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Cell Senescence (cell + senescence)
Selected AbstractsOXIDIZED LOW-DENSITY LIPOPROTEIN INDUCES ENDOTHELIAL PROGENITOR CELL SENESCENCE, LEADING TO CELLULAR DYSFUNCTIONCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 7 2004Toshio Imanishi SUMMARY 1.,Recent studies have revealed an association between coronary risk factors and both the number and function of bone marrow-derived endothelial progenitor cells (EPC). We investigated the effect of oxidized low-density lipoprotein (ox-LDL) on the senescence of EPC, leading to cellular dysfunction. 2.,Endothelial progenitor cells were isolated from human peripheral blood and characterized. The exposure of cultured EPC to ox-LDL (10 µg/mL) significantly accelerated the rate of senescence compared with control during 20 days in culture as determined by acidic ,-galactosidase staining. Oxidized LDL-induced EPC senescence was significantly inhibited by pretreatment with either lectin-like ox-LDL receptor-1 (LOX-1) antibody (Ab) or atorvastatin (P < 0.01). 3.,Because cellular senescence is critically influenced by telomerase, which elongates telomeres, we measured telomerase activity using a polymerase chain reaction,ELISA-based assay. Oxidized LDL significantly diminished telomerase activity to approximately 50%, an effect that was significantly abolished by pretreatment with either LOX-1 Ab or atorvastatin (P < 0.01). 4.,We examined whether ox-LDL-induced EPC senescence translates into EPC dysfunction. An MTS assay disclosed an inhibitory effect of ox-LDL on EPC proliferation. In a Matrigel assay, EPC treated with ox-LDL were less likely to participate in network fomation compared with controls. 5.,In conclusions, ox-LDL accelerates the onset of EPC senescence, which may be related to telomerase inactivation. Oxidized LDL-induced EPC senescence leads to the impairment of proliferative capacity and network formation. [source] Effects of Donor Age and Cell Senescence on Kidney Allograft SurvivalAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2009A. Melk The biological processes responsible for somatic cell senescence contribute to organ aging and progression of chronic diseases, and this may contribute to kidney transplant outcomes. We examined the effect of pre-existing donor aging on the performance of kidney transplants, comparing mouse kidney isografts and allografts from old versus young donors. Before transplantation, old kidneys were histologically normal, but displayed an increased expression of senescence marker p16INK4a. Old allografts at day 7 showed a more rapid emergence of epithelial changes and a further increase in the expression of p16INK4a. Similar but much milder changes occurred in old isografts. These changes were absent in young allografts at day 7, but emerged by day 21. The expression of p16INK4a remained low in young kidney allografts at day 7, but increased with severe rejection at day 21. Isografts from young donors showed no epithelial changes and no increase in p16INK4a. The measurements of the alloimmune response,infiltrate, cytology, expression of perforin, granzyme B, IFN-, and MHC,were not increased in old allografts. Thus, old donor kidneys display abnormal parenchymal susceptibility to transplant stresses and enhanced induction of senescence marker p16INK4a, but were not more immunogenic. These data are compatible with a key role of somatic cell senescence mechanisms in kidney transplant outcomes by contributing to donor aging, being accelerated by transplant stresses, and imposing limits on the capacity of the tissue to proliferate. [source] Airway Epithelial Cell Senescence in the Lung AllograftAMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2008S. M. Parker Chronic lung allograft dysfunction, manifesting as bronchiolitis obliterans syndrome (BOS), is characterized by airway epithelial injury, impaired epithelial regeneration and subsequent airway remodeling. Increased cellular senescence has been reported in renal and liver allografts affected by chronic allograft dysfunction but the significance of cellular senescence in the airway epithelium of the transplanted lung is unknown. Thirty-four lung transplant recipients, 20 with stable graft function and 14 with BOS, underwent transbronchial lung biopsy and histochemical studies for senescence markers in small airways. Compared to nontransplant control lung tissue (n = 9), lung allografts demonstrate significantly increased airway epithelial staining for senescence-associated beta galactosidase (SA ,-gal) (p = 0.0215), p16ink4a (p = 0.0002) and p21waf1/cip (p = 0.0138) but there was no difference in expression of these markers between stable and BOS affected recipients (p > 0.05). This preliminary cross-sectional study demonstrates that cellular senescence occurs with increased frequency in the airway epithelium of the lung allograft but does not establish any association between airway epithelial senescence and BOS. A prospective longitudinal study is required to better address any potential causal association between airway epithelial senescence in stable allograft recipients and the subsequent development of BOS. [source] Expression of psoriasis-associated fatty acid-binding protein in senescent human dermal microvascular endothelial cellsEXPERIMENTAL DERMATOLOGY, Issue 9 2004Moon Kyung Ha Abstract:, Aging is associated with the progressive pathophysiologic modification of endothelial cells. In vitro endothelial cell senescence is accompanied by proliferative activity failure and by perturbations in gene and protein expressions. Moreover, this cellular senescence in culture has been proposed to reflect processes that occur in aging organisms. In order to observe the changing patterns of protein expression in senescent human dermal microvascular endothelial cells (HDMECs), proteins obtained from both early- and late-passaged HDMECs were separated by two-dimensional electrophoresis, visualized by silver staining, and quantified by image processing. Proteins of interest were extracted by in-gel digestion with trypsin and quantified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), by searching the National Center for Biotechnology Information protein-sequence database. More than 2000 spots were detected by 2D electrophoresis within a linear pH range of 3,10. Twenty-two major differentially expressed spots were observed in serially passaged HDMECs and identified with high confidence by MALDI-TOF-MS. One of these spots was found to be a 14,15 kDa psoriasis-associated fatty acid-binding protein (PA-FABP) with high affinity for long-chain fatty acids. The expression of PA-FABP was confirmed to be elevated in senescent HDMECs (passage 20) by fluorescence-activated cell sorting (FACS), confocal laser microscopy, and by immunohistochemistry in aged human skin tissue. Our results suggest that the overexpression of FABP in cultured senescent HDMECs is closely related to skin aging. [source] The load of short telomeres, estimated by a new method, Universal STELA, correlates with number of senescent cellsAGING CELL, Issue 3 2010Laila Bendix Summary Short telomeres are thought to trigger senescence, most likely through a single , or a group of few , critically shortened telomeres. Such short telomeres are thought to result from a combination of gradual linear shortening resulting from the end replication problem, reflecting the division history of the cell, superimposed by a more stochastic mechanism, suddenly causing a significant shortening of a single telomere. Previously, studies that have tried to explore the role of critically shortened telomeres have been hampered by methodological problems. With the method presented here, Universal STELA, we have a tool that can directly investigate the relationship between senescence and the load of short telomeres. The method is a variant of the chromosome-specific STELA method but has the advantage that it can demonstrate short telomeres regardless of chromosome. With Universal STELA, we find a strong correlation between the load of short telomeres and cellular senescence. Further we show that the load of short telomeres is higher in senescent cells compared to proliferating cells at the same passage, offering an explanation of premature cell senescence. This new method, Universal STELA, offers some advantages compared to existing methods and can be used to explore many of the unanswered questions in telomere biology including the role that telomeres play in cancer and aging. [source] DNA damage response and cellular senescence in tissues of aging miceAGING CELL, Issue 3 2009Chunfang Wang Summary The impact of cellular senescence onto aging of organisms is not fully clear, not at least because of the scarcity of reliable data on the mere frequency of senescent cells in aging tissues. Activation of a DNA damage response including formation of DNA damage foci containing activated H2A.X (,-H2A.X) at either uncapped telomeres or persistent DNA strand breaks is the major trigger of cell senescence. Therefore, ,-H2A.X immunohistochemistry (IHC) was established by us as a reliable quantitative indicator of senescence in fibroblasts in vitro and in hepatocytes in vivo and the age dependency of DNA damage foci accumulation in ten organs of C57Bl6 mice was analysed over an age range from 12 to 42 months. There were significant increases with age in the frequency of foci-containing cells in lung, spleen, dermis, liver and gut epithelium. In liver, foci-positive cells were preferentially found in the centrilobular area, which is exposed to higher levels of oxidative stress. Foci formation in the intestine was restricted to the crypts. It was not associated with either apoptosis or hyperproliferation. That telomeres shortened with age in both crypt and villus enterocytes, but telomeres in the crypt epithelium were longer than those in villi at all ages were confirmed by us. Still, there was no more than random co-localization between ,-H2A.X foci and telomeres even in crypts from very old mice, indicating that senescence in the crypt enterocytes is telomere independent. The results suggest that stress-dependent cell senescence could play a causal role for aging of mice. [source] Enhanced glycogenesis is involved in cellular senescence via GSK3/GS modulationAGING CELL, Issue 6 2008Yong-Hak Seo Summary Glycogen biogenesis and its response to physiological stimuli have often been implicated in age-related diseases. However, their direct relationships to cell senescence and aging have not been clearly elucidated. Here, we report the central involvement of enhanced glycogenesis in cellular senescence. Glycogen accumulation, glycogen synthase (GS) activation, and glycogen synthase kinase 3 (GSK3) inactivation commonly occurred in diverse cellular senescence models, including the liver tissues of aging F344 rats. Subcytotoxic concentrations of GSK3 inhibitors (SB415286 and LiCl) were sufficient to induce cellular senescence with increased glycogenesis. Interestingly, the SB415286-induced glycogenesis was irreversible, as were increased levels of reactive oxygen species and gain of senescence phenotypes. Blocking GSK3 activity using siRNA or dominant negative mutant (GSK3,-K85A) also effectively induced senescence phenotypes, and GS knock-down significantly attenuated the stress-induced senescence phenotypes. Taken together, these results clearly demonstrate that augmented glycogenesis is not only common, but is also directly linked to cellular senescence and aging, suggesting GSK3 and GS as novel modulators of senescence, and providing new insight into the metabolic backgrounds of aging and aging-related pathogenesis. [source] Identification of tryptase- and chymase-related gene clusters in human mast cells using microarraysALLERGY, Issue 3 2006C. Dahl Tryptase and chymase are the two major granular proteases present in human mast cell (MC)s. We used oligonucleotide microarray to measure the levels of approximately 22 000 transcripts in cord blood-derived MCs at 4 weeks, 8 weeks, 12 weeks and 18 weeks in culture. Tryptase (TPSB2) was expressed at the highest level among all transcripts and its expression level reached a plateau at 8 weeks. On the other hand, the expression level of chymase (CMAI) doubled every 4,6 weeks. A similar tendency was found at the protein levels with FACS analysis. After filtering the transcripts with MC-specificity, hierarchical clustering analysis identified 494 and 81 transcripts in the same clusters with tryptase and chymase, respectively. MC-specific genes, KIT and HDC were found in the tryptase cluster. In the chymase cluster, a critical suppressor for cell senescence, BMI1 and the several related genes were found, suggesting that chymase expression may be closely related to cell senescence/quiescence events. [source] REVIEW ARTICLE: How to make a melanoma: what do we know of the primary clonal events?PIGMENT CELL & MELANOMA RESEARCH, Issue 1 2008Dorothy C. Bennett Summary Rapid advances have been made in our knowledge of the commonest genetic and epigenetic alterations found in human sporadic melanomas. Valuable recent contributions came from analyses of gene copy number by comparative genome hybridization, and from large-scale gene expression profiling. All of the commonest affected genes encode regulatory components. Loci with established importance in melanoma, like CDKN2A, BRAF and PTEN, have been joined by some less familiar genes including transcription factor sequences TBX2 and STK11 (LKB). This knowledge is reviewed in relation to the cellular signaling pathways affected by these molecules, their biological outcomes, and the implications as to what changes are required overall to generate a melanoma. The data support a model in which genesis of melanoma requires changes that (1) initiate clonal expansion, (2) overcome cell senescence, and (3) reduce apoptosis. [source] Effects of Donor Age and Cell Senescence on Kidney Allograft SurvivalAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2009A. Melk The biological processes responsible for somatic cell senescence contribute to organ aging and progression of chronic diseases, and this may contribute to kidney transplant outcomes. We examined the effect of pre-existing donor aging on the performance of kidney transplants, comparing mouse kidney isografts and allografts from old versus young donors. Before transplantation, old kidneys were histologically normal, but displayed an increased expression of senescence marker p16INK4a. Old allografts at day 7 showed a more rapid emergence of epithelial changes and a further increase in the expression of p16INK4a. Similar but much milder changes occurred in old isografts. These changes were absent in young allografts at day 7, but emerged by day 21. The expression of p16INK4a remained low in young kidney allografts at day 7, but increased with severe rejection at day 21. Isografts from young donors showed no epithelial changes and no increase in p16INK4a. The measurements of the alloimmune response,infiltrate, cytology, expression of perforin, granzyme B, IFN-, and MHC,were not increased in old allografts. Thus, old donor kidneys display abnormal parenchymal susceptibility to transplant stresses and enhanced induction of senescence marker p16INK4a, but were not more immunogenic. These data are compatible with a key role of somatic cell senescence mechanisms in kidney transplant outcomes by contributing to donor aging, being accelerated by transplant stresses, and imposing limits on the capacity of the tissue to proliferate. [source] Increased Expression of Senescence-Associated Cell Cycle Inhibitor p16INK4a in Deteriorating Renal Transplants and Diseased Native KidneyAMERICAN JOURNAL OF TRANSPLANTATION, Issue 6 2005Anette Melk Some features of kidney transplants with dysfunction overlap the lesions of aging, such as tubular atrophy and interstitial fibrosis (TA/IF) without major glomerular abnormalities. Somatic cell limitations could contribute to deterioration in aging and disease states. Since expression of p16INK4a, a cell cycle inhibitor associated with somatic cell senescence in vitro, is induced in aged kidney, we studied whether kidneys with dysfunction and TA/IF manifested increased p16INK4a expression. We performed p16INK4a immunostaining on transplanted kidneys and native kidneys with chronic renal diseases. At implantation, transplants manifested little TA/IF, and nuclear p16INK4a immunostaining was consistent with age. However, transplants biopsied for abnormal function displaying TA/IF showed strong nuclear and cytoplasmic p16INK4a staining, beyond the amount predicted for age. Both atrophic and non-atrophic nephrons displayed increased p16INK4a, suggesting that it was not simply a feature of atrophy. Epithelial p16INK4a staining was not increased in transplants with good function, but was increased in diseased native kidneys. The finding of increased p16INK4a expression in renal transplants and diseased kidneys with TA/IF and impaired function supports the concept that some cell senescence changes that accompany aging are also induced by injury and disease stresses. Thus, aging, injury and disease may share common pathways involving somatic cell senescence. [source] Enhancement of intervertebral disc cell senescence by WNT/,-catenin signaling,induced matrix metalloproteinase expressionARTHRITIS & RHEUMATISM, Issue 10 2010Akihiko Hiyama Objective To determine whether intervertebral disc (IVD) cells express ,-catenin and to assess the role of the WNT/,-catenin signaling pathway in cellular senescence and aggrecan synthesis. Methods The expression of ,-catenin messenger RNA (mRNA) and protein in rat IVD cells was assessed by using several real-time reverse transcription,polymerase chain reaction, Western blot, immunohistochemical, and immunofluorescence analyses. The effect of WNT/,-catenin on nucleus pulposus (NP) cells was examined by transfection experiments, an MTT assay, senescence-associated ,-galactosidase staining, a cell cycle analysis, and a transforming growth factor (TGF,)/bone morphogenetic protein (BMP) pathway,focused microarray analysis. Results We found that ,-catenin mRNA and protein were expressed in discs in vivo and that rat NP cells exhibited increased ,-catenin mRNA and protein upon stimulation with lithium chloride, a known activator of WNT signaling. LiCl treatment inhibited the proliferation of NP cells in a time- and dose-dependent manner. In addition, there was an increased level of cellular senescence in LiCl-treated cells. Long-term treatment with LiCl induced cell cycle arrest and promoted subsequent apoptosis in NP cells. Activation of WNT/,-catenin signaling also regulated the expression of aggrecan. We also demonstrated that WNT/,-catenin signaling induced the expression of matrix metalloproteinases (MMPs) and TGF, in NP cells. Conclusion The activation of WNT/,-catenin signaling promotes cellular senescence and may modulate MMP and TGF, signaling in NP cells. We hypothesize that the activation of WNT/,-catenin signaling may lead to an increased breakdown of the matrix, thereby promoting IVD degeneration. [source] Premature aging of the immune system in children with juvenile idiopathic arthritisARTHRITIS & RHEUMATISM, Issue 7 2008Martina Prelog Objective Juvenile idiopathic arthritis (JIA) is an autoimmune disease of the young. The pathogenesis is not completely understood. Premature aging, associated thymic involution, and compensatory autoproliferation could play important roles in the pathogenesis of autoimmunity. We undertook this study to determine whether patients with JIA demonstrate premature immunosenescence. Methods To test this hypothesis, we measured 3 indicators of aging: the percentages and total counts of peripheral blood naive T cells, the frequency of T cell receptor excision circles (TRECs) in naive T cells, and telomeric erosion and Ki-67 expression as estimates of the replicative history of homeostatic proliferation. Results JIA patients showed an accelerated loss of CD4+,CD45RA+,CD62L+ naive T cells with advancing age and a compensatory increase in the number of CD4+,CD45RO+ memory T cells. JIA patients demonstrated a significantly decreased frequency of TRECs in CD4+,CD45RA+ naive T cells compared with age-matched healthy donors (P = 0.002). TREC numbers correlated with age only in healthy donors (P = 0.0001). Telomeric erosion in CD4+,CD45RA+ naive T cells was increased in JIA patients (P = 0.01). The percentages of Ki-67,positive CD4+,CD45RA+ naive T cells were increased in JIA patients (P = 0.001) and correlated with disease duration (P = 0.003), which was also an independent factor contributing to telomeric erosion (P = 0.04). Conclusion Our findings suggest that age-inappropriate T cell senescence and disturbed T cell homeostasis may contribute to the development of JIA. In patients with JIA, dysfunction in the ability to reconstitute the T cell compartment should be considered when exploring new therapeutic strategies. [source] Telomerase: not just for the elongation of telomeres,BIOESSAYS, Issue 2 2006Rodrigo T. Calado Telomerase RNA component (TERC) and telomerase reverse transcriptase (TERT) function together to elongate telomeres and to protect chromosomal ends. Recent studies have discovered that overexpression of telomerase's TERT subunit promoted epidermal stem-cell mobilization, hair growth and stem-cell proliferation without changes in length of telomeres.1,2 This telomerase functional characteristic is TERC independent and is operated through a mechanism other than telomere elongation. These findings open new doors for future explorations to understand telomerase function and its interaction with other cell components in the regulation of cell senescence and tumorigenesis. BioEssays 28: 109,112, 2006. © 2006 Wiley periodicals, Inc. [source] | |||||||||||||