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.

概括 衰老研究的主要目标之一是发现可以延长寿命和Healthspan的干预措施， 健康的生活。在当前的建议中，我们将重点放在新的治疗方面：限制 饮食中的磷酸盐和钾。在地标研究寿命扩展的背景下 碳和硫的限制，饮食中磷酸盐和钾的作用几乎完全已经完全 老龄化研究界通过了。在使用酵母作为模型系统的初步实验中，我们 已经看到，相对于标准条件，磷酸盐和钾限制可将寿命延长至24％。 这种效果是针对人类健康的衰老研究的特别令人信服的目标，因为任何临床 应用可以利用当前可用的磷酸盐和钾饥饿的药物。到 但是，启用任何这样的翻译事业，我们必须对持续的寿命足够了解 这些方案以设计有效的治疗方法。我们建议将无脊椎动物模型系统用于一系列 快速，相对便宜且结论性的实验，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AIM 1中，我们使用严格的微流体系统将这些药物筛选在酵母中 寿命测定，我们研究了遗传和环境微量营养素的机制 饥饿会产生其影响。在AIM 2中，我们筛选了最引人注目的药物，以影响生命周期和 线虫蠕虫中的HealthSpan。这些实验将共同作为测试pro-的跳板 哺乳动物系统中的寿命，亲养护治疗和基因。