Role of ATGL and lipid metabolism in healthspan

项目总结 改变饮食或锻炼影响健康的生物学基础--增加 在没有疾病的情况下的寿命--还没有完全被理解。最近关于苍蝇和蠕虫的数据突出了 脂解的潜在作用，即储存在脂滴(LDs)中的三酰甘油(TAG)的分解代谢，作为一个因素 这促进了健康寿命。然而，将脂肪分解与健康寿命改变联系起来的机制并不是 为人所知。此外，还没有研究评估脂肪分解在哺乳动物健康寿命调节中的作用或 脂肪分解和饮食的相互作用，这在很大程度上决定了LDS的组成，从而决定了它们的信号转导 属性。因此，本应用程序的目的是确定脂解作用的机制 影响健康寿命，并确定膳食脂肪成分对这些影响的贡献。我们 假设脂肪分解是一个关键的信号节点，通过改变脂肪酸来推动健康 发信号。我们基于我们实验室的初步数据来定义一个信号轴链接 脂肪甘油三酯脂肪酶(ATGL)催化脂解为sirtuin 1(SIRT1)活性及其下游信号转导 激活叉头盒蛋白01(FOXO1)。我们还表明，果蝇同源基因的过度表达 ATGL，Brummer(BMM)，延长寿命与SIRT1和FOXO1作为关键调节因子的已知角色一致 寿命的长短。为了验证我们的假设，我们将利用果蝇和老鼠模型的优势来测试 具体目标如下：目标1：描述脂解作用影响的信号通路 果蝇的健康寿命。我们将使用果蝇模型来剖析BMM-Sir2(Fly SIRT1)的线性 同源)-dFOXO(Fly FOXO1同源)信号轴在调节健康寿命中的作用。目标2：确定 饮食和ATGL对小鼠健康寿命的影响。这些研究将探索协同效应 饮食中的脂质成分和ATGL的过度表达对寿命和衰老相关下降的影响 小鼠的新陈代谢。目的3：研究ATGL与自噬的相互作用。在这个目标中， 将测试ATGL对自噬的影响以及自噬在调节信号和寿命中的作用 ATGL/BMM在苍蝇和哺乳动物模型中的延伸效应。这些研究将是第一次 全面定义ATGL催化的脂解作用在健康中的作用以及它如何与其他 参与寿命调节的生理因素。这些研究具有创新性，因为它们将使用新颖的 苍蝇和老鼠模型将已知的影响寿命的个别因素(如饮食)链接到一个具有凝聚力的模型中 这更好地解释了健康跨度监管。拟议的工作意义重大，因为它将极大地推动 我们对脂代谢这一未被充分研究的领域的理解是导致衰老的一个因素 提供对新的或改进的饮食、行为或药物途径的实质性见解，以促进 健康跨度。

PROJECT SUMMARY The biological underpinnings through which changes in diet or exercise influence healthspan - increased lifespan in the absence of disease - are not fully understood. Recent data in flies and worms have highlighted a potential role for lipolysis, the catabolism of triacylglycerol (TAG) stored within lipid droplets (LDs), as a factor that promotes healthspan. However, the mechanisms linking lipolysis to alterations in healthspan are not known. In addition, no studies have evaluated the role of lipolysis in healthspan regulation in mammals or the interaction of lipolysis and diet, which largely determines the composition of LDs and, therefore, their signaling properties. Thus, the objective of this application is to define the mechanisms through which lipolysis influences healthspan and to determine the contribution of dietary lipid composition to these effects. We hypothesize that lipolysis is a key signaling node that drives healthspan through alterations in fatty acid signaling. We base this hypothesis on preliminary data from our laboratory defining a signaling axis linking adipose triglyceride lipase (ATGL)-catalyzed lipolysis to sirtuin 1 (SIRT1) activity and downstream signaling to activate forkhead box protein 01 (FOXO1). We also show that overexpression of the Drosophila homolog of ATGL, brummer (Bmm), increases lifespan consistent the known roles of SIRT1 and FOXO1 as key regulators of lifespan. To test our hypothesis, we will utilize the strengths of both Drosophila and mouse models to test the following specific aims: Aim 1: To delineate the signaling pathway through which lipolysis influences healthspan in Drosophila. We will use Drosophila models to dissect the linearity of the Bmm-Sir2 (fly SIRT1 homolog)-dFOXO (fly FOXO1 homolog) signaling axis in regulating healthspan. Aim 2: To determine the interactions between diet and ATGL on healthspan in mice. These studies will explore the synergy between dietary lipid composition and ATGL overexpression on lifespan and aging-related declines in metabolism in mice. Aim 3: To characterize the interaction between ATGL and autophagy. In this aim, will test the effects of ATGL on autophagy and the role of autophagy in mediating the signaling and lifespan extending effects of ATGL/Bmm in both fly and mammalian models. These studies will be the first to comprehensively define the role of ATGL-catalyzed lipolysis in healthspan and how it interacts other physiological factors involved in lifespan regulation. These studies are innovative because they will use novel fly and mouse models to link individual factors known to influence lifespan such as diet into a cohesive model that better explains healthspan regulation. The proposed work is significant because it will greatly advance our understanding into the understudied area of lipid metabolism as a factor contributing to aging and will provide substantial insights into new or improved dietary, behavorial or pharmaceutical avenues to promote healthspan.