title: Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice.
abstract: While reports suggest a single dose of senolytics may improve vasomotor function, the structural and functional impact of long-term senolytic treatment is unknown. To determine whether long-term senolytic treatment improves vasomotor function, vascular stiffness, and intimal plaque size and composition in aged or hypercholesterolemic mice with established disease. Senolytic treatment (intermittent treatment with Dasatinib + Quercetin via oral gavage) resulted in significant reductions in senescent cell markers (TAF(+) cells) in the medial layer of aorta from aged and hypercholesterolemic mice, but not in intimal atherosclerotic plaques. While senolytic treatment significantly improved vasomotor function (isolated organ chamber baths) in both groups of mice, this was due to increases in nitric oxide bioavailability in aged mice and increases in sensitivity to NO donors in hypercholesterolemic mice. Genetic clearance of senescent cells in aged normocholesterolemic INK-ATTAC mice phenocopied changes elicited by D+Q. Senolytics tended to reduce aortic calcification (alizarin red) and osteogenic signaling (qRT-PCR, immunohistochemistry) in aged mice, but both were significantly reduced by senolytic treatment in hypercholesterolemic mice. Intimal plaque fibrosis (picrosirius red) was not changed appreciably by chronic senolytic treatment. This is the first study to demonstrate that chronic clearance of senescent cells improves established vascular phenotypes associated with aging and chronic hypercholesterolemia, and may be a viable therapeutic intervention to reduce morbidity and mortality from cardiovascular diseases.
authors: Department of Surgery, Mayo Clinic, Rochester, MN, USA.
authors: Carolyn M
authors: CM
authors: Roos
authors: Department of Surgery, Mayo Clinic, Rochester, MN, USA.
authors: Bin
authors: B
authors: Zhang
authors: Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors: Allyson K
authors: AK
authors: Palmer
authors: Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.|Newcastle University Institute for Aging, Newcastle University, Newcastle Upon Tyne, UK.
authors: Mikolaj B
authors: MB
authors: Ogrodnik
authors: Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors: Tamar
authors: T
authors: Pirtskhalava
authors: Department of Surgery, Mayo Clinic, Rochester, MN, USA.
authors: Nassir M
authors: NM
authors: Thalji
authors: Department of Surgery, Mayo Clinic, Rochester, MN, USA.
authors: Michael
authors: M
authors: Hagler
authors: Newcastle University Institute for Aging, Newcastle University, Newcastle Upon Tyne, UK.
authors: Diana
authors: D
authors: Jurk
authors: Department of Surgery, Mayo Clinic, Rochester, MN, USA.
authors: Leslie A
authors: LA
authors: Smith
authors: Department of Surgery, Mayo Clinic, Rochester, MN, USA.
authors: Grace
authors: G
authors: Casaclang-Verzosa
authors: Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors: Yi
authors: Y
authors: Zhu
authors: Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors: Marissa J
authors: MJ
authors: Schafer
authors: Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors: Tamara
authors: T
authors: Tchkonia
authors: Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.|Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.
authors: James L
authors: JL
authors: Kirkland
authors: Department of Surgery, Mayo Clinic, Rochester, MN, USA.|Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.|Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.
authors: Jordan D
authors: JD
authors: Miller
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D050197:Atherosclerosis / Q000473:pathology* / Q000503:physiopathology*; D016922:Cellular Senescence / Q000187:drug effects*; D004249:DNA Damage; D000069439:Dasatinib / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006937:Hypercholesterolemia / Q000150:complications / Q000473:pathology; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014666:Vasomotor System / Q000503:physiopathology*
chemical_list: D009569:Nitric Oxide; D011794:Quercetin; D000069439:Dasatinib
keywords: aging; atherosclerosis; calcification; endothelial function; fibrosis; senescence