Multi-Target Botanical Complex Attenuates Cellular Senescence via Bidirectional P21/P53/SIRT1 Regulation: Dual Model Validation

Cellular senescence is a pivotal driver of aging and age-related diseases. This study aims to systematically investigate the anti-senescence effects and molecular mechanisms of a multi-component botanical complex (SBT) using both a D-galactose-induced senescence model in H9c2 cardiomyocytes and an H₂O₂-induced accelerated aging model in zebrafish. The SBT complex comprises <i>Solms-laubachia eurycarpa</i>, <i>Bergenia purpurascens</i>, <i>Laccifer lacca</i>, and <i>Glycyrrhiza uralensis</i>. Results demonstrated that SBT treatment significantly enhanced cell viability (increased from 52% to 85%) and reduced senescence-associated β-galactosidase (SA-β-gal) activity (from 41.2% to 20%). At the molecular level, SBT exerted bidirectional regulation of the P21/P53/SIRT1 axis, coordinately downregulating the pro-senescence proteins P53 and P21 while upregulating the longevity-associated deacetylase SIRT1. It also modulated the balance of apoptosis-related genes by suppressing <i>Bax</i> and enhancing <i>Bcl-2</i> expression. In the zebrafish model, SBT significantly strengthened the antioxidant defense system, as indicated by increased activities of superoxide dismutase (SOD) and catalase (CAT), elevated glutathione (GSH) levels, and reduced malondialdehyde (MDA) content. These findings confirm that SBT exerts potent anti-senescence effects through bidirectional regulation of the P21/P53/SIRT1 signaling axis, enhanced antioxidant capacity, and inhibition of apoptosis, thereby providing a mechanistic foundation for the development of natural product-based interventions against aging and related diseases.