The Mechanism of Plumbagin-induced Stress Resistance and Lifespan Extension

白花丹素诱导抗应激和延长寿命的机制

• 批准号: 8628633
• 负责人: Suzanne Elizabeth Berezovsky
• 金额: $ 5.39万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8628633
• 关键词: Affect; Age of Onset; Aging; Amino Acids; Bacterial Infections; Biological Assay; Brain Injuries; Caenorhabditis elegans; Caloric Restriction; Cells; Chemicals; Cysteine; Disease; Dose; Epitopes; Eukaryota; Exposure to; Fluorescence; Genes; Genetic Transcription; Genome; Goals; Health; Heat Stress Disorders; Heat-Shock Response; Human; Hydrogen Peroxide; Institution; Intake; Intervention; Ischemic Stroke; Knowledge; Life; Link; Longevity; Lysine; Mammalian Cell; Mammals; Mediating; Methods; Modeling; Modification; Molecular; Molecular Chaperones; Monitor; Mus; Mutagens; Mutation; Mycoses; Naphthoquinones; Normal Cell; Organism; Oxidants; Oxidative Stress; Parasites; Pathway interactions; Pharmacologic Substance; Pharmacological Treatment; Phenotype; Plants; Process; Proteins; Publishing; Quality of life; Quinones; Radiation; Research; Resistance; Role; Saccharomyces cerevisiae; Saccharomycetales; Side; Signal Pathway; Signal Transduction; Stress; Stroke; Sulfhydryl Compounds; Testing; Toxin; Virus; Vitamin K 3; Western Blotting; Work; Yeasts; adduct; age related; aging population; base; biological adaptation to stress; career; covalent bond; genome wide association study; improved; mutant; plumbagin; public health relevance; response; sensor; small molecule; stressor; transcription factor; tumor

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.

描述(由申请人提供)：延缓衰老和与年龄相关疾病的发病的药物治疗将是非常有价值的。这些化合物已经通过兴奋作用的研究得到了鉴定。兴奋效应，或兴奋效应，是一种进化上保守的现象，在这种现象中，温和的应激可以诱导对更强的应激(自身保护)和不同的应激(交叉保护)的抵抗，可能是通过诱导对环境应激的一般保护机制。这一反应的有益影响已被证明包括延长寿命。了解可延长寿命和抗应激能力的兴奋效应的机制基础，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。白藜芦醇是一种天然存在的毒素，已被证明在多种生物体中都能产生兴奋效应。低剂量的白花丹诱导萌芽酵母酿酒酵母对高剂量的耐受，使线虫的寿命延长，并在中风模型中保护小鼠免受脑损伤。我发现，诱导对高剂量产生耐受性的低剂量白花丹也显著延长了酿酒酵母的寿命。在任何生物体中，都不知道参与白花蛇毒兴奋作用的途径。这项拟议的研究的目标是确定低剂量的白花丹提高酿酒酵母的抗逆性和寿命的机制。白藜芦醇是一种萘醌类化合物，可以与细胞蛋白质发生反应。白铅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水平的0.1%。因此，白花蛇毒可能被特定的蛋白质感知，我已经确定了白花蛇毒诱导的自身保护所必需的两个候选者。在三个特定的目标中，该项目探索了一种假设，即少量蛋白质感受到低水平的铅黄素，这些蛋白质随后启动信号级联反应，诱导自我保护和延长寿命。目标1将确定白花蛇毒激素途径是否与其他已知的延长寿命和压力保护治疗的途径相同或不同，如减少卡路里摄入量、热应激和氧化应激。目标2将测试候选的白花蛇毒感觉蛋白是否与白花蛇毒蛋白形成共价键。目的3将确定与候选感受器相关的信号通路的激活是否足以概括白花蛇毒的兴奋效应，并将使用全基因组方法识别白花蛇毒诱导抗逆所需的基因。这项工作的成功完成将展示小分子如何延长寿命，并将提供必要的知识，以设计出能够改善人类健康和长寿的药物干预措施。