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Senolytics reduce coronavirus-related mortality in old mice.
Science. 2021 07 16; 373(6552)Sci

Abstract

The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically ill to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells (SnCs) become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 spike protein-1, increasing expression of viral entry proteins and reducing antiviral gene expression in non-SnCs through a paracrine mechanism. Old mice acutely infected with pathogens that included a SARS-CoV-2-related mouse β-coronavirus experienced increased senescence and inflammation, with nearly 100% mortality. Targeting SnCs by using senolytic drugs before or after pathogen exposure significantly reduced mortality, cellular senescence, and inflammatory markers and increased antiviral antibodies. Thus, reducing the SnC burden in diseased or aged individuals should enhance resilience and reduce mortality after viral infection, including that of SARS-CoV-2.

Authors+Show Affiliations

Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA. Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.Department of Laboratory Medicine and Pathology and Center of Immunology, University of Minnesota, Minneapolis, MN, USA.Department of Laboratory Medicine and Pathology and Center of Immunology, University of Minnesota, Minneapolis, MN, USA.Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.Department of Epidemiology and Biostatistics, School of Public Health, Indiana University-Bloomington, Bloomington, IN, USA.Department of Epidemiology and Biostatistics, School of Public Health, Indiana University-Bloomington, Bloomington, IN, USA.Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA. Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.Masonic Cancer Center Comparative Pathology Shared Resource, University of Minnesota, St. Paul, MN, USA. Department of Veterinary Population Medicine, University of Minnesota, St. Paul, MN, USA.Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA. Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, USA.Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA. Division of Endocrinology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.Masonic Cancer Center Comparative Pathology Shared Resource, University of Minnesota, St. Paul, MN, USA. Department of Veterinary Population Medicine, University of Minnesota, St. Paul, MN, USA.Department of Epidemiology and Biostatistics, School of Public Health, Indiana University-Bloomington, Bloomington, IN, USA.Department of Laboratory Medicine and Pathology and Center of Immunology, University of Minnesota, Minneapolis, MN, USA.Department of Dermatology, Mayo Clinic, Rochester, MN, USA.Department of Dermatology, Mayo Clinic, Rochester, MN, USA.Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA. Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA.Division of Allergic Diseases, Department of Medicine, Mayo Clinic, Rochester, MN, USA.Department of Laboratory Medicine and Pathology and Center of Immunology, University of Minnesota, Minneapolis, MN, USA. probbins@umn.edu kirkland.james@mayo.edu lniedern@umn.edu tchkonia.tamar@mayo.edu hamil062@umn.edu.Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA. probbins@umn.edu kirkland.james@mayo.edu lniedern@umn.edu tchkonia.tamar@mayo.edu hamil062@umn.edu. Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA. probbins@umn.edu kirkland.james@mayo.edu lniedern@umn.edu tchkonia.tamar@mayo.edu hamil062@umn.edu.Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA. probbins@umn.edu kirkland.james@mayo.edu lniedern@umn.edu tchkonia.tamar@mayo.edu hamil062@umn.edu. Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA. Division of General Internal Medicine, Department of Medicine, Mayo Clinic, Rochester, MN, USA.Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA. probbins@umn.edu kirkland.james@mayo.edu lniedern@umn.edu tchkonia.tamar@mayo.edu hamil062@umn.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34103349

Citation

Camell, Christina D., et al. "Senolytics Reduce Coronavirus-related Mortality in Old Mice." Science (New York, N.Y.), vol. 373, no. 6552, 2021.
Camell CD, Yousefzadeh MJ, Zhu Y, et al. Senolytics reduce coronavirus-related mortality in old mice. Science. 2021;373(6552).
Camell, C. D., Yousefzadeh, M. J., Zhu, Y., Prata, L. G. P. L., Huggins, M. A., Pierson, M., Zhang, L., O'Kelly, R. D., Pirtskhalava, T., Xun, P., Ejima, K., Xue, A., Tripathi, U., Espindola-Netto, J. M., Giorgadze, N., Atkinson, E. J., Inman, C. L., Johnson, K. O., Cholensky, S. H., ... Robbins, P. D. (2021). Senolytics reduce coronavirus-related mortality in old mice. Science (New York, N.Y.), 373(6552). https://doi.org/10.1126/science.abe4832
Camell CD, et al. Senolytics Reduce Coronavirus-related Mortality in Old Mice. Science. 2021 07 16;373(6552) PubMed PMID: 34103349.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Senolytics reduce coronavirus-related mortality in old mice. AU - Camell,Christina D, AU - Yousefzadeh,Matthew J, AU - Zhu,Yi, AU - Prata,Larissa G P Langhi, AU - Huggins,Matthew A, AU - Pierson,Mark, AU - Zhang,Lei, AU - O'Kelly,Ryan D, AU - Pirtskhalava,Tamar, AU - Xun,Pengcheng, AU - Ejima,Keisuke, AU - Xue,Ailing, AU - Tripathi,Utkarsh, AU - Espindola-Netto,Jair Machado, AU - Giorgadze,Nino, AU - Atkinson,Elizabeth J, AU - Inman,Christina L, AU - Johnson,Kurt O, AU - Cholensky,Stephanie H, AU - Carlson,Timothy W, AU - LeBrasseur,Nathan K, AU - Khosla,Sundeep, AU - O'Sullivan,M Gerard, AU - Allison,David B, AU - Jameson,Stephen C, AU - Meves,Alexander, AU - Li,Ming, AU - Prakash,Y S, AU - Chiarella,Sergio E, AU - Hamilton,Sara E, AU - Tchkonia,Tamara, AU - Niedernhofer,Laura J, AU - Kirkland,James L, AU - Robbins,Paul D, Y1 - 2021/06/08/ PY - 2020/08/25/received PY - 2021/01/28/revised PY - 2021/06/02/accepted PY - 2021/6/10/pubmed PY - 2021/9/9/medline PY - 2021/6/9/entrez JF - Science (New York, N.Y.) JO - Science VL - 373 IS - 6552 N2 - The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically ill to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells (SnCs) become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 spike protein-1, increasing expression of viral entry proteins and reducing antiviral gene expression in non-SnCs through a paracrine mechanism. Old mice acutely infected with pathogens that included a SARS-CoV-2-related mouse β-coronavirus experienced increased senescence and inflammation, with nearly 100% mortality. Targeting SnCs by using senolytic drugs before or after pathogen exposure significantly reduced mortality, cellular senescence, and inflammatory markers and increased antiviral antibodies. Thus, reducing the SnC burden in diseased or aged individuals should enhance resilience and reduce mortality after viral infection, including that of SARS-CoV-2. SN - 1095-9203 UR - https://www.unboundmedicine.com/medline/citation/34103349/Senolytics_reduce_coronavirus-related_mortality_in_old_mice. L2 - https:///www.science.org/doi/10.1126/science.abe4832?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -