Ketogenic oscillations and neurometabolic healthspan

生酮振荡和神经代谢健康寿命

基本信息

批准号：
10646300
负责人：
Peter A Crawford
金额：
$ 38.55万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646300
关键词：
3-hydroxy-3-methylglutaryl-coenzyme A Address Adipose tissue Age Months Aging Anatomy Attention Body Composition Brain Brain region Caloric Restriction Carbohydrates Catabolism Chronic Clinical Trials Coenzyme A-Transferases Cognition Cognitive Dissection Energy Intake Engineering Epilepsy Exercise Fasting Fatty acid glycerol esters Female Future Genetic Genotype Health Hepatic Hepatocyte Homeostasis Human Impaired cognition Individual Intermittent fasting Intervention Kansas Ketone Bodies Ketones Ketoses Ketosis Knock-out Link Lipolysis Liver LoxP-flanked allele Maintenance Measures Mediating Memory Metabolic Metabolic Diseases Metabolic dysfunction Metabolism Minnesota Mitochondria Modeling Mus Nerve Degeneration Neurons Nutritional Outcome Peripheral Phenotype Physical Function Play Recurrence Research Personnel Role Running Starvation Testing Time-restricted feeding Tracer Unhealthy Diet Universities Work aging brain brain health clinically relevant cognitive function diet and exercise executive function experimental study feeding genetic manipulation glucose metabolism healthspan healthy aging improved indexing innovation interest ketogenesis ketogenic diet ketogentic lifestyle intervention lipid metabolism male metabolic phenotype metabolome middle age mode of exercise mouse model nonhuman primate novel oxidation physical inactivity preservation prevent response sedentary stable isotope succinyl-coenzyme A synergism therapeutic target tool transcriptome treatment optimization western diet

项目摘要

Project Summary Poor diet and chronic physical inactivity synergize with aging to induce physical decline and cognitive dysfunction. As a result, there is a current push to test various diet and exercise modalities that can improve metabolic health, preserve cognition, and expand health span. Both various forms of caloric restriction and exercise have been shown to provide benefits for metabolism, cognition, and physical function. One popular notion is that fuel oscillations alternating between carbohydrate and fat utilization are beneficial for long term metabolic and cognitive health. A key corollary is that ketone metabolism, triggered by carbohydrate restriction and fat catabolism, may mediate the observed benefits. Indeed, exploiting ketone body metabolism has garnered recent attention as a tool to improve both peripheral metabolism and treat impaired cognition in aging individuals. Rationale for ketone metabolism in brain health originates from the benefits of ketogenic diets or starvation for seizure disorders. Due to the robust stimulation of adipose tissue lipolysis and increased fat oxidation in the liver, exercise is another trigger for hepatic ketogenesis, raising the question of whether the beneficial relationship between brain health and exercise could at least in part be transduced by ketone metabolism. Currently there are large clinical trials testing if ketogenic diets can mitigate or treat cognitive decline and neurodegenerative conditions associated with aging, however, studies investigating mechanisms of action are lacking. This proposal will fill this void by leveraging novel genetic mouse models and cutting-edge approaches to test the central hypothesis that nutritional and exercise-mediated oscillations of integrated ketone metabolism improve neurometabolic health span. Studying mice with selective loss of either hepatic ketogenesis or neuronal ketone oxidation will allow independent dissection of the mechanistic roles of integrated ketone metabolism in mediating the well-described benefits of intermittent fasting (Aim 1) and exercise (Aim 2), which are both established models that provoke ketosis and ketone utilization by the brain, while also improving metabolic and cognitive phenotypes. The specific roles of ketone metabolism on caloric intake; body composition; whole-body energy homeostasis, glucose metabolism, lipid metabolism, and ketone turnover; cognitive function, including memory and executive function; mitochondrial function in brain; metabolic flux (quantified using stable isotope tracers) in brain; as well as the metabolome and transcriptome of discrete anatomic brain regions will all be quantified. Both male and female mice will be examined in mid-life (12 months of age) after chronic Western diet feeding when differences in health span will emerge via cognition, physical function, and metabolic phenotypes. By defining the independent roles of both hepatic ketogenesis and neuronal ketone body oxidation in health span-promoting interventions, the results will optimize therapies to be tested in future clinical trials. Moreover, this work will elucidate specific therapeutic targets linking metabolism, cognition, and physical function in aging.

项目摘要饮食不良和慢性身体不活跃与衰老协同作用，诱导身体下降和认知功能障碍。结果，目前有一个可以测试各种饮食和运动方式可以改善的推动力代谢健康，保留认知并扩大健康范围。各种形式的热量限制和运动已被证明可以为新陈代谢，认知和身体机能提供好处。一个流行概念是，碳水化合物和脂肪利用之间交替交替的燃料振荡在长期内是有益的代谢和认知健康。一个关键的推论是，酮代谢是由碳水化合物限制触发的和脂肪分解代谢可能会介导观察到的好处。确实，利用酮体代谢已获得最近的关注是改善外周代谢和治疗衰老个体认知受损的工具。大脑健康中酮代谢的基本原理源于生酮饮食的益处或饥饿的益处癫痫发作。由于脂肪组织脂解的强大刺激和肝脏中脂肪氧化增加，锻炼是肝生酮发生的另一个触发因素，提出了一个有益关系的问题在大脑健康和运动之间至少可以部分通过酮代谢转导。目前在那里如果生酮饮食可以减轻或治疗认知能力下降和神经退行性，是否进行大型临床试验测试然而，与衰老相关的条件缺乏研究调查作用机制的研究。这个建议通过利用新型的遗传小鼠模型和尖端测试中心的方法来填补这一空白假设综合酮代谢的营养和运动介导的振荡可以改善神经代谢健康跨度。研究肝酮作用或神经元酮的选择性丧失的小鼠氧化将允许独立解剖整合酮代谢的机械作用间歇性禁食（AIM 1）和练习（AIM 2）的良好描述的好处，它们都建立大脑引起酮症和酮利用的模型，同时也改善了代谢和认知表型。酮代谢在热量摄入中的特定作用；身体成分；全身能量稳态，葡萄糖代谢，脂质代谢和酮更新；认知功能，包括记忆和执行功能；大脑中的线粒体功能；代谢通量（使用稳定的同位素示踪剂定量）脑;以及离散解剖脑区域的代谢组和转录组以及转录组都将被量化。两个都慢性西方饮食喂养后，将在中期（12个月大）中检查雄性和雌性小鼠健康跨度的差异将通过认知，身体功能和代谢表型出现。通过定义肝酮作用和神经元酮体氧化在促进健康跨度中的独立作用干预措施，结果将在将来的临床试验中优化要测试的疗法。而且，这项工作将阐明特定的治疗靶标连接衰老中的代谢，认知和身体功能。