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.

项目概要 在我们题为“通过反向禁食延长寿命”的申请中，我们提出了一种连接能量的新模型 新陈代谢和衰老。在这个模型中，长寿机制是由能量不足触发的，其中食物 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，在保持食物摄入量恒定的同时增加能量消耗（反向禁食） 还应该产生能量不足，从而延长寿命。 在此应用中，我们使用线虫来测试这些想法。我们发现G蛋白偶联受体SER-7 控制能量消耗。血清素激活 SER-7 会剂量依赖性地增加能量需求， 线粒体呼吸，以及随后的食物摄入。在野生型 N2 动物中，能量需求增加 外源性血清素始终与食物摄入量的同等增加相匹配，从而防止 能源短缺的产生。测试了八种不同的长寿突变体，我们发现上调的能力 除其中一种外，所有这些动物的能量消耗和食物摄入都受到严格限制，这表明存在一种 长寿突变体的一般节能机制。例如，daf-2(e1370) 突变体大约有一半 野生型动物的呼吸和食物摄入速率，以及它们对血清素的反应的食物摄入量为 严重短打。然而，我们发现了一个 daf-2 突变体，其呼吸和食物摄入量几乎是野生型的 轮廓。只有高浓度的外源性血清素的反应才会稍微减弱，这表明 daf-2(e1370) 中观察到的拟议节能机制并未激活。我们发现缺乏能量—— 保存机制在于 daf-2 突变体提高了 dauer 途径的代谢设定点 触发。结果是，当动物的食量已经是人类的两倍时，它就会激活多尔途径。 与野生型非常相似。这种 daf-2 突变体首次证实了反向禁食假说。这表明它 只要能量消耗高于能量消耗，就有可能产生长寿且吃得过多的动物。 能量摄入。该应用旨在识别禁食/饥饿引起的节能机制并 研究表明，它的失活将使许多长寿突变体能够暴饮暴食并长寿。