scholarly journals p53 Isoforms in Cellular Senescence- and Ageing-Associated Biological and Physiological Functions

2019 ◽  
Vol 20 (23) ◽  
pp. 6023 ◽  
Author(s):  
Kaori Fujita
Keyword(s):  
Cellular Senescence ◽  
Human Fibroblasts ◽  
Full Length ◽  
Protein Isoforms ◽  
Specific Cell ◽  
Gene Expressions ◽  
Related Disorder ◽  
Immune System Activation ◽  
Age Related ◽  
P53 Isoforms

Cellular senescence, a term originally used to define the characteristics of normal human fibroblasts that reached their replicative limit, is an important factor for ageing, age-related diseases including cancer, and cell reprogramming. These outcomes are mediated by senescence-associated changes in gene expressions, which sometimes lead to the secretion of pro-inflammatory factors, or senescence-associated secretory phenotype (SASP) that contribute to paradoxical pro-tumorigenic effects. p53 functions as a transcription factor in cell-autonomous responses such as cell-cycle control, DNA repair, apoptosis, and cellular senescence, and also non-cell-autonomous responses to DNA damage by mediating the SASP function of immune system activation. The human TP53 gene encodes twelve protein isoforms, which provides an explanation for the pleiotropic p53 function on cellular senescence. Recent reports suggest that some short isoforms of p53 may modulate gene expressions in a full-length p53-dependent and -independent manner, in other words, some p53 isoforms cooperate with full-length p53, whereas others operate independently. This review summarizes our current knowledge about the biological activities and functions of p53 isoforms, especially Δ40p53, Δ133p53α, and p53β, on cellular senescence, ageing, age-related disorder, reprogramming, and cancer. Numerous cellular and animal model studies indicate that an unbalance in p53 isoform expression in specific cell types causes age-related disorders such as cancer, premature ageing, and degenerative diseases.

scholarly journals Targeting cellular senescence in cancer and aging: roles of p53 and its isoforms

2020 ◽  
Vol 41 (8) ◽  
pp. 1017-1029 ◽  
Author(s):  
Jessica Beck ◽  
Casmir Turnquist ◽  
Izumi Horikawa ◽  
Curtis Harris
Keyword(s):  
Cellular Senescence ◽  
Therapeutic Potential ◽  
P53 Protein ◽  
Tp53 Gene ◽  
Suppressor Gene ◽  
Cellular Reprogramming ◽  
Protein Isoforms ◽  
Age Related ◽  
Alternative Mrna Splicing ◽  
P53 Isoforms

Abstract Cellular senescence and the associated secretory phenotype (SASP) promote disease in the aged population. Targeting senescent cells by means of removal, modulation of SASP or through cellular reprogramming represents a novel therapeutic avenue for treating cancer- and age-related diseases such as neurodegeneration, pulmonary fibrosis and renal disease. Cellular senescence is partly regulated by the TP53 gene, a critical tumor suppressor gene which encodes 12 or more p53 protein isoforms. This review marks a significant milestone of 40 years of Carcinogenesis publication history and p53 research and 15 years of p53 isoform research. The p53 isoforms are produced through initiation at alternative transcriptional and translational start sites and alternative mRNA splicing. These truncated p53 isoform proteins are endogenously expressed in normal human cells and maintain important functional roles, including modulation of full-length p53-mediated cellular senescence, apoptosis and DNA repair. In this review, we discuss the mechanisms and functions of cellular senescence and SASP in health and disease, the regulation of cellular senescence by p53 isoforms, and the therapeutic potential of targeting cellular senescence to treat cancer- and age-associated diseases.

scholarly journals Cellular Senescence in the Lung: The Central Role of Senescent Epithelial Cells

2020 ◽  
Vol 21 (9) ◽  
pp. 3279 ◽  
Author(s):  
Christine Hansel ◽  
Verena Jendrossek ◽  
Diana Klein
Keyword(s):  
Cell Cycle ◽  
Cellular Senescence ◽  
Inflammatory Diseases ◽  
Cancer Tissue ◽  
Gene Expressions ◽  
Proliferating Cells ◽  
Differentiated Cells ◽  
Tissue Degeneration ◽  
Age Related

Cellular senescence is a key process in physiological dysfunction developing upon aging or following diverse stressors including ionizing radiation. It describes the state of a permanent cell cycle arrest, in which proliferating cells become resistant to growth-stimulating factors. Senescent cells differ from quiescent cells, which can re-enter the cell cycle and from finally differentiated cells: morphological and metabolic changes, restructuring of chromatin, changes in gene expressions and the appropriation of an inflammation-promoting phenotype, called the senescence-associated secretory phenotype (SASP), characterize cellular senescence. The biological role of senescence is complex, since both protective and harmful effects have been described for senescent cells. While initially described as a mechanism to avoid malignant transformation of damaged cells, senescence can even contribute to many age-related diseases, including cancer, tissue degeneration, and inflammatory diseases, particularly when senescent cells persist in damaged tissues. Due to overwhelming evidence about the important contribution of cellular senescence to the pathogenesis of different lung diseases, specific targeting of senescent cells or of pathology-promoting SASP factors has been suggested as a potential therapeutic approach. In this review, we summarize recent advances regarding the role of cellular (fibroblastic, endothelial, and epithelial) senescence in lung pathologies, with a focus on radiation-induced senescence. Among the different cells here, a central role of epithelial senescence is suggested.

scholarly journals Δ133p53α Protects Human Astrocytes from Amyloid-Beta Induced Senescence and Neurotoxicity

2021 ◽  
Author(s):  
Kyra Ungerleider ◽  
Delphine Lissa ◽  
Jessica A Beck ◽  
Izumi Horikawa ◽  
Curtis C Harris
Keyword(s):  
Dna Damage ◽  
Amyloid Beta ◽  
Cellular Senescence ◽  
Dominant Negative ◽  
Full Length ◽  
Negative Regulator ◽  
Pharmacological Agents ◽  
Human Astrocytes ◽  
Age Related ◽  
Enhanced Expression

Cellular senescence is an important contributor to aging and age-related diseases such as Alzheimer's disease (AD). Senescent cells are characterized by a durable cell proliferation arrest and the acquisition of a proinflammatory senescence-associated secretory phenotype (SASP), which participates in the progression of neurodegenerative disorders. Clearance of senescent glial cells in an AD mouse model prevented cognitive decline suggesting pharmacological agents targeting cellular senescence might provide novel therapeutic approaches for AD. Δ133p53α, a natural protein isoform of p53, was previously shown to be a negative regulator of cellular senescence in primary human astrocytes, with clinical implications from its diminished expression in brain tissues from AD patients. Here we show that treatment of proliferating human astrocytes with amyloid-beta oligomers (Aβ), an endogenous pathogenic agent of AD, results in reduced expression of Δ133p53α, as well as induces the cells to become senescent and express proinflammatory SASP cytokines such as IL-6, IL-1β and TNFα. Our data suggest that Aβ-induced astrocyte cellular senescence is associated with accelerated DNA damage, and upregulation of full-length p53 and its senescence-inducing target gene p21WAF1. We also show that exogenously enhanced expression of Δ133p53α rescues human astrocytes from Aβ-induced cellular senescence and SASP through both protection from DNA damage and dominant-negative inhibition of full-length p53, leading to inhibition of Aβ-induced, astrocyte-mediated neurotoxicity. The results presented here demonstrate that Δ133p53α manipulation could modulate cellular senescence in the context of AD, possibly opening new therapeutic avenues.

scholarly journals Cellular Senescence in Adrenocortical Biology and Its Disorders

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3474
Author(s):  
Xin Gao ◽  
Faping Li ◽  
Bin Liu ◽  
Yuxiong Wang ◽  
Yishu Wang ◽  
...  
Keyword(s):  
Adrenal Cortex ◽  
Cellular Senescence ◽  
Human Fibroblasts ◽  
Zona Glomerulosa ◽  
Adrenal Androgen ◽  
Senescent Phenotype ◽  
Age Related ◽  
Endocrine Organs ◽  
Age Dependent ◽  
Sexual Characteristics

Cellular senescence is considered a physiological process along with aging and has recently been reported to be involved in the pathogenesis of many age-related disorders. Cellular senescence was first found in human fibroblasts and gradually explored in many other organs, including endocrine organs. The adrenal cortex is essential for the maintenance of blood volume, carbohydrate metabolism, reaction to stress and the development of sexual characteristics. Recently, the adrenal cortex was reported to harbor some obvious age-dependent features. For instance, the circulating levels of aldosterone and adrenal androgen gradually descend, whereas those of cortisol increase with aging. The detailed mechanisms have remained unknown, but cellular senescence was considered to play an essential role in age-related changes of the adrenal cortex. Recent studies have demonstrated that the senescent phenotype of zona glomerulosa (ZG) acts in association with reduced aldosterone production in both physiological and pathological aldosterone-producing cells, whereas senescent cortical-producing cells seemed not to have a suppressed cortisol-producing ability. In addition, accumulated lipofuscin formation, telomere shortening and cellular atrophy in zona reticularis cells during aging may account for the age-dependent decline in adrenal androgen levels. In adrenocortical disorders, including both aldosterone-producing adenoma (APA) and cortisol-producing adenoma (CPA), different cellular subtypes of tumor cells presented divergent senescent phenotypes, whereby compact cells in both APA and CPA harbored more senescent phenotypes than clear cells. Autonomous cortisol production from CPA reinforced a local cellular senescence that was more severe than that in APA. Adrenocortical carcinoma (ACC) was also reported to harbor oncogene-induced senescence, which compensatorily follows carcinogenesis and tumor progress. Adrenocortical steroids can induce not only a local senescence but also a periphery senescence in many other tissues. Therefore, herein, we systemically review the recent advances related to cellular senescence in adrenocortical biology and its associated disorders.

scholarly journals Cellular Senescence in Sarcopenia: Possible Mechanisms and Therapeutic Potential

2022 ◽  
Vol 9 ◽  
Author(s):  
Yongyu He ◽  
Wenqing Xie ◽  
Hengzhen Li ◽  
Hongfu Jin ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Progression ◽  
Cellular Senescence ◽  
Therapeutic Potential ◽  
Health Care Expenditures ◽  
Cellular Tissue ◽  
Related Disorder ◽  
Muscle Stem Cells ◽  
Age Related ◽  
New Findings

Aging promotes most degenerative pathologies in mammals, which are characterized by progressive decline of function at molecular, cellular, tissue, and organismal levels and account for a host of health care expenditures in both developing and developed nations. Sarcopenia is a prominent age-related disorder in musculoskeletal system. Defined as gradual and generalized chronic skeletal muscle disorder, sarcopenia involves accelerated loss of muscle mass, strength and function, which is associated with increased adverse functional outcomes and evolutionally refers to muscle wasting accompanied by other geriatric syndromes. More efforts have been made to clarify mechanisms underlying sarcopenia and new findings suggest that it may be feasible to delay age-related sarcopenia by modulating fundamental mechanisms such as cellular senescence. Cellular senescence refers to the essentially irreversible growth arrest mainly regulated by p53/p21CIP1 and p16INK4a/pRB pathways as organism ages, possibly detrimentally contributing to sarcopenia via muscle stem cells (MuSCs) dysfunction and the senescence-associated secretory phenotype (SASP) while cellular senescence may have beneficial functions in counteracting cancer progression, tissue regeneration and wound healing. By now diverse studies in mice and humans have established that targeting cellular senescence is a powerful strategy to alleviating sarcopenia. However, the mechanisms through which senescent cells contribute to sarcopenia progression need to be further researched. We review the possible mechanisms involved in muscle stem cells (MuSCs) dysfunction and the SASP resulting from cellular senescence, their associations with sarcopenia, current emerging therapeutic opportunities based on targeting cellular senescence relevant to sarcopenia, and potential paths to developing clinical interventions genetically or pharmacologically.

scholarly journals Cellular senescence in musculoskeletal homeostasis, diseases, and regeneration

Bone Research ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Mei Wan ◽  
Elise F. Gray-Gaillard ◽  
Jennifer H. Elisseeff
Keyword(s):  
Musculoskeletal Disorders ◽  
Cellular Senescence ◽  
Musculoskeletal System ◽  
Musculoskeletal Diseases ◽  
Specific Cell ◽  
Initial Growth ◽  
Bone Homeostasis ◽  
Age Related ◽  
Promising Therapeutic Approach

AbstractEmerging insights into cellular senescence highlight the relevance of senescence in musculoskeletal disorders, which represent the leading global cause of disability. Cellular senescence was initially described by Hayflick et al. in 1961 as an irreversible nondividing state in in vitro cell culture studies. We now know that cellular senescence can occur in vivo in response to various stressors as a heterogeneous and tissue-specific cell state with a secretome phenotype acquired after the initial growth arrest. In the past two decades, compelling evidence from preclinical models and human data show an accumulation of senescent cells in many components of the musculoskeletal system. Cellular senescence is therefore a defining feature of age-related musculoskeletal disorders, and targeted elimination of these cells has emerged recently as a promising therapeutic approach to ameliorate tissue damage and promote repair and regeneration of the skeleton and skeletal muscles. In this review, we summarize evidence of the role of senescent cells in the maintenance of bone homeostasis during childhood and their contribution to the pathogenesis of chronic musculoskeletal disorders, including osteoporosis, osteoarthritis, and sarcopenia. We highlight the diversity of the senescent cells in the microenvironment of bone, joint, and skeletal muscle tissue, as well as the mechanisms by which these senescent cells are involved in musculoskeletal diseases. In addition, we discuss how identifying and targeting senescent cells might positively affect pathologic progression and musculoskeletal system regeneration.

scholarly journals Deep Learning Shows Cellular Senescence Is a Barrier to Cancer Development

2021 ◽  
Author(s):  
Indra Heckenbach ◽  
Michael Ben Ezra ◽  
Garik V Mkrtchyan ◽  
Jakob Sture Madsen ◽  
Malte Hasle Nielsen ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Human Fibroblasts ◽  
Protective Role ◽  
Premature Aging ◽  
Cancer Development ◽  
Malignant Neoplasms ◽  
Age Related ◽  
Murine Liver ◽  
Exclusive Or

Cellular senescence is a critical component of aging and many age-related diseases, but understanding its role in human health is challenging in part due to the lack of exclusive or universal markers. Using neural networks, we achieve high accuracy in predicting senescence state and type from the nuclear morphology of DAPI-stained human fibroblasts, murine astrocytes and fibroblasts derived from premature aging diseases in vitro. After generalizing this approach, the predictor recognizes an increasing rate of senescent cells with age in H&E-stained murine liver tissue and human dermal biopsies. Evaluating corresponding medical records reveals that individuals with increased senescent cells have a significantly decreased rate of malignant neoplasms, lending support for the protective role of senescence in limiting cancer development. In sum, we introduce a novel predictor of cellular senescence and apply it to diagnostic medical images, indicating cancer occurs more frequently for those with a lower rate of senescence.

scholarly journals Nuclear morphology is a deep learning biomarker of senescence across tissues and species

2021 ◽  
Author(s):  
Indra Heckenbach ◽  
Garik Mkrtchyan ◽  
Michael Ben Ezra ◽  
Daniela Bakula ◽  
Jakob Madsen ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Human Fibroblasts ◽  
Positive Association ◽  
Protective Role ◽  
Premature Aging ◽  
Malignant Neoplasms ◽  
Nuclear Morphology ◽  
Age Related ◽  
Murine Liver ◽  
Exclusive Or

Abstract Cellular senescence is a critical component of aging and many age-related diseases, but understanding its role in human health is challenging in part due to the lack of exclusive or universal markers. Using neural networks, we achieve high accuracy in predicting senescence state and type from the nuclear morphology of DAPI-stained human fibroblasts, murine astrocytes, murine neurons, and fibroblasts derived from premature aging diseases in culture. After generalizing this approach, the predictor recognizes an increasing rate of senescent cells with age in H&E-stained murine liver tissue and human dermal biopsies, suggesting that alterations in nuclear morphology is a universal feature of senescence. Evaluating corresponding medical records reveals that individuals with a higher rate of senescent cells have a significantly decreased rate of malignant neoplasms, lending support for the protective role of senescence in limiting cancer development. Additionally, we find a positive association with lower significance for other conditions, including osteoporosis, osteoarthritis, hypertension, cerebral infarction, hyperlipidemia, and hypercholesteremia. In sum, we introduce a predictor of cellular senescence based on nuclear morphology that is applicable across tissues and species and is associated with health outcomes in humans.

scholarly journals Cellular Senescence in Lung Fibrosis

2021 ◽  
Vol 22 (13) ◽  
pp. 7012
Author(s):  
Fernanda Hernandez-Gonzalez ◽  
Rosa Faner ◽  
Mauricio Rojas ◽  
Alvar Agustí ◽  
Manuel Serrano ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cellular Senescence ◽  
Lung Fibrosis ◽  
Lung Diseases ◽  
Physiological Mechanism ◽  
Lung Parenchyma ◽  
Scar Tissue ◽  
Interstitial Lung Diseases ◽  
Cellular Damage ◽  
Age Related

Fibrosing interstitial lung diseases (ILDs) are chronic and ultimately fatal age-related lung diseases characterized by the progressive and irreversible accumulation of scar tissue in the lung parenchyma. Over the past years, significant progress has been made in our incomplete understanding of the pathobiology underlying fibrosing ILDs, in particular in relation to diverse age-related processes and cell perturbations that seem to lead to maladaptation to stress and susceptibility to lung fibrosis. Growing evidence suggests that a specific biological phenomenon known as cellular senescence plays an important role in the initiation and progression of pulmonary fibrosis. Cellular senescence is defined as a cell fate decision caused by the accumulation of unrepairable cellular damage and is characterized by an abundant pro-inflammatory and pro-fibrotic secretome. The senescence response has been widely recognized as a beneficial physiological mechanism during development and in tumour suppression. However, recent evidence strengthens the idea that it also drives degenerative processes such as lung fibrosis, most likely by promoting molecular and cellular changes in chronic fibrosing processes. Here, we review how cellular senescence may contribute to lung fibrosis pathobiology, and we highlight current and emerging therapeutic approaches to treat fibrosing ILDs by targeting cellular senescence.

scholarly journals Cellular Senescence and Mammalian Healthspan

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 742-742
Author(s):  
Judith Campisi
Keyword(s):  
Growth Factors ◽  
Cell Fate ◽  
Cellular Senescence ◽  
Complex Cell ◽  
Transgenic Mouse Models ◽  
Bioactive Lipids ◽  
Age Related ◽  
Mammalian Tissues ◽  
Secretory Phenotype ◽  
Near Future

Abstract Cellular senescence is a complex cell fate, often induced by stress or damage, that can be beneficial or deleterious, depending on the physiological context and age of the organism. A prominent feature of senescent cells is a multi-faceted senescence-associated secretory phenotype (SASP), which includes growth factors, cytokine and chemokines, growth factors, proteases, bioactive lipids and metabolites. Senescent cells increase with age in most, if not all, mammalian tissues. Through the use of transgenic mouse models, senescent cells are now known to causally drive numerous age-related pathologies, largely through the SASP. Eliminating senescent cells, genetically or through the use of senolytic/senomorphic agents, can improve the health span, at least in mice, and hold promise for extension to humans in the near future.

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