Anti-Aging Effects of Vaccinium bracteatum Thunb. Leaves Extracts via Activation of the Nrf2 Antioxidant Pathway

Vaccinium bracteatum Thunb. leaves (VBTL), a traditional medicinal plant historically consumed as food in certain regions of China, have been documented to possess potent in vitro antioxidant activity. However, its in vivo anti-aging effects and underlying mechanisms remain to be fully elucidated. Therefore, this study aimed to evaluate its anti-aging efficacy to support its potential value as a functional food constituent for healthy aging. Anti-aging efficacy was systematically assessed using D-galactose-induced aging mice, a Caenorhabditis elegans model, and an H2O2-induced cellular senescence model. Key active constituents were identified via untargeted metabolomics. In D-galactose-induced aging mice, VBTL extracts effectively ameliorated oxidative stress, significantly increasing the activities of endogenous antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT), while reducing malondialdehyde (MDA) levels. In Caenorhabditis elegans, VBTL extended lifespan, reduced lipofuscin accumulation, and demonstrated no reproductive toxicity. Untargeted metabolomics identified xanthotoxol as a key active constituent, which was then selected for mechanistic investigation. In a cellular senescence model, xanthotoxol alleviated H2O2-induced oxidative stress, significantly enhanced SOD activity, reduced reactive oxygen species (ROS) and MDA levels, inhibited senescence-associated β-galactosidase (SA-β-gal) activity and the expression of senescence-associated secretory phenotype (SASP) factors (IL-6, MMP1, MMP3), and downregulated the expression of genes in the P53/P21/P16 signaling pathway. Mechanistically, xanthotoxol activated the Nrf2 signaling pathway, promoting the expression of its downstream targets heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). This study demonstrates that VBTL and its active compound xanthotoxol exert anti-aging effects across multiple models by modulating the Nrf2 pathway, providing both theoretical and experimental foundations for developing VBTL as a novel, safe, and effective natural ingredient in anti-aging functional foods.