Abstract
SummaryWhile 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.
Highlights
SummaryWhile reports suggest a single dose of senolytics may improve vasomotor function, the structural and functional impact of longterm senolytic treatment is unknown
Risk factors for ischemic heart disease include hypercholesterolemia, arterial stiffness, chronic inflammation, hypertension, metabolic syndrome, and aging (Eckel et al, 2013). These risk factors contribute to impaired endothelial function (Feletou & Vanhoutte, 2006), which can contribute to arterial remodeling and accelerate atherosclerotic plaque formation and expansion (Landmesser et al, 2004)
Recent work suggests senescent cell burden can be dramatically increased by chronological aging or in models of progeria (Lecka-Czernik et al, 1997; Baker et al, 2004; Varela et al, 2005), high-fat feeding (Shi et al, 2007), diabetes (Verzola et al, 2008), tobacco exposure (Nyunoya et al, 2006), or atherosclerosis (Wang & Bennett, 2012), and short-term treatment with ‘senolytic’ drugs in chronologically aged or progeroid mice alleviates several aging-related phenotypes (Zhu et al, 2015a,b)
Summary
While reports suggest a single dose of senolytics may improve vasomotor function, the structural and functional impact of longterm 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. 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. 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
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