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

Aging Cell
Yi ZhuJames L Kirkland

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...Continue Reading

References

Mar 1, 1996·General Pharmacology·C K Chen, C R Pace-Asciak
Dec 2, 1999·Genes & Development·S R DattaM E Greenberg
May 8, 2000·International Journal of Cancer. Journal International Du Cancer·S H LeechU Zangemeister-Wittke
Dec 10, 2003·Oncogene·Jordan S Fridman, Scott W Lowe
Oct 27, 2004·Apoptosis : an International Journal on Programmed Cell Death·M OsakiH Ito
May 19, 2005·Cancer Research·Andrei L Gartel, Senthil K Radhakrishnan
Jul 30, 2005·World Journal of Gastroenterology : WJG·Christian HafnerThomas Vogt
Oct 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aravind SubramanianJill P Mesirov
Oct 14, 2005·Journal of Cellular Physiology·Mauro PiantelliPier Giorgio Natali
Feb 4, 2006·Science·Utz HerbigJohn M Sedivy
Apr 20, 2006·Clinical and Experimental Pharmacology & Physiology·Machha AjayMohd Rais Mustafa
Apr 25, 2006·American Journal of Physiology. Heart and Circulatory Physiology·Michel Félétou, Paul M Vanhoutte
Sep 21, 2006·American Journal of Physiology. Endocrinology and Metabolism·Tamara TchkoniaJames L Kirkland
Dec 6, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Feng R LuoFrancis Y Lee
Jul 24, 2007·Bioinformatics·Aravind SubramanianJill P Mesirov
Jun 11, 2008·Molecular and Cellular Biology·Anwaar AhmadLaura J Niedernhofer
Jul 18, 2008·Cancer Research·Laura TonnettiToni M Antalis
Aug 30, 2008·Cell·Valery KrizhanovskyScott W Lowe
Jan 10, 2009·Thrombosis and Haemostasis·David J SchneiderBurton E Sobel
Feb 13, 2009·Journal of the National Cancer Institute·Céline Delloye-BourgeoisAgnès Bernet
May 5, 2009·Cell·Karen H Vousden, Carol Prives
May 20, 2009·Circulation·Dao-Fu DaiPeter S Rabinovitch
Jun 2, 2009·The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences·Nathan K LeBrasseurThomas A Brown
Jan 29, 2010·The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences·Mark J CartwrightJames L Kirkland
Feb 23, 2010·Oncogene·D Goldschneider, P Mehlen
Aug 13, 2010·Aging Cell·Tamara TchkoniaJames L Kirkland
May 27, 2011·DNA Repair·Siobhán Q GreggLaura J Niedernhofer
Jun 15, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Juan Carlos MonteroAtanasio Pandiella
Dec 14, 2011·Breast Cancer Research and Treatment·Siying WangJia Luo
Dec 29, 2011·Proceedings of the National Academy of Sciences of the United States of America·Mireille DelhaseMakoto Nakanishi
May 12, 2012·Cancer Discovery·Sarat Chandarlapaty
Jun 19, 2012·The Journal of Clinical Investigation·Jeremy S TilstraPaul D Robbins
Aug 7, 2012·Journal of Cellular and Molecular Medicine·Hong-Qing XiLin Chen
Jan 1, 2011·Pathobiology of Aging & Age Related Diseases·Martijn E T DolléHarry van Steeg
Nov 20, 2012·Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology·Fang CuiHong Shi
Dec 15, 2012·Experimental Gerontology·James L Kirkland
Jan 1, 2013·Anti-cancer Agents in Medicinal Chemistry·Ansgar Bruning
Mar 5, 2013·The Journal of Clinical Investigation·Tamara TchkoniaJames L Kirkland

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Citations

Oct 30, 2015·International Journal of Molecular Sciences·Maximina H Yun
Feb 4, 2016·Nature·Jesús Gil, Dominic J Withers
Feb 24, 2016·Frontiers in Genetics·Naina Bhatia-DeyAntonei B Csoka
Apr 5, 2016·The Canadian Journal of Cardiology·Hao Yin, J Geoffrey Pickering
Oct 22, 2016·Mechanisms of Ageing and Development·Giulia AccardiGiuseppina Candore
Feb 21, 2016·Indian Heart Journal·Sundeep Mishra
Mar 1, 2016·Kidney International·LaTonya J HicksonLilach O Lerman
Sep 4, 2015·Biogerontology·Llilians Calvo GonzalezFrancis Rodier
Nov 19, 2015·Proceedings of the National Academy of Sciences of the United States of America·Ming XuJames L Kirkland
Jan 20, 2016·Science·Matt KaeberleinGeorge M Martin
Jan 17, 2016·Seminars in Cancer Biology·Flavia RibezzoBjörn Schumacher
Jan 7, 2016·Nature Medicine·Hartmut Geiger
Mar 1, 2016·Experimental Gerontology·Allyson K Palmer, James L Kirkland
Mar 5, 2016·Cell Stem Cell·Sally E Trabucco, Hong Zhang
Dec 10, 2015·Nature Medicine·Bennett G ChildsJan M van Deursen
Oct 21, 2015·Current Opinion in Clinical Nutrition and Metabolic Care·Peter StenvinkelPaul G Shiels
Sep 24, 2015·Fitoterapia·Gabriele D'Andrea
Apr 5, 2016·Mechanisms of Ageing and Development·Ari BarzilaiYosef Shiloh
Oct 6, 2015·Cell Regeneration·Hoi-Hung CheungWai-Yee Chan
Apr 10, 2016·Archives of Biochemistry and Biophysics·F Triana-MartínezM Königsberg
Apr 7, 2016·Nature Communications·Reut YosefValery Krizhanovsky
Jul 15, 2015·Rejuvenation Research·Andrew R Mendelsohn, James W Larrick
Apr 12, 2015·Ageing Research Reviews·John Tower
Apr 16, 2016·American Journal of Respiratory and Critical Care Medicine·Jodie BirchJoão F Passos
Jun 23, 2015·Pharmacology & Therapeutics·Serge AdnotJorge Boczkowski
May 11, 2016·Trends in Molecular Medicine·Natasha C ChangMichael A Rudnicki
May 18, 2016·Ageing Research Reviews·Yosef Shiloh, Howard M Lederman
May 20, 2016·Nature Reviews. Rheumatology·Richard F LoeserBrian O Diekman
May 24, 2016·International Journal of Molecular Sciences·Paula K Bautista-NiñoAnton J M Roks
May 24, 2016·Ageing Research Reviews·Mantas MatjusaitisAlexandra Stolzing
May 26, 2016·Mammalian Genome : Official Journal of the International Mammalian Genome Society·Sara E Wells, Ilaria Bellantuono
Jun 1, 2016·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Ming XuJames L Kirkland
Jun 2, 2016·Journal of Hepatology·Aloysious D Aravinthan, Graeme J M Alexander
Jun 1, 2016·Biogerontology·Graeme L Close, James E Brown
Jun 5, 2016·Experimental Gerontology·Derek M HuffmanNathan K LeBrasseur
Jul 4, 2016·Maturitas·Hayley LeesLynne S Cox
Jul 16, 2016·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Amaia Lujambio
Jul 28, 2016·Ageing Research Reviews·Hamidreza Pazoki-ToroudiSeyed Mohammad Nabavi
Oct 5, 2016·JCI Insight·Michihiro HashimotoMasataka Sugimoto
Aug 16, 2016·The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences·Ming XuJames L Kirkland
Aug 16, 2016·Ageing Research Reviews·Alexander M VaisermanAlexander K Koliada
Jul 9, 2016·Radiation Research·Yingying WangDaohong Zhou

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Datasets Mentioned

BETA
GSE66236

Methods Mentioned

BETA
transfection
PCR
transgenic
ELISA
fluorescence microscopy

Software Mentioned

GSEA
Gene Set Enrichment Analysis
Cytoscape
ATPLite

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