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

Mahoney, Sophia A.; Venkatasubramanian, Ravinandan; Darrah, Mary A.; Ludwig, Katelyn R.; VanDongen, Nicholas S.; Greenberg, Nathan T.; Longtine, Abigail G.; Hutton, David A.; Brunt, Vienna E.; Campisi, Judith; Melov, Simon; Seals, Douglas R.; Rossman, Matthew J.; Clayton, Zachary S.

doi:10.1111/acel.14060

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

Journal Article · Thu Dec 07 04:00:00 EST 2023 · Aging Cell

DOI:https://doi.org/10.1111/acel.14060· OSTI ID:2470948

Mahoney, Sophia A. ^[1]; Venkatasubramanian, Ravinandan ^[1]; Darrah, Mary A. ^[1]; Ludwig, Katelyn R. ^[1]; VanDongen, Nicholas S. ^[1]; Greenberg, Nathan T. ^[1]; Longtine, Abigail G. ^[1]; Hutton, David A. ^[1]; ^[1]; ^[2]; ^[3]; Seals, Douglas R. ^[1]; Rossman, Matthew J. ^[1]; ^[1]

University of Colorado, Boulder, CO (United States)
Buck Institute for Research on Aging, Novato, CA (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Buck Institute for Research on Aging, Novato, CA (United States)

Cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to age-related arterial dysfunction, in part, by promoting oxidative stress and inflammation, which reduce the bioavailability of the vasodilatory molecule nitric oxide (NO). In the present study, we assessed the efficacy of fisetin, a natural compound, as a senolytic to reduce vascular cell senescence and SASP factors and improve arterial function in old mice. We found that fisetin decreased cellular senescence in human endothelial cell culture. In old mice, vascular cell senescence and SASP-related inflammation were lower 1 week after the final dose of oral intermittent (1 week on—2 weeks off—1 weeks on dosing) fisetin supplementation. Old fisetin-supplemented mice had higher endothelial function. Leveraging old p16-3MR mice, a transgenic model allowing genetic clearance of p16^INK4A-positive senescent cells, we found that ex vivo removal of senescent cells from arteries isolated from vehicle- but not fisetin-treated mice increased endothelium-dependent dilation, demonstrating that fisetin improved endothelial function through senolysis. Enhanced endothelial function with fisetin was mediated by increased NO bioavailability and reduced cellular- and mitochondrial-related oxidative stress. Arterial stiffness was lower in fisetin-treated mice. Ex vivo genetic senolysis in aorta rings from p16-3MR mice did not further reduce mechanical wall stiffness in fisetin-treated mice, demonstrating lower arterial stiffness after fisetin was due to senolysis. Lower arterial stiffness with fisetin was accompanied by favorable arterial wall remodeling. The findings from this study identify fisetin as promising therapy for clinical translation to target excess cell senescence to treat age-related arterial dysfunction.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH); American Heart Association (AHA)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2470948

Journal Information:: Aging Cell, Journal Name: Aging Cell Journal Issue: 3 Vol. 23; ISSN 1474-9718

Publisher:: Anatomical Society - WileyCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
Cell Biology
Geriatrics & Gerontology
aging
arterial stiffness
cellular senescence
endothelial function
nutraceutical
vascular dysfunction

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

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