The DOI matches its Crossref record; 220 of the 220 references it cites were found in a registry or an index; 9 of the 159 sources its claims cite were checked for support.
COVID-19 and cellular senescence
Open accessAbstract
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.
Overview
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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.
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Claims the paper makes
65 Not checked yet · 26 Own interpretation · 3 Partly supported · 1 No basis given · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ COVID-19 and cellular senescence > Introduction
What the sources say
- Partly supportedcites [27] Camell, C. D. et al. Senolytics reduce coronavirus-related mortality in old mice. Science https://doi.org/10.1126/science.abe4832 (2021). sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) proposes that SARS-CoV-2 S1 amplifies the secretory response of preexisting senescent cells and that the resulting factors drive secondary senescence. This supports a possible indirect route to new senescent cells, but the paper presents it as a hypothesis; it does not establish virus-induced senescence through multiple mechanisms. (LLM, conf=0.85)
- Supportedcites [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
The Properties of VIS section reports that cells infected with authentic SARS-CoV-2 displayed senescence and concludes that SARS-CoV-2 infection of respiratory epithelial cells induces cellular senescence. This directly supports the attributed claim. (LLM, conf=0.94)
- Supportedcites [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
The Introduction states that both a Spike-pseudotyped virus and genuine SARS-CoV-2 induced senescence in human cells. The Abstract likewise reports senescence induction in previously non-senescent human cells, directly supporting the attributed claim. (LLM, conf=0.95)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“when comparing samples of nasopharyngeal mucosa from patients with COVID-19 to pre-pandemic biopsy samples from individuals without a manifest respiratory tract infection, a panel of senescence markers was shown to robustly discriminate these two groups, with significantly higher reactivity in samples from patients with COVID-19 (refs.28,29,44,52).”
§ COVID-19 and cellular senescence > Senescence in patients with COVID-19
What the sources say
- Partly supportedcites [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). sourceExperimental — accuracy not yet measured
The ‘Cellular senescence in patients with COVID-19’ section reports robust reactivity of a panel of senescence markers in COVID-19 nasopharyngeal specimens but not in non-COVID-19 specimens. The ‘Additional information’ section identifies the controls as pre-October 2019 archival samples from people without significant clinical signs of respiratory infection. Fig. 2a quantifies the staining, but the passages do not establish statistical significance for the higher reactivity claimed in the citing sentence. (LLM, conf=0.84)
- Partly supportedcites [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). sourceExperimental — accuracy not yet measured
The Results section ('Lung p16INK4a+ senescent cell burden') reports more p16INK4a-positive cells in lung tissue from patients who died with SARS-CoV-2 than in controls. It does not report a panel of markers discriminating nasopharyngeal mucosa samples from COVID-19 patients and pre-pandemic controls. The cited study supports the direction of the senescence-marker finding, but not the specified tissue, comparison, or panel. (LLM, conf=0.88)
- Partly supportedcites [44] Evangelou, K. et al. Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: possible implications for viral mutagenesis. Eur. Respir. J. https://doi.org/10.1183/13993003.02951-2021 (2022). sourceExperimental — accuracy not yet measured
The Results section (‘Senescence in SARS-CoV-2-infected cells’; page unavailable) reports significantly higher senescence-marker staining in COVID-19 tissue than in non-COVID-19 controls. But the Tissues section specifies that these were lung samples, not nasopharyngeal mucosa biopsies; the paper therefore does not establish the claimed discrimination between nasopharyngeal groups. (LLM, conf=0.86)
- Partly supportedcites [52] D’Agnillo, F. et al. Lung epithelial and endothelial damage, loss of tissue repair, inhibition of fibrinolysis, and cellular senescence in fatal COVID-19. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.abj7790 (2021). sourceExperimental — accuracy not yet measured
The Results section ('Increased cellular senescence of epithelium and endothelium in COVID-19 lungs'; page unavailable) reports higher p21 staining in COVID-19 lung tissue than in normal lung tissue. The Methods identify the controls as non-COVID lung specimens. The paper does not report a comparison of nasopharyngeal mucosa with pre-pandemic biopsies or show that a marker panel discriminated those groups. (LLM, conf=0.87)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Recent advances point to cellular senescence, an ageing-related switch in cellular state, as a critical regulator of SARS-CoV-2-evoked hyperinflammation.”
§ COVID-19 and cellular senescence > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“SASP-driven spreading of cellular senescence uncouples tissue injury from direct SARS-CoV-2-inflicted cellular damage in a paracrine fashion”
§ COVID-19 and cellular senescence > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“SARS-CoV-2, like other viruses, can induce senescence and exacerbates the senescence-associated secretory phenotype (SASP)”
§ COVID-19 and cellular senescence > Abstract
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ COVID-19 and cellular senescence > Introduction
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and can further amplify the SASP by increasing the burden of senescent cells.”
§ COVID-19 and cellular senescence > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“isolated recombinant S protein has been shown to increase the SASP in senescent ACE2-expressing cells27,29”
§ COVID-19 and cellular senescence > Virus-evoked cellular stress
What the sources say
- Not checked yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The direct induction of senescence through infection with SARS-CoV-2 was demonstrated in vitro with a SARS-CoV-2-susceptible kidney cell line (Vero) as detected by an increase in lipofuscin (Box 1), the secretion of SASP factors, including IL-1β, IL-6 and IL-8, and the DNA damage mark γH2A.X, as well as a loss of Ki67 expression44”
§ COVID-19 and cellular senescence > Virus-evoked cellular stress
What the sources say
- Not checked yetcites [44] Evangelou, K. et al. Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: possible implications for viral mutagenesis. Eur. Respir. J. https://doi.org/10.1183/13993003.02951-2021 (2022). source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Similar analyses of lung specimens from patients with COVID-19, consistent with multiple independent patient datasets29,44,52, also showed much stronger signs of senescence compared to SARS-CoV-2 negative controls28.”
§ COVID-19 and cellular senescence > Senescence in patients with COVID-19
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [44] Evangelou, K. et al. Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: possible implications for viral mutagenesis. Eur. Respir. J. https://doi.org/10.1183/13993003.02951-2021 (2022). source
- Not checked yetcites [52] D’Agnillo, F. et al. Lung epithelial and endothelial damage, loss of tissue repair, inhibition of fibrinolysis, and cellular senescence in fatal COVID-19. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.abj7790 (2021). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Probably not a substantial claim. 4
- It may state two separate claims as one. 35
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ COVID-19 and cellular senescence > Macrophages in senescence spreading
What the sources say
- Supportedcites [27] Camell, C. D. et al. Senolytics reduce coronavirus-related mortality in old mice. Science https://doi.org/10.1126/science.abe4832 (2021). source
The Discussion describes the authors’ “Amplifier/Rheostat” hypothesis: pathogen-associated signals intensify the inflammatory SASP of existing senescent cells, exacerbating systemic inflammation and driving secondary senescence. The Fig. 6 caption likewise says this response could amplify acute systemic inflammation and the spread of senescence. The citing sentence presents this as a hypothesis, consistent with the source. (LLM, conf=0.94)
- Partly supportedcites [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). sourceExperimental — accuracy not yet measured
In the Article section (page unavailable), Lee et al. hypothesize that senescence and its SASP contribute to the inflammatory features of COVID-19. The ‘Cellular senescence in patients with COVID-19’ section also describes evidence consistent with paracrine spread of senescence. Our copy does not name a ‘SASP amplifier/rheostat model’ or establish the proposed response across pathogens generally, rather than SARS-CoV-2. (LLM, conf=0.84)
hedgeddirect- Asserted: fails — The authors may not put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The authors may not put it forward as true. It may state two separate claims as one.
- Supported
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ COVID-19 and cellular senescence > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“VIS appears to be a universal stress response in host cells and can be induced by many different virus species.”
§ COVID-19 and cellular senescence > Virus-evoked cellular stress
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“SASP factors can contribute to a ‘cytokine storm’, tissue-destructive immune cell infiltration, endothelialitis (endotheliitis), fibrosis and microthrombosis.”
§ COVID-19 and cellular senescence > Abstract
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ COVID-19 and cellular senescence > Introduction
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ COVID-19 and cellular senescence > Virus-evoked cellular stress
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [51] Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ COVID-19 and cellular senescence > Virus-evoked cellular stress
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ COVID-19 and cellular senescence > Virus-evoked cellular stress
What the sources say
- Not checked yetcites [55] Dou, Z. et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature https://doi.org/10.1038/nature24050 (2017). source
- Not checked yetcites [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 yetcites [57] Miller, K. N. et al. Cytoplasmic DNA: sources, sensing, and role in aging and disease. Cell 184, 5506–5526 (2021). source
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“giving rise to the hypothesis that more extensive senescence underlies more profound COVID-19 pathobiology.”
§ COVID-19 and cellular senescence > Senescence in patients with COVID-19
hedgeddirect- Asserted: fails — The authors may not put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The authors may not put it forward as true.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Collectively, the data indicate that activated monocytes and decreased T cell activity characterize hyperinflammation in severe COVID-19.”
§ COVID-19 and cellular senescence > Macrophages in senescence spreading
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ COVID-19 and cellular senescence > Senescence-induced COVID-19 pathology
What the sources say
- Not checked yetcites [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 yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ COVID-19 and cellular senescence > Senescence-induced COVID-19 pathology
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ COVID-19 and cellular senescence > Macrophages in senescence spreading
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ COVID-19 and cellular senescence > Macrophages in senescence spreading
What the sources say
- Not checked yetcites [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 yetcites [61] Desai, N. et al. Temporal and spatial heterogeneity of host response to SARS-CoV-2 pulmonary infection. Nat. Commun. 11, 6319 (2020). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ COVID-19 and cellular senescence > Senescence-induced COVID-19 pathology
What the sources say
- Not checked yetcites [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
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ COVID-19 and cellular senescence > Senescence-induced COVID-19 pathology
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ COVID-19 and cellular senescence > Senolytic strategies > In vivo testing of senolytics in COVID-19
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ COVID-19 and cellular senescence > Senolytic strategies > In vivo testing of senolytics in COVID-19
What the sources say
- Not checked yetcites [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 yetcites [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
- Not checked yetcites [128] Birch, J. & Gil, J. Senescence and the SASP: many therapeutic avenues. Genes Dev. 34, 1565–1576 (2020). source
- Not checked yetcites [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
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ COVID-19 and cellular senescence > Senolytic strategies > In vitro findings with senolytics in VIS
What the sources say
- Not checked yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ COVID-19 and cellular senescence > Senolytic strategies > In vitro findings with senolytics in VIS
What the sources say
- Not checked yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“These prostaglandins are known to promote senescence and the SASP135–137.”
§ COVID-19 and cellular senescence > Senolytic strategies > In vivo testing of senolytics in COVID-19
What the sources say
- Not checked yetcites [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
- Not checked yetcites [136] Gonçalves, S. et al. COX2 regulates senescence secretome composition and senescence surveillance through PGE(2). Cell Rep. 34, 108860 (2021). source
- Not checked yetcites [137] Wiley, C. D. et al. Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis. Cell Metab. 33, 1124–1136.e5 (2021). source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ COVID-19 and cellular senescence > Senolytic strategies > In vivo testing of senolytics in COVID-19
What the sources say
- Not checked yetcites [134] Wong, L.-Y. R. et al. Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19. Nature 605, 146–151 (2022). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ COVID-19 and cellular senescence > Senolytic strategies > In vivo testing of senolytics in COVID-19
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ COVID-19 and cellular senescence > Senolytic strategies > In vivo testing of senolytics in COVID-19
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ COVID-19 and cellular senescence > Conclusions and outlook
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ COVID-19 and cellular senescence > VIS and vaccination
What the sources say
- Not checked yetcites [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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ COVID-19 and cellular senescence > VIS and vaccination
What the sources say
- Not checked yetcites [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
- Not checked yetcites [150] Corbett, K. S. et al. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature 586, 567–571 (2020). source
- Not checked yetcites [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
- Not checked yetcites [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
- Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [156] Wang, Z. et al. mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants. Nature 592, 616–622 (2021). source
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ COVID-19 and cellular senescence > Senolytic strategies > In vivo testing of senolytics in COVID-19
What the sources say
- Not checked yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ COVID-19 and cellular senescence > Conclusions and outlook
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ COVID-19 and cellular senescence > Conclusions and outlook
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ COVID-19 and cellular senescence > Conclusions and outlook
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ COVID-19 and cellular senescence > Conclusions and outlook
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Flavonoids, such as fisetin or quercetin, are freely available ‘over-the-counter’ agents and have favourable safety profiles168.”
§ COVID-19 and cellular senescence > Conclusions and outlook
What the sources say
- Not checked yetcites [168] Kashyap, D. et al. Fisetin and quercetin: promising flavonoids with chemopreventive potential. Biomolecules https://doi.org/10.3390/biom9050174 (2019). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ COVID-19 and cellular senescence > Conclusions and outlook
What the sources say
- Not checked yetcites [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 yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Persistent senescent cells are known to exert detrimental long-term effects on organ function and can promote tumorigenesis33,96,112,177,178.”
§ COVID-19 and cellular senescence > Conclusions and outlook
What the sources say
- Not checked yetcites [33] Lee, S. & Schmitt, C. A. The dynamic nature of senescence in cancer. Nat. Cell Biol. 21, 94–101 (2019). source
- Not checked yetcites [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 yetcites [112] Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018). source
- Not checked yetcites [177] Milanovic, M. et al. Senescence-associated reprogramming promotes cancer stemness. Nature 553, 96–100 (2018). source
- Not checked yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ COVID-19 and cellular senescence > Conclusions and outlook
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“For example, type 1 diabetes mellitus was linked to enterovirus infections185 and multiple sclerosis to Epstein–Barr virus (EBV) infections186.”
§ COVID-19 and cellular senescence > Conclusions and outlook
What the sources say
- Not checked yetcites [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 yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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.”
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?
In the citing paper
“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]
Citations
Cites
Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schiergens, T. S., Herrler, G., Wu, N.-H., Nitsche, A., et al. (2020) · Cell · doi:10.1016/j.cell.2020.02.052 · Cited by 20,286
Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine
Polack, F. P., Thomas, S. J., Kitchin, N., Absalon, J., Gurtman, A., Lockhart, S., Perez, J. L., Pérez Marc, G., Moreira, E. D., Zerbini, C., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2034577 · Cited by 14,592
Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine
Baden, L. R., El Sahly, H. M., Essink, B., Kotloff, K., Frey, S., Novak, R., Diemert, D., Spector, S. A., Rouphael, N., Creech, C. B., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2035389 · Cited by 10,119
The serial cultivation of human diploid cell strains
Hayflick, L., & Moorhead, P. S. (1961) · Experimental Cell Research · doi:10.1016/0014-4827(61)90192-6 · Cited by 8,508
A biomarker that identifies senescent human cells in culture and in aging skin in vivo.
Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rubelj, I., & Pereira-Smith, O. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.20.9363 · Cited by 7,477
Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19
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Metadata
- 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
- Published
- 2022-10-05
- Volume
- 23
- Issue
- 4
- Pages
- 251-263
- ISSN
- 1474-1733 (ISSN-L)
- 1474-1741
- 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
- bronze
- doi.org
- Licence
- Locations
- Nature reviews. Immunology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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.
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