Aging significantly increases susceptibility to chronic diseases, underscoring the need for effective interventions. Flavonoids from Lycium barbarum leaves (LBLF), which are notably more abundant in the leaves than in the berries, have demonstrated anti-aging properties. However, their underlying mechanisms remain unclear, thereby limiting their further development. To address this gap, the present study aims to systematically evaluate the anti-aging potential of LBLF using integrated in vitro and in vivo approaches. In the experimental procedure, LBLF was tested at concentrations ranging from 20 to 60 μg/mL in vitro and at doses of 50 to 120 mg/kg in vivo. For this purpose, hydrogen peroxide-stressed Human glioblastoma cell line T98G (T98G cells) and D-galactose-induced aging mice were employed as models, in which oxidative stress markers and cellular senescence indicators were assessed. Additionally, RNA-Seq analysis of hippocampal tissue was performed to identify key differentially expressed genes and related pathways. The results suggest that the anti-aging effects of LBLF may be associated with changes in oxidative stress-related and cell adhesion-related pathways. Specifically, LBLF downregulated Keap1 and upregulated Nrf2 and HO-1 in the Keap1-Nrf2/HO-1 pathway, while increasing antioxidant enzyme activity and reducing malondialdehyde levels (p < 0.05). Transcriptomic analysis identified 402 differentially expressed genes, with significant enrichment in the cell adhesion pathway (FDR < 0.05), including upregulation of Cdh1 (1.38-fold) and downregulation of Cldn1 (1.45-fold) (p < 0.05). In short, these results indicate that LBLF alleviates oxidative stress via the Keap1-Nrf2/HO-1 axis and modulates the cell adhesion pathway, collectively exerting anti-aging effects. In summary, this study preliminarily proposes potential molecular targets of LBLF and provides supporting evidence for the pharmacological application of LBLF.
