Screening potassium and phosphate binder drugs for lifespan and healthspan effects in invertebrates

筛选钾和磷酸盐结合剂药物对无脊椎动物寿命和健康的影响

• 批准号: 9379421
• 负责人: Rachel Beth Brem
• 金额: $ 9.7万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9379421
• 关键词: Age; Aging; Area; Biological Assay; Biological Availability; Biological Models; Biology of Aging; Caenorhabditis elegans; Caloric Restriction; Carbon; Chelating Agents; Clinic; Communities; Data; Diet; Dose; Employee Strikes; Environment; Formulation; Genes; Genetic; Goals; Growth; Health; Human; Inorganic Phosphate Transporter; Intervention; Invertebrates; Life; Literature; Longevity; Maps; Measures; Microfluidics; Micronutrients; Modeling; Mus; Nematoda; Neurologic; Nutrient; Patients; Pharmaceutical Preparations; Potassium; Potassium Phosphate; Preclinical Drug Evaluation; Publishing; Regimen; Reporting; Research; Role; Series; Starvation; Sulfur; System; Testing; Work; Yeasts; cell motility; clinical application; design; dietary restriction; effective therapy; experimental study; fly; healthy aging; inhibitor/antagonist; inorganic phosphate; mimetics; novel; overexpression; response; screening; uptake

SUMMARY One of the main goals of aging research is to discover interventions that can prolong lifespan and healthspan, the healthy years of life. In the current proposal we focus on a novel treatment toward this end: the restriction of phosphate and potassium in the diet. Against a backdrop of landmark studies of lifespan extension under restriction of carbon and sulfur, the role of dietary phosphate and potassium has been almost completely passed over by the aging research community. In preliminary experiments using yeast as a model system, we have seen that phosphate and potassium restriction extends lifespan up to 24% relative to standard conditions. This effect is a particularly compelling target for aging research focused on human health, since any clinical applications could make use of currently available drug mimetics of phosphate and potassium starvation. To enable any such translational undertaking, however, we must know enough about the longevity evoked by these regimens to design effective treatments. We propose to use invertebrate model systems for a series of rapid, relatively cheap, and conclusive experiments to establish which phosphate and potassium binder drugs extend lifespan and how. In Aim 1 we screen these drugs in yeast using a rigorous microfluidic system for lifespan assays, and we investigate the mechanisms by which genetic and environmental micronutrient starvations exert their effects. In Aim 2 we screen the most compelling drugs for effects on lifespan and healthspan in nematode worms. Together, these experiments will serve as a springboard for the testing of pro- lifespan, pro-healthspan treatments and genes in mammalian systems.

摘要 老龄化研究的主要目标之一是发现可以延长寿命和健康寿命的干预措施， 生命中的健康岁月。在目前的提案中，我们将重点放在一种新的治疗方法上：限制 饮食中的磷酸盐和钾。在关于延长寿命的里程碑式研究的背景下 限制碳和硫，饮食中磷和钾的作用几乎完全 被老龄化研究界忽视了。在以酵母为模型系统的初步实验中，我们 与标准条件相比，限制磷和钾可以延长寿命高达24%。 对于关注人类健康的老龄化研究来说，这种效应是一个特别引人注目的目标，因为任何临床 应用可以利用目前可用的磷酸盐和钾素饥饿的药物模拟物。至 然而，要实现任何这样的翻译承诺，我们必须对由 这些养生法可以设计出有效的治疗方法。我们建议将无脊椎动物模型系统用于一系列 快速、相对便宜和确凿的实验，以确定哪种磷酸盐和钾粘合剂药物 延长寿命以及如何延长寿命。在目标1中，我们使用严格的微流控系统在酵母中筛选这些药物 寿命分析，我们调查了遗传和环境微量营养素的机制 饥饿会发挥它们的作用。在目标2中，我们筛选出最有说服力的药物，以延长寿命和 线虫的健康寿命。总而言之，这些实验将成为测试PRO- 哺乳动物系统中的寿命、促进健康的治疗和基因。