Unlocking the Potential of Curcumae Rhizoma Aqueous Extract in Stress Resistance and Extending Lifespan in Caenorhabditis elegans

The enhancement of stress resistance is crucial for delaying aging and extending a healthy lifespan. Traditional Chinese medicine (TCM), a cherished treasure of Chinese heritage, has shown potential in mitigating stress and promoting longevity. This study integrates network pharmacology and in vivo analysis to investigate the mechanisms and effects of <i>Curcumae Rhizoma</i> (<i>C. Rhizoma</i>), known as "E Zhu" in Chinese. Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS) identified 10 active compounds in its aqueous extract, interacting with 128 stress-related targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed pathways such as stress response, FoxO signaling, and insulin resistance. In <i>Caenorhabditis elegans</i>, 10 mg/mL of <i>C. Rhizoma</i> aqueous extract improved resistance to UV, thermal, oxidative, and pathogen-induced stress, extending lifespan in a dose-dependent manner. Mechanistically, it reduced reactive oxygen species (ROS), increased superoxide dismutase (SOD) activity, and enhanced UV resistance via the insulin/IGF-1 pathway and DAF-16 translocation. Molecular docking highlighted hexahydrocurcumin (HHC) and related compounds as key bioactives. Furthermore, we also observed that <i>C. Rhizoma</i> aqueous extract significantly extended both the lifespan and healthspan of nematodes. These findings highlight the potential of <i>C. Rhizoma</i> in stress mitigation and longevity promotion, offering valuable insights into the therapeutic applications of TCM.