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 在我们题为”通过反向禁食延长寿命”的申请中，我们提出了一种新的模型， 新陈代谢和衰老。在这个模型中，长寿机制是由能量不足引发的， 摄入量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，同时保持食物摄入量不变（反向禁食） 也会导致能量不足从而延长寿命 在这个应用程序中，我们使用C。elegans来测试这些想法。我们发现G蛋白偶联受体SER-7 控制能量消耗。5-羟色胺对SER-7的激活剂量依赖性地增加能量需求， 线粒体呼吸和随后的食物摄入。在野生型N2动物中， 外源性5-羟色胺始终与食物摄入量的等量增加相匹配， 产生能量赤字。测试八种不同的长寿突变体，我们发现， 能量消耗和食物摄入都受到严格限制，但其中一个，揭示了存在一个 长寿突变体的一般节能机制。例如，daf-2（e1370）突变体具有大约一半的 野生型动物的呼吸和食物摄入率，以及它们响应于血清素的食物摄入， 严重短打。然而，我们鉴定了一个daf-2突变体，它具有几乎野生型的呼吸和食物摄取 profile.只有对高浓度外源性5-羟色胺的反应稍微迟钝，这表明 daf-2（e1370）中观察到的拟议节能机制未激活。我们发现缺乏能量- DAF-2突变体中的节省机制提高了代谢设定点， 被触发了其结果是，当动物已经吃了两倍的食物时， 就像野生型一样。这个daf-2突变体是反向禁食假说的第一个证实。这表明， 是可能产生的动物，活得长，吃得过多，只要能量消耗高于 能量摄入本申请旨在确定禁食/饥饿诱导的节能机制， 表明它的失活将使许多长寿突变体吃得过多而活得更长。