Senescent cells accumulate with age and produce tissue dysfunction through their pro-growth, pro-inflammatory signaling. Here researchers report on an example of fisetin supplementation reducing the burden of senescent cells in the vasculature of old mice. It also improves other measures of tissue health. The dose used here is not as high as that in the first mouse study to show fisetin clearing senescent cells, but the dosing schedule is longer.
There remains some question as to whether fisetin at suitably high doses will in fact prove to be usefully senolytic in humans, capable of clearing senescent cells to the same degree as in mice. Currently the dasatinib and quercetin combination is the only senolytic with solid human data to show that it works as well in our species as it does in mice. Questions about fisetin will hopefully be answered by the publication of results from ongoing clinical trials sometime in the next few years. If it does turn out to be as good in humans as it is in mice, that will be of great benefit to health in later life.
Age-related vascular endothelial dysfunction is mediated by excess reactive oxygen species (ROS) - mitochondria being a key source - which can reduce nitric oxide (NO) bioavailability. Cellular senescence, a fundamental mechanism of aging, may exacerbate mitochondrial ROS and be a potential therapeutic target to combat age-related vascular dysfunction. This study ran to determine if treatment with the natural flavonoid fisetin improves endothelial function with aging by suppressing cellular senescence, scavenging excess whole-cell and mitochondrial ROS, and increasing NO bioavailability.
Old (27 mo) male C57BL/6 mice were treated with fisetin (50 mg/kg/day) by oral gavage following a 1 week on - 2 week off - 1 week on dosing paradigm. Endothelial function was assessed by ex vivo carotid artery endothelium-dependent dilation (EDD) and endothelium-independent dilation (EID) to increasing doses of acetylcholine and sodium nitroprusside, respectively. Electron paramagnetic resonance (EPR) spectroscopy was used to assess vascular mitochondrial ROS.
EDD was greater in fisetin versus control mice (Peak EDD [%]: 97 ± 1 vs 84 ± 3). Fisetin-treated mice had lower vascular abundance of p16, an established marker of cellular senescence (.12 ± .01 vs .19 ± .02 chemiluminescence units). Fisetin-treated mice had lower mitochondrial ROS (2527 ±440 vs 6603 ± 1956 AU). Further, Fisestin-treated mice had lower abundance of vascular p-p66SHC, a recognized marker of mitochondrial oxidative stress (.029 ± .003 vs .049 ± .008 CU) and greater abundance of Mn superoxide dismutase, a mitochondrial antioxidant enzyme (.41 ± .1 vs .20 ± .02 CU).
In conclusion, fisetin supplementation may be a novel strategy to target excess cellular senescence and thereby reduce mitochondrial ROS to improve NO-mediated endothelial function with aging.