Phenotypic screening and structure-activity-guided design produced two fisetin-derived flavonoids, SR29384 and SR31133, that killed senescent cells more potently and more selectively than fisetin across multiple senescent cell types. In aged and progeroid mice, both compounds lowered tissue senescence burden and improved physical function and other healthspan measures. Mechanistic work points to PARP1, CDK2, and possibly BCL-xL as the pathways driving selective apoptosis in senescent cells.
Key Points
- Two fisetin analogs outperform fisetin in potency and selectivity
- Aged and progeroid mice showed reduced senescence, better physical function
- PARP1, CDK2, and BCL-xL implicated in selective senescent-cell apoptosis
Longevity Analysis
Senescent cells accumulate as a persistent source of inflammatory signaling that distorts how surrounding tissue communicates, degrades repair capacity, and constrains physical function. Removing that burden rather than suppressing its downstream effects addresses interference at its origin — the same logic that makes clearance strategies distinct from symptom management. Fisetin's poor bioavailability has been the practical ceiling on its clinical use, so analogs engineered for greater potency and selectivity move the question from whether senolytic clearance works toward which molecule, at what dose, and on what schedule.
Original published by Wiley Aging Cell, by Lei Justan Zhang, Rahagir Salekeen, Carolina Soto‐Palma, Qiuming Wu, Yuanjun He, Osama Elsallabi, Bilel Bdiri, Brian Hughes, Allancer Nunes, Wandi Xu, Borui Zhang, Abdalla Mohamed, Sara J. McGowan, Luise Angelini, Ryan O'Kelly, Theodore M. Kamenecka, Laura J. Niedernhofer, Paul D. Robbins .