MUFA-SIRT1 signaling as a central node regulating healthspan

项目摘要 大量营养素除了提供能量之外还起着多种作用，其中许多营养素和/或其组合物是必需的。 下游代谢物充当信号分子以协调细胞代谢和功能。的确， 许多营养传感途径（如mTOR，AMPK和sirtuins）已经进化，使我们能够响应 特定的营养素/代谢物，这反过来又影响健康。Sirtuins在很大程度上被认为是由 氧化还原，由此高水平的NAD（sirtuin反应中的辅因子和低能电荷的指示剂）驱动 去乙酰化酶催化的靶蛋白的脱酰作用。SIRT 1是研究最多的sirtuin，是一个关键的营养传感节点 它调节过多的细胞功能，以促进寿命延长和健康衰老。因此，在本发明中， 人们对使用SIRT 1活化化合物（STAC）来预防或治疗广泛的 与衰老有关的疾病。膳食常量营养素、营养感知和健康寿命之间的联系 历史上集中于热量或蛋白质限制，对饮食脂质的关注有限。但 越来越多的文献将单不饱和脂肪酸（MUFA）与改善健康联系起来。 除了对模式生物的寿命和健康衰老的积极影响外，膳食MUFA还被认为是一种有益的物质。 在流行病学研究中，它们与广泛的健康益处有关， 橄榄油，被认为有助于地中海饮食的好处。尽管有这些研究， 关于MUFA产生有益健康效应的生物学基础。我们有 先前表明，脂滴分解（即脂解）增加SIRT 1和下游PGC-1a/PPAR-1。 在营养缺乏期间，作为增加线粒体生物发生和功能的手段的信号。 我们的初步数据首次显示，从脂解中特异性释放的MUFA被贩运到 在细胞核中，它们变构激活SIRT 1朝向选择的乙酰化肽底物。这一发现 使MUFA成为SIRT 1的第一个已知的内源性变构激活剂。此外，我们表明， 通过与白藜芦醇类似的机制激活SIRT 1，这表明MUFA信号转导可能调节SIRT 1的表达。 对外源性SIRT 1激活剂的反应。根据这些初步数据，本申请的目的是 进一步表征MUFA作为内源性SIRT 1激活剂的作用。我们假设MUFA 选择性地激活SIRT 1，以调节对多种已知影响的饮食干预的反应。 健康寿命。为了验证我们的目的，我们提出了以下目标：目标1：定义MUFA如何调节 SIRT 1底物选择性。目的2：表征MUFA/橄榄油对SIRT 1依赖性的作用， healthspan.目的3：确定MUFA在介导对STAC或热量的反应中的作用。 限制.待建议研究完成后，我们会进一步加深对 SIRT 1生物学允许精细的方法来激活SIRT 1以促进健康衰老。

PROJECT SUMMARY Macronutrients serve a multitude of roles beyond provision of energy, with numerous nutrients and/or their downstream metabolites acting as signaling molecules to coordinate cellular metabolism and function. Indeed, numerous nutrient sensing pathways (e.g. mTOR, AMPK and sirtuins) have evolved allowing us to respond to specific nutrients/metabolites, which in turn impacts healthspan. Sirtuins are largely thought to be driven by redox, whereby high levels of NAD, a cofactor in the sirtuin reaction and indicator of low energy charge, drives sirtuin-catalyzed deacylation of target proteins. SIRT1, the most-studied sirtuin, is a key nutrient sensing node that regulates a plethora of cellular functions to promote lifespan extension and healthy aging. As a result, there is immense interest in the use of SIRT1 activating compounds (STACs) to prevent or treat a wide range of aging-related disease. The links between dietary macronutrients, nutrient sensing and healthspan have historically focused upon caloric or protein restriction with limited attention given to dietary lipids. However, a small and growing body of literature has linked monounsaturated fatty acids (MUFAs) to improved healthspan. In addition to positive effects on lifespan and healthy aging in model organisms, dietary MUFAs have been linked to wide-ranging health benefits in epidemiological studies and, since they are a primary constituent of olive oil, thought to contribute to the benefits of the Mediterranean Diet. Despite these studies, little is known about the biological underpinnings through which MUFAs elicit their beneficial health effects. We have previously shown that lipid droplet catabolism (i.e. lipolysis) increases SIRT1 and downstream PGC-1a/PPAR- a signaling as a means to increase mitochondrial biogenesis and function during times of nutrient deprivation. Our preliminary data show for the first time that MUFAs released specifically from lipolysis are trafficked to the nucleus where they allosterically activate SIRT1 towards select acetylated peptide substrates. This discovery makes MUFAs the first-known endogenous allosteric activators of SIRT1. Moreover, we show that MUFAs activate SIRT1 through a similar mechanism to resveratrol suggesting that MUFA signaling may modulate the response to exogenous SIRT1 activators. Based on these preliminary data, the objective of this application is to further characterize the role of MUFAs as endogenous SIRT1 activators. We hypothesize that MUFAs selectively activate SIRT1 to modulate the response to numerous dietary interventions known to impact healthspan. To test our objective, we propose the following aims: Aim 1: To define how MUFAs modulate SIRT1 substrate selectivity. Aim 2: To characterize the SIRT1-dependent effects of MUFAs/olive oil on healthspan. Aim 3: To determine the contribution of MUFAs in mediating the response to STACs or caloric restriction. Upon completion of the proposes studies, we will have further expanded our understanding of SIRT1 biology allowing for refined approaches to activate SIRT1 to promote healthy aging.