Senolytic treatment with fisetin reverses age-related endothelial dysfunction partially mediated by SASP factor CXCL12

作者：Sophia Mahoney, Krystyna Mazan-Mamczarz, Dimitrios Tsitsipatis, Nicholas S. VanDongen, Charnae' Henry-Smith, Ada N. Okereke, Rachel B Munk, Sanna Darvish, Kevin Murray, Supriyo De, Myriam Gorospe, Douglas R. Seals, Matthew J. Rossman, A. G. Herman, Zachary S. Clayton · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.08.13.670216 · 被引用次数：3 · 研究领域：Flavonoids in Medical Research、Clusterin in disease pathology、Biomarkers in Disease Mechanisms

ABSTRACT Background Advancing age is the strongest risk factor for cardiovascular diseases (CVDs), primarily due to progressive vascular endothelial dysfunction. Cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to age-related endothelial dysfunction by promoting mitochondrial oxidative stress and inflammation, which reduce nitric oxide (NO) bioavailability. However, the molecular changes in senescent endothelial cells and their role in endothelial dysfunction with aging remain incompletely unclear. As such, in this study we sought to identify the endothelial cell senescence-related signalling pathways, endothelial-derived SASP factors, and their impact on endothelial function with aging. Methods Single-cell transcriptomics was performed on aortas from young (6 months) and old (27 months) mice with and without in vivo senolytic treatment with fisetin (100 mg/kg/day administered in an intermittent dosing paradigm) to characterize endothelial cell senescence and transcript expression changes. Circulating levels of SASP factors were measured to validate transcriptional changes. Plasma exposure and protein addition and inhibiton experiments were conducted in isolated mouse arteries and cultured human endothelial cells to determine the causal role of the circulating SASP milieu and specific SASP factors in mediating endothelial dysfunction and underlying mechanisms-of-action. Results Senescent endothelial cells exhibited elevated expression of...