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.

项目总结/摘要 随着全球人口的平均年龄持续上升，找到不仅能促进长寿， 但健康是关键。例如，衰老是许多疾病发展和进展的主要因素， 神经系统疾病，并增加了医疗保健系统的财政负担，提出了新的挑战 在我们的社会中，为了幸福和情感健康。在这方面，人们很有兴趣确定 健康的老龄化是否可以得到加强。我们的实验室发现了一种环境因素 对线虫模式生物秀丽隐杆线虫寿命和神经变性的影响 （C. elegans）。当线虫长期暴露于更高浓度（20倍）的这种环境中时， 由于这一因素，它们的寿命较短，并表现出多巴胺能神经元的神经变性。反之，当 长期暴露于低浓度（5倍），它们的寿命更长，不会显示神经退行性病变。的 我们发现的因子是由常见的土壤细菌链霉菌产生的分泌代谢产物 委内瑞拉（S. ven）。与许多显示激素反应的物质类似，我已经确定， 代谢物通过转录因子fos-16/FOXO发挥作用。这种转录因子调节寿命 通过激活或抑制与氧化应激反应相关的信号分子。在这 建议，我将使用C。进一步研究暴露后衰老过程的差异 对高（20 X）和低（5 X）浓度的S.甚至代谢产物。目的1旨在研究激素活性氧 诱导后暴露于不同浓度的S.甚至代谢产物。这将通过a） 通过使用体内和离体测定法检查ROS水平的差异来定量细胞改变，和B） 调查S.的影响。甚至代谢产物的ATP水平。我假设是5倍。即使代谢产物也会引起轻度 ROS的诱导有利于C. elegans，而20 X将做相反的事情。在第二章中，我们将讨论一个... 16-依赖性长寿反应激兴奋反应的机制将寻求使用 老化分析和来自先前转录组学分析的差异表达基因（DEG）的qPCR。我 先前确定的20个DEG与daf-16和/或daf-2相关;其中几个与 我有兴趣进一步研究氧化还原酶过程。我假设兴奋反应是 影响胰岛素/IGF-1信号通路，从而赋予延长的寿命表型， 蠕虫暴露于5X代谢物。我还提出，代谢物改变了β-16的表达， 依赖基因，特别是参与氧化还原过程的DEG，从而影响寿命。最后， 确定这种激素的分子特征将说明受先前的激素水平影响的信号通路。 确定了神经毒素，并可能提供一个有前途的方法，为确定治疗目标的年龄- 相关疾病。