Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice

By Carolyn M. Roos, Bin Zhang, Allyson K. Palmer, M. Ogrodnik, T. Pirtskhalava, Nassir M. Thalji, Michael A. Hagler, D. Jurk, Leslie A. Smith, Grace Casaclang-Verzosa and 5 more. Aging Cell, 2016

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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.

Subfields: Immunology, Physiology

View Paper: https://www.semanticscholar.org/paper/514a1745fdcaa363ef332e1ba6461a9de83345f2

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Citations in the corpus

Epigenetics and aging (2016, background): “An exciting new way to improve health span and, subsequently, life span inmice is to specifically kill off senescent cells with senolytic agents (230).”
Fisetin is a senotherapeutic that extends health and lifespan (2018, background): “In addition, D + Q treatment decreases vascular calcification and increases vascular reactivity in hypercholesterolemic, high fat diet fed ApoE mice after three monthly 3 day treatment courses [34].”
Cellular senescence drives age-dependent hepatic steatosis (2017, positive): “We note that deletion of p16 INK4a -expressing cells improves multiple ageing phenotypes in progeroid mice 10 and extends healthspan parameters in wild-type chronically aged mice and may increase their median lifespan 11,27,42 .”
Mechanisms of Vascular Aging (2018, background): “Importantly, long-term senolytic treatment was also shown to improve endothelial function in mouse models of aging.(127)”
Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease (2019, background): “These included age-related declines in cardiac regenerative capacity, frailty, muscle weakness, reduced daily activity, decreased running endurance on a treadmill, and osteoporosis [3,5,9,28,32].”
Cellular Senescence: A Translational Perspective (2017, methodology): “Using several different approaches in preclinical studies, the combination of D+ Q as well as N were shown to clear senescent cells in vivo (Zhu et al., 2015a; Zhu et al., 2015b; Roos et al., 2016; Schafer et al., 2017; Chang et al., 2016).”
Aging and aging-related diseases: from molecular mechanisms to interventions and treatments (2022, background): “The INK-ATTAC “suicide” transgene encoding inducible caspase 8 is expressed specifically in senescent cells and specifically kills senescent cells in mice.(284,559,612) In an old INKATTC mouse model, administration of AP20187 has been found to specifically eliminate p16-positive cells.”
Role of smooth muscle cells in vascular calcification: implications in atherosclerosis and arterial stiffness (2018, background): “Trials of senolytic compounds, such as Dasatinib and Quercetin, in mice led to reduced senescence cell markers in the medial layer of the vasculature, however, their effects on calcification have yet to be tested.(45) Figure 2 VSMC differentiation in intimal and medial calcification.”
Endothelial Dysfunction in Atherosclerotic Cardiovascular Diseases and Beyond: From Mechanism to Pharmacotherapies (2021, background): “…(Sasaki et al., 2020), chlorogenic acid (Hada et al., 2020), and senolytic therapies [B-cell lymphoma 2 inhibitor ABT263 (Zhu et al., 2016), quercetin/dasatinib cocktail (Roos et al., 2016)] improve endothelium-dependent vasodilation and endothelial dysfunction in hypercholesterolemic conditions.”
Targeting cellular senescence prevents age-related bone loss in mice (2017, background): “(4) Anti-resorptive therapy inhibits or eliminates OCs and decreases bone resorption; owing to (5) coupling, there is a concomitant reduction in bone formation.”
Physiological frailty index (PFI): quantitative in-life estimate of individual biological age in mice (2017, positive): “com 957 AGING vascular, frailty-related, osteoporotic, neurological, radiation-induced, and other phenotypes and disorders in chronologically aged, progeroid, and high fat-fed atherosclerosis-prone mice, consistent with our observations in mice from which senescent cells had been removed by inducing”