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

总结 衰老研究的主要目标之一是发现可以延长寿命和健康的干预措施， 健康的生命岁月在目前的建议中，我们专注于一种新的治疗方法：限制 磷酸盐和钾的含量。在对人类寿命延长的里程碑式研究的背景下， 限制碳和硫，膳食磷和钾的作用几乎已经完全 被老龄化研究界忽略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，磷酸盐和钾的限制将寿命延长了24%。 这种效应对于关注人类健康的衰老研究来说是一个特别引人注目的目标，因为任何临床研究都是如此。 应用可以利用目前可获得的磷酸盐和钾饥饿的药物模拟物。到 然而，我们必须充分认识到， 来设计有效的治疗方法。我们建议使用无脊椎动物模型系统的一系列 快速，相对便宜和结论性的实验，以确定哪些磷酸盐和钾结合剂药物 如何延长寿命在目标1中，我们使用严格的微流体系统在酵母中筛选这些药物， 寿命测定，我们调查的机制，遗传和环境微量营养素 饥饿会产生影响。在目标2中，我们筛选了最引人注目的药物对寿命的影响， 蠕虫的健康寿命总之，这些实验将作为测试亲- 寿命、促进健康的治疗和哺乳动物系统中的基因。

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.