Novel Flavonoid Senotherapeutics Identified by Phenotypic Drug Discovery Reduce Senescence and Improve Multiple Markers of Healthspan.

Senescent cells are a key driver of aging and contribute to many age-related diseases. Senolytics, agents that selectively eliminate senescent cells, offer a promising therapeutic strategy to treat age-related diseases but face significant barriers to clinical translation. Fisetin, a natural flavonoid senolytic, has progressed to clinical trials but is limited by suboptimal efficacy and poor bioavailability. To address these challenges, we developed two novel fisetin-derived flavonoid senolytics, SR29384 and SR31133, using an integrative phenotypic drug discovery approach. These compounds exhibit enhanced senolytic activity, targeting a broad range of senescent cell types, reducing tissue senescence, and improving healthspan-associated parameters in mouse models of aging. Mechanistic investigations combining transcriptomics, machine learning, network pharmacology, and molecular docking revealed that these novel senolytics may target key molecular pathways, including PARP1, CDK2, and possibly BCL-xL to selectively induce apoptosis in senescent cells. These findings provide novel senolytics with high translational potential for clinical applications in promoting healthy aging and treating age-related diseases.