Long-term dasatinib plus quercetin effects on aging outcomes and inflammation in nonhuman primates: implications for senolytic clinical trial design

Ruggiero, Alistaire; Vemuri, Ravichandra; Blawas, Megan; Long, Masha; DeStephanis, Darla; Williams, Abigail G.; Chen, Haiying; Justice, Jamie N.; Macauley, Shannon L.; Day, Marc; Kavanagh, Kylie

doi:10.1007/s11357-023-00830-5

Cited by 22 publications

(7 citation statements)

References 57 publications

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“…Furthermore, although quercetin has a synergistic effect with some chemotherapy medications, additional studies are needed to determine whether it has a synergistic effect with other chemotherapy agents. In addition, preclinical studies of dasatinib in combination with quercetin for anti‐aging have been carried out extensively, and its anti‐aging effects were validated in non‐human primates, [91] where the combination of drugs reduced the overall cellular burden of aging rather than targeting a single organ or structure, which opened up the possibility of application to humans. In addition, the combination of dasatinib and quercetin has potential in the treatment of age‐dependent intervertebral disc degeneration, [92] diabetic nephropathy [93] and in the regulation of intestinal microorganisms [94] .…”

Section: Discussionmentioning

confidence: 99%

Research Progress on Quercetin's Biological Activity and Structural Modification Based on Its Antitumor Effects

Guo,

Zeng,

Sun

et al. 2023

ChemistrySelect

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Quercetin is a naturally existing flavonoid with numerous physiological effects, including antitumor activity. It functions as an antitumor agent by inducing apoptosis and inhibiting tumor cell development, preventing tumor cell invasion and metastasis, and reversing tumor multidrug resistance. Quercetin has limited therapeutic usefulness due to its low water solubility, poor oral absorption, and low bioavailability. New quercetin derivatives are being developed and manufactured via a variety of methods to address inadequacies and for utilization in disease prevention and therapy. The synthesis and anticancer effects of quercetin derivatives, as well as the structure‐activity relationship of quercetin derivatives, were explored, and the unique dosage forms of these derivatives were summarized to serve as a reference for future quercetin research and development.

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Section: Discussionmentioning

confidence: 99%

Research Progress on Quercetin's Biological Activity and Structural Modification Based on Its Antitumor Effects

Guo,

Zeng,

Sun

et al. 2023

ChemistrySelect

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show abstract

“…122 A senolytic combination of dasatinib and quercetin has been reported to suppress inflamm-aging by augmenting anti-inflammatory responses in immune functions and preventing the accumulation of senescent cells in a preclinical trial. 123 Treatment with quercetin ameliorates advanced glycation end-products-induced premature senescence and SASP in human gingival fibroblasts and has been implicated in the amelioration of inflamm-aging in diabetic periodontitis. 124 Administration of quercetin in mice alleviates atherosclerotic lesions in arterial lumina by suppressing inflammatory cytokines and cellular senescence.…”

Section: Cellular Senescence Augments Inflamm-agingmentioning

confidence: 99%

“…The alkaloid dendrobine suppresses cellular senescence and SASP in chondrocytes which alleviates the progression of inflammation and osteoarthritis in rats 122 . A senolytic combination of dasatinib and quercetin has been reported to suppress inflamm‐aging by augmenting anti‐inflammatory responses in immune functions and preventing the accumulation of senescent cells in a preclinical trial 123 . Treatment with quercetin ameliorates advanced glycation end‐products‐induced premature senescence and SASP in human gingival fibroblasts and has been implicated in the amelioration of inflamm‐aging in diabetic periodontitis 124 .…”

Section: Cellular Senescence and Inflamm‐aging: Decoding The Relation...mentioning

confidence: 99%

Exploring the emerging bidirectional association between inflamm‐aging and cellular senescence in organismal aging and disease

Sharma

2024

Cell Biochemistry & Function

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There is strong evidence that most individuals in the elderly population are characterized by inflamm‐aging which refers to a subtle increase in the systemic pro‐inflammatory environment and impaired innate immune activation. Although a variety of distinct factors are associated with the progression of inflamm‐aging, emerging research is demonstrating a dynamic relationship between the processes of cellular senescence and inflamm‐aging. Cellular senescence is a recognized factor governing organismal aging, and through a characteristic secretome, accumulating senescent cells can induce and augment a pro‐inflammatory tissue environment that provides a rationale for immune system‐independent activation of inflamm‐aging and associated diseases. There is also accumulating evidence that inflamm‐aging or its components can directly accelerate the development of senescent cells and ultimately senescent cell burden in tissues in a likely vicious inflammatory loop. The present review is intended to describe the emerging senescence‐based molecular etiology of inflamm‐aging as well as the dynamic reciprocal interactions between inflamm‐aging and cellular senescence. Therapeutic interventions concurrently targeting cellular senescence and inflamm‐aging are discussed and limitations as well as research opportunities have been deliberated. An effort has been made to provide a rationale for integrating inflamm‐aging with cellular senescence both as an underlying cause and therapeutic target for further studies.

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“…The combination treatment of dasatinib (D), a tyrosine kinase inhibitor, with quercetin (Q), a flavonoid and antioxidant, has proven highly effective in inducing apoptosis in senescent cells in vitro across multiple cell types, as well as in multiple animal models. D&Q treatment in human umbilical vein endothelial cells (HUVECs) demonstrated a senolytic effect, alleviating senescence via the inhibition of autocrine and paracrine actions of the SASP [80] . D&Q treatment in nonhuman primates also reduced SASP factors, increased immune function, and improved intestinal barrier function [81] .…”

Section: Targeting Senescent Endothelial Cells To Improve Vascular Fu...mentioning

confidence: 99%

Targeting vascular senescence in cardiovascular disease with aging

Hall,

Lesniewski

2024

J Cardiovasc Aging

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Aging is a major risk factor for atherosclerosis and cardiovascular disease (CVD). Two major age-associated arterial phenotypes, endothelial dysfunction and large elastic arterial stiffness, are autonomous predictors of future CVD diagnosis and contribute to the progression of CVD in older adults. Senescent cells lose the capacity to proliferate but remain metabolically active and secrete inflammatory factors termed senescence-associated secretory phenotype (SASP), leading to an increase in inflammation and oxidative stress. Accumulation of senescent cells is linked with the progression of age-related diseases and has been known to play a role in cardiovascular disease. In this brief review, we describe the characteristics and mechanisms of senescent cell accumulation and how senescent cells promote endothelial dysfunction and arterial stiffness. We focus on a range of novel therapeutic strategies aimed at reducing the burden of endothelial dysfunction leading to atherosclerosis through targeting senescent cells. Studies have begun to investigate a specific class of drugs that are able to selectively eliminate senescent cells, termed senolytics, which have shown great promise in reversing the aging phenotype and ameliorating pathologies in age-related disorders, creating a new opportunity for aging research. Generating therapies targeting the elimination of senescent cells would improve health span and increase longevity, making senolytics a promising therapy for cardiovascular diseases.

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Long-term dasatinib plus quercetin effects on aging outcomes and inflammation in nonhuman primates: implications for senolytic clinical trial design

Cited by 22 publications

References 57 publications

Research Progress on Quercetin's Biological Activity and Structural Modification Based on Its Antitumor Effects

Research Progress on Quercetin's Biological Activity and Structural Modification Based on Its Antitumor Effects

Exploring the emerging bidirectional association between inflamm‐aging and cellular senescence in organismal aging and disease

Targeting vascular senescence in cardiovascular disease with aging

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