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 The Senescence-Associated Secretory Phenotype (SASP) in the Challenging Future of Cancer Therapy and Age-Related Diseases

Biology ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 485
Author(s):  
Lorenzo Cuollo ◽  
Fabrizio Antonangeli ◽  
Angela Santoni ◽  
Alessandra Soriani
Keyword(s):  
Cancer Therapy ◽  
Molecular Mechanisms ◽  
Therapeutic Strategies ◽  
Senescent Cell ◽  
Pharmacological Intervention ◽  
Tissue Microenvironment ◽  
Age Related ◽  
Secretory Phenotype ◽  
Novel Therapeutic Strategies ◽  
Novel Therapeutic

Cellular senescence represents a robust tumor-protecting mechanism that halts the proliferation of stressed or premalignant cells. However, this state of stable proliferative arrest is accompanied by the Senescence-Associated Secretory Phenotype (SASP), which entails the copious secretion of proinflammatory signals in the tissue microenvironment and contributes to age-related conditions, including, paradoxically, cancer. Novel therapeutic strategies aim at eliminating senescent cells with the use of senolytics or abolishing the SASP without killing the senescent cell with the use of the so-called “senomorphics”. In addition, recent works demonstrate the possibility of modifying the composition of the secretome by genetic or pharmacological intervention. The purpose is not to renounce the potent immunostimulatory nature of SASP, but rather learning to modulate it for combating cancer and other age-related diseases. This review describes the main molecular mechanisms regulating the SASP and reports the evidence of the feasibility of abrogating or modulating the SASP, discussing the possible implications of both strategies.

scholarly journals Length-independent telomere damage drives cardiomyocyte senescence

2018 ◽  
Author(s):  
Rhys Anderson ◽  
Anthony Lagnado ◽  
Damien Maggiorani ◽  
Anna Walaszczyk ◽  
Emily Dookun ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Dna Damage ◽  
Risk Factor ◽  
Cell Division ◽  
Cardiac Dysfunction ◽  
Cardiovascular Health ◽  
Myocardial Hypertrophy ◽  
Telomere Shortening ◽  
Age Related ◽  
Secretory Phenotype

AbstractAgeing is the biggest risk factor for cardiovascular health and is associated with increased incidence of cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age-related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post-mitotic cardiomyocytes and investigate if clearance of senescent cells attenuates age related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescent-like phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction, and crucially can occur independently of cell-division and telomere length. Length-independent telomere damage in cardiomyocytes activates the classical senescence-inducing pathways, p21CIP and p16INK4a and results in a non-canonical senescence-associated secretory phenotype. Pharmacological or genetic clearance of senescent cells in mice alleviates myocardial hypertrophy and fibrosis, detrimental features of cardiac ageing, and promotes cardiomyocyte regeneration. Our data describes a mechanism by which senescence can occur and contribute to ageing in post-mitotic tissues.

scholarly journals Protein Oxidative Damage at the Crossroads of Cellular Senescence, Aging, and Age-Related Diseases

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Martin A. Baraibar ◽  
Liang Liu ◽  
Emad K. Ahmed ◽  
Bertrand Friguet
Keyword(s):  
Lipid Peroxidation ◽  
Protein Modification ◽  
Replicative Senescence ◽  
Human Fibroblasts ◽  
Potential Effect ◽  
Senescent Phenotype ◽  
Intermediate Metabolism ◽  
Age Related ◽  
Cellular Pathways

Protein damage mediated by oxidation, protein adducts formation with advanced glycated end products and with products of lipid peroxidation, has been implicated during aging and age-related diseases, such as neurodegenerative diseases. Increased protein modification has also been described upon replicative senescence of human fibroblasts, a valid model for studying agingin vitro. However, the mechanisms by which these modified proteins could impact on the development of the senescent phenotype and the pathogenesis of age-related diseases remain elusive. In this study, we performedin silicoapproaches to evidence molecular actors and cellular pathways affected by these damaged proteins. A database of proteins modified by carbonylation, glycation, and lipid peroxidation products during aging and age-related diseases was built and compared to those proteins identified during cellular replicative senescencein vitro. Common cellular pathways evidenced by enzymes involved in intermediate metabolism were found to be targeted by these modifications, although different tissues have been examined. These results underscore the potential effect of protein modification in the impairment of cellular metabolism during aging and age-related diseases.

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 CSB promoter downregulation via histone H3 hypoacetylation is an early determinant of replicative senescence

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Clément Crochemore ◽  
Cristina Fernández-Molina ◽  
Benjamin Montagne ◽  
Audrey Salles ◽  
Miria Ricchetti
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Nitrosative Stress ◽  
Replicative Senescence ◽  
Histone H3 ◽  
Independent Manner ◽  
Normal Cells ◽  
Age Related ◽  
Damage Response ◽  
P21 Promoter

AbstractCellular senescence has causative links with ageing and age-related diseases, however, it remains unclear if progeroid factors cause senescence in normal cells. Here, we show that depletion of CSB, a protein mutated in progeroid Cockayne syndrome (CS), is the earliest known trigger of p21-dependent replicative senescence. CSB depletion promotes overexpression of the HTRA3 protease resulting in mitochondrial impairments, which are causally linked to CS pathological phenotypes. The CSB promoter is downregulated by histone H3 hypoacetylation during DNA damage-response. Mechanistically, CSB binds to the p21 promoter thereby downregulating its transcription and blocking replicative senescence in a p53-independent manner. This activity of CSB is independent of its role in the repair of UV-induced DNA damage. HTRA3 accumulation and senescence are partially rescued upon reduction of oxidative/nitrosative stress. These findings establish a CSB/p21 axis that acts as a barrier to replicative senescence, and link a progeroid factor with the process of regular ageing in human.

scholarly journals Nucleophosmin Is Required for DNA Integrity and p19Arf Protein Stability

2005 ◽  
Vol 25 (20) ◽  
pp. 8874-8886 ◽  
Author(s):  
Emanuela Colombo ◽  
Paola Bonetti ◽  
Eros Lazzerini Denchi ◽  
Paola Martinelli ◽  
Raffaella Zamponi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Genetic Alterations ◽  
Dna Integrity ◽  
Senescent Phenotype ◽  
Tumor Suppressive Function ◽  
Proliferation In Vitro

ABSTRACT Nucleophosmin (NPM) is a nucleolar phosphoprotein that binds the tumor suppressors p53 and p19Arf and is thought to be indispensable for ribogenesis, cell proliferation, and survival after DNA damage. The NPM gene is the most frequent target of genetic alterations in leukemias and lymphomas, though its role in tumorigenesis is unknown. We report here the first characterization of a mouse NPM knockout strain. Lack of NPM expression results in accumulation of DNA damage, activation of p53, widespread apoptosis, and mid-stage embryonic lethality. Fibroblasts explanted from null embryos fail to grow and rapidly acquire a senescent phenotype. Transfer of the NPM mutation into a p53-null background rescued apoptosis in vivo and fibroblast proliferation in vitro. Cells null for both p53 and NPM grow faster than control cells and are more susceptible to transformation by activated oncogenes, such as mutated Ras or overexpressed Myc. In the absence of NPM, Arf protein is excluded from nucleoli and is markedly less stable. Our data demonstrate that NPM regulates DNA integrity and, through Arf, inhibits cell proliferation and are consistent with a putative tumor-suppressive function of NPM.

scholarly journals The Role of microRNAs in Organismal and Skin Aging

2020 ◽  
Vol 21 (15) ◽  
pp. 5281
Author(s):  
Marta Gerasymchuk ◽  
Viktoriia Cherkasova ◽  
Olga Kovalchuk ◽  
Igor Kovalchuk
Keyword(s):  
Replicative Senescence ◽  
Skin Aging ◽  
Dermal Fibroblasts ◽  
Telomere Maintenance ◽  
Sirtuin 1 ◽  
Aging Effects ◽  
Inhibition Of Proliferation ◽  
Biomarkers Of Aging ◽  
Age Related

The aging process starts directly after birth and lasts for the entire lifespan; it manifests itself with a decline in an organism’s ability to adapt and is linked to the development of age-related diseases that eventually lead to premature death. This review aims to explore how microRNAs (miRNAs) are involved in skin functioning and aging. Recent evidence has suggested that miRNAs regulate all aspects of cutaneous biogenesis, functionality, and aging. It has been noted that some miRNAs were down-regulated in long-lived individuals, such as let-7, miR-17, and miR-34 (known as longevity-related miRNAs). They are conserved in humans and presumably promote lifespan prolongation; conversely, they are up-regulated in age-related diseases, like cancers. The analysis of the age-associated cutaneous miRNAs revealed the increased expression of miR-130, miR-138, and miR-181a/b in keratinocytes during replicative senescence. These miRNAs affected cell proliferation pathways via targeting the p63 and Sirtuin 1 mRNAs. Notably, miR-181a was also implicated in skin immunosenescence, represented by the Langerhans cells. Dermal fibroblasts also expressed increased the levels of the biomarkers of aging that affect telomere maintenance and all phases of the cellular life cycle, such as let-7, miR-23a-3p, 34a-5p, miR-125a, miR-181a-5p, and miR-221/222-3p. Among them, the miR-34 family, stimulated by ultraviolet B irradiation, deteriorates collagen in the extracellular matrix due to the activation of the matrix metalloproteinases and thereby potentiates wrinkle formation. In addition to the pro-aging effects of miRNAs, the plausible antiaging activity of miR-146a that antagonized the UVA-induced inhibition of proliferation and suppressed aging-related genes (e.g., p21WAF-1, p16, and p53) through targeting Smad4 has also been noticed. Nevertheless, the role of miRNAs in skin aging is still not fully elucidated and needs to be further discovered and explained.

scholarly journals Antiaging Effect of Pine Pollen in Human Diploid Fibroblasts and in a Mouse Model Induced by D-Galactose

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Gen-Xiang Mao ◽  
Ling-Di Zheng ◽  
Yong-Bao Cao ◽  
Zhuo-Mei Chen ◽  
Yuan-Dong Lv ◽  
...  
Keyword(s):  
Replicative Senescence ◽  
Advanced Glycation Endproducts ◽  
Accelerated Aging ◽  
Inhibitory Effect ◽  
Aging Effects ◽  
Glycation Endproducts ◽  
Human Diploid Fibroblasts ◽  
Age Related ◽  
Pine Pollen

The present paper was designed to investigate the effect of pine pollen against aging in human diploid fibroblast 2BS cells and in an accelerated aging model, which was established by subcutaneous injections with D-galactose daily for 8 weeks in C57BL/6J mice. Pine pollen (1 mg/mL and 2 mg/mL) is proved to delay the replicative senescence of 2BS cells as evidenced by enhanced cell proliferation, decreased SA-β-Gal activity, and reversed expression of senescence-associated molecular markers, such as p53,p21Waf1,p16INK4a, PTEN, andp27Kip1in late PD cells. Besides, pine pollen reversed D-galactose-induced aging effects in neural activity and inflammatory cytokine levels, as indicated by improved memory latency time and reduced error rate in step-down test and decreased concentrations of IL-6 and TNF-α in model mice. Similar to the role of AGEs (advanced glycation endproducts) formation inhibitor aminoguanidine (AG), pine pollen inhibited D-galactose-induced increment of AGEs levels thus reversed the aging phenotypes in model mice. Furthermore, the declined antioxidant activity was obviously reversed upon pine pollen treatment, which may account for its inhibitory effect on nonenzymatic glycation (NEG)in vivo. Our finding presents pine pollen as an attractive agent with potential to retard aging and attenuate age-related diseases in humans.

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.

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