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.

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.

scholarly journals Ablation of XP-V gene causes adipose tissue senescence and metabolic abnormalities

2015 ◽  
Vol 112 (33) ◽  
pp. E4556-E4564 ◽  
Author(s):  
Yih-Wen Chen ◽  
Robert A. Harris ◽  
Zafer Hatahet ◽  
Kai-ming Chou
Keyword(s):  
Dna Damage ◽  
Adipose Tissue ◽  
Cellular Senescence ◽  
Metabolic Abnormalities ◽  
Visceral Fat Accumulation ◽  
The Metabolic Syndrome ◽  
Radiation Induced ◽  
V Gene ◽  
Factor Α ◽  
Contrast Reduction

Obesity and the metabolic syndrome have evolved to be major health issues throughout the world. Whether loss of genome integrity contributes to this epidemic is an open question. DNA polymerase η (pol η), encoded by the xeroderma pigmentosum (XP-V) gene, plays an essential role in preventing cutaneous cancer caused by UV radiation-induced DNA damage. Herein, we demonstrate that pol η deficiency in mice (pol η−/−) causes obesity with visceral fat accumulation, hepatic steatosis, hyperleptinemia, hyperinsulinemia, and glucose intolerance. In comparison to WT mice, adipose tissue from pol η−/− mice exhibits increased DNA damage and a greater DNA damage response, indicated by up-regulation and/or phosphorylation of ataxia telangiectasia mutated (ATM), phosphorylated H2AX (γH2AX), and poly[ADP-ribose] polymerase 1 (PARP-1). Concomitantly, increased cellular senescence in the adipose tissue from pol η−/− mice was observed and measured by up-regulation of senescence markers, including p53, p16Ink4a, p21, senescence-associated (SA) β-gal activity, and SA secretion of proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) as early as 4 wk of age. Treatment of pol η−/− mice with a p53 inhibitor, pifithrin-α, reduced adipocyte senescence and attenuated the metabolic abnormalities. Furthermore, elevation of adipocyte DNA damage with a high-fat diet or sodium arsenite exacerbated adipocyte senescence and metabolic abnormalities in pol η−/− mice. In contrast, reduction of adipose DNA damage with N-acetylcysteine or metformin ameliorated cellular senescence and metabolic abnormalities. These studies indicate that elevated DNA damage is a root cause of adipocyte senescence, which plays a determining role in the development of obesity and insulin resistance.

scholarly journals Autolysosomal degradation of cytosolic chromatin fragments antagonizes oxidative stress–induced senescence

2020 ◽  
Vol 295 (14) ◽  
pp. 4451-4463 ◽  
Author(s):  
Xiaojuan Han ◽  
Honghan Chen ◽  
Hui Gong ◽  
Xiaoqiang Tang ◽  
Ning Huang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cellular Senescence ◽  
Bafilomycin A1 ◽  
Nih3t3 Cells ◽  
Present Evidence ◽  
Chromatin Fragment ◽  
Secretory Phenotype ◽  
Peroxide Stress

Oxidative stress-induced DNA damage, the senescence-associated secretory phenotype (SASP), and impaired autophagy all are general features of senescent cells. However, the cross-talk among these events and processes is not fully understood. Here, using NIH3T3 cells exposed to hydrogen peroxide stress, we show that stress-induced DNA damage provokes the SASP largely via cytosolic chromatin fragment (CCF) formation, which activates a cascade comprising cGMP-AMP synthase (cGAS), stimulator of interferon genes protein (STING), NF-κB, and SASP, and that autolysosomal function inhibits this cascade. We found that CCFs accumulate in senescent cells with activated cGAS-STING-NF-κB signaling, promoting SASP and cellular senescence. We also present evidence that the persistent accumulation of CCFs in prematurely senescent cells is partially associated with a defect in DNA-degrading activity in autolysosomes and reduced abundance of activated DNase 2α. Intriguingly, we found that metformin- or rapamycin-induced activation of autophagy significantly lessened the size and levels of CCFs and repressed the activation of the cGAS-STING-NF-κB-SASP cascade and cellular senescence. These effects of autophagy activators indicated that autolysosomal function contributes to CCF clearance and SASP suppression, further supported by the fact that the lysosome inhibitor bafilomycin A1 blocked the role of autophagy-mediated CCF clearance and senescence repression.

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 Mechanisms and Regulation of Cellular Senescence

2021 ◽  
Vol 22 (23) ◽  
pp. 13173
Author(s):  
Lauréline Roger ◽  
Fanny Tomas ◽  
Véronique Gire
Keyword(s):  
Dna Damage ◽  
Cellular Senescence ◽  
Cell Types ◽  
Feedback Loops ◽  
Cellular Structures ◽  
Damage Response ◽  
Different Types ◽  
Secretory Phenotype ◽  
Different Cell Types ◽  
Different Tissues

Cellular senescence entails a state of an essentially irreversible proliferative arrest in which cells remain metabolically active and secrete a range of pro-inflammatory and proteolytic factors as part of the senescence-associated secretory phenotype. There are different types of senescent cells, and senescence can be induced in response to many DNA damage signals. Senescent cells accumulate in different tissues and organs where they have distinct physiological and pathological functions. Despite this diversity, all senescent cells must be able to survive in a nondividing state while protecting themselves from positive feedback loops linked to the constant activation of the DNA damage response. This capacity requires changes in core cellular programs. Understanding how different cell types can undergo extensive changes in their transcriptional programs, metabolism, heterochromatin patterns, and cellular structures to induce a common cellular state is crucial to preventing cancer development/progression and to improving health during aging. In this review, we discuss how senescent cells continuously evolve after their initial proliferative arrest and highlight the unifying features that define the senescent state.

scholarly journals Histone Variant H2A.J Marks Persistent DNA Damage and Triggers the Secretory Phenotype in Radiation-Induced Senescence

2020 ◽  
Vol 21 (23) ◽  
pp. 9130
Author(s):  
Anna Isermann ◽  
Carl Mann ◽  
Claudia E. Rübe
Keyword(s):  
Electron Microscopy ◽  
Dna Damage ◽  
Molecular Mechanisms ◽  
Human Fibroblasts ◽  
Histone Variant ◽  
Epigenetic Mechanism ◽  
Premature Senescence ◽  
Biological Phenomena ◽  
Radiation Induced ◽  
Secretory Phenotype

Irreparable double-strand breaks (DSBs) in response to ionizing radiation (IR) trigger prolonged DNA damage response (DDR) and induce premature senescence. Profound chromatin reorganization with formation of senescence-associated heterochromatin foci (SAHF) is an essential epigenetic mechanism for controlling the senescence-associated secretory phenotype (SASP). To decipher molecular mechanisms provoking continuous DDR leading to premature senescence, radiation-induced DSBs (53BP1-foci) and dynamics of histone variant H2A.J incorporation were analyzed together with chromatin re-modeling in human fibroblasts after IR exposure. High-resolution imaging by transmission electron microscopy revealed that persisting 53BP1-foci developed into DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS), consistently located at the periphery of SAHFs. Quantitative immunogold-analysis by electron microscopy revealed that H2A.J, steadily co-localizing with 53BP1, is increasingly incorporated into DNA-SCARS during senescence progression. Strikingly, shRNA-mediated H2A.J depletion in fibroblasts modified senescence-associated chromatin re-structuring and abolished SASP, thereby shutting down the production of inflammatory mediators. These findings provide mechanistic insights into biological phenomena of SASP and suggest that H2A.J inhibition could ablate SASP, without affecting the senescence-associated growth arrest.

scholarly journals Radiation induced pulmonary fibrosis as a model of progressive fibrosis: Contributions of DNA damage, inflammatory response and cellular senescence genes

2017 ◽  
Vol 43 (3) ◽  
pp. 134-149 ◽  
Author(s):  
Tyler A. Beach ◽  
Carl J. Johnston ◽  
Angela M. Groves ◽  
Jacqueline P. Williams ◽  
Jacob N. Finkelstein
Keyword(s):  
Dna Damage ◽  
Pulmonary Fibrosis ◽  
Inflammatory Response ◽  
Cellular Senescence ◽  
Radiation Induced

scholarly journals cGAS is essential for cellular senescence

2017 ◽  
Vol 114 (23) ◽  
pp. E4612-E4620 ◽  
Author(s):  
Hui Yang ◽  
Hanze Wang ◽  
Junyao Ren ◽  
Qi Chen ◽  
Zhijian J. Chen
Keyword(s):  
Dna Damage ◽  
Cellular Senescence ◽  
Proliferating Cells ◽  
Antitumor Effects ◽  
Embryonic Fibroblasts ◽  
Dna Damaging Agents ◽  
Damage Response ◽  
Secretory Phenotype ◽  
Spontaneous Immortalization

Cellular senescence is a natural barrier to tumorigenesis and it contributes to the antitumor effects of several therapies, including radiation and chemotherapeutic drugs. Senescence also plays an important role in aging, fibrosis, and tissue repair. The DNA damage response is a key event leading to senescence, which is characterized by the senescence-associated secretory phenotype (SASP) that includes expression of inflammatory cytokines. Here we show that cGMP-AMP (cGAMP) synthase (cGAS), a cytosolic DNA sensor that activates innate immunity, is essential for senescence. Deletion of cGAS accelerated the spontaneous immortalization of mouse embryonic fibroblasts. cGAS deletion also abrogated SASP induced by spontaneous immortalization or DNA damaging agents, including radiation and etoposide. cGAS is localized in the cytoplasm of nondividing cells but enters the nucleus and associates with chromatin DNA during mitosis in proliferating cells. DNA damage leads to accumulation of damaged DNA in cytoplasmic foci that contain cGAS. In human lung adenocarcinoma patients, low expression of cGAS is correlated with poor survival. These results indicate that cGAS mediates cellular senescence and retards immortalization. This is distinct from, and complementary to, the role of cGAS in activating antitumor immunity.

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