Mouse data has consistently shown fisetin to be senolytic, capable of selectively destroying the senescent cells that accumulate in tissues with age. Doses most often used are equivalent to around 20 mg/kg in humans, but dosing strategies range from a one-time course of treatment of a few days to intermittent doses provided over months. Unfortunately, despite planned and actually undertaken human trials of fisetin supplementation, there is still no published data of its senolytic capacity in humans. The dasatinib and quercertin combination and the locally delivered senolytic developed by UNITY Biotechnology before they ran out of funds remain the only senolytics with human data for clearance of senescent cells.
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.
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. Senescent endothelial cells exhibited elevated expression of SASP factors, particularly Cxcl12, which was reversed by fisetin supplementation, with responses also reflected in circulating CXCL12 concentrations. Plasma from old mice impaired endothelial function by inducing vascular cell senescence, reducing NO, increasing mitochondrial oxidative stress, and promoting endothelial-to-mesenchymal transition-effects partially driven by CXCL12 and prevented by fisetin.
