The Mechanism of Plumbagin-induced Stress Resistance and Lifespan Extension

描述（由申请人提供）：延缓衰老和年龄相关疾病发病的药物治疗将是非常有价值的。这些化合物已经通过激效研究得到了鉴定。激效或激效效应是一种进化上保守的现象，在这种现象中，轻微的压力可以诱导对更强烈的压力（自我保护）和不同的压力（交叉保护）的抵抗，可能是通过诱导对环境压力的一般保护机制来实现的。这种反应的有益影响已被证明包括延长寿命。了解增加寿命和抗逆性的激效效应的机制基础，将阐明控制衰老的一般机制，并提出可以调节这一过程的药物干预措施。白桦白花素是一种自然产生的毒素，已被证明可在多种生物体中引起激效。低剂量的白桦素诱导出芽酵母对高剂量的酿酒酵母产生耐受性，延长秀丽隐杆线虫的寿命，并在中风模型中保护小鼠免受脑损伤。我发现，诱导对高剂量的耐受性的低剂量白桦素也显著增加了酿酒葡萄球菌的寿命。在任何生物体中，参与白桦白素激效的途径尚不清楚。提出的研究目标是确定低剂量白桦素促进酿酒酵母抗逆性和寿命的机制。白马菊素是萘醌类化合物，能与细胞蛋白发生反应。白丹素在微摩尔浓度下诱导抗逆性，约为其他萘醌产生相同效果所需浓度的0.1%。因此，铅铅金可能被特定的蛋白质感知，我已经确定了两个候选蛋白，它们是铅铅金诱导的自身保护所必需的。在三个具体目标中，该项目探索了一种假设，即少量蛋白质可以感知低水平的白桦素，这些蛋白质随后启动信号级联，从而诱导自我保护和延长寿命。目的1将确定白桦素的致热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将测试候选白桦素感测蛋白是否与白桦素形成共价键。目的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铅白丹素的激效，并将使用全基因组方法确定铅白丹素诱导的抗逆性所需的基因。这项工作的成功完成将展示小分子如何延长寿命，并将为设计能够改善人类健康和寿命的药理干预提供必要的知识。

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.