Total saponins from Panax ginseng delay aging and cellular senescence via PI3K-AKT pathway in a rapid dual-system screening model of aging.

BACKGROUND: Aging, as an inevitable biological process, is an inevitable process of multisystem functional decline, with cellular senescence being one of its hallmarks. Although total saponins from Panax ginseng (TSG) offer health benefits, its precise anti-aging mechanisms have not been fully elucidated. METHODS: A rapid dual-system screening model of aging was established using tert-butyl hydrogen peroxide (tBHP) to induce senescence in human umbilical vein endothelial cells (HUVECs) and Caenorhabditis elegans (C. elegans). Anti-aging effects and key components of TSG were evaluated via fluorescent staining, Western blotting (WB), and biochemical and behavioral analysis. Bioinformatics analysis, WB, AKT activator and loss-of-function mutants in C. elegans were used to clarify TSG's anti-aging and anti-cellular senescence effects via PI3K-AKT signaling. RESULTS: TSG alleviated oxidative stress, enhanced antioxidant capacity and reduced β-galactosidase activity, indicating delayed aging. It also modulated senescence-related markers and increased Ki-67, supporting its role in promoting proliferation and suppressing cellular senescence. Among 20 ginsenosides screened, PPD, F1 and Rh1 were identified as the principal active components. Network pharmacology and experimental validation revealed the PI3K-AKT pathway as central to TSG's effects. AKT1 and PI3K were confirmed as the targets, with decreased phosphorylation levels observed. TSG's anti-aging effects were partly abolished in loss-of-function mutant worms akt-1;akt-2 and age-1, substantiating the essential role of PI3K-AKT signaling in vivo. CONCLUSION: This study establishes a rapid dual-system model for aging research, and demonstrates that TSG and its principal ginsenosides (PPD, F1 and Rh1) mitigate aging and cellular senescence through the PI3K-AKT pathway by downregulating PI3K/AKT phosphorylation.