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Results for “Cellular Senescence”

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PubMed1993

[Telomere, cellular senescence and transformation].

Telomere is the structure which is located on both ends of individual chromosomes in eukaryotes. The DNA sequence of the telomere consists of Guanine-rich tandem repeat, i.e., (TTAGGG)n in man. Telomere protects the end of the chromosome from fusion or deletion and maintains the stability of the chromosome and is synthesized by telomerase, a ribonucleoprotein. Telomere reduction is observed with cell senescence and immortalization, both in vivo and in vitro. Thus, telomere is considered to be a "clock" which measures the life span of cells, and its length is altered by cellular senescence and immortalization.

Aging↗

PubMed1997

Lysyl oxidase, cellular senescence and tumor suppression.

Replicative senescence may provide a mechanism of tumor suppression and tumor suppressor genes of the extracellular matrix, like lysyl oxidase, may play a role in cellular senescence. To test this hypothesis and determine whether the extracellular matrix may serve as a marker, the steady-state levels of human lysyl oxidase, alpha-I type III collagen and beta-actin transcripts were assessed in various cell lines during in vitro passage. Northern hybridization analysis showed a significant increase in the levels of progeria fibroblast extracellular matrix mRNAs immediately preceding senescence. The levels of these mRNAs were unaffected in age-matched normal fibroblast and fetal fibroblast cell lines.

Actins↗

PubMed2003

Apoptosis, necrosis and cellular senescence: chaperone occupancy as a potential switch.

Chaperone function plays a key role in repairing proteotoxic damage and in the maintenance of cell survival. Here we compare the regulatory role of molecular chaperones (heat shock proteins, stress proteins) in cellular senescence, apoptosis and necrosis. We also review the current data on chaperone level and function in aging cells, and list some possible therapeutic interventions. Finally, we postulate a hypothesis, that increasing chaperone occupancy might be an important event which forces cells out of the normal cell cycle towards senescence. In the case of severe stress, this may lead to apoptosis or, following lethal stress, to cell necrosis.

Animals↗

PubMedDate not supplied

Reactive oxygen species as mediators of cellular senescence.

Aging has often been viewed as a random process arising from the accumulation of both genetic and epigenetic changes. Increasingly, the notion that aging is a stochastic process is being supplanted by the concept that maximum lifespan of an organism is tightly regulated. This knowledge has led to a growing overlap between classical signal transduction paradigms and the biology of aging. We review certain specific examples where these seemingly disparate disciplines intersect. In particular, we review the concept that intracellular reactive oxygen species function as signalling molecules and that oxidants play a central role as mediators of cellular senescence.

Animals↗

PubMed1996

Down-regulation of nuclear binding activities of OXBOX-REBOX transcription factors during cellular senescence.

Functional capacity of mitochondria declines during aging and this impairment may have a major role in aging process. Several observations indicate that transcriptional efficiency is reduced during aging. Our purpose was to find out whether aging and cellular senescence affect the nuclear binding activities of transcription factors which bind to OXBOX-REBOX sequence present in promoter regions of numerous nuclear genes encoding mitochondrial proteins. These factors regulate and coordinate the expression of mitochondrial proteins. We observed a strong down-regulation in the nuclear binding activities of OXBOX-REBOX factors in replicatively senesced human WI-38 and IMR-90 fibroblasts. On the contrary, SV-40 immortalization highly increased the nuclear binding activities. A considerable down-regulation of OXBOX-REBOX factors was also observed in UVB-irradiated WI-38 fibroblasts. Irradiation induced photoaging in fibroblasts which involved cell cycle arrest and senescent morphology. Interestingly, the nuclear binding activities of OXBOX-REBOX factors were also prominently decreased in the liver of Wistar rats at the age of 30 months but not yet at the age of 18 months. Our results suggest that the down-regulation of OXBOX-REBOX factors could affect the expression level of mitochondrial proteins encoded in nucleus and hence induce disturbances in mitochondrial function and promote the cellular aging process.

Animals↗

PubMed2004

IGFBP-3, a marker of cellular senescence, is overexpressed in human papillomavirus-immortalized cervical cells and enhances IGF-1-induced mitogenesis.

Human ectocervical cells, following retroviral transduction with the human papillomavirus type 16 E6/E7 oncogenes, are altered in their array of transcribed cellular genes, including increased mRNA for the insulin-like growth factor binding protein 3 (IGFBP-3). IGFBP-3 expression is associated with cellular senescence, and its addition to many cell types inhibits growth or induces apoptosis. By immunoblotting and enzyme-linked immunosorbent assay methods, we demonstrate that late-passage, immortalized E6/E7-transduced cells secrete high levels of IGFBP-3 (25 ng/ml), which represent a 500-fold increase compared to levels in early-passage, nonimmortalized transduced cells (<0.05 ng/ml). Concomitantly, these late-passage cervical cells exhibit an increase in sensitivity to IGF-1, including enhanced phosphorylation of the IGF receptor (IGF-R) and insulin receptor substrate as well as increased DNA synthesis (5-fold) and cell proliferation (3.7-fold). However, there was no change in the level of IGF-R in these cells (surface or total), and the cells did not synthesize IGF-1, indicating that these arms of the IGF pathway were independently regulated and not responsible for the augmented signaling. Consistent with a causal relationship between IGFBP-3 expression and enhanced IGF-1 responses, we found that early-passage cells could be converted to the late-passage, IGF-1-responsive phenotype by preincubation with IGFBP-3. Thus, in contrast to findings with some cell types, IGFBP-3 expression in cervical cells is associated with augmented IGF-1 signaling and cell proliferation and correlates with the timing of cellular immortalization.

Cell Division↗

PubMed2002

A quantitative model of cellular senescence influence on cancer and longevity.

Contrary to the paradigm that cancer incidence increases indefinitely with age, significant data now suggest cancer incidence may markedly reduce beyond age 80 years for humans and beyond 800 days for mice, and is not inevitable. We show that increasing cellular senescence with age is a possible cause of this reduction, since senescent cells are removed from the pool of cells that retain proliferative ability necessary for cancer. We further show that animal interventions appearing to alter senescence, p53 mutation and melatonin dosing, support the prediction that increasing senescence rate reduces cancer while reducing lifespan, and vice versa. Studies of environmental agents associated with increased cancer might be re-examined to find if there is an association with longevity increases, which may markedly alter our view of such agents. We also show that if an agent functions by slowing both senescence and carcinogenesis, longevity is increased while reducing cancer. Dietary restriction is the only known intervention that accomplishes this, but there may be others.

Aging↗

PubMed2006

Downregulation of transcription factor, Sp1, during cellular senescence.

We found that the protein level of Sp1 transcription factor decreases as normal human fibroblasts undergo replicative aging. Sp1 also undergoes a rapid decrease in the protein level and activity in MCF-7 cells that are induced to a state of cellular senescence. In the cells treated with other DNA damaging chemicals such as actinomycin D and H(2)O(2), the Sp1 level decreased progressively as well. Inhibition of ATM/ATR kinases prevented this downregulation, suggesting that DNA damage signaling is involved in the regulation of the Sp1. This decrease in Sp1 protein level is due to the accelerated proteasomal degradation since a proteasome inhibitor, ALLN, blocked this downregulation. Therefore, the global decrease in gene transcription frequently reported in aging cells and tissues could be attributed at least in part to the decrease in Sp1 level.

Ataxia Telangiectasia Mutated Proteins↗

PubMed2004

Akt-induced cellular senescence: implication for human disease.

Reduction-of-function mutations in components of the insulin/insulin-like growth factor-1/Akt pathway have been shown to extend the lifespan in organisms ranging from yeast to mice. It has also been reported that activation of Akt induces proliferation and survival of mammalian cells, thereby promoting tumorigenesis. We have recently shown that Akt activity increases with cellular senescence and that inhibition of Akt extends the lifespan of primary cultured human endothelial cells. Constitutive activation of Akt promotes senescence-like arrest of cell growth via a p53/p21-dependent pathway, leading to endothelial dysfunction. This novel role of Akt in regulating the cellular lifespan may contribute to various human diseases including atherosclerosis and diabetes mellitus.

Animals↗

PubMedDate not supplied

Age-dependent response of primary human dermal fibroblasts to oxidative stress: cell survival, pro-survival kinases, and entrance into cellular senescence.

A central question in cell biology is how cells become senescent. After a finite number of cell divisions, normal cultured human cells enter a state of irreversible growth arrest, termed "replicative senescence." Alternatively, oxidative stress in the form of hydrogen peroxide (H(2)O(2)) can render human dermal fibroblasts (HDFs) nonproliferative and quiescent, a phenomenon known as stress-induced premature senescence (SIPS). Although critical to the understanding of the pathophysiological basis of many diseases, there is no research to date that has simultaneously examined the interactions between age, oxidative stress, and SIPS. Therefore, the goals of this study were to examine in concert the interactions between these three factors in primary HDFs, and to test our central hypothesis that aging lowers the ability of primary HDFs to respond to oxidative stress. Our data provide, for the first time, evidence that aging dramatically reduces the capacity of primary HDFs to respond to the challenge of hydrogen peroxide. Specifically, aged HDFs showed decreased cell viability, decreased phosphorylation (activation) of pro-survival kinases (Akt and ERK 1/2), and increased entrance into a senescent state when compared with their younger counterparts. Another important conclusion of this study is that blockade of transforming growth factor-beta1 had a pronounced "rescue effect" in the aged, preventing entrance of HDFs into cellular senescence.

Adolescent↗

PubMed2002

Oncogenic ras and p53 cooperate to induce cellular senescence.

Oncogenic activation of the mitogen-activated protein (MAP) kinase cascade in murine fibroblasts initiates a senescence-like cell cycle arrest that depends on the ARF/p53 tumor suppressor pathway. To investigate whether p53 is sufficient to induce senescence, we introduced a conditional murine p53 allele (p53(val135)) into p53-null mouse embryonic fibroblasts and examined cell proliferation and senescence in cells expressing p53, oncogenic Ras, or both gene products. Conditional p53 activation efficiently induced a reversible cell cycle arrest but was unable to induce features of senescence. In contrast, coexpression of oncogenic ras or activated mek1 with p53 enhanced both p53 levels and activity relative to that observed for p53 alone and produced an irreversible cell cycle arrest that displayed features of cellular senescence. p19(ARF) was required for this effect, since p53(-/-) ARF(-/-) double-null cells were unable to undergo senescence following coexpression of oncogenic Ras and p53. Although the levels of exogenous p53 achieved in ARF-null cells were relatively low, the stabilizing effects of p19(ARF) on p53 could not explain the cooperation between oncogenic Ras and p53 in promoting senescence. Hence, enforced p53 expression without oncogenic ras in p53(-/-) mdm2(-/-) double-null cells produced extremely high p53 levels but did not induce senescence. Taken together, our results indicate that oncogenic activation of the MAP kinase pathway in murine fibroblasts converts p53 into a senescence inducer through both quantitative and qualitative mechanisms.

Animals↗

PubMed1996

Evidence that transcriptional activation by p53 plays a direct role in the induction of cellular senescence.

Wild-type p53 is necessary for the growth arrest of human diploid fibroblasts (HDF) (and many other cell types) at the end of their proliferative lifespan. Although p53 may actively mediate senescence, possibly in response to telomere erosion, it is however equally possible that it is merely a permissive factor required for response to some other inducer. To address this question, we have generated stable transfectants of early passage HDF, represented here by clone LacZ21, in which expression of a beta-galactosidase reporter construct reflects p53 transactivation activity. During continuous passage, the proportion of beta-gal positive LacZ21 cells remained below 2% for 25 population doublings (pd), first became significantly increased after 29 pd, and thereafter increased rapidly, reaching a maximum of 88% in fully-senescent cells (32 pd), which exceeded the response observed following an optimum dose (20 J/m2) of u.v. radiation. Correspondingly, the proportion of cells incorporating bromodeoxyuridine (BrdU) (initially 45-50%) began to fall at 29 pd and thereafter dropped rapidly to below 1% by pd 32. There was therefore a near-perfect reciprocal relationship between reporter construct expression and DNA synthesis as cells approached senescence. Furthermore, a dominant-negative p53 mutant (introduced by retroviral transduction) rescued LacZ21 cells from senescence and generated colonies with extended lifespan in which beta-gal expression was totally abolished. These data, although not excluding the need for other p53 functions, strongly suggest that p53-mediated transactivation of growth regulatory genes is a direct trigger, rather than a permissive factor, for cellular senescence.

Cell Line↗

PubMed1992

Telomere positional effects and the regulation of cellular senescence.

Normal cells have a limited capacity to proliferate but the molecular clock that regulates the onset of cellular senescence remains unidentified. The ends of chromosomes--telomeres--have been shown to shorten progressively with age in normal cells. Here, we present a working model of how telomeric shortening may induce programmed changes in the regulation of cellular proliferation.

Cell Death↗

PubMed2006

Cellular senescence impairs circadian expression of clock genes in vitro and in vivo.

Circadian rhythms are regulated by a set of clock genes that form transcriptional feedback loops and generate circadian oscillation with a 24-hour cycle. Aging alters a broad spectrum of physiological, endocrine, and behavioral rhythms. Although recent evidence suggests that cellular aging contributes to various age-associated diseases, its effects on the circadian rhythms have not been examined. We report here that cellular senescence impairs circadian rhythmicity both in vitro and in vivo. Circadian expression of clock genes in serum-stimulated senescent cells was significantly weaker compared with that in young cells. Introduction of telomerase completely prevented this reduction of clock gene expression associated with senescence. Stimulation by serum activated the cAMP response element-binding protein, but the activation of this signaling pathway was significantly weaker in senescent cells. Treatment with activators of this pathway effectively restored the impaired clock gene expression of senescent cells. When young cells were implanted into young mice or old mice, the implanted cells were effectively entrained by the circadian rhythm of the recipients. In contrast, the entrainment of implanted senescent cells was markedly impaired. These results suggest that senescence decreases the ability of cells to transmit circadian signals to their clocks and that regulation of clock gene expression may be a novel strategy for the treatment of age-associated impairment of circadian rhythmicity.

Animals↗

PubMed2004

When cells get stressed: an integrative view of cellular senescence.

Cells entering a state of senescence undergo a permanent cell cycle arrest, accompanied by a set of functional and morphological changes. Senescence of cells occurs following an extended period of proliferation in culture or in response to various physiologic stresses, yet little is known about the role this phenomenon plays in vivo. The study of senescence has focused largely on its hypothesized role as a barrier to extended cell division, governed by a division-counting mechanism in the form of telomere length. Here, we discuss the biological functions of cellular senescence and suggest that it should be viewed in terms of its role as a general cellular stress response program, rather than strictly as a barrier to unlimited cycles of cell growth and division. We also discuss the relative roles played by telomere shortening and telomere uncapping in the induction of senescence.

Animals↗

PubMedDate not supplied

Cellular senescence in the glaucomatous outflow pathway.

The mechanisms responsible for the progressive malfunction of the trabecular meshwork (TM)-Schlemm's canal (SC) conventional outflow pathway tissue in primary open angle glaucoma (POAG) are still not fully understood. To determine whether POAG is characterized by an accumulation of senescent cells, similar to what has been described in other diseases, we have compared the levels of the senescence marker senescence-associated-beta-galactosidase (SA-beta-gal) in the outflow pathway cells of POAG and age-matched control donors. POAG donors demonstrated a statistically significant fourfold increase in the percentage of SA-beta-gal positive cells. These results suggest a potential role for cellular senescence in the pathophysiology of the outflow pathway.

Aged↗

PubMed2006

Induction of apoptosis and cellular senescence in mice lacking transcription elongation factor, Elongin A.

Elongin A is a transcription elongation factor that increases the overall rate of mRNA chain elongation by RNA polymerase II. To gain more insight into the physiological functions of Elongin A, we generated Elongin A-deficient mice. Elongin A homozygous mutant (Elongin A(-/-)) embryos demonstrated a severely retarded development and died at between days 10.5 and 12.5 of gestation, most likely due to extensive apoptosis. Moreover, mouse embryonic fibroblasts (MEFs) derived from Elongin A(-/-) embryos exhibited not only increased apoptosis but also senescence-like growth defects accompanied by the activation of p38 MAPK and p53. Knockdown of Elongin A in MEFs by RNA interference also dramatically induced the senescent phenotype. A study using inhibitors of p38 MAPK and p53 and the generation of Elongin A-deficient mice with p53-null background suggests that both the p38 MAPK and p53 pathways are responsible for the induction of senescence-like phenotypes, whereas additional signaling pathways appear to be involved in the mediation of apoptosis in Elongin A(-/-) cells. Taken together, our results suggest that Elongin A is required for the transcription of genes essential for early embryonic development and downregulation of its activity is tightly associated with cellular senescence.

Animals↗

PubMed1995

Kinetics of 125I-PDGF binding and down-regulation of PDGF receptor in human arterial smooth muscle cell strains during cellular senescence in vitro.

Platelet-derived growth factor (PDGF) is one of the major mitogens in serum to stimulate replication of human smooth muscle cells (SMCs) in culture. Previous studies using human fibroblasts failed to demonstrate changes in the receptor systems for growth factors during cellular senescence. We investigated the kinetics of 125I-PDGF(-BB) binding and down-regulation of the PDGF receptor in three human arterial SMC strains during cellular aging. The number of specific 125I-PDGF binding sites per cell increased slightly at a population doubling level (PDL) of 60%-80% of life span and then decreased at the PDL above 90%. The number of receptors per cell-surface area decreased with increasing in vitro age. The apparent Kd for the 125I-PDGF binding decreased with in vitro senescence. The internalization and degradation of 125I-PDGF per receptor were significantly reduced in senescent SMCs and the amount of 125I-PDGF that escaped degradation and was recycled back to the cell surface was significantly greater in senescent SMCs than young cells. Furthermore, down-regulation of the PDGF receptor was significantly greater in senescent SMCs than young cells. Immunoblot studies demonstrated that changes in beta-subunit of the PDGF receptor accounted for those in the studies using 125I-PDGF and that tyrosine phosphorylation of the PDGF receptor was significantly greater in young SMCs than aged cells. Our results suggest that age-related changes in the receptor systems for PDGF may be important contributors to the failure of DNA synthesis in senescent SMCs.

Arteries↗