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Results for “Cellular Senescence”

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At least 73 records · Page 4Linked to original sources

PubMed2004

Mechanisms of cellular senescence in human and mouse cells.

Telomere erosion is considered to be the main cause of the onset of replicative senescence. However, recent findings suggest that a senescent phenotype can be induced by a variety of other stimuli that act independently of telomeres. Moreover, telomere-dependent replicative senescence depends on the species of cell origin, in particular whether cells are of human or rodent origin. In addition, the tissue of origin may also dictate the pathway by which cells undergo replicative senescence. In this Review article, we categorize cellular senescence into two types, which for simplicity we term intrinsic or extrinsic senescence, focus on the differences between human and mouse cells, and discuss the roles of the p53 and pRb tumor suppressor pathways in cellular senescence.

Animals↗

PubMed2002

Cellular senescence and tissue aging in vivo.

A long-standing controversy concerns the relevance of cellular senescence, defined and observed as a cell culture phenomenon, to tissue aging in vivo. Here the evidence on this topic is reviewed. The main conclusions are as follows. First, telomere shortening, the principal known mediator of cellular senescence, occurs in many human tissues in aging. Second, it is not clear whether this results in cellular senescence or in some other cell fate (e.g., crisis). Third, rodents probably are not appropriate experimental models for these questions, because of important differences in telomere biology between rodent cells and cells from long-lived mammals (e.g., human or bovine cells). Fourth, better and more comprehensive observations on aging human tissues are needed to answer the question of the occurrence of senescent cells in tissues, and new experimental approaches are needed to elucidate the consequences of telomere shortening in tissues in aging.

Animals↗

PubMed2002

Novel pathways associated with bypassing cellular senescence in human prostate epithelial cells.

Cellular senescence forms a barrier that inhibits the acquisition of an immortal phenotype, a critical feature in tumorigenesis. The inactivation of multiple pathways that positively regulate senescence are required for immortalization. To identify these pathways in an unbiased manner, we performed DNA microarray analyses to assess the expression of 20,000 genes in human prostate epithelial cells (HPECs) passaged to senescence. These gene expression patterns were then compared with those of HPECs immortalized with the human Papillomavirus 16 E7 oncoprotein. Senescent cells display gene expression patterns that reflect their nonproliferative, differentiated phenotype and express secretory proteases and extracellular matrix components. A comparison of genes transcriptionally up-regulated in senescence to those in which expression is significantly down-regulated in immortalized HPECs identified three genes: the chemokine BRAK, DOC1, and a member of the insulin-like growth factor axis, IGFBP-3. Expression of these genes is found to be uniformly lost in human prostate cancer cell lines and xenografts, and previously, their inactivation was documented in tumor samples. Thus, these genes may function in novel pathways that regulate senescence and are inactivated during immortalization. These changes may be critical not only in allowing cells to bypass senescence in vitro but in the progression of prostate cancer in vivo.

Aged↗

PubMed2000

IP(3), IP(3) receptor, and cellular senescence.

Herein we demonstrate that replicative cellular senescence in vitro results in sharply reduced inositol 1,4,5-trisphosphate (IP(3)) receptor levels, reduced mitogen-evoked IP(3) formation and Ca(2+) release, and Ca(2+) store depletion. Human diploid fibroblasts (HDFs) underwent either 30 mean population doublings [mean population doublings (MPDs) thymidine labeling index (TI) >92% ("young") or between 53 and 58 MPDs (TI < 28%; "senescent")]. We found that the cytosolic Ca(2+) release triggered by either ionomycin or by several IP(3)-generating mitogens, namely bradykinin, thrombin, platelet-derived growth factor (PDGF), and epidermal growth factor (EGF), was attenuated markedly in senescent HDFs. Notably, the triggered cytosolic Ca(2+) transients were of a smaller magnitude in senescent HDFs. However, the response latency seen with both PDGF and EGF was greater for senescent cells. Finally, a smaller proportion of senescent HDFs showed oscillations. In parallel, IP(3) formation in response to bradykinin or EGF was also attenuated in senescent HDFs. Furthermore, senescent HDFs displayed a sharply diminished Ca(2+) release response to intracellularly applied IP(3). Finally, to compare IP(3) receptor protein levels directly in young and senescent HDFs, their microsomal membranes were probed in Western blots with a highly specific anti-IP(3) receptor antiserum, Ab(40). A approximately 260-kDa band corresponding to the IP(3) receptor protein was noted; its intensity was reduced by approximately 50% in senescent cells. Thus, we suggest that reduced IP(3) receptor expression, lowered IP(3) formation, and Ca(2+) release, as well as Ca(2+) store depletion, all contribute to the deficient Ca(2+) signaling seen in HDFs undergoing replicative senescence.

Bradykinin↗

PubMed1999

Identification of a gene at 16q24.3 that restores cellular senescence in immortal mammary tumor cells.

We have mapped a cellular senescence gene, SEN16, within a genetic distance of 3 - 7 cM, at 16q24.3. Microcell mediated transfer of a normal human chromosome 16, 16q22-qter or 16q23-qter restored cellular senescence in four immortal cell lines, derived from human and rat mammary tumors. The resumption of indefinite cell proliferation, concordant with the segregation of the donor chromosome, confirmed the presence of a senescence gene at 16q23-qter. While microcell hybrids were maintained in selection medium to retain the donor chromosome, sporadic immortal revertant clones arose among senescent cells. Reversion to immortal growth could occur due to inactivation of the senescence gene either by a mutation or a deletion. The analysis for chromosome 16 specific DNA markers, in revertant clones of senescent microcell hybrids, revealed a consensus deletion, spanning a genetic interval of approximately 3 - 7 cM at 16q24.3.

Adenocarcinoma↗

PubMed1992

A conserved region in human and Chinese hamster X chromosomes can induce cellular senescence of nickel-transformed Chinese hamster cell lines.

Cellular senescence is the genetically programmed cessation of cellular proliferation. We have recently mapped a putative senescence gene(s) on the X chromosome of Chinese hamster embryo (CHE) cells. In the present study, we have utilized microcell-mediated chromosome transfer (microcell fusion) to test whether: (i) the human X chromosome exhibits similar genetic potential to induce senescence and (ii) the deletion or inactivation of the X-linked senescence gene(s) in CHE cells is associated with nickel-induced immortalization. A normal CHE or human X chromosome was first introduced into mouse-cell hybrids, then transferred by microcell fusion into a nickel-transformed, immortal male CHE cell line (Ni-2/TGR) with an X deletion (Xq1). Microcell fusion of the normal CHE X chromosome into tumorigenic Ni-2/TGR cells yielded senescence of all X recipient clones. The normal human X chromosome induced dominant senescence of tumorigenic Ni-2/TGR cells in only 17% of the resulting microcell hybrids (14/81). Karyotypic analyses of 13 non-senescing human X chromosome-derived microcell hybrid clones revealed that none of these clones retained the complete X. A normal CHE X chromosome induced senescence of 75% of hybrids obtained with another immortal and tumorigenic nickel-transformed male CHE cell line (Ni-6/TGR), which exhibited no visible deletion of the X chromosome, while the normal human X chromosome, only induced senescence in 19% of these hybrids. Transfer of the normal CHE or human X chromosome into spontaneously transformed and tumorigenic cell lines, CHO/TGR or V79/TGR, had little or no effect on their growth. These data suggest that both human and CHE cells possess similar X-linked genetic activities that regulate the process of cellular senescence, and that in Chinese hamster cells nickel-induced immortalization but not that of CHO or V79 cells is associated with inactivation of an X-linked senescence gene.

Animals↗

PubMed2026

Luteolin is associated with alleviation of cigarette smoke-induced cellular senescence and inflammation in mice involving the CREB/c-Fos/NQO1 pathway.

Cigarette smoke (CS) exposure is a major risk factor for chronic obstructive pulmonary disease (COPD) and is closely associated with cellular senescence. Previous studies have demonstrated the efficacy of luteolin in treating aging-related symptoms. This study aims to elucidate the therapeutic potential of luteolin against CS-induced cellular senescence. Using a CS-exposed mouse model and cigarette smoke extract (CSE) treated mouse lung epithelial cells (TC-1), we demonstrate that luteolin significantly attenuates CS-induced histopathological alterations and inflammatory cytokine release while alleviating cellular senescence. Transcriptome sequencing suggests that NQO1 and Fos may serve as a common molecular target for both CS-induced pathology and luteolin treatment. Subsequent Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) enrichment analysis and pathway validation experiments revealed that the cAMP agonist Forskolin inhibits senescence marker expression by activating the CREB pathway, exhibiting a mechanism similar to that of luteolin. Notably, luteolin activation of this pathway may not depend on PKA activation. Ultimately, the study found that luteolin mitigates inflammatory responses and prevents lung epithelial cell senescence via the CREB/c-Fos/NQO1 pathway. These findings not only suggest the pivotal role of NQO1 in regulating CS-induced cellular senescence but also underscore the potential of luteolin as a therapeutic drug.

Animals↗

PubMed2003

Relief of oxidative stress by ascorbic acid delays cellular senescence of normal human and Werner syndrome fibroblast cells.

Primary human cells have a definite life span and enter into cellular senescence before ceasing cell growth. Oxidative stress produced by aerobic metabolism has been shown to accelerate cellular senescence. Here, we demonstrated that ascorbic acid, used as an antioxygenic reagent, delayed cellular senescence in a continuous culture of normal human embryonic cells, human adult skin fibroblast cells, and Werner syndrome (WS) cells. The results using human embryonic cells showed that treatment with ascorbic acid phospholic ester magnesium salt (APM) decreased the level of oxidative stress, and extended the replicative life span. The effect of APM to extend the replicative life span was also shown in normal human adult cells and WS cells. To understand the mechanism of extension of cellular life span, we determined the telomere lengths of human embryonic cells, both with and without APM treatment, and demonstrated that APM treatment reduced the rate of telomere shortening. The present results indicate that constitutive oxidative stress plays a role in determining the replicative life span and that suppression of oxidative stress by an antioxidative agent, APM, extends the replicative life span by reducing the rate of telomere shortening.

Antioxidants↗

PubMed1980

Loss of gene repression activity: a theory of cellular senescence.

Recent evidence bearing on cellular senescence has come from cell fusion and clonal lifespan studies. To date, no model has been developed that is consistent with the recent findings. The purpose of this paper is to present a mechanism for cell senescence that is qualitatively consistent with the experimental evidence.

Animals↗

PubMed2005

Inhibitory role of peroxiredoxin II (Prx II) on cellular senescence.

Reactive oxygen species (ROS) were generated in all oxygen-utilizing organisms. Peroxiredoxin II (Prx II) as one of antioxidant enzymes may play a protective role against the oxidative damage caused by ROS. In order to define the role of Prx II in organismal aging, we evaluated cellular senescence in Prx II(-/-) mouse embryonic fibroblast (MEF). As compared to wild type MEF, cellular senescence was accelerated in Prx II(-/-) MEF. Senescence-associated (SA)-beta-galactosidase (Gal)-positive cell formation was about 30% higher in Prx II(-/-) MEF. N-Acetyl-l-cysteine (NAC) treatment attenuated SA-beta-Gal-positive cell formation. Prx II(-/-) MEF exhibited the higher G2/M (41%) and lower S (1.6%) phase cells as compared to 24% and 7.3% [corrected] in wild type MEF, respectively. A high increase in the p16 and a slight increase in the p21 and p53 levels were detected in PrxII(-/-) MEF cells. The cellular senescence of Prx II(-/-) MEF was correlated with the organismal aging of Prx II(-/-) mouse skin. While extracellular signal-regulated kinase (ERK) and p38 activation was detected in Prx II(-/-) MEF, ERK and c-Jun N-terminal kinase (JNK) activation was detected in Prx II(-/-) skin. These results suggest that Prx II may function as an enzymatic antioxidant to prevent cellular senescence and skin aging.

Acetylcysteine↗

PubMed1994

A gene involved in control of human cellular senescence on human chromosome 1q.

Normal cells in culture exhibit limited division potential and have been used as a model for cellular senescence. In contrast, tumor-derived or carcinogen- or virus-transformed cells are capable of indefinite division. Fusion of normal human diploid fibroblasts with immortal human cells yielded hybrids having limited life spans, indicating that cellular senescence was dominant. Fusions of various immortal human cell lines with each other led to the identification of four complementation groups for indefinite division. The purpose of this study was to determine whether human chromosome 1 could complement the recessive immortal defect of human cell lines assigned to one of the four complementation groups. Using microcell fusion, we introduced a single normal human chromosome 1 into immortal human cell lines representing the complementation groups and determined that it caused loss of proliferative potential of an osteosarcoma-derived cell line (TE85), a cytomegalovirus-transformed lung fibroblast cell line (CMV-Mj-HEL-1), and a Ki-ras(+)-transformed derivative of TE85 (143B TK-), all of which were assigned to complementation group C. This chromosome 1 caused no change in proliferative potential of cell lines representing the other complementation groups. A derivative of human chromosome 1 that had lost most of the q arm by spontaneous deletion was unable to induce senescence in any of the immortal cell lines. This finding indicates that the q arm of human chromosome 1 carries a gene or set of genes which is altered in the cell lines assigned to complementation group C and is involved in the control of cellular senescence.

Bone Neoplasms↗

PubMed2003

Iron accumulation during cellular senescence in human fibroblasts in vitro.

Iron accumulates as a function of age in several tissues in vivo and is associated with the pathology of numerous age-related diseases. The molecular basis of this change may be due to a loss of iron homeostasis at the cellular level. Therefore, changes in iron content in primary human fibroblast cells (IMR-90) were studied in vitro as a model of cellular senescence. Total iron content increased exponentially during cellular senescence, resulting in 10-fold higher levels of iron compared with young cells. Low-dose hydrogen peroxide (H2O2) induced early senescence in IMR-90s and concomitantly accelerated iron accumulation. Furthermore, senescence-related and H2O2-stimulated iron accumulation was attenuated by N-tert-butylhydroxylamine (NtBHA), a mitochondrial antioxidant that delays senescence in vitro. However, SV40-transformed, immortalized IMR-90s showed no time-dependent changes in metal content in culture or when treated with H2O2 and/or NtBHA. These data indicate that iron accumulation occurs during normal cellular senescence in vitro. This accumulation of iron may contribute to the increased oxidative stress and cellular dysfunction seen in senescent cells.

Cell Division↗

PubMed2004

Cellular senescence requires CDK5 repression of Rac1 activity.

Cellular senescence is a tumor-suppressive process characterized by an irreversible cell cycle exit, a unique morphology, and expression of senescence-associated beta-galactosidase (SA-beta-Gal). We report here a role for CDK5 in induction of senescent cytoskeletal changes. CDK5 activation is upregulated in senescing cells. The increased activity of CDK5 further reduces GTPase Rac1 activity and Pak activation. The repression of the activity of the GTPase Rac1 by CDK5 is required for expression of the senescent phenotype. CDK5 regulation of Rac1 activity is necessary for actin polymerization accompanying senescent morphology in response to expression of pRb, activated Ras, or continuous passage. Inhibition of CDK5 attenuates SA-beta-Gal expression and blocks actin polymerization. These results point to a unique, nonneuronal role for CDK5 in regulation of Rac1 activity in senescence, illuminating the mechanisms underlying induction of senescence and the senescent shape change.

Actins↗

PubMed1995

Restoration of the cellular senescence program and repression of telomerase by human chromosome 3.

Telomeres, at the end of chromosomes, shorten with each cell division, resulting in cellular senescence. Tumor cells, unlike normal somatic cells, express a telomerase that maintains the telomere length. Deletion of a gene(s) on chromosome 3 is common in human renal cell carcinoma (RCC) and reintroduction of a normal chromosome 3 into an RCC immortal cell line restored the program of cellular senescence. The loss of indefinite growth potential was associated with the loss of telomerase activity and shortening of telomeres in the RCC cells with a normal chromosome 3. However, microcell hybrids that escaped from senescence and microcell hybrids with an introduced chromosome 7 or 11 maintained telomere lengths and telomerase activity similar to those of the parental RCC23. Thus, restoration of the cellular senescence program by chromosome 3 is associated with repression of telomerase function in RCC cells.

Base Sequence↗

PubMed1996

Genetic regulation of telomerase in a multiple pathways model to cellular senescence.

Hybrids between immortal cells and normal cells senesce, indicating that immortal cells have lost, mutated or inactivated genes that are required for the program of senescence in normal cells. Genes involved in the senescence program have been mapped to over 10 different genetic loci by introduction of normal human chromosomes via microcell fusion. Multiple pathways of cellular senescence have also been demonstrated by chromosome transfer, indicating that the functions of the mapped senescence genes are probably different. One possibility is that one or more of these senescence genes may suppress telomerase activity in immortal cells, resulting in telomere shortening and cellular senescence. To test this hypothesis, telomerase activity and the length of terminal restriction fragments (TRFs) have been examined in microcell hybrids. The loss of indefinite growth potential was either with or without the loss of telomerase activity activity and shortening of telomeres in the microcell hybrids containing the introduced chromosome. The findings suggest that telomerase regulation is one of multiple pathways to cellular senescence.

Cellular Senescence↗

PubMed1995

Alteration of DNA and RNA binding activity of human telomere binding proteins occurs during cellular senescence.

The loss of telomere sequences during in vitro and in vivo aging suggests that mechanisms affecting telomere length may have important consequences in cellular senescence. In this study, we have found that the activity of single-stranded telomere binding proteins is increased in nuclear extracts prepared from senescent human diploid fibroblasts compared to actively growing cells. Since single-stranded telomere binding proteins are closely related to RNA binding proteins, we examined the binding activity of several major RNA binding proteins to RNA by uv cross-linking. The level of activity was greatly diminished and the overall pattern of uv cross-linked products were altered in extracts prepared from senescent cells. Furthermore, Western analysis revealed a concurrent decrease in senescent extracts of the protein level for many RNA binding proteins, including those which bind to telomere sequence. Although the reduction in the level of these proteins parallels the reduced activity in RNA binding, the paradoxical increased telomere binding activity exhibited by extracts from older cells suggests a complex relationship between these proteins with RNA and DNA. Moreover, the reduced RNA binding activity of these proteins indicates that the biochemical function of several RNA binding proteins is compromised during cellular senescence, raising an intriguing possibility that a change in pre-mRNA metabolism may contribute to the multitude of changes in gene expression observed in cellular senescence.

Base Sequence↗

PubMed2003

Cellular senescence in the pathogenesis of benign prostatic hyperplasia.

BACKGROUND: Senescent cells accumulate in tissues with age and show changes in protein expression that may influence the function of adjacent cells and contribute to the development of tissue pathologies associated with aging. Benign prostatic hyperplasia (BPH) is an extremely common disease of older men characterized by increased growth of prostatic epithelial and stromal cells. In BPH, there is an increased expression of Il-1alpha by prostatic epithelial cells that results in elevated expression of FGF7 by stromal cells, which in turn is strongly correlated with epithelial proliferation. METHODS: Human BPH tissue and primary cultures of prostatic epithelial cells were analyzed by histochemical and quantitative assays for senescence-associated beta galactosidase (SA-beta gal). Il-1alpha expression was localized by immunohistochemistry and Il-1alpha tissue content determined by enzyme-linked immunoabsorption assay. RESULTS: Expression of Il-1alpha is significantly increased in vitro when cultured prostatic epithelial cells undergo senescence. In BPH tissue a substantial population of epithelial cells express senescence-associated beta galactosidase (SA-beta gal), a marker of cellular senescence. By quantitative assay, SA-beta gal activity is correlated with both tissue levels of Il-1alpha and the severity of BPH. CONCLUSIONS: One mechanism driving BPH in older men is the accumulation of senescent epithelial cells expressing Il-1alpha, which in turn increases FGF7 secretion and proliferation of non-senescent epithelial cells. Thus there is a mechanistic linkage between cellular senescence and one of the most common pathologies of older men.

Cellular Senescence↗

PubMed2005

Recombinant alpha2(IV)NC1 domain inhibits tumor cell-extracellular matrix interactions, induces cellular senescence, and inhibits tumor growth in vivo.

Cellular interaction with the extracellular matrix is thought to be a critical event in controlling angiogenesis and tumor growth. In our previous studies, genetically distinct noncollagenous (NC) domains of type-IV collagen were shown to interact with integrin receptors expressed on the surface of endothelial cells. Moreover, these NC1 domains were shown to inhibit angiogenesis in vivo. Here, we provide evidence that a recombinant form of the alpha2(IV)NC1 domain of type-IV collagen could bind integrins alpha1beta1 and alphavbeta3 expressed on melanoma cells and inhibit tumor cell adhesion in a ligand-specific manner. Systemic administration of recombinant alpha2(IV)NC1 domain potently inhibited M21 melanoma tumor growth within full thickness human skin and exhibited a dose-dependent inhibition of tumor growth in nude mice. Interestingly, alpha2(IV)NC1 domain enhanced cellular senescence in tumor cells in vitro and in vivo. Taken together, these results suggest that recombinant alpha2(IV)NC1 domain is not only a potent anti-angiogenic reagent, but it also directly impacts tumor cell behavior. Thus, alpha2(IV)NC1 domain represents a potent inhibitor of tumor growth by impacting both endothelial and tumor cell compartments.

Animals↗