The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs
Yi-Yi Zhu,Tamara Tchkonia,Tamar Pirtskhalava,Adam C. Gower,Husheng Ding,Nino Giorgadze,Allyson K. Palmer,Yuji Ikeno,Yuji Ikeno,Gene B. Hubbard,Gene B. Hubbard,Marc E. Lenburg,Steven P. O'Hara,Nicholas F. LaRusso,Jordan D. Miller,Carolyn M Roos,Grace C Verzosa,Nathan K. LeBrasseur,Jonathan D. Wren,Joshua N. Farr,Sundeep Khosla,Michael B. Stout,Sara J. McGowan,Heike Fuhrmann-Stroissnigg,Aditi U. Gurkar,Jing-jing Zhao,Debora Colangelo,Akaitz Dorronsoro,Yuan Yuan Ling,Amira S. Barghouthy,Diana C. Navarro,Tokio Sano,Paul D. Robbins,Laura J. Niedernhofer,James L. Kirkland +34 more
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TLDR
The results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.Abstract:
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(-/∆) 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.read more
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Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor
TL;DR: Coppe et al. as mentioned in this paper showed that human cells induced to senesce by genotoxic stress secrete myriad factors associated with inflammation and malignancy, including interleukin (IL)-6 and IL-8.
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Cellular senescence in aging and age-related disease: from mechanisms to therapy
TL;DR: 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 are discussed.
Journal ArticleDOI
Cellular Senescence: Defining a Path Forward
Vassilis G. Gorgoulis,Peter D. Adams,Andrea Alimonti,Dorothy C. Bennett,Oliver Bischof,Cleo L. Bishop,Judith Campisi,Manuel Collado,Konstantinos Evangelou,Gerardo Ferbeyre,Jesús Gil,Eiji Hara,Valery Krizhanovsky,Diana Jurk,Andrea B. Maier,Masashi Narita,Laura J. Niedernhofer,João F. Passos,Paul D. Robbins,Clemens A. Schmitt,John M. Sedivy,Konstantinos Vougas,Thomas von Zglinicki,Daohong Zhou,Manuel Serrano,Marco Demaria +25 more
TL;DR: A consensus from the International Cell Senescence Association (ICSA) is presented, defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers.
Journal ArticleDOI
Hallmarks of Cellular Senescence.
TL;DR: The molecular regulators of senescence phenotypes and how they are used for identifying senescent cells in vitro and in vivo are described and the importance that these levels of regulations have in the development of therapeutic targets is highlighted.
Journal ArticleDOI
Senolytics improve physical function and increase lifespan in old age
Ming Xu,Ming Xu,Tamar Pirtskhalava,Joshua N. Farr,Bettina M. Weigand,Bettina M. Weigand,Allyson K. Palmer,Megan M. Weivoda,Christina L. Inman,Mikolaj Ogrodnik,Mikolaj Ogrodnik,Christine M Hachfeld,Daniel G. Fraser,Jennifer L Onken,Kurt O. Johnson,Grace C Verzosa,Larissa G.P. Langhi,Moritz Weigl,Nino Giorgadze,Nathan K. LeBrasseur,Jordan D. Miller,Diana Jurk,Ravinder J. Singh,David B. Allison,David B. Allison,Keisuke Ejima,Keisuke Ejima,Gene B. Hubbard,Yuji Ikeno,Yuji Ikeno,Hajrunisa Cubro,Vesna D. Garovic,Xiaonan Hou,S. John Weroha,Paul D. Robbins,Laura J. Niedernhofer,Sundeep Khosla,Tamara Tchkonia,James L. Kirkland +38 more
TL;DR: It is demonstrated 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, and a senolytic can reverse this dysfunction and potently increase lifespan in aged mice.
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Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor
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Karen H. Vousden,Carol Prives +1 more
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Journal ArticleDOI
Clearance of p16 Ink4a -positive senescent cells delays ageing-associated disorders
Darren J. Baker,Tobias Wijshake,Tamar Tchkonia,Nathan K. LeBrasseur,Bennett G. Childs,Bart van de Sluis,James L. Kirkland,Jan M. van Deursen +7 more
TL;DR: 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.