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      Skeletal Aging and Osteoporosis: Mechanisms and Therapeutics

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          Abstract

          Bone is a dynamic organ maintained by tightly regulated mechanisms. With old age, bone homeostasis, which is maintained by an intricate balance between bone formation and bone resorption, undergoes deregulation. Oxidative stress-induced DNA damage, cellular apoptosis, and cellular senescence are all responsible for this tissue dysfunction and the imbalance in the bone homeostasis. These cellular mechanisms have become a target for therapeutics to treat age-related osteoporosis. Genetic mouse models have shown the importance of senescent cell clearance in alleviating age-related osteoporosis. Furthermore, we and others have shown that targeting cellular senescence pharmacologically was an effective tool to alleviate age- and radiation-induced osteoporosis. Senescent cells also have an altered secretome known as the senescence associated secretory phenotype (SASP), which may have autocrine, paracrine, or endocrine function. The current review discusses the current and potential pathways which lead to a senescence profile in an aged skeleton and how bone homeostasis is affected during age-related osteoporosis. The review has also discussed existing therapeutics for the treatment of osteoporosis and rationalizes for novel therapeutic options based on cellular senescence and the SASP as an underlying pathogenesis of an aging bone.

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          The senescence-associated secretory phenotype: the dark side of tumor suppression.

          Cellular senescence is a tumor-suppressive mechanism that permanently arrests cells at risk for malignant transformation. However, accumulating evidence shows that senescent cells can have deleterious effects on the tissue microenvironment. The most significant of these effects is the acquisition of a senescence-associated secretory phenotype (SASP) that turns senescent fibroblasts into proinflammatory cells that have the ability to promote tumor progression.
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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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              The serial cultivation of human diploid cell strains.

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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                29 March 2021
                April 2021
                : 22
                : 7
                : 3553
                Affiliations
                [1 ]Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55902, USA
                [2 ]Department of Internal Medicine, Division of Geriatric Medicine and Gerontology, Mayo Clinic, Rochester, MN 55902, USA
                [3 ]Robert and Arlene Kogod Aging Center, Mayo Clinic, Rochester, MN 55902, USA
                [4 ]Department of Zoology, University of Lucknow, University Rd, Babuganj, Hasanganj, Lucknow, Uttar Pradesh 226007, India; jrajawat@ 123456gmail.com
                Author notes
                [* ]Correspondence: chandra.abhishek1@ 123456mayo.edu ; Tel.: +1-507-266-1847
                Article
                ijms-22-03553
                10.3390/ijms22073553
                8037620
                33805567
                92fda751-d3af-416f-a82e-eca527afa6b3
                © 2021 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
                : 25 February 2021
                : 25 March 2021
                Categories
                Review

                Molecular biology
                osteoporosis,senescence,sasp,aging,radiation,senotherapeutic
                Molecular biology
                osteoporosis, senescence, sasp, aging, radiation, senotherapeutic

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