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

酮酯饮食可改善与年龄相关的记忆力和肌肉质量下降

• 批准号: 10360505
• 负责人: JON J. RAMSEY
• 金额: $ 17.71万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10360505
• 关键词: Acetoacetates; Adherence; Adult; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Blood; Brain; Brain region; Carbohydrates; Catabolism; Clinical Trials; Cognition; Consumption; Data; Development; Diet; Elderly; Energy Metabolism; Enzymes; Episodic memory; Esters; Exercise; Exhibits; Fasting; Fatty Acids; Female; Fiber; Foundations; Future; Glucose; Hippocampus (Brain); Hour; Human; Impaired cognition; Impairment; Individual; Inflammasome; Insulin Resistance; Intake; Intervention; Ketone Bodies; Ketones; Ketosis; Knowledge; Learning; Link; Lipids; Measures; Memory; Memory Loss; Metabolic; Metabolism; Mus; Muscle; Muscle Weakness; Muscle function; Muscular Atrophy; Nature; Neonatal; Neurosciences; Nutrient; Nutritional; Oral; Organ; Oxidative Stress; Performance; Persons; Phosphorylation; Physical Function; Physical activity; Preventive measure; Protein Biosynthesis; Quality of life; Rattus; Research; Retrieval; Rodent; Running; SLC2A1 gene; Series; Short-Term Memory; Signaling Molecule; Skeletal Muscle; Source; Supplementation; Surveys; Symptoms; Systems Biology; Testing; Therapeutic; Time; Tissues; United States; Visual; Work; age related; age-related muscle loss; aged; aging brain; aging population; behavior change; beta-Hydroxybutyrate; brain health; cognitive testing; diet and exercise; dietary control; dietary restriction; enzyme activity; executive function; fatty acid oxidation; glucose metabolism; glucose transport; glucose uptake; graduate student; human old age (65+); improved; insulin sensitivity; ketogenic diet; ketogentic; long term memory; loss of function; male; memory recognition; metabolomics; middle age; mild cognitive impairment; multidisciplinary; muscle form; muscle metabolism; muscle strength; novel; object recognition; physical conditioning; preservation; prevent; response; sarcopenia; training opportunity

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.

项目摘要（Abstract）： 全球65岁及以上的人口比例正在增长，预计到2050年将达到近17%。老化 与器官和组织功能的进行性下降有关，导致认知改变， 物理功能。特别是，大脑老化表现为执行功能，工作记忆， 和情景记忆，与年龄相关的肌肉减少症导致肌肉无力和活动能力受损。两 这些都可能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-羟基丁酸和乙酰乙酸，是重要的分子提供能量的大脑 在发育、禁食和锻炼期间。我们的研究表明，酮体的水平随着年龄的增长而下降。 这是重要的，因为葡萄糖转运到大脑中会随着年龄的增长而受损。有趣的是， GLUT 1（将葡萄糖转运到大脑中）下降，MCT 1（将酮体转运到大脑中） 在老年大鼠的海马体中增加，海马体是学习和 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，酮作为替代燃料来源 categories受损。此外，3-羟基丁酸盐已显示出抑制NLRP 3炎性体， 其激活与年龄相关的肌肉减少症有关。生酮饮食的一个主要问题是 长期坚持，以及其对纤维和必需营养素摄入的限制性。增加 因此，通过补充剂降低血液中的酮浓度对于老龄化人群是有益的。 在目的1中，我们提出确定补充酮单酯（（R）-3-羟基丁基-（R）-3-羟基丁基-（R） 3-羟基丁酸酯（3-HBHB）），其已显示增加循环3-羟基丁酸酯浓度， 通过一系列认知测试，在基线和饮食7周后，对老年小鼠的长期记忆产生影响。 然后，我们将确定海马转运蛋白、代谢酶和代谢物如何响应变化 血液中酮的水平增加，以提供对酮酯如何影响 海马功能在我们的第二个目标，我们将比较肌肉质量，力量，和自愿的身体 活动的小鼠提供3-HBHB与小鼠对照饮食，然后确定如何机械骨骼 肌肉质量和代谢受酮酯饮食的影响。从这项研究中获得的知识可以 对人口老龄化有重要影响，并可能成为发展的基础。 预防与年龄相关的记忆力衰退和肌肉减少症的稳健治疗。