MUFA-SIRT1 signaling as a central node regulating healthspan

MUFA-SIRT1信号作为调节健康寿命的中心节点

• 批准号: 10432079
• 负责人: Douglas G Mashek
• 金额: $ 31.78万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10432079
• 关键词: Aging; Animal Model; Animals; Attention; Biogenesis; Biological; Biology; Caloric Restriction; Catabolism; Cell Nucleus; Cell physiology; Charge; Clinical Trials; Data; Deacetylation; Development; Diet; Dietary Factors; Dietary Fats; Dietary Intervention; Disease; Dose; FRAP1 gene; Fasting; Glean; Gold; Health; Health Benefit; Human; Link; Lipids; Lipolysis; Literature; Longevity; Machine Learning; Macronutrients Nutrition; Maps; Mediating; Mediterranean Diet; Metabolism; Mitochondria; Modeling; Monounsaturated Fatty Acids; Mus; Nutrient; Nutritional; Oils; Olive oil preparation; Olives - dietary; Outcome; Oxidation-Reduction; PPAR alpha; Pathway interactions; Peptides; Pharmacologic Substance; Proteins; Proteomics; Reaction; Research; Resveratrol; Role; SIRT1 gene; Signal Transduction; Signaling Molecule; Sirtuins; Source; Testing; Therapeutic; Time; Work; analog; base; cofactor; deacylation; detection of nutrient; dietary; epidemiology study; healthspan; healthy aging; improved; innovation; interest; middle age; mutant mouse model; novel; nutrient deprivation; polyphenol; prevent; red wine; response

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.

项目概要 常量营养素除了提供能量外还具有多种作用，其中包括多种营养素和/或其 下游代谢物充当信号分子来协调细胞代谢和功能。的确， 许多营养感应途径（例如 mTOR、AMPK 和 Sirtuins）已经进化，使我们能够对 特定的营养素/代谢物，进而影响健康寿命。 Sirtuins 很大程度上被认为是由 氧化还原，高水平的 NAD（sirtuin 反应中的辅助因子和低能量电荷的指示剂）驱动 Sirtuin 催化的靶蛋白脱酰作用。 SIRT1 是研究最多的 Sirtuin，是关键的营养传感节点 它调节大量的细胞功能，以促进寿命延长和健康衰老。因此， 人们对使用 SIRT1 激活化合物 (STAC) 来预防或治疗多种疾病产生了浓厚的兴趣。 与衰老相关的疾病。膳食大量营养素、营养感应和健康寿命之间的联系 历史上关注的是热量或蛋白质限制，而对膳食脂质的关注有限。然而，一个 越来越多的文献将单不饱和脂肪酸 (MUFA) 与延长健康寿命联系起来。 除了对模型生物体的寿命和健康衰老产生积极影响外，饮食中的单不饱和脂肪酸 (MUFA) 已被 在流行病学研究中，它们与广泛的健康益处有关，并且，因为它们是 橄榄油，被认为有助于地中海饮食的好处。尽管有这些研究，但人们知之甚少 关于 MUFA 产生有益健康影响的生物学基础。我们有 先前表明，脂滴分解代谢（即脂肪分解）会增加 SIRT1 和下游 PGC-1a/PPAR- 一种信号传导作为营养缺乏期间增加线粒体生物发生和功能的手段。 我们的初步数据首次表明，脂肪分解中专门释放的 MUFA 被贩运到 它们变构激活 SIRT1 以选择乙酰化肽底物。这一发现 使 MUFA 成为第一个已知的 SIRT1 内源性变构激活剂。此外，我们表明 MUFA 通过与白藜芦醇类似的机制激活 SIRT1，表明 MUFA 信号传导可能调节 对外源性 SIRT1 激活剂的反应。基于这些初步数据，该应用程序的目标是 进一步表征 MUFA 作为内源性 SIRT1 激活剂的作用。我们假设 MUFA 选择性激活 SIRT1 来调节对已知影响的多种饮食干预措施的反应 healthspan.为了测试我们的目标，我们提出以下目标： 目标 1：定义 MUFA 如何调节 SIRT1 底物选择性。目标 2：表征 MUFA/橄榄油对 SIRT1 的依赖性影响 健康寿命。目标 3：确定 MUFA 在调节 STAC 或热量反应中的贡献 限制。完成建议研究后，我们将进一步扩展我们对 SIRT1 生物学允许采用精细方法来激活 SIRT1 以促进健康衰老。