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PreprintCited by 80Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsSingle-cell and spatial transcriptomics

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Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology

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Aguado, Julio, Amarilla, Alberto A., Taherian Fard, Atefeh, Albornoz, Eduardo A., Tyshkovskiy, Alexander, Schwabenland, Marius, Chaggar, Harman K., Modhiran, Naphak, Gómez-Inclán, Cecilia, Javed, Ibrahim, Baradar, Alireza A., Liang, Benjamin, Dharmaratne, Malindrie, Pietrogrande, Giovanni, Padmanabhan, Pranesh, Freney, Morgan E., Parry, Rhys, Sng, Julian D.J., Isaacs, Ariel, Khromykh, Alexander A., Rojas-Fernandez, Alejandro, Davis, Thomas P., Prinz, Marco, Bengsch, Bertram, Gladyshev, Vadim N., Woodruff, Trent M., Mar, Jessica C., Watterson, Daniel, Wolvetang, Ernst J.·2023·Nature Aging
DOI 10.1101/2023.01.17.524329PMC PMC10724067

Preprint — published as 10.1038/s43587-023-00519-6 · Paper page

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Abstract

Aging is the primary risk factor for most neurodegenerative diseases, and recently coronavirus disease 2019 (COVID-19) has been associated with severe neurological manifestations that can eventually impact neurodegenerative conditions in the long-term. The progressive accumulation of senescent cells in vivo strongly contributes to brain aging and neurodegenerative co-morbidities but the impact of virus-induced senescence in the aetiology of neuropathologies is unknown. Here, we show that senescent cells accumulate in physiologically aged brain organoids of human origin and that senolytic treatment reduces inflammation and cellular senescence; for which we found that combined treatment with the senolytic drugs dasatinib and quercetin rejuvenates transcriptomic human brain aging clocks. We further interrogated brain frontal cortex regions in postmortem patients who succumbed to severe COVID-19 and observed increased accumulation of senescent cells as compared to age-matched control brains from non-COVID-affected individuals. Moreover, we show that exposure of human brain organoids to SARS-CoV-2 evoked cellular senescence, and that spatial transcriptomic sequencing of virus-induced senescent cells identified a unique SARS-CoV-2 variant-specific inflammatory signature that is different from endogenous naturally-emerging senescent cells. Importantly, following SARS-CoV-2 infection of human brain organoids, treatment with senolytics blocked viral retention and prevented the emergence of senescent corticothalamic and GABAergic neurons. Furthermore, we demonstrate in human ACE2 overexpressing mice that senolytic treatment ameliorates COVID-19 brain pathology following infection with SARS-CoV-2. In vivo treatment with senolytics improved SARS-CoV-2 clinical phenotype and survival, alleviated brain senescence and reactive astrogliosis, promoted survival of dopaminergic neurons, and reduced viral and senescence-associated secretory phenotype gene expression in the brain. Collectively, our findings demonstrate SARS-CoV-2 can trigger cellular senescence in the brain, and that senolytic therapy mitigates senescence-driven brain aging and multiple neuropathological sequelae caused by neurotropic viruses, including SARS-CoV-2.

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Metadata

Authors
Aguado, J., Amarilla, A. A., Taherian Fard, A., Albornoz, E. A., Tyshkovskiy, A., Schwabenland, M., Chaggar, H. K., Modhiran, N., Gómez-Inclán, C., Javed, I., Baradar, A. A., Liang, B., Dharmaratne, M., Pietrogrande, G., Padmanabhan, P., Freney, M. E., Parry, R., Sng, J. D. J., Isaacs, A., Khromykh, A. A., Rojas-Fernandez, A., Davis, T. P., Prinz, M., Bengsch, B., Gladyshev, V. N., Woodruff, T. M., Mar, J. C., Watterson, D., & Wolvetang, E. J.
Affiliations
  • The University of Queensland (AU)
  • Brigham and Women's Hospital (US)
  • University of Freiburg (DE)
  • Broad Institute (US)
Corresponding author
Aguado, Julio
ORCID
Venue
Nature Aging
Publisher
openRxiv
Published
2023-01-18
Volume
3
Issue
12
Pages
1561-1575
ISSN
2662-8465 (ISSN-L)
DOI
10.1101/2023.01.17.524329
PMC
PMC10724067
OpenAlex
W4388626094
Cited by
80
References
3
Citations by year
2026: 29 · 2025: 29 · 2024: 17 · 2023: 5
FWCI
14.21
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Nature Aging (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UniSA Research Outputs Repository (University of South Australia) (submittedVersion, cc-by)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, cc-by)
Funders
  • Brigham and Women's Hospital
  • Children's Hospital Foundation
  • Broad Institute
  • University of Oxford
  • Deutsche Forschungsgemeinschaft (413517907)
  • Fondation Jérôme Lejeune
  • University of South Australia
  • University of Queensland (UQECR2058457)
  • Albert-Ludwigs-Universität Freiburg
  • Universidad Austral de Chile
  • Lomonosov Moscow State University
  • Agencia Nacional de Investigación y Desarrollo (3220635, 1200427)
  • Medical Research Council
  • Australian Research Council (DP210103401)
  • National Health and Medical Research Council (2012883, 2001408, 2009957)
  • Queensland Brain Institute
  • Medizinische Fakultät der Albert-Ludwigs-Universität Freiburg
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
Keywords
senolytic therapy, cellular senescence, brain aging, SARS-CoV-2, human brain organoids, age-related inflammation, dopaminergic neurons, neuroinflammation, viral replication, neurodegeneration
MeSH terms
COVID-19, SARS-CoV-2, Senotherapeutics, Aged, Aging, Animals, Brain, Humans, Mice

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