Thursday, April 25, 2024
4/25/2024
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.
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