BACKGROUND: The kidney, as a central metabolic organ, is highly susceptible to age-related deterioration. Over time, structural integrity progressively declines, leading to measurable reductions in renal function. Herba Cistanches, a well-known traditional anti-aging medicinal herb, is rich in phenylethanol glycosides (PhGs), which constitute its principal bioactive constituents. Despite its established pharmacological significance, the potential protective role of Cistanche phenylethanol glycosides (CPhGs) in mitigating kidney aging, along with the molecular mechanisms underlying such effects, remains insufficiently elucidated.
PURPOSE: This study aims to explore the molecular mechanisms and effects of CPhGs on kidney aging.
METHODS: In this study, a mouse aging model and an HK-2 cell aging model were established using D-galactose induction to simulate age-related renal damage. Renal function, histopathological changes, and aging-associated biomarkers were comprehensively assessed through histological examinations and molecular assays. To clarify the potential therapeutic mechanisms of CPhGs, network pharmacology, transcriptomic profiling, and bioinformatics analyses were integrated to identify signaling pathways and key targets. The predicted interactions and mechanistic pathways were next confirmed through molecular docking, molecular dynamics simulations, and Western blot analysis, providing robust evidence for the renal protective effects of CPhGs against aging.
RESULTS: In vivo, administration of CPhGs significantly enhanced renal function, mitigated histopathological damage, reduced SA-β-gal positivity, upregulated Klotho expression, and lowered the levels of SASP factors, including IL-6, TNF-α, TGF-β1, and MCP-1. In vitro, CPhGs markedly decreased ROS accumulation, improved mitochondrial function, and reduced cellular senescence (CS) markers. Integrated transcriptomic and network pharmacology analyses revealed the STAT1, P53 and cGAS-STING signaling pathways as pivotal mediators of the anti-aging effects of CPhGs. Subsequent experimental validation confirmed that CPhGs downregulated the protein expression of P53, P21, and P16, regulated apoptosis-associated proteins Bax and Bcl-2, and inhibited the expression of STAT1, cGAS, STING, and NF-κB, thereby providing mechanistic insight into their renoprotective and anti-aging properties.
CONCLUSIONS: CPhGs exerts protective effects against kidney aging primarily by modulating the STAT1, P53 and cGAS-STING signaling pathways, reducing oxidative stress, apoptosis, and inflammation, while concurrently restoring normal cell cycle progression. Collectively, these results suggest the therapeutic potential of CPhGs as a promising intervention for age-related kidney disorders, offering mechanistic insights that may guide future clinical applications.
