Ginseng Oligopeptides Promote Longevity and Enhance Stress Resistance in Caenorhabditis elegans via the DAF-16/FOXO Pathway

<b>Background:</b> Ginseng oligopeptides (GOPs), small bioactive peptides with potent antioxidant capacity and high bioavailability, have shown promise in promoting healthy aging; however, their underlying molecular mechanisms remain largely unexplored. <b>Methods:</b> Using the model organism <i>Caenorhabditis elegans</i> (<i>C. elegans</i>), we comprehensively evaluated the anti-aging effects of GOPs on lifespan, locomotion, oxidative stress, and gene expression. Integrated phenotypic assays and transcriptomic analyses were conducted to elucidate GOP-mediated molecular mechanisms. The transgenic strain TJ356 (DAF-16::GFP) and the loss-of-function mutant CF1038 [<i>daf-16</i>(mu86)] were employed to functionally validate the role of the DAF-16/FOXO pathway. <b>Results:</b> GOP supplementation significantly extended median lifespan by approximately 11.5% and improved age-related locomotion decline in <i>C. elegans</i>. Transcriptomic profiling identified 1928 differentially expressed genes (DEGs) enriched in metabolic, antioxidant defense, and longevity-regulating pathways. GOPs upregulated key antioxidant and stress-response genes (<i>gst-4</i>, <i>sod-5</i>, <i>mtl-1</i>) and longevity-related regulators (<i>daf-16</i>, <i>lin-31</i>, <i>Y51B9A.9</i>, and <i>daf-12</i>), while downregulating <i>ins-7</i>, an insulin-like peptide. Moreover, GOPs enhanced cytochrome P450-related detoxification and vitamin-dependent (retinol, ascorbate, and riboflavin) metabolic pathways, establishing a multidimensional antioxidant defense network. Phenotypic validation confirmed that GOPs markedly reduced reactive oxygen species (ROS) levels and lipofuscin accumulation (<i>p</i> < 0.001). Notably, GOPs promoted DAF-16 nuclear translocation in TJ356 worms, whereas the lifespan-extending effects were abolished in CF1038 mutants, highlighting the essential role of DAF-16/FOXO in mediating GOP effects. <b>Conclusions:</b> GOPs delay aging in <i>C. elegans</i> by activating the DAF-16/FOXO signaling cascade and reinforcing antioxidant networks, thereby maintaining redox and metabolic homeostasis. These findings provide novel mechanistic evidence supporting GOPs as promising dietary antioxidants for promoting healthy aging through modulation of conserved redox and longevity pathways.