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Cells
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The Molecular Mechanism of Cellular Senescence
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The Molecular Mechanism of Cellular Senescence

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Aging".

Deadline for manuscript submissions: closed (15 February 2023) | Viewed by 13500

Special Issue Editors

Dr. Isabella Saggio

E-Mail Website
Guest Editor
Department of Biology and Biotechnology, “Charles Darwin” Sapienza University of Rome, 00185 Rome, Italy
Interests: progeria; aging; telomeres; DNA damage; cancer; nuclear envelope integrity; ESCRT machinery; genome stability; virology
Dr. Romina Burla

E-Mail Website
Guest Editor
1. CNR Institute of Molecular Biology and Pathology, 00185 Rome, Italy
2. Department of Biology and Biotechnology, “Charles Darwin” Sapienza University of Rome, 00185 Rome, Italy
Interests: progeria; aging; telomeres; DNA damage; cancer; nuclear envelope integrity; ESCRT machinery; genome stability

Special Issue Information

Dear Colleagues,

Cellular senescence is a complex cellular program mainly characterized by the induction of proliferation arrest. It is triggered by several stresses, both endogenous and exogenous, including telomere dysfunction, oncogene activation and persistent DNA damage. Senescent cells are characterized by an altered metabolic activity and modified gene expression and also acquired a secretory phenotype (SASP) having a paracrine effect on surrounding tissues. Cellular senescence compromises tissue repair and regeneration, contributing to aging and aging-related diseases. On the other hand, cellular senescence is an anti-tumor mechanism, countering the proliferation of cancer cells and tumor progression. These properties have encouraged the rapid development of senotherapies for the elimination of senescent cells or of their effects.

The aim of this Special Issue is to collect and discuss updated findings related to this fast-evolving area of study. Relevant topics include, but are not limited to: molecular biomarkers of cellular senescence suitable for its in vivo and in vitro studies; the identification of senescence-associated molecular signatures; molecular triggers of cellular senescence; molecular and cellular changes induced by senescence; the molecular and organismal effect of SASP; the role of cellular senescence in aging and aging-related diseases, in inflammation and fibrosis, in development and in cancer progression; novel therapeutic approaches based on the induction of senescence; and advances and limitations of senotherapies.

Prof. Dr. Isabella Saggio
Dr. Romina Burla
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cellular senescence
  • aging
  • aging-related diseases
  • cancer
  • inflammaging
  • DNA damage
  • telomere damage
  • mitophagy
  • senescence-associated secretory phenotype (SASP)
  • stem cell exhaustion
  • senolytic drugs
  • senomorphic
  • geroprotectors

Published Papers (5 papers)

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Research

24 pages, 5206 KiB  
Article
Heterogeneity of Cellular Senescence: Cell Type-Specific and Senescence Stimulus-Dependent Epigenetic Alterations
by Katarzyna Malgorzata Kwiatkowska, Eleni Mavrogonatou, Adamantia Papadopoulou, Claudia Sala, Luciano Calzari, Davide Gentilini, Maria Giulia Bacalini, Daniele Dall’Olio, Gastone Castellani, Francesco Ravaioli, Claudio Franceschi, Paolo Garagnani, Chiara Pirazzini and Dimitris Kletsas
Cells 2023, 12(6), 927; https://doi.org/10.3390/cells12060927 - 17 Mar 2023
Cited by 5 | Viewed by 2515
Abstract
The aim of the present study was to provide a comprehensive characterization of whole genome DNA methylation patterns in replicative and ionizing irradiation- or doxorubicin-induced premature senescence, exhaustively exploring epigenetic modifications in three different human cell types: in somatic diploid skin fibroblasts and [...] Read more.
The aim of the present study was to provide a comprehensive characterization of whole genome DNA methylation patterns in replicative and ionizing irradiation- or doxorubicin-induced premature senescence, exhaustively exploring epigenetic modifications in three different human cell types: in somatic diploid skin fibroblasts and in bone marrow- and adipose-derived mesenchymal stem cells. With CpG-wise differential analysis, three epigenetic signatures were identified: (a) cell type- and treatment-specific signature; (b) cell type-specific senescence-related signature; and (c) cell type-transversal replicative senescence-related signature. Cluster analysis revealed that only replicative senescent cells created a distinct group reflecting notable alterations in the DNA methylation patterns accompanying this cellular state. Replicative senescence-associated epigenetic changes seemed to be of such an extent that they surpassed interpersonal dissimilarities. Enrichment in pathways linked to the nervous system and involved in the neurological functions was shown after pathway analysis of genes involved in the cell type-transversal replicative senescence-related signature. Although DNA methylation clock analysis provided no statistically significant evidence on epigenetic age acceleration related to senescence, a persistent trend of increased biological age in replicative senescent cultures of all three cell types was observed. Overall, this work indicates the heterogeneity of senescent cells depending on the tissue of origin and the type of senescence inducer that could be putatively translated to a distinct impact on tissue homeostasis. Full article
(This article belongs to the Special Issue The Molecular Mechanism of Cellular Senescence)
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19 pages, 9195 KiB  
Article
Role of Histone Variant H2A.J in Fine-Tuning Chromatin Organization for the Establishment of Ionizing Radiation-Induced Senescence
by Mutaz A. Abd Al-razaq, Benjamin M. Freyter, Anna Isermann, Gargi Tewary, Adèle Mangelinck, Carl Mann and Claudia E. Rübe
Cells 2023, 12(6), 916; https://doi.org/10.3390/cells12060916 - 16 Mar 2023
Cited by 2 | Viewed by 1832
Abstract
Purpose: Radiation-induced senescence is characterized by profound changes in chromatin organization with the formation of Senescence-Associated-Heterochromatin-Foci (SAHF) and DNA-Segments-with-Chromatin-Alterations-Reinforcing-Senescence (DNA-SCARS). Importantly, senescent cells also secrete complex combinations of pro-inflammatory factors, referred as Senescence-Associated-Secretory-Phenotype (SASP). Here, we analyzed the epigenetic mechanism of histone variant [...] Read more.
Purpose: Radiation-induced senescence is characterized by profound changes in chromatin organization with the formation of Senescence-Associated-Heterochromatin-Foci (SAHF) and DNA-Segments-with-Chromatin-Alterations-Reinforcing-Senescence (DNA-SCARS). Importantly, senescent cells also secrete complex combinations of pro-inflammatory factors, referred as Senescence-Associated-Secretory-Phenotype (SASP). Here, we analyzed the epigenetic mechanism of histone variant H2A.J in establishing radiation-induced senescence. Experimental Design: Primary and genetically-modified lung fibroblasts with down- or up-regulated H2A.J expression were exposed to ionizing radiation and were analyzed for the formation of SAHF and DNA-SCARS by immunofluorescence microscopy. Dynamic changes in chromatin organization and accessibility, transcription factor recruitment, and transcriptome signatures were mapped by ATAC-seq and RNA-seq analysis. The secretion of SASP factors and potential bystander effects were analyzed by ELISA and RT-PCR. Lung tissue of mice exposed to different doses were analyzed by the digital image analysis of H2A.J-immunohistochemistry. Results: Differential incorporation of H2A.J has profound effects on higher-order chromatin organization and on establishing the epigenetic state of senescence. Integrative analyses of ATAC-seq and RNA-seq datasets indicate that H2A.J-associated changes in chromatin accessibility of regulatory regions decisively modulates transcription factor recruitment and inflammatory gene expression, resulting in an altered SASP secretome. In lung parenchyma, pneumocytes show dose-dependent H2A.J expression in response to radiation-induced DNA damage, therefore contributing to pro-inflammatory tissue reactions. Conclusions: The fine-tuned incorporation of H2A.J defines the epigenetic landscape for driving the senescence programme in response to radiation-induced DNA damage. Deregulated H2A.J deposition affects chromatin remodeling, transcription factor recruitment, and the pro-inflammatory secretome. Our findings provide new mechanistic insights into DNA-damage triggered epigenetic mechanisms governing the biological processes of radiation-induced injury. Full article
(This article belongs to the Special Issue The Molecular Mechanism of Cellular Senescence)
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19 pages, 2483 KiB  
Article
Merkel Cell Polyomavirus Large T Antigen Induces Cellular Senescence for Host Growth Arrest and Viral Genome Persistence through Its Unique Domain
by Alexander M. Pham, Luz E. Ortiz, Aron E. Lukacher and Hyun Jin Kwun
Cells 2023, 12(3), 380; https://doi.org/10.3390/cells12030380 - 20 Jan 2023
Viewed by 2173
Abstract
Senescent cells accumulate in the host during the aging process and are associated with age-related pathogeneses, including cancer. Although persistent senescence seems to contribute to many aspects of cellular pathways and homeostasis, the role of senescence in virus-induced human cancer is not well [...] Read more.
Senescent cells accumulate in the host during the aging process and are associated with age-related pathogeneses, including cancer. Although persistent senescence seems to contribute to many aspects of cellular pathways and homeostasis, the role of senescence in virus-induced human cancer is not well understood. Merkel cell carcinoma (MCC) is an aggressive skin cancer induced by a life-long human infection of Merkel cell polyomavirus (MCPyV). Here, we show that MCPyV large T (LT) antigen expression in human skin fibroblasts causes a novel nucleolar stress response, followed by p21-dependent senescence and senescence-associated secretory phenotypes (SASPs), which are required for MCPyV genome maintenance. Senolytic and navitoclax treatments result in decreased senescence and MCPyV genome levels, suggesting a potential therapeutic for MCC prevention. Our results uncover the mechanism of a host stress response regulating human polyomavirus genome maintenance in viral persistency, which may lead to targeted intervention for MCC. Full article
(This article belongs to the Special Issue The Molecular Mechanism of Cellular Senescence)
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20 pages, 4936 KiB  
Article
Therapy-Induced Stromal Senescence Promoting Aggressiveness of Prostate and Ovarian Cancer
by Elisa Pardella, Erica Pranzini, Ilaria Nesi, Matteo Parri, Pietro Spatafora, Eugenio Torre, Angela Muccilli, Francesca Castiglione, Massimiliano Fambrini, Flavia Sorbi, Paolo Cirri, Anna Caselli, Martin Puhr, Helmut Klocker, Sergio Serni, Giovanni Raugei, Francesca Magherini and Maria Letizia Taddei
Cells 2022, 11(24), 4026; https://doi.org/10.3390/cells11244026 - 13 Dec 2022
Cited by 10 | Viewed by 2604
Abstract
Cancer progression is supported by the cross-talk between tumor cells and the surrounding stroma. In this context, senescent cells in the tumor microenvironment contribute to the development of a pro-inflammatory milieu and the acquisition of aggressive traits by cancer cells. Anticancer treatments induce [...] Read more.
Cancer progression is supported by the cross-talk between tumor cells and the surrounding stroma. In this context, senescent cells in the tumor microenvironment contribute to the development of a pro-inflammatory milieu and the acquisition of aggressive traits by cancer cells. Anticancer treatments induce cellular senescence (therapy-induced senescence, TIS) in both tumor and non-cancerous cells, contributing to many detrimental side effects of therapies. Thus, we focused on the effects of chemotherapy on the stromal compartment of prostate and ovarian cancer. We demonstrated that anticancer chemotherapeutics, regardless of their specific mechanism of action, promote a senescent phenotype in stromal fibroblasts, resulting in metabolic alterations and secretion of paracrine factors, sustaining the invasive and clonogenic potential of both prostate and ovarian cancer cells. The clearance of senescent stromal cells, through senolytic drug treatment, reverts the malignant phenotype of tumor cells. The clinical relevance of TIS was validated in ovarian and prostate cancer patients, highlighting increased accumulation of lipofuscin aggregates, a marker of the senescent phenotype, in the stromal compartment of tissues from chemotherapy-treated patients. These data provide new insights into the potential efficacy of combining traditional anticancer strategies with innovative senotherapy to potentiate anticancer treatments and overcome the adverse effects of chemotherapy. Full article
(This article belongs to the Special Issue The Molecular Mechanism of Cellular Senescence)
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18 pages, 40423 KiB  
Article
Oxidative Glucose Metabolism Promotes Senescence in Vascular Endothelial Cells
by Leonie K. Stabenow, Darya Zibrova, Claudia Ender, Dario L. Helbing, Katrin Spengler, Christian Marx, Zhao-Qi Wang and Regine Heller
Cells 2022, 11(14), 2213; https://doi.org/10.3390/cells11142213 - 16 Jul 2022
Cited by 10 | Viewed by 3745
Abstract
Vascular aging is based on the development of endothelial dysfunction, which is thought to be promoted by senescent cells accumulating in aged tissues and is possibly affected by their environment via inflammatory mediators and oxidative stress. Senescence appears to be closely interlinked with [...] Read more.
Vascular aging is based on the development of endothelial dysfunction, which is thought to be promoted by senescent cells accumulating in aged tissues and is possibly affected by their environment via inflammatory mediators and oxidative stress. Senescence appears to be closely interlinked with changes in cell metabolism. Here, we describe an upregulation of both glycolytic and oxidative glucose metabolism in replicative senescent endothelial cells compared to young endothelial cells by employing metabolic profiling and glucose flux measurements and by analyzing the expression of key metabolic enzymes. Senescent cells exhibit higher glycolytic activity and lactate production together with an enhanced expression of lactate dehydrogenase A as well as increases in tricarboxylic acid cycle activity and mitochondrial respiration. The latter is likely due to the reduced expression of pyruvate dehydrogenase kinases (PDHKs) in senescent cells, which may lead to increased activity of the pyruvate dehydrogenase complex. Cellular and mitochondrial ATP production were elevated despite signs of mitochondrial dysfunction, such as an increased production of reactive oxygen species and extended mitochondrial mass. A shift from glycolytic to oxidative glucose metabolism induced by pharmacological inhibition of PDHKs in young endothelial cells resulted in premature senescence, suggesting that alterations in cellular glucose metabolism may act as a driving force for senescence in endothelial cells. Full article
(This article belongs to the Special Issue The Molecular Mechanism of Cellular Senescence)
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