The Mechanism of Plumbagin-induced Stress Resistance and Lifespan Extension

描述（由申请人提供）：延迟衰老和年龄相关疾病发作的药物治疗将是非常有价值的。这些化合物已经通过毒物兴奋效应的研究被鉴定出来。激效（Hormesis）或激效效应（Hormetic effect）是一种进化上保守的现象，其中轻度胁迫可以诱导对更强烈胁迫（自我保护）和不同胁迫（交叉保护）的抗性，可能是通过诱导对环境胁迫的一般保护机制。这种反应的有益影响已被证明包括延长寿命。了解增加寿命和抗应激性的激素效应的机制基础将阐明控制衰老的一般机制，并建议可以调节这一过程的药理学干预。白花丹素是一种天然存在的毒素，已被证明在广泛的生物体中引起激素效应。低剂量的白花丹素诱导芽殖酵母酿酒酵母对高剂量的耐受性，导致线虫秀丽隐杆线虫的寿命延长，并在中风模型中保护小鼠免受脑损伤。我发现，低剂量的白花丹素诱导耐受高剂量也显着增加寿命在S。啤酒。白花丹素兴奋效应中涉及的途径在任何生物体中都是未知的。这项研究的目的是确定低剂量的白花丹素促进S.啤酒。白花丹素是一种萘醌，是一类可以与细胞蛋白质反应的化合物。白花丹素在微摩尔浓度下诱导胁迫抗性，约为其他萘醌产生相同效果所需水平的0.1%。因此，白花丹素可能被特定的蛋白质感知，我已经确定了白花丹素诱导的自我保护所需的两个候选人。在三个具体目标中，该项目探索了一种假设，即低水平的白花丹素被少量蛋白质感知，这些蛋白质随后启动信号级联反应以诱导自我保护和寿命延长。目的1将确定白花丹素激素途径是否与其他已知的延长寿命和应激保护治疗（如减少卡路里摄入、热应激和氧化应激）的途径相同或不同。目的2将测试候选白花丹素感测蛋白是否与白花丹素形成共价键。目标3将确定与候选传感器相关的信号通路的激活是否足以概括白花丹素的激素效应，并将使用全基因组方法鉴定白花丹素诱导的胁迫抗性所需的基因。这项工作的成功完成将展示小分子如何延长寿命，并将提供设计可以改善人类健康和寿命的药理学干预所需的基本知识。

DESCRIPTION (provided by applicant): Pharmacological treatments that delay aging and the onset of age-related diseases would be highly valuable. Such compounds have been identified though the study of hormesis. Hormesis, or the hormetic effect, is an evolutionarily conserved phenomenon in which a mild stress can induce resistance to a more intense stress (autoprotection) and to different stresses (cross-protection), presumably by the induction of general protective mechanisms against environmental stress. The beneficial effects of this response have been shown to include lifespan extension. Understanding the mechanistic basis of a hormetic effect that increases lifespan and stress resistance will elucidate general mechanisms that control aging and suggest pharmacological interventions that can regulate this process. Plumbagin is a naturally occurring toxin that has been shown to elicit the hormetic effect in a wide range of organisms. Low doses of plumbagin induce tolerance to high doses in the budding yeast Saccharomyces cerevisiae, cause lifespan extension in the worm Caenorhabditis elegans, and protect mice against brain damage in a model of stroke. I found that low doses of plumbagin that induce tolerance to a high dose also significantly increase lifespan in S. cerevisiae. The pathways involved in plumbagin hormesis are not known in any organism. The goal of the proposed research is to determine the mechanism by which low doses of the plumbagin promote stress resistance and longevity in S. cerevisiae. Plumbagin is a naphthoquinone, a class of compounds that can react with cellular proteins. Plumbagin induces stress resistance at micromolar concentrations, about 0.1% the level required for other naphthoquinones to produce the same effect. Thus, plumbagin may be sensed by specific proteins, and I have identified two candidates that are required for plumbagin-induced autoprotection. In three specific aims, this project explores the hypothesis that low levels of plumbagin are sensed by a small number of proteins which subsequently initiate a signaling cascade to induce autoprotection and lifespan extension. Aim 1 will determine if the plumbagin hormetic pathway is the same as, or distinct from, pathways for other known lifespan-extending and stress protection treatments such as reduced calorie intake, heat stress and oxidative stress. Aim 2 will test if candidate plumbagin sensing proteins form covalent bonds with plumbagin. Aim 3 will determine if activation of signaling pathways associated with candidate sensors is sufficient to recapitulate the hormetic effects of plumbagin, and will identify genes required for plumbagin-induced stress resistance using whole genome approaches. Successful completion of this work will show how a small molecule can extend lifespan, and will provide essential knowledge required to devise pharmacological interventions that can improve human health and longevity.