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

• Published in: Metabolomics 2023-06, Vol.19 (6), p.58-58, Article 58
• Main Authors: Phan, Hong-Duc, Nguyen, Tin Tin Manh, Lee, Sujin, Seo, Munjun, An, Yong Jin, de Guzman, Arvie Camille V.
• Format: Article
• Language: English
• Subjects: Acetaminophen - metabolism; Analgesics; Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Cell Biology; Chromatography, Liquid; Detoxification; Developmental Biology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene expression; Glutathione; Glutathione - metabolism; Life Sciences; Life span; Liquid chromatography; Longevity - genetics; Mammals - metabolism; Mass spectroscopy; Metabolism; Metabolites; Metabolomics; Molecular Medicine; NADP - metabolism; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; NMR; Nuclear magnetic resonance; Original Article; Oxidative stress; Paracetamol; Phosphocholine; Redox reactions; RNA-mediated interference; Tandem Mass Spectrometry; Transcriptomics; Worms
• ISSN: 1573-3890; 1573-3882; 1573-3890
• DOI: 10.1007/s11306-023-02022-w

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.