Treatment with the senolytics dasatinib/quercetin reduces SARS‐CoV ‐2‐related mortality in mice
Andrés Pastor‐fernández, Antonio R Bertos, Arantzazu Sierra‐ramírez, Javier Del Moral‐salmoral, Javier Merino, Ana I De Ávila, Cristina Olagüe, Ricardo Villares, Gloria González‐aseguinolaza, María Ángeles Rodríguez, Manuel Fresno, Nuria Gironés, Matilde Bustos, Cristian Smerdou, Pablo Jose Fernandez‐marcos, Cayetano Von Kobbe
Aging Cell, doi:10.1111/acel.13771
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 proinflammatory 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.
| Histological processing The samples fixed in 10% neutral buffered formalin solution (Panreac Química, SLU) were mounted in synthetic paraffin with a melting point of 56 °C (Casa Álvarez Material Científico), using a Citadel 2000 Tissue Processor (Thermo Fisher Scientific), with an automatic program applying alcohols of increasing concentration and xylene substitute (Citrus Clearing Solvent, Thermo Fisher Scientific). Blocks were made in a cold plate block forming unit (Histo Star Embedding Workstation, Thermo Fisher Scientific) . Histological sections were obtained with a rotary microtome (Finesse Me+ Microtome, Thermo Fisher Scientific) at 3-4 μm thickness. A Gemini AS Automated Slide Stainer (Thermo Fisher Scientific) was used to stain the sections with hematoxylin-eosin and finally mounted using a CTM6 Coverslipper (Thermo Fisher Scientific), with a xylene-based mounting medium (ClearVue Mountant, Thermo Fisher Scientific).
| Immunohistochemistry (IHC) Tissue samples were cut at 3 μm thickness, mounted on superfrost®plus slides and dried overnight. For IHC, an automated immunostaining platform was used (Autostainer Link, Dako or Ventana Discovery ULTRA; Roche). Antigen retrieval was performed with CC1 32 min, only for p21 and High pH buffer, Dako, Agilent (p19 and SARS-CoV-2 nucleocapsid); endogenous peroxidase was blocked (hydrogen peroxide at 3%) and slides were then incubated with the appropriate primary antibody as detailed: rat monoclonal anti-p21 CIP1 (291H;..
References
Blagosklonny, From causes of aging to death from COVID-19, Aging
Boumaza, Gay, Mezouar, Bestion, Diallo et al., Monocytes and macrophages, targets of severe acute respiratory syndrome coronavirus 2: The clue for coronavirus disease 2019 immunoparalysis, The Journal of Infectious Diseases,
doi:10.1093/infdis/jiab044Camell, Yousefzadeh, Zhu, Prata, Huggins et al., Senolytics reduce coronavirus-related mortality in old mice, Science,
doi:10.1126/science.abe4832Cayetano Von Kobbe, None
Chen, Lau, Lamirande, Paddock, Bartlett et al., Cellular immune responses to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in senescent BALB/c mice: CD4 + T cells are important in control of SARS-CoV infection, Journal of Virology,
doi:10.1128/jvi.01281-09Daamen, Bachali, Owen, Kingsmore, Hubbard et al., Comprehensive transcriptomic analysis of COVID-19 blood, lung, and airway, Scientific Reports,
doi:10.1038/s41598-021-86002-xEvangelou, Veroutis, Paschalaki, Foukas, Lagopati et al., Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: Possible implications for viral mutagenesis, The European Respiratory Journal,
doi:10.1183/13993003.02951-2021Golden, Cline, Zeng, Garrison, Carey et al., Human angiotensin-converting enzyme 2 transgenic mice infected with SARS-CoV-2 develop severe and fatal respiratory disease, JCI Insight,
doi:10.1172/jci.insight.142032Idda, Mcclusky, Lodde, Munk, Abdelmohsen et al., Survey of senescent cell markers with age in human tissues, Aging,
doi:10.18632/aging.102903Islam, Chamberlain, Mui, Little, Elevated Interleukin-10 levels in COVID-19: Potentiation of proinflammatory responses or impaired anti-inflammatory action?, Frontiers in Immunology,
doi:10.3389/fimmu.2021.677008Kirkland, Tchkonia, Senolytic drugs: From discovery to translation (review), Journal of Internal Medicine,
doi:10.1111/joim.13141Lee, Peng, Yang, Liou, Liao et al., C-C chemokine Ligand-5 is critical for facilitating macrophage infiltration in the early phase of liver ischemia/reperfusion injury, Scientific Reports,
doi:10.1038/s41598-017-03956-7Lee, Yu, Trimpert, Benthani, Mairhofer et al., Virus-induced senescence is a driver and therapeutic target in COVID-19, Nature,
doi:10.1038/s41586-021-03995-1Li, Jiang, Li, Lin, Wang et al., Clinical and pathological investigation of patients with severe COVID-19, JCI Insight,
doi:10.1172/jci.insight.138070Ling, Chen, Lui, Wong, Wong et al., Longitudinal cytokine profile in patients with mild to critical COVID-19, Frontiers in Immunology,
doi:10.3389/fimmu.2021.763292Maghazachi, Al-Aoukaty, Schall, C-C chemokines induce the chemotaxis of NK and IL-2-activated NK cells: Role for G proteins, Journal of Immunology
Malavolta, Giacconi, Brunetti, Provinciali, Maggi, Exploring the relevance of senotherapeutics for the current SARS-CoV-2 emergency and similar future global health threats, Cell,
doi:10.3390/cells9040909Mccray, Jr, Pewe, Wohlford-Lenane, Hickey et al., Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus, Journal of Virology,
doi:10.1128/JVI.02012-06Mchugh, Gil, Senescence and aging: Causes, consequences, and therapeutic avenues, Journal of Cell Biology,
doi:10.1083/jcb.201708092Mohiuddin, Kasahara, The emerging role of cellular senescence in complications of COVID-19, Cancer Treatment and Research Communications,
doi:10.1016/j.ctarc.2021.100399Nehme, Borghesan, Mackedenski, Bird, Demaria, Cellular senescence as a potential mediator of COVID-19 severity in the elderly, Aging Cell,
doi:10.1111/acel.13237Oladunni, Park, Pino, Gonzalez, Akhter et al., Lethality of SARS-CoV-2 infection in K18 human angiotensinconverting enzyme 2 transgenic mice, Nature Communications,
doi:10.1038/s41467-020-19891-7Ovadya, Krizhanovsky, Li, Karamanis, Ognibene et al., Severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with COVID-19 in the Bronx, The Journal of Clinical Investigation,
doi:10.1016/j.metabol.2020.154262Palmer, Xu, Zhu, Pirtskhalava, Weivoda et al., Targeting senescent cells alleviates obesityinduced metabolic dysfunction, Aging Cell,
doi:10.1111/acel.12950Rathnasinghe, Strohmeier, Amanat, Gillespie, Krammer et al., Comparison of transgenic and adenovirus hACE2 mouse models for SARS-CoV-2 infection, Emerging Microbes & Infections,
doi:10.1080/22221751.2020.1838955Ruan, Yang, Wang, Jiang, Song, Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China, Intensive Care Medicine,
doi:10.1007/s00134-020-05991-xSchafer, White, Iijima, Haak, Ligresti et al., Cellular senescence mediates fibrotic pulmonary disease, Nature Communications,
doi:10.1038/ncomms14532Schall, Bacon, Toy, Goeddel, Selective attraction of monocytes and T lymphocytes of the memory phenotype by cytokine RANTES, Nature,
doi:10.1038/347669a0Sierra-Ramirez, López-Aceituno, Costa-Machado, Plaza, Barradas et al., Transient metabolic improvement in obese mice treated with navitoclax or dasatinib/ quercetin, Aging,
doi:10.18632/aging.103607Tsuji, Minami, Hashimoto, Konishi, Suzuki et al., SARS-CoV-2 infection triggers paracrine senescence and leads to a sustained senescence-associated inflammatory response, Nature Aging,
doi:10.1038/s43587-022-00170-7Vaz De Paula, De Azevedo, Nagashima, Martins, Malaquias et al., SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function, Scientific Reports,
doi:10.1038/s41590-020-0778-2Yang, Shen, Li, Yuan, Wei et al., Plasma IP-10 and MCP-3 levels are highly associated with disease severity and predict the progression of COVID-19, The Journal of Allergy and Clinical Immunology,
doi:10.1016/j.jaci.2020.04.027Yinda, Port, Bushmaker, Offei Owusu, Purushotham et al., K18-hACE2 mice develop respiratory disease resembling severe COVID-19, PLoS Pathogens,
doi:10.1371/journal.ppat.1009195Zhang, Kishimoto, Grammatikakis, Gottimukkala, Cutler et al., Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer's disease model, Nature Neuroscience,
doi:10.1038/s41593-019-0372-9Zhao, Qin, Zhang, Li, Liang et al., Longitudinal COVID-19 profiling associates IL-1RA and IL-10 with disease severity and RANTES with mild disease, JCI Insight,
doi:10.1172/jci.insight.139834Zheng, Wong, Li, Verma, Ortiz et al., Treatment with the senolytics dasatinib/quercetin reduces SARS-CoV-2-related mortality in mice, The New England Journal of Medicine
DOI record:
{
"DOI": "10.1111/acel.13771",
"ISSN": [
"1474-9718",
"1474-9726"
],
"URL": "http://dx.doi.org/10.1111/acel.13771",
"alternative-id": [
"10.1111/acel.13771"
],
"assertion": [
{
"group": {
"label": "Publication History",
"name": "publication_history"
},
"label": "Received",
"name": "received",
"order": 0,
"value": "2022-04-22"
},
{
"group": {
"label": "Publication History",
"name": "publication_history"
},
"label": "Accepted",
"name": "accepted",
"order": 1,
"value": "2022-12-20"
},
{
"group": {
"label": "Publication History",
"name": "publication_history"
},
"label": "Published",
"name": "published",
"order": 2,
"value": "2023-01-26"
}
],
"author": [
{
"ORCID": "http://orcid.org/0000-0002-8060-073X",
"affiliation": [
{
"name": "Metabolic Syndrome Group‐BIOPROMET Madrid Institute for Advanced Studies‐IMDEA Food, CEI UAM+CSIC Madrid Spain"
}
],
"authenticated-orcid": false,
"family": "Pastor‐Fernández",
"given": "Andrés",
"sequence": "first"
},
{
"affiliation": [
{
"name": "Department of Internal Medicine and Surgical Animal, Faculty of Veterinary/VISAVET Centre Complutense University of Madrid Madrid Spain"
}
],
"family": "Bertos",
"given": "Antonio R.",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Metabolic Syndrome Group‐BIOPROMET Madrid Institute for Advanced Studies‐IMDEA Food, CEI UAM+CSIC Madrid Spain"
}
],
"family": "Sierra‐Ramírez",
"given": "Arantzazu",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Departamento de Biología Molecular Universidad Autónoma de Madrid (UAM) Madrid Spain"
},
{
"name": "Centro de Biología Molecular Severo Ochoa (CSIC‐UAM) Consejo Superior de Investigaciones Científicas (CSIC) Madrid Spain"
}
],
"family": "del Moral‐Salmoral",
"given": "Javier",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Departamento de Biología Molecular Universidad Autónoma de Madrid (UAM) Madrid Spain"
},
{
"name": "Centro de Biología Molecular Severo Ochoa (CSIC‐UAM) Consejo Superior de Investigaciones Científicas (CSIC) Madrid Spain"
}
],
"family": "Merino",
"given": "Javier",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Centro de Biología Molecular Severo Ochoa (CSIC‐UAM) Consejo Superior de Investigaciones Científicas (CSIC) Madrid Spain"
},
{
"name": "Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III Madrid Spain"
}
],
"family": "de Ávila",
"given": "Ana I.",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Division of Gene Therapy and Regulation of Gene Expression CIMA Universidad de Navarra Pamplona Spain"
}
],
"family": "Olagüe",
"given": "Cristina",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Centro Nacional de Biotecnología (CNB‐CSIC) Consejo Superior de Investigaciones Científicas (CSIC) Madrid Spain"
}
],
"family": "Villares",
"given": "Ricardo",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Division of Gene Therapy and Regulation of Gene Expression CIMA Universidad de Navarra Pamplona Spain"
}
],
"family": "González‐Aseguinolaza",
"given": "Gloria",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Institute of Biomedicine of Seville (IBiS), Spanish National Research Council (CSIC) University of Seville, Virgen del Rocio University Hospital Seville Spain"
}
],
"family": "Rodríguez",
"given": "María Ángeles",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Departamento de Biología Molecular Universidad Autónoma de Madrid (UAM) Madrid Spain"
},
{
"name": "Centro de Biología Molecular Severo Ochoa (CSIC‐UAM) Consejo Superior de Investigaciones Científicas (CSIC) Madrid Spain"
}
],
"family": "Fresno",
"given": "Manuel",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Departamento de Biología Molecular Universidad Autónoma de Madrid (UAM) Madrid Spain"
},
{
"name": "Centro de Biología Molecular Severo Ochoa (CSIC‐UAM) Consejo Superior de Investigaciones Científicas (CSIC) Madrid Spain"
}
],
"family": "Gironés",
"given": "Nuria",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Institute of Biomedicine of Seville (IBiS), Spanish National Research Council (CSIC) University of Seville, Virgen del Rocio University Hospital Seville Spain"
}
],
"family": "Bustos",
"given": "Matilde",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Division of Gene Therapy and Regulation of Gene Expression CIMA Universidad de Navarra Pamplona Spain"
}
],
"family": "Smerdou",
"given": "Cristian",
"sequence": "additional"
},
{
"ORCID": "http://orcid.org/0000-0003-3515-4125",
"affiliation": [
{
"name": "Metabolic Syndrome Group‐BIOPROMET Madrid Institute for Advanced Studies‐IMDEA Food, CEI UAM+CSIC Madrid Spain"
}
],
"authenticated-orcid": false,
"family": "Fernandez‐Marcos",
"given": "Pablo Jose",
"sequence": "additional"
},
{
"ORCID": "http://orcid.org/0000-0003-3895-3790",
"affiliation": [
{
"name": "Centro de Biología Molecular Severo Ochoa (CSIC‐UAM) Consejo Superior de Investigaciones Científicas (CSIC) Madrid Spain"
}
],
"authenticated-orcid": false,
"family": "von Kobbe",
"given": "Cayetano",
"sequence": "additional"
}
],
"container-title": "Aging Cell",
"container-title-short": "Aging Cell",
"content-domain": {
"crossmark-restriction": true,
"domain": [
"onlinelibrary.wiley.com"
]
},
"created": {
"date-parts": [
[
2023,
1,
27
]
],
"date-time": "2023-01-27T07:39:19Z",
"timestamp": 1674805159000
},
"deposited": {
"date-parts": [
[
2023,
1,
27
]
],
"date-time": "2023-01-27T07:39:25Z",
"timestamp": 1674805165000
},
"funder": [
{
"DOI": "10.13039/501100004587",
"award": [
"COV20‐00755",
"COV20‐00792"
],
"doi-asserted-by": "publisher",
"name": "Instituto de Salud Carlos III"
},
{
"DOI": "10.13039/501100004837",
"award": [
"SAF2017‐85766‐R",
"PID2020‐114077RB‐I00",
"RYC‐2017‐22335",
"PID2020‐113888RB‐I00"
],
"doi-asserted-by": "publisher",
"name": "Ministerio de Ciencia e Innovación"
},
{
"DOI": "10.13039/501100016970",
"award": [
"CSIC‐COV19‐014"
],
"doi-asserted-by": "publisher",
"name": "China Shipbuilding Industry"
}
],
"indexed": {
"date-parts": [
[
2023,
1,
28
]
],
"date-time": "2023-01-28T06:10:22Z",
"timestamp": 1674886222064
},
"is-referenced-by-count": 0,
"issued": {
"date-parts": [
[
2023,
1,
26
]
]
},
"language": "en",
"license": [
{
"URL": "http://creativecommons.org/licenses/by/4.0/",
"content-version": "vor",
"delay-in-days": 0,
"start": {
"date-parts": [
[
2023,
1,
26
]
],
"date-time": "2023-01-26T00:00:00Z",
"timestamp": 1674691200000
}
},
{
"URL": "http://doi.wiley.com/10.1002/tdm_license_1.1",
"content-version": "tdm",
"delay-in-days": 0,
"start": {
"date-parts": [
[
2023,
1,
26
]
],
"date-time": "2023-01-26T00:00:00Z",
"timestamp": 1674691200000
}
}
],
"link": [
{
"URL": "https://onlinelibrary.wiley.com/doi/pdf/10.1111/acel.13771",
"content-type": "application/pdf",
"content-version": "vor",
"intended-application": "text-mining"
},
{
"URL": "https://onlinelibrary.wiley.com/doi/full-xml/10.1111/acel.13771",
"content-type": "application/xml",
"content-version": "vor",
"intended-application": "text-mining"
},
{
"URL": "https://onlinelibrary.wiley.com/doi/pdf/10.1111/acel.13771",
"content-type": "unspecified",
"content-version": "vor",
"intended-application": "similarity-checking"
}
],
"member": "311",
"original-title": [],
"prefix": "10.1111",
"published": {
"date-parts": [
[
2023,
1,
26
]
]
},
"published-online": {
"date-parts": [
[
2023,
1,
26
]
]
},
"publisher": "Wiley",
"reference": [
{
"DOI": "10.1038/s41586‐021‐03553‐9",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_2_1"
},
{
"DOI": "10.18632/aging.103493",
"article-title": "From causes of aging to death from COVID‐19",
"author": "Blagosklonny M. V.",
"doi-asserted-by": "crossref",
"first-page": "1004",
"journal-title": "Aging",
"key": "e_1_2_10_3_1",
"volume": "12",
"year": "2020"
},
{
"DOI": "10.1093/infdis/jiab044",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_4_1"
},
{
"DOI": "10.1126/science.abe4832",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_5_1"
},
{
"DOI": "10.1128/jvi.01281‐09",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_6_1"
},
{
"DOI": "10.1038/s41598‐021‐86002‐x",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_7_1"
},
{
"DOI": "10.1172/jci.insight.150107",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_8_1"
},
{
"DOI": "10.1183/13993003.02951‐2021",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_9_1"
},
{
"DOI": "10.1172/jci.insight.142032",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_10_1"
},
{
"DOI": "10.1016/S0140‐6736(20)30183‐5",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_11_1"
},
{
"DOI": "10.3389/fimmu.2021.677008",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_12_1"
},
{
"DOI": "10.1111/joim.13141",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_13_1"
},
{
"DOI": "10.18632/aging.102903",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_14_1"
},
{
"DOI": "10.1038/s41598‐017‐03956‐7",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_15_1"
},
{
"DOI": "10.1038/s41586‐021‐03995‐1",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_16_1"
},
{
"DOI": "10.1172/jci.insight.138070",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_17_1"
},
{
"DOI": "10.3389/fimmu.2021.763292",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_18_1"
},
{
"DOI": "10.4049/jimmunol.153.11.4969",
"article-title": "C‐C chemokines induce the chemotaxis of NK and IL‐2‐activated NK cells: Role for G proteins",
"author": "Maghazachi A. A.",
"doi-asserted-by": "crossref",
"first-page": "4969",
"journal-title": "Journal of Immunology",
"key": "e_1_2_10_19_1",
"volume": "153",
"year": "1994"
},
{
"DOI": "10.3389/fphar.2020.600369",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_20_1"
},
{
"DOI": "10.3390/cells9040909",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_21_1"
},
{
"DOI": "10.1016/j.cyto.2015.05.023",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_22_1"
},
{
"DOI": "10.1128/JVI.02012‐06",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_23_1"
},
{
"DOI": "10.1083/jcb.201708092",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_24_1"
},
{
"DOI": "10.1016/j.ctarc.2021.100399",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_25_1"
},
{
"DOI": "10.1111/acel.13237",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_26_1"
},
{
"DOI": "10.1038/s41467‐020‐19891‐7",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_27_1"
},
{
"DOI": "10.1172/jCI95149",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_28_1"
},
{
"DOI": "10.1016/j.metabol.2020.154262",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_29_1"
},
{
"DOI": "10.1111/acel.12950",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_30_1"
},
{
"DOI": "10.1080/22221751.2020.1838955",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_31_1"
},
{
"DOI": "10.1007/s00134‐020‐05991‐x",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_32_1"
},
{
"DOI": "10.1038/ncomms14532",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_33_1"
},
{
"DOI": "10.1038/347669a0",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_34_1"
},
{
"DOI": "10.18632/aging.103607",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_35_1"
},
{
"DOI": "10.1038/s43587‐022‐00170‐7",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_36_1"
},
{
"DOI": "10.1038/s41598‐020‐75659‐5",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_37_1"
},
{
"key": "e_1_2_10_38_1",
"unstructured": "WHO.WHO Coronavirus (COVID‐19) dashboard.https://covid19.who.int"
},
{
"DOI": "10.1038/s41590‐020‐0778‐2",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_39_1"
},
{
"DOI": "10.1016/j.jaci.2020.04.027",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_40_1"
},
{
"DOI": "10.1016/j.jinf.2020.03.037",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_41_1"
},
{
"DOI": "10.1371/journal.ppat.1009195",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_42_1"
},
{
"DOI": "10.1038/s41593‐019‐0372‐9",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_43_1"
},
{
"DOI": "10.1172/jci.insight.139834",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_44_1"
},
{
"DOI": "10.1038/s41586‐020‐2943‐z",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_45_1"
},
{
"DOI": "10.1056/NEJMoa2001017",
"doi-asserted-by": "publisher",
"key": "e_1_2_10_46_1"
}
],
"reference-count": 45,
"references-count": 45,
"relation": {},
"resource": {
"primary": {
"URL": "https://onlinelibrary.wiley.com/doi/10.1111/acel.13771"
}
},
"score": 1,
"short-title": [],
"source": "Crossref",
"subject": [
"Cell Biology",
"Aging"
],
"subtitle": [],
"title": "Treatment with the senolytics dasatinib/quercetin reduces\n <scp>SARS‐CoV</scp>\n ‐2‐related mortality in mice",
"type": "journal-article",
"update-policy": "http://dx.doi.org/10.1002/crossmark_policy"
}
