The struggle of a good friend getting old: cellular senescence in viral responses and therapy
Open accessAbstract
Cellular senescence is a state of stable cell cycle arrest associated with macromolecular alterations and secretion of pro-inflammatory cytokines and molecules. Senescence-associated phenotypes restrict damage propagation and activate immune responses, two essential processes involved in response to viral infections. However, excessive accumulation and persistence of senescent cells can become detrimental and promote pathology and dysfunctions. Various pharmacological interventions, including antiviral therapies, lead to aberrant and premature senescence. Here, we review the molecular mechanisms by which viral infections and antiviral therapy induce senescence. We highlight the importance of these processes in attenuating viral dissemination and damage propagation, but also how prematurely induced senescent cells can promote detrimental adverse effects in humans. We describe which sequelae due to viral infections and treatment can be partly due to excessive and aberrant senescence. Finally, we propose that pharmacological strategies which eliminate senescent cells or suppress their secretory phenotype could mitigate side effects and alleviate the onset of additional morbidities. These strategies can become extremely beneficial in patients recovering from viral infections or undergoing antiviral therapy.
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Written from the paper’s full text.
TL;DR
This review argues that cellular senescence acts as an antiviral defense mechanism—restricting viral replication and promoting immune clearance—but can also drive pathology when senescent cells accumulate prematurely after viral infection or antiviral therapy. It proposes that senolytics or SASP modulators could mitigate adverse effects in patients recovering from viral infections or on antiviral therapy.
Key findings
- Cellular senescence is a stable cell cycle arrest with a pro-inflammatory SASP; the cGAS–STING pathway, IFN-β, NF-κB, and TLR2/A-SAAs regulate both growth arrest and inflammation, and viral infections induce senescence markers (SA-β-gal, p16, p21, IL-6, IL-8) in multiple cell types, with the ROS inhibitor N-acetyl-L-cysteine preventing senescence induction.
- Senescent cells can restrict viral virulence: lower VSV titres were obtained in bleomycin-induced senescent MEFs versus non-senescent MEFs, and similar results were seen in A549 and HRASV12-expressing MCF7 cells and with dengue virus in replicative senescent HUVECs; in vivo, intranasal VSV yielded no lung titres in bleomycin-treated mice, with NK and dendritic cell infiltrates present.
- Oncoviruses evade senescence: HPV E6/E7 target p53 and pRB; HBV HBx reduces p16, p53, and p21 or methylates the p16 promoter; KSHV LANA, v-cyclin, and v-FLIP inhibit senescence; EBV LMP1 reduces p16 promoter activity and promotes nuclear export of Ets2.
- Antiviral therapy induces senescence (AVTIS): NRTIs, NNRTIs, and protease inhibitors induce senescence markers in vitro and some in vivo; protease inhibitors act partly via prelamin A accumulation through ZMPSTE24 inhibition; HIV patients show immunosenescence and age-associated diseases, and in COVID-19 approximately 70% of deaths are reported from ARDS while around 30% of ICU patients display thrombotic complications; senolytics and SASP modulators are proposed as potential therapies.
Methods
- Design: narrative review; no primary experiments or systematic review methodology are described.
- Data/sample: synthesis of published in vitro, in vivo, and clinical/cohort evidence on viral infections, antiviral therapies, cellular senescence, immunosenescence, and age-associated diseases.
- Main analysis: qualitative integration of molecular mechanisms and proposed therapeutic strategies, including senolytics and SASP modulators.
Limitations
- Stated in the paper: only a relatively small number of virus-induced senescence studies are available; the mechanism of ROS production in VIS cells remains poorly understood; most AVTIS investigations used single agents rather than HAART combinations, possibly underestimating effects; NNRTI studies used only immortalized cancer or stem cell lines; EBV findings in fibroblasts need recapitulation in B cells; no evidence yet exists on whether antiretroviral compounds induce senescence in adipocytes in vitro; and it is difficult to delineate HIV virus versus antiretroviral drug contributions to immunosenescence.
- Evident from the text: as a narrative review, it lacks a systematic search, risk-of-bias assessment, or quantitative synthesis; many conclusions rely on cell culture and animal models or correlative clinical associations, and one cited COVID-19 senescence finding is a preprint.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 103 cited sources checked · 0 supported · 0 flagged
- Premisecitation
HIV proteins Tat and Nef and protease inhibitors lopinavir and atazanavir are capable of inducing senescence in BM-MSCs.
“These conflicts are possibly reconciled by reports that find both HIV proteins Tat and Nef and protease inhibitors lopinavir and atazanavir are capable of inducing senescence in BM‐MSCs.”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
There is divergence as to whether reduced BMD in HIV patients is due to HIV retrovirus or protease inhibitor therapy.
“HIV patients are consistently reported to display reduced BMD and increased risk of developing osteoporosis, although there is some divergence as to whether this phenomenon occurs due to the HIV retrovirus or protease inhibitor therapy (Tebas et al, 2000; Bruera et al, 2003; Amiel et al, 2004; Brown & Qaqish, 2006).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
AVTIS induction by protease inhibitors is dependent upon immature processing of lamin A.
“Therefore, AVTIS induction by protease inhibitors is dependent upon immature processing of lamin A.”
Quote in the paperSubstantial claim - Premisecitation
Senescent cells are capable of inducing paracrine senescence via the SASP.
“Since senescent cells are capable of inducing paracrine senescence via the SASP (Acosta et al, 2013), it is possible that AVTIS induction in somatic cells in vivo promote senescence‐like phenotypes in immune cells.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Acosta et al, 2013 source
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- Interpretationnone given
Excessive accumulation and persistence of senescent cells can become detrimental and promote pathology and dysfunctions.
“However, excessive accumulation and persistence of senescent cells can become detrimental and promote pathology and dysfunctions.”
Quote in the paperNot a substantial claim
- Premisecitation
T-cell telomere length declines with age.
“T‐cell telomere length declines with age (Rufer et al, 1999), suggesting they have undergone replicative senescence from repetitive divisions.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Rufer et al, 1999 source
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- Premisecitation
Some antiviral drugs are capable of inducing antiviral therapy-induced senescence (AVTIS) in mammalian cells in vitro.
“Interestingly, some of these drugs have been reported to be capable of inducing antiviral therapy‐induced senescence (AVTIS) in mammalian cells in vitro.”
Quote in the paperSubstantial claim - Premisecitation
CD4+ T cell telomere lengths are not shorter in HIV patients compared to healthy individuals.
“Telomere lengths of CD8+ T cells are shorter in HIV patients compared to healthy individuals, but this observation was not found in CD4+ T cells.”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationcitation
T cells undergo replicative senescence from repetitive divisions due to age-related telomere shortening.
“T‐cell telomere length declines with age (Rufer et al, 1999), suggesting they have undergone replicative senescence from repetitive divisions.”
Quote in the paperSubstantial claim - Interpretationreasoning
HAART may promote immunosenescence through other aspects, such as exhausting the hematopoietic stem cell pool.
“Although HAART may limit viral replication in CD4+ T lymphocytes and limit ageing of these cells, they may promote immunosenescence through other aspects, e.g. by exhausting the hematopoietic stem cell pool, as mentioned previously (section 2).”
Quote in the paperNot a substantial claim - Premisecitation
CD8+ T cell telomere lengths are shorter in HIV patients compared to healthy individuals.
“Telomere lengths of CD8+ T cells are shorter in HIV patients compared to healthy individuals, but this observation was not found in CD4+ T cells.”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Specific deletion of p16 in T cells enhances immune function in aged mice.
“p16+ T cells are likely to have a reduced immune capacity as specific deletion of p16 in these cells enhances immune function in aged mice (Liu et al, 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Liu et al, 2011 source
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- Premisecitation
HIV-infected individuals, even children and young adults, display an immunosenescent phenotype.
“HIV‐infected individuals, even in children and young adults, display an immunosenescent phenotype (Chiappini et al, 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chiappini et al, 2018 source
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- Premisecitation
Natural accumulation of senescent cells in mammals during ageing contributes to development of various age-associated diseases.
“The natural accumulation of senescent cells in mammals during ageing contributes to the development of various age‐associated diseases (Baker et al, 2016; Calcinotto et al, 2019; Borghesan et al, 2020).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
In aged mice, SASP promotes decreased BMD by inhibiting osteoblast-mediated bone mineralisation and stimulating osteoclast differentiation.
“In aged mice, the SASP promotes decreased BMD from inhibition of osteoblasts‐mediated bone mineralisation and stimulation of osteoclast differentiation from progenitor cells (Farr et al, 2017).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Farr et al, 2017 source
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- Interpretationcitation
Mounting evidence suggests activation of senescence responses upon viral infections.
“Although a small relatively number of studies are available, mounting evidence suggests the activation of senescence responses upon viral infections.”
Quote in the paperSubstantial claim - Premisecitation
The shorter telomere lengths in CD8+ T cells in HIV patients are independent of antiretroviral therapy status.
“These finds were also independent on whether HIV patients were on antiretroviral therapy (Effros et al, 1996; Wolthers et al, 1996; Palmer et al, 1997).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
p16 levels are increased in CD4+ T cells, but not CD8+ T cells, in HIV patients untreated with HAART compared to uninfected individuals.
“However, p16 levels are increased in CD4+, but not CD8+, T cells in HIV patients untreated with HAART, compared to uninfected individuals (Nelson et al, 2012; Pereira Ribeiro et al, 2016).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
One mechanism by which viruses may induce premature onset of age-related diseases is by compromising immune-mediated clearance of senescent cells.
“Therefore, one mechanism by which viruses may induce the premature onset of various age‐related diseases is by compromising the immune‐mediated clearance of senescent cells.”
Quote in the paperSubstantial claim - Interpretationcitation
Senescent cells inhibit virulence.
“Interestingly, senescent cells have themselves been shown to inhibit virulence.”
Quote in the paperSubstantial claim - Premisecitation
HAART-treated HIV patients have p16 levels comparable to uninfected controls in T cells.
“HAART‐treated HIV patients displayed p16 levels comparable to uninfected controls in T cells (Nelson et al, 2012; Pereira Ribeiro et al, 2016).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
CD4+/CD8+ ratios remain low in HIV patients receiving HAART.
“However, CD4+/CD8+ ratios are still low in patients receiving HAART (Serrano‐Villar et al, 2014).”
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- Premisecitation
HIV is only capable of infecting CD4+ T cells.
“As HIV is only capable of infecting CD4+ T cells (Wilen et al, 2012), it is possible that the virus directly induces VIS in these cells.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wilen et al, 2012 source
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- Interpretationcitation
p16+ T cells likely have reduced immune capacity.
“p16+ T cells are likely to have a reduced immune capacity as specific deletion of p16 in these cells enhances immune function in aged mice (Liu et al, 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Liu et al, 2011 source
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- Interpretationnone given
Various pharmacological interventions, including antiviral therapies, lead to aberrant and premature senescence.
“Various pharmacological interventions, including antiviral therapies, lead to aberrant and premature senescence.”
Quote in the paperNot a substantial claim - Premisecitation
Certain hallmarks of cellular senescence are found in T cells from HIV patients.
“Interestingly, certain hallmarks of cellular senescence are also found in T cells from patients with HIV (Effros et al, 1996; Wolthers et al, 1996; Palmer et al, 1997; Nelson et al, 2012; Pereira Ribeiro et al, 2016).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
In osteoporotic patients, bone balance shifts towards bone resorption.
“However, this balance shifts towards bone resorption in osteoporotic patients (Tu et al, 2018).”
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- Premisecitation
p16 levels positively associate with age in T cells.
“p16 levels also positively associate with age in this cell type (Liu et al, 2009).”
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- Interpretationcitation
HIV may independently contribute to cardiovascular risk via gp120/Tat-induced senescence in aortic endothelial cells.
“The HIV virus may also independently contribute to cardiovascular risk as HIV proteins gp120 and Tat can induce senescence in aortic endothelial cells (Hijmans et al, 2018).”
Quote in the paperSubstantial claim - Interpretationcitation
HIV-induced senescence in astrocytes/microglia is likely mediated by Tat-dependent downregulation of SIRT3.
“This process is likely to be mediated by a Tat‐dependent downregulation of SIRT3, as the enzyme is found to be downregulated in the prefrontal cortex of HIV patients, along with an upregulation of p16 and p21 (Thangaraj et al, 2021).”
Quote in the paperSubstantial claim - Interpretationreasoning
Protease inhibitor administration in HIV patients may induce atherosclerosis through induction of vascular endothelial cell senescence, leading to dysregulated endothelial health and foam cell formation.
“Therefore, it is possible that protease inhibitor administration in HIV patients induces atherosclerosis through induction of vascular endothelial cell senescence, which leads to dysregulated endothelial health and foam cell formation.”
Quote in the paperSubstantial claim - Premisecitation
Protease inhibitors and NRTIs can induce p16 and p21 expression in human adipose tissue.
“To our knowledge, no evidence yet exists on whether antiretroviral compounds can induce senescence in adipocytes in vitro, but it has been demonstrated that protease inhibitors and NRTIs can induce p16 and p21 expression in human adipose tissue (Caron et al, 2007, 2008).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationcitation
Pathological links exist between Alzheimer's disease and HAD.
“Moreover, brains from post‐mortem HIV patients display increased levels of deposited amyloid beta (Aβ) and hyperphosphorylated tau compared to age‐matched controls, suggesting pathological links exist between Alzheimer’s disease and HAD (Green et al, 2005; Anthony et al, 2006; Achim et al, 2009).”
Quote in the paperNot a substantial claim - Premisecitation
Senescent cells in adipose tissue contribute to metabolic dysfunction by inducing impairments in glucose homeostasis and insulin sensitivity.
“Senescent cells in adipose tissue contribute to metabolic dysfunction as they induce impairments in glucose homeostasis and insulin sensitivity (Palmer et al, 2019), although precise mechanisms are currently unknown.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Palmer et al, 2019 source
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- Premisecitation
Some HIV patients develop severe HAND (HAD) with motor and cognitive symptoms typical of Alzheimer patients.
“Although this condition is normally mild, some patients can develop a highly severe form of HAND known as HIV‐associated dementia (HAD), associated with extreme motor and cognitive symptoms typical of Alzheimer patients (Kaul, 2009).”
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- Interpretationreasoning
AVTIS induction in adipose tissue induces metabolic dysfunction and onset of diabetes in HIV patients.
“Overall, these results suggest that AVTIS induction in adipose tissue induces metabolic dysfunction and onset of diabetes in HIV patients, but the exact role of senescence in promoting metabolic disease in this context remains to be further investigated.”
Quote in the paperSubstantial claim - Premisecitation
Matrix metalloproteinase secretion from foamy macrophages triggers plaque degradation.
“Matrix metalloproteinase secretion from these cells also trigger plaque degradation (Childs et al, 2016).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Childs et al, 2016 source
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- Premisecitation
Brains from post-mortem HIV patients display increased levels of deposited Aβ and hyperphosphorylated tau compared to age-matched controls.
“Moreover, brains from post‐mortem HIV patients display increased levels of deposited amyloid beta (Aβ) and hyperphosphorylated tau compared to age‐matched controls, suggesting pathological links exist between Alzheimer’s disease and HAD (Green et al, 2005; Anthony et al, 2006; Achim et al, 2009).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
A fraction of dysfunctional endothelial cells in atherosclerotic plaques is senescent.
“Importantly, a fraction of dysfunctional endothelial cells in atherosclerotic plaques is senescent (Minamino et al, 2002) and secretes vascular cell adhesion molecule 1 (VCAM‐1) to recruit and differentiate monocytes into foam cell macrophages (Davignon & Ganz, 2004; Childs et al, 2018).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Minamino et al, 2002 source
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- Premisecitation
Exposure to antiretroviral therapy drives the association between HIV and increased type II diabetes incidence, rather than HIV infection per se.
“Cohort studies have found that the incidence of type II diabetes is increased in individuals with HIV compared to the general population, but exposure to antiretroviral therapy is reported to drive this association, rather than HIV infection per se.”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Senescent endothelial cells in atherosclerotic plaques secrete VCAM-1 to recruit and differentiate monocytes into foam cell macrophages.
“Importantly, a fraction of dysfunctional endothelial cells in atherosclerotic plaques is senescent (Minamino et al, 2002) and secretes vascular cell adhesion molecule 1 (VCAM‐1) to recruit and differentiate monocytes into foam cell macrophages (Davignon & Ganz, 2004; Childs et al, 2018).”
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- cites Childs et al, 2018 source
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- Premisecitation
The association between HIV and increased type II diabetes incidence is independent of age and obesity.
“Results were also independent on age or whether patients were obese, suggesting traditional risk factors are not involved (Tripathi et al, 2014; Samad et al, 2017; Hernandez‐Romieu et al, 2017).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
Insulin sensitivity is decreased in healthy individuals treated with NRTI stavudine.
“Insulin sensitivity was also decreased in healthy individuals treated with the NRTI stavudine (Fleischman et al, 2007).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Fleischman et al, 2007 source
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- Interpretationreasoning
VIS and AVTIS of BM-MSCs in HIV patients compromise osteoblastic potential, leading to reduced BMD and increased risk of osteoporosis.
“Overall, these results suggest that VIS and AVTIS of BM‐MSC in HIV patients compromise their osteoblastic potential, leading to reduced BMD and increased risk of osteoporosis.”
Quote in the paperSubstantial claim - Premisecitation
Incidence of type II diabetes is increased in individuals with HIV compared to general population.
“Cohort studies have found that the incidence of type II diabetes is increased in individuals with HIV compared to the general population, but exposure to antiretroviral therapy is reported to drive this association, rather than HIV infection per se.”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationreasoning
HIV-mediated senescence of brain cells could lead to cognitive decline in HIV patients.
“Therefore, HIV‐mediated senescence of these cells could lead to cognitive decline in HIV patients.”
Quote in the paperSubstantial claim - Premisecitation
Protease inhibitors induce senescence in human arterial endothelial cells in vitro.
“Protease inhibitors are reported to induce senescence in human arterial endothelial cells in vitro.”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
HIV proteins gp120 and Tat can induce senescence in aortic endothelial cells.
“The HIV virus may also independently contribute to cardiovascular risk as HIV proteins gp120 and Tat can induce senescence in aortic endothelial cells (Hijmans et al, 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hijmans et al, 2018 source
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- Premisecitation
Astrocytes from Alzheimer patients have increased p16 protein levels compared to age-matched controls.
“Increased p16 protein levels can be observed in astrocytes from Alzheimer patients compared to age‐matched controls (Bhat et al, 2012), while tau‐containing neurofibrillary tangles in neurons of Alzheimer patients also display increased expression of p16 mRNA, along with upregulation of an inflammatory transcriptome (Musi et al, 2018).”
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- Premisecitation
ACE2 is expressed in the brain and heart.
“Since the receptor for SARS‐Cov‐2, angiotensin‐converting enzyme 2 (ACE2) is expressed in the brain and heart (Hamming et al, 2004), it is possible that viral‐mediated entry of these cells induces VIS and localised inflammation leading to tissue dysfunction.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hamming et al, 2004 source
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- Interpretationnone given
Inflammation may already be high in lungs of older individuals due to age-associated increase of senescent cells.
“However, inflammation may already be high in lungs of older individuals owing to an age‐associated increase of senescent cells.”
Quote in the paperNot a substantial claim - Premisecitation
Tocilizumab and sarilumab have been approved for use against COVID-19 after promising clinical results in severely ill patients.
“Two inhibitors of the IL‐6 receptor, tocilizumab and sarilumab, have also recently been approved for use against the disease after promising clinical results in severely ill patients (Wise, 2020).”
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- Premisecitation
HSP90 inhibitors (geldanamycin) and flavonoids (quercetin) exert senolytic properties by interfering with AKT pathway.
“HSP90 inhibitors such as geldanamycin, or natural flavonoids such as quercetin, have been demonstrated to exert senolytic properties by interfering with this pathway (Zhu et al, 2015; Fuhrmann‐Stroissnigg et al, 2017; Kirkland et al, 2017).”
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Senescence promotes clotting via secretion of certain SASP molecules.
“For example, around 30% of SARS‐Cov‐2 patients in intensive care units display thrombotic complications (Klok et al, 2020), and senescence is reported to promote clotting via the secretion of certain SASP molecules (Wiley et al, 2019).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wiley et al, 2019 source
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- Interpretationnone given
Immune-mediated clearance of infected cells could be compromised due to age-associated immunosenescence.
“Moreover, immune‐mediated clearance of infected cells could also be compromised because of age‐associated immunosenescence.”
Quote in the paperNot a substantial claim - Premisecitation
Senolytics typically target SCAPs, survival pathways used by senescent cells to maintain viability.
“Senolytics typically target senescent cell anti‐apoptotic pathways (SCAPs), survival pathways utilised by senescent cells to maintain their viability (Soto‐Gamez et al, 2019).”
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- Premisecitation
Glucocorticoids have anti-inflammatory properties by repressing IL-6 secretion via inhibition of NF-κB activity.
“Glucocorticoids are a group of steroid hormones which have anti‐inflammatory properties by repressing IL‐6 secretion via inhibition of NF‐κB activity (Laberge et al, 2012).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Laberge et al, 2012 source
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- Premisecitation
AKT pathway is another SCAP used by senescent cells to maintain survival.
“The AKT pathway is another SCAP used by senescent cells to maintain survival.”
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Dexamethasone blunts the SASP in models of senescent cancer cells.
“Dexamethasone is an approved glucocorticoid (Dexamethasone in Hospitalized Patients with Covid‐19—Preliminary Report, 2020) and has been demonstrated to blunt the SASP, albeit in models of senescent cancer cells (Ge et al, 2018; Buhl et al, 2019).”
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- cites Buhl et al, 2019 source
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- Premisecitation
SASP modulators are being trialled to reduce mortality in hospitalised COVID-19 patients due to potential in repressing cytokine storm.
“SASP modulators are actively being trialled to reduce mortality in hospitalised COVID‐19 patients, owing to their potential in repressing the detrimental cytokine storm (Nehme et al, 2020).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Nehme et al, 2020 source
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- Interpretationnone given
HIV patients treated with protease inhibitors may benefit from pravastatin or zoledronic acid because they may prevent senescence induced by prelamin A accumulation.
“Moreover, HIV patients treated with protease inhibitors may also benefit from treatment with pravastatin or zoledronic acid, as they may prevent senescence induced by accumulation of prelamin A.”
Quote in the paperSubstantial claim - Premisecitation
ABT-263 sensitises retinal pigment epithelium cells and macrophages infected with influenza, herpes simplex, or measles to undergo cell death.
“Interestingly, ABT‐263 has been shown to sensitise retinal pigment epithelium cells and macrophages infected with a variety of virus types (influenza, herpes simplex, measles) to undergo cell death (Kakkola et al, 2013).”
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- Premisecitation
Phase 2 trials reported that zoledronic acid prevents bone loss in HAART-treated HIV patients.
“Phase 2 trials have reported that zoledronic acid prevents bone loss in HAART‐treated HIV patients (Ofotokun et al, 2016).”
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- May combine two claims. 19
- Classified as probably not a substantial claim. 11
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Interpretationnone givenSenescence-associated phenotypes restrict damage propagation and activate immune responses, two essential processes involved in response to viral infections.
“Senescence‐associated phenotypes restrict damage propagation and activate immune responses, two essential processes involved in response to viral infections.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationHIV patients display reduced BMD and increased risk of osteoporosis.
“HIV patients are consistently reported to display reduced BMD and increased risk of developing osteoporosis, although there is some divergence as to whether this phenomenon occurs due to the HIV retrovirus or protease inhibitor therapy (Tebas et al, 2000; Bruera et al, 2003; Amiel et al, 2004; Brown & Qaqish, 2006).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
InterpretationreasoningHAART may limit viral replication in CD4+ T lymphocytes and limit ageing of these cells.
“Although HAART may limit viral replication in CD4+ T lymphocytes and limit ageing of these cells, they may promote immunosenescence through other aspects, e.g. by exhausting the hematopoietic stem cell pool, as mentioned previously (section 2).”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningInnate immune pathways enforce both growth arrest to inhibit viral replication and prevent further spread of pathogens, as well as expression of SASP molecules and NK cell ligands to promote immunosurveillance and clearance of infected cells.
“Overall, these results suggest innate immune pathways enforce both growth arrest to inhibit viral replication and prevent further spread of pathogens, as well as expression of SASP molecules and NK cell ligands to promote immunosurveillance and clearance of infected cells.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationMice with impaired capacity to eliminate senescent cells display increased accumulation of senescent cells, premature ageing signs, and shortened lifespans.
“Mice engineered with an impaired capacity to eliminate senescent cells display increased natural accumulation of senescent cells, premature signs of ageing and shortened lifespans compared to wild‐type animals (Ovadya et al, 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ovadya et al, 2018 source
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Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationAVTIS induction in somatic cells in vivo may promote senescence-like phenotypes in immune cells.
“Since senescent cells are capable of inducing paracrine senescence via the SASP (Acosta et al, 2013), it is possible that AVTIS induction in somatic cells in vivo promote senescence‐like phenotypes in immune cells.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningHIV may directly induce VIS in CD4+ T cells.
“As HIV is only capable of infecting CD4+ T cells (Wilen et al, 2012), it is possible that the virus directly induces VIS in these cells.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationSenescent human arterial endothelial cells induced by protease inhibitors display reduced e-NOS expression and increased VCAM-1 secretion.
“Importantly, these senescent cells displayed reduced expression of endothelial nitric oxide synthase (e‐NOS), an enzyme responsible for NO synthesis, and increased secretion of VCAM‐1 (Lefèvre et al, 2010; Auclair et al, 2014; Afonso et al, 2017).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationSenescent BM-MSCs do not effectively differentiate into osteoblasts and deposit reduced calcium in vitro.
“Importantly, senescent BM‐MSCs do not be effectively differentiated into osteoblasts and deposit reduced levels of calcium in vitro (Hernandez‐Vallejo et al, 2013; Beaupere et al, 2015).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationSIRT3 is downregulated in prefrontal cortex of HIV patients, along with upregulation of p16 and p21.
“This process is likely to be mediated by a Tat‐dependent downregulation of SIRT3, as the enzyme is found to be downregulated in the prefrontal cortex of HIV patients, along with an upregulation of p16 and p21 (Thangaraj et al, 2021).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Thangaraj et al, 2021 source
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May combine two claims.
PremisecitationIn mice on high-fat diet, administration of efavirenz and emtricitabine decreased glucose tolerance and increased insulin resistance.
“When mice fed on a high‐fat diet were also administered with the NNRTI efavirenz and NRTI emtricitabine, there was a decrease in glucose tolerance and increase in insulin resistance (Pepin et al, 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Pepin et al, 2018 source
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PremisecitationSenescent astrocytes and microglia accumulate in a tau-dependent mouse model of AD and contribute to cognitive decline.
“Senescent astrocytes and microglia accumulate in a tau‐dependent mouse model of AD where they contribute to cognitive decline in these mice (Bussian et al, 2018; Zhang et al, 2019).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationTau-containing neurofibrillary tangles in neurons of Alzheimer patients display increased p16 mRNA expression and upregulation of an inflammatory transcriptome.
“Increased p16 protein levels can be observed in astrocytes from Alzheimer patients compared to age‐matched controls (Bhat et al, 2012), while tau‐containing neurofibrillary tangles in neurons of Alzheimer patients also display increased expression of p16 mRNA, along with upregulation of an inflammatory transcriptome (Musi et al, 2018).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Musi et al, 2018 source
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAtherosclerosis is an age-associated vascular disease characterised by plaque formation in arterial vessels, which can lead to cardiovascular disorders.
“Atherosclerosis is an age‐associated vascular disease characterised by the formation of plaques in arterial vessels, which can lead to the development of various cardiovascular disorders including myocardial infarction, stroke and sudden cardiac death (Tabas et al, 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Tabas et al, 2015 source
Not checked in the free run.
May combine two claims.
PremisecitationHIV patients have higher risk of cardiovascular events, even higher in those treated with protease inhibitors.
“HIV patients have been found to have a higher risk of cardiovascular events, which was even higher in patients treated with protease inhibitors (Friis‐Moller et al, 2007; Islam et al, 2012; Shah et al, 2018).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationIn mice, excessive caloric intake results in accumulation of ROS in adipose tissue and increased expression of senescence and inflammatory markers (p21, TNF, CCL2).
“In mice, excessive caloric intake results in an accumulation of reactive oxygen species in adipose tissue and increased expression of various senescence and inflammatory markers such as p21, TNF and CCL2 (Minamino et al, 2009).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Minamino et al, 2009 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningCellular senescence could play a key role in viral infections and ageing, either through antiviral defence pathways or somatic cell senescence upon viral exposure.
“However, cellular senescence could play a key role, either because of the engagement of antiviral defence pathways or because different types of somatic cells can be reengaged to enter senescence upon exposure to viral infection.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S4 (based).
Interpretationnone givenSenolytics or SASP modulators may be beneficial in alleviating onset of age-associated symptoms in patients with chronic viral infections, such as HIV patients on antiretroviral therapy.
“As well as benefiting patients suffering from acute viral infections like SARS‐Cov‐2, they may also be beneficial in alleviating onset of age‐associated symptoms in patients with chronic viral infections, such as HIV patients on antiretroviral therapy.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDexamethasone is an approved glucocorticoid.
“Dexamethasone is an approved glucocorticoid (Dexamethasone in Hospitalized Patients with Covid‐19—Preliminary Report, 2020) and has been demonstrated to blunt the SASP, albeit in models of senescent cancer cells (Ge et al, 2018; Buhl et al, 2019).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Dexamethasone in Hospitalized Patients with Covid‐19—Preliminary Report, 2020
Not checked in the free run.
Probably not a substantial claim: may not pass S4 (based).
Interpretationnone givenSimilar phenomena might happen for other viruses, including SARS-CoV-2.
“Most experimental evidence is based on the correlation between HIV VIS and the premature onset of various age‐associated pathologies, but similar phenomena might well happen for other viruses, including SARS‐Cov‐2.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationApproximately 70% of COVID-19 deaths occur from ARDS, with age being one of the most significant risk factors.
“Approximately 70% of COVID‐19 deaths are reported to occur from ARDS with age being one of the most significant risk factors (Hojyo et al, 2020; Jordan et al, 2020).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAround 30% of SARS-CoV-2 patients in intensive care units display thrombotic complications.
“For example, around 30% of SARS‐Cov‐2 patients in intensive care units display thrombotic complications (Klok et al, 2020), and senescence is reported to promote clotting via the secretion of certain SASP molecules (Wiley et al, 2019).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Klok et al, 2020 source
Not checked in the free run.
Classified as probably not a substantial claim.
InterpretationcitationViral-mediated entry of brain and heart cells may induce VIS and localised inflammation leading to tissue dysfunction.
“Since the receptor for SARS‐Cov‐2, angiotensin‐converting enzyme 2 (ACE2) is expressed in the brain and heart (Hamming et al, 2004), it is possible that viral‐mediated entry of these cells induces VIS and localised inflammation leading to tissue dysfunction.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningCellular senescence could be an important factor in how COVID-19 manifests, especially in lungs, and why older people have higher mortality.
“This could be an important factor in how COVID‐19 manifests, especially in the lungs, and why older people suffer from higher mortality (illustrated in Fig 4).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S4 (based).
Interpretationnone givenIn young individuals, SARS-CoV-2 entry into lung alveolar cells may induce senescence and SASP to limit viral infection and trigger immune-mediated clearance.
“In young individuals, SARS‐Cov‐2 entry into lung alveolar cells may induce senescence and a SASP, in order to limit viral infection and trigger immune‐mediated clearance of infected cells.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone givenSASP may induce paracrine senescence to limit viral infection in neighbouring lung cells.
“The SASP may additionally induce paracrine senescence in order to limit viral infection in neighbouring lung cells.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationABT-263 is a senolytic that inhibits BCL-2 family anti-apoptotic proteins, which are typically upregulated in senescent cells.
“ABT‐263 is one senolytic and functions to inhibit the BCL‐2 family of anti‐apoptotic proteins, which are typically upregulated in senescent cells (Zhu et al, 2016; Chang et al, 2016).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationNeurological and cardiovascular complications are common in COVID-19 patients.
“Neurological and cardiovascular complications are also common observations in COVID‐19 patients (Ellul et al, 2020; Zheng et al, 2020).”
Quote in the paperNot a substantial claim0 of 2 sources checked
The paper relies on this without support.
The biological links between viral infections and ageing are still poorly characterised.
“The biological links between viral infections and ageing are still poorly characterised (see also Box 1).”
The paper relies on this without support.
No evidence exists on whether antiretroviral compounds can induce senescence in adipocytes in vitro.
“To our knowledge, no evidence yet exists on whether antiretroviral compounds can induce senescence in adipocytes in vitro”
The paper relies on this without support.
No evidence exists on whether senolytics can sensitise viral-infected cells to die.
“To our knowledge, there is no evidence on whether these senolytics can sensitise viral‐infected cells to die”
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?
Virus-induced senescence appears to be a universal stress response in host cells and can be triggered by many virus species.
“VIS appears to be a universal stress response in host cells and can be induced by many different virus species.”
From COVID-19 and cellular senescence (2023) · cites this paper as [37]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
LMP1 mechanism names different exported transcription factors
MinorThe text attributes LMP1's effect to nuclear export of Ets2, but the title of the cited Ohtani et al. reference identifies the exported factors as E2F4/5.
“mainly by mediating the export of the Ets2 transcription from the nucleus into the cytoplasm (Ohtani et al, 2003).”
“Ohtani N, Brennan P, Gaubatz S, Sanij E, Hertzog P, Wolvetang E, Ghysdael J, Rowe M, Hara E (2003) Epstein‐Barr virus LMP1 blocks p16INK4a‐RB pathway by promoting nuclear export of E2F4/5.”
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Mechanisms and Regulation of Cellular Senescence
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Immune Senescence, Immunosenescence and Aging
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- Authors
- Kohli, J., Veenstra, I., & Demaria, M.
- Affiliations
- University Medical Center Groningen (NL)
- Corresponding author
- Demaria, Marco
- Venue
- The EMBO Reports
- Published
- 2021-03-18
- Volume
- 22
- Issue
- 4
- Pages
- e52243-e52243
- ISSN
- 1469-221X (ISSN-L)
- 1469-3178
- PMC
- PMC8024996
- OpenAlex
- W3137945281
- Semantic Scholar
- 9ba4b8debf2b935df5a885792d3bf1df6f70fc1a
- Cited by
- 52
- References
- 153
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 9 · 2023: 10 · 2022: 15 · 2021: 11
- FWCI
- 1.50
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- EMBO Reports (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- KWF Kankerbestrijding
- H2020 Marie Skłodowska-Curie Actions
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- cellular senescence, viral infection, antiviral therapy, premature senescence, senescence-associated secretory phenotype, inflammatory cytokines, cell cycle arrest, senolytics, viral dissemination
- MeSH terms
- Aging, Humans, Phenotype, Cytokines, Cellular Senescence, Friends, Cell Cycle Checkpoints
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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