Tier 3 — preclinical

Intermittent supplementation with fisetin improves arterial function in old mice by decreasing cellular senescence

Mahoney SA, Venkatasubramanian R, Darrah MA, Ludwig KR, VanDongen NS, Greenberg NT, Longtine AG, Hutton DA, Brunt VE, Campisi J, Melov S, Seals DR, Rossman MJ, Clayton ZS

Aging Cell 2023 Volume 23, issue 3, article e14060

Bibliography

DOI: 10.1111/acel.14060
PubMed: PMID 38062873
PubMed Central: PMC10928570
Funding: US National Institutes of Health grants (University of Colorado Boulder Department of Integrative Physiology); full grant numbers listed in the article's acknowledgments.
Competing interests: Not explicitly detailed in the retrieved abstract/metadata; readers should consult the full-text Conflict of Interest statement for details.

Study snapshot

Design	In vivo study in old mice given intermittent oral fisetin supplementation, with ex vivo arterial function testing (endothelium-dependent dilation, arterial stiffness), genetic senolysis using p16-3MR transgenic mice, and in vitro human endothelial cell senescence assays.
Model	Old C57BL/6 mice and old p16-3MR transgenic mice (allowing genetic clearance of p16-positive senescent cells); primary human endothelial cell culture.
Sample	Group sizes not fully specified in the retrieved abstract; study used young and old mouse cohorts with and without fisetin supplementation and with and without genetic/pharmacologic senolysis.
Intervention	Oral intermittent fisetin supplementation in an on-off-on schedule (1 week on, 2 weeks off, 1 week on) in old mice; genetic (ganciclovir-induced) senescent cell clearance in p16-3MR mice for comparison.
Duration	Arterial and senescence outcomes assessed 1 week after the final dose of the intermittent fisetin regimen.
Endpoints	Vascular cell senescence markers and SASP-related inflammation; Endothelium-dependent dilation (endothelial function); Nitric oxide bioavailability and cellular/mitochondrial oxidative stress; Arterial stiffness (mechanical wall stiffness); Arterial wall remodeling

What the study showed, in plain terms

This University of Colorado Boulder ageing-research group tested whether taking fisetin intermittently, rather than continuously, could clear out senescent ('zombie') cells from blood vessels in old mice and restore healthier artery function.

Old mice given a pulsed fisetin schedule (a week on, two weeks off, then a week on again) had fewer senescent vascular cells and lower levels of the inflammatory secretions those cells produce, one week after their last dose.

These fisetin-treated old mice also had better endothelial function - the blood vessel lining's ability to relax and dilate via nitric oxide - and stiffer, less flexible arteries were softened by fisetin.

To prove the benefit truly came from clearing senescent cells (rather than a coincidental drug effect), the researchers used a special mouse strain that lets senescent cells be cleared genetically. When they did this in mice already treated with fisetin, there was no further improvement - meaning fisetin's benefit already worked by the same route (senolysis) that direct genetic clearance would achieve.

This is one of the more rigorous senolytic-mechanism papers behind fisetin's cardiovascular reputation, but it remains a mouse study; the intermittent human dosing regimens marketed for fisetin senolytic use have not been validated against this specific pulsed schedule in people.

Key findings

Intermittent oral fisetin reduced vascular cell senescence and SASP-related inflammation in old mice
Fisetin-supplemented old mice had higher endothelium-dependent dilation (endothelial function)
Fisetin's endothelial benefit was mediated by increased nitric oxide bioavailability and reduced oxidative stress
Genetic senescent-cell clearance in vehicle-treated (not fisetin-treated) mice reproduced the endothelial benefit, confirming a senolytic mechanism
Arterial stiffness was lower in fisetin-treated old mice, with favourable arterial wall remodeling
Further genetic senolysis in fisetin-treated mice did not additionally reduce arterial stiffness, consistent with fisetin already acting via senolysis

What this study can and cannot tell us

All data are from mouse models; no human arterial function or senescence marker data are included in this study.

The intermittent dosing schedule used (1 week on-2 weeks off-1 week on) is a specific research protocol and has not been directly validated against continuous dosing or against typical human supplement regimens.