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.
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Data availability
The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request.
Abbreviations
- NMR:
-
Nuclear magnetic resonance
- LC–MS/MS:
-
Tandem mass spectrometry
- AMP/ATP:
-
Adenosine monophosphate/adenosine triphosphate
- GSHt:
-
Total glutathione
- NADPH:
-
Reduced nicotinamide adenine dinucleotide phosphate
- GSSG:
-
Glutathione disulfide
- GSTs:
-
Glutathione-S-transferase
- UGTs:
-
UDP-glucuronyl transferase
- GSH:
-
Sulfhydryl form glutathione
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Basic Science Research Program supported this research through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (NRF-2020R1A6A3A01099440).
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Conceptualization, H-DP*, TTMN*, YJA, and ACVdG; literature search, H-DP*, TTMN*, YJA. and ACVdG; Methodology: H-DP*, TTMN*, YJA, SL, MS and ACVdG figures and Tables, H-DP*, TTMN*, SL, and MS; data analysis, H-DP*, TTMN*, YJA. and ACVdG; data interpretation H-DP*, TTMN*, SL, MS, YJA and ACVdG; funding acquisition, YJA; Writing—original draft preparation:, H-DP and ACVdG. Writing—review, and editing: ACVdG. Supervision, ACVdG.
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Phan, HD., Nguyen, T.T.M., Lee, S. et al. The metabolic contribution of SKN-1/Nrf2 to the lifespan of Caenorhabditis elegans. Metabolomics 19, 58 (2023). https://doi.org/10.1007/s11306-023-02022-w
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DOI: https://doi.org/10.1007/s11306-023-02022-w