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. 2023 Jun 8;19(6):58.
doi: 10.1007/s11306-023-02022-w.

The metabolic contribution of SKN-1/Nrf2 to the lifespan of Caenorhabditis elegans

Hong-Duc Phan #  1 , Tin Tin Manh Nguyen #  1   2 , Sujin Lee  1 , Munjun Seo  1 , Yong Jin An  3 , Arvie Camille V de Guzman  4
Affiliations

The metabolic contribution of SKN-1/Nrf2 to the lifespan of Caenorhabditis elegans

Hong-Duc Phan et al. Metabolomics. .

Abstract

Background and aims: SKN-1, a C. elegans transcription factor analogous to the mammalian NF-E2-related factor (Nrf2), has been known to promote oxidative stress resistance aiding nematodes' longevity. Although SKN-1's functions suggest its implication in lifespan modulation through cellular metabolism, the actual mechanism of how metabolic rearrangements contribute to SKN-1's lifespan modulation has yet to be well characterized. Therefore, we performed the metabolomic profiling of the short-lived skn-1-knockdown C. elegans.

Methods: We analyzed the metabolic profile of the skn-1-knockdown worms with nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-tandem mass spectrometry (LC-MS/MS) and obtained distinctive metabolomic profiles compared to WT worms. We further extended our study with gene expression analysis to examine the expression level of genes encoding all metabolic enzymes.

Results: A significant increase in the phosphocholine and AMP/ATP ratio, potential biomarkers of aging, was observed, accompanied by a decrease in the transsulfuration metabolites, NADPH/NADP+ ratio, and total glutathione (GSHt), which are known to be involved in oxidative stress defense. skn-1-RNAi worms also exhibited an impairment in the phase II detoxification system, confirmed by the lower conversion rate of paracetamol to paracetamol-glutathione. By further examining the transcriptomic profile, we found a decrease in the expression of cbl-1, gpx, T25B9.9, ugt, and gst, which are involved in GSHt and NADPH synthesis as well as in the phase II detoxification system.

Conclusion: Our multi-omics results consistently revealed that the cytoprotective mechanisms, including cellular redox reactions and xenobiotic detoxification system, contribute to the roles of SKN-1/Nrf2 in the lifespan of worms.

Keywords: 13C-labeling; Caenorhabditis elegans; HSQC; Metabolomics; Paracetamol; Phase II detoxification.

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References

    1. An, J. H., & Blackwell, T. K. (2003). SKN-1 links C. elegans mesendodermal specification to a conserved oxidative stress response. Genes & Development, 17(15), 1882–1893. https://doi.org/10.1101/gad.1107803 - DOI
    1. An, J. H., Vranas, K., Lucke, M., Inoue, H., Hisamoto, N., Matsumoto, K., & Blackwell, T. K. (2005). Regulation of the Caenorhabditis elegans oxidative stress defense protein SKN-1 by glycogen synthase kinase-3. Proceedings of the National Academy of Sciences of the United States of America, 102(45), 16275–16280. https://doi.org/10.1073/pnas.0508105102 - DOI - PubMed - PMC
    1. An, Y. J., Xu, W. J., Jin, X., Wen, H., Kim, H., Lee, J., & Park, S. (2012). Metabotyping of the C. elegans sir-2.1 mutant using in vivo labeling and 13C-heteronuclear multidimensional NMR metabolomics. ACS Chemical Biology, 7(12), 2012–2018. https://doi.org/10.1021/cb3004226 - DOI - PubMed
    1. Apfeld, J., O’Connor, G., McDonagh, T., DiStefano, P. S., & Curtis, R. (2004). The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes & Development, 18(24), 3004–3009. https://doi.org/10.1101/gad.1255404 - DOI
    1. Back, P., Braeckman, B. P., & Matthijssens, F. (2012). Review article ROS in aging Caenorhabditis elegans: damage or signaling? Oxidative Medicine and Cellular Longevity, 2012, 14. https://doi.org/10.1155/2012/608478 - DOI

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