MUFA-SIRT1 signaling as a central node regulating healthspan

MUFA-SIRT1 信号传导作为调节健康寿命的中心节点

• 批准号: 10711019
• 负责人: Douglas G Mashek
• 金额: $ 31.76万
• 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/10711019
• 关键词: Aging; Alzheimer disease prevention; Alzheimer' s disease related dementia; Biology; Brain; Caloric Restriction; Clinical Trials; Cognition; Consumption; Data; Development; Diet; Dietary Factors; Dietary Fats; Dietary Intervention; Disease; Eating; Fasting; Glean; Health; Health Benefit; Human; Impaired cognition; Impairment; Intervention Studies; Laboratories; Link; Lipolysis; Mediating; Mediterranean Diet; Monounsaturated Fatty Acids; Mus; Nerve Degeneration; Nervous System Physiology; Neurodegenerative Disorders; Neurologic; Neurophysiology - biologic function; Nutritional; Oils; Olive oil preparation; Outcome; Pathology; Pathway interactions; Pattern; Phenols; Proteins; SIRT1 gene; Signal Transduction; Testing; Therapeutic; aging brain; detection of nutrient; epidemiology study; healthspan; improved; lipid metabolism; middle age; novel therapeutics; preclinical trial; prevent; small molecule

Diet is a major regulator of most if not all aging-related diseases. The Mediterranean Diet is widely regarded as the gold standard of diets due to its ability to reduce a wide range of aging-related diseases resulting in improved healthspan. While numerous components of the Mediterranean Diet likely contribute to its health benefits, extra virgin olive oil has emerged as a major constituent underlying these effects. Indeed, both epidemiological and interventional studies have linked extra virgin olive oil consumption to improved health benefits including reductions in cognitive decline and neurodegenerative diseases. Extra virgin olive oil is largely comprised of oil enriched in monounsaturated fatty acids (MUFA) as well as a diverse class of phenolic compounds. Interestingly, both MUFAs and the many phenols found in extra virgin olive oil have been shown in pre-clinical and clinical trials to have positive effects on cognition and in the prevention of Alzheimer’s Disease and related dementias. Our laboratory has found the MUFAs are allosteric activators of sirtuin 1 (SIRT1), a key nutrient sensing protein that regulates a plethora of pathways controlling aging-related pathologies. Numerous phenols, including some found in extra virgin olive oil, also can activate SIRT1 to improve aging related outcomes and, as we have shown, these small molecules likely activate SIRT1 through the same mechanism as MUFAs. Thus, deciphering the health benefits of MUFAs vs non-lipid components in olive oil, and the extent to which SIRT1 allosteric activation mediates these effects, would greatly advance our understanding of the Mediterranean Diet, the health benefits of olive oil, and SIRT1 biology. In addition, MUFA signaling to SIRT1 occurs upon conditions that stimulate lipolysis such as fasting or caloric restriction suggesting that diet composition and eating patterns are co-dependent. Based upon these data, we hypothesize that MUFAs and extra virgin olive oil phenols will prevent declines in cognition and neurological impairments via SIRT1 activation and will modulate the effects of caloric restriction. To test our hypothesis, we will conduct the following two aims. 1) To test the effects of extra virgin olive oil MUFAs and phenols signaling via SIRT1 on aging-related neurodegeneration. In this aim, we will feed wild-type or SIRT1 E222K mice, which lack responsiveness to SIRT1 allosteric activators, diets enriched in olive oil with high or low phenolic content and comprehensively characterize neurological function and cognition. 2) To determine impact of olive oil and caloric restriction alone or in combination on neurodegeneration. We will feed middle- aged mice diets with low or high MUFA along under ad libitum or caloric restriction conditions to determine if the interaction between these two dietary interventions impacts cognition and neural function. We expect these studies to advance our understanding into how dietary lipids and caloric restriction impact the aging brain, which will help define new mechanisms underlying neurodegenerative diseases and open new therapeutic avenues targeting lipid metabolism.

饮食是大多数（如果不是全部）与衰老相关疾病的主要调节因素。地中海饮食被广泛认可 作为饮食的黄金标准，因为它能够减少多种与衰老相关的疾病，从而导致 改善健康寿命。虽然地中海饮食的许多成分可能有助于其健康 好处，特级初榨橄榄油已成为这些影响的主要成分。确实，两者 流行病学和干预研究已将特级初榨橄榄油的消费与改善健康联系起来 好处包括减少认知能力下降和神经退行性疾病。特级初榨橄榄油是 主要由富含单不饱和脂肪酸 (MUFA) 的油以及多种酚类物质组成 化合物。有趣的是，特级初榨橄榄油中发现的单不饱和脂肪酸和许多酚类物质均已被证明 在临床前和临床试验中对认知和预防阿尔茨海默病产生积极影响 疾病和相关痴呆症。我们实验室发现MUFA是sirtuin 1的变构激活剂 (SIRT1)，一种关键的营养传感蛋白，可调节多种控制衰老相关的途径 病理学。许多酚类，包括特级初榨橄榄油中的一些酚类，也可以激活 SIRT1 改善衰老相关结果，正如我们所表明的，这些小分子可能通过以下方式激活 SIRT1： 与 MUFA 的机制相同。因此，解读 MUFA 与非脂质成分的健康益处 橄榄油中的 SIRT1 变构激活介导这些效应的程度，将极大地推进 我们对地中海饮食、橄榄油的健康益处以及 SIRT1 生物学的了解。此外， MUFA 向 SIRT1 发出信号在刺激脂肪分解的条件下发生，例如禁食或热量限制 表明饮食成分和饮食模式是相互依赖的。根据这些数据，我们 假设 MUFA 和特级初榨橄榄油酚类物质可以预防认知和神经功能下降 SIRT1 激活会造成损伤，并调节热量限制的影响。为了检验我们的假设， 我们将实现以下两个目标。 1) 测试特级初榨橄榄油MUFA和酚类的效果 SIRT1 信号传导与衰老相关的神经退行性疾病有关。为此，我们将饲喂野生型或 SIRT1 E222K 对 SIRT1 变构激活剂缺乏反应的小鼠，富含橄榄油的饮食具有高或低 酚含量并综合表征神经功能和认知。 2）确定 橄榄油和热量限制单独或组合对神经退行性变的影响。我们将喂养中 老年小鼠在随意或热量限制条件下采用低或高 MUFA 饮食，以确定是否 这两种饮食干预措施之间的相互作用会影响认知和神经功能。我们期望 这些研究加深了我们对饮食脂质和热量限制如何影响衰老的理解 脑，这将有助于定义神经退行性疾病的新机制并开辟新的领域 针对脂质代谢的治疗途径。