Senolytic agents lessen the severity of abdominal aortic aneurysm in aged mice

Parvizi, Mojtaba; Franchi, Federico; Arendt, Bonnie K.; Ebtehaj, Sanam; Rodriguez-Porcel, Martin; Lanza, Ian R.

doi:10.1016/j.exger.2021.111416

Cited by 16 publications

(10 citation statements)

References 42 publications

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“…Senescent VSMCs seem to cause the vessel wall to be weakened against hemodynamic pressure, contributing to aneurysm formation. D+Q reduces Ang II-induced abdominal aortic aneurysm (AAA) size in aged mice [285]. UBX1967, a BCL-xL small molecule inhibitor, appears to reduce ischemic retinopathy in an oxygen-induced mouse retinopathy model [286].…”

Section: Cardiovascular Diseases That Senotherapeutics May Potentiall...mentioning

confidence: 99%

Senescent Cells: A Therapeutic Target in Cardiovascular Diseases

Suda

Paul

Minamino

et al. 2023

Cells

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Senescent cell accumulation has been observed in age-associated diseases including cardiovascular diseases. Senescent cells lack proliferative capacity and secrete senescence-associated secretory phenotype (SASP) factors that may cause or worsen many cardiovascular diseases. Therapies targeting senescent cells, especially senolytic drugs that selectively induce senescent cell removal, have been shown to delay, prevent, alleviate, or treat multiple age-associated diseases in preclinical models. Some senolytic clinical trials have already been completed or are underway for a number of diseases and geriatric syndromes. Understanding how cellular senescence affects the various cell types in the cardiovascular system, such as endothelial cells, vascular smooth muscle cells, fibroblasts, immune cells, progenitor cells, and cardiomyocytes, is important to facilitate translation of senotherapeutics into clinical interventions. This review highlights: (1) the characteristics of senescent cells and their involvement in cardiovascular diseases, focusing on the aforementioned cardiovascular cell types, (2) evidence about senolytic drugs and other senotherapeutics, and (3) the future path and clinical potential of senotherapeutics for cardiovascular diseases.

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Section: Cardiovascular Diseases That Senotherapeutics May Potentiall...mentioning

confidence: 99%

Senescent Cells: A Therapeutic Target in Cardiovascular Diseases

Suda

Paul

Minamino

et al. 2023

Cells

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“…Therefore, for rats in the CCI + DQ group, 5 mg/kg dasatinib (SML2589, Sigma–Aldrich, Darmstadt, Germany) plus 50 mg/kg quercetin (Q4951, Sigma–Aldrich) were dissolved together in a solvent comprising 60% Phosal, 10% ethanol, and 30% polyethylene glycol-400, and gavaged daily, starting on the first postoperative day and continuing throughout the study. The above doses of dasatinib and quercetin were selected based on previous studies [ 17 – 19 ]. An equal volume of solvent was gavaged to rats in the CCI + Veh group over a comparable time period as that of the CCI rats receiving dasatinib and quercetin.…”

Section: Methodsmentioning

confidence: 99%

Astrocyte senescence-like response related to peripheral nerve injury-induced neuropathic pain

Cheng

Deng

et al. 2023

Cell Mol Biol Lett

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Background Peripheral nerve damage causes neuroinflammation, which plays a critical role in establishing and maintaining neuropathic pain (NeP). The mechanisms contributing to neuroinflammation remain poorly elucidated, and pharmacological strategies for NeP are limited. Thus, in this study, we planned to explore the possible link between astrocyte senescence and NeP disorders following chronic sciatic nerve injury. Methods An NeP animal model was established by inducing chronic constrictive injury (CCI) to the sciatic nerve in adult rats. A senolytic drug combination of dasatinib and quercetin was gavaged daily from the first postoperative day until the end of the study. Paw mechanical withdrawal threshold (PMWT) and paw thermal withdrawal latency (PTWL) were evaluated to assess behaviors in response to pain in the experimental rats. Senescence-associated β-galactosidase staining, western blot analysis, and immunofluorescence were applied to examine the levels of proinflammatory factors and severity of the senescence-like response in the spinal cord. Lipopolysaccharide (LPS) was administered to induce senescence of spinal astrocytes in primary cultures in vitro, to explore the potential impacts of senescence on the secretion of proinflammatory factors. Furthermore, single-cell RNA sequencing (scRNA-seq) was conducted to identify senescence-related molecular responses in spinal astrocytes under neuropathic pain. Results Following sciatic nerve CCI, rats exhibited reduced PMWT and PTWL, increased levels of spinal proinflammatory factors, and an enhanced degree of senescence in spinal astrocytes. Treatment with dasatinib and quercetin effectively attenuated spinal neuroinflammation and mitigated the hypersensitivities of the rats subjected to sciatic nerve CCI. Mechanistically, the dasatinib-quercetin combination reversed senescence in LPS-stimulated primary cultured astrocytes and decreased the levels of proinflammatory factors. The scRNA-seq data revealed four potential senescence-related genes in the spinal astrocyte population, and the expression of clusterin (CLU) protein was validated via in vitro experiments. Conclusion The findings indicate the potential role of astrocyte senescence in neuroinflammation following peripheral nerve injury, and suggest that targeting CLU activation in astrocytes might provide a novel therapeutic strategy to treat NeP. Graphical abstract

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“…In an arteriovenous fistula chronic kidney disease mouse model, dasatinib and quercetin treatment significantly reduced p16 Ink4a venous expression, indicating reduction in SC ( 81 ). Pre-treatment with this senotherapeutic combination has also been shown to reduce the quantity of SC in arterial walls and lessened the severity of abdominal aortic aneurysms in mice given angiotensin II ( 87 ).…”

Section: Preclinical Evidence For Senotherapeuticsmentioning

confidence: 99%

The potential for senotherapy as a novel approach to extend life quality in veterinary medicine

Williams,

Chow,

Dow

et al. 2024

Front. Vet. Sci.

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Cellular senescence, a condition where cells undergo arrest and can assume an inflammatory phenotype, has been associated with initiation and perpetuation of inflammation driving multiple disease processes in rodent models and humans. Senescent cells secrete inflammatory cytokines, proteins, and matrix metalloproteinases, termed the senescence associated secretory phenotype (SASP), which accelerates the aging processes. In preclinical models, drug interventions termed “senotherapeutics” selectively clear senescent cells and represent a promising strategy to prevent or treat multiple age-related conditions in humans and veterinary species. In this review, we summarize the current available literature describing in vitro evidence for senotheraputic activity, preclinical models of disease, ongoing human clinical trials, and potential clinical applications in veterinary medicine. These promising data to date provide further justification for future studies identifying the most active senotherapeutic combinations, dosages, and routes of administration for use in veterinary medicine.

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Senolytic agents lessen the severity of abdominal aortic aneurysm in aged mice

Cited by 16 publications

References 42 publications

Senescent Cells: A Therapeutic Target in Cardiovascular Diseases

Senescent Cells: A Therapeutic Target in Cardiovascular Diseases

Astrocyte senescence-like response related to peripheral nerve injury-induced neuropathic pain

The potential for senotherapy as a novel approach to extend life quality in veterinary medicine

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