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

项目摘要/摘要 随着全球人口平均年龄的持续上升，寻找不仅能延长寿命的策略， 但健康状况是至关重要的。例如，衰老是许多疾病发生和发展的主要因素。 神经疾病，它增加了医疗系统的财政负担，提出了新的挑战 在我们的社会中，关爱和情感健康。在这方面，有很多人有兴趣确定 能否促进健康老龄化。我们的实验室已经确定了一种具有刺激作用的环境因素 线虫模式生物秀丽线虫对寿命和神经退行性变的影响 (线虫)。当线虫长期暴露在较高浓度(20倍)的环境中时 因子，它们的寿命较短，并表现出多巴胺能神经元的神经退化。相反，当 长期暴露在低浓度(5倍)下，他们活得更长，不会表现出神经退化。这个 我们发现的因子是一种由土壤常见细菌链霉菌产生的分泌性代谢产物 Venezuelae(S.ven)。与许多显示兴奋反应的物质类似，我已经确定这一点 代谢产物通过转录因子DAF-16/FOXO发挥作用。这种转录因子调节长寿。 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，我将利用线虫进一步研究暴露后衰老过程中的差异 至高浓度(20倍)和低浓度(5倍)的S.ven代谢物。目标1寻求调查钟表ROS 暴露于不同浓度的S.ven代谢物后的诱导。这将通过以下方式解决) 通过使用体内和体外试验检查ROS水平的差异来量化细胞变化 研究硫代谢物对三磷酸腺苷水平的影响。我假设5X。S。温的代谢物会引起轻微的。 对线虫有利的ROS诱导，而20X则相反。在目标2中，我将研究一个DAF- 依赖16岁的长寿反应。刺激反应的潜在机制将通过以下方法进行探索 来自先前转录分析的差异表达基因的老化分析和定量聚合酶链式反应。我 之前确定的与DAF-16和/或DAF-2相关的20个DEG；其中几个与 我有兴趣进一步研究的氧化还原酶过程。我假设这种刺激的反应是 影响胰岛素/IGF-1信号通路以授予延长寿命的表型 蠕虫暴露在5X代谢物中。我还认为，代谢物正在改变DAF-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。最终， 定义这种霍梅蛋白的分子特征将说明受先前 鉴定了神经毒素，并可能为识别衰老的治疗靶点提供一种有前途的方法。 相关的障碍。

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.