scholarly journals Cellular senescence contributes to radiation-induced hyposalivation by affecting the stem/progenitor cell niche

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Xiaohong Peng ◽  
Yi Wu ◽  
Uilke Brouwer ◽  
Thijmen van Vliet ◽  
Boshi Wang ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Cellular Senescence ◽  
Progenitor Cell ◽  
Tissue Degeneration ◽  
Cycle Arrest ◽  
Radiation Induced ◽  
Secretory Phenotype ◽  
Cell Niche ◽  
Gland Function ◽  
Formation Efficiency

Abstract Radiotherapy for head and neck cancer is associated with impairment of salivary gland function and consequent xerostomia, which has a devastating effect on the quality of life of the patients. The mechanism of radiation-induced salivary gland damage is not completely understood. Cellular senescence is a permanent state of cell cycle arrest accompanied by a secretory phenotype which contributes to inflammation and tissue deterioration. Genotoxic stresses, including radiation-induced DNA damage, are known to induce a senescence response. Here, we show that radiation induces cellular senescence preferentially in the salivary gland stem/progenitor cell niche of mouse models and patients. Similarly, salivary gland-derived organoids show increased expression of senescence markers and pro-inflammatory senescence-associated secretory phenotype (SASP) factors after radiation exposure. Clearance of senescent cells by selective removal of p16Ink4a-positive cells by the drug ganciclovir or the senolytic drug ABT263 lead to increased stem cell self-renewal capacity as measured by organoid formation efficiency. Additionally, pharmacological treatment with ABT263 in mice irradiated to the salivary glands mitigates tissue degeneration, thus preserving salivation. Our data suggest that senescence in the salivary gland stem/progenitor cell niche contributes to radiation-induced hyposalivation. Pharmacological targeting of senescent cells may represent a therapeutic strategy to prevent radiotherapy-induced xerostomia.

Radiation-Induced Loss of Salivary Gland Function Is Driven by Cellular Senescence and Prevented by IL6 Modulation

2016 ◽  
Vol 76 (5) ◽  
pp. 1170-1180 ◽  
Author(s):  
Yitzhak Marmary ◽  
Revital Adar ◽  
Svetlana Gaska ◽  
Annette Wygoda ◽  
Alexander Maly ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Cellular Senescence ◽  
Salivary Gland Function ◽  
Radiation Induced ◽  
Gland Function

scholarly journals Irradiation Accelerates Plaque Formation and Cellular Senescence in Flow‐Altered Carotid Arteries of Apolipoprotein E Knock‐Out Mice

2021 ◽  
Author(s):  
Yu Yamamoto ◽  
Manabu Minami ◽  
Kazumichi Yoshida ◽  
Manabu Nagata ◽  
Takeshi Miyata ◽  
...  
Keyword(s):  
Dna Damage ◽  
Apolipoprotein E ◽  
Cellular Senescence ◽  
Carotid Arteries ◽  
Kinase Inhibitors ◽  
Mice Model ◽  
Knock Out ◽  
Post Operation ◽  
Radiation Induced ◽  
Secretory Phenotype

Background Chronic inflammation through cellular senescence, known as the senescence‐associated secretory phenotype, is a mechanism of various organ diseases, including atherosclerosis. Particularly, ionizing radiation (IR) contributes to cellular senescence by causing DNA damage. Although previous clinical studies have demonstrated that radiotherapy causes atherosclerosis as a long‐term side effect, the detailed mechanism is unclear. This study was conducted to investigate the relationship between radiation‐induced atherosclerosis and senescence‐associated secretory phenotype in murine carotid arteries. Methods and Results Partial ligation of the left carotid artery branches in 9‐week‐old male apolipoprotein E‐deficient mice was performed to induce atherosclerosis. The mice received total body irradiation at a dose of 6 Gy using gamma rays at 2 weeks post operation. We compared the samples collected 4 weeks after IR with unirradiated control samples. The IR and control groups presented pathologically progressive lesions in 90.9% and 72.3% of mice, respectively. Plaque volume, macrophage accumulation, and phenotype switching of vascular smooth muscle cells were advanced in the IR group. Irradiated samples showed increased persistent DNA damage response (53BP1 [p53 binding protein 1]), upregulated cyclin‐dependent kinase inhibitors (p16INK4a and p21), and elevated inflammatory chemokines expression (monocyte chemotactic protein‐1, keratinocyte‐derived chemokine, and macrophage inflammatory protein 2). Conclusions IR promoted plaque growth in murine carotid arteries. Our findings support the possibility that senescence‐associated secretory phenotype aggravates atherogenesis in irradiated artery. This mice model might contribute to mechanism elucidation of radiation‐induced atherosclerosis.

Deciphering the mechanism for induction of senescence-associated secretory phenotype (SASP) and its role in ageing and cancer development

2019 ◽  
Vol 166 (4) ◽  
pp. 289-295 ◽  
Author(s):  
Naoko Ohtani
Keyword(s):  
Immune Responses ◽  
Cancer Progression ◽  
Cellular Senescence ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Cycle Arrest ◽  
Secreted Factors ◽  
Suppression Mechanism ◽  
Secretory Phenotype ◽  
Sting Pathway

Abstract Cellular senescence is an irreversible form of cell cycle arrest that can be induced by persistent DNA damage, and is well known to function as an important tumour suppression mechanism. Cellular senescence is detected in aged organisms; thus, it is also recognized as a hallmark of organismal ageing. Unlike apoptotic cells, senescent cells can survive for long periods of time. Recently, it has been shown that the late stage of senescent cells are capable of expressing a variety of secreted proteins such as cytokines, chemokines and proteases, and this condition is now known as senescence-associated secretory phenotype (SASP). These secreted factors are involved in myriad of physiological functions including tissue repair and clearance of damaged cells. Alternatively, these factors may promote detrimental effects, such as chronic inflammation or cancer progression, should the SASP persist. Recent scientific advances have indicated that innate immune responses, particularly involving the cGAS–STING pathway, trigger SASP induction. Therefore, developing a strategy to regulate SASP may provide scientific insights for the management of age-associated diseases and the implementation of healthy ageing in the future.

scholarly journals Diverse Roles of Cellular Senescence in Skeletal Muscle Inflammation, Regeneration, and Therapeutics

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuki Saito ◽  
Takako S. Chikenji
Keyword(s):  
Skeletal Muscle ◽  
Cellular Senescence ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Neuromuscular Disorders ◽  
Muscle Stem Cells ◽  
Related Disease ◽  
Tissue Degeneration ◽  
Cycle Arrest ◽  
Age Related

Skeletal muscle undergoes vigorous tissue remodeling after injury. However, aging, chronic inflammatory diseases, sarcopenia, and neuromuscular disorders cause muscle loss and degeneration, resulting in muscular dysfunction. Cellular senescence, a state of irreversible cell cycle arrest, acts during normal embryonic development and remodeling after tissue damage; when these processes are complete, the senescent cells are eliminated. However, the accumulation of senescent cells is a hallmark of aging tissues or pathological contexts and may lead to progressive tissue degeneration. The mechanisms responsible for the effects of senescent cells have not been fully elucidated. Here, we review current knowledge about the beneficial and detrimental effects of senescent cells in tissue repair, regeneration, aging, and age-related disease, especially in skeletal muscle. We also discuss how senescence of muscle stem cells and muscle-resident fibro-adipogenic progenitors affects muscle pathologies or regeneration, and consider the possibility that immunosenescence leads to muscle pathogenesis. Finally, we explore senotherapy, the therapeutic targeting of senescence to treat age-related disease, from the standpoint of improving muscle regeneration.

scholarly journals Insights from In Vivo Studies of Cellular Senescence

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 954
Author(s):  
Luis I. Prieto ◽  
Sara I. Graves ◽  
Darren J. Baker
Keyword(s):  
Cellular Senescence ◽  
Cell Biology ◽  
Senescent Cell ◽  
In Vivo Studies ◽  
Cycle Arrest ◽  
Mammalian Cell Lines ◽  
Age Related ◽  
Cell Accumulation ◽  
Secretory Phenotype

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.

scholarly journals Stilbene Compounds Inhibit Tumor Growth by the Induction of Cellular Senescence and the Inhibition of Telomerase Activity

2019 ◽  
Vol 20 (11) ◽  
pp. 2716 ◽  
Author(s):  
Yu-Hsuan Lee ◽  
Yu-Ying Chen ◽  
Ya-Ling Yeh ◽  
Ying-Jan Wang ◽  
Rong-Jane Chen
Keyword(s):  
Cellular Senescence ◽  
Current Knowledge ◽  
Gene Expression Pattern ◽  
Telomerase Activity ◽  
Clinical Utilization ◽  
Cycle Arrest ◽  
Suppression Mechanism ◽  
Secretory Phenotype ◽  
Clinical Potential ◽  
Stilbene Compounds

Cellular senescence is a state of cell cycle arrest characterized by a distinct morphology, gene expression pattern, and secretory phenotype. It can be triggered by multiple mechanisms, including those involved in telomere shortening, the accumulation of DNA damage, epigenetic pathways, and the senescence-associated secretory phenotype (SASP), and so on. In current cancer therapy, cellular senescence has emerged as a potent tumor suppression mechanism that restrains proliferation in cells at risk for malignant transformation. Therefore, compounds that stimulate the growth inhibition effects of senescence while limiting its detrimental effects are believed to have great clinical potential. In this review article, we first review the current knowledge of the pro- and antitumorigeneic functions of senescence and summarize the key roles of telomerase in the regulation of senescence in tumors. Second, we review the current literature regarding the anticancer effects of stilbene compounds that are mediated by the targeting of telomerase and cell senescence. Finally, we provide future perspectives on the clinical utilization of stilbene compounds, especially resveratrol and pterostilbene, as novel cancer therapeutic remedies. We conclude and propose that stilbene compounds may induce senescence and may potentially be used as the therapeutic or adjuvant agents for cancers with high telomerase activity.

scholarly journals Skeletal Aging and Osteoporosis: Mechanisms and Therapeutics

2021 ◽  
Vol 22 (7) ◽  
pp. 3553
Author(s):  
Abhishek Chandra ◽  
Jyotika Rajawat
Keyword(s):  
Cellular Senescence ◽  
Endocrine Function ◽  
Bone Homeostasis ◽  
Cellular Mechanisms ◽  
Treatment Of Osteoporosis ◽  
Age Related ◽  
Cell Clearance ◽  
Cellular Apoptosis ◽  
Radiation Induced ◽  
Secretory Phenotype

Bone is a dynamic organ maintained by tightly regulated mechanisms. With old age, bone homeostasis, which is maintained by an intricate balance between bone formation and bone resorption, undergoes deregulation. Oxidative stress-induced DNA damage, cellular apoptosis, and cellular senescence are all responsible for this tissue dysfunction and the imbalance in the bone homeostasis. These cellular mechanisms have become a target for therapeutics to treat age-related osteoporosis. Genetic mouse models have shown the importance of senescent cell clearance in alleviating age-related osteoporosis. Furthermore, we and others have shown that targeting cellular senescence pharmacologically was an effective tool to alleviate age- and radiation-induced osteoporosis. Senescent cells also have an altered secretome known as the senescence associated secretory phenotype (SASP), which may have autocrine, paracrine, or endocrine function. The current review discusses the current and potential pathways which lead to a senescence profile in an aged skeleton and how bone homeostasis is affected during age-related osteoporosis. The review has also discussed existing therapeutics for the treatment of osteoporosis and rationalizes for novel therapeutic options based on cellular senescence and the SASP as an underlying pathogenesis of an aging bone.

scholarly journals Cellular Senescence: Mechanisms and Therapeutic Potential

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1769
Author(s):  
Zehuan Liao ◽  
Han Lin Yeo ◽  
Siaw Wen Wong ◽  
Yan Zhao
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cellular Senescence ◽  
Biological Process ◽  
Therapeutic Potential ◽  
Biological Processes ◽  
Limb Patterning ◽  
Cycle Arrest ◽  
Major Interest ◽  
Secretory Phenotype

Cellular senescence is a complex and multistep biological process which cells can undergo in response to different stresses. Referring to a highly stable cell cycle arrest, cellular senescence can influence a multitude of biological processes—both physiologically and pathologically. While phenotypically diverse, characteristics of senescence include the expression of the senescence-associated secretory phenotype, cell cycle arrest factors, senescence-associated β-galactosidase, morphogenesis, and chromatin remodelling. Persistent senescence is associated with pathologies such as aging, while transient senescence is associated with beneficial programmes, such as limb patterning. With these implications, senescence-based translational studies, namely senotherapy and pro-senescence therapy, are well underway to find the cure to complicated diseases such as cancer and atherosclerosis. Being a subject of major interest only in the recent decades, much remains to be studied, such as regarding the identification of unique biomarkers of senescent cells. This review attempts to provide a comprehensive understanding of the diverse literature on senescence, and discuss the knowledge we have on senescence thus far.

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