Longevity & AgingNew Fisetin-Derived Senolytics Outperform the Original and Extend Healthspan in Mice
Researchers at the University of Minnesota designed two fisetin-derived flavonoid compounds — SR29384 and SR31133 — using phenotypic drug discovery and structure-activity relationship optimization. In senescent cell cultures, both compounds killed senescent cells more efficiently and selectively than fisetin. In aged and progeroid mouse models, they reduced tissue senescence markers and improved physical function and healthspan parameters. Mechanistic analysis using transcriptomics, machine learning, and molecular docking pointed to PARP1, CDK2, and possibly BCL-xL as key targets driving selective apoptosis in senescent cells. The compounds represent an advance over fisetin's poor bioavailability and weak potency, offering translational promise for treating age-related diseases.
