The DOI matches its Crossref record; 220 of the 220 references it cites were found in a registry or an index; 17 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.
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Claims the paper makes
63 Not checked yet · 26 Own interpretation · 5 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
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In addition to BCL-2 family members, SCAPs are mediated by SRC family tyrosine kinases as well as pro-survival pathways related to serpin, heat shock protein and p21CIP1 (refs.99–104).”
§ COVID-19 and cellular senescence > Senolytic strategies
What the sources say
- Partly supportedcites [99] Zhu, Y. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015). sourceExperimental — accuracy not yet measured
The Results (Senolytic siRNAs; page unavailable) identify p21, the serpin PAI-2, and BCL-xL as targets whose knockdown reduced senescent-cell survival; the Discussion also describes p21 and serpins as potential senolytic targets. Our copy does not identify SRC-family tyrosine kinases or heat-shock proteins as components of these pro-survival pathways (searched: “SRC family tyrosine kinases” and “heat shock protein”). (LLM, conf=0.87)
- Partly supportedcites [100] Chang, J. et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22, 78–83 (2016). sourceExperimental — accuracy not yet measured
The passage labeled Abstract (page not provided) reports that BCL-2 and BCL-xL protect senescent cells from apoptotic death. It does not identify SRC-family kinases or pathways related to serpin, heat shock proteins, or p21CIP1 as mediators of senescent-cell survival; searches for those terms found no supporting passage. (LLM, conf=0.86)
- Partly supportedcites [101] Zhu, Y. et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 15, 428–435 (2016). sourceExperimental — accuracy not yet measured
The Introduction and Results section on Bcl-2 family protein signatures describe Bcl-2 family members as anti-apoptotic factors on which some senescent cells may depend. The passages found do not identify SRC family tyrosine kinases or serpin-, heat-shock-protein-, or p21CIP1-related pathways as senescent-cell anti-apoptotic pathways. Page numbers were not available in our copy. (LLM, conf=0.88)
- Partly supportedcites [102] Fuhrmann-Stroissnigg, H. et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat. Commun. 8, 422 (2017). sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) identifies Bcl-2/Bcl-XL, p53/p21, and serpine anti-apoptotic pathways, while the Results and Discussion (page unavailable) describe HSP90-dependent survival signaling in senescent cells. Our copy does not identify SRC-family tyrosine kinases as mediators of these pathways, so it does not support that part of the sentence. (LLM, conf=0.84)
- Partly supportedcites [103] Zhu, Y. et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging 9, 955–963 (2017). sourceExperimental — accuracy not yet measured
The Introduction identifies senescence-associated pro-survival networks involving BCL-2/BCL-XL, p53/p21/serpines, and dependence receptor/tyrosine kinases; the Discussion repeats these pathway categories. Our copy does not specify SRC-family kinases or identify a heat-shock-protein pathway, so those parts of the attributed claim are unsupported. (LLM, conf=0.87)
- Partly supportedcites [104] Yousefzadeh, M. J. et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine 36, 18–28 (2018). sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) says senescent cells resist apoptosis through SCAPs and identifies BCL-2-family inhibitors as a way to target them. It does not identify SRC-family kinases, serpins, heat-shock proteins, or p21CIP1 as SCAP pathways. The Results treat p21CIP1 as a senescence marker, while the References list a study of HSP90 inhibitors without making the claimed pathway connection. (LLM, conf=0.85)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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- 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
“Further corroborating and extending these preclinical findings to the human condition, two randomized clinical trials (NCT04578158 and NCT04861298) that, in addition to standard care, used a special formulation of quercetin with enhanced oral bioavailability as an early intervention in patients with mild COVID-19 symptoms, met their clinical end points143–145.”
§ COVID-19 and cellular senescence > Senolytic strategies > In vivo testing of senolytics in COVID-19
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
- Partly supportedcites [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). sourceExperimental — accuracy not yet measured
The Patients and Methods section identifies this randomized study as NCT04578158 and describes adding a bioavailable quercetin formulation to standard care for outpatients with mild-to-moderate COVID-19. The Results and Conclusions report improved clinical outcomes. This paper does not establish that the second named trial, NCT04861298, met its endpoints, so it supports the claim for only one of the two trials. (LLM, conf=0.90)
- Supportedcites [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
The Methods (Ethical Considerations; page unavailable) identify this paper’s trial as NCT04861298. Its Methods describe randomized add-on treatment with a quercetin formulation in COVID-19 outpatients, and the Conclusions report preliminary, significant improvements in virus clearance, symptom frequency, LDH and ferritin. This source supports the claim for the second of the two trials; the citing sentence has multiple citations and does not require this paper alone to document both. (LLM, conf=0.89)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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- 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
“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.
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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
“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.
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- 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.
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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.
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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
“Collectively, these observations indicate that ROS levels appear to play a crucial role in triggering VIS in the context of SARS-CoV-2 infection.”
§ COVID-19 and cellular senescence > Virus-evoked cellular stress
hedgedconditional- 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
“SARS-CoV-2 mRNA was detectable by in situ hybridization in many but not all VIS-positive samples, suggesting that VIS may persist beyond the initial infection28,61,62”
§ 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 [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 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
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.
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
“This demonstrates that SARS-CoV-2-related cytokine production by infected cells is dependent on an intact capacity of these cells to enter cellular senescence.”
§ COVID-19 and cellular senescence > Virus-evoked cellular stress
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
“These observations indicate that viral entry causes high levels of cytokine secretion in host cells via the induction of VIS.”
§ COVID-19 and cellular senescence > Virus-evoked cellular stress
hedgeddirect- 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
“senescence markers, such as p16INK4a, p21CIP1, H3K9me3 and lipofuscin (detected by the GL13-SenTraGorTM reagent in fixed tissues60), as well as IL-8 (a component of the SASP) were markedly elevated in samples from the upper respiratory mucosa from patients with COVID-19 (ref.28)”
§ 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 [60] Barbouti, A. et al. In situ evidence of cellular senescence in thymic epithelial cells (TECs) during human thymic involution. Mech. Ageing Dev. 177, 88–90 (2019). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- 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
“This model might also explain the increased risk of a cytokine storm and adverse outcomes after SARS-CoV-2 infection in the elderly or in individuals with chronic conditions associated with an increased burden of senescent cells such as obesity, diabetes or previous chemotherapy.”
§ COVID-19 and cellular senescence > Macrophages in senescence spreading
hedgedconditional- 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
“were also strongly elevated in the serum of patients with COVID-19 compared to healthy controls28,52,67–70.”
§ 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 [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
- Not checked yetcites [67] Messner, C. B. et al. Ultra-high-throughput clinical proteomics reveals classifiers of COVID-19 infection. Cell Syst. 11, 11–24.e4 (2020). source
- Not checked yetcites [68] Demichev, V. et al. A time-resolved proteomic and prognostic map of COVID-19. Cell Syst. https://doi.org/10.1016/j.cels.2021.05.005 (2021). source
- Not checked yetcites [69] Sacco, K. et al. Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19. Nat. Med. 28, 1050–1062 (2022). source
- Not checked yetcites [70] COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium. A blood atlas of COVID-19 defines hallmarks of disease severity and specificity. Cell 185, 916–938 (2022). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“WHO-graded clinical severity of COVID-19 correlated positively with increasing concentrations of the pro-inflammatory SASP cytokine IL-6, the coagulation-related SASP representative SERPINA3 and D-Dimer-based clotting activity28.”
§ 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
plaincorrelational- 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
“Bulk and single-cell transcriptomic analyses further support the concept that SARS-CoV-2-triggered senescence drives pathology in COVID-19.”
§ COVID-19 and cellular senescence > Senescence in patients with COVID-19
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In the paper
“the senescent state can spread to non-senescent and, potentially, to non-infected cells as the increase in SASP evoked by viral infection can lead to the induction of paracrine senescence63,71,72.”
§ COVID-19 and cellular senescence > Macrophages in senescence spreading
What the sources say
- Not checked yetcites [63] Acosta, J. C. et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 15, 978–990 (2013). source
- Not checked yetcites [71] Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018 (2008). source
- Not checked yetcites [72] Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008). source
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In the paper
“in vitro and in vivo experiments have shown that resident and non-resident macrophages in the vicinity of SASP-producing virus-infected epithelial cells can undergo paracrine secondary senescence or acquire a senescence-like condition28,63,66,77,78.”
§ 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 [63] Acosta, J. C. et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 15, 978–990 (2013). source
- Not checked yetcites [66] Chua, R. L. et al. COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis. Nat. Biotechnol. 38, 970–979 (2020). source
- Not checked yetcites [77] Hall, B. M. et al. p16(Ink4a) and senescence-associated β-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli. Aging 9, 1867–1884 (2017). source
- Not checked yetcites [78] Behmoaras, J. & Gil, J. Similarities and interplay between senescent cells and macrophages. J. Cell Biol. https://doi.org/10.1083/jcb.202010162 (2021). source
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In the paper
“lungs from patients who died from severe COVID-19 showed higher levels of p16INK4a-positive cells compared to lungs from individuals who died from other causes29.”
§ COVID-19 and cellular senescence > Senescence in patients with COVID-19
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
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In the paper
“SARS-CoV-2 infection was shown to induce polarization of peripheral blood immune cell subsets that is typical for ageing and includes the expression of genes associated with inflammation and senescence82.”
§ COVID-19 and cellular senescence > Macrophages in senescence spreading
What the sources say
- Not checked yetcites [82] Zheng, Y. et al. A human circulating immune cell landscape in aging and COVID-19. Protein Cell 11, 740–770 (2020). source
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In the paper
“The disease-promoting effects of senescence-primed macrophages in different organs (see below) is likely to be further aggravated by the age-related burden of pre-existing senescent cells (Fig. 2).”
§ COVID-19 and cellular senescence > Macrophages in senescence spreading
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In the paper
“SARS-CoV-2 triggers a profibrotic response in CD14+CD163+ macrophages, which promotes manifest pulmonary fibrosis and acute respiratory distress syndrome (Box 1)”
§ COVID-19 and cellular senescence > Macrophages in senescence spreading
What the sources say
- 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
- Not checked yetcites [80] Schafer, M. J. et al. Cellular senescence mediates fibrotic pulmonary disease. Nat. Commun. 8, 14532 (2017). source
- Not checked yetcites [81] Wendisch, D. et al. SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis. Cell https://doi.org/10.1016/j.cell.2021.11.033 (2021). source
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In the paper
“coronavirus susceptibility genes, among them CD147, CD26 and ANPEP (encoding aminopeptidase N; see ref.82 for details), are upregulated with age.”
§ COVID-19 and cellular senescence > Macrophages in senescence spreading
What the sources say
- Not checked yetcites [82] Zheng, Y. et al. A human circulating immune cell landscape in aging and COVID-19. Protein Cell 11, 740–770 (2020). source
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In the paper
“The SCAPs vary between different types of senescent cells (for example, between senescent human endothelial cells versus fat cell progenitors).”
§ COVID-19 and cellular senescence > Senolytic strategies
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In the paper
“These effects represent highly disease-relevant components of COVID-19-related immunothrombosis, which were detected to a much lesser extent if the supernatant from virus-infected but senescence-resistant cells was tested28 (Fig. 2).”
§ 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
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In the paper
“By contrast, the culture supernatant of equally virus-infected but senescence-incapable cells failed to evoke these cellular effects28.”
§ 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
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In the paper
“Overall, these in vitro observations suggest an essential, secretome-dependent role of VIS and senescence in general in the pathobiological manifestation of the infection27–29.”
§ COVID-19 and cellular senescence > Senescence-induced COVID-19 pathology
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
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In the paper
“VIS cells, pre-existing senescent cells in the elderly and in those with underlying conditions, and SASP-induced secondary senescent cells appear to play a key role in the development of severe COVID-19.”
§ COVID-19 and cellular senescence > Senolytic strategies
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In the paper
“Hence, a characteristic shared across senescent cells, especially those with a profound SASP, is their enhanced insensitivity to pro-apoptotic signals, which is mediated via upregulation of anti-apoptotic BCL-2 family members or kinase networks that promote pro-survival signalling — collectively referred to as senescent cell anti-apoptotic pathways (SCAPs)98,99.”
§ COVID-19 and cellular senescence > Senolytic strategies
What the sources say
- Not checked yetcites [98] Kirkland, J. L. & Tchkonia, T. Cellular senescence: a translational perspective. EBioMedicine 21, 21–28 (2017). source
- Not checked yetcites [99] Zhu, Y. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015). source
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In the paper
“A fundamental property and dependency of senescent cells is their protection from apoptotic death despite the stresses they encounter98.”
§ COVID-19 and cellular senescence > Senolytic strategies
What the sources say
- Not checked yetcites [98] Kirkland, J. L. & Tchkonia, T. Cellular senescence: a translational perspective. EBioMedicine 21, 21–28 (2017). source
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In the paper
“Similarly, the inhibition of pro-inflammatory JAK signalling in the same model was shown to attenuate pathogenesis by reducing the infiltration of monocytes to the lung130–132.”
§ COVID-19 and cellular senescence > Senolytic strategies > In vivo testing of senolytics in COVID-19
What the sources say
- Not checked yetcites [130] Hubackova, S., Krejcikova, K., Bartek, J. & Hodny, Z. IL1- and TGFbeta-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induced paracrine ‘bystander senescence’. Aging 4, 932–951 (2012). source
- Not checked yetcites [131] Xu, M. et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc. Natl Acad. Sci. Usa. 112, E6301–E6310 (2015). source
- Not checked yetcites [132] Dobosh, B. et al. Baricitinib attenuates the proinflammatory phase of COVID-19 driven by lung-infiltrating monocytes. Cell Rep. https://doi.org/10.1016/j.celrep.2022.110945 (2022). source
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In the paper
“This suggests therapeutic opportunities in COVID-19 for senolytic agents that interfere with SCAPs, thereby inducing apoptosis in VIS cells and in pre-existing senescent and secondary senescent cells.”
§ COVID-19 and cellular senescence > Senolytic strategies
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In the paper
“These observations provide further evidence for the pathogenic connection between senescence, SASP and severe COVID-19.”
§ COVID-19 and cellular senescence > Senolytic strategies > In vivo testing of senolytics in COVID-19
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In the paper
“Strikingly, the broadly elevated levels of SASP-typical cytokines and interleukins — among them granulocyte colony-stimulating factor (G-CSF), IFNγ, IL-1α, IL-7, IL-17A, TNF and vascular endothelial growth factor (VEGF) — that were detected (despite the challenge to do this at the protein level in hamsters) in the serum of infected animals, were reduced by all agents tested to levels that were”
§ 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
“In animal models of fatal COVID-19, senolytic regimens based on flavonoids, such as the dasatinib and quercetin combination or fisetin, enhanced survival rates28.”
§ 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
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In the paper
“Indeed, the expression of BCL-xL and BCL-w and the activity of SRC, AKT and p38 kinases were found to be elevated in retrovirus-infected fibroblast models of VIS, in SARS-CoV-2-infected hamsters and in patients with COVID-19 (ref.28).”
§ COVID-19 and cellular senescence > Senolytic strategies
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
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In the paper
“Particularly pronounced effects were observed in the Roborovski dwarf hamster model, where treatment with a combination of dasatinib and quercetin resulted in significantly attenuated disease features with respect to the overall pneumonia score, bronchial epithelial hyperplasia and alveolar damage28.”
§ 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
“A machine learning-based assessment of 45 FDA-approved drugs for their potential to be repurposed as antiviral agents in COVID-19 failed to predict a significant direct anti-viral activity of navitoclax and dasatinib, further underscoring that the mode of action of these agents in COVID-19 might be indirect, for example, through the selective elimination of senescent cells117.”
§ COVID-19 and cellular senescence > Senolytic strategies > In vitro findings with senolytics in VIS
What the sources say
- Not checked yetcites [117] Verma, A. K. & Aggarwal, R. Repurposing potential of FDA-approved and investigational drugs for COVID-19 targeting SARS-CoV-2 spike and main protease and validation by machine learning algorithm. Chem. Biol. Drug Des. 97, 836–853 (2021). source
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In the paper
“Nearly all of the aged mice exposed to NME died within 2 weeks, whereas there was no mortality observed in younger mice27.”
§ COVID-19 and cellular senescence > Senolytic strategies > In vivo testing of senolytics in COVID-19
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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Treatment before and/or following NME exposure with the senolytic fisetin or the combination of dasatinib and quercetin reduced mortality.”
§ COVID-19 and cellular senescence > Senolytic strategies > In vivo testing of senolytics in COVID-19
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In the paper
“Age-related elevations of eicosanoid levels, especially prostaglandin D2 (PGD2), were detected in mouse models of SARS-CoV infection133.”
§ COVID-19 and cellular senescence > Senolytic strategies > In vivo testing of senolytics in COVID-19
What the sources say
- Not checked yetcites [133] Zhao, J., Zhao, J., Legge, K. & Perlman, S. Age-related increases in PGD(2) expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice. J. Clin. Invest. 121, 4921–4930 (2011). source
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In the paper
“Within 7 days following NME exposure, the expression of senescence markers (such as p16INK4a and p21CIP1) and SASP factors (such as IL-6, CCL2 and TNF) in liver, lung and kidney significantly increased in old mice compared to young mice27.”
§ COVID-19 and cellular senescence > Senolytic strategies > In vivo testing of senolytics in COVID-19
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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Notably, the mitigating activity observed when these agents were applied prior to NME exposure reflects a reduction of the pre-existing load of senescent cells, and not a direct antimicrobial mechanism, as the key mode of action.”
§ COVID-19 and cellular senescence > Senolytic strategies > In vivo testing of senolytics in COVID-19
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In the paper
“A cohort of aged INK-ATTAC transgenic mice, in which cells with high INK4a promoter activity, which is indicative of senescence, can be forced to undergo apoptosis138,139, exhibited increased resilience to pathogens, including the mouse hepatitis virus (MHV, a mouse β-coronavirus), when p16INK4a-high senescent cells were subjected to ATTAC-dependent depletion27.”
§ COVID-19 and cellular senescence > Senolytic strategies > In vivo testing of senolytics in COVID-19
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 [138] Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011). source
- Not checked yetcites [139] Xu, M. et al. Targeting senescent cells enhances adipogenesis and metabolic function in old age. eLife 4, e12997 (2015). source
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In the paper
“Consistent with this view, convalescent plasma or recombinant therapeutic S protein-targeted antibodies achieved modest or mixed results in preventing severe COVID-19 (however, the emergence of SARS-CoV-2 VOC with mutations in the spike protein that may allow the evasion of neutralizing antibodies may further complicate the interpretation of these results) (refs.65,162,167).”
§ COVID-19 and cellular senescence > VIS and vaccination
What the sources say
- Not checked yetcites [65] Estcourt, L. J. et al. Effect of convalescent plasma on organ support-free days in critically ill patients with COVID-19: a randomized clinical trial. JAMA https://doi.org/10.1001/jama.2021.18178 (2021). source
- Not checked yetcites [162] Hoffmann, M. et al. The Omicron variant is highly resistant against antibody-mediated neutralization: Implications for control of the COVID-19 pandemic. Cell 185, 447–456.e11 (2022). source
- Not checked yetcites [167] Cohen, M. S. et al. Effect of Bamlanivimab vs Placebo on incidence of COVID-19 among residents and staff of skilled nursing and assisted living facilities: a randomized clinical trial. JAMA 326, 46–55 (2021). source
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In the paper
“Of note, a recent clinical pilot study exploring a lecithin-based formulation of quercetin in combination with dasatinib as a senolytic treatment for idiopathic pulmonary fibrosis, an age-related and senescence-associated disease also occurring as a fibrotic complication in the course of COVID-19 (refs.52,80,81,146), showed encouraging signals of clinical improvement as evaluated by walk distance,”
§ COVID-19 and cellular senescence > Senolytic strategies > In vivo testing of senolytics in COVID-19
What the sources say
- Not checked yetcites [147] Justice, J. N. et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine 40, 554–563 (2019). source
plainconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“It is becoming increasingly clear that community protection owing to reduced viral loads in infected but fully vaccinated individuals is diminishing over time159, thereby facilitating further outbreaks and the rapid expansion of new VOCs160–162.”
§ COVID-19 and cellular senescence > VIS and vaccination
What the sources say
- Not checked yetcites [159] Levine-Tiefenbrun, M. et al. Viral loads of delta-variant SARS-CoV-2 breakthrough infections after vaccination and booster with BNT162b2. Nat. Med. https://doi.org/10.1038/s41591-021-01575-4 (2021). source
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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
“In essence, the early elimination of spike peptide-presenting VIS cells either by exogenous pharmacological intervention using prototypic senolytics or by endogenous immune clearance, especially by vaccination-primed spike peptide-specific T cells or a virus-specific T cell response elicited by previous SARS-CoV-2 infection, targets a critical pathogenic inflexion point for COVID-19.”
§ COVID-19 and cellular senescence > VIS and vaccination
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In the paper
“However, pre-existing SARS-CoV-2-specific cytotoxic T cells can selectively eliminate infected cells — similar to the removal of VIS cells by early senolytic intervention.”
§ COVID-19 and cellular senescence > VIS and vaccination
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In the paper
“More specifically, senescent cells are, at least in part, cleared by cells of both the innate and adaptive immune systems76,173–175 if such clearing function is not compromised, which remains to be studied in greater detail in the context of COVID-19 (ref.176).”
§ COVID-19 and cellular senescence > Conclusions and outlook
What the sources say
- Not checked yetcites [76] Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007). source
- Not checked yetcites [173] Reimann, M. et al. Adaptive T-cell immunity controls senescence-prone MyD88- or CARD11-mutant B-cell lymphomas. Blood 137, 2785–2799 (2021). source
- Not checked yetcites [174] Kang, T. W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011). source
- Not checked yetcites [175] Arora, S. et al. Invariant natural killer T cells coordinate removal of senescent cells. Med 2, 938–950 (2021). source
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- Based: passes — The paper gives a reason why it holds.
In the paper
“As recently shown in mice, the accumulation of (pre-)senescent cells during ageing primes for particularly SASP-intense VIS manifestation upon SARS-CoV-2 infection27, even if the senescent status of host cells might suppress further virus propagation as currently debated41,43.”
§ 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
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
“The underlying reasons for the well-established higher risk in the elderly or in individuals with chronic disease to experience severe COVID-19 or to succumb to SARS-CoV-2 infection are multifactorial84,93.”
§ COVID-19 and cellular senescence > Conclusions and outlook
What the sources say
- Not checked yetcites [84] Bartleson, J. M. et al. SARS-CoV-2, COVID-19 and the ageing immune system. Nat. Aging 1, 769–782 (2021). source
- Not checked yetcites [93] Wissler Gerdes, E. O. et al. Role of senescence in the chronic health consequences of COVID-19. Transl. Res. https://doi.org/10.1016/j.trsl.2021.10.003 (2021). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Encouragingly, the senolytic agent navitoclax was shown to significantly reduce extended signs of cellular senescence and SASP in SARS-CoV-2-infected mice that survived beyond 2 weeks after infection at a time when the virus was no longer detectable62.”
§ COVID-19 and cellular senescence > Conclusions and outlook
What the sources say
- 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
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.
- 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.
- 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
“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.
- 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
“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.
- 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
“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.
- 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
“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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- 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
“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.
- 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.
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.
- 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
“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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It may state two separate claims as one.
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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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.
- 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
“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.
- 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
“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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- 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
“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.
- 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
“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.
- 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
“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.
- 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
“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.
- 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
“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.
- 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
“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.
- 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
“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.
- 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.
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.
- 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.
None of the sources cited for this claim have been checked yet.
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.
- 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.
None of the sources cited for this claim have been checked yet.
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.
- 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
“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.
- 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.
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
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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.
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Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19
Ackermann, M., Verleden, S. E., Kuehnel, M., Haverich, A., Welte, T., Laenger, F., Vanstapel, A., Werlein, C., Stark, H., Tzankov, A., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2015432 · Cited by 5,613
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,218
Nalbandian, A., Sehgal, K., Gupta, A., Madhavan, M. V., McGroder, C., Stevens, J. S., Cook, J. R., Nordvig, A. S., Shalev, D., Sehrawat, T. S., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01283-z · Cited by 4,862
Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders
Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., van de Sluis, B., Kirkland, J. L., & van Deursen, J. M. (2011) · Nature · doi:10.1038/nature10600 · Cited by 3,670
Self-citationAn mRNA Vaccine against SARS-CoV-2 — Preliminary Report
Jackson, L. A., Anderson, E. J., Rouphael, N. G., Roberts, P. C., Makhene, M., Coler, R. N., McCullough, M. P., Chappell, J. D., Denison, M. R., Stevens, L. J., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2022483 · Cited by 3,237
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Self-citation
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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