LIPID SIGNALING IN REGULATION OF LONGEVITY

描述（申请人提供）：脂质代谢在人类健康和长寿中起着关键作用。脂质代谢在衰老过程中发生根本性变化，导致许多与年龄相关的疾病，如糖尿病、神经退行性疾病和癌症的发生。脂肪组织作为脂质代谢的主要部位，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，人们对脂质代谢如何与寿命控制相结合仍然知之甚少。脂质不仅是细胞结构和能量消耗的重要生物分子，而且是积极参与转录反应和信号转导的信号信使。脂肪酸结合蛋白家族已被确定为脂质信使的伴侣蛋白，以促进其细胞作用。脂肪酶诱导的脂肪分解是一个典型的代谢过程来分解脂肪，这是最近被证明产生脂质信使是必不可少的调节能量代谢。在初步研究中，我们将LIPL-4定性为秀丽隐杆线虫的溶酶体酸性脂肪酶。其在脂肪储存组织中的构成表达诱导脂肪分解并延长生物体寿命，这需要核激素受体NHR- 49信号的活性。此外，一种亲脂代谢产物油基乙醇酰胺（OEA）和一种脂肪酸结合蛋白LBP-8在lipl -4介导的长寿调控中发挥了关键作用。这些研究提示了一种新的长寿机制，即脂肪酶诱导的脂肪分解通过激活特定的脂质信使和脂质信号来促进长寿。本研究旨在通过以下具体目标来剖析脂酶诱导的脂解在调节寿命中的新功能：1)表征脂质信使OEA在调节生物体寿命中的作用。2)研究LBP-8在脂肪酶介导的长寿中的作用机制。3)研究与生物体寿命有关的细胞生物能变化。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、生化和转录分析方法，剖析这一新的长寿途径的分子机制。这些研究将对脂质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.