Characterizing the impacts of a novel environmental contributor on ROS hormesis and aging in C. elegans

表征新型环境贡献者对线虫 ROS 兴奋作用和衰老的影响

• 批准号: 10287981
• 负责人: Jennifer L Thies
• 金额: $ 6.26万
• 依托单位: UNIVERSITY OF ALABAMA IN TUSCALOOSA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10287981
• 关键词: 5' -AMP-activated protein kinase; Address; Affect; Age; Aging; Animal Model; Animals; Bacteria; Binding Sites; Bioinformatics; Biological Assay; Biological Process; Caenorhabditis elegans; Candidate Disease Gene; Cells; Chronic; Data; Defect; Development; Disease; Dose; Environmental Risk Factor; Exhibits; Exposure to; Financial Hardship; Fluorescence; Genes; Genetic; Health; Healthcare Systems; Human; IGF-1 Signaling Pathway; Impairment; Insulin; Insulin Signaling Pathway; Knowledge; Life; Longevity; MAPK8 gene; Measures; Mediating; Messenger RNA; Mitochondria; Molecular; Molecular Profiling; Morphology; Nematoda; Nerve Degeneration; Neurotoxins; Oxidative Stress; Oxidoreductase; Pathway interactions; Pattern; Phenotype; Population; Process; Production; Protein Kinase; Reactive Oxygen Species; Regulation; Reporter; Reporting; Signal Pathway; Signal Repression; Signal Transduction; Signaling Molecule; Societies; Soil; Source; Streptomyces; Stress; Up-Regulation; Well in self; age related; biological adaptation to stress; caregiving; combat; differential expression; dopaminergic neuron; gene product; healthspan; healthy aging; improved; in vivo; insight; insulin signaling; interest; mutant; nervous system disorder; novel; protein function; proteotoxicity; response; transcription factor; transcriptomics

Project Summary/Abstract As the average age of the global population continues to rise, finding strategies to promote not only longevity, but healthspan, is critical. For example, aging is a major factor in the development and progression of many neurological disorders, and it increases the financial burden on healthcare systems, presenting new challenges within our society for caregiving and emotional wellbeing. In this regard, there is much interest in determining whether healthy aging can be enhanced. Our lab has identified an environmental factor that has a hormetic effect on both lifespan and neurodegeneration in the nematode model organism, Caenorhabditis elegans (C. elegans). When nematodes are chronically exposed to higher concentrations (20X) of this environmental factor, they have shorter lifespans and exhibit neurodegeneration of dopaminergic neurons. Conversely, when chronically exposed to low concentrations (5X), they live longer and do not display neurodegeneration. The factor we discovered is a secreted metabolite produced by the common soil bacterium Streptomyces venezuelae (S. ven). Similar to many substances that display hormetic responses, I have determined that this metabolite functions via the transcription factor DAF-16/FOXO. This transcription factor regulates longevity through the activation or repression of signaling molecules associated with oxidative stress responses. In this proposal, I will utilize C. elegans to further investigate the differences in the aging process following exposure to high (20X) and low (5X) concentrations of the S. ven metabolite. Aim 1 seeks to investigate hormetic ROS induction following exposure to different concentrations of S. ven metabolite. This will be addressed via a) Quantifying cellular alterations by examining differences in ROS levels using in vivo and ex vivo assays and b) Investigating the impact of S. ven metabolite on ATP levels. I hypothesize 5X S. ven metabolite will cause mild ROS induction that is beneficial to C. elegans, while 20X will do the opposite. In Aim 2, I will examine a DAF- 16-dependent longevity response. The mechanism underlying the hormetic response will be sought using aging analyses and qPCR on differentially expressed genes (DEGs) from a prior transcriptomic analysis. I previously identified 20 DEGs associated with daf-16 and/or daf-2; of which several are associated with oxidoreductase processes that I am interested in further pursuing. I hypothesize that the hormetic response is impacting the insulin/IGF-1 signaling pathway to confer the extended lifespan phenotype observed when worms are exposed to 5X metabolite. I also propose that the metabolite is altering the expression of DAF-16- dependent genes, particularly DEGs involved in oxidoreduction processes thus impacting longevity. Ultimately, defining a molecular signature of this hormetin will illustrate signaling pathways influenced by a previously identified neurotoxin, and could provide a promising approach for the identification of treatment targets for age- related disorders.

项目摘要/摘要 随着全球人口的平均年龄不断上升，寻找不仅促进寿命的策略 但是HealthSpan至关重要。例如，衰老是许多人开发和发展的主要因素 神经系统疾病，并增加了医疗保健系统的财务负担，提出了新的挑战 在我们的护理和情感福祉的社会中。在这方面，确定有很大的兴趣 健康衰老是否可以增强。我们的实验室已经确定了一个具有刺激性的环境因素 秀丽隐杆线虫的线虫模型生物中的寿命和神经变性的影响 （秀丽隐杆线虫）。当线虫长期暴露于该环境的较高浓度（20倍）时 因素，它们的寿命较短，并且表现出多巴胺能神经元的神经退行性。相反，什么时候 长期暴露于低浓度（5倍），它们的寿命更长，并且不显示神经变性。这 我们发现的因素是由普通土壤细菌产生的分泌代谢产物 委内瑞拉（S. Ven）。类似于许多表现出刺激性反应的物质，我确定 通过转录因子DAF-16/FOXO的代谢物功能。该转录因子调节寿命 通过激活或抑制与氧化应激反应相关的信号分子。在这个 提案，我将利用秀丽隐杆线虫进一步研究暴露后衰老过程的差异 到高（20倍）和低（5倍）浓度的S. ven代谢物。 AIM 1试图研究刺激性ROS 暴露于不同浓度的VEN代谢产物后的诱导。这将通过a解决） 通过使用体内和体内测定和b检查ROS水平的差异来量化细胞改变 研究S. ven代谢产物对ATP水平的影响。我假设5x S. Ven代谢产物会导致轻度 ROS诱导对秀丽隐杆线虫有益，而20倍则会相反。在AIM 2中，我将检查一个DAF- 16依赖性寿命响应。将寻求刺激性响应的机制 通过先前的转录组分析对差异表达基因（DEG）进行衰老分析和QPCR。我 先前鉴定出与DAF-16和/或DAF-2相关的20度；其中几个与 我有兴趣进一步追求的氧化还原酶过程。我假设刺激性反应是 影响胰岛素/IGF-1信号传导途径，以赋予观察到的延长寿命表型 蠕虫暴露于5倍代谢物。我还建议代谢产物正在改变DAF-16-的表达 依赖基因，特别是参与氧化过程的DEG，从而影响寿命。最终， 定义该激素的分子特征将说明受到先前影响的信号通路 确定的神经毒素，可以为鉴定年龄的治疗目标提供有希望的方法 相关疾病。