Fisetin Supplementation Attenuates Premature Vascular Aging Induced by Doxorubicin via Suppression of Cellular Senescence and Mitochondrial Oxidative Stress.

Abstract

The genotoxic agent doxorubicin induces premature vascular aging, defined by vascular endothelial dysfunction and aortic stiffening. Excess vascular cell senescence and the accompanying senescence-associated secretory phenotype (SASP) are key mechanisms underlying doxorubicin-induced vascular dysfunction, in part, by promoting excess mitochondrial oxidative stress, which reduces the bioavailability of the vasodilatory molecule nitric oxide (NO). In the present study, we assessed if the natural senolytic fisetin mitigates doxorubicin-induced cellular senescence and the SASP to improve vascular function following doxorubicin administration and explored the underlying mechanisms. Young adult (6 months) mice were treated with doxorubicin, followed by oral, intermittent fisetin supplementation (100 mg/kg/day; 1 week on treatment-2 weeks off treatment-1 week on treatment). Vascular endothelial function, aortic stiffness, cellular senescence markers, SASP expression, NO bioavailability, and mitochondrial oxidative stress were assessed. Parallel experiments in human aortic endothelial cells were conducted to provide further mechanistic insight. Fisetin mitigated excess vascular cell senescence and the SASP in young mice administered doxorubicin and reversed doxorubicin-induced endothelial dysfunction (p < 0.001) and aortic stiffening (p < 0.001), in part through suppression of excess cellular senescence, higher NO bioavailability, and lower mitochondrial oxidative stress. Modulation of the circulating SASP (plasma) also contributed to the observed vascular improvements with fisetin. In vitro, fisetin reduced cellular senescence in doxorubicin-exposed endothelial cells, supporting isolated artery and in vivo observations. These findings identify oral intermittent fisetin supplementation as a promising therapeutic strategy for targeting excess cellular senescence to improve vascular function in settings of premature vascular aging.