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: 10646427
• 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/10646427
• 关键词: Acetylation; Aging; 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; 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; cofactor; deacylation; detection of nutrient; dietary; epidemiology study; healthspan; healthy aging; improved; innovation; interest; middle age; model organism; 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.

项目摘要 大量营养素在能量提供的众多，具有多种营养和/或它们的能源之外，发挥了多种作用。 下游代谢产物充当信号分子，以配合细胞代谢和功能。的确， 许多营养感应途径（例如MTOR，AMPK和SIRTUINS）已进化，使我们能够做出回应 特定的营养/代谢产物，进而影响HealthSpan。 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电荷指标 靶蛋白的Sirtuin催化脱酰化。 SIRT1是最研究的Sirtuin，是一个关键的营养传感节点 这可以调节大量细胞功能，以促进寿命延伸和健康衰老。因此， 对于使用SIRT1激活化合物（Stacs）以防止或治疗广泛范围，人们非常感兴趣 与衰老有关的疾病。饮食大量营养素，营养感应和健康范围之间的联系具有 从历史上看，关注热量或蛋白质限制，对饮食脂质的关注有限。但是， 较小的文献繁多的体系将单不饱和脂肪酸（MUFA）与改善的健康范围联系起来。 除了对模型生物中的寿命和健康衰老的积极影响外，饮食MUFA一直是 与流行病学研究中的广泛健康益处有关，并且由于它们是 橄榄油，被认为有助于地中海饮食的益处。尽管进行了这些研究，但鲜为人知 关于MUFA引起其有益健康影响的生物基础。我们有 先前表明脂质液滴分解代谢（即脂解）增加了SIRT1和下游PGC-1A/PPAR- 信号作为在营养剥夺时期增加线粒体生物发生和功能的手段。 我们的初步数据显示，MUFA专门从脂解释放的人被贩运到 核将它们变构朝向选择的乙酰化肽底物激活SIRT1。这个发现 使MUFA成为SIRT1的首个已知的内源性变构激活剂。而且，我们证明了穆法斯 通过类似的机制激活SIRT1，表明MUFA信号可能会调节 对外源SIRT1激活剂的响应。基于这些初步数据，此应用程序的目的是 进一步将MUFA作为内源性SIRT1激活剂的作用。我们假设Mufas 选择性激活SIRT1以调节对已知影响的众多饮食干预措施的反应 HealthSpan。为了测试我们的目标，我们提出以下目的：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依赖性效果 HealthSpan。目标3：确定MUFA在介导对Stacs或热量的反应中的贡献 限制。提出的研究完成后，我们将进一步扩展我们对 SIRT1生物学允许使用精制方法激活SIRT1以促进健康的衰老。