Conv. Plasma
Nigella Sativa

All quercetin studies
Meta analysis
study COVID-19 treatment researchQuercetinQuercetin (more..)
Melatonin Meta
Metformin Meta
Azvudine Meta
Bromhexine Meta Molnupiravir Meta
Budesonide Meta
Colchicine Meta
Conv. Plasma Meta Nigella Sativa Meta
Curcumin Meta Nitazoxanide Meta
Famotidine Meta Paxlovid Meta
Favipiravir Meta Quercetin Meta
Fluvoxamine Meta Remdesivir Meta
Hydroxychlor.. Meta Thermotherapy Meta
Ivermectin Meta

All Studies   Meta Analysis    Recent:   

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

Aguado et al., bioRxiv, doi:10.1101/2023.01.17.524329
Jan 2023  
  Source   PDF   All Studies   Meta AnalysisMeta
Quercetin for COVID-19
22nd treatment shown to reduce risk in July 2021
*, now known with p = 0.0031 from 11 studies.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
4,000+ studies for 60+ treatments.
In Vitro and animal study showing that senolytics including dasatinib + quercetin improve survival and mitigate neuropathological sequelae of SARS-CoV-2.
Authors show that SARS-CoV-2 can initiate cellular senescence in the brains of COVID-19 patients and in human brain organoids, and that senolytics inhibit SARS-CoV-2 and senescence in human brain organoids.
With K18-hACE2 mice, authors show that senolytics dasatinib + quercetin, fisetin, and navitoclax improved clinical scores and mortality, and mitigated COVID-19 brain pathology. The highest survival rate was seen with dasatinib + quercetin.
In Silico studies predict inhibition of SARS-CoV-2, or minimization of side effects, with quercetin or metabolites via binding to the spike Note A, Alavi, Azmi (B), Chandran, Kandeil, Mandal, Moschovou, Nguyen, Pan, Thapa (B), Şimşek, Mpro Note B, Akinwumi, Alanzi, Ibeh, Kandeil, Mandal, Moschovou, Nguyen, Qin, Rehman, Sekiou (B), Singh, Thapa (B), Wang, Zhang, Shaik, Waqas, RNA-dependent RNA polymerase Note C, Corbo, PLpro Note D, Ibeh, Zhang, ACE2 Note E, Chandran, Ibeh, Qin, Thapa (B), Şimşek, Alkafaas, TMPRSS2 Note F, Chandran, helicase Note G, Alanzi, Singh (B), endoribonuclease Note H, Alavi, cathepsin L Note I, Ahmed, Wnt-3 Note J, Chandran, FZD Note K, Chandran, LRP6 Note L, Chandran, ezrin Note M, Chellasamy, ADRP Note N, Nguyen, NRP1 Note O, Şimşek, EP300 Note P, Hasanah, PTGS2 Note Q, Qin, HSP90AA1 Note R, Qin, Hasanah, matrix metalloproteinase 9 Note S, Sai Ramesh, IL-6 Note T, Yang, Yang (B), IL-10 Note U, Yang, VEGFA Note V, Yang (B), and RELA Note W, Yang (B) proteins. In Vitro studies demonstrate efficacy in Calu-3 Note X, DiGuilio, A549 Note Y, Yang, HEK293-ACE2+ Note Z, Singh (C), Huh-7 Note AA, Pan, Caco-2 Note AB, Roy, Vero E6 Note AC, Kandeil, El-Megharbel, Roy, mTEC Note AD, Wu, and RAW264.7 Note AE, Wu cells. Animal studies demonstrate efficacy in K18-hACE2 mice Note AF, Aguado, db/db mice Note AG, Wu, Wu (B), BALB/c mice Note AH, Shaker, and rats El-Megharbel (B). Quercetin reduced proinflammatory cytokines and protected lung and kidney tissue against LPS-induced damage in mice Shaker.
Aguado et al., 18 Jan 2023, Australia, preprint, 29 authors, this trial uses multiple treatments in the treatment arm (combined with dasatinib) - results of individual treatments may vary. Contact:
This PaperQuercetinAll
Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology
Julio Aguado, Alberto A Amarilla, Atefeh Taherian Fard, Eduardo A Albornoz, Alexander Tyshkovskiy, Marius Schwabenland, Harman K Chaggar, Naphak Modhiran, Cecilia Gómez-Inclán, Ibrahim Javed, Alireza A Baradar, Benjamin Liang, Malindrie Dharmaratne, Giovanni Pietrogrande, Pranesh Padmanabhan, Morgan E Freney, Rhys Parry, Julian D J Sng, Ariel Isaacs, Alexander A Khromykh, Alejandro Rojas-Fernandez, Thomas P Davis, Marco Prinz, Bertram Bengsch, Vadim N Gladyshev, Trent M Woodruff, Jessica C Mar, Daniel Watterson, Ernst J Wolvetang
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 senescenceassociated 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. .
was calculated by the indicated statistical tests, using R or Prism software. In figure legends, n indicates the number of independent experiments or biological replicates. Competing Interests The authors declare no competing interests. Contributions JA and HC generated human brain organoids. JA, HC, AT, ATF, MD, MS, AA, GP, EA, NM, BL, AI, DP, IJ, AB, MF, RP, JS, CG, TW, JM and EW contributed to acquisition, analysis, or interpretation of data. AAA, EA, NM and BL participated in the infections and treatments of mice and monitored their clinical performance. JA, ATF and AT analysed transcriptomic data. JA, AA, AF, EA, JM and EW contributed to experimental design. JA planned and supervised the project and wrote the paper. All authors edited and approved the final version of this article. Supplementary Figure legends Supplementary Figure 4 a Supplementary Figure 5
Aguado, Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson-Gilford Progeria Syndrome, Nat Commun,
Aguado, Inhibition of the cGAS-STING pathway ameliorates the premature senescence hallmarks of Ataxia-Telangiectasia brain organoids, Aging Cell, doi:10.1111/acel.13468
Albornoz, SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein, Mol Psychiatry
Amarilla, A versatile reverse genetics platform for SARS-CoV-2 and other positive-strand RNA viruses, Nat Commun,
Amarilla, An Optimized High-Throughput Immuno-Plaque Assay for SARS-CoV-2, Front Microbiol, doi:10.3389/fmicb.2021
Bussian, Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline, Nature, doi:10.1038/s41586-018-0543-y
Cantuti-Castelvetri, Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity, Science, doi:10.1126/science.abd2985
Ceban, Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis, Brain Behav Immun, doi:10.1016/j.bbi.2021
Chaib, Tchkonia, Kirkland, Cellular senescence and senolytics: the path to the clinic, Nat Med, doi:10.1038/s41591-022-01923-y
Chinta, Cellular Senescence Is Induced by the Environmental Neurotoxin Paraquat and Contributes to Neuropathology Linked to Parkinson's Disease, Cell Rep, doi:10.1016/j.celrep.2017.12.092
Choutka, Jansari, Hornig, Iwasaki, Unexplained post-acute infection syndromes, Nat Med, doi:10.1038/s41591-
Danaher, Advances in mixed cell deconvolution enable quantification of cell types in spatial transcriptomic data, Nat Commun,
Davis, Mccorkell, Vogel, Topol, Long COVID: major findings, mechanisms and recommendations, Nat Rev Microbiol
Di Micco, Krizhanovsky, Baker, Di Fagagna, Cellular senescence in ageing: from mechanisms to therapeutic opportunities, Nat Rev Mol Cell Biol,
Douaud, SARS-CoV-2 is associated with changes in brain structure in UK Biobank, Nature, doi:10.1038/s41586-022-04569-5
Escartin, Reactive astrocyte nomenclature, definitions, and future directions, Nat Neurosci,
Freund, Laberge, Demaria, Campisi, Lamin B1 loss is a senescenceassociated biomarker, Mol Biol Cell, doi:10.1091/mbc.E11-10-0884
Gasek, Kuchel, Kirkland, Xu, Strategies for Targeting Senescent Cells in Human Disease, Nat Aging, doi:10.1038/s43587-
Golia, Interplay between inflammation and neural plasticity: Both immune activation and suppression impair LTP and BDNF expression, Brain Behav Immun, doi:10.1016/j.bbi.2019
Hartung, Fatigue and cognitive impairment after COVID-19: A prospective multicentre study, EClinicalMedicine, doi:10.1016/j.eclinm.2022.101651
He, Abe, Akaishi, Oral administration of fisetin promotes the induction of hippocampal long-term potentiation in vivo, J Pharmacol Sci, doi:10.1016/j.jphs.2017.12.008
Isaacs, Nucleocapsid Specific Diagnostics for the Detection of Divergent SARS-CoV-2 Variants, Front Immunol, doi:10.3389/fimmu.2022.926262
Kim, Matney, Blankenship, Hestrin, Brown, Layer 6 corticothalamic neurons activate a cortical output layer, layer 5a, J Neurosci, doi:10.1523/JNEUROSCI.1325
Krasieva, Ehren, O'sullivan, Tromberg, Maher, Cell and brain tissue imaging of the flavonoid fisetin using label-free two-photon microscopy, Neurochem Int, doi:10.1016/j.neuint.2015.08.003
Kulasinghe, Transcriptomic profiling of cardiac tissues from SARS-CoV-2 patients identifies DNA damage, Immunology, doi:10.1111/imm.13577
Lee, Virus-induced senescence is a driver and therapeutic target in COVID-19, Nature, doi:10.1038/s41586-021-03995-1
Liberzon, The Molecular Signatures Database (MSigDB) hallmark gene set collection, Cell Syst, doi:10.1016/j.cels.2015.12.004
Lopez-Otin, Blasco, Partridge, Serrano, Kroemer, Hallmarks of aging: An expanding universe, Cell, doi:10.1016/j.cell.2022.11.001
Love, Huber, Anders, Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2, Genome Biol,
Mavrikaki, Lee, Solomon, Slack, Severe COVID-19 is associated with molecular signatures of aging in the human brain, Nature Aging, doi:10.1038/s43587-022-00321-w
Mccray, Jr, Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus, J Virol, doi:10.1128/JVI
Meinhardt, Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19, Nat Neurosci,
Monje, Iwasaki, The neurobiology of long COVID, Neuron, doi:10.1016/j.neuron.2022.10.006
Musi, Tau protein aggregation is associated with cellular senescence in the brain, Aging Cell, doi:10.1111/acel.12840
Nalbandian, Post-acute COVID-19 syndrome, Nat Med, doi:10.1038/s41591-021-01283-z
Nelke, Schroeter, Pawlitzki, Meuth, Ruck, Cellular senescence in neuroinflammatory disease: new therapies for old cells?, Trends Mol Med, doi:10.1016/j.molmed.2022.07.003
Ogrodnik, Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis, Cell Metab, doi:10.1016/j.cmet.2018.12.008
Ogrodnik, Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice, Aging Cell, doi:10.1111/acel.13296
Pellegrini, SARS-CoV-2 Infects the Brain Choroid Plexus and Disrupts the Blood-CSF Barrier in Human Brain Organoids, Cell Stem Cell, doi:10.1016/j.stem.2020
Ramani, SARS-CoV-2 targets neurons of 3D human brain organoids, EMBO J, doi:10.15252/embj.2020106230
Rosen, Kurtishi, Vazquez-Jimenez, Moller, The Intersection of Parkinson's Disease, Viral Infections, and COVID-19, Mol Neurobiol,
Samudyata, SARS-CoV-2 promotes microglial synapse elimination in human brain organoids, Mol Psychiatry
Schumacher, Pothof, Vijg, Hoeijmakers, Fagagna, A DNA damage checkpoint response in telomere-initiated senescence, Nature, doi:10.1038/s41586-021-03307-732
Schwabenland, Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T-cell interactions, Immunity, doi:10.1016/j.immuni.2021.06.002
Sepe, DNA damage response at telomeres boosts the transcription of SARS-CoV-2 receptor ACE2 during aging, EMBO Rep, doi:10.15252/embr.202153658
Silva, The bystander effect contributes to the accumulation of senescent cells in vivo, Aging Cell, doi:10.1111/acel.12848
Song, Neuroinvasion of SARS-CoV-2 in human and mouse brain, J Exp Med, doi:10.1084/jem.20202135
Spudich, Nath, Nervous system consequences of COVID-19, Science, doi:10.1126/science.abm2052
Stein, SARS-CoV-2 infection and persistence in the human body and brain at autopsy, Nature, doi:10.1038/s41586-022-05542-y
Subramanian, Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles, Proc Natl Acad Sci U S A, doi:10.1073/pnas.0506580102
Taquet, Geddes, Husain, Luciano, Harrison, 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records, Lancet Psychiatry, doi:10.1016/S2215-0366
Tyshkovskiy, Identification and Application of Gene Expression Signatures Associated with Lifespan Extension, Cell Metab, doi:10.1016/j.cmet.2019.06.018
Valenzuela Nieto, Potent neutralization of clinical isolates of SARS-CoV-2 D614 and G614 variants by a monomeric, sub-nanomolar affinity nanobody, Sci Rep, doi:10.1038/s41598-021-82833-w
Xu, Xie, Al-Aly, Long-term neurologic outcomes of COVID-19, Nat Med, doi:10.1038/s41591-022-02001-z
Zhang, SARS-CoV-2 infects human neural progenitor cells and brain organoids, Cell Res, doi:10.1038/s41422-020-0390-x
Zhang, Senolytic therapy alleviates Abeta-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer's disease model, Nat Neurosci,
Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
  or use drag and drop