The University of Colorado Boulder has registered a trial of fisetin, a compound that clears senescent cells in mouse experiments, to test whether it improves artery dilation in people aged 65 and older

The University of Colorado Boulder has registered a trial of fisetin, a compound that clears senescent cells in mouse experiments, to test whether it improves artery dilation in people aged 65 and older

Record NCT07871162 appeared on ClinicalTrials.gov on October 13: 136 participants will be randomly assigned to receive fisetin or a placebo. The dose is 2 mg per kilogram of body weight per day, given in three-day courses with two-week breaks. The trial is scheduled to start in November 2026 and is funded by the US National Institute on Aging.

Arteries become less able to dilate with age as less nitric oxide, a gas that relaxes blood vessels, remains available in their walls. This is one mechanism behind the increase in cardiovascular risk. Trial lead Matthew Rossman attributes this loss of nitric oxide partly to senescent cells. These cells have stopped dividing but release inflammatory signals that cause mitochondria in blood vessel cells to produce more oxygen radicals, reactive molecules that react with nitric oxide. Fisetin, a plant compound found in fruits and vegetables, is classified as a senolytic, a substance that clears senescent cells. Of ten related compounds tested in laboratory cell experiments in 2018, it had the strongest senolytic effect.

The primary outcome is brachial artery dilation after temporary compression: a cuff is tightened around the arm and then released, and ultrasound measures the percentage increase in the artery’s diameter. A healthy endothelium, the artery’s inner lining, releases nitric oxide, allowing greater dilation. A pooled analysis of 35 studies involving 17 280 people found that each additional percentage point of dilation was associated with a 12% lower risk of cardiovascular events.

In a 2024 study coauthored by Rossman, old mice received courses of fisetin, and their blood vessels were examined one to two weeks after the final dose, once the compound had cleared from the blood. The researchers removed the carotid artery and applied acetylcholine, which stimulates the endothelium to release nitric oxide. Arteries from fisetin-treated mice dilated more: 97% versus 81% in untreated mice. When a genetic method was used to remove senescent cells from these arteries, dilation increased from 76% to 90% in control mice but remained unchanged in fisetin-treated mice, at 93% and 92%. The authors concluded that fisetin acts through these cells: after treatment, there were none left to remove.

Fisetin had previously been tested in humans in pilot trial NCT06133634 at the same university. It involved 41 participants and two three-day courses separated by 14 days. In an American Physiology Summit abstract, the authors report that artery dilation increased from 3,9% to 5,5% in the fisetin group and from 4,4% to 4,5% in the placebo group. Participants also received a single large dose of MitoQ, an antioxidant that acts in mitochondria. If radicals are still limiting dilation, MitoQ improves it. MitoQ improved dilation before treatment and after placebo, but produced no further improvement after fisetin. The authors concluded that fisetin improves blood vessel function partly by suppressing mitochondrial radicals.

The new trial will use six courses instead of two, with the primary measurement taken at three months. The MitoQ test will be repeated. Researchers will assess markers of senescent cells in the endothelium and blood to determine whether the effect is linked to reduced cellular senescence. They will also measure cerebral blood flow and conduct cognitive tests. Trials at the Mayo Clinic, Northwestern University and Cedars-Sinai Medical Center, where fisetin is being tested for its effects on the lungs, use ten times the Boulder dose: approximately 20 mg per kilogram on two consecutive days.

The trial’s grant covers five years, with 809 971 dollars allocated for the first year.