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The enormous societal impact of the ongoing COVID-19 pandemic has been particularly harsh for some social groups, such as the elderly. Recently, it has been suggested that senescent cells could play a central role in pathogenesis by exacerbating the pro-inflammatory immune response against SARS-CoV-2. Therefore, the selective clearance of senescent cells by senolytic drugs may be useful as a therapy to ameliorate the symptoms of COVID-19 in some cases. Using the established COVID-19 murine model K18-hACE2, we demonstrated that a combination of the senolytics dasatinib and quercetin (D/Q) significantly reduced SARS-CoV-2-related mortality, delayed its onset, and reduced the number of other clinical symptoms. The increase in senescent markers that we detected in the lungs in response to SARS-CoV-2 may be related to the post-COVID-19 sequelae described to date. These results place senescent cells as central targets for the treatment of COVID-19, and make D/Q a new and promising therapeutic tool., This work was supported by grants from the Instituto de Salud Carlos III (ISCIII), COV20-00755 (C.V.K.) and COV20-00792 (M.B., M.A.R.), Apadrina la Ciencia (C.S., C.O., G.G.A.), the AECC Scientific Foundation, PRDMA18011PAST, SIRTBIO- LABAE18008FERN (P.J.F.M., A.P., A.S.R.), the RETOS projects Programme of Ministerio de Ciencia e Innovación (MICINN), SAF2017-85766-R and PID2020-114077RB-I00 (P.J.F.M., A.P., A.S.R.), Ramon y Cajal Award from MICINN, RYC-2017-22335 (P.J.F.M., A.P., A.S.R.), Proyecto REACT from REACT/European Union/FEDER, COVTRAVI-19-CM U (J.M.S., M.F., N.G.), grant from Consejo Superior de Investigaciones Científicas (CSIC), CSIC-COV19-014 (A.I.d.Á), PID2020-113888RB-I00 from MICINN (A.I.d.Á), and the European Commission–Next Generation EU (regulation EU 2020/2094), through the CSIC's Global Health Platform (PTI+ Global Health) (A.I.d.Á). The RT–qPCR reactions were provided by the Genomics and NGS Core Facility (GENGS) at the Centro de Biología Molecular Severo Ochoa (CBMSO, CSIC-UAM) Madrid, Spain, which obtains general funding from both institutions. The GENGS facility is part of the PTI+ Global Health (CSIC) (http://www.cbm.uam.es/genomica).

In the course of experiments aimed at deciphering the inhibition mechanism of mycophenolic acid and ribavirin in hepatitis C virus (HCV) infection, we observed an inhibitory effect of the nucleoside guanosine (Gua). Here, we report that Gua, and not the other standard nucleosides, inhibits HCV replication in human hepatoma cells. Gua did not directly inhibit the in vitro polymerase activity of NS5B, but it modified the intracellular levels of nucleoside di- and tri-phosphates (NDPs and NTPs), leading to deficient HCV RNA replication and reduction of infectious progeny virus production. Changes in the concentrations of NTPs or NDPs modified NS5B RNA polymerase activity in vitro, in particular de novo RNA synthesis and template switching. Furthermore, the Gua-mediated changes were associated with a significant increase in the number of indels in viral RNA, which may account for the reduction of the specific infectivity of the viral progeny, suggesting the presence of defective genomes. Thus, a proper NTP:NDP balance appears to be critical to ensure HCV polymerase fidelity and minimal production of defective genomes., CP is supported by the Miguel Servet program (grants CP14/00121 and CP19/00001) of the Instituto de Salud Carlos III cofinanced by FEDER. CP has received funding from Ministerio de Ciencia, Innovacio´n y Universidades (grant BFU2017-91384-EXP), from Instituto de Salud Carlos III (grants PI18/00210 and PI21/00139), from Fundación La Marato´ (grant 525/C/2021), and from CSIC (grant CSIC-COV19-014). ED has received funding from CIBERehd (Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III), from Ministerio de Economía y Competitividad (grants SAF2014-52400-R, SAF2017-87846-R, and PID2020-113888RB-I00), and from Comunidad de Madrid/FEDER (grants S2013/ABI-2906 PLATESA, and S2018/BAA-4370 PLATESA2). AM has received funding from Ministerio de Economía y Competitividad (grants SAF2016-80451-P, PID2019-106068GB-I00, EQC2018-004420-P, and EQC2018-004631-P), and Plan Propio of Universidad de Castilla-La Mancha. A.G-P and L.DM have received funding from Consejería de Transformación Económica, Industria, Conocimiento y Universidades, Junta de Andalucía, cofinanced by FEDER and FSE (grants BIO-264, and P10-CVI-6561) and Plan Propio of Universidad de Málaga.