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)衰老相关疾病的主要调节因素。地中海饮食被广泛认为 作为饮食的黄金标准，因为它能够减少一系列与衰老有关的疾病，导致 提高了健康寿命。虽然地中海饮食的许多成分可能有助于它的健康 除了好处，特级初榨橄榄油已经成为这些影响的主要成分。事实上，两者都是 流行病学和干预性研究已将食用特级初榨橄榄油与改善健康联系在一起。 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)的油以及多种酚类组成 化合物。有趣的是，特级初榨橄榄油中发现的多不饱和脂肪酸和许多酚都已被发现。 在临床前和临床试验中对认知和预防阿尔茨海默氏症有积极影响 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，调节过多的控制衰老相关的途径 病理学。许多酚，包括特级初榨橄榄油中发现的一些酚，也可以激活SIRT1以 改善与衰老相关的结果，正如我们已经表明的那样，这些小分子可能通过 与多不饱和脂肪酸的作用机制相同。因此，破译MUFAs与非脂类成分对健康的好处 在橄榄油中，以及SIRT1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、橄榄油的健康益处以及SIRT1生物学的了解。此外, SIRT1的MUFA信号发生在刺激脂肪分解的条件下，如禁食或热量限制 这表明饮食结构和饮食模式是相互依存的。根据这些数据，我们 假设多不饱和脂肪酸和特级初榨橄榄油酚将防止认知和神经功能下降 通过激活SIRT1损伤，并将调节卡路里限制的效果。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MUFAs和酚类物质的影响 SIRT1在衰老相关神经退行性变中的信号转导。为此，我们将饲喂野生型或SIRT1 E222K 对SIRT1变构激活剂缺乏反应性的小鼠，饮食中富含或高或低的橄榄油 酚类含量，并全面表征神经功能和认知。2)确定 单独或联合使用橄榄油和卡路里限制对神经退变的影响。我们会喂饱中间的- 在随意或卡路里限制的条件下，喂食低或高MUFA的老龄小鼠，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 这些研究促进了我们对饮食脂肪和热量限制如何影响衰老的理解 大脑，这将有助于定义神经退行性疾病的新机制，并打开新的 针对脂类代谢的治疗途径。