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Here, we found that RG-7112, a potent mouse double-minute two protein inhibitor, selectively kills senescent IVD cells through apoptosis. Gene expression pathway analysis was used to compare the functional networks of genes affected by RG-7112, a pure synthetic senolytic with o-Vanillin a natural and anti-inflammatory senolytic. Both affected a functional gene network related to cell death and survival. O-Vanillin also affected networks related to cell cycle progression as well as connective tissue development and function. Both senolytics effectively decreased the senescence-associated secretory phenotype (SASP) of IVD cells. Furthermore, bioavailability and efficacy were verified ex vivo in the physiological environment of degenerating intact human discs where a single dose improved disc matrix homeostasis. Matrix improvement correlated with a reduction in senescent cells and SASP, supporting a translational potential of targeting senescent cells as a therapeutic intervention.<\/jats:p>","DOI":"10.7554\/elife.54693","type":"journal-article","created":{"date-parts":[[2020,8,21]],"date-time":"2020-08-21T08:00:41Z","timestamp":1597996841000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.54693","source":"Crossref","is-referenced-by-count":120,"title":["Senotherapeutic drugs for human intervertebral disc degeneration and low back pain"],"prefix":"10.7554","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0703-3898","authenticated-orcid":true,"given":"Hosni","family":"Cherif","sequence":"first","affiliation":[{"name":"Orthopaedic Research Lab, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada"},{"name":"McGill Scoliosis and Spine Group, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4812-059X","authenticated-orcid":true,"given":"Daniel G","family":"Bisson","sequence":"additional","affiliation":[{"name":"Orthopaedic Research Lab, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada"},{"name":"McGill Scoliosis and Spine Group, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Mannarino","sequence":"additional","affiliation":[{"name":"Orthopaedic Research Lab, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada"},{"name":"McGill Scoliosis and Spine Group, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oded","family":"Rabau","sequence":"additional","affiliation":[{"name":"McGill Scoliosis and Spine Group, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada"},{"name":"Shriner\u2019s Hospital for Children, 1003 Decarie Blvd, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean A","family":"Ouellet","sequence":"additional","affiliation":[{"name":"McGill Scoliosis and Spine Group, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada"},{"name":"Shriner\u2019s Hospital for Children, 1003 Decarie Blvd, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1288-2149","authenticated-orcid":true,"given":"Lisbet","family":"Haglund","sequence":"additional","affiliation":[{"name":"Orthopaedic Research Lab, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada"},{"name":"McGill Scoliosis and Spine Group, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada"},{"name":"Shriner\u2019s Hospital for Children, 1003 Decarie Blvd, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2020,8,21]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1016\/j.cell.2008.03.038","article-title":"Chemokine signaling via the CXCR2 receptor reinforces senescence","volume":"133","author":"Acosta","year":"2008","journal-title":"Cell"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"978","DOI":"10.1038\/ncb2784","article-title":"A complex secretory program orchestrated by the inflammasome controls paracrine senescence","volume":"15","author":"Acosta","year":"2013","journal-title":"Nature Cell Biology"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"2167","DOI":"10.1158\/0008-5472.CAN-08-3772","article-title":"A role for CXCR2 in senescence, but what about in Cancer?","volume":"69","author":"Acosta","year":"2009","journal-title":"Cancer Research"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1002\/ca.22404","article-title":"Why do some intervertebral discs degenerate, when others (in the same spine) do not?","volume":"28","author":"Adams","year":"2015","journal-title":"Clinical Anatomy"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1302\/0301-620X.65B2.6826631","article-title":"The effect of fatigue on the lumbar intervertebral disc","volume":"65","author":"Adams","year":"1983","journal-title":"The Journal of Bone and Joint Surgery. 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