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.

项目总结 除了提供能量之外，大量营养素具有多种作用，具有大量的营养和/或其 下游代谢产物作为信号分子来协调细胞的新陈代谢和功能。的确， 许多营养感应途径(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，由此高水平的NAD，一个在sirtuin反应中的辅助因子和低能量电荷的指示器，驱动 Sirtuin催化的靶蛋白脱酰化。SIRT1是研究最多的sirtuin，是一个关键的营养传感节点 这调节了过多的细胞功能，以促进寿命延长和健康衰老。结果, 人们对使用SIRT1激活化合物(STAC)来预防或治疗广泛的疾病非常感兴趣 与衰老相关的疾病。膳食中的大量营养素、营养感知和健康寿命之间的联系有 历史上侧重于卡路里或蛋白质的限制，而对饮食脂质的关注有限。然而，a 越来越多的文献将单不饱和脂肪酸(MUFAs)与延长健康寿命联系在一起。 除了对模式生物的寿命和健康衰老有积极影响外，膳食中的MUFAs还 与流行病学研究中广泛的健康益处有关，而且由于它们是 橄榄油，被认为有助于地中海饮食的好处。尽管有这些研究，但人们对此知之甚少 关于多不饱和脂肪酸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(即脂解)增加了SIRT1和下游的PGC-1a/PPAR- A信号作为在营养缺乏时增加线粒体生物合成和功能的一种手段。 我们的初步数据首次显示，从脂肪分解中释放的MUFA被贩运到 在细胞核中，它们变构激活SIRT1，朝向选择的乙酰化肽底物。这一发现 使MUFAs成为第一个已知的SIRT1内源性变构激活剂。此外，我们还证明了MUFA 通过与白藜芦醇类似的机制激活SIRT1，提示MUFA信号可能调制 对外源SIRT1激活剂的反应。基于这些初步数据，此应用程序的目标是 进一步研究MUFAs作为内源性SIRT1激活剂的作用。我们假设多不饱和脂肪酸 选择性地激活SIRT1以调节对许多已知影响的饮食干预的反应 健康跨度。为了测试我们的目标，我们提出了以下目标：目标1：定义MUFA如何调节 SIRT1底物选择性。目的2：研究MUFAs/橄榄油的SIRT1依赖效应。 健康跨度。目的3：确定MUFAs在调节对STAC或热量的反应中的作用 限制。在完成建议研究后，我们会进一步扩大对 SIRT1生物学允许精细的方法激活SIRT1以促进健康衰老。