Fisetin Clears Senescent Cells Through the Pi3k‐Akt‐Bcl‐2/Bcl‐xl Pathway to Alleviate Diabetic Aortic Aging

ABSTRACT Vascular aging is a major contributor to age‐related cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2DM) induced early arterial aging and excessive senescent cells (SCs) burden in vessels. Inhibiting cellular senescence or eliminating SCs could effectively improve aging‐related CVDs. Fisetin, a flavonoid extracted from cotinus coggygria scop, has shown potential in alleviating aging by clearing SCs. This study investigated the unexplored mechanisms and efficacy of fisetin in alleviating T2DM‐related aortic aging. The T2DM mouse model was induced using a high‐fat diet and low‐dose streptozotocin injection. Chronic fisetin treatment's protective effects against aortic aging were assessed via senescence‐associated beta‐galactosidase (SA‐β‐Gal) staining, histopathology, and vasomotor function. RNA‐sequencing and western blotting identified relevant signaling pathways and protein expression. Fisetin's effects on SCs and senescence‐associated secretory phenotype (SASP) factors were evaluated through cell viability, apoptosis, and co‐culture assays. Docking simulations suggested fisetin as a potential Phosphoinositide 3‐kinase (Pi3k) inhibitor. In vivo, chronic fisetin treatment reduced aortic SCs burden, alleviating T2DM‐related and natural aortic aging. In vitro, fisetin selectively induced apoptosis of senescent endothelial cells via regulating the Pi3k‐Protein Kinase B (Akt)‐B‐cell lymphoma (Bcl)‐2/Bcl‐xl pathway and suppressed SASP and its detrimental effects. Furthermore, fisetin combined with metformin therapy showed superior anti‐aging effects on T2DM‐related aortic aging compared to metformin monotherapy. In conclusion, chronic fisetin treatment alleviates T2DM‐related aortic aging via clearing the SCs burden and abrogating the SASP factors. Fisetin combined with metformin therapy might be a potential therapeutic strategy for T2DM‐related CVDs.