scholarly journals Exosomes are key regulators of non-cell autonomous communication in senescence

2018 ◽  
Author(s):  
Michela Borghesan ◽  
Juan Fafián-Labora ◽  
Paula Carpintero-Fernández ◽  
Pilar Ximenez-Embun ◽  
Hector Peinado ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Cellular Phenotype ◽  
Senescent Phenotype ◽  
Tissue Degeneration ◽  
Cycle Arrest ◽  
Age Related ◽  
Form Part ◽  
Reporter Systems ◽  
Inflammatory Proteins ◽  
Secretory Phenotype

SUMMARYSenescence is a cellular phenotype characterized by an irreversible cell cycle arrest and the secretion of inflammatory proteins, denominated senescence-associated secretory phenotype (SASP). The SASP is important in influencing the behavior of neighboring cells and altering the microenvironment; yet, until now this role has been mainly attributed to soluble factors. Here, we report that extracellular vesicles also alter the environment by transmitting the senescent phenotype to other cells via exosomes (extracellular vesicles of endocytic origin). A combination of functional assays, Cre-/oxP reporter systems, proteomic analysis and RNAi screens confirm that exosomes form part of the senescent secretome and mediate paracrine senescence via the activation of a non-canonical interferon (IFN) pathway. Altogether, we speculate that exosomes could be drivers of tissue degeneration both locally and systemically during aging and age- related disease.

scholarly journals Translational control during cellular senescence

2020 ◽  
Author(s):  
Matthew J. Payea ◽  
Carlos Anerillas ◽  
Ravi Tharakan ◽  
Myriam Gorospe
Keyword(s):  
Translational Control ◽  
Ribosome Biogenesis ◽  
Rrna Processing ◽  
Proliferating Cells ◽  
Cycle Arrest ◽  
Nucleolar Stress ◽  
Specific Proteins ◽  
Inflammatory Proteins ◽  
Secretory Phenotype

Senescence is a state of long-term cell-cycle arrest that arises in cells that have incurred sub-lethal damage. While senescent cells no longer replicate, they remain metabolically active and further develop unique and stable phenotypes that are not present in proliferating cells. On one hand, senescent cells increase in size, maintain an active mTORC1 complex, and produce and secrete a substantial amount of inflammatory proteins as part of the senescence associated secretory phenotype (SASP). On the other hand, these pro-growth phenotypes contrast with the p53-mediated growth arrest typical of senescent cells that is associated with nucleolar stress and an inhibition of rRNA processing and ribosome biogenesis. In sum, translation in senescent cells paradoxically comprises both a global repression of translation triggered by DNA damage and a select increase in the translation of specific proteins, including SASP factors.

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 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 Senescence-associated extracellular vesicle release plays a role in senescence-associated secretory phenotype (SASP) in age-associated diseases

2020 ◽  
Author(s):  
Yoko Tanaka ◽  
Akiko Takahashi
Keyword(s):  
Dna Damage ◽  
Molecular Mechanisms ◽  
Extracellular Vesicle ◽  
The Body ◽  
Vesicle Release ◽  
Gene Pathway ◽  
Age Related ◽  
Suppression Mechanism ◽  
Inflammatory Proteins ◽  
Secretory Phenotype

Abstract Cellular senescence is an important tumour suppression mechanism that inhibits the proliferation of damaged cells. In senescent cells, irreparable DNA damage causes accumulation of genomic DNA fragments in the cytoplasm, which are recognized by the cyclic GMP-AMP synthase–stimulator of interferon gene pathway, resulting in secretion of numerous inflammatory proteins. This phenomenon is called senescence-associated secretory phenotype, and results in multiple physiological or pathological processes in the body. In addition, DNA damage also increases small extracellular vesicle release from senescent cells. This review presents recent insights into the molecular mechanisms and biological functions of senescence-associated extracellular vesicle release that is associated with age-related diseases, particularly cancer.

scholarly journals IPF lung fibroblasts have a senescent phenotype

2017 ◽  
Vol 313 (6) ◽  
pp. L1164-L1173 ◽  
Author(s):  
Diana Álvarez ◽  
Nayra Cárdenes ◽  
Jacobo Sellarés ◽  
Marta Bueno ◽  
Catherine Corey ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Human Lung ◽  
Transforming Growth Factor Β ◽  
Lung Fibroblasts ◽  
Senescent Phenotype ◽  
Age Related ◽  
Fibrotic Process ◽  
A Cell ◽  
Secretory Phenotype ◽  
Senescence Phenotype

The mechanisms of aging that are involved in the development of idiopathic pulmonary fibrosis (IPF) are still unclear. Although it has been hypothesized that the proliferation and activation of human lung fibroblasts (hLFs) are essential in IPF, no studies have assessed how this process works in an aging lung. Our goal was to elucidate if there were age-related changes on primary hLFs isolated from IPF lungs compared with age-matched controls. We investigated several hallmarks of aging in hLFs from IPF patients and age-matched controls. IPF hLFs have increased cellular senescence with higher expression of β-galactosidase, p21, p16, p53, and cytokines related to the senescence-associated secretory phenotype (SASP) as well as decreased proliferation/apoptosis compared with age-matched controls. Additionally, we observed shorter telomeres, mitochondrial dysfunction, and upon transforming growth factor-β stimulation, increased markers of endoplasmic reticulum stress. Our data suggest that IPF hLFs develop senescence resulting in a decreased apoptosis and that the development of SASP may be an important contributor to the fibrotic process observed in IPF. These results might change the existing paradigm, which describes fibroblasts as aberrantly activated cells, to a cell with a senescence phenotype.

scholarly journals GH and Senescence: A New Understanding of Adult GH Action

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Vera Chesnokova ◽  
Shlomo Melmed
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Replicative Senescence ◽  
Aging Effects ◽  
Tissue Microenvironment ◽  
Senescent Phenotype ◽  
Age Related ◽  
Benign Nature ◽  
Secretory Phenotype ◽  
Somatic Copy Number Alterations

Abstract Replicative senescence occurs due to an inability to repair DNA damage and activation of p53/p21 and p16INK4 pathways. It is considered a preventive mechanism for arresting proliferation of DNA-damaged cells. Stably senescent cells are characterized by a senescence-associated secretory phenotype (SASP), which produces and secretes cytokines, chemokines, and/or matrix metalloproteinases depending on the cell type. SASP proteins may increase cell proliferation, facilitating conversion of premalignant to malignant tumor cells, triggering DNA damage, and altering the tissue microenvironment. Further, senescent cells accumulate with age, thereby aggravating age-related tissue damage. Here, we review a heretofore unappreciated role for growth hormone (GH) as a SASP component, acting in an autocrine and paracrine fashion. In senescent cells, GH is activated by DNA-damage-induced p53 and inhibits phosphorylation of DNA repair proteins ATM, Chk2, p53, and H2AX. Somatotroph adenomas containing abundant intracellular GH exhibit increased somatic copy number alterations, indicative of DNA damage, and are associated with induced p53/p21. As this pathway restrains proliferation of DNA-damaged cells, these mechanisms may underlie the senescent phenotype and benign nature of slowly proliferating pituitary somatotroph adenomas. In highly proliferative cells, such as colon epithelial cells, GH induced in response to DNA damage suppresses p53, thereby triggering senescent cell proliferation. As senescent cells harbor unrepaired DNA damage, GH may enable senescent cells to evade senescence and reenter the cell cycle, resulting in acquisition of harmful mutations. These mechanisms, at least in part, may underlie pro-aging effects of GH observed in animal models and in patients with chronically elevated GH levels.

scholarly journals Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype

2021 ◽  
Vol 9 ◽  
Author(s):  
Ruchi Kumari ◽  
Parmjit Jat
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cellular Senescence ◽  
Molecular Mechanisms ◽  
Growth Arrest ◽  
Dependent Manner ◽  
Tissue Repair And Regeneration ◽  
Cycle Arrest ◽  
Age Related ◽  
Secretory Phenotype

Cellular senescence is a stable cell cycle arrest that can be triggered in normal cells in response to various intrinsic and extrinsic stimuli, as well as developmental signals. Senescence is considered to be a highly dynamic, multi-step process, during which the properties of senescent cells continuously evolve and diversify in a context dependent manner. It is associated with multiple cellular and molecular changes and distinct phenotypic alterations, including a stable proliferation arrest unresponsive to mitogenic stimuli. Senescent cells remain viable, have alterations in metabolic activity and undergo dramatic changes in gene expression and develop a complex senescence-associated secretory phenotype. Cellular senescence can compromise tissue repair and regeneration, thereby contributing toward aging. Removal of senescent cells can attenuate age-related tissue dysfunction and extend health span. Senescence can also act as a potent anti-tumor mechanism, by preventing proliferation of potentially cancerous cells. It is a cellular program which acts as a double-edged sword, with both beneficial and detrimental effects on the health of the organism, and considered to be an example of evolutionary antagonistic pleiotropy. Activation of the p53/p21WAF1/CIP1 and p16INK4A/pRB tumor suppressor pathways play a central role in regulating senescence. Several other pathways have recently been implicated in mediating senescence and the senescent phenotype. Herein we review the molecular mechanisms that underlie cellular senescence and the senescence associated growth arrest with a particular focus on why cells stop dividing, the stability of the growth arrest, the hypersecretory phenotype and how the different pathways are all integrated.

scholarly journals Cellular Senescence in Kidney Fibrosis: Pathologic Significance and Therapeutic Strategies

2020 ◽  
Vol 11 ◽  
Author(s):  
Jie Xu ◽  
Lili Zhou ◽  
Youhua Liu
Keyword(s):  
Cellular Senescence ◽  
Premature Aging ◽  
Fine Tuning ◽  
Ckd Progression ◽  
Kidney Fibrosis ◽  
Cycle Arrest ◽  
Age Related ◽  
Secretory Phenotype ◽  
Characteristic Features ◽  
Aging Kidney

Age-related disorders such as chronic kidney disease (CKD) are increasingly prevalent globally and pose unprecedented challenges. In many aspects, CKD can be viewed as a state of accelerated and premature aging. Aging kidney and CKD share many common characteristic features with increased cellular senescence, a conserved program characterized by an irreversible cell cycle arrest with altered transcriptome and secretome. While developmental senescence and acute senescence may positively contribute to the fine-tuning of embryogenesis and injury repair, chronic senescence, when unresolved promptly, plays a crucial role in kidney fibrogenesis and CKD progression. Senescent cells elicit their fibrogenic actions primarily by secreting an assortment of inflammatory and profibrotic factors known as the senescence-associated secretory phenotype (SASP). Increasing evidence indicates that senescent cells could be a promising new target for therapeutic intervention known as senotherapy, which includes depleting senescent cells, modulating SASP and restoration of senescence inhibitors. In this review, we discuss current understanding of the role and mechanism of cellular senescence in kidney fibrosis. We also highlight potential options of targeting senescent cells for the treatment of CKD.

scholarly journals The Rise and the Death of Senescent Cells: From Mechanisms to Interventions

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 300-300
Author(s):  
Marco Demaria
Keyword(s):  
Cell Cycle ◽  
Inflammatory Factors ◽  
Low Grade ◽  
Human Aging ◽  
Health Span ◽  
Cycle Arrest ◽  
Age Related ◽  
Secretory Phenotype ◽  
Tissue Aging ◽  
Improve Health

Abstract Aging is at the root of age-related diseases and therapies targeting basic age-associated mechanisms have the potential to extend healthy lifespan. A common feature of older organisms is the accumulation of senescent cells – cells that have irreversibly lost the capacity to undergo replication. Senescent cells are characterized by an irreversible cell cycle arrest and by the Senescence-Associated Secretory Phenotype (SASP), which include many tissue remodeling and pro-inflammatory factors. Senescent cells are intermittently present during embryogenesis and in young organisms. On the contrary senescent cells accumulate and persist in aging tissues. Significantly, these persistent senescent cells can drive low-grade chronic inflammation, and their genetic or pharmacological elimination is sufficient to delay a number of diseases and to improve health span. Here, I will discuss the mechanisms by which senescent cells can promote tissue aging and dysfunction and the potential of targeting senescent cells to delay human aging.

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