Lifespan extension by reverse fasting

通过反向禁食延长寿命

• 批准号: 10575272
• 负责人: Michael Petrascheck
• 金额: $ 27.15万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10575272
• 关键词: Aging; Animal Feed; Animals; CD2 Antigens; Caenorhabditis elegans; Candidate Disease Gene; Cyclic AMP; Diet; Dose; Eating; Energy Intake; Energy Metabolism; Energy Supply; Energy consumption; Equilibrium; Fasting; Fatigue; Future; G-Protein-Coupled Receptors; Gene Expression; Generations; Genes; Health; Hyperphagia; Insulin; Intake; Intervention; Link; Longevity; Measures; Mediating; Metabolic; Mitochondria; Modeling; Pathway interactions; Phenotype; Predisposition; RNA Interference; Respiration; Serotonin; Signal Transduction; Starvation; Testing; Time; empowerment; experimental study; feeding; follow-up; knock-down; mutant; prevent; reduced food intake; response; serotonin receptor; trigger point

Project Summary In our application entitled" Lifespan extension by reverse fasting," we propose a new model connecting energy metabolism and aging. In this model, longevity mechanisms are triggered by an energy deficit in which the food intake does not provide enough energy to match the animal's energy expenditure (classical fasting). This model further suggests that increasing energy expenditure while keeping food intake constant (reverse fasting) should also generate an energy deficit that triggers longevity. In this application, we use C. elegans to test these ideas. We find that the G protein-coupled receptor SER-7 controls energy expenditure. Activation of SER-7 by serotonin dose-dependently increases energy demand, mitochondrial respiration, and subsequently food intake. In wild-type N2 animals increasing energy demand by exogenous serotonin is consistently matched by an equivalent increase in food intake, preventing the generation of an energy deficit. Testing eight different longevity mutants, we find that the ability to upregulate energy expenditure and food intake is severely restricted in all but one of them, revealing the existence of a general energy-saving mechanism in longevity mutants. For example, daf-2(e1370) mutants have roughly half the respiration and food intake rate of wild-type animals, and their food intake in response to serotonin is severely bunted. However, we identified a daf-2 mutant with an almost wild-type respiration and food intake profile. Only the response to exogenous serotonin at high concentrations is slightly blunted, suggesting the proposed energy-saving mechanism observed in daf-2(e1370) is not active. We find that the lack of an energy- saving mechanism in that daf-2 mutant elevates the metabolic set point at which the dauer pathway is triggered. The result is an animal that activates the dauer pathway at a point when it already eats twice as much as wild type. This daf-2 mutant is the first confirmation of the reverse fasting hypothesis. It shows that it is possible to generate animals that live long and overeat, as long as the energy expenditure is higher than the energy intake. This application aims to identify the fasting/starvation-induced energy-saving mechanism and to show that its inactivation will enable many longevity mutants to overeat and live long.

项目摘要 在我们的申请中，标题为“通过反向禁食延长寿命扩展”，我们提出了一个连接能量的新模型 代谢和衰老。在此模型中，寿命机制是由食物的能量不足触发的 进气口不能提供足够的能量来匹配动物的能量消耗（经典禁食）。这 模型进一步表明，增加能量消耗的同时保持食物摄入量的恒定（反向禁食） 还应该产生触发寿命的能源不足。 在此应用程序中，我们使用秀丽隐杆线虫来测试这些想法。我们发现G蛋白偶联受体Ser-7 控制能源支出。 5-羟色胺剂量依赖性地增加能量需求的Ser-7激活， 线粒体呼吸，然后是食物摄入量。在野生型N2动物中，动物增加了能源需求 外源5-羟色胺始终与食物摄入量的同等增加相匹配，以防止 产生能源不足。测试八个不同的寿命突变体，我们发现上调的能力 能量消耗和食物摄入量在其中一个以外的全部受到严格限制，揭示了存在的存在 长寿突变体中的一般节能机制。例如，DAF-2（E1370）突变体的突变体大约一半 野生型动物的呼吸和食物摄入率以及对5-羟色胺的食物摄入量是 严重束缚。但是，我们确定了一个几乎野生型呼吸和食物摄入的DAF-2突变体 轮廓。仅在高浓度下对外源性羟色胺的反应略微钝化，这表明 在DAF-2（E1370）中观察到的拟议的节能机制不活跃。我们发现缺乏能量 - 在该DAF-2突变体中，保存机制提高了Dauer途径的代谢设定点 触发。结果是一种动物，该动物在已经吃了两倍的时候就激活了道路途径 和野生型一样。该DAF-2突变体是反向禁食假设的首次证实。它表明它 只要能量支出高于 能量摄入。该应用程序旨在确定禁食/​​饥饿引起的节能机制，并 证明其灭活将使许多寿命突变体能够暴饮暴食和长寿。