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.

饮食是大多数与衰老有关的疾病的主要调节剂。广泛考虑地中海饮食 作为饮食的黄金标准，由于其能够减少多种与衰老有关的疾病的能力，导致 改进的HealthSpan。尽管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组成部分。确实，两个 流行病学和介入的研究已将特级初榨橄榄油消耗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 在很大程度上积累了富含单不饱和脂肪酸（MUFA）和潜水酚类类的油 化合物。有趣的是，已经显示了Mufas和在特级初榨橄榄油中发现的许多酚 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。我们的实验室发现MUFA是Sirtuin 1的变构激活剂 （SIRT1），一种关键的营养感应蛋白，可调节控制衰老相关的大量途径 病理。许多苯酚，包括在特级初榨橄榄油中发现的苯酚，也可以将SIRT1激活到 改善与衰老相关的结果，正如我们所表明的，这些小分子可能通过 与Mufas相同的机制。那，破译MUFA与非脂质组件的健康益处 在橄榄油以及SIRT1变构激活的程度上，这些效果将很大的进步 我们对地中海饮食，橄榄油的健康益处和SIRT1生物学的理解。此外， 对SIRT1的MUFA信号传导发生在刺激脂肪分解（例如禁食或热量限制）的条件下 表明饮食成分和饮食模式是共同依赖的。基于这些数据，我们 假设Mufas和特级初榨橄榄油酚会阻止认知和神经系统下降 通过SIRT1激活的损伤将调节热量限制的影响。为了检验我们的假设， 我们将执行以下两个目标。 1）测试特级初榨橄榄油Mufas和苯酚的影响 通过SIRT1发出与衰老相关的神经变性的信号。在此目标中，我们将喂食野生型或SIRT1 E222K 对SIRT1变构激活剂的反应性的小鼠，饮食富含高或低的橄榄油 酚类含量并全面地表征神经功能和认知。 2）确定 橄榄油和热量限制的影响或联合对神经退行性的影响。我们将喂入中间 在随意或热量限制条件下沿着低或高MUFA的老年小鼠饮食 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 这些研究以促进我们对饮食脂质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开放新机制 针对脂质代谢的治疗途径。