The senescent bystander effect is caused by ROS-activated NF-κB signalling

Nelson, Glyn; Kucheryavenko, Olena; Wordsworth, James; Zglinicki, Thomas von

doi:10.1016/j.mad.2017.08.005

Cited by 190 publications

(150 citation statements)

References 42 publications

(78 reference statements)

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“…Senescence can also spread from senescent to naïve fibroblasts in the ageing fibrotic lung as a consequence of the "bystander effect". 28 Regardless of the reason(s) for increased IPF-LF senescence, these cells are likely to have important roles in IPF because of their resistance to apoptosis, myofibroblast-like features and development of a SASP.…”

Section: Discussionmentioning

confidence: 54%

“…Higher levels of LF senescence may also be a consequence of secondary events in IPF pathology, such as the replicative senescence that occurs during the fibroproliferative phase of the disease. Senescence can also spread from senescent to naïve fibroblasts in the ageing fibrotic lung as a consequence of the “bystander effect” . Regardless of the reason(s) for increased IPF‐LF senescence, these cells are likely to have important roles in IPF because of their resistance to apoptosis, myofibroblast‐like features and development of a SASP.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts

Schuliga

Pechkovsky

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et al. 2018

J Cellular Molecular Medi

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Increasing evidence highlights that senescence plays an important role in idiopathic pulmonary fibrosis (IPF). This study delineates the specific contribution of mitochondria and the superoxide they form to the senescent phenotype of lung fibroblasts from IPF patients (IPF‐LFs). Primary cultures of IPF‐LFs exhibited an intensified DNA damage response (DDR) and were more senescent than age‐matched fibroblasts from control donors (Ctrl‐LFs). Furthermore, IPF‐LFs exhibited mitochondrial dysfunction, exemplified by increases in mitochondrial superoxide, DNA, stress and activation of mTORC1. The DNA damaging agent etoposide elicited a DDR and augmented senescence in Ctrl‐LFs, which were accompanied by disturbances in mitochondrial homoeostasis including heightened superoxide production. However, etoposide had no effect on IPF‐LFs. Mitochondrial perturbation by rotenone involving sharp increases in superoxide production also evoked a DDR and senescence in Ctrl‐LFs, but not IPF‐LFs. Inhibition of mTORC1, antioxidant treatment and a mitochondrial targeting antioxidant decelerated IPF‐LF senescence and/or attenuated pharmacologically induced Ctrl‐LF senescence. In conclusion, increased superoxide production by dysfunctional mitochondria reinforces lung fibroblast senescence via prolongation of the DDR. As part of an auto‐amplifying loop, mTORC1 is activated, altering mitochondrial homoeostasis and increasing superoxide production. Deeper understanding the mechanisms by which mitochondria contribute to fibroblast senescence in IPF has potentially important therapeutic implications.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts

Schuliga

Pechkovsky

Read

et al. 2018

J Cellular Molecular Medi

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“…Indeed, the cell cycle arrest and the release of proinflammatory cytokines and chemokines that characterize cellular senescence are strikingly similar to the features observed by many cells during an antiviral response. Senescence can also be induced by prolonged signaling of cytokines, such as β-interferon, in response to viral infection [51] and the SASP can induce senescence in neighboring cells [52] which have a high probability of being infected. Moreover, many viruses encode inhibitors of programmed cell death to subvert the host responses during infection [53], suggesting that chronic viral infection may contribute to the resistance to apoptosis hypothesized for some senescent cells that accumulate with aging [30].…”

Section: Cellular Senescence and Response To Virusesmentioning

confidence: 99%

Exploring the Relevance of Senotherapeutics for the Current SARS-CoV-2 Emergency and Similar Future Global Health Threats

Malavolta

Giacconi

Brunetti

et al. 2020

Cells

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The higher death rate caused by COVID-19 in older people, especially those with comorbidities, is a challenge for biomedical aging research. Here we explore the idea that an exacerbated inflammatory response, in particular that mediated by IL-6, may drive the deleterious consequences of the infection. Data shows that other RNA viruses, such as influenza virus, can display enhanced replication efficiency in senescent cells, suggesting that the accumulation of senescent cells with aging and age-related diseases may play a role in this phenomenon. However, at present, we are completely unaware of the response to SARS-CoV and SARS-COV-2 occurring in senescent cells. We deem that this is a priority area of research because it could lead to the development of several therapeutic strategies based on senotherapeutics or prevent unsuccessful attempts. Two of these senotherapeutics, azithromycin and ruxolitinib, are currently undergoing testing for their efficacy in treating COVID-19. The potential of these strategies is not only for ameliorating the consequences of the current emergence of SARS-CoV-2, but also for the future emergence of new viruses or mutated ones for which we are completely unprepared and for which no vaccines are available.

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“…174,175 In fact, cancer cells may actively reprogram autophagy in stromal cells to promote cancer progression. 174,175 In fact, cancer cells may actively reprogram autophagy in stromal cells to promote cancer progression.…”

Section: Expression Of Cell Stress Regulators Affects Cancer Prognosismentioning

confidence: 99%

“…Disruption of tissue capacity to regulate autophagy can generate a suitable niche for senescent stromal cells that can either enhance tumor growth or provide a niche for metastatic cancer cells. 174,175 In fact, cancer cells may actively reprogram autophagy in stromal cells to promote cancer progression. 176,177 On the other hand, cancer cells treated with antimitotic drugs may escape mitotic arrest by entering interphase without proper chromosome segregation.…”

Section: Cell Stress Regulators Are Partially Redundant: Impact On Camentioning

confidence: 99%

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

2019

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Chloroquines are 4-aminoquinoline-based drugs mainly used to treat malaria. At pharmacological concentrations, they have significant effects on tissue homeostasis, targeting diverse signaling pathways in mammalian cells. A key target pathway is autophagy, which regulates macromolecule turnover in the cell. In addition to affecting cellular metabolism and bioenergetic flow equilibrium, autophagy plays a pivotal role at the interface between inflammation and cancer progression. Chloroquines consequently have critical effects in tissue metabolic activity and importantly, in key functions of the immune system. In this article, we will review the work addressing the role of chloroquines in the homeostasis of mammalian tissue, and the potential strengths and weaknesses concerning their use in cancer therapy.

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The senescent bystander effect is caused by ROS-activated NF-κB signalling

Abstract: Graphical abstract

Cited by 190 publications

References 42 publications

Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts

Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts

Exploring the Relevance of Senotherapeutics for the Current SARS-CoV-2 Emergency and Similar Future Global Health Threats

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

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