Journal
AGING-US
Volume 12, Issue 9, Pages 8221-8240Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/aging.103135
Keywords
cellular senescence; senolytics; apoptosis; FAK; p38
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Funding
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT and Future Planning [2019R1F1A105976, 2019R1I1A1A01058142]
- Medical Research Center Program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT and Future Planning [2015R1A5A2009124]
- National Research Foundation of Korea [2019R1I1A1A01058142] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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The selective removal of senescent cells by senolytics is suggested as a potential approach to reverse aging and extend lifespan. Using high-throughput screening with replicative senescence of human diploid fibroblasts (HDFs), we identified a novel senolytic drug R406 that showed selective toxicity in senescent cells. Using flow cytometry and caspase expression analysis, we confirmed that R406 caused apoptotic cell death along with morphological changes in senescent cells. Interestingly, R406 altered the cell survival-related molecular processes including the inhibition of phosphorylation of the focal adhesion kinase (FAK) and p38 mitogen-activated protein kinase (MAPK) in senescent cells. This pattern was not observed in other known senolytic agent ABT263. Correspondingly, apoptotic cell death in senescent cells was induced by simultaneously blocking the FAK and p38 pathways. Taken together, we suggest that R406 acts as a senolytic drug by inducing apoptosis and reducing cell attachment capacity.
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