COVID-19 and cellular senescence

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.”

What the sources say

• Supported

  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)

  cites [27] Camell, C. D. et al. Senolytics reduce coronavirus-related mortality in old mice. Science https://doi.org/10.1126/science.abe4832 (2021). source
• Partly supported

  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)

  cites [28] Lee, S. et al. Virus-induced senescence is driver and therapeutic target in COVID-19. Nature https://doi.org/10.1038/s41586-021-03995-1 (2021). sourceExperimental — accuracy not yet measured

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.”

In the paper

“VIS appears to be a universal stress response in host cells and can be induced by many different virus species.”

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

In the paper

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

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.”

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).”

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

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”

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

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”

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

In the paper

“giving rise to the hypothesis that more extensive senescence underlies more profound COVID-19 pathobiology.”

In the paper

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

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.”

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

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.”

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.”

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).”

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

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.”

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

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.”

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

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.”

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

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).”

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

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.”

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

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.”

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

In the paper

“These prostaglandins are known to promote senescence and the SASP135–137.”

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

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).”

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

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.”

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.”

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.”

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

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).”

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

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.”

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

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.”

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

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.”

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

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.”

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

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.”

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.”

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

In the paper

“Flavonoids, such as fisetin or quercetin, are freely available ‘over-the-counter’ agents and have favourable safety profiles168.”

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

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.”

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

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.”

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

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.”

In the paper

“For example, type 1 diabetes mellitus was linked to enterovirus infections185 and multiple sclerosis to Epstein–Barr virus (EBV) infections186.”

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