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 Human Aging DNA Methylation Signatures are Conserved but Accelerated in Cultured Fibroblasts

2019 ◽  
Author(s):  
Gabriel Sturm ◽  
Andres Cardenas ◽  
Marie-Abèle Bind ◽  
Steve Horvath ◽  
Shuang Wang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Replicative Senescence ◽  
Human Fibroblasts ◽  
High Temporal Resolution ◽  
Global Changes ◽  
Mrna Levels ◽  
Cultured Fibroblasts ◽  
Age Related ◽  
Epigenetic Aging

SummaryAging is associated with progressive and site-specific changes in DNA methylation (DNAm). These global changes are captured by DNAm clocks that accurately predict chronological age in humans but relatively little is known about how clocks perform in vitro. Here we culture primary human fibroblasts across the cellular lifespan (∼6 months) and use four different DNAm clocks to show that age-related DNAm signatures are conserved and accelerated in vitro. The Skin & Blood clock shows the best linear correlation with chronological time (r=0.90), including during replicative senescence. Although similar in nature, the rate of epigenetic aging is approximately 62x times faster in cultured cells than in the human body. Consistent with in vivo data, cells aged under hyperglycemic conditions exhibit an approximately three years elevation in baseline DNAm age. Moreover, candidate gene-based analyses further corroborate the conserved but accelerated biological aging process in cultured fibroblasts. Fibroblasts mirror the established DNAm topology of the age-related ELOVL2 gene in human blood and the rapid hypermethylation of its promoter cg16867657, which correlates with a linear decrease in ELOVL2 mRNA levels across the lifespan. Using generalized additive modeling on twelve timepoints across the lifespan, we also show how single CpGs exhibit loci-specific, linear and nonlinear trajectories that reach rates up to −47% (hypomethylation) to +23% (hypermethylation) per month. Together, these high temporal resolution global, gene-specific, and single CpG data highlight the conserved and accelerated nature of epigenetic aging in cultured fibroblasts, which may constitute a system to evaluate age-modifying interventions across the lifespan.Graphical Abstract

scholarly journals Iron-citrate can induce cell senescent phenotype in human fibroblasts in vitro

2009 ◽  
Vol 15 (S3) ◽  
pp. 15-16
Author(s):  
L. Matos ◽  
H. Almeida
Keyword(s):  
Cell Injury ◽  
Replicative Senescence ◽  
Human Fibroblasts ◽  
Human Diploid Fibroblasts ◽  
Senescent Phenotype ◽  
Redox Active ◽  
Stress Induced Premature Senescence ◽  
Beta Galactosidase

AbstractAfter a number of replications, human diploid fibroblasts (HDFs) in culture lose the ability to divide, become insensitive to further proliferation and enter a state of replicative senescence (RS). Subcytotoxic doses of several stressful agents such as hydrogen peroxide, tertbutylhydroperoxide or ethanol, are able to cause stress-induced premature senescence (SIPS) in HDFs in vitro. Such senescent cells display many features of RS as growth arrest, senescence associated beta-galactosidase (SA beta-gal), cell enlargement and overexpression of several genes (e.g., p21, TGF beta-1,IGFBP3). During ageing, iron accumulates in several tissues in vivo, and also in senescent HDFs in vitro. Due to its redox-active properties, it promotes hydroxyl radical production (Fenton reaction) and eventually leads to cell injury. Free radical reactions are known to cause the accumulation of intracellular damage resulting in ageing. Iron may thus be able to cause SIPS. The main objective of the present study was to investigate whether the exposure of HDFs to a subcytotoxic concentration of iron is able to cause SIPS.

scholarly journals Loss-of-function of p53 isoform Δ113p53 accelerates brain aging in zebrafish

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Ting Zhao ◽  
Shengfan Ye ◽  
Zimu Tang ◽  
Liwei Guo ◽  
Zhipeng Ma ◽  
...  
Keyword(s):  
Replicative Senescence ◽  
Brain Aging ◽  
Ventricular Zone ◽  
Human Fibroblasts ◽  
Cell Lineage ◽  
Lineage Tracing ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Antioxidant Genes ◽  
Age Related

AbstractReactive oxygen species (ROS) stress has been demonstrated as potentially critical for induction and maintenance of cellular senescence, and been considered as a contributing factor in aging and in various neurological disorders including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). In response to low-level ROS stress, the expression of Δ133p53, a human p53 isoform, is upregulated to promote cell survival and protect cells from senescence by enhancing the expression of antioxidant genes. In normal conditions, the basal expression of Δ133p53 prevents human fibroblasts, T lymphocytes, and astrocytes from replicative senescence. It has been also found that brain tissues from AD and ALS patients showed decreased Δ133p53 expression. However, it is uncharacterized if Δ133p53 plays a role in brain aging. Here, we report that zebrafish Δ113p53, an ortholog of human Δ133p53, mainly expressed in some of the radial glial cells along the telencephalon ventricular zone in a full-length p53-dependent manner. EDU-labeling and cell lineage tracing showed that Δ113p53-positive cells underwent cell proliferation to contribute to the neuron renewal process. Importantly, Δ113p53M/M mutant telencephalon possessed less proliferation cells and more senescent cells compared to wild-type (WT) zebrafish telencephalon since 9-months old, which was associated with decreased antioxidant genes expression and increased level of ROS in the mutant telencephalon. More interestingly, unlike the mutant fish at 5-months old with cognition ability, Δ113p53M/M zebrafish, but not WT zebrafish, lost their learning and memory ability at 19-months old. The results demonstrate that Δ113p53 protects the brain from aging by its antioxidant function. Our finding provides evidence at the organism level to show that depletion of Δ113p53/Δ133p53 may result in long-term ROS stress, and finally lead to age-related diseases, such as AD and ALS in humans.

Antioxidant activities and lipid peroxidation status in human follicular fluid: age-dependent change

Zygote ◽  
2021 ◽  
pp. 1-5
Author(s):  
H. Debbarh ◽  
N. Louanjli ◽  
S. Aboulmaouahib ◽  
M. Jamil ◽  
L. Ahbbas ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Follicular Fluid ◽  
Maternal Age ◽  
Antioxidant Activities ◽  
Human Follicular Fluid ◽  
Age Related ◽  
Group I ◽  
Group Ii ◽  
Scavenging Efficiency

Summary Maternal age is a significant factor influencing in vitro fertilization (IVF) outcomes. Oxidative stress (OS) is one of the major causes of age-related cellular and molecular damage. The purpose of this work was to investigate the correlation between maternal age with intrafollicular antioxidants and OS markers in follicular fluid (FF), and also to determine the OS status in patients of advanced age. This study was a prospective study including 201 women undergoing IVF whose age was between 24 and 45 years old. FF samples were obtained from mature follicles at the time of oocyte retrieval. After treatment of FF, lipid peroxidation levels (MDA) and enzyme activities such as superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR) and glutathione (GSH) level were evaluated using spectrophotometry. The results indicated that the age cutoff point for increasing the MDA level was fixed at 37 years, allowing the study to be differentiated into two age groups. Group I included patients whose age was less than 37 years, and group II included patients whose age was greater than or equal 37 years. Statistical analysis revealed that MDA and GSH levels and GR activity were significantly higher in group II compared with group I. The SOD and CAT activities were significantly less in group II compared with group I. We concluded that from 37 years old a reproductive ageing was accompanied by a change in the antioxidant pattern in FF that impaired reactive oxygen species scavenging efficiency.

scholarly journals Neuroprotective Effects of a Variety of Pomegranate Juice Extracts against MPTP-Induced Cytotoxicity and Oxidative Stress in Human Primary Neurons

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Nady Braidy ◽  
Subash Selvaraju ◽  
Musthafa Mohamed Essa ◽  
Ragini Vaishnav ◽  
Samir Al-Adawi ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Pomegranate Juice ◽  
Neuroprotective Effects ◽  
Age Related ◽  
Therapeutic Value ◽  
Human Neurons ◽  
Environmental Toxin ◽  
Endogenous Antioxidant ◽  
Therapeutic Compounds

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is an environmental toxin which selectively induces oxidative damage and mitochondrial and proteasomal dysfunctions to dopaminergic neurons in the substantia nigra leading to Parkinsonian syndrome in animal models and humans. MPTP is one of the most widely usedin vitromodels to investigate the pathophysiology of Parkinson's disease (PD) and, screen for novel therapeutic compounds that can slow down or ameliorate this progressive degenerative disease. We investigated the therapeutic effect of pomegranate juice extracts (PJE), Helow, Malasi, Qusum, and Hamadh against MPTP-induced neurotoxicity in primary human neurons by examining extracellular LDH activity, intracellular NAD+and ATP levels, and endogenous antioxidant levels including lipid peroxidation products, catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, and reduced glutathione (GSH) levels. MPTP induced a reduction in SOD and GPx activities and intracellular NAD+, ATP, and GSH levels parallel to an increase in extracellular LDH and CAT activities, although lipid peroxidation was not altered. We report that helow and malasi can ameliorate MPTP-induced neurotoxicity by attenuating the observed changes in redox function to a greater extent than qusum and hamedh. Selected PJE varieties may exhibit properties which may be of therapeutic value to slow down age-related degeneration and neurodegeneration in particular.

scholarly journals Uncoupling between Phenotypic Senescence and Cell Cycle Arrest in Aging p21-Deficient Fibroblasts

2000 ◽  
Vol 20 (18) ◽  
pp. 6741-6754 ◽  
Author(s):  
Vjekoslav Dulić ◽  
Georges-Edouard Beney ◽  
Guillaume Frebourg ◽  
Linda F. Drullinger ◽  
Gretchen H. Stein
Keyword(s):  
Cell Cycle ◽  
Replicative Senescence ◽  
Cyclin E ◽  
Human Fibroblasts ◽  
Population Expansion ◽  
Cell Cycle Checkpoints ◽  
Critical Event ◽  
Human Diploid Fibroblasts ◽  
Senescent Phenotype ◽  
Molecular Events

ABSTRACT Irreversible G1 arrest in senescent human fibroblasts is mediated by two inhibitors of cyclin-dependent kinases (Cdks), p21Cip1/SDI1/WAF1 and p16Ink4A. To determine the physiological and molecular events that specifically require p21, we studied senescence in human diploid fibroblasts expressing the human papillomavirus type 16 E6 oncogene, which confers low p21 levels via enhanced p53 degradation. We show that in late-passage E6 cells, high Cdk activity drives the cell cycle, but population expansion is slowed down by crisis-like events, probably owing to defective cell cycle checkpoints. At the end of lifespan, terminal-passage E6 cells exhibited several aspects of the senescent phenotype and accumulated unphosphorylated pRb and p16. However, both replication and cyclin-Cdk2 kinase activity were still not blocked, demonstrating that phenotypic and replicative senescence are uncoupled in the absence of normal p21 levels. At this stage, E6 cells also failed to upregulate p27 and inactivate cyclin-Cdk complexes in response to serum deprivation. Eventually, irreversible G1 arrest occurred coincident with inactivation of cyclin E-Cdk2 owing to association with p21. Similarly, when p21−/− mouse embryo fibroblasts reached the end of their lifespan, they had the appearance of senescent cells yet, in contrast to their wild-type counterparts, they were deficient in downregulating bromodeoxyuridine incorporation, cyclin E- and cyclin A-Cdk2 activity, and inhibiting pRb hyperphosphorylation. These data support the model that the critical event ensuring G1arrest in senescence is p21-dependent Cdk inactivation, while other aspects of senescent phenotype appear to occur independently of p21.

scholarly journals Regulation of a Senescence Checkpoint Response by the E2F1 Transcription Factor and p14ARF Tumor Suppressor

2000 ◽  
Vol 20 (1) ◽  
pp. 273-285 ◽  
Author(s):  
Goberdhan P. Dimri ◽  
Koji Itahana ◽  
Meileen Acosta ◽  
Judith Campisi
Keyword(s):  
Transcription Factor ◽  
Tumor Suppressor ◽  
Replicative Senescence ◽  
Human Fibroblasts ◽  
Critical Role ◽  
Ectopic Expression ◽  
Binding Activity ◽  
Human Cells ◽  
Senescent Phenotype ◽  
Normal Human

ABSTRACT Normal cells do not divide indefinitely due to a process known as replicative senescence. Human cells arrest growth with a senescent phenotype when they acquire one or more critically short telomeres as a consequence of cell division. Recent evidence suggests that certain types of DNA damage, chromatin remodeling, and oncogenic forms of Ras or Raf can also elicit a senescence response. We show here that E2F1, a multifunctional transcription factor that binds the retinoblastoma (pRb) tumor suppressor and that can either promote or suppress tumorigenesis, induces a senescent phenotype when overexpressed in normal human fibroblasts. Normal human cells stably arrested proliferation and expressed several markers of replicative senescence in response to E2F1. This activity of E2F1 was independent of its pRb binding activity but dependent on its ability to stimulate gene expression. The E2F1 target gene critical for the senescence response appeared to be the p14ARF tumor suppressor. Replicatively senescent human fibroblasts overexpressed p14ARF, and ectopic expression of p14ARF in presenescent cells induced a phenotype similar to that induced by E2F1. Consistent with a critical role for p14ARF, cells with compromised p53 function were immune to senescence induction by E2F1, as were cells deficient in p14ARF. Our findings support the idea that the senescence response is a critical tumor-suppressive mechanism, provide an explanation for the apparently paradoxical roles of E2F1 in oncogenesis, and identify p14ARF as a potentially important mediator of the senescent phenotype.

scholarly journals Retinoblastoma ( Rb ) promotes senescence of corneal endothelial cells by inhibiting the activation of E2F2

2020 ◽  
Author(s):  
Alan Jiang ◽  
longbing Mao ◽  
sujuan Duan ◽  
yanyan Zhang ◽  
xing Liu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Function ◽  
Corneal Endothelial Cells ◽  
Senescent Phenotype ◽  
Age Related ◽  
Passage Number ◽  
Fuchs Endothelial Dystrophy ◽  
Rb Gene ◽  
And Migration

Abstract Background Senescence-like changes occur in aging Corneal endothelial cells (CECs), and these changes are associated with decreased vision and age-related corneal diseases. such as Fuchs endothelial dystrophy (FED), chronic corneal allograft dysfunction (CCAD). Such changes have also been shown to cultured cell in vitro after passaging. Therefore, studying the mechanism of CEC senescence would aid in the development of anti-senescence treatment, which would benefit FED and CCAD. The tumor suppressor retinoblastoma (RB) gene product pRB triggers senescent growth arrest when inactivated. In this study, we used siRNA treatment to evaluate whether RB knockdown could suppress CEC senescence, and we investigated relevant molecular mechanisms.Methods RCECs were obtained and were cultured with or without siRb. Senescent cells were detected with a β-galactosidase senescence staining kit. The gene p21, which is associated with a senescent phenotype, was measured by RT-PCR. The morphology and migration of cultured RCECs were examined by phase-contrast microscopy. ZO-1 and N-Cadherin, which are involved in pump and barrier functions, were assessed by immunofluorescence. Cell cycle assessment was performed using a flow cytometer (BD FACSCalibur).Results As the cells were passaged, the number of senescent RCECs, the levels of the senescence-related gene p21, and the levels of senescence-associated secretory factors increased. SiRNA-mediated knockdown of RB led to suppression of cell senescence and the SASP. Furthermore, RB intervention increased the numbers of cells at the G2/M and S phase but did not influence the cell function or migratory ability. Knockdown of RB promoted the activation of E2F2.Conclusions We demonstrated that as the cells increased in passage number, the number of senescent RCECs, the levels of the senescence-related genes p21, and the levels of senescence-associated secretory factors increased. Retinoblastoma (Rb) promoted the senescence of corneal endothelial cells by inhibiting the activation of E2F2.

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 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.

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