A rationally designed fluorescence probe achieves highly specific and long‐term detection of senescence in vitro and in vivo

Abstract Senescent cells (SnCs) are implicated in aging and various age‐related pathologies. Targeting SnCs can treat age‐related diseases and extend health span. However, precisely tracking and visualizing of SnCs is still challenging, especially in in vivo environments. Here, we developed a near‐infrared (NIR) fluorescent probe (XZ1208) that targets β‐galactosidase (β‐Gal), a well‐accepted biomarker for cellular senescence. XZ1208 can be cleaved rapidly by β‐Gal and produces a strong fluorescence signal in SnCs. We demonstrated the high specificity and sensitivity of XZ1208 in labeling SnCs in naturally aged, total body irradiated (TBI), and progeroid mouse models. XZ1208 achieved a long‐term duration of over 6 days in labeling senescence without causing significant toxicities and accurately detected the senolytic effects of ABT263 on eliminating SnCs. Furthermore, XZ1208 was applied to monitor SnCs accumulated in fibrotic diseases and skin wound healing models. Overall, we developed a tissue‐infiltrating NIR probe and demonstrated its excellent performance in labeling SnCs in aging and senescence‐associated disease models, indicating great potential for application in aging studies and diagnosis of senescence‐associated diseases.