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（如果不是所有）与衰老有关的疾病的主要调节器。地中海饮食被广泛认为 作为饮食的黄金标准，因为它能够减少各种与衰老有关的疾病， 改善健康。虽然地中海饮食的许多成分可能有助于其健康 橄榄油的好处，特级初榨橄榄油已成为这些效果的主要成分。事实上，两者 流行病学和干预性研究已经将特级初榨橄榄油的消费与改善健康联系起来 益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）以及多种酚类化合物的油组成。 化合物.有趣的是，在特级初榨橄榄油中发现的MUFA和许多酚类物质都被证明是 在临床前和临床试验中， 疾病和相关的痴呆症。我们实验室发现MUFA是sirtuin 1的变构激活剂 （SIRT 1），一种关键的营养传感蛋白，调节多种控制衰老相关的途径。 病理学许多酚类，包括一些在特级初榨橄榄油中发现的酚类，也可以激活SIRT 1， 改善与衰老相关的结果，正如我们所展示的，这些小分子可能通过以下途径激活SIRT 1： 与MUFA相同的机制。因此，解读MUFA与非脂质成分的健康益处 以及SIRT 1变构激活介导这些效应的程度，将大大提高 我们对地中海饮食的理解，橄榄油的健康益处和SIRT 1生物学。此外，本发明还提供了一种方法， MUFA向SIRT 1的信号传导发生在刺激脂解的条件下，如禁食或热量限制 这表明饮食组成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可以预防认知和神经功能的下降， 通过SIRT 1激活的损伤，并将调节热量限制的效果。为了检验我们的假设， 我们会致力达致以下两个目标。1)为了测试特级初榨橄榄油MUFA和酚类的效果， 通过SIRT 1对衰老相关的神经退行性变进行信号传导。为此，我们将野生型或SIRT 1 E222 K 缺乏对SIRT 1变构激活剂反应性的小鼠，饮食富含橄榄油， 酚类物质含量，综合表征神经功能和认知功能。2)以确定 橄榄油和热量限制单独或组合对神经变性影响。我们会喂中间- 在自由采食或热量限制条件下，用低或高MUFA沿着饲喂老年小鼠，以确定 这两种饮食干预之间的相互作用影响认知和神经功能。我们预计 这些研究有助于我们进一步了解饮食中的脂质和热量限制如何影响衰老。 大脑，这将有助于确定神经退行性疾病的新机制，并开辟新的 针对脂质代谢的治疗途径。