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      Cellular Senescence: A Translational Perspective

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          Abstract

          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.

          Highlights

          • •

            Cellular senescence is among the aging processes underlying chronic diseases, loss of resilience, and geriatric syndromes.

          • •

            Senolytics selectively induce senescent cell apoptosis. They delay or alleviate multiple disorders in preclinical studies.

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            If senolytics are demonstrated to be effective and safe in clinical trials, they could be transformative.

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          The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs

          Yi-Yi Zhu, Tamara Tchkonia, Tamar Pirtskhalava … (2015)
          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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            Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.

            Darren J. Baker, Tobias Wijshake, Tamar Tchkonia … (2012)
            Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells. Senescent cells accumulate in various tissues and organs with ageing and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16(Ink4a), to design a novel transgene, INK-ATTAC, for inducible elimination of p16(Ink4a)-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16(Ink4a)-positive senescent cells upon drug treatment. In tissues--such as adipose tissue, skeletal muscle and eye--in which p16(Ink4a) contributes to the acquisition of age-related pathologies, life-long removal of p16(Ink4a)-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.
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              Naturally occurring p16Ink4a-positive cells shorten healthy lifespan

              Darren J. Baker, Bennett Childs, Matej Durik … (2016)
              Cellular senescence, a stress-induced irreversible growth arrest often characterized by p16Ink4a expression and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time and have been speculated to play a role in aging. To explore the physiological relevance and consequences of naturally occurring senescent cells, we used a previously established transgene, INK-ATTAC, to induce apoptosis in p16Ink4a-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. Here we show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. Clearance of p16Ink4a-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels, and adipocytes, respectively. Thus, p16Ink4a-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in multiple organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan.
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                Author and article information

                Contributors
                James L. Kirkland
                Journal
                Journal ID (nlm-ta): EBioMedicine
                Journal ID (iso-abbrev): EBioMedicine
                Title: EBioMedicine
                Publisher: Elsevier
                ISSN (Electronic): 2352-3964
                Publication date PMC-release: 12 April 2017
                Publication date Collection: July 2017
                Publication date (Electronic): 12 April 2017
                Volume: 21
                Pages: 21-28
                Affiliations
                Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, United States
                Author notes
                [* ]Corresponding author at: Cellular Senescence Program, Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First Street, S.W., Rochester, MN 55905, United States.Cellular Senescence ProgramRobert and Arlene Kogod Center on AgingMayo Clinic200 First Street, S.W.RochesterMN55905United States kirkland.james@ 123456mayo.edu
                Article
                Publisher ID: S2352-3964(17)30154-8
                DOI: 10.1016/j.ebiom.2017.04.013
                PMC ID: 5514381
                PubMed ID: 28416161
                SO-VID: f317a7a0-0981-46fe-b969-10c8d1f785c6
                Copyright © © 2017 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 13 March 2017
                Date revision received : 6 April 2017
                Date accepted : 6 April 2017
                Categories
                Subject: Review

                Keywords: senolytics,sasp inhibitors,dasatinib,quercetin,navitoclax,fisetin,a1331852,a1155463,senescent cell anti-apoptotic pathways (scaps)
                Data availability:
                Keywords: senolytics, sasp inhibitors, dasatinib, quercetin, navitoclax, fisetin, a1331852, a1155463, senescent cell anti-apoptotic pathways (scaps)

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