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Cells
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The Role of Cellular Senescence in Health, Disease, and Aging
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The Role of Cellular Senescence in Health, Disease, and Aging

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

Deadline for manuscript submissions: 5 September 2025 | Viewed by 16934

Special Issue Editor

Dr. Yasumichi Inoue

E-Mail Website
Guest Editor
Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan
Interests: cancer; cell cycle; cellular senescence; endoplasmic reticulum stress; molecular target drugs; p53; transcriptional regulation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

As the human population ages, people are faced with various health challenges brought on by old age. The concept of the senescence of an individual is also gaining acceptance as a result of the greater understanding of the senescence of the cells that make up the organism. Senescence research has been a very active field in recent years, as the role of aging in disease and physiological processes has become clearer and as aging-based therapeutic interventions have become more promising. In particular, the extension of human life spans via the removal of senescent cells must be seen as an epoch-making event. These groundbreaking matters are produced through the accumulation of deep basic research and the challenge of clinical application on cellular senescence.

This Special Issue provides an open access forum to compile a collection of original research and review articles on the role of cellular senescence in health, disease and aging. We welcome submissions on a wide range of research topics, including molecular mechanisms of cellular senescence and the pathogenesis of diseases such as cancer and age-related diseases caused by cellular senescence.

Dr. Yasumichi Inoue
Guest Editor

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

  • apoptosis
  • cancer
  • cell cycle
  • DNA damage
  • metabolic diseases
  • oxidative stress
  • senolysis
  • senescence
  • therapeutic approach

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Published Papers (7 papers)

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Research

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12 pages, 1574 KiB  
Article
Genome Instability and Senescence Are Markers of Cornelia de Lange Syndrome Cells
by Maddalena Di Nardo, Ian D. Krantz and Antonio Musio
Cells 2024, 13(23), 2025; https://doi.org/10.3390/cells13232025 - 7 Dec 2024
Viewed by 1389
Abstract
Cornelia de Lange syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder. Pathogenic variants in genes encoding the structural subunits and regulatory proteins of the cohesin complex (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the primary [...] Read more.
Cornelia de Lange syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder. Pathogenic variants in genes encoding the structural subunits and regulatory proteins of the cohesin complex (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the primary contributors to the pathogenesis of CdLS. Pathogenic variations in these genes disrupt normal cohesin function, leading to the syndrome’s diverse and complex clinical presentation. In this study, we discovered that cells harboring variants in the NIPBL, SMC1A and HDAC8 genes exhibit spontaneous genome instability, elevated oxidative stress and premature cellular aging. These findings suggest that cohesin plays a critical role in maintaining proper cellular function and highlight its contribution to the pathophysiology seen in the related diagnoses. Full article
(This article belongs to the Special Issue The Role of Cellular Senescence in Health, Disease, and Aging)
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21 pages, 8084 KiB  
Article
Stimuli-Specific Senescence of Primary Human Lung Fibroblasts Modulates Alveolar Stem Cell Function
by Maria Camila Melo-Narváez, Nora Bramey, Fenja See, Katharina Heinzelmann, Beatriz Ballester, Carina Steinchen, Eshita Jain, Kathrin Federl, Qianjiang Hu, Deepesh Dhakad, Jürgen Behr, Oliver Eickelberg, Ali Önder Yildirim, Melanie Königshoff and Mareike Lehmann
Cells 2024, 13(13), 1129; https://doi.org/10.3390/cells13131129 - 29 Jun 2024
Cited by 3 | Viewed by 2798
Abstract
Aging is the main risk factor for chronic lung diseases (CLDs) including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Accordingly, hallmarks of aging like cellular senescence are increased in these patients in different lung cell types including fibroblasts. However, little [...] Read more.
Aging is the main risk factor for chronic lung diseases (CLDs) including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Accordingly, hallmarks of aging like cellular senescence are increased in these patients in different lung cell types including fibroblasts. However, little is known about the different triggers that induce a senescence phenotype in different disease backgrounds and its role in CLD pathogenesis. Therefore, we characterized senescence in primary human lung fibroblasts (phLF) from control, IPF, or COPD patients at baseline and after exposure to disease-relevant insults (H2O2, bleomycin, TGF-β1) and studied their capacity to support progenitor cell potential in a lung organoid model. Bulk-RNA sequencing revealed that phLF from IPF and COPD activate different transcriptional programs but share a similar senescence phenotype at baseline. Moreover, H2O2 and bleomycin but not TGF-β1 induced senescence in phLF from different disease origins. Exposure to different triggers resulted in distinct senescence programs in phLF characterized by different SASP profiles. Finally, co-culture with bleomycin- and H2O2-treated phLF reduced the progenitor cell potential of alveolar epithelial progenitor cells. In conclusion, phLF from COPD and IPF share a conserved senescence response that varies depending on the insult and impairs alveolar epithelial progenitor capacity ex vivo. Full article
(This article belongs to the Special Issue The Role of Cellular Senescence in Health, Disease, and Aging)
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22 pages, 5875 KiB  
Article
In Vitro Investigation of Therapy-Induced Senescence and Senescence Escape in Breast Cancer Cells Using Novel Flow Cytometry-Based Methods
by Fanni Tóth, Zahra Moftakhar, Federica Sotgia and Michael P. Lisanti
Cells 2024, 13(10), 841; https://doi.org/10.3390/cells13100841 - 15 May 2024
Cited by 3 | Viewed by 3014
Abstract
Although cellular senescence was originally defined as an irreversible form of cell cycle arrest, in therapy-induced senescence models, the emergence of proliferative senescence-escaped cancer cells has been reported by several groups, challenging the definition of senescence. Indeed, senescence-escaped cancer cells may contribute to [...] Read more.
Although cellular senescence was originally defined as an irreversible form of cell cycle arrest, in therapy-induced senescence models, the emergence of proliferative senescence-escaped cancer cells has been reported by several groups, challenging the definition of senescence. Indeed, senescence-escaped cancer cells may contribute to resistance to cancer treatment. Here, to study senescence escape and isolate senescence-escaped cells, we developed novel flow cytometry-based methods using the proliferation marker Ki-67 and CellTrace CFSE live-staining. We investigated the role of a novel senescence marker (DPP4/CD26) and a senolytic drug (azithromycin) on the senescence-escaping ability of MCF-7 and MDA-MB-231 breast cancer cells. Our results show that the expression of DPP4/CD26 is significantly increased in both senescent MCF-7 and MDA-MB-231 cells. While not essential for senescence induction, DPP4/CD26 contributed to promoting senescence escape in MCF-7 cells but not in MDA-MB-231 cells. Our results also confirmed the potential senolytic effect of azithromycin in senescent cancer cells. Importantly, the combination of azithromycin and a DPP4 inhibitor (sitagliptin) demonstrated a synergistic effect in senescent MCF-7 cells and reduced the number of senescence-escaped cells. Although further research is needed, our results and novel methods could contribute to the investigation of the mechanisms of senescence escape and the identification of potential therapeutic targets. Indeed, DPP4/CD26 could be a promising marker and a novel target to potentially decrease senescence escape in cancer. Full article
(This article belongs to the Special Issue The Role of Cellular Senescence in Health, Disease, and Aging)
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19 pages, 5885 KiB  
Article
GDF15 Modulates the Zoledronic-Acid-Induced Hyperinflammatory Mechanoresponse of Periodontal Ligament Fibroblasts
by Ann Nitzsche, Christoph-Ludwig Hennig, Katrin von Brandenstein, Annika Döding, Ulrike Schulze-Späte, Judit Symmank and Collin Jacobs
Cells 2024, 13(2), 147; https://doi.org/10.3390/cells13020147 - 12 Jan 2024
Cited by 1 | Viewed by 2438
Abstract
Orthodontic tooth movement (OTM) is thought to be impeded by bisphosphonate (BP) therapy, mainly due to increased osteoclast apoptosis and changes in the periodontal ligament (PdL), a connecting tissue between the alveolar bone and teeth. PdL cells, mainly fibroblasts (PdLFs), are crucial regulators [...] Read more.
Orthodontic tooth movement (OTM) is thought to be impeded by bisphosphonate (BP) therapy, mainly due to increased osteoclast apoptosis and changes in the periodontal ligament (PdL), a connecting tissue between the alveolar bone and teeth. PdL cells, mainly fibroblasts (PdLFs), are crucial regulators in OTM by modulating force-induced local inflammatory processes. Recently, we identified the TGF-β/BMP superfamily member GDF15 as an important modulator in OTM, promoting the pro-inflammatory mechanoresponses of PdLFs. The precise impact of the highly potent BP zoledronate (ZOL) on the mechanofunctionality of PdLFs is still under-investigated. Therefore, the aim of this study was to further characterize the ZOL-induced changes in the initial inflammatory mechanoresponse of human PdLFs (hPdLFs) and to further clarify a potential interrelationship with GDF15 signaling. Thus, two-day in vitro treatment with 0.5 µM, 5 µM and 50 µM of ZOL altered the cellular properties of hPdLFs partially in a concentration-dependent manner. In particular, exposure to ZOL decreased their metabolic activity, the proliferation rate, detected using Ki-67 immunofluorescent staining, and survival, analyzed using trypan blue. An increasing occurrence of DNA strand breaks was observed using TUNEL and an activated DNA damage response was demonstrated using H2A.X (phosphoS139) staining. While the osteogenic differentiation of hPdLFs was unaffected by ZOL, increased cellular senescence was observed using enhanced p21Waf1/Cip1/Sdi1 and β-galactosidase staining. In addition, cytokine-encoding genes such as IL6, IL8, COX2 and GDF15, which are associated with a senescence-associated secretory phenotype, were up-regulated by ZOL. Subsequently, this change in the hPdLF phenotype promoted a hyperinflammatory response to applied compressive forces with an increased expression of the pro-inflammatory markers IL1β, IL6 and GDF15, as well as the activation of monocytic THP1 cells. GDF15 appeared to be particularly relevant to these changes, as siRNA-mediated down-regulation balanced these hyperinflammatory responses by reducing IL-1β and IL-6 expression (IL1B p-value < 0.0001; IL6 p-value < 0.001) and secretion (IL-1β p-value < 0.05; IL-6 p-value < 0.001), as well as immune cell activation (p-value < 0.0001). In addition, ZOL-related reduced RANKL/OPG values and inhibited osteoclast activation were enhanced in GDF15-deficient hPdLFs (both p-values < 0.0001; all statistical tests: one-way ANOVA, Tukey’s post hoc test). Thus, GDF15 may become a promising new target in the personalized orthodontic treatment of bisphosphonatepatients. Full article
(This article belongs to the Special Issue The Role of Cellular Senescence in Health, Disease, and Aging)
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Review

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27 pages, 2781 KiB  
Review
p63: A Master Regulator at the Crossroads Between Development, Senescence, Aging, and Cancer
by Lakshana Sruthi Sadu Murari, Sam Kunkel, Anala Shetty, Addison Bents, Aayush Bhandary and Juan Carlos Rivera-Mulia
Cells 2025, 14(1), 43; https://doi.org/10.3390/cells14010043 - 3 Jan 2025
Viewed by 2165
Abstract
The p63 protein is a master regulatory transcription factor that plays crucial roles in cell differentiation, adult tissue homeostasis, and chromatin remodeling, and its dysregulation is associated with genetic disorders, physiological and premature aging, and cancer. The effects of p63 are carried out [...] Read more.
The p63 protein is a master regulatory transcription factor that plays crucial roles in cell differentiation, adult tissue homeostasis, and chromatin remodeling, and its dysregulation is associated with genetic disorders, physiological and premature aging, and cancer. The effects of p63 are carried out by two main isoforms that regulate cell proliferation and senescence. p63 also controls the epigenome by regulating interactions with histone modulators, such as the histone acetyltransferase p300, deacetylase HDAC1/2, and DNA methyltransferases. miRNA-p63 interactions are also critical regulators in the context of cancer metastasis. This review aims to elaborate on the diverse roles of p63, focusing on disease, development, and the mechanisms controlling genome organization and function. Full article
(This article belongs to the Special Issue The Role of Cellular Senescence in Health, Disease, and Aging)
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23 pages, 1210 KiB  
Review
The Hippo Signaling Pathway Manipulates Cellular Senescence
by Chiharu Miyajima, Mai Nagasaka, Hiromasa Aoki, Kohki Toriuchi, Shogo Yamanaka, Sakura Hashiguchi, Daisuke Morishita, Mineyoshi Aoyama, Hidetoshi Hayashi and Yasumichi Inoue
Cells 2025, 14(1), 13; https://doi.org/10.3390/cells14010013 - 26 Dec 2024
Cited by 1 | Viewed by 1465
Abstract
The Hippo pathway, a kinase cascade, coordinates with many intracellular signals and mediates the regulation of the activities of various downstream transcription factors and their coactivators to maintain homeostasis. Therefore, the aberrant activation of the Hippo pathway and its associated molecules imposes significant [...] Read more.
The Hippo pathway, a kinase cascade, coordinates with many intracellular signals and mediates the regulation of the activities of various downstream transcription factors and their coactivators to maintain homeostasis. Therefore, the aberrant activation of the Hippo pathway and its associated molecules imposes significant stress on tissues and cells, leading to cancer, immune disorders, and a number of diseases. Cellular senescence, the mechanism by which cells counteract stress, prevents cells from unnecessary damage and leads to sustained cell cycle arrest. It acts as a powerful defense mechanism against normal organ development and aging-related diseases. On the other hand, the accumulation of senescent cells without their proper removal contributes to the development or worsening of cancer and age-related diseases. A correlation was recently reported between the Hippo pathway and cellular senescence, which preserves tissue homeostasis. This review is the first to describe the close relationship between aging and the Hippo pathway, and provides insights into the mechanisms of aging and the development of age-related diseases. In addition, it describes advanced findings that may lead to the development of tissue regeneration therapies and drugs targeting rejuvenation. Full article
(This article belongs to the Special Issue The Role of Cellular Senescence in Health, Disease, and Aging)
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18 pages, 973 KiB  
Review
New Possibilities for Evaluating the Development of Age-Related Pathologies Using the Dynamical Network Biomarkers Theory
by Kazutaka Akagi, Keiichi Koizumi, Makoto Kadowaki, Isao Kitajima and Shigeru Saito
Cells 2023, 12(18), 2297; https://doi.org/10.3390/cells12182297 - 17 Sep 2023
Cited by 2 | Viewed by 2417
Abstract
Aging is the slowest process in a living organism. During this process, mortality rate increases exponentially due to the accumulation of damage at the cellular level. Cellular senescence is a well-established hallmark of aging, as well as a promising target for preventing aging [...] Read more.
Aging is the slowest process in a living organism. During this process, mortality rate increases exponentially due to the accumulation of damage at the cellular level. Cellular senescence is a well-established hallmark of aging, as well as a promising target for preventing aging and age-related diseases. However, mapping the senescent cells in tissues is extremely challenging, as their low abundance, lack of specific markers, and variability arise from heterogeneity. Hence, methodologies for identifying or predicting the development of senescent cells are necessary for achieving healthy aging. A new wave of bioinformatic methodologies based on mathematics/physics theories have been proposed to be applied to aging biology, which is altering the way we approach our understand of aging. Here, we discuss the dynamical network biomarkers (DNB) theory, which allows for the prediction of state transition in complex systems such as living organisms, as well as usage of Raman spectroscopy that offers a non-invasive and label-free imaging, and provide a perspective on potential applications for the study of aging. Full article
(This article belongs to the Special Issue The Role of Cellular Senescence in Health, Disease, and Aging)
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