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Cited by 153Telomeres, Telomerase, and SenescenceCOVID-19 Clinical Research StudiesSARS-CoV-2 and COVID-19 Research

COVID-19 and cellular senescence

Open access
Schmitt, Clemens A., Tchkonia, Tamar, Niedernhofer, Laura J., Robbins, Paul D., Kirkland, James L., Lee, Soyoung·2023·Nature Reviews Immunology
DOI 10.1038/s41577-022-00785-2PMC PMC9533263
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Abstract

The clinical severity of coronavirus disease 2019 (COVID-19) is largely determined by host factors. Recent advances point to cellular senescence, an ageing-related switch in cellular state, as a critical regulator of SARS-CoV-2-evoked hyperinflammation. SARS-CoV-2, like other viruses, can induce senescence and exacerbates the senescence-associated secretory phenotype (SASP), which is comprised largely of pro-inflammatory, extracellular matrix-degrading, complement-activating and pro-coagulatory factors secreted by senescent cells. These effects are enhanced in elderly individuals who have an increased proportion of pre-existing senescent cells in their tissues. SASP factors can contribute to a 'cytokine storm', tissue-destructive immune cell infiltration, endothelialitis (endotheliitis), fibrosis and microthrombosis. SASP-driven spreading of cellular senescence uncouples tissue injury from direct SARS-CoV-2-inflicted cellular damage in a paracrine fashion and can further amplify the SASP by increasing the burden of senescent cells. Preclinical and early clinical studies indicate that targeted elimination of senescent cells may offer a novel therapeutic opportunity to attenuate clinical deterioration in COVID-19 and improve resilience following infection with SARS-CoV-2 or other pathogens.

AI snapshot

Written from the paper’s full text.

TL;DR

This Perspective proposes that SARS-CoV-2 can trigger virus-induced senescence and amplify the senescence-associated secretory phenotype, linking pre-existing senescent cell burden to severe COVID-19 hyperinflammation. It argues that senolytic agents may offer an early therapeutic strategy and reviews supporting preclinical and early clinical evidence.

Key findings

  • SARS-CoV-2 infection can drive a full senescence response in susceptible cells, marked by p16INK4a, p21CIP1, H3K9me3, γH2A.X, lipofuscin, SA-β-gal activity, and SASP factors; such markers are elevated in airway and lung samples from patients with COVID-19 and correlate with disease severity.
  • SASP factors spread senescence to neighboring cells, prime macrophages toward an inflammatory state, and are linked to endothelial damage, NET formation, platelet activation, microthrombosis, and fibrosis; severity correlated with IL-6, SERPINA3, and D-dimer-based clotting activity, and patients with lung microthrombosis had higher SASP-typical factors.
  • Senolytics such as navitoclax, fisetin, and dasatinib plus quercetin killed virus-induced senescent cells in vitro; in animal models they reduced SASP cytokines to near-uninfected levels, improved lung pathology, and improved survival. In aged mice exposed to mouse pathogens, nearly all died within 2 weeks versus no mortality in younger mice, and senolytic treatment reduced mortality.
  • Two randomized trials of a bioavailable quercetin formulation in mild COVID-19 met their clinical endpoints; pooled analysis showed better avoidance of hospitalization, oxygen need, intensive care referral, and death. Fisetin trials in COVID-19 are ongoing.

Methods

  • This is a Perspective/narrative review, not a primary experimental study; it synthesizes cited in vitro, animal-model, patient histologic/transcriptomic, and clinical trial evidence.
  • The main analysis is conceptual: it develops a mechanistic model in which virus-induced senescence and SASP act as an amplifier of COVID-19 hyperinflammation, then evaluates senolytic strategies.
  • No new sample, dataset, or statistical analysis is reported by the authors; numerical results come from the cited studies.

Limitations

  • The authors state that a causal relationship between senescence extent and COVID-19 severity has not yet been demonstrated, that no single marker definitively identifies senescence, and that fixation of clinical samples prevents in situ SA-β-gal assays; they also call for more in vivo confirmation in senescence-compromised models.
  • The authors note debate over whether macrophages undergo classic senescence versus a senescence-like state, limited data on T cell senescence in COVID-19, and the need for further clinical studies to optimize senolytic regimens, timing, toxicity, and effects on viral clearance.
  • Evident from the text: as a Perspective, the evidence is largely correlative and preclinical, depends on cited studies, and some clinical support comes from early or small trials; proposed links to long COVID and autoimmunity remain speculative.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41577-022-00785-2

Cites

220 of 220 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 159 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    Cellular senescence acts as a key regulator of the hyperinflammation caused by SARS-CoV-2.

    “Recent advances point to cellular senescence, an ageing-related switch in cellular state, as a critical regulator of SARS-CoV-2-evoked hyperinflammation.”
    Quote in the paperSubstantial claim
  • Premisecitation

    SARS-CoV-2 is able to induce cellular senescence.

    “Recently, it was found that SARS-CoV-2 can evoke a form of cellular senescence, virus-induced senescence (VIS) (Box 1), through multiple mechanisms27–29”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [27] Camell, C. D. et al. Senolytics reduce coronavirus-related mortality in old mice. Science https://doi.org/10.1126/science.abe4832 (2021). source

      Not checked in the free run.

    • cites [28] Lee, S. et al. Virus-induced senescence is driver and therapeutic target in COVID-19. Nature https://doi.org/10.1038/s41586-021-03995-1 (2021). source

      Not checked in the free run.

    • cites [29] Tripathi, U. et al. SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3. Aging 13, 21838–21854 (2021). source

      Not checked in the free run.

  • Interpretationreasoning

    SASP-driven spread of senescence separates tissue injury from direct cellular damage by SARS-CoV-2 through paracrine mechanisms.

    “SASP-driven spreading of cellular senescence uncouples tissue injury from direct SARS-CoV-2-inflicted cellular damage in a paracrine fashion”
    Quote in the paperNot a substantial claim
  • Premisecitation

    SARS-CoV-2 worsens the senescence-associated secretory phenotype (SASP).

    “SARS-CoV-2, like other viruses, can induce senescence and exacerbates the senescence-associated secretory phenotype (SASP)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [27] Camell, C. D. et al. Senolytics reduce coronavirus-related mortality in old mice. Science https://doi.org/10.1126/science.abe4832 (2021). source

      Not checked in the free run.

    • cites [28] Lee, S. et al. Virus-induced senescence is driver and therapeutic target in COVID-19. Nature https://doi.org/10.1038/s41586-021-03995-1 (2021). source

      Not checked in the free run.

    • cites [29] Tripathi, U. et al. SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3. Aging 13, 21838–21854 (2021). source

      Not checked in the free run.

  • Interpretationnone given

    A tendency toward senescence-governed immune escalation, linked to ageing or chronic disease, can be acutely triggered by SARS-CoV-2 and lead to severe disease.

    “we propose that a propensity to senescence-governed immune escalation, which can be related to ageing or chronic disease, can also be acutely triggered by SARS-CoV-2 infection and lead to severe disease.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 35
  • Classified as probably not a substantial claim. 4

  • May combine two claims.

    Interpretationreasoning

    Preclinical and early clinical studies suggest that eliminating senescent cells may reduce clinical worsening in COVID-19 and improve resilience after infection.

    “Preclinical and early clinical studies indicate that targeted elimination of senescent cells may offer a novel therapeutic opportunity to attenuate clinical deterioration in COVID-19 and improve resilience following infection with SARS-CoV-2 or other pathogens.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Virus-induced senescence appears to be a universal stress response in host cells and can be triggered by many virus species.

    “VIS appears to be a universal stress response in host cells and can be induced by many different virus species.”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [28] Lee, S. et al. Virus-induced senescence is driver and therapeutic target in COVID-19. Nature https://doi.org/10.1038/s41586-021-03995-1 (2021). source

      Not checked in the free run.

    • cites [29] Tripathi, U. et al. SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3. Aging 13, 21838–21854 (2021). source

      Not checked in the free run.

    • cites [34] Chuprin, A. et al. Cell fusion induced by ERVWE1 or measles virus causes cellular senescence. Genes Dev. 27, 2356–2366 (2013). source

      Not checked in the free run.

    • cites [35] Li, J. et al. Merkel cell polyomavirus large T antigen disrupts host genomic integrity and inhibits cellular proliferation. J. Virol. 87, 9173–9188 (2013). source

      Not checked in the free run.

    • cites [36] Martínez, I. et al. Induction of DNA double-strand breaks and cellular senescence by human respiratory syncytial virus. Virulence 7, 427–442 (2016). source

      Not checked in the free run.

    • cites [37] Kohli, J., Veenstra, I. & Demaria, M. The struggle of a good friend getting old: cellular senescence in viral responses and therapy. EMBO Rep. 22, e52243 (2021). source

      Not checked in the free run.

    • cites [38] Seoane, R., Vidal, S., Bouzaher, Y. H., El Motiam, A. & Rivas, C. The interaction of viruses with the cellular senescence response. Biology https://doi.org/10.3390/biology9120455 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    SASP factors can drive cytokine storm, tissue-destructive immune cell infiltration, endothelialitis, fibrosis, and microthrombosis.

    “SASP factors can contribute to a ‘cytokine storm’, tissue-destructive immune cell infiltration, endothelialitis (endotheliitis), fibrosis and microthrombosis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Selective removal of senescent cells by senolytics, or of VIS cells through spike protein-based vaccination, could prevent or lessen severe COVID-19.

    “we propose that the selective removal of senescent cells by candidate agents, termed senolytics, or of VIS cells as a collateral result of SARS-CoV-2 spike (S) protein-based vaccination, could prevent or mitigate severe COVID-19.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cells lacking functional p53 or overexpressing JMJD2c fail to enter VIS and lack a SASP after SARS-CoV-2 infection.

    “in vitro experiments showed that cells that lack functional p53 or overexpress the H3K9me3 demethylase JMJD2c46,50 — which therefore cannot enter senescence in response to pro-senescent oncogenes such as Ras-G12V or Braf-V600E46,51 — also failed to enter VIS and lacked a SASP upon infection with SARS-CoV-2 (ref.28).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [28] Lee, S. et al. Virus-induced senescence is driver and therapeutic target in COVID-19. Nature https://doi.org/10.1038/s41586-021-03995-1 (2021). source

      Not checked in the free run.

    • cites [46] Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997). source

      Not checked in the free run.

    • cites [50] Yu, Y. et al. Targeting the senescence-overriding cooperative activity of structurally unrelated H3K9 demethylases in melanoma. Cancer Cell 33, 322–336 (2018). source

      Not checked in the free run.

    • cites [51] Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    SARS-CoV-2 infection of senescent cells may amplify their pro-inflammatory SASP, potentially creating a positive feedback loop dependent on VIS.

    “It is therefore conceivable that SARS-CoV-2 infection of senescent cells may amplify their pro-inflammatory SASP, potentially inducing a positive feedback loop in a VIS-dependent manner29”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Tripathi, U. et al. SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3. Aging 13, 21838–21854 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescence-associated DNA damage is sensed through the cGAS-STING pathway, which activates IRF3 and NF-κB and induces interferon and SASP responses.

    “Senescence-associated DNA damage is sensed via the cGAS–STING pathway, which activates the transcription factors interferon regulatory factor 3 (IRF3) and NF-κB, thereby inducing an interferon and SASP response55–58”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [55] Dou, Z. et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature https://doi.org/10.1038/nature24050 (2017). source

      Not checked in the free run.

    • cites [56] Gluck, S. et al. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat. Cell Biol. 19, 1061–1070 (2017). source

      Not checked in the free run.

    • cites [57] Miller, K. N. et al. Cytoplasmic DNA: sources, sensing, and role in aging and disease. Cell 184, 5506–5526 (2021). source

      Not checked in the free run.

    • cites [58] Decout, A., Katz, J. D., Venkatraman, S. & Ablasser, A. The cGAS–STING pathway as a therapeutic target in inflammatory diseases. Nat. Rev. Immunol. 21, 548–569 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted). May combine two claims.

    Interpretationcitation

    Senescent cells acutely reinforce systemic inflammatory responses to pathogens and facilitate the spread of senescence, as described by the SASP amplifier/rheostat model.

    “We suspect that senescent cells acutely reinforce systemic inflammatory responses to pathogens and facilitate the spread of senescence, a hypothesis termed the ‘SASP amplifier/rheostat model’27,28.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [27] Camell, C. D. et al. Senolytics reduce coronavirus-related mortality in old mice. Science https://doi.org/10.1126/science.abe4832 (2021). source

      Not checked in the free run.

    • cites [28] Lee, S. et al. Virus-induced senescence is driver and therapeutic target in COVID-19. Nature https://doi.org/10.1038/s41586-021-03995-1 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationreasoning

    More extensive senescence underlies more profound COVID-19 pathobiology.

    “giving rise to the hypothesis that more extensive senescence underlies more profound COVID-19 pathobiology.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Activated monocytes and reduced T cell activity characterize hyperinflammation in severe COVID-19.

    “Collectively, the data indicate that activated monocytes and decreased T cell activity characterize hyperinflammation in severe COVID-19.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Exposure to supernatant from VIS cells induced macrophage activation marked by an M1-like polarization profile, CD86 upregulation, and signs of secondary macrophage senescence detected by SA-β-gal staining and senescence-typical gene expression.

    “it was demonstrated that exposure to the supernatant of VIS cells induced macrophage activation that was marked by an M1-like polarization profile79,89, CD86 upregulation and signs of secondary macrophage senescence as detected by SA-β-gal staining and senescence-typical gene expression.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [79] Roussel, M. et al. Mass cytometry deep phenotyping of human mononuclear phagocytes and myeloid-derived suppressor cells from human blood and bone marrow. J. Leukoc. Biol. 102, 437–447 (2017). source

      Not checked in the free run.

    • cites [89] Li, X. et al. The flavonoid quercetin ameliorates liver inflammation and fibrosis by regulating hepatic macrophages activation and polarization in mice. Front. Pharmacol. 9, 72 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Although the extent of senescence correlates strongly with COVID-19 severity, a causal relationship between these processes has not yet been demonstrated.

    “Despite the strong correlation between the extent of senescence (including VIS) and COVID-19 severity, a causal relationship between these processes is yet to be demonstrated.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    The rising production of SASP-related factors in severe COVID-19 appears to result from direct induction of primary senescence in virus-susceptible cells by SARS-CoV-2, paracrine senescence of neighbouring cells, and systemic effects of the SASP on distant cells.

    “Overall, the escalating production of SASP-related factors in patients with severe COVID-19 appears to be mediated by the direct induction of primary senescence in virus-susceptible cells by SARS-CoV-2 infection, the paracrine senescence effects on adjacent cells and the systemic impact of the SASP even on distant cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Lungs from patients with severe COVID-19 show much higher infiltration by CD86+ macrophages and stronger SASP-reminiscent cytokine expression than controls.

    “lungs from patients with severe COVID-19 exhibited much higher levels of infiltration by CD86+ macrophages and much stronger SASP-reminiscent cytokine expression compared to lungs from patients who died without notable signs of a respiratory infection and who were not infected with SARS-CoV-2 (refs.28,61).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [28] Lee, S. et al. Virus-induced senescence is driver and therapeutic target in COVID-19. Nature https://doi.org/10.1038/s41586-021-03995-1 (2021). source

      Not checked in the free run.

    • cites [61] Desai, N. et al. Temporal and spatial heterogeneity of host response to SARS-CoV-2 pulmonary infection. Nat. Commun. 11, 6319 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Complement activation aggravates tissue injury in COVID-19 by inducing excessive T cell cytotoxicity through immune complex-induced and T cell receptor-independent degranulation, potentially linking VIS and the SASP to uncontrolled T cell-mediated tissue damage.

    “Of note, complement activation has recently been shown to aggravate tissue injury in patients with COVID-19 by inducing excessive T cell cytotoxicity via immune complex-induced and T cell receptor-independent degranulation, thereby potentially linking VIS and the SASP to uncontrolled T cell-mediated tissue damage92.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] Georg, P. et al. Complement activation induces excessive T cell cytotoxicity in severe COVID-19. Cell https://doi.org/10.1016/j.cell.2021.12.040 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Conditioned medium from senescent cells rich in SASP-associated factors evoked paracrine senescence in endothelial cells or triggered complement-mediated cytolysis, promoted NET formation by neutrophils, activated platelets, and accelerated clotting.

    “Specifically, conditioned medium from senescent cells that is rich in SASP-associated factors evoked paracrine senescence in endothelial cells or triggered their complement-mediated cytolysis, promoted NET formation by neutrophils, activated platelets, and accelerated clotting.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Lee, S. et al. Virus-induced senescence is driver and therapeutic target in COVID-19. Nature https://doi.org/10.1038/s41586-021-03995-1 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Navitoclax, fisetin, or a combination of dasatinib and quercetin quantitatively eliminated senescent cells in situ and improved at least some central histopathological findings of SARS-CoV-2 infection in the lung in all mentioned animal models.

    “Navitoclax, fisetin, or a combination of dasatinib and quercetin were found to quantitatively eliminate senescent cells in situ and to improve at least some of the central histopathological findings of SARS-CoV-2 infection in the lung in all the animal models mentioned28.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Lee, S. et al. Virus-induced senescence is driver and therapeutic target in COVID-19. Nature https://doi.org/10.1038/s41586-021-03995-1 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Targeting the cGAS-STING axis with the small-molecule STING inhibitor H-151 had a SASP-suppressing, senomorphic effect and led to reduced lung pathology and prolonged survival in a human ACE2-transgenic mouse model of COVID-19.

    “Targeting of the cGAS–STING axis, which induces type I interferons and other SASP factors, with the small-molecule STING inhibitor H-151 had a SASP-suppressing, senomorphic effect28,121,128,129 and led to reduced lung pathology and prolonged survival in a human ACE2-transgenic mouse model of COVID-19 (ref.59).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [28] Lee, S. et al. Virus-induced senescence is driver and therapeutic target in COVID-19. Nature https://doi.org/10.1038/s41586-021-03995-1 (2021). source

      Not checked in the free run.

    • cites [121] Zhang, L., Pitcher, L. E., Prahalad, V., Niedernhofer, L. J. & Robbins, P. D. Recent advances in the discovery of senolytics. Mech. Ageing Dev. 200, 111587 (2021). source

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    • cites [128] Birch, J. & Gil, J. Senescence and the SASP: many therapeutic avenues. Genes Dev. 34, 1565–1576 (2020). source

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    • cites [129] Hao, X., Wang, C. & Zhang, R. Chromatin basis of the senescence-associated secretory phenotype. Trends Cell Biol. https://doi.org/10.1016/j.tcb.2021.12.003 (2022). source

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    • cites [59] Di Domizio, J. et al. The cGAS-STING pathway drives type I IFN immunopathology in COVID-19. Nature https://doi.org/10.1038/s41586-022-04421-w (2022). source

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  • May combine two claims.

    Premisecitation

    SARS-CoV-2 Alpha and Beta variants elicited a significantly stronger pro-inflammatory SASP upon infection compared to the ancestral strain, and these VIS cells exhibited excellent susceptibility to the aforementioned senolytics in vitro, comparable to cells infected with the ancestral virus.

    “Importantly, the SARS-CoV-2 Alpha and Beta variants elicited a significantly stronger pro-inflammatory SASP upon infection compared to the ancestral SARS-CoV-2 strain, and these VIS cells exhibited excellent susceptibility to the aforementioned senolytics in vitro, comparable to cells infected with the ancestral virus28.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Lee, S. et al. Virus-induced senescence is driver and therapeutic target in COVID-19. Nature https://doi.org/10.1038/s41586-021-03995-1 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Navitoclax, fisetin, and a combination of dasatinib and quercetin demonstrated significant cytotoxic activity against VIS cells in vitro, leaving uninfected or virus-infected but genetically senescence-incapable cells virtually unaffected.

    “Navitoclax, fisetin, and a combination of dasatinib and quercetin demonstrated significant cytotoxic activity against VIS cells (including human nasal epithelial cells exposed to SARS-CoV-2) in vitro, leaving uninfected or virus-infected but genetically senescence-incapable cells virtually unaffected28.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Lee, S. et al. Virus-induced senescence is driver and therapeutic target in COVID-19. Nature https://doi.org/10.1038/s41586-021-03995-1 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These prostaglandins promote senescence and the SASP.

    “These prostaglandins are known to promote senescence and the SASP135–137.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [135] Yang, H. H., Kim, C., Jung, B., Kim, K. S. & Kim, J. R. Involvement of IGF binding protein 5 in prostaglandin E(2)-induced cellular senescence in human fibroblasts. Biogerontology 12, 239–252 (2011). source

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    • cites [136] Gonçalves, S. et al. COX2 regulates senescence secretome composition and senescence surveillance through PGE(2). Cell Rep. 34, 108860 (2021). source

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    • cites [137] Wiley, C. D. et al. Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis. Cell Metab. 33, 1124–1136.e5 (2021). source

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  • May combine two claims.

    Premisecitation

    Levels of PGD2 and related prostaglandins were increased in older individuals and in individuals infected with SARS-CoV-2.

    “The levels of PGD2 and related prostaglandins were also found to be increased in older individuals and in individuals infected with SARS-CoV-2 (ref.134).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Wong, L.-Y. R. et al. Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19. Nature 605, 146–151 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The therapeutic benefit of senescent cell depletion was evident both before and after infection.

    “Of note, the therapeutic benefit was evident not only if the senescent cell burden was reduced prior to infection but also following infection, consistent with an increased burden of senescent cells that persists following pathogen encounter.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The clinical trials indicated that quercetin exerts meaningful senolytic activity when tested as a single agent in individuals with SARS-CoV-2 infection and appeared to have relevant clinical potential to prevent severe COVID-19.

    “The clinical trials underscored that quercetin exerts meaningful senolytic activity when tested as a single agent in individuals with SARS-CoV-2 infection and appeared to have relevant clinical potential to prevent severe COVID-19.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Rapidly expanding evidence implicates cellular senescence as a host cell response to viral infection in general and to SARS-CoV-2 in particular.

    “Rapidly expanding evidence implicates cellular senescence as a host cell response to viral infection in general and to SARS-CoV-2 in particular, similar to other cellular insults such as telomere dysfunction, oncogene activation or chemotherapy27–29.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [27] Camell, C. D. et al. Senolytics reduce coronavirus-related mortality in old mice. Science https://doi.org/10.1126/science.abe4832 (2021). source

      Not checked in the free run.

    • cites [28] Lee, S. et al. Virus-induced senescence is driver and therapeutic target in COVID-19. Nature https://doi.org/10.1038/s41586-021-03995-1 (2021). source

      Not checked in the free run.

    • cites [29] Tripathi, U. et al. SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3. Aging 13, 21838–21854 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increasing numbers of breakthrough infections occur in vaccinated individuals, including those with detectable antibody responses, but disease severity is less pronounced in vaccinated compared to unvaccinated COVID-19 patients.

    “Increasing numbers of breakthrough infections in vaccinated individuals, including those with detectable antibody responses, are observed, albeit with increasing evidence that disease severity is less pronounced in vaccinated compared to unvaccinated patients with COVID-19 (ref.158).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [158] Butt, A. A. et al. Outcomes among patients with breakthrough SARS-CoV-2 infection after vaccination. Int. J. Infect. Dis. 110, 353–358 (2021). source

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    Premisecitation

    The majority of COVID-19 vaccines evoke humoral and cellular immune responses against the SARS-CoV-2 spike protein; these responses may not prevent infection but robustly protect against severe COVID-19 for certain periods of time.

    “The majority of COVID-19 vaccines are designed to evoke humoral and cellular immune responses against the SARS-CoV-2 spike protein — responses that may not prevent infection but robustly protect against severe COVID-19, at least for certain periods of time11,150–157.”
    Quote in the paperSubstantial claim0 of 9 sources checked
    • cites [11] Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 383, 2603–2615 (2020). source

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    • cites [150] Corbett, K. S. et al. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature 586, 567–571 (2020). source

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    • cites [151] Jackson, L. A. et al. An mRNA vaccine against SARS-CoV-2 — preliminary report. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2022483 (2020). source

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    • cites [152] Mulligan, M. J. et al. Phase 1/2 study of COVID-19 RNA vaccine BNT162b1 in adults. Nature https://doi.org/10.1038/s41586-020-2639-4 (2020). source

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    • cites [153] Sahin, U. et al. COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses. Nature 586, 594–599 (2020). source

      Not checked in the free run.

    • cites [154] Oberhardt, V. et al. Rapid and stable mobilization of CD8+ T cells by SARS-CoV-2 mRNA vaccine. Nature 597, 268–273 (2021). source

      Not checked in the free run.

    • cites [155] Sahin, U. et al. BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans. Nature 595, 572–577 (2021). source

      Not checked in the free run.

    • cites [156] Wang, Z. et al. mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants. Nature 592, 616–622 (2021). source

      Not checked in the free run.

    • cites [157] Kissler, S. M. et al. Viral dynamics of SARS-CoV-2 variants in vaccinated and unvaccinated persons. N. Engl. J. Med. 385, 2489–2491 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A collective analysis of both trials demonstrated a significantly better outcome in terms of avoiding hospitalization, need for oxygen, referral to the intensive care unit and death.

    “Specifically, a collective analysis of both trials demonstrated a significantly better outcome in terms of avoiding hospitalization, need for oxygen, referral to the intensive care unit and death28.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Lee, S. et al. Virus-induced senescence is driver and therapeutic target in COVID-19. Nature https://doi.org/10.1038/s41586-021-03995-1 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A large variety of viruses have been shown to induce senescence in vitro and in vivo, whereas no VIS phenotype was observed upon infection with the mild seasonal influenza A (H1N1) virus in Syrian hamsters.

    “A large variety of viruses have been shown to induce senescence in vitro and in vivo27,28,38, whereas no VIS phenotype was observed upon infection with the mild seasonal influenza A (H1N1) virus in Syrian hamsters62, implying that not all virus infections might be susceptible to senolytic strategies.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [27] Camell, C. D. et al. Senolytics reduce coronavirus-related mortality in old mice. Science https://doi.org/10.1126/science.abe4832 (2021). source

      Not checked in the free run.

    • cites [28] Lee, S. et al. Virus-induced senescence is driver and therapeutic target in COVID-19. Nature https://doi.org/10.1038/s41586-021-03995-1 (2021). source

      Not checked in the free run.

    • cites [38] Seoane, R., Vidal, S., Bouzaher, Y. H., El Motiam, A. & Rivas, C. The interaction of viruses with the cellular senescence response. Biology https://doi.org/10.3390/biology9120455 (2020). source

      Not checked in the free run.

    • cites [62] Tsuji, S. et al. SARS-CoV-2 infection triggers paracrine senescence and leads to a sustained senescence-associated inflammatory response. Nat. Aging https://doi.org/10.1038/s43587-022-00170-7 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    COVID-19-related VIS may aggravate age-related pathologies via enhanced SASP-mediated inflammation, as demonstrated for cardiovascular diseases and diabetes in preclinical models, and might further deteriorate immune competence by inducing senescence in immune cells.

    “COVID-19-related VIS may also aggravate age-related pathologies via enhanced SASP-mediated inflammation29,169, as demonstrated for cardiovascular diseases and diabetes in preclinical models170, and might further deteriorate immune competence by inducing senescence in immune cells171,172.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [29] Tripathi, U. et al. SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3. Aging 13, 21838–21854 (2021). source

      Not checked in the free run.

    • cites [169] Bektas, A., Schurman, S. H., Franceschi, C. & Ferrucci, L. A public health perspective of aging: do hyper-inflammatory syndromes such as COVID-19, SARS, ARDS, cytokine storm syndrome, and post-ICU syndrome accelerate short- and long-term inflammaging? Immun. Ageing 17, 23 (2020). source

      Not checked in the free run.

    • cites [170] Ma, Y. et al. SARS-CoV-2 infection aggravates chronic comorbidities of cardiovascular diseases and diabetes in mice. Anim. Model. Exp. Med. 4, 2–15 (2021). source

      Not checked in the free run.

    • cites [171] De Biasi, S. et al. Marked T cell activation, senescence, exhaustion and skewing towards TH17 in patients with COVID-19 pneumonia. Nat. Commun. 11, 3434 (2020). source

      Not checked in the free run.

    • cites [172] Cox, L. S. et al. Tackling immunosenescence to improve COVID-19 outcomes and vaccine response in older adults. Lancet Healthy Longev. 1, e55–e57 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Senescence operates as a central pathogenic principle in severe COVID-19 and may also be a general feature of other viral infections that induce hyperinflammatory responses.

    “Although alternative mechanisms independent from VIS may contribute to the hyperinflammation observed in severe COVID-19, senescence operates as a central pathogenic principle in severe COVID-19 and may also be a general feature of other viral infections that induce hyperinflammatory responses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the two COVID-19 trials, quercetin was generally well tolerated with no apparent toxicity and no particular side effects reported by patients.

    “Specifically, in the two COVID-19 trials referred to above, quercetin was generally well tolerated with no apparent toxicity and no particular side effects were reported by the patients143–145.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [143] Di Pierro, F. et al. Quercetin phytosome® as a potential candidate for managing COVID-19. Minerva Gastroenterol. https://doi.org/10.23736/s1121-421x.20.02771-3 (2020). source

      Not checked in the free run.

    • cites [144] Di Pierro, F. et al. Possible therapeutic effects of adjuvant quercetin supplementation against early-stage COVID-19 infection: a prospective, randomized, controlled, and open-label study. Int. J. Gen. Med. 14, 2359–2366 (2021). source

      Not checked in the free run.

    • cites [145] Di Pierro, F. et al. Potential clinical benefits of Quercetin in the early stage of COVID-19: results of a second, pilot, randomized, controlled and open-label clinical trial. Int. J. Gen. Med. 14, 2807–2816 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Flavonoids such as fisetin or quercetin are freely available over-the-counter agents and have favourable safety profiles.

    “Flavonoids, such as fisetin or quercetin, are freely available ‘over-the-counter’ agents and have favourable safety profiles168.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [168] Kashyap, D. et al. Fisetin and quercetin: promising flavonoids with chemopreventive potential. Biomolecules https://doi.org/10.3390/biom9050174 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    EBV infection induces expression of p16INK4a or p21CIP1, which act as a primary host defence against virus propagation, and EBV-positive cells losing expression of these mediators are selected for in manifest chronic infection.

    “EBV infection has long been known to induce the expression of central signalling mediators of the senescence response such as p16INK4a or p21CIP1. These proteins act as a primary host defence against virus propagation, and EBV-positive cells losing expression of these mediators subsequently get selected for in manifest chronic infection187,188.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [187] Yang, X., He, Z., Xin, B. & Cao, L. LMP1 of Epstein-Barr virus suppresses cellular senescence associated with the inhibition of p16INK4a expression. Oncogene 19, 2002–2013 (2000). source

      Not checked in the free run.

    • cites [188] Chen, Y. L. et al. The Epstein-Barr virus replication and transcription activator, Rta/BRLF1, induces cellular senescence in epithelial cells. Cell Cycle 8, 58–65 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Persistent senescent cells are known to exert detrimental long-term effects on organ function and can promote tumorigenesis.

    “Persistent senescent cells are known to exert detrimental long-term effects on organ function and can promote tumorigenesis33,96,112,177,178.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [33] Lee, S. & Schmitt, C. A. The dynamic nature of senescence in cancer. Nat. Cell Biol. 21, 94–101 (2019). source

      Not checked in the free run.

    • cites [96] Gasek, N. S., Kuchel, G. A., Kirkland, J. L. & Xu, M. Strategies for targeting senescent cells in human disease. Nat. Aging 1, 870–879 (2021). source

      Not checked in the free run.

    • cites [112] Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018). source

      Not checked in the free run.

    • cites [177] Milanovic, M. et al. Senescence-associated reprogramming promotes cancer stemness. Nature 553, 96–100 (2018). source

      Not checked in the free run.

    • cites [178] Wyld, L. et al. Senescence and cancer: a review of clinical implications of senescence and senotherapies. Cancers https://doi.org/10.3390/cancers12082134 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    So far, no evidence has been reported for SARS-CoV-2-induced senescent cells promoting tumorigenesis, and no direct pro-tumorigenic role has been attributed to SARS-CoV-2.

    “So far, no evidence has been reported for SARS-CoV-2-induced senescent cells in this regard and no direct pro-tumorigenic role has been attributed to SARS-CoV-2.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Increasing evidence supports viral infections as triggers of autoimmune diseases in general; type 1 diabetes mellitus has been linked to enterovirus infections and multiple sclerosis to Epstein-Barr virus infections.

    “For example, type 1 diabetes mellitus was linked to enterovirus infections185 and multiple sclerosis to Epstein–Barr virus (EBV) infections186.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [185] Op de Beeck, A. & Eizirik, D. L. Viral infections in type 1 diabetes mellitus–why the β cells? Nat. Rev. Endocrinol. 12, 263–273 (2016). source

      Not checked in the free run.

    • cites [186] Bjornevik, K. et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science https://doi.org/10.1126/science.abj8222 (2022). source

      Not checked in the free run.

37 of 37

  • The paper relies on this without support.

    The clinical severity of COVID-19 is largely determined by host factors.

    “The clinical severity of coronavirus disease 2019 (COVID-19) is largely determined by host factors.”

  • The paper relies on this without support.

    The most destructive phase of immune activation often occurs when viral mRNA is no longer detectable.

    “Interestingly, the most destructive phase of immune activation often occurs when the viral mRNA is no longer detectable.”

  • The paper relies on this without support.

    Elderly individuals have an increased proportion of pre-existing senescent cells in their tissues.

    “These effects are enhanced in elderly individuals who have an increased proportion of pre-existing senescent cells in their tissues.”

  • The paper relies on this without support.

    There is a significant unmet medical need for therapeutics to treat severe COVID-19 in unvaccinated or immunosuppressed individuals, elderly patients, and patients with chronic disease conditions.

    “there is still a significant unmet medical need for therapeutics to treat severe courses of disease in unvaccinated or immunosuppressed individuals as well as in elderly patients and patients with chronic disease conditions.”

  • The authors state this as an assumption.

    Viral entry and replication in vaccinated individuals would induce VIS and could trigger a cytokine storm that may lead to severe COVID-19.

    “The fact that viral entry and replication occur despite successful vaccination is interesting as VIS would be the assumed consequence and could trigger a cytokine storm potentially leading to severe COVID-19.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • SARS-CoV-2 infection triggers a cytokine storm, inflammation, cellular senescence, age-related immunosenescence, and diminished physiological reserves in the respiratory system and other organs.

    “Infection with SARS-CoV-2 triggers a cytokine storm, inflammation, cellular senescence, age-related immunosenescence, as well as diminished physiological reserves in the respiratory system and other organs.276,277”

    From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [277]

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Related

Authors
Schmitt, C. A., Tchkonia, T., Niedernhofer, L. J., Robbins, P. D., Kirkland, J. L., & Lee, S.
Affiliations
  • Johannes Kepler University of Linz (AT)
  • Mayo Clinic (US)
  • University of Minnesota (US)
Corresponding author
  • Schmitt, Clemens A.
  • Lee, Soyoung
ORCID
Venue
Nature Reviews Immunology
Publisher
Springer Science and Business Media LLC
Published
2022-10-05
Volume
23
Issue
4
Pages
251-263
ISSN
  • 1474-1733 (ISSN-L)
  • 1474-1741
DOI
10.1038/s41577-022-00785-2
PMC
PMC9533263
OpenAlex
W4301595953
Cited by
153
References
220
Citations by year
2026: 28 · 2025: 34 · 2024: 44 · 2023: 45 · 2022: 2
FWCI
4.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature reviews. Immunology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
Keywords
COVID-19 pandemic, SARS-CoV-2, cellular senescence, senescence-associated secretory phenotype, hyperinflammation, cytokine storm, extracellular matrix degradation, complement activation, coagulation, endothelial inflammation, fibrosis, microvascular thrombosis, paracrine senescence, senolytics, senolytic therapy, aging, elderly patients
MeSH terms
COVID-19, SARS-CoV-2, Aging, Humans, Cellular Senescence

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

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