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Molecular Mechanisms to Target Cellular Senescence in Aging and Disease
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Molecular Mechanisms to Target Cellular Senescence in Aging and Disease

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

Deadline for manuscript submissions: closed (30 April 2020) | Viewed by 139017

Special Issue Editors

Prof. Dr. Antonio Paolo Beltrami

E-Mail Website
Guest Editor
Department of Medicine, University of Udine, Udine, Italy
Interests: heart failure; adult stem cells; cell senescence; mechanotransduction; extracellular vesicles
Special Issues, Collections and Topics in MDPI journals
Dr. Marco Malavolta

E-Mail Website
Guest Editor
Advanced Technology Center for Aging Research, Scientific Technological Area, IRCCS INRCA, Ancona, Italy
Interests: biology of aging; biogerontology; experimenetal gerontology; geroscience; cellular senescence
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The term cellular senescence indicates a complex cellular response to a variety of stressors that results in the permanent withdrawal of potentially damaged cells from the cell cycle. Further, cellular senescence is associated with a modification of the secretome, promoting extracellular matrix remodeling, recruitment of inflammatory cells, angiogenesis, cell de-differentiation, and induction of cellular senescence in a paracrine fashion. It is conceivable that cellular senescence has been positively selected by evolution both as a barrier to avoid cancerogenesis and to promote tissue repair. However, with aging, senescent cells progressively accumulate in tissues, thus reducing the organism’s capacity to replace lost cells either with normal wear and tear processes or following damage. The immune system plays a special role in these phenomena, as changes in the immune system associated with age may contribute to reduce senescence immunesurveillance (the elimination of senescent cells mediated by the immune system), thus promoting the accumulation of senescent cells in tissues. As a result, the organism becomes more and more vulnerable to minor injuries, while chronic, age-related pathologies develop. An accumulating body of literature is supporting the causal role played by the accumulation of senescent cells in the pathophysiology of most age-related pathologies. Indeed, genetic and drug-based interventions have been tested, aiming at eradicating senescent cells from old tissues with the intent to prevent chronic pathologies and delay aging.

This Special Issue aims to collect a series of original research and review articles addressing the exciting and emerging field of cellular senescence in aging and age-related pathologies. We would like to put the emphasis on the molecular mechanism that is responsible for the phenomenon and that could be targeted both for diagnostics and therapeutic purposes. Suggested potential topics may be: stem cell senescence in age-related pathologies; mechanisms of proteostasis failure in chronic pathologies; mechanisms of immune surveillance failure in aging and disease; senolytic and rejuvenating therapies; exosomes as therapeutic or diagnostic tools; and new models to study cell senescence in aging.

Prof. Dr. Antonio Paolo Beltrami
Dr. Marco Malavolta
Guest Editors

Manuscript Submission Information

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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
  • proteostasis
  • inflammation
  • inflammaging
  • immunosenescence
  • stem cells
  • exosomes
  • extracellular vesicles
  • senolytics
  • aging

Published Papers (22 papers)

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Editorial

Jump to: Research, Review

4 pages, 520 KiB  
Editorial
Molecular Mechanisms to Target Cellular Senescence in Aging and Disease
by Serena Marcozzi, Antonio Paolo Beltrami and Marco Malavolta
Cells 2022, 11(23), 3732; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11233732 - 23 Nov 2022
Cited by 3 | Viewed by 1726
Abstract
Cellular senescence is a state of irreversible cell cycle arrest in response to several stressors, including DNA damage, increased cellular oxidative stress, telomere shortening, oncogene activation, and a deep epigenetic remodeling [...] Full article
(This article belongs to the Special Issue Molecular Mechanisms to Target Cellular Senescence in Aging and Disease)
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Research

Jump to: Editorial, Review

21 pages, 3925 KiB  
Article
IFN-γ and TNF Induce Senescence and a Distinct Senescence-Associated Secretory Phenotype in Melanoma
by Lorenzo Homann, Maximilian Rentschler, Ellen Brenner, Katharina Böhm, Martin Röcken and Thomas Wieder
Cells 2022, 11(9), 1514; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11091514 - 30 Apr 2022
Cited by 15 | Viewed by 3626
Abstract
Immune checkpoint blockade (ICB) therapy is a central pillar of melanoma treatment leading to durable response rates. Important mechanisms of action of ICB therapy include disinhibition of CD4+ and CD8+ T cells. Stimulated CD4+ T helper 1 cells secrete the [...] Read more.
Immune checkpoint blockade (ICB) therapy is a central pillar of melanoma treatment leading to durable response rates. Important mechanisms of action of ICB therapy include disinhibition of CD4+ and CD8+ T cells. Stimulated CD4+ T helper 1 cells secrete the effector cytokines interferon-gamma (IFN-γ) and tumor necrosis factor alpha (TNF), which induce senescence in tumor cells. Besides being growth-arrested, senescent cells are metabolically active and secrete a large spectrum of factors, which are summarized as senescence-associated secretory phenotype (SASP). This secretome affects the tumor growth. Here, we compared the SASP of cytokine-induced senescent (CIS) cells with the SASP of therapy-induced senescent (TIS) cells. Therefore, we established in vitro models for CIS and TIS in melanoma. The human melanoma cell lines SK-MEL-28 and WM115 were treated with the cytokines IFN-γ and TNF as CIS, the chemotherapeutic agent doxorubicin, and the cell cycle inhibitor palbociclib as TIS. Then, we determined several senescence markers, i.e., growth arrest, p21 expression, and senescence-associated β-galactosidase (SA-β-gal) activity. For SASP analyses, we measured the regulation and secretion of several common SASP factors using qPCR arrays, protein arrays, and ELISA. Each treatment initiated a stable growth arrest, enhanced SA-β-gal activity, and—except palbociclib—increased the expression of p21. mRNA and protein analyses revealed that gene expression and secretion of SASP factors were severalfold stronger in CIS than in TIS. Finally, we showed that treatment with the conditioned media (CM) derived from cytokine- and palbociclib-treated cells induced senescence characteristics in melanoma cells. Thus, we conclude that senescence induction via cytokines may lead to self-sustaining senescence surveillance of melanoma. Full article
(This article belongs to the Special Issue Molecular Mechanisms to Target Cellular Senescence in Aging and Disease)
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Graphical abstract

18 pages, 7215 KiB  
Article
Senescence Induction by Combined Ionizing Radiation and DNA Damage Response Inhibitors in Head and Neck Squamous Cell Carcinoma Cells
by Clara Dobler, Tina Jost, Markus Hecht, Rainer Fietkau and Luitpold Distel
Cells 2020, 9(9), 2012; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9092012 - 01 Sep 2020
Cited by 19 | Viewed by 3184
Abstract
DNA damage response inhibitors (DDRi) may selectively enhance the inactivation of tumor cells in combination with ionizing radiation (IR). The induction of senescence may be the key mechanism of tumor cell inactivation in this combinatorial treatment. In the current study the effect of [...] Read more.
DNA damage response inhibitors (DDRi) may selectively enhance the inactivation of tumor cells in combination with ionizing radiation (IR). The induction of senescence may be the key mechanism of tumor cell inactivation in this combinatorial treatment. In the current study the effect of combined IR with DDRi on the induction of senescence was studied in head and neck squamous cell carcinoma (HNSCC) cells with different human papilloma virus (HPV) status. The integrity of homologous recombination (HR) was assessed in two HPV positive, two HPV negative HNSCC, and two healthy fibroblast cell cultures. Cells were treated with the DDRi CC-115 (DNA-dependent protein kinase, DNA-pK; dual mammalian target of rapamycin, mTor), VE-822 (ATR; ataxia telangiectasia and Rad3-related kinase), and AZD0156 (ATM; ataxia telangiectasia mutated kinase) combined with IR. Effects on senescence, apoptosis, necrosis, and cell cycle were analyzed by flow cytometry. The fibroblast cell lines generally tolerated IR or combined treatment better than the tumor cell lines. The ATM and ATR inhibitors were effectively inducing senescence when combined with IR. The DNA-PK inhibitor was not an important inductor of senescence. HPV status and HR activity had a limited influence on the efficacy of DDRi. Induction of senescence and necrosis varied individually among the cell lines due to molecular heterogeneity and the involvement of DNA damage response pathways in senescence induction. Full article
(This article belongs to the Special Issue Molecular Mechanisms to Target Cellular Senescence in Aging and Disease)
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20 pages, 2910 KiB  
Article
DNA Damage- But Not Enzalutamide-Induced Senescence in Prostate Cancer Promotes Senolytic Bcl-xL Inhibitor Sensitivity
by Nicolas Malaquin, Arthur Vancayseele, Sophie Gilbert, Laureen Antenor-Habazac, Marc-Alexandre Olivier, Zakia Ait Ali Brahem, Fred Saad, Guila Delouya and Francis Rodier
Cells 2020, 9(7), 1593; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9071593 - 01 Jul 2020
Cited by 31 | Viewed by 5255
Abstract
Cellular senescence is a natural tumor suppression mechanism defined by a stable proliferation arrest. In the context of cancer treatment, cancer cell therapy-induced senescence (TIS) is emerging as an omnipresent cell fate decision that can be pharmacologically targeted at the molecular level to [...] Read more.
Cellular senescence is a natural tumor suppression mechanism defined by a stable proliferation arrest. In the context of cancer treatment, cancer cell therapy-induced senescence (TIS) is emerging as an omnipresent cell fate decision that can be pharmacologically targeted at the molecular level to enhance the beneficial aspects of senescence. In prostate cancer (PCa), TIS has been reported using multiple different model systems, and a more systematic analysis would be useful to identify relevant senescence manipulation molecular targets. Here we show that a spectrum of PCa senescence phenotypes can be induced by clinically relevant therapies. We found that DNA damage inducers like irradiation and poly (ADP-ribose) polymerase1 (PARP) inhibitors triggered a stable PCa-TIS independent of the p53 status. On the other hand, enzalutamide triggered a reversible senescence-like state that lacked evidence of cell death or DNA damage. Using a small senolytic drug panel, we found that senescence inducers dictated senolytic sensitivity. While Bcl-2 family anti-apoptotic inhibitor were lethal for PCa-TIS cells harboring evidence of DNA damage, they were ineffective against enzalutamide-TIS cells. Interestingly, piperlongumine, which was described as a senolytic, acted as a senomorphic to enhance enzalutamide-TIS proliferation arrest without promoting cell death. Overall, our results suggest that TIS phenotypic hallmarks need to be evaluated in a context-dependent manner because they can vary with senescence inducers, even within identical cancer cell populations. Defining this context-dependent spectrum of senescence phenotypes is key to determining subsequent molecular strategies that target senescent cancer cells. Full article
(This article belongs to the Special Issue Molecular Mechanisms to Target Cellular Senescence in Aging and Disease)
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20 pages, 6244 KiB  
Article
Blood Serum Stimulates p38-Mediated Proliferation and Changes in Global Gene Expression of Adult Human Cardiac Stem Cells
by Anna L. Höving, Kazuko E. Schmidt, Madlen Merten, Jassin Hamidi, Ann-Katrin Rott, Isabel Faust, Johannes F. W. Greiner, Jan Gummert, Barbara Kaltschmidt, Christian Kaltschmidt and Cornelius Knabbe
Cells 2020, 9(6), 1472; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9061472 - 16 Jun 2020
Cited by 13 | Viewed by 3162
Abstract
During aging, senescent cells accumulate in various tissues accompanied by decreased regenerative capacities of quiescent stem cells, resulting in deteriorated organ function and overall degeneration. In this regard, the adult human heart with a generally low regenerative potential is of extreme interest as [...] Read more.
During aging, senescent cells accumulate in various tissues accompanied by decreased regenerative capacities of quiescent stem cells, resulting in deteriorated organ function and overall degeneration. In this regard, the adult human heart with a generally low regenerative potential is of extreme interest as a target for rejuvenating strategies with blood borne factors that might be able to activate endogenous stem cell populations. Here, we investigated for the first time the effects of human blood plasma and serum on adult human cardiac stem cells (hCSCs) and showed significantly increased proliferation capacities and metabolism accompanied by a significant decrease of senescent cells, demonstrating a beneficial serum-mediated effect that seemed to be independent of age and sex. However, RNA-seq analysis of serum-treated hCSCs revealed profound effects on gene expression depending on the age and sex of the plasma donor. We further successfully identified key pathways that are affected by serum treatment with p38-MAPK playing a regulatory role in protection from senescence and in the promotion of proliferation in a serum-dependent manner. Inhibition of p38-MAPK resulted in a decline of these serum-mediated beneficial effects on hCSCs in terms of decreased proliferation and accelerated senescence. In summary, we provide new insights in the regulatory networks behind serum-mediated protective effects on adult human cardiac stem cells. Full article
(This article belongs to the Special Issue Molecular Mechanisms to Target Cellular Senescence in Aging and Disease)
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15 pages, 4133 KiB  
Article
Application of Oxidative Stress to a Tissue-Engineered Vascular Aging Model Induces Endothelial Cell Senescence and Activation
by Ellen E. Salmon, Jason J. Breithaupt and George A. Truskey
Cells 2020, 9(5), 1292; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9051292 - 22 May 2020
Cited by 13 | Viewed by 3663
Abstract
Clinical studies have established a connection between oxidative stress, aging, and atherogenesis. These factors contribute to senescence and inflammation in the endothelium and significant reductions in endothelium-dependent vasoreactivity in aged patients. Tissue-engineered blood vessels (TEBVs) recapitulate the structure and function of arteries and [...] Read more.
Clinical studies have established a connection between oxidative stress, aging, and atherogenesis. These factors contribute to senescence and inflammation in the endothelium and significant reductions in endothelium-dependent vasoreactivity in aged patients. Tissue-engineered blood vessels (TEBVs) recapitulate the structure and function of arteries and arterioles in vitro. We developed a TEBV model for vascular senescence and examined the relative influence of endothelial cell and smooth muscle cell senescence on vasoreactivity. Senescence was induced in 2D endothelial cell cultures and TEBVs by exposure to 100 µM H2O2 for one week to model chronic oxidative stress. H2O2 treatment significantly increased senescence in endothelial cells and mural cells, human neonatal dermal fibroblasts (hNDFs), as measured by increased p21 levels and reduced NOS3 expression. Although H2O2 treatment induced senescence in both the endothelial cells (ECs) and hNDFs, the functional effects on the vasculature were endothelium specific. Expression of the leukocyte adhesion molecule vascular cell adhesion molecule 1 (VCAM-1) was increased in the ECs, and endothelium-dependent vasodilation decreased. Vasoconstriction and endothelium-independent vasodilation were preserved despite mural cell senescence. The results suggest that the functional effects of vascular cell senescence are dominated by the endothelium. Full article
(This article belongs to the Special Issue Molecular Mechanisms to Target Cellular Senescence in Aging and Disease)
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18 pages, 2042 KiB  
Article
SIV Infection and the HIV Proteins Tat and Nef Induce Senescence in Adipose Tissue and Human Adipose Stem Cells, Resulting in Adipocyte Dysfunction
by Jennifer Gorwood, Tina Ejlalmanesh, Christine Bourgeois, Matthieu Mantecon, Cindy Rose, Michael Atlan, Delphine Desjardins, Roger Le Grand, Bruno Fève, Olivier Lambotte, Jacqueline Capeau, Véronique Béréziat and Claire Lagathu
Cells 2020, 9(4), 854; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9040854 - 01 Apr 2020
Cited by 19 | Viewed by 3679
Abstract
Background: Aging is characterized by adipose tissue senescence, inflammation, and fibrosis, with trunk fat accumulation. Aging HIV-infected patients have a higher risk of trunk fat accumulation than uninfected individuals—suggesting that viral infection has a role in adipose tissue aging. We previously demonstrated that [...] Read more.
Background: Aging is characterized by adipose tissue senescence, inflammation, and fibrosis, with trunk fat accumulation. Aging HIV-infected patients have a higher risk of trunk fat accumulation than uninfected individuals—suggesting that viral infection has a role in adipose tissue aging. We previously demonstrated that HIV/SIV infection and the Tat and Nef viral proteins were responsible for adipose tissue fibrosis and impaired adipogenesis. We hypothesized that SIV/HIV infection and viral proteins could induce adipose tissue senescence and thus lead to adipocyte dysfunctions. Methods: Features of tissue senescence were evaluated in subcutaneous and visceral adipose tissues of SIV-infected macaques and in human adipose stem cells (ASCs) exposed to Tat or Nef for up to 30 days. Results: p16 expression and p53 activation were higher in adipose tissue of SIV-infected macaques than in control macaques, indicating adipose tissue senescence. Tat and Nef induced higher senescence in ASCs, characterized by higher levels of senescence-associated beta-galactosidase activity, p16 expression, and p53 activation vs. control cells. Treatment with Tat and Nef also induced oxidative stress and mitochondrial dysfunction. Prevention of oxidative stress (using N-acetyl-cysteine) reduced senescence in ASCs. Adipocytes having differentiated from Nef-treated ASCs displayed alterations in adipogenesis with lower levels of triglyceride accumulation and adipocyte marker expression and secretion, and insulin resistance. Conclusion: HIV/SIV promotes adipose tissue senescence, which in turn may alter adipocyte function and contribute to insulin resistance. Full article
(This article belongs to the Special Issue Molecular Mechanisms to Target Cellular Senescence in Aging and Disease)
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Graphical abstract

12 pages, 1829 KiB  
Article
3,4-Dihydroxybenzalacetone (DBL) Prevents Aging-Induced Myocardial Changes in Senescence-Accelerated Mouse-Prone 8 (SAMP8) Mice
by Vijayasree V. Giridharan, Vengadeshprabhu Karupppagounder, Somasundaram Arumugam, Yutaka Nakamura, Ashrith Guha, Tatiana Barichello, Joao Quevedo, Kenichi Watanabe, Tetsuya Konishi and Rajarajan A. Thandavarayan
Cells 2020, 9(3), 597; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9030597 - 03 Mar 2020
Cited by 4 | Viewed by 3109
Abstract
Aging is a predominant risk factor for the development and progression of cardiovascular complications. Physiologically and anatomically, the heart undergoes numerous changes that result in poor cardiac function in the elderly population. Recently, several studies have provided promising results, confirming the ability of [...] Read more.
Aging is a predominant risk factor for the development and progression of cardiovascular complications. Physiologically and anatomically, the heart undergoes numerous changes that result in poor cardiac function in the elderly population. Recently, several studies have provided promising results, confirming the ability of the senescence-accelerated mouse-prone 8 (SAMP8) model to accurately model age-related cardiovascular alterations. In this study, using a murine model of senescence, SAMP8, we aimed to investigate the effect of 3,4-dihydroxybenzalacetone (DBL), a catechol-containing phenylpropanoid derivative isolated from Inonotus obliquus (Chaga), on cardiac aging. DBL was administered at the doses of 10 mg/kg and 20 mg/kg by oral gavage to SAMP8 mice to examine aging-mediated cardiac changes, such as oxidative DNA damage, oxygen radical antioxidant capacity (ORAC) value, fibrosis, inflammation, and apoptosis. The treatment with DBL at both doses significantly reduced aging-mediated oxidative DNA damage, and simultaneously increased the ORAC value in the SAMP8 assay. Cardiac fibrosis was assessed with Azan-Mallory staining, and the number of cardiac remodeling markers was found to be significantly reduced after the treatment with DBL. We also observed a decrease in cardiomyocyte apoptosis as measured by the terminal transferase-mediated dUTP nick end labeling (TUNEL) staining method and the caspase-3 levels in SAMP8 mice compared with senescence-resistant control (SAMR1) mice. The findings from this study suggest that DBL has a potentially beneficial effect on aging-mediated myocardial alterations. Further studies are warranted to confirm the promising potential of this catechol compound against aging-associated myocardial dysfunction. Full article
(This article belongs to the Special Issue Molecular Mechanisms to Target Cellular Senescence in Aging and Disease)
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Graphical abstract

14 pages, 3078 KiB  
Article
Towards Age-Related Anti-Inflammatory Therapy: Klotho Suppresses Activation of ER and Golgi Stress Response in Senescent Monocytes
by Jennifer Mytych, Przemysław Sołek, Agnieszka Będzińska, Kinga Rusinek, Aleksandra Warzybok, Anna Tabęcka-Łonczyńska and Marek Koziorowski
Cells 2020, 9(2), 261; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9020261 - 21 Jan 2020
Cited by 19 | Viewed by 3819
Abstract
Immunosenescence in monocytes has been shown to be associated with several biochemical and functional changes, including development of senescence-associated secretory phenotype (SASP), which may be inhibited by klotho protein. To date, it was believed that SASP activation is associated with accumulating DNA damage. [...] Read more.
Immunosenescence in monocytes has been shown to be associated with several biochemical and functional changes, including development of senescence-associated secretory phenotype (SASP), which may be inhibited by klotho protein. To date, it was believed that SASP activation is associated with accumulating DNA damage. However, some literature data suggest that endoplasmic reticulum and Golgi stress pathways may be involved in SASP development. Thus, the aim of this study was to investigate the role of klotho protein in the regulation of immunosenescence-associated Golgi apparatus and ER stress response induced by bacterial antigens in monocytes. We provide evidence that initiation of immunosenescent-like phenotype in monocytes is accompanied by activation of CREB34L and TFE3 Golgi stress response and ATF6 and IRE1 endoplasmic reticulum stress response, while klotho overexpression prevents these changes. Further, these changes are followed by upregulated secretion of proinflammatory cytokines, which final modification takes place exclusively in the Golgi apparatus. In conclusion, we provide for the first time evidence of klotho involvement in the crosstalk on the line ER-Golgi, which may, in turn, affect activation of SASP. This data may be useful for a novel potential target for therapy in age-related and chronic inflammatory conditions. Full article
(This article belongs to the Special Issue Molecular Mechanisms to Target Cellular Senescence in Aging and Disease)
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15 pages, 3702 KiB  
Article
Visfatin Induces Senescence of Human Dental Pulp Cells
by Chang Youp Ok, Sera Park, Hye-Ock Jang, Takashi Takata, Moon-Kyoung Bae, Yong-Deok Kim, Mi Heon Ryu and Soo-Kyung Bae
Cells 2020, 9(1), 193; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9010193 - 12 Jan 2020
Cited by 12 | Viewed by 3843
Abstract
Dental pulp plays an important role in the health of teeth. The aging of teeth is strongly related to the senescence of dental pulp cells. A novel adipokine, visfatin, is closely associated with cellular senescence. However, little is known about the effect of [...] Read more.
Dental pulp plays an important role in the health of teeth. The aging of teeth is strongly related to the senescence of dental pulp cells. A novel adipokine, visfatin, is closely associated with cellular senescence. However, little is known about the effect of visfatin on the senescence of human dental pulp cells (hDPCs). Here, it was found that in vivo visfatin levels in human dental pulp tissues increase with age and are upregulated in vitro in hDPCs during premature senescence activated by H2O2, suggesting a correlation between visfatin and senescence. In addition, visfatin knockdown by small interfering RNA led to the reduction in hDPC senescence; however, treatment with exogenous visfatin protein induced the senescence of hDPCs along with increased NADPH consumption, which was reversed by FK866, a chemical inhibitor of visfatin. Furthermore, visfatin-induced senescence was associated with both the induction of telomere damage and the upregulation of senescence-associated secretory phenotype (SASP) factors as well as NF-κB activation, which were all inhibited by FK866. Taken together, these results demonstrate, for the first time, that visfatin plays a pivotal role in hDPC senescence in association with telomere dysfunction and the induction of SASP factors. Full article
(This article belongs to the Special Issue Molecular Mechanisms to Target Cellular Senescence in Aging and Disease)
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Graphical abstract

18 pages, 6828 KiB  
Article
Diversity of the Senescence Phenotype of Cancer Cells Treated with Chemotherapeutic Agents
by Agnieszka Bojko, Joanna Czarnecka-Herok, Agata Charzynska, Michal Dabrowski and Ewa Sikora
Cells 2019, 8(12), 1501; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8121501 - 23 Nov 2019
Cited by 71 | Viewed by 7811
Abstract
It is acknowledged that cancer cells are able to undergo senescence in response to clinically used chemotherapeutics. Moreover, recent years have provided evidence that some drugs can selectively remove senescent cells. Therefore, it is essential to properly identify and characterize senescent cells, especially [...] Read more.
It is acknowledged that cancer cells are able to undergo senescence in response to clinically used chemotherapeutics. Moreover, recent years have provided evidence that some drugs can selectively remove senescent cells. Therefore, it is essential to properly identify and characterize senescent cells, especially when it comes to cancer. Senescence was induced in various cancer cell lines (A549, SH-SY-5Y, HCT116, MDA-MB-231, and MCF-7) following treatment with doxorubicin, irinotecan, methotrexate, 5-fluorouracil, oxaliplatin, or paclitaxel. Treatment with tested chemotherapeutics resulted in upregulation of p21 and proliferation arrest without cytotoxicity. A comparative analysis with the use of common senescence markers (i.e., morphology, SA-β-galactosidase, granularity, secretory phenotype, and the level of double-stranded DNA damage) revealed a large diversity in response to the chemotherapeutics used. The strongest senescence inducers were doxorubicin, irinotecan, and methotrexate; paclitaxel had an intermediate effect and oxaliplatin and 5-fluorouracil did not induce senescence. In addition, different susceptibility of cancer cells to senescence was observed. A statistical analysis aimed at finding any relationship between the senescence markers applied did not show clear correlations. Moreover, increased SA-β-gal activity coupled with p21 expression proved not to be an unequivocal senescence marker. This points to a need to simultaneously analyze multiple markers, given their individual limitations. Full article
(This article belongs to the Special Issue Molecular Mechanisms to Target Cellular Senescence in Aging and Disease)
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Review

Jump to: Editorial, Research

21 pages, 2629 KiB  
Review
Molecular Mechanisms to Target Cellular Senescence in Hepatocellular Carcinoma
by Constanze Mittermeier, Andreas Konopa and Susanne Muehlich
Cells 2020, 9(12), 2540; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9122540 - 25 Nov 2020
Cited by 19 | Viewed by 3508
Abstract
Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer-related death and is the most common type of liver cancer. Due to the current paucity of drugs for HCC therapy there is a pressing need to develop new therapeutic concepts. In recent [...] Read more.
Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer-related death and is the most common type of liver cancer. Due to the current paucity of drugs for HCC therapy there is a pressing need to develop new therapeutic concepts. In recent years, the role of Serum Response Factor (SRF) and its coactivators, Myocardin-Related Transcription Factors A and B (MRTF-A and -B), in HCC formation and progression has received considerable attention. Targeting MRTFs results in HCC growth arrest provoked by oncogene-induced senescence. The induction of senescence acts as a tumor-suppressive mechanism and therefore gains consideration for pharmacological interventions in cancer therapy. In this article, we describe the key features and the functional role of senescence in light of the development of novel drug targets for HCC therapy with a focus on MRTFs. Full article
(This article belongs to the Special Issue Molecular Mechanisms to Target Cellular Senescence in Aging and Disease)
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31 pages, 1971 KiB  
Review
Targeting Cardiac Stem Cell Senescence to Treat Cardiac Aging and Disease
by Eleonora Cianflone, Michele Torella, Flavia Biamonte, Antonella De Angelis, Konrad Urbanek, Francesco S. Costanzo, Marcello Rota, Georgina M. Ellison-Hughes and Daniele Torella
Cells 2020, 9(6), 1558; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9061558 - 26 Jun 2020
Cited by 74 | Viewed by 7791
Abstract
Adult stem/progenitor are a small population of cells that reside in tissue-specific niches and possess the potential to differentiate in all cell types of the organ in which they operate. Adult stem cells are implicated with the homeostasis, regeneration, and aging of all [...] Read more.
Adult stem/progenitor are a small population of cells that reside in tissue-specific niches and possess the potential to differentiate in all cell types of the organ in which they operate. Adult stem cells are implicated with the homeostasis, regeneration, and aging of all tissues. Tissue-specific adult stem cell senescence has emerged as an attractive theory for the decline in mammalian tissue and organ function during aging. Cardiac aging, in particular, manifests as functional tissue degeneration that leads to heart failure. Adult cardiac stem/progenitor cell (CSC) senescence has been accordingly associated with physiological and pathological processes encompassing both non-age and age-related decline in cardiac tissue repair and organ dysfunction and disease. Senescence is a highly active and dynamic cell process with a first classical hallmark represented by its replicative limit, which is the establishment of a stable growth arrest over time that is mainly secondary to DNA damage and reactive oxygen species (ROS) accumulation elicited by different intrinsic stimuli (like metabolism), as well as external stimuli and age. Replicative senescence is mainly executed by telomere shortening, the activation of the p53/p16INK4/Rb molecular pathways, and chromatin remodeling. In addition, senescent cells produce and secrete a complex mixture of molecules, commonly known as the senescence-associated secretory phenotype (SASP), that regulate most of their non-cell-autonomous effects. In this review, we discuss the molecular and cellular mechanisms regulating different characteristics of the senescence phenotype and their consequences for adult CSCs in particular. Because senescent cells contribute to the outcome of a variety of cardiac diseases, including age-related and unrelated cardiac diseases like diabetic cardiomyopathy and anthracycline cardiotoxicity, therapies that target senescent cell clearance are actively being explored. Moreover, the further understanding of the reversibility of the senescence phenotype will help to develop novel rational therapeutic strategies. Full article
(This article belongs to the Special Issue Molecular Mechanisms to Target Cellular Senescence in Aging and Disease)
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25 pages, 4698 KiB  
Review
Experimental Models of Sarcopenia: Bridging Molecular Mechanism and Therapeutic Strategy
by Sakulrat Mankhong, Sujin Kim, Sohee Moon, Hyo-Bum Kwak, Dong-Ho Park and Ju-Hee Kang
Cells 2020, 9(6), 1385; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9061385 - 02 Jun 2020
Cited by 69 | Viewed by 14632
Abstract
Sarcopenia has been defined as a progressive decline of skeletal muscle mass, strength, and functions in elderly people. It is accompanied by physical frailty, functional disability, falls, hospitalization, and mortality, and is becoming a major geriatric disorder owing to the increasing life expectancy [...] Read more.
Sarcopenia has been defined as a progressive decline of skeletal muscle mass, strength, and functions in elderly people. It is accompanied by physical frailty, functional disability, falls, hospitalization, and mortality, and is becoming a major geriatric disorder owing to the increasing life expectancy and growing older population worldwide. Experimental models are critical to understand the pathophysiology of sarcopenia and develop therapeutic strategies. Although its etiologies remain to be further elucidated, several mechanisms of sarcopenia have been identified, including cellular senescence, proteostasis imbalance, oxidative stress, and “inflammaging.” In this article, we address three main aspects. First, we describe the fundamental aging mechanisms. Next, we discuss both in vitro and in vivo experimental models based on molecular mechanisms that have the potential to elucidate the biochemical processes integral to sarcopenia. The use of appropriate models to reflect sarcopenia and/or its underlying pathways will enable researchers to understand sarcopenia and develop novel therapeutic strategies for sarcopenia. Lastly, we discuss the possible molecular targets and the current status of drug candidates for sarcopenia treatment. In conclusion, the development of experimental models for sarcopenia is essential to discover molecular targets that are valuable as biochemical biomarkers and/or therapeutic targets for sarcopenia. Full article
(This article belongs to the Special Issue Molecular Mechanisms to Target Cellular Senescence in Aging and Disease)
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33 pages, 381 KiB  
Review
Nicotine in Senescence and Atherosclerosis
by Ann Marie Centner, Pradeep G. Bhide and Gloria Salazar
Cells 2020, 9(4), 1035; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9041035 - 22 Apr 2020
Cited by 34 | Viewed by 7007
Abstract
Cigarette smoke is a known exacerbator of age-related pathologies, such as cardiovascular disease (CVD), atherosclerosis, and cellular aging (senescence). However, the role of nicotine and its major metabolite cotinine is yet to be elucidated. Considering the growing amount of nicotine-containing aerosol use in [...] Read more.
Cigarette smoke is a known exacerbator of age-related pathologies, such as cardiovascular disease (CVD), atherosclerosis, and cellular aging (senescence). However, the role of nicotine and its major metabolite cotinine is yet to be elucidated. Considering the growing amount of nicotine-containing aerosol use in recent years, the role of nicotine is a relevant public health concern. A number of recent studies and health education sites have focused on nicotine aerosol-induced adverse lung function, and neglected cardiovascular (CV) impairments and diseases. A critical review of the present scientific literature leads to the hypothesis that nicotine mediates the effects of cigarette smoke in the CV system by increasing MAPK signaling, inflammation, and oxidative stress through NADPH oxidase 1 (Nox1), to induce vascular smooth muscle cell (VSMC) senescence. The accumulation of senescent VSMCs in the lesion cap is detrimental as it increases the pathogenesis of atherosclerosis by promoting an unstable plaque phenotype. Therefore, nicotine, and most likely its metabolite cotinine, adversely influence atherosclerosis. Full article
(This article belongs to the Special Issue Molecular Mechanisms to Target Cellular Senescence in Aging and Disease)
13 pages, 761 KiB  
Review
Insights from In Vivo Studies of Cellular Senescence
by Luis I. Prieto, Sara I. Graves and Darren J. Baker
Cells 2020, 9(4), 954; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9040954 - 13 Apr 2020
Cited by 20 | Viewed by 9335
Abstract
Cellular senescence is the dynamic process of durable cell-cycle arrest. Senescent cells remain metabolically active and often acquire a distinctive bioactive secretory phenotype. Much of our molecular understanding in senescent cell biology comes from studies using mammalian cell lines exposed to stress or [...] Read more.
Cellular senescence is the dynamic process of durable cell-cycle arrest. Senescent cells remain metabolically active and often acquire a distinctive bioactive secretory phenotype. Much of our molecular understanding in senescent cell biology comes from studies using mammalian cell lines exposed to stress or extended culture periods. While less well understood mechanistically, senescence in vivo is becoming appreciated for its numerous biological implications, both in the context of beneficial processes, such as development, tumor suppression, and wound healing, and in detrimental conditions, where senescent cell accumulation has been shown to contribute to aging and age-related diseases. Importantly, clearance of senescent cells, through either genetic or pharmacological means, has been shown to not only extend the healthspan of prematurely and naturally aged mice but also attenuate pathology in mouse models of chronic disease. These observations have prompted an investigation of how and why senescent cells accumulate with aging and have renewed exploration into the characteristics of cellular senescence in vivo. Here, we highlight our molecular understanding of the dynamics that lead to a cellular arrest and how various effectors may explain the consequences of senescence in tissues. Lastly, we discuss how exploitation of strategies to eliminate senescent cells or their effects may have clinical utility. Full article
(This article belongs to the Special Issue Molecular Mechanisms to Target Cellular Senescence in Aging and Disease)
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12 pages, 683 KiB  
Review
Exploring the Relevance of Senotherapeutics for the Current SARS-CoV-2 Emergency and Similar Future Global Health Threats
by Marco Malavolta, Robertina Giacconi, Dario Brunetti, Mauro Provinciali and Fabrizio Maggi
Cells 2020, 9(4), 909; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9040909 - 08 Apr 2020
Cited by 49 | Viewed by 11391
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Molecular Mechanisms to Target Cellular Senescence in Aging and Disease)
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18 pages, 1470 KiB  
Review
The Immune Response Against Human Cytomegalovirus Links Cellular to Systemic Senescence
by John J. Heath and Michael D. Grant
Cells 2020, 9(3), 766; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9030766 - 20 Mar 2020
Cited by 30 | Viewed by 6155
Abstract
Aging reflects long-term decline in physiological function and integrity. Changes arise at a variable pace governed by time-dependent and -independent mechanisms that are themselves complex, interdependent and variable. Molecular decay produces inferior cells that eventually dominate over healthy counterparts in tissues they comprise. [...] Read more.
Aging reflects long-term decline in physiological function and integrity. Changes arise at a variable pace governed by time-dependent and -independent mechanisms that are themselves complex, interdependent and variable. Molecular decay produces inferior cells that eventually dominate over healthy counterparts in tissues they comprise. In a form of biological entropy, progression from molecular through cellular to tissue level degeneration culminates in organ disease or dysfunction, affecting systemic health. To better understand time-independent contributors and their potential modulation, common biophysical bases for key molecular and cellular changes underlying age-related physiological deterioration must be delineated. This review addresses the potential contribution of cytomegalovirus (CMV)-driven T cell proliferation to cellular senescence and immunosenescence. We first describe molecular processes imposing cell cycle arrest, the foundation of cellular senescence, then focus on the unique distribution, phenotype and function of CMV-specific CD8+ T cells in the context of cellular senescence and “inflammaging”. Their features position CMV infection as a pathogenic accelerant of immune cell proliferation underlying immune senescence. In human immunodeficiency virus (HIV) infection, where increased inflammation and exaggerated anti-CMV immune responses accelerate immune senescence, CMV infection has emerged as a major factor in unhealthy aging. Thus, we speculate on mechanistic links between CMV-specific CD8+ T-cell expansion, immune senescence and prevalence of age-related disorders in HIV infection. Full article
(This article belongs to the Special Issue Molecular Mechanisms to Target Cellular Senescence in Aging and Disease)
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19 pages, 1009 KiB  
Review
Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases
by Ping Song, Junqing An and Ming-Hui Zou
Cells 2020, 9(3), 671; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9030671 - 10 Mar 2020
Cited by 95 | Viewed by 13232
Abstract
Senescent cells are generally characterized by permanent cell cycle arrest, metabolic alteration and activation, and apoptotic resistance in multiple organs due to various stressors. Excessive accumulation of senescent cells in numerous tissues leads to multiple chronic diseases, tissue dysfunction, age-related diseases and organ [...] Read more.
Senescent cells are generally characterized by permanent cell cycle arrest, metabolic alteration and activation, and apoptotic resistance in multiple organs due to various stressors. Excessive accumulation of senescent cells in numerous tissues leads to multiple chronic diseases, tissue dysfunction, age-related diseases and organ ageing. Immune cells can remove senescent cells. Immunaging or impaired innate and adaptive immune responses by senescent cells result in persistent accumulation of various senescent cells. Although senolytics—drugs that selectively remove senescent cells by inducing their apoptosis—are recent hot topics and are making significant research progress, senescence immunotherapies using immune cell-mediated clearance of senescent cells are emerging and promising strategies to fight ageing and multiple chronic diseases. This short review provides an overview of the research progress to date concerning senescent cell-caused chronic diseases and tissue ageing, as well as the regulation of senescence by small-molecule drugs in clinical trials and different roles and regulation of immune cells in the elimination of senescent cells. Mounting evidence indicates that immunotherapy targeting senescent cells combats ageing and chronic diseases and subsequently extends the healthy lifespan. Full article
(This article belongs to the Special Issue Molecular Mechanisms to Target Cellular Senescence in Aging and Disease)
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18 pages, 3810 KiB  
Review
The Histone Code of Senescence
by Harikrishnareddy Paluvai, Eros Di Giorgio and Claudio Brancolini
Cells 2020, 9(2), 466; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9020466 - 18 Feb 2020
Cited by 42 | Viewed by 6309
Abstract
Senescence is the end point of a complex cellular response that proceeds through a set of highly regulated steps. Initially, the permanent cell-cycle arrest that characterizes senescence is a pro-survival response to irreparable DNA damage. The maintenance of this prolonged condition requires the [...] Read more.
Senescence is the end point of a complex cellular response that proceeds through a set of highly regulated steps. Initially, the permanent cell-cycle arrest that characterizes senescence is a pro-survival response to irreparable DNA damage. The maintenance of this prolonged condition requires the adaptation of the cells to an unfavorable, demanding and stressful microenvironment. This adaptation is orchestrated through a deep epigenetic resetting. A first wave of epigenetic changes builds a dam on irreparable DNA damage and sustains the pro-survival response and the cell-cycle arrest. Later on, a second wave of epigenetic modifications allows the genomic reorganization to sustain the transcription of pro-inflammatory genes. The balanced epigenetic dynamism of senescent cells influences physiological processes, such as differentiation, embryogenesis and aging, while its alteration leads to cancer, neurodegeneration and premature aging. Here we provide an overview of the most relevant histone modifications, which characterize senescence, aging and the activation of a prolonged DNA damage response. Full article
(This article belongs to the Special Issue Molecular Mechanisms to Target Cellular Senescence in Aging and Disease)
28 pages, 1025 KiB  
Review
Beyond Tumor Suppression: Senescence in Cancer Stemness and Tumor Dormancy
by Francisco Triana-Martínez, María Isabel Loza and Eduardo Domínguez
Cells 2020, 9(2), 346; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9020346 - 03 Feb 2020
Cited by 66 | Viewed by 7256
Abstract
Here, we provide an overview of the importance of cellular fate in cancer as a group of diseases of abnormal cell growth. Tumor development and progression is a highly dynamic process, with several phases of evolution. The existing evidence about the origin and [...] Read more.
Here, we provide an overview of the importance of cellular fate in cancer as a group of diseases of abnormal cell growth. Tumor development and progression is a highly dynamic process, with several phases of evolution. The existing evidence about the origin and consequences of cancer cell fate specification (e.g., proliferation, senescence, stemness, dormancy, quiescence, and cell cycle re-entry) in the context of tumor formation and metastasis is discussed. The interplay between these dynamic tumor cell phenotypes, the microenvironment, and the immune system is also reviewed in relation to cancer. We focus on the role of senescence during cancer progression, with a special emphasis on its relationship with stemness and dormancy. Selective interventions on senescence and dormancy cell fates, including the specific targeting of cancer cell populations to prevent detrimental effects in aging and disease, are also reviewed. A new conceptual framework about the impact of synthetic lethal strategies by using senogenics and then senolytics is given, with the promise of future directions on innovative anticancer therapies. Full article
(This article belongs to the Special Issue Molecular Mechanisms to Target Cellular Senescence in Aging and Disease)
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21 pages, 2227 KiB  
Review
Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging
by Matilde Alique, Elsa Sánchez-López, Guillermo Bodega, Chiara Giannarelli, Julia Carracedo and Rafael Ramírez
Cells 2020, 9(1), 195; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9010195 - 13 Jan 2020
Cited by 45 | Viewed by 7530
Abstract
Aging is one of the hottest topics in biomedical research. Advances in research and medicine have helped to preserve human health, leading to an extension of life expectancy. However, the extension of life is an irreversible process that is accompanied by the development [...] Read more.
Aging is one of the hottest topics in biomedical research. Advances in research and medicine have helped to preserve human health, leading to an extension of life expectancy. However, the extension of life is an irreversible process that is accompanied by the development of aging-related conditions such as weakness, slower metabolism, and stiffness of vessels. It also debated that aging can be considered an actual disease with aging-derived comorbidities, including cancer or cardiovascular disease. Currently, cardiovascular disorders, including atherosclerosis, are considered as premature aging and represent the first causes of death in developed countries, accounting for 31% of annual deaths globally. Emerging evidence has identified hypoxia-inducible factor-1α as a critical transcription factor with an essential role in aging-related pathology, in particular, regulating cellular senescence associated with cardiovascular aging. In this review, we will focus on the regulation of senescence mediated by hypoxia-inducible factor-1α in age-related pathologies, with particular emphasis on the crosstalk between endothelial and vascular cells in age-associated atherosclerotic lesions. More specifically, we will focus on the characteristics and mechanisms by which cells within the vascular wall, including endothelial and vascular cells, achieve a senescent phenotype. Full article
(This article belongs to the Special Issue Molecular Mechanisms to Target Cellular Senescence in Aging and Disease)
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