Quercetin alleviates MSG-induced oxidative toxicity and lifespan deterioration in Caenorhabditis elegans associated with SKN-1–gst-4 detoxification and DAF-16–dependent stress resilience

Boya Ouyang; Quanyong Wu; Zebin Zou; Jingyimei Liang; Dominique Delmas; Hui Cao; Jesus Simal-Gandara; Jianbo Xiao

Resumen:

Background Monosodium glutamate (MSG) is widely consumed as a dietary flavor enhancer; however, its long-term effects following developmental exposure, particularly regarding oxidative toxicity and lifespan deterioration, remain poorly understood. Purpose This study aimed to investigate MSG-induced oxidative toxicity and lifespan deterioration following developmental exposure, and to elucidate the protective mechanisms of quercetin (Que), with a focus on detoxification and stress-response pathways. Methods Using Caenorhabditis elegans, lifespan, locomotion, reproductive output, and stress resistance were assessed. Oxidative stress markers, including ROS, SOD, CAT, and GSH, were measured. Targeted metabolomics focusing on amino acids and TCA cycle intermediates, RNA-seq analysis, and pathway validation using a gst-4p::GFP reporter strain and daf-16(mu86) mutant were performed. Results Developmental MSG exposure significantly shortened lifespan, impaired locomotor performance, and altered reproductive patterns without affecting body length. MSG increased ROS accumulation, reduced SOD and CAT activities, and depleted GSH, thereby decreasing resistance to heat and H₂O₂ stress. Metabolomic profiling revealed widespread depletion of amino acids and TCA cycle intermediates, suggesting alterations in energy metabolism. Transcriptomic analysis demonstrated disruption of detoxification and redox networks, particularly involving glutathione metabolism and SKN-1/Nrf2 and DAF-16/FOXO pathways. Functional analyses suggested that MSG suppressed SKN-1–gst-4–associated detoxification responses, whereas Que partially restored gst-4-associated detoxification output. Notably, Que-mediated protection against lifespan deterioration was markedly attenuated in daf-16(mu86) mutants. Conclusion Developmental MSG exposure induces persistent oxidative toxicity and lifespan deterioration through disruption of redox homeostasis, metabolic balance, and detoxification capacity. Que partially mitigates these effects, which are associated with SKN-1–gst-4 detoxification and DAF-16–dependent stress resilience.