Ketogenic oscillations and neurometabolic healthspan

生酮振荡和神经代谢健康寿命

• 批准号: 10456247
• 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
• 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/10456247
• 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; 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; health difference; 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; therapeutic target; tool; transcriptome; treatment optimization; western diet

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 不良饮食和长期缺乏体力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，目前有一种趋势是测试各种可以改善的饮食和锻炼方式 新陈代谢健康，保持认知，扩大健康跨度。各种形式的卡路里限制和 运动已被证明对新陈代谢、认知和身体机能有好处。一个很受欢迎的 这种想法是，碳水化合物和脂肪利用之间交替的燃料振荡对长期有益。 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，可能会调节观察到的好处。事实上，利用酮体新陈代谢已经获得了 最近，注意作为一种工具，既可以改善外周代谢，也可以治疗老年人认知障碍。 酮代谢对大脑健康的理论基础源于生酮饮食或饥饿对 癫痫发作障碍。由于脂肪组织脂肪分解的强劲刺激和肝脏中脂肪氧化的增加， 运动是肝酮体生成的另一个触发因素，这引发了这样一个问题：这种有益的关系 大脑健康和运动之间的关系至少在一定程度上可以通过酮类代谢来传递。目前在那里 是否有大型临床试验测试生酮饮食是否可以缓解或治疗认知功能减退和神经退行性变 然而，与衰老相关的条件，缺乏对其作用机制的研究。这项建议 将通过利用新的遗传小鼠模型和尖端方法来测试中央 营养和运动介导的整体酮代谢振荡改善假说 神经代谢健康跨度。研究肝酮生成或神经酮选择性缺失的小鼠 氧化将允许独立地剖析集成酮代谢在调节中的机制作用 间歇性禁食(目标1)和锻炼(目标2)的好处都是公认的 激发酮和酮被大脑利用的模型，同时也改善新陈代谢和认知 表型。酮类代谢对热量摄入、身体成分、全身能量的特殊作用 动态平衡、葡萄糖代谢、脂肪代谢和酮代谢；认知功能，包括记忆 和执行功能；大脑中的线粒体功能；代谢流量(使用稳定同位素示踪剂量化) 大脑；以及大脑不同解剖区域的代谢组和转录组都将被量化。两者都有 雄性和雌性小鼠将在中年(12个月大)时进行检查，在长期西方饮食喂养后 健康跨度的差异将通过认知、身体功能和新陈代谢表型而显现。通过定义 肝酮体发生和神经元酮体氧化在健康促进中的独立作用 干预措施，结果将优化治疗，以便在未来的临床试验中进行测试。此外，这项工作将 阐明衰老过程中新陈代谢、认知和身体功能的具体治疗目标。