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      Senolytics Improve Physical Function and Increase Lifespan in Old Age

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      1 , 10 , 1 , 1 , 1 , 2 , 1 , 1 , 1 , 1 , 2 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 2 , 3 , 4 , 4 , 5 , 5 , 6 , 7 , 7 , 8 , 8 , 9 , 9 , 1 , 1 , 1
      Nature medicine
      aging, cellular senescence, frailty, dasatinib, quercetin

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          Abstract

          Physical function declines in old age, portending disability, increased health expenditures, and mortality. Cellular senescence, leading to tissue dysfunction, may contribute to these consequences of aging, but whether senescence can directly drive age-related pathology and be targeted therapeutically is still unclear. Here we demonstrate that transplanting relatively small numbers of senescent cells into young mice is sufficient to cause persistent physical dysfunction, as well as to spread cellular senescence to host tissues. Transplanting even fewer senescent cells had the same effect in older recipients, accompanied by reduced survival, indicating the potency of senescent cells in shortening health- and life-span. The senolytic cocktail, dasatinib plus quercetin, which causes selective elimination of senescent cells, decreased the number of naturally-occurring senescent cells and their secretion of frailty-related pro-inflammatory cytokines in explants of human adipose tissue. Moreover, intermittent oral administration of senolytics to both senescent cell-transplanted younger and naturally-aged mice alleviated physical dysfunction and increased post-treatment survival by 36% while reducing mortality hazard to 65%. Our study provides proof-of-concept evidence that senescent cells can cause physical dysfunction and decreased survival even in young mice, while senolytics can enhance remaining health- and lifespan in old mice.

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          Most cited references34

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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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            Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype.

            Cellular senescence permanently arrests cell proliferation, often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). Loss of mitochondrial function can drive age-related declines in the function of many post-mitotic tissues, but little is known about how mitochondrial dysfunction affects mitotic tissues. We show here that several manipulations that compromise mitochondrial function in proliferating human cells induce a senescence growth arrest with a modified SASP that lacks the IL-1-dependent inflammatory arm. Cells that underwent mitochondrial dysfunction-associated senescence (MiDAS) had lower NAD+/NADH ratios, which caused both the growth arrest and prevented the IL-1-associated SASP through AMPK-mediated p53 activation. Progeroid mice that rapidly accrue mtDNA mutations accumulated senescent cells with a MiDAS SASP in vivo, which suppressed adipogenesis and stimulated keratinocyte differentiation in cell culture. Our data identify a distinct senescence response and provide a mechanism by which mitochondrial dysfunction can drive aging phenotypes.
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              Cellular Senescence: A Translational Perspective

              Cellular senescence entails essentially irreversible replicative arrest, apoptosis resistance, and frequently acquisition of a pro-inflammatory, tissue-destructive senescence-associated secretory phenotype (SASP). Senescent cells accumulate in various tissues with aging and at sites of pathogenesis in many chronic diseases and conditions. The SASP can contribute to senescence-related inflammation, metabolic dysregulation, stem cell dysfunction, aging phenotypes, chronic diseases, geriatric syndromes, and loss of resilience. Delaying senescent cell accumulation or reducing senescent cell burden is associated with delay, prevention, or alleviation of multiple senescence-associated conditions. We used a hypothesis-driven approach to discover pro-survival Senescent Cell Anti-apoptotic Pathways (SCAPs) and, based on these SCAPs, the first senolytic agents, drugs that cause senescent cells to become susceptible to their own pro-apoptotic microenvironment. Several senolytic agents, which appear to alleviate multiple senescence-related phenotypes in pre-clinical models, are beginning the process of being translated into clinical interventions that could be transformative.
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                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                10 May 2018
                09 July 2018
                August 2018
                09 January 2019
                : 24
                : 8
                : 1246-1256
                Affiliations
                [1 ]Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, USA
                [2 ]Newcastle University Institute for Ageing and Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK
                [3 ]Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, USA
                [4 ]Department of Epidemiology & Biostatistics, School of Public Health, Indiana University-Bloomington and Nathan Shock Center on Comparative Energetics and Aging, University of Alabama at Birmingham, 1025 E 7th St, Bloomington, IN 47405, USA
                [5 ]Barshop Institute for Longevity and Aging Studies and Department of Pathology, University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, TX 78245, USA
                [6 ]Geriatric Research Education and Clinical Center, South Texas Veterans Healthcare System, 15355 Lambda Drive, San Antonio, TX 78245, USA
                [7 ]Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, USA
                [8 ]Department of Oncology, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, USA
                [9 ]Department of Molecular Medicine, Center on Aging, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA
                [10 ]University of Connecticut Center on Aging, UConn Health, 263 Farmington Avenue, Farmington, CT 06030, USA (after 6/8/2018)
                Author notes
                [* ]To whom correspondence should be addressed at: Mayo Clinic Robert and Arlene Kogod Center on Aging, 200 First St., S.W., Rochester, MN 55905, Telephone: (507) 266-9151, Fax: (507) 293-3853, kirkland.james@ 123456mayo.edu ; xu.ming@ 123456mayo.edu ( mixu@ 123456uchc.edu , after 6/8/2018); tchkonia.tamar@ 123456mayo.edu

                Note: Ming Xu will move to University of Connecticut Center on Aging after 6/8/2018. The email will be changed to mixu@ 123456uchc.edu by then.

                Article
                NIHMS966845
                10.1038/s41591-018-0092-9
                6082705
                29988130
                f5fbb6bb-2647-4251-b0d9-f294baf4ea62

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                Medicine
                aging,cellular senescence,frailty,dasatinib,quercetin
                Medicine
                aging, cellular senescence, frailty, dasatinib, quercetin

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