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.

项目概要不良饮食和长期缺乏身体活动与衰老协同作用，导致身体衰退和认知能力下降功能障碍。因此，目前正在推动测试各种可以改善健康的饮食和运动方式。代谢健康，保持认知，延长健康寿命。各种形式的热量限制和运动已被证明对新陈代谢、认知和身体机能有益。热门之一概念是碳水化合物和脂肪利用之间交替的燃料振荡有利于长期代谢和认知健康。一个关键的推论是，由碳水化合物限制引发的酮代谢和脂肪分解代谢，可能会介导观察到的益处。事实上，利用酮体代谢已经获得了最近作为改善外周代谢和治疗老年人认知受损的工具而受到关注。酮代谢对大脑健康的影响源于生酮饮食或饥饿的好处癫痫症。由于肝脏中脂肪组织脂肪分解的强烈刺激和脂肪氧化的增加，运动是肝生酮的另一个触发因素，这提出了这样的问题：这种有益关系是否存在？大脑健康和运动之间的关系至少部分可以通过酮代谢来转换。目前有大型临床试验正在测试生酮饮食是否可以减轻或治疗认知能力下降和神经退行性疾病然而，对于与衰老相关的情况，缺乏作用机制的研究。这个提议将通过利用新颖的基因小鼠模型和尖端方法来测试中央功能来填补这一空白假设营养和运动介导的综合酮代谢的振荡改善神经代谢健康跨度。研究选择性丧失肝生酮或神经元酮的小鼠氧化将允许独立剖析整合酮代谢在介导中的机制作用间歇性禁食（目标 1）和锻炼（目标 2）的好处已得到充分描述激发酮症和大脑利用酮的模型，同时还能改善代谢和认知表型。酮代谢对热量摄入的具体作用；身体成分；全身能量体内平衡、葡萄糖代谢、脂质代谢和酮周转；认知功能，包括记忆和执行职能；大脑中的线粒体功能；代谢通量（使用稳定同位素示踪剂量化）脑;以及离散大脑解剖区域的代谢组和转录组都将被量化。两个都雄性和雌性小鼠在长期西方饮食喂养后将在中年（12个月大）进行检查健康跨度的差异将通过认知、身体机能和代谢表型而显现出来。通过定义肝生酮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，其结果将优化未来临床试验中待测试的疗法。此外，这项工作将阐明与衰老过程中的新陈代谢、认知和身体功能相关的具体治疗目标。