Ketone ester diet to ameliorate age-related decline in memory and muscle mass

项目摘要(摘要)： 全球65岁及以上人口的比例正在增长，预计到2050年将达到近17%。老龄化 与器官和组织功能的进行性下降有关，导致认知和 身体机能。特别是，大脑老化表现为执行功能、工作记忆、 以及情景记忆，以及与年龄相关的骨量减少会导致肌肉无力和行动不便。两个都是 这些都会对生活质量产生深远的影响，特别是对那些患有阿尔茨海默病的人。 酮体，3-羟基丁酸酯和乙酰乙酸酯，是为大脑提供能量的重要分子。 在发育、禁食和运动过程中。我们的工作表明，酮体的水平随着年龄的增长而下降。 这一点很重要，因为葡萄糖进入大脑的运输随着年龄的增长而受损。有趣的是，虽然富足 GLUT1(负责将葡萄糖输送到大脑)的活性下降，MCT1(负责将酮体输送到大脑) 已被证明在老年大鼠的海马体中增加，海马体是学习和学习必不可少的大脑区域 形成新的长期记忆。最近的研究表明，生酮饮食有益于 对年龄相关记忆的影响，这表明当葡萄糖摄取时，酮可以作为替代燃料来源 分解代谢受损。此外，3-羟基丁酸酯已被证明能抑制NLRP3炎症体， 它的激活与年龄相关的石棺减少症有关。生酮饮食的一个主要问题是低血压 长期坚持，以及其在纤维和基本营养摄入方面的限制性。渐增 因此，通过补充血液中的酮浓度将对老龄化的人口有利。 在目标1中，我们建议确定补充酮单酯((R)-3-羟丁基-(R)-(R)- 3-羟基丁酸酯(3-HBHb)，其已被证明可增加循环中的3-羟基丁酸酯浓度， 通过在基线和节食7周后进行一系列认知测试，对衰老小鼠的长期记忆进行研究。 然后我们将确定海马体转运蛋白、代谢酶和代谢物是如何变化的。 以提高血中酮的水平，以提供对酮酯如何影响的机械理解 海马体功能。在我们的第二个目标中，我们将比较肌肉质量、力量和自愿体能 给小鼠提供3-hbHb的小鼠的活动，然后从机械上确定骨骼有多大 肌肉质量和新陈代谢受酮酯饮食的影响。从这项研究中获得的知识可以 对老龄化人口有重要影响，并可能成为发展的基础 强有力的治疗方法，以防止与年龄相关的记忆力衰退和骨质疏松症。

Project Summary (Abstract): The global proportion of individuals 65 and older is growing and is expected to reach nearly 17% by 2050. Aging is associated with a progressive decline in organ and tissue function resulting in alterations in cognition and physical function. In particular, brain aging is manifested as impairments in executive function, working memory, and episodic memory, and age-related sarcopenia leads to muscle weakness and impaired mobility. Both of these can have a profound impact on the quality of life, particularly for those suffering from Alzheimer’s disease. Ketone bodies, 3-hydroxybutyrate and acetoacetate, are important molecules providing energy to the brain during development, fasting, and exercise. Our work has shown that levels of ketone bodies decrease with aging. This is significant as glucose transport into the brain is impaired with aging. Interestingly, while the abundance of GLUT1 (which transports glucose into the brain) declines, MCT1 (which transport ketone bodies into the brain) has been shown to increase in the hippocampus of aged rats, the brain region essential for learning and formation of new long-term memories. Recent studies have shown that a ketogenic diet results in beneficial effects on age-related memory, which suggest ketones serve as an alternate fuel source when glucose uptake and catabolism is impaired. Additionally, 3-hydroxybuyrate has been shown to inhibit the NLRP3 inflammasome, activation of which has been linked with age-related sarcopenia. A major issue with the ketogenic diet is the low long-term adherence, and its restrictive nature with respect to fiber and essential nutrient intake. Increasing ketone concentrations in the blood through a supplement would therefore be of benefit for an aging population. In aim 1, we propose to determine the effect of supplementation of a ketone monoester ((R)-3-hydroxybutyl-(R)- 3-hydroxybutyrate (3-HBHB)), which has been shown to increase circulating 3-hydroxybutyrate concentrations, on long-term memory in aged mice through a series of cognitive tests at baseline and after 7 weeks on the diet. We will then determine how hippocampal transporters, metabolic enzymes, and metabolites change in response to increased levels of ketones in the blood to provide a mechanistic understanding of how ketone esters impact hippocampal function. In our second aim, we will compare the muscle mass, strength, and voluntary physical activity of mice provided 3-HBHB with mice on a control diet, and then determine mechanistically how skeletal muscle mass and metabolism is affected by the ketone ester diet. The knowledge gained from this study could have important implications for the aging population, and could represent a foundation on which to develop robust therapeutic treatments to prevent age-related memory decline and sarcopenia.