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      Senescent Microvesicles: A Novel Advance in Molecular Mechanisms of Atherosclerotic Calcification

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          Abstract

          Atherosclerosis, a chronic inflammatory disease that causes the most heart attacks and strokes in humans, is the leading cause of death in the developing world; its principal clinical manifestation is coronary artery disease. The development of atherosclerosis is attributed to the aging process itself (biological aging) and is also associated with the development of chronic diseases (premature aging). Both aging processes produce an increase in risk factors such as oxidative stress, endothelial dysfunction and proinflammatory cytokines (oxi-inflamm-aging) that might generate endothelial senescence associated with damage in the vascular system. Cellular senescence increases microvesicle release as carriers of molecular information, which contributes to the development and calcification of atherosclerotic plaque, as a final step in advanced atherosclerotic plaque formation. Consequently, this review aims to summarize the information gleaned to date from studies investigating how the senescent extracellular vesicles, by delivering biological signalling, contribute to atherosclerotic calcification.

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          Most cited references124

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          Aging, Cellular Senescence, and Cancer

          For most species, aging promotes a host of degenerative pathologies that are characterized by debilitating losses of tissue or cellular function. However, especially among vertebrates, aging also promotes hyperplastic pathologies, the most deadly of which is cancer. In contrast to the loss of function that characterizes degenerating cells and tissues, malignant (cancerous) cells must acquire new (albeit aberrant) functions that allow them to develop into a lethal tumor. This review discusses the idea that, despite seemingly opposite characteristics, the degenerative and hyperplastic pathologies of aging are at least partly linked by a common biological phenomenon: a cellular stress response known as cellular senescence. The senescence response is widely recognized as a potent tumor suppressive mechanism. However, recent evidence strengthens the idea that it also drives both degenerative and hyperplastic pathologies, most likely by promoting chronic inflammation. Thus, the senescence response may be the result of antagonistically pleiotropic gene action.
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            Cellular senescence in aging and age-related disease: from mechanisms to therapy.

            Cellular senescence, a process that imposes permanent proliferative arrest on cells in response to various stressors, has emerged as a potentially important contributor to aging and age-related disease, and it is an attractive target for therapeutic exploitation. A wealth of information about senescence in cultured cells has been acquired over the past half century; however, senescence in living organisms is poorly understood, largely because of technical limitations relating to the identification and characterization of senescent cells in tissues and organs. Furthermore, newly recognized beneficial signaling functions of senescence suggest that indiscriminately targeting senescent cells or modulating their secretome for anti-aging therapy may have negative consequences. Here we discuss current progress and challenges in understanding the stressors that induce senescence in vivo, the cell types that are prone to senesce, and the autocrine and paracrine properties of senescent cells in the contexts of aging and age-related diseases as well as disease therapy.
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              The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs

              The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1 −/Δ mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1 −/Δ mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                09 July 2018
                July 2018
                : 19
                : 7
                : 2003
                Affiliations
                [1 ]Biology Systems Department, Physiology, Alcala University, Alcala de Henares, 28805 Madrid, Spain; manuel.ramirez@ 123456uah.es
                [2 ]Cardiovascular Joint Research Unit, University Francisco de Vitoria/University Hospital Ramon y Cajal Research Unit (IRYCIS), 28223 Madrid, Spain; rrcarracedo@ 123456hotmail.com
                [3 ]Biomedicine and Biotechnology Department, Alcala University, Alcala de Henares, 28805 Madrid, Spain; guillermo.bodega@ 123456uah.es
                [4 ]Department of Genetic, Physiology and Microbiology, Faculty of Biology, Complutense University/Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), 28040 Madrid, Spain; julcar01@ 123456ucm.es
                Author notes
                [* ]Correspondence: matilde.alique@ 123456uah.es ; Tel.: +34-918-85-64-36
                [†]

                These authors share senior authorship.

                Author information
                https://orcid.org/0000-0002-7912-1133
                https://orcid.org/0000-0002-8391-2245
                https://orcid.org/0000-0002-8422-812X
                https://orcid.org/0000-0003-4598-339X
                Article
                ijms-19-02003
                10.3390/ijms19072003
                6073566
                29987251
                38f89cf8-0474-4eb1-9751-34879c2c263a
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 21 May 2018
                : 05 July 2018
                Categories
                Review

                Molecular biology
                atherosclerosis,microvesicles,senescence,endothelial senescence,vascular calcification,aging

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