要部位，在无脊椎动物和脊椎动物的衰老过程中都发挥着重要的内分泌作用。然而，人们对脂类代谢如何与寿命控制相结合仍知之甚少。脂类不仅是细胞结构和能量消耗的关键生物分子，也是积极参与转录反应和信号转导的信号信使。一个脂肪酸结合蛋白家族已被确定为脂质信使的伴侣，以促进其细胞作用。脂肪酶诱导的脂肪分解是一种典型的分解脂肪的代谢过程，最近被证明产生了调节能量代谢所必需的脂质信使。在前期的研究中，我们将Lipl-4鉴定为秀丽线虫中的一种溶酶体酸性脂肪酶。它在脂肪储存组织中的组成性表达诱导脂肪分解，延长机体寿命，这需要核激素受体NHR-49信号的激活。此外，亲脂代谢产物油酰乙醇胺(OEA)和脂肪酸结合蛋白LBP-8在LIPL-4介导的长寿调节中起着关键作用。这些研究表明了一种新的长寿机制，即脂肪酶诱导的脂解通过激活特定的脂质信使和脂质信号来促进长寿。本提案试图通过以下具体目的剖析脂肪酶诱导的脂解在调节长寿中的新功能：1)表征脂质信使OEA在调节生物体长寿中的作用。2)研究LBP-8在脂肪酶介导的长寿中的作用机制。3)研究与生物体长寿有关的细胞生物能量变化。我们将应用尖端的高通量代谢组学和无标记化学成像技术，结合遗传、生化和转录图谱方法，剖析这一新的长寿途径背后的分子机制。这些研究将为脂代谢影响衰老过程的分子机制提供新的见解，并为改善老年人的代谢健康提供新的治疗靶点。

DESCRIPTION (provided by applicant): Lipid metabolism plays a key role in human health and longevity. Lipid metabolism undergoes fundamental changes during aging, which attributes to the development of many age-associated diseases, such as diabetes mellitus, neurodegenerative disorder and cancer. As a major site of lipid metabolism, adipose tissue exerts crucial endocrine effects on the aging process in both invertebrate and vertebrate organisms. However, it remains poorly understood how lipid metabolism is coupled to lifespan control. Lipids are not only crucial biological molecules for cellular structure and energy consumption, but also signaling messengers actively involved in transcriptional response and signal transduction. A family of fatty acid binding proteins has been identified as chaperones of lipid messengers to facilitate their cellular effects. Lipase-induced lipolysis is a canonical metabolic process to break down fat, which is recently shown to produce lipid messengers that are essential for the regulation of energy metabolism. During the preliminary studies, we characterized LIPL-4 as a lysosomal acid lipase in Caenorhabditis elegans. Its constitute expression in the fat storage tissue induces lipolysis as well as prolongs organism lifespan, which requires the activity of nuclear hormone receptor NHR- 49 signaling. Furthermore, a lipophilic metabolite oleoylethanolamide (OEA) and a fatty acid binding protein LBP-8 were identified that play crucial roles in the regulation of the LIPL-4-mediated longevity. These studie suggest a novel longevity mechanism that lipase-induced lipolysis promotes longevity via activating specific lipid messengers and lipid signaling. This proposal seeks to dissect the novel functions of lipase-induced lipolysis in the regulation of longevity through the following specific aims: 1) characterize the effects of the lipid messenger OEA in the regulation of organism longevity. 2) Study the mechanism by which LBP-8 functions in the lipase-mediated longevity. 3) Investigate cellular bioenergetic changes that are responsible for organism longevity. We will apply cutting- edge high-throughput metabolomics and label-free chemical imaging techniques combining with genetic, biochemical and transcriptional profiling approaches to dissect the molecular mechanisms underlying this new longevity pathway. These studies will yield new insights to the molecular mechanisms by which lipid metabolism affects the aging process, and also provide novel therapeutic targets to improve metabolic health in elderly.