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Sample records for survival cd127 senescence

  1. Partial recovery of senescence and differentiation disturbances in CD8(+) T cell effector-memory cells in HIV-1 infection after initiation of anti-retroviral treatment.

    Science.gov (United States)

    Eberhard, J M; Ahmad, F; Hong, H S; Bhatnagar, N; Keudel, P; Schulze Zur Wiesch, J; Schmidt, R E; Meyer-Olson, D

    2016-11-01

    Immune senescence as well as disturbed CD8(+) T cell differentiation are a hallmark of chronic HIV infection. Here, we investigated to what extent immune senescence is reversible after initiation of anti-retroviral treatment (ART). Peripheral blood mononuclear cells (PBMCs) from a cohort of HIV patients with different disease courses, including untreated viral controllers (n = 10), viral non-controllers (n = 16) and patients on ART (n = 20), were analysed and compared to uninfected controls (n = 25) by flow cytometry on bulk and HIV-specific major histocompatibility complex (MHC) class I tetramer(+) CD8(+) T cells for expression of the memory markers CCR7 and CD45RO, as well as the senescence marker CD57 and the differentiation and survival marker CD127. Furthermore, a subset of patients was analysed longitudinally before and after initiation of ART. Frequencies of CD57(+) CD8(+) T cells decreased after initiation of ART in central memory (Tcm) but not in effector memory T cell populations (TemRO and TemRA). The frequency of CD127(+) CD8(+) cells increased in Tcm and TemRO. We observed a reduction of CD127(-) T cells in Tcm, TemRO and partially in TemRA subsets after initiation of ART. Importantly, HIV-specific CD8(+) TemRO cells predominantly displayed a CD127(-) CD57(+) phenotype in untreated HIV-patients, whereas the CD127(+) CD57(-) phenotype was under-represented in these patients. The frequency of the CD127(+) CD57(-) CD8(+) T cell subpopulation correlated strongly with absolute CD4(+) counts in HIV-infected patients before and after initiation of ART. These findings can be interpreted as a phenotypical correlate of CD8(+) memory T cell differentiation and the premature 'ageing' of the immune system, which was even observed in successfully virally suppressed HIV patients. © 2016 British Society for Immunology.

  2. The Rarity of Survival to Old Age Does Not Drive the Evolution of Senescence

    OpenAIRE

    Wensink, Maarten Jan; Caswell, Hal; Baudisch, Annette

    2016-01-01

    The evolution of senescence is often explained by arguing that, in nature, few individuals survive to be old and hence it is evolutionarily unimportant what happens to organisms when they are old. A corollary to this idea is that extrinsically imposed mortality, because it reduces the chance of surviving to be old, favors the evolution of senescence. We show that these ideas, although widespread, are incorrect. Selection leading to senescence does not depend directly on survival to old age, b...

  3. The forms and fitness cost of senescence : Age-specific recapture, survival, reproduction, and reproductive value in a wild bird population

    NARCIS (Netherlands)

    Bouwhuis, Sandra; Choquet, Remi; Sheldon, Ben C.; Verhulst, Simon

    Longitudinal studies of senescence accumulate rapidly from natural populations. However, it is largely unknown whether different fitness components senesce in parallel, how reproductive and survival senescence contribute to declines in reproductive value, and how large the fitness cost of senescence

  4. Age-specific survival and reproductive probabilities: evidence for senescence in male fallow deer (Dama dama)

    National Research Council Canada - National Science Library

    A. G. McElligott; R. Altwegg; T. J. Altwegg

    2002-01-01

    ...–fitting model revealed that fallow bucks have four life–history stages: yearling, pre–reproductive, prime–age and senescent. Pre–reproductive males (2 and 3 years old) had the highest survival...

  5. Decreased CD127 Expression on CD4+ T-Cells and Elevated Frequencies of CD4+CD25+CD127− T-Cells in Children with Long-Lasting Type 1 Diabetes

    Directory of Open Access Journals (Sweden)

    Marcin Moniuszko

    2013-01-01

    Full Text Available Pathobiology of type 1 diabetes (T1D is predominantly associated with T-cell-related actions. Homeostasis of majority of T-cells is critically dependent on signals mediated by CD127 (interleukin-7 receptor, IL-7R. In contrast, regulatory T-cells express very little CD127 and thereby may be delineated by CD4+CD25+CD127− phenotype. Here we aimed to analyze CD127 expression on CD4+ and CD8+ T-cells and enumerate CD4+CD25+CD127− T-cells in long-lasting T1D. T-cells were analyzed by flow cytometry and immunologic data were correlated with vascular, metabolic, and inflammatory parameters. We demonstrated significantly decreased CD127 levels on CD4+, but not CD8+, T cells in T1D pediatric patients. Interestingly, frequencies of CD4+CD25+CD127− T-cells were significantly enhanced in T1D children and correlated well with frequencies of CD34+CD144+ endothelial progenitor cells and CD4+CD25− T-cells. Levels of CD127 on both CD4+ and CD8+ T-cells in T1D patients were not correlated to each other or HbA1C. Interestingly, however, CD127 levels on CD4+ T-cells were significantly correlated to frequencies of CD4+CD25+CD127− T-cells, whereas CD127 levels on CD8+ T-cells were significantly correlated to concentrations of VEGF and triglycerides. Our data indicate that CD127 expression is differentially modulated on CD4+ and CD8+ T-cells in the course of T1D. Moreover, we demonstrated that, in contrast to recent-onset T1D, long-lasting T1D is associated with enhancement of T-cells with regulatory phenotype.

  6. Blockade of CD127 Exerts a Dichotomous Clinical Effect in Marmoset Experimental Autoimmune Encephalomyelitis

    NARCIS (Netherlands)

    Dunham, Jordon; Lee, Li-Fen; van Driel, Nikki; Laman, Jon D.; Ni, Irene; Zhai, Wenwu; Tu, Guang-Huan; Lin, John C.; Bauer, Jan; 't Hart, Bert A.; Kap, Yolanda S.

    Non-human primate models of human disease have an important role in the translation of a new scientific finding in lower species into an effective treatment. In this study, we tested a new therapeutic antibody against the IL-7 receptor alpha chain (CD127), which in a C57BL/6 mouse model of

  7. Regulation of Cytokine Secretion in Human CD127(+) LTi-like Innate Lymphoid Cells by Toll-like Receptor 2

    NARCIS (Netherlands)

    Crellin, Natasha K.; Trifari, Sara; Kaplan, Charles D.; Satoh-Takayama, Naoko; Di Santo, James P.; Spits, Hergen

    2010-01-01

    Lymphoid tissue inducer cells are members of an emerging family of innate lymphoid cells (ILC). Although these cells were originally reported to produce cytokines such as interleukin-17 (IL-17) and IL-22, we demonstrate here that human CD127(+)RORC(+) and CD56(+)CD127(+) LTi-like ILC also express

  8. The Rarity of Survival to Old Age Does Not Drive the Evolution of Senescence.

    Science.gov (United States)

    Wensink, Maarten J; Caswell, Hal; Baudisch, Annette

    2017-01-01

    The evolution of senescence is often explained by arguing that, in nature, few individuals survive to be old and hence it is evolutionarily unimportant what happens to organisms when they are old. A corollary to this idea is that extrinsically imposed mortality, because it reduces the chance of surviving to be old, favors the evolution of senescence. We show that these ideas, although widespread, are incorrect. Selection leading to senescence does not depend directly on survival to old age, but on the shape of the stable age distribution, and we discuss the implications of this important distinction. We show that the selection gradient on mortality declines with age even in the hypothetical case of zero mortality, when survivorship does not decline. Changing the survivorship function by imposing age independent mortality has no affect on the selection gradients. A similar result exists for optimization models: age independent mortality does not change the optimal result. We propose an alternative, brief explanation for the decline of selection gradients, and hence the evolution of senescence.

  9. Interactive effects of senescence and natural disturbance on the annual survival probabilities of snail kites

    Science.gov (United States)

    Reichert, Brian E.; Martin, J.; Kendall, William L.; Cattau, Christopher E.; Kitchens, Wiley M.

    2010-01-01

    Individuals in wild populations face risks associated with both intrinsic (i.e. aging) and external (i.e. environmental) sources of mortality. Condition-dependent mortality occurs when there is an interaction between such factors; however, few studies have clearly demonstrated condition-dependent mortality and some have even argued that condition-dependent mortality does not occur in wild avian populations. Using large sample sizes (2084 individuals, 3746 re-sights) of individual-based longitudinal data collected over a 33 year period (1976-2008) on multiple cohorts, we used a capture-mark-recapture framework to model age-dependent survival in the snail kite Rostrhamus sociabilis plumbeus population in Florida. Adding to the growing amount of evidence for actuarial senescence in wild populations, we found evidence of senescent declines in survival probabilities in adult kites. We also tested the hypothesis that older kites experienced condition-dependent mortality during a range-wide drought event (2000-2002). The results provide convincing evidence that the annual survival probability of senescent kites was disproportionately affected by the drought relative to the survival probability of prime-aged adults. To our knowledge, this is the first evidence of condition-dependent mortality to be demonstrated in a wild avian population, a finding which challenges recent conclusions drawn in the literature. Our study suggests that senescence and condition-dependent mortality can affect the demography of wild avian populations. Accounting for these sources of variation may be particularly important to appropriately compute estimates of population growth rate, and probabilities of quasi-extinctions.

  10. Comparative analyses of longevity and senescence reveal variable survival benefits of living in zoos across mammals.

    Science.gov (United States)

    Tidière, Morgane; Gaillard, Jean-Michel; Berger, Vérane; Müller, Dennis W H; Bingaman Lackey, Laurie; Gimenez, Olivier; Clauss, Marcus; Lemaître, Jean-François

    2016-11-07

    While it is commonly believed that animals live longer in zoos than in the wild, this assumption has rarely been tested. We compared four survival metrics (longevity, baseline mortality, onset of senescence and rate of senescence) between both sexes of free-ranging and zoo populations of more than 50 mammal species. We found that mammals from zoo populations generally lived longer than their wild counterparts (84% of species). The effect was most notable in species with a faster pace of life (i.e. a short life span, high reproductive rate and high mortality in the wild) because zoos evidently offer protection against a number of relevant conditions like predation, intraspecific competition and diseases. Species with a slower pace of life (i.e. a long life span, low reproduction rate and low mortality in the wild) benefit less from captivity in terms of longevity; in such species, there is probably less potential for a reduction in mortality. These findings provide a first general explanation about the different magnitude of zoo environment benefits among mammalian species, and thereby highlight the effort that is needed to improve captive conditions for slow-living species that are particularly susceptible to extinction in the wild.

  11. Dynamic analysis of CD127 expression on memory CD8 T cells from patients with chronic hepatitis B during telbivudine treatment

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    Lv Guocai

    2010-08-01

    Full Text Available Abstract Background Accumulating evidence supports the theory that expression of CD127 on CD8 T cells during the process of antiviral immune response indicates a subset of effect CD8 T cells that successfully develop into fully protective memory. CD8 T cells expression of CD127 may be used as a predictor to evaluate disease status in chronic viral infection. The aim of this study was to investigate the CD127 expression level on different subsets of CD8 T cell and explore the relationship between CD127 expression on CD8 memory T cells and serum hepatitis B virus (HBV DNA and hepatitis B e antigen (HBeAg levels in patients with chronic hepatitis B (CHB. We also aimed to investigate the CD127 expression pattern on CD8 memory T cells of CHB patients who were treated with Telbivudine. Methods/Results Twenty HBeAg-positive CHB patients were selected and treated with telbivudine 600 mg/day for 48 weeks. The memory CD8 T cells were characterized by expression of CD45RA and CD27 markers. CD127 expression on the CD8 T-cell surface was measured by four-colour flow cytometry. Our results showed that CD127 expression on memory CD8 T cells was reduced in CHB patients. There was a strong negative correlation between CD127 expression on memory CD8 T cells and serum HBV DNA and HBeAg levels in CHB patients. Moreover, successful antiviral therapy increased CD127 expression on CD8 memory T cells as well as on HBV-specific CD8 T cells in CHB patients. Conclusion These results suggest that diminished CD127 expression on CD8 memory T cells of CHB patients is a potential mechanism explaining cellular immune function impairment in CHB infection, and that CD127 expression on CD8 memory T cells is a useful indicator for evaluating the effects of anti-HBV therapy.

  12. Staphylococcus aureus convert neonatal conventional CD4(+) T cells into FOXP3(+) CD25(+) CD127(low) T cells via the PD-1/PD-L1 axis.

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    Rabe, Hardis; Nordström, Inger; Andersson, Kerstin; Lundell, Anna-Carin; Rudin, Anna

    2014-03-01

    The gut microbiota provides an important stimulus for the induction of regulatory T (Treg) cells in mice, whether this applies to newborn children is unknown. In Swedish children, Staphylococcus aureus has become a common early colonizer of the gut. Here, we sought to study the effects of bacterial stimulation on neonatal CD4(+) T cells for the induction of CD25(+) CD127(low) Treg cells in vitro. The proportion of circulating CD25(+) CD127(low) Treg cells and their expression of FOXP3, Helios and CTLA-4 was examined in newborns and adults. To evaluate if commensal gut bacteria could induce Treg cells, CellTrace violet-stained non-Treg cells from cord or peripheral blood from adults were co-cultured with autologous CD25(+) CD127(low) Treg cells and remaining mononuclear cells and stimulated with S. aureus. Newborns had a significantly lower proportion of CD25(+) CD127(low) Treg cells than adults, but these cells were Helios(+) and CTLA-4(+) to a higher extent than in adults. FOXP3(+) CD25(+) CD127(low) T cells were induced mainly in neonatal CellTrace-stained non-Treg cells after stimulation with S. aureus. In cell cultures from adults, S. aureus induced CD25(+) CD127(low) T cells only if sorted naive CD45RA(+) non-Treg cells were used, but these cells expressed less FOXP3 than those induced from newborns. Sorted neonatal CD25(+) CD127(low) T cells from S. aureus-stimulated cultures were still suppressive. Finally, blocking PD-L1 during stimulation reduced the induction of FOXP3(+) CD25(+) CD127(low) T cells. These results suggest that newborns have a higher proportion of circulating thymically derived Helios(+) Treg cells than adults and that S. aureus possess an ability to convert neonatal conventional CD4(+) T cells into FOXP3(+) CD25(+) CD127(low) Treg cells via the PD-1/PD-L1 axis. © 2013 The Authors. Immunology published by John Wiley & Sons Ltd.

  13. Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC(+) CD127(+) natural killer-like cells

    NARCIS (Netherlands)

    Cupedo, Tom; Crellin, Natasha K.; Papazian, Natalie; Rombouts, Elwin J.; Weijer, Kees; Grogan, Jane L.; Fibbe, Willem E.; Cornelissen, Jan J.; Spits, Hergen

    2009-01-01

    The human body contains over 500 individual lymph nodes, yet the biology of their formation is poorly understood. Here we identify human lymphoid tissue-inducer cells (LTi cells) as lineage-negative RORC(+) CD127(+) cells with the functional ability to interact with mesenchymal cells through

  14. Functional genetic screen for genes involved in senescence: role of Tid1, a homologue of the Drosophila tumor suppressor l(2)tid, in senescence and cell survival.

    Science.gov (United States)

    Tarunina, Marina; Alger, Lynsey; Chu, Grace; Munger, Karl; Gudkov, Andrei; Jat, Parmjit S

    2004-12-01

    We performed a genetic suppressor element screen to identify genes whose inhibition bypasses cellular senescence. A normalized library of fragmented cDNAs was used to select for elements that promote immortalization of rat embryo fibroblasts. Fragments isolated by the screen include those with homology to genes that function in intracellular signaling, cellular adhesion and contact, protein degradation, and apoptosis. They include mouse Tid1, a homologue of the Drosophila tumor suppressor gene l(2)tid, recently implicated in modulation of apoptosis as well as gamma interferon and NF-kappaB signaling. We show that GSE-Tid1 enhances immortalization by human papillomavirus E7 and simian virus 40 T antigen and cooperates with activated ras for transformation. Expression of Tid1 is upregulated upon cellular senescence in rat and mouse embryo fibroblasts and premature senescence of REF52 cells triggered by activated ras. In accordance with this, spontaneous immortalization of rat embryo fibroblasts is suppressed upon ectopic expression of Tid1. Modulation of endogenous Tid1 activity by GSE-Tid1 or Tid1-specific RNA interference alleviates the suppression of tumor necrosis factor alpha-induced NF-kappaB activity by Tid1. We also show that NF-kappaB sequence-specific binding is strongly downregulated upon senescence in rat embryo fibroblasts. We therefore propose that Tid1 contributes to senescence by acting as a repressor of NF-kappaB signaling.

  15. Effects of elevated CO2 and shade on the decomposition of senesced tree foliage: impacts on the growth and survival of treehole mosquitoes

    Science.gov (United States)

    R. Malcolm Strand; Daniel A. Herms; Michael G. Kaufman; Mark E. Kubiske; William J. Mattson; Edward D. Walker; Kurt S. Pregitzer; Richard W. Merritt

    1996-01-01

    We tested the hypothesis that growth, survival, and reproductive capacity of treehole mosquitoes can be affected by alterations of forest sunlight and CO2 levels. Larval Aedes triseriatus were fed naturally senesced , abscised foliage from red oak (Quercus rubra) and paper birch (Betula papyrifera...

  16. Survival of egg-laying controlling neuroendocrine cells during reproductive senescence of a mollusc

    NARCIS (Netherlands)

    Janse, C.

    2004-01-01

    During brain aging neuronal degradation occurs. In some neurons this may result in degeneration and cell death, still other neurons may survive and maintain their basic properties. The present study deals with survival of the egg-laying controlling neuroendocrine caudodorsal cells (CDCs) during

  17. Reduced IL-7R T Cell Expression and Increased Plasma sCD127 in Late Presenting HIV-Infected Individuals

    DEFF Research Database (Denmark)

    Hartling, Hans J; Jespersen, Sofie; Gaardbo, Julie C

    2017-01-01

    BACKGROUND: Late presentation of HIV infection is associated with reduced chance of optimal immune recovery after initiating combination antiretroviral therapy (cART). Interleukin-7 (IL-7) and the corresponding receptor, IL-7 receptor (IL-7R) made up of CD127 and CD132, are crucial for T cell...... homeostasis. This study aimed to describe IL-7R and IL-7 before and after initiation of cART in late presenting HIV-infected individuals, and the impact on immune recovery and T cell subset distribution after initiation of cART. METHODS: A total of 100 HIV-infected individuals initiating cART were included...... in a prospective study. Samples were collected at baseline and after 6, 12, and 24 months of cART. Proportion and expression {[median fluorescence intensity (MFI)]} of IL-7R on T cells, and plasma concentrations of soluble CD127 (sCD127) and IL-7 were determined. RESULTS: The IL-7R expression was reduced in late...

  18. Bim-mediated apoptosis and PD-1/PD-L1 pathway impair reactivity of PD1(+)/CD127(-) HCV-specific CD8(+) cells targeting the virus in chronic hepatitis C virus infection.

    Science.gov (United States)

    Larrubia, Juan R; Benito-Martínez, Selma; Miquel, Joaquín; Calvino, Miryam; Sanz-de-Villalobos, Eduardo; González-Praetorius, Alejandro; Albertos, Sonia; García-Garzón, Silvia; Lokhande, Megha; Parra-Cid, Trinidad

    2011-01-01

    PD-1 molecule promotes anergy and IL-7 receptor (CD127) induces an anti-apoptotic effect on T cells. Correlation between PD-1/CD127 phenotype and hepatitis C virus (HCV)-specific CD8(+) cell reactivity in resolved infection (RI) after treatment and persistent HCV-infection (PI) was analysed. Directly ex vivo, PD-1 and CD127 expression on HCV-specific CD8(+) cells displayed a positive and negative correlation, respectively with viraemia. Proliferation after stimulation on PD-1(-)/CD127(+) cells from RI cases was preserved, while it was impaired on PD-1(+)/CD127(-) cells from PI patients. PD1(+)/CD127(+) population was observed in PI, and these maintained expansion ability but they did not target the virus. Frequency of PI cases with HCV-specific CD8(+) cell proliferation increased after anti-PD-L1 and anti-apoptotic treatment. Bim expression on HCV-specific CD8(+) cells from PI patients was enhanced. In conclusion, during chronic HCV infection non-reactive HCV-specific CD8(+) cells targeting the virus are PD-1(+)/CD127(-)/Bim(+) and, blocking apoptosis and PD-1/PD-L1 pathway on them enhances in vitro reactivity. Copyright © 2011 Elsevier Inc. All rights reserved.

  19. CD4+CD25+CD127low regulatory T cells play predominant anti-tumor suppressive role in hepatitis B virus associated hepatocellular carcinoma

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    Shreya eSharma

    2015-02-01

    Full Text Available Background:Hepatocellular carcinoma (HCC is the second leading cause of cancer death worldwide and hepatitis B is one of the commonest causes. T regulatory cells (Tregs are strong immunomodulators and are likely to play a major role in HCC development. HBV infection is reported to induce expansion of Tregs. We investigated the CD4+CD25+CD127-veFoxP3+ Tregs in HBV related HCC as compared to non-HBV-HCC. Patients and Methods: Whole blood Immunophenotyping was analysed by multicolor flow cytometry in patients with HBV related HCC (HBV-HCC, n=17, non-HBV-HCC (n=22; NASH =16, alcohol related=6 and chronic hepatitis B infection (CHBV; n=10.T regulatory cells and functionality was checked by in vitro suppression assays using CD4+ CD25+ CD127low T regulatory cells. Levels of serum alpha fetoprotein(AFP,expression of FoxP3, IL-10, PD-1, TGF-β and Notch in Tregs and liver explants was analyzed by flow cytometry, immuno-histochemistry and quantitative RT-PCR.Results:CD4+CD25+hi and Foxp3 expression in CD4+CD25+hiCD127low was significantly increased (P=0.04, P=0.007 in HBVHCC compared to non-HBVHCC and CHBV patients. HBVHCC also showed high IL-10and TGF-β secreting CD4+CD25+hiTregs.The PD1 expression in CD4+CD25+hi was significantly decreased in the HBVHCC than non-HBVHCC. In HBVHCC, AFP levels were significantly high (median 941, range 2-727940 than non-HBVHCC (median 13.5, range 2-18,900. In HBVHCC,patients with high AFP (range;3982-727940 ng/ml showed positive correlation with Foxp3 expression in CD4+CD25+hi CD127low(r=0.857,p=0.014. Reduced PD1 expression in HBVHCC also had negative correlation with FOXP3 in CD4+CD25+hi CD127low(r=-0.78, p=0.04. However, AFP levels in non-HBVHCC showed negative correlation with (R=-0.67, p=0.005 with CD4+CD25+hi Tregs. Conclusions:Our results demonstrates that CD4+ CD25+hi Tregs from HBVHCC patients have decreased expression of PD-1, resulting in higher IL-10 and TGF-β secretion. Increased suppressive ability of

  20. CD127 expression, exhaustion status and antigen specific proliferation predict sustained virologic response to IFN in HCV/HIV co-infected individuals.

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    Hassen Kared

    Full Text Available Hepatitis C virus (HCV infection is a major cause of morbidity and mortality in the HIV co-infected population. Interferon-alpha (IFN-α remains a major component of anti-HCV therapy despite its deleterious effects on the immune system. Furthermore, IFN-α was recently shown to diminish the size of the latent HIV reservoir. The objectives of this study were to monitor the impact of IFN-α on T cell phenotype and proliferation of HIV and HCV-specific T cells during IFN therapy, and to identify immune markers that can predict the response to IFN in HICV/HIV co-infected patients. We performed longitudinal analyses of T cell numbers, phenotype and function in co-infected patients undergoing IFN-α therapy with different outcomes including IFN-α non-responders (NR (n = 9 and patients who achieved sustained virologic response (SVR (n = 19. We examined the expression of activation (CD38, HLA-DR, functional (CD127 and exhaustion markers (PD1, Tim-3, CD160 and CD244 on total CD4 and CD8 T cells before, during and after therapy. In addition, we examined the HIV- and HCV-specific proliferative responses against HIV-p24 and HCV-NS3 proteins. Frequencies of CD127+ CD4 T cells were higher in SVR than in NR patients at baseline. An increase in CD127 expression on CD8 T cells was observed after IFN-α therapy in all patients. In addition, CD8 T cells from NR patients expressed a higher exhaustion status at baseline. Finally, SVR patients exhibited higher proliferative response against both HIV and HCV antigens at baseline. Altogether, SVR correlated with higher expression of CD127, lower T cell exhaustion status and better HIV and HCV proliferative responses at baseline. Such factors might be used as non-invasive methods to predict the success of IFN-based therapies in co-infected individuals.

  1. Dysregulation of CD4+CD25+CD127lowFOXP3+ regulatory T cells in HIV-infected pregnant women

    DEFF Research Database (Denmark)

    Kolte, Lilian; Gaardbo, Julie C; Karlsson, Ingrid

    2010-01-01

    Pregnancy represents a major challenge to immunologic tolerance. How the fetal "semiallograft" evades maternal immune attack is unknown. Pregnancy success may involve alteration of both central (thymic) and peripheral tolerance mechanisms. HIV infection is characterized by CD4(+) T-cell depletion...... prospectively during pregnancy and postpartum. A significant expansion of CD4(+)CD25(+)CD127(low)FoxP3(+) regulatory T cells indicating alteration of peripheral tolerance was seen during second trimester, but only in HIV-negative women. HIV-infected women had lower CD4 counts, lower thymic output and Th-2...

  2. Significance of the frequency of CD4+CD25+CD127- T-cells in patients with pulmonary tuberculosis and diabetes mellitus.

    Science.gov (United States)

    Sun, Qin; Zhang, Qing; Xiao, Heping; Cui, Haiyan; Su, Bo

    2012-07-01

    Pulmonary tuberculosis and diabetes mellitus (DM) are closely associated. The objective of this study was to determine whether the expression of CD4+CD25+CD127- T-cells (regulatory T-cells (Treg)) is associated with diabetic pulmonary tuberculosis. Flow cytometry was used to determine the frequencies of CD4+CD25+ and CD4+CD25+CD127- T-cells in peripheral blood, bronchoalveolar lavage fluid (BALF) and pleural effusions from 120 patients (30 with pulmonary tuberculosis and DM (TBDM), 30 with pulmonary tuberculosis without DM (TB), 30 with tuberculous pleurisy without DM (TBP) and 30 healthy volunteers). The concentrations of interferon (IFN)-γ and interleukin (IL)-10 in BALF and pleural effusions were determined by enzyme-linked immunosorbent assay. Treg frequencies in peripheral blood were significantly higher in patients with TBDM, TB and TBP than in the control group, with the frequency in TBDM being the highest (P tuberculosis and DM, the imbalance between Treg and effector T-cells at pathological sites may be associated with weakened immunity and clinical manifestations of TB. © 2012 The Authors. Respirology © 2012 Asian Pacific Society of Respirology.

  3. LAP TGF-Beta Subset of CD4+CD25+CD127− Treg Cells is Increased and Overexpresses LAP TGF-Beta in Lung Adenocarcinoma Patients

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    Lorenzo Islas-Vazquez

    2015-01-01

    Full Text Available Lung cancer is the leading cause of cancer death worldwide. Adenocarcinoma, the most commonly diagnosed histologic type of lung cancer, is associated with smoking. Cigarette smoke promotes inflammation on the airways, which might be mediated by Th17 cells. This inflammatory environment may contribute to tumor development. In contrast, some reports indicate that tumors may induce immunosuppressive Treg cells to dampen immune reactivity, supporting tumor growth and progression. Thus, we aimed to analyze whether chronic inflammation or immunosuppression predominates at the systemic level in lung adenocarcinoma patients, and several cytokines and Th17 and Treg cells were studied. Higher proportions of IL-17-producing CD4+ T-cells were found in smoking control subjects and in lung adenocarcinoma patients compared to nonsmoking control subjects. In addition, lung adenocarcinoma patients increased both plasma concentrations of IL-2, IL-4, IL-6, and IL-10, and proportions of Latency Associated Peptide (LAP TGF-β subset of CD4+CD25+CD127− Treg cells, which overexpressed LAP TGF-β. This knowledge may lead to the development of immunotherapies that could inhibit the suppressor activity mediated by the LAP TGF-β subset of CD4+CD25+CD127− Treg cells to promote reactivity of immune cells against lung adenocarcinoma cells.

  4. Dysregulation of CD4+CD25+CD127lowFOXP3+ regulatory T cells in HIV-infected pregnant women

    DEFF Research Database (Denmark)

    Kolte, Lilian; Gaardbo, Julie C; Karlsson, Ingrid

    2010-01-01

    , chronic immune activation, and altered lymphocyte subsets. We studied immunologic consequences of pregnancy in 20 HIV-infected women receiving highly active antiretroviral therapy (HAART), and for comparison in 16 HIV-negative women. Lymphocyte subsets, thymic output, and cytokine profiles were measured...... prospectively during pregnancy and postpartum. A significant expansion of CD4(+)CD25(+)CD127(low)FoxP3(+) regulatory T cells indicating alteration of peripheral tolerance was seen during second trimester, but only in HIV-negative women. HIV-infected women had lower CD4 counts, lower thymic output and Th-2...... course of HIV infection. However, despite HAART during pregnancy, HIV-infected women display different immunologic profiles from HIV-negative women, which may have importance for the induction of fetal-maternal tolerance and in part explain the increased risk of abortion in HIV-infected women....

  5. Physiological and pathological consequences of cellular senescence.

    Science.gov (United States)

    Burton, Dominick G A; Krizhanovsky, Valery

    2014-11-01

    Cellular senescence, a permanent state of cell cycle arrest accompanied by a complex phenotype, is an essential mechanism that limits tumorigenesis and tissue damage. In physiological conditions, senescent cells can be removed by the immune system, facilitating tumor suppression and wound healing. However, as we age, senescent cells accumulate in tissues, either because an aging immune system fails to remove them, the rate of senescent cell formation is elevated, or both. If senescent cells persist in tissues, they have the potential to paradoxically promote pathological conditions. Cellular senescence is associated with an enhanced pro-survival phenotype, which most likely promotes persistence of senescent cells in vivo. This phenotype may have evolved to favor facilitation of a short-term wound healing, followed by the elimination of senescent cells by the immune system. In this review, we provide a perspective on the triggers, mechanisms and physiological as well as pathological consequences of senescent cells.

  6. Assessment of the frequency of regulatory T cells (CD4+CD25+CD127-) in children with hemophilia A: relation to factor VIII inhibitors and disease severity.

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    El-Asrar, Mohamed Abo; Hamed, Ahmed El-Saeed; Darwish, Yasser Wagih; Ismail, Eman Abdel Rahman; Ismail, Noha Ali

    2016-01-01

    A rapidly growing evidence showed that regulatory T cells (Tregs) play a crucial role in tolerance to coagulation factors and may be involved in the pathogenesis of inhibitor formation in patients with hemophilia. We determined the percentage of Tregs (CD4CD25CD127) in 45 children with hemophilia A compared with 45 healthy controls, and assessed their relation to the clinical characteristics of patients and factor VIII (FVIII) inhibitors. Patients were studied stressing on frequency of bleeding attacks, joint pain, history of viral hepatitis, and the received therapy (FVIII precipitate/cryotherapy). FVIII activity and FVIII inhibitors were assessed with flow cytometric analysis of CD4CD25CD127 Tregs. According to residual FVIII activity levels, 30 patients (66.7%) had mild/moderate hemophilia A, whereas 15 (33.3%) patients had severe hemophilia A. The frequency of Tregs was significantly lower among all patients with hemophilia A compared with controls (2.59 ± 1.1 versus 3.73 ± 1.12%; P = 0.002). Tregs were significantly decreased among patients with FVIII inhibitors compared with the inhibitor-negative group (P hemophilia A had lower Tregs levels than those without (P = 0.34 and P = 0.011, respectively). A significant positive correlation was found between the percentage of Tregs and FVIII among hemophilia A patients. ROC curve analysis revealed that the cut-off value of Tregs at 1.91% could differentiate patients with and without FVIII inhibitors, with a sensitivity of 100% and a specificity of 91.3%. We suggest that alteration in the frequency of Tregs in young patients with hemophilia A may contribute to inhibitor formation and disease severity.

  7. Cellular Senescence: A Translational Perspective

    Directory of Open Access Journals (Sweden)

    James L. Kirkland

    2017-07-01

    Full Text Available Cellular senescence entails essentially irreversible replicative arrest, apoptosis resistance, and frequently acquisition of a pro-inflammatory, tissue-destructive senescence-associated secretory phenotype (SASP. Senescent cells accumulate in various tissues with aging and at sites of pathogenesis in many chronic diseases and conditions. The SASP can contribute to senescence-related inflammation, metabolic dysregulation, stem cell dysfunction, aging phenotypes, chronic diseases, geriatric syndromes, and loss of resilience. Delaying senescent cell accumulation or reducing senescent cell burden is associated with delay, prevention, or alleviation of multiple senescence-associated conditions. We used a hypothesis-driven approach to discover pro-survival Senescent Cell Anti-apoptotic Pathways (SCAPs and, based on these SCAPs, the first senolytic agents, drugs that cause senescent cells to become susceptible to their own pro-apoptotic microenvironment. Several senolytic agents, which appear to alleviate multiple senescence-related phenotypes in pre-clinical models, are beginning the process of being translated into clinical interventions that could be transformative.

  8. Cellular Senescence: A Translational Perspective.

    Science.gov (United States)

    Kirkland, James L; Tchkonia, Tamara

    2017-07-01

    Cellular senescence entails essentially irreversible replicative arrest, apoptosis resistance, and frequently acquisition of a pro-inflammatory, tissue-destructive senescence-associated secretory phenotype (SASP). Senescent cells accumulate in various tissues with aging and at sites of pathogenesis in many chronic diseases and conditions. The SASP can contribute to senescence-related inflammation, metabolic dysregulation, stem cell dysfunction, aging phenotypes, chronic diseases, geriatric syndromes, and loss of resilience. Delaying senescent cell accumulation or reducing senescent cell burden is associated with delay, prevention, or alleviation of multiple senescence-associated conditions. We used a hypothesis-driven approach to discover pro-survival Senescent Cell Anti-apoptotic Pathways (SCAPs) and, based on these SCAPs, the first senolytic agents, drugs that cause senescent cells to become susceptible to their own pro-apoptotic microenvironment. Several senolytic agents, which appear to alleviate multiple senescence-related phenotypes in pre-clinical models, are beginning the process of being translated into clinical interventions that could be transformative. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  9. Androgen receptor drives cellular senescence.

    Directory of Open Access Journals (Sweden)

    Yelena Mirochnik

    Full Text Available The accepted androgen receptor (AR role is to promote proliferation and survival of prostate epithelium and thus prostate cancer progression. While growth-inhibitory, tumor-suppressive AR effects have also been documented, the underlying mechanisms are poorly understood. Here, we for the first time link AR anti-cancer action with cell senescence in vitro and in vivo. First, AR-driven senescence was p53-independent. Instead, AR induced p21, which subsequently reduced ΔN isoform of p63. Second, AR activation increased reactive oxygen species (ROS and thereby suppressed Rb phosphorylation. Both pathways were critical for senescence as was proven by p21 and Rb knock-down and by quenching ROS with N-Acetyl cysteine and p63 silencing also mimicked AR-induced senescence. The two pathways engaged in a cross-talk, likely via PML tumor suppressor, whose localization to senescence-associated chromatin foci was increased by AR activation. All these pathways contributed to growth arrest, which resolved in senescence due to concomitant lack of p53 and high mTOR activity. This is the first demonstration of senescence response caused by a nuclear hormone receptor.

  10. Tr-1-like CD4+CD25-CD127-/lowFOXP3- cells are the main source of interleukin 10 in patients with cutaneous leishmaniasis due to Leishmania braziliensis.

    Science.gov (United States)

    Costa, Diego L; Cardoso, Tiago M; Queiroz, Adriano; Milanezi, Cristiane M; Bacellar, Olívia; Carvalho, Edgar M; Silva, João S

    2015-03-01

    CD4(+)CD25(+)FOXP3(+) regulatory T cells have long been shown to mediate susceptibility to Leishmania infection, mainly via interleukin 10 production. In this work, we showed that the main sources of interleukin 10 in peripheral blood mononuclear cells (PBMCs) from patients with cutaneous leishmaniasis due to Leishmania braziliensis are CD4(+)CD25(-)CD127(-/low)FOXP3(-) cells. Compared with uninfected controls, patients with CL had increased frequencies of circulating interleukin 10-producing CD4(+)CD25(-)CD127(-/low) cells, which efficiently suppressed tumor necrosis factor α production by the total PBMC population. Also, in CL lesions, interleukin 10 was mainly produced by CD4(+)CD25(-) cells, and interleukin 10 messenger RNA expression was associated with interleukin 27, interleukin 21, and interferon γ expression, rather than with FOXP3 or transforming growth factor β expressions. Active production of both interleukin 27 and interleukin 21, together with production of interferon γ and interleukin 10, was also detected in the lesions. Since these cytokines are associated with the differentiation and activity of Tr-1 cells, our results suggest that this cell population may play an important role in the immunomodulation of CL. Therefore, development of treatments that interfere with this pathway may lead to faster parasite elimination. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  11. Delayed Senescence

    Science.gov (United States)

    2004-01-01

    Researcher Dr. Yi Li developed a technique to manipulate certain characteristics of plant growth such as anit-senescence. For example, the tobacco leaf was clipped from a transgenic plant (right), and a wildtype plant (left). During ground-based laboratory studies, both leaves were left in a darkened area for 4 months. When retrieved, the wildtype plant leaf was dried-out and the transgenic leaf remained fresh and green. A variation of this technology that involves manipulating plant hormones has been conducted in space-based studies on tomato plants through BioServe Space Technologies. The transport and distribution of auxin, an important plant hormone has shown to be influenced by microgravity, which could lead to improving the quality of fruits and vegetables grown on Earth.

  12. Senescence responsive transcriptional element

    Science.gov (United States)

    Campisi, Judith; Testori, Alessandro

    1999-01-01

    Recombinant polynucleotides have expression control sequences that have a senescence responsive element and a minimal promoter, and which are operatively linked to a heterologous nucleotide sequence. The molecules are useful for achieving high levels of expression of genes in senescent cells. Methods of inhibiting expression of genes in senescent cells also are provided.

  13. Mutation accumulation and the catastrophic senescence of Pacific salmon

    CERN Document Server

    Penna, T J P; Stauffer, D; Stauffer, Dietrich

    1995-01-01

    The bit-string model of biological aging is used to simulate the catastrophic senescence of Pacific Salmon. We have shown that reproduction occuring only once and at a fixed age is the only ingredient needed to explain the catastrophic senescence according the mutation accumulation theory. Several results are presented, some of them with up to 10^8 fishes, showing how the survival rates in catastrophic senescence are affected by changes in the parameters of the model.

  14. Spatial variation in senescence rates in a bird metapopulation

    OpenAIRE

    Holand, Håkon; Kvalnes, Thomas; Gamelon, Marlène; Tufto, Jarle; Jensen, Henrik; Pärn, Henrik; Ringsby, Thor Harald; Sæther, Bernt-Erik

    2016-01-01

    Investigating factors which affect the decline in survival with age, i.e. actuarial senescence, is important in order to understand how demographic rates vary in wild populations. Although the evidence for the occurrence of actuarial senescence in wild populations is growing, very few studies have compared actuarial senescence rates between wild populations of the same species. We used data from a long-time study of demography of house sparrows (Passer domesticus) to investigate differences i...

  15. Spatial variation in senescence rates in a bird metapopulation.

    Science.gov (United States)

    Holand, H; Kvalnes, T; Gamelon, M; Tufto, J; Jensen, H; Pärn, H; Ringsby, T H; Sæther, B-E

    2016-07-01

    Investigating factors which affect the decline in survival with age, i.e. actuarial senescence, is important in order to understand how demographic rates vary in wild populations. Although the evidence for the occurrence of actuarial senescence in wild populations is growing, very few studies have compared actuarial senescence rates between wild populations of the same species. We used data from a long-time study of demography of house sparrows (Passer domesticus) to investigate differences in rates of actuarial senescence between habitats and sub-populations. We also investigated whether rates of actuarial senescence differed between males and females. We found that rates of actuarial senescence showed large spatial variation. We also found that the onset of actuarial senescence varied between sub-populations. However, these differences were not significantly explained by a general difference in habitat type. We also found no significant difference in actuarial senescence rates between males and females. This study shows that senescence rates in natural populations may vary significantly between sub-populations and that failing to account for such differences may give a biased estimate of senescence rates of a species.

  16. [Senescence and cellular immortality].

    Science.gov (United States)

    Trentesaux, C; Riou, J-F

    2010-11-01

    Senescence was originally described from the observation of the limited ability of normal cells to grow in culture, and may be generated by telomere erosion, accumulation of DNA damages, oxidative stress and modulation of oncogenes or tumor suppressor genes. Senescence corresponds to a cellular response aiming to control tumor progression by limiting cell proliferation and thus constitutes an anticancer barrier. Senescence is observed in pre-malignant tumor stages and disappears from malignant tumors. Agents used in standard chemotherapy also have the potential to induce senescence, which may partly explain their therapeutic activities. It is possible to restore senescence in tumors using targeted therapies that triggers telomere dysfunction or reactivates suppressor genes functions, which are essential for the onset of senescence.

  17. Senescence is not inevitable

    DEFF Research Database (Denmark)

    Jones, Owen; Vaupel, James W.

    2017-01-01

    Senescence, the physiological deterioration resulting in an increase in mortality and decline in fertility with age, is widespread in the animal kingdom and has often been regarded as an inescapable feature of all organisms. This essay briefly describes the history of the evolutionary theoretical...... ideas on senescence. The canonical evolutionary theories suggest that increasing mortality and decreasing fertility should be ubiquitous. However, increasing empirical data demonstrates that senescence may not be as universal a feature of life as once thought and that a diversity of demographic...... trajectories exists. These empirical observations support theoretical work indicating that a wide range of mortality and fertility trajectories is indeed possible, including senescence, negligible senescence and even negative senescence (improvement). Although many mysteries remain in the field...

  18. Negative Correlation between Circulating CD4+FOXP3+CD127− Regulatory T Cells and Subsequent Antibody Responses to Infant Measles Vaccine but Not Diphtheria–Tetanus–Pertussis Vaccine Implies a Regulatory Role

    Directory of Open Access Journals (Sweden)

    Jorjoh Ndure

    2017-08-01

    Full Text Available Regulatory T cells (Tregs play a key homeostatic role by suppressing immune responses. They have been targeted in mouse and human cancer studies to improve vaccine immunogenicity and tumor clearance. A number of commercially available drugs and experimental vaccine adjuvants have been shown to target Tregs. Infants have high numbers of Tregs and often have poor responses to vaccination, yet the role Tregs play in controlling vaccine immunogenicity has not been explored in this age group. Herein, we explore the role of CD4+FOXP3+CD127− Tregs in controlling immunity in infant males and females to vaccination with diphtheria–tetanus–whole cell pertussis (DTP and/or measles vaccine (MV. We find correlative evidence that circulating Tregs at the time of vaccination suppress antibody responses to MV but not DTP; and Tregs 4 weeks after DTP vaccination may suppress vaccine-specific cellular immunity. This opens the exciting possibility that Tregs may provide a future target for improved vaccine responses in early life, including reducing the number of doses of vaccine required. Such an approach would need to be safe and the benefits outweigh the risks, thus further research in this area is required.

  19. 17AAG Treatment Accelerates Doxorubicin Induced Cellular Senescence: Hsp90 Interferes with Enforced Senescence of Tumor Cells

    Directory of Open Access Journals (Sweden)

    Upasana Sarangi

    2012-01-01

    Full Text Available Hsp90 chaperone has been identified as an attractive pharmacological target to combat cancer. However, some metastatic tumors either fail to respond to Hsp90 inhibition or show recovery necessitating irreversible therapeutic strategies. In response to this enforced senescence has been proposed as an alternate strategy. Here, we demonstrate that inhibiting Hsp90 with 17AAG sensitizes human neuroblastoma to DNA damage response mediated cellular senescence. Among individual and combination drug treatments, 17AAG pre-treatment followed by doxorubicin treatment exhibited senescence-like characteristics such as increased nucleus to cytoplasm ratio, cell cycle arrest, SA- β -gal staining and the perpetual increase in SAHF. Doxorubicin induced senescence signaling was mediated by p53-p21 CIP/WAF-1 and was accelerated in the absence of functional Hsp90. Sustained p16 INK4a and H3K4me3 expressions correlating with unaffected telomerase activation annulled replicative senescence and appraised stress induced senescence. Despite increases in [(ROSi] and [(Ca 2+ i], a concomitant increase in cellular antioxidant defense system suggested oxidation independent senescence activation. Sustained activation of survival (Akt and proliferative (ERK1/2 kinases fosters robustness of cells. Invigorating senescent cells with growth factor or snooping with mTOR or PI3 kinase inhibitors compromised cell survival but not senescence. Intriguingly, senescence-associated secretory factors from the senescence cells manifested established senescence in neuroblastoma, which offers clinical advantage to our approach. Our study discusses tumor selective functions of Hsp90 and discusses irrefutable strategies of Hsp90 inhibition in anticancer treatments.

  20. Assessing senescence patterns in populations of large mammals

    Directory of Open Access Journals (Sweden)

    Gaillard, J.-M.

    2004-06-01

    Full Text Available Theoretical models such as those of Gompertz and Weibull are commonly used to study senescence in survival for humans and laboratory or captive animals. For wild populations of vertebrates, senescence in survival has more commonly been assessed by fitting simple linear or quadratic relationships between survival and age. By using appropriate constraints on survival parameters in Capture-Mark-Recapture (CMR models, we propose a first analysis of the suitability of the Gompertz and the two-parameter Weibull models for describing aging-related mortality in free-ranging populations of ungulates. We first show how to handle the Gompertz and the two-parameter Weibull models in the context of CMR analyses. Then we perform a comparative analysis of senescence patterns in both sexes of two ungulate species highly contrasted according to the intensity of sexual selection. Our analyses provide support to the Gompertz model for describing senescence patterns in ungulates. Evolutionary implications of our results are discussed

  1. Biomarkers of cell senescence

    Science.gov (United States)

    Dirmi, Goberdhan P.; Campisi, Judith; Peacocke, Monica

    1996-01-01

    The present invention provides a biomarker system for the in vivo and in vitro assessment of cell senescence. In the method of the present invention, .beta.-galactosidase activity is utilized as a means by which cell senescence may be assessed either in in vitro cell cultures or in vivo.

  2. Senescence Meets Dedifferentiation

    Directory of Open Access Journals (Sweden)

    Yemima Givaty Rapp

    2015-06-01

    Full Text Available Senescence represents the final stage of leaf development but is often induced prematurely following exposure to biotic and abiotic stresses. Leaf senescence is manifested by color change from green to yellow (due to chlorophyll degradation or to red (due to de novo synthesis of anthocyanins coupled with chlorophyll degradation and frequently culminates in programmed death of leaves. However, the breakdown of chlorophyll and macromolecules such as proteins and RNAs that occurs during leaf senescence does not necessarily represent a one-way road to death but rather a reversible process whereby senescing leaves can, under certain conditions, re-green and regain their photosynthetic capacity. This phenomenon essentially distinguishes senescence from programmed cell death, leading researchers to hypothesize that changes occurring during senescence might represent a process of trans-differentiation, that is the conversion of one cell type to another. In this review, we highlight attributes common to senescence and dedifferentiation including chromatin structure and activation of transposable elements and provide further support to the notion that senescence is not merely a deterioration process leading to death but rather a unique developmental state resembling dedifferentiation.

  3. Senescence vs. sustenance

    DEFF Research Database (Denmark)

    Baudisch, Annette; Vaupel, James W.

    2010-01-01

    Humans, and many other species, suffer senescence: mortality increases and fertility decreases with adult age. Some species, however, enjoy sustenance: mortality and fertility remain constant. Here we develop simple but general evolutionary-demographic models to explain the conditions that favor...... senescence vs. sustenance. The models illustrate how mathematical demography can deepen understanding of the evolution of aging....

  4. Senescence in fishes

    Energy Technology Data Exchange (ETDEWEB)

    Woodhead, A.D.

    1979-01-01

    A long-standing theory, that there is a fundamental difference in aging between fishes and higher vertebrates, is still alive in the minds of many. In 1932, Bidder proposed that aging was causatively related to the cessation of growth at sexual maturity. Fish, which continue to grow throughout their lives, would not age, and therefore were potentially immortal. His ideas were clearly disproven by Comfort, who established that the survival curves of a laboratory population of guppies, Poecilia reticulata, were very similar to those of a small mammal population under laboratory conditions. Recent data from field and laboratory studies, including histological evidence, amply confirm the occurrence of senescence in fishes. Natural death in fish has been associated with reproduction. There is good evidence for a number of species which shows that, with increasing size, the gonad forms a greater proportion of total body weight. In older, larger fish, extensive energy depletion for reproduction is suggested as an important factor in mortality. Reproductive modifications in older fish are also noted.

  5. Survival

    Data.gov (United States)

    U.S. Geological Survey, Department of the Interior — These data provide information on the survival of California red-legged frogs in a unique ecosystem to better conserve this threatened species while restoring...

  6. MicroRNA-34a regulation of endothelial senescence

    Energy Technology Data Exchange (ETDEWEB)

    Ito, Takashi; Yagi, Shusuke [Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, West Henrietta, NY 14586 (United States); Yamakuchi, Munekazu, E-mail: munekazu_yamakuchi@urmc.rochester.edu [Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, West Henrietta, NY 14586 (United States)

    2010-08-06

    Research highlights: {yields} MicroRNA-34a (miR-34a) regulates senescence and cell cycle progression in endothelial cells. {yields} MiR-34a expression increases during endothelial cell senescence and in older mice. {yields} SIRT1 is a miR-34a target gene in endothelial cells. {yields} SIRT1 mediates the effects of miR-34a upon cell senescence in endothelial cells. -- Abstract: Endothelial senescence is thought to play a role in cardiovascular diseases such as atherosclerosis. We hypothesized that endothelial microRNAs (miRNAs) regulate endothelial survival and senescence. We found that miR-34a is highly expressed in primary endothelial cells. We observed that miR-34a expression increases in senescent human umbilical cord vein endothelial cells (HUVEC) and in heart and spleen of older mice. MiR-34a over-expression induces endothelial cell senescence and also suppresses cell proliferation by inhibiting cell cycle progression. Searching for how miR-34a affects senescence, we discovered that SIRT1 is a target of miR-34a. Over-expressing miR-34a inhibits SIRT1 protein expression, and knocking down miR-34a enhances SIRT1 expression. MiR-34a triggers endothelial senescence in part through SIRT1, since forced expression of SIRT1 blocks the ability of miR-34a to induce senescence. Our data suggest that miR-34a contributes to endothelial senescence through suppression of SIRT1.

  7. New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463

    OpenAIRE

    Zhu, Yi; Doornebal, Ewald J.; Pirtskhalava, Tamar; Giorgadze, Nino; Wentworth, Mark; Fuhrmann-Stroissnigg, Heike; Niedernhofer, Laura J.; Robbins, Paul D.; Tchkonia, Tamara; Kirkland, James L.

    2017-01-01

    Senescent cells accumulate with aging and at sites of pathology in multiple chronic diseases. Senolytics are drugs that selectively promote apoptosis of senescent cells by temporarily disabling the pro-survival pathways that enable senescent cells to resist the pro-apoptotic, pro-inflammatory factors that they themselves secrete. Reducing senescent cell burden by genetic approaches or by administering senolytics delays or alleviates multiple age- and disease-related adverse phenotypes in prec...

  8. New agents that target senescent cells: The flavone, fisetin, and the BCL-X-L inhibitors, A1331852 and A1155463

    National Research Council Canada - National Science Library

    Zhu, Yi; Doornebal, Ewald J; Pirtskhalava, Tamar; Giorgadze, Nino; Wentworth, Mark; Fuhrmann-Stroissnigg, Heike; Niedernhofer, Laura J; Robbins, Paul D; Tchkonia, Tamara; Kirkland, James L

    2017-01-01

    .... Senolytics are drugs that selectively promote apoptosis of senescent cells by temporarily disabling the pro-survival pathways that enable senescent cells to resist the pro-apoptotic, pro-inflammatory...

  9. Drying Without Senescence in Resurrection Plants

    Directory of Open Access Journals (Sweden)

    Cara Ashleigh Griffiths

    2014-02-01

    Full Text Available Research into extreme drought tolerance in resurrection plants using species such as Craterostigma plantagineum, Craterostigma wilmsii, Xerophyta humilis, Tortula ruralis and Sporobolus stapfianus has provided some insight into the desiccation tolerance mechanisms utilized by these plants to allow them to persist under extremely adverse environmental conditions. Some of the mechanisms used to ensure cellular preservation during severe dehydration appear to be peculiar to resurrection plants. Apart from the ability to preserve vital cellular components during drying and rehydration, such mechanisms include the ability to down-regulate growth-related metabolism rapidly in response to changes in water availability, and the ability to inhibit dehydration-induced senescence programs enabling reconstitution of photosynthetic capacity quickly following a rainfall event. Currently, very little is known about the molecular mechanisms that resurrection plants employ to avoid undergoing drought-related senescence during the desiccation process. To survive desiccation, dehydration in the perennial resurrection grass S. stapfianus must proceed slowly over a period of 7 days or more. Leaves detached from the plant before 60% relative water content (RWC is attained are desiccation-sensitive indicating that desiccation tolerance is conferred in vegetative tissue of S. stapfianus when the leaf RWC has declined to 60%. Whilst some older leaves remaining attached to the plant during dehydration will senesce, suggesting dehydration-induced senescence may be influenced by leaf age or the rate of dehydration in individual leaves, the majority of leaves do not senesce. Rather these leaves dehydrate to air-dryness and revive fully following rehydration. Hence it seems likely that there are genes expressed in younger leaf tissues of resurrection plants that enable suppression of drought-related senescence pathways. As very few studies have directly addressed this

  10. Senescence and nutrient remobilization in crop plants

    DEFF Research Database (Denmark)

    Gregersen, Per L

    2011-01-01

    Summary This chapter contains sections titled: Abstract Introduction The senescence process Degradation and transport Regulation of senescence Conclusions: the dilemma of senescence Reference......Summary This chapter contains sections titled: Abstract Introduction The senescence process Degradation and transport Regulation of senescence Conclusions: the dilemma of senescence Reference...

  11. Cellular Senescence: A Translational Perspective

    OpenAIRE

    Kirkland, James L.; Tamara Tchkonia

    2017-01-01

    Cellular senescence entails essentially irreversible replicative arrest, apoptosis resistance, and frequently acquisition of a pro-inflammatory, tissue-destructive senescence-associated secretory phenotype (SASP). Senescent cells accumulate in various tissues with aging and at sites of pathogenesis in many chronic diseases and conditions. The SASP can contribute to senescence-related inflammation, metabolic dysregulation, stem cell dysfunction, aging phenotypes, chronic diseases, geriatric sy...

  12. The case for negative senescence

    DEFF Research Database (Denmark)

    Vaupel, James W; Baudisch, Annette; Dölling, Martin

    2004-01-01

    Negative senescence is characterized by a decline in mortality with age after reproductive maturity, generally accompanied by an increase in fecundity. Hamilton (1966) ruled out negative senescence: we adumbrate the deficiencies of his model. We review empirical studies of various plants and some...... kinds of animals that may experience negative senescence and conclude that negative senescence may be widespread, especially in indeterminate-growth species for which size and fertility increase with age. We develop optimization models of life-history strategies that demonstrate that negative senescence...

  13. Plant senescence and crop productivity

    DEFF Research Database (Denmark)

    Gregersen, Per L.; Culetic, Andrea; Boschian, Luca

    2013-01-01

    Senescence is a developmental process which in annual crop plants overlaps with the reproductive phase. Senescence might reduce crop yield when it is induced prematurely under adverse environmental conditions. This review covers the role of senescence for the productivity of crop plants...... plants, the expression of the IPT gene under control of senescence-associated promoters has been the most successful. The promoters employed for senescence-regulated expression contain cis-elements for binding of WRKY transcription factors and factors controlled by abscisic acid. In most crops...

  14. Senescence in Fungi

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 7; Issue 3. Senescence in Fungi. Anthony Deepak D'souza Ramesh Maheshwari. General Article Volume 7 Issue 3 March 2002 pp 51-55. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/reso/007/03/0051-0055 ...

  15. The frequency of CD127low expressing CD4+CD25high T regulatory cells is inversely correlated with human T lymphotrophic virus type-1 (HTLV-1 proviral load in HTLV-1-infection and HTLV-1-associated myelopathy/tropical spastic paraparesis

    Directory of Open Access Journals (Sweden)

    Chieia Marco

    2008-07-01

    Full Text Available Abstract Background CD4+CD25high regulatory T (TReg cells modulate antigen-specific T cell responses, and can suppress anti-viral immunity. In HTLV-1 infection, a selective decrease in the function of TReg cell mediated HTLV-1-tax inhibition of FOXP3 expression has been described. The purpose of this study was to assess the frequency and phenotype of TReg cells in HTLV-1 asymptomatic carriers and in HTLV-1-associated neurological disease (HAM/TSP patients, and to correlate with measures of T cell activation. Results We were able to confirm that HTLV-I drives activation, spontaneous IFNγ production, and proliferation of CD4+ T cells. We also observed a significantly lower proportion of CTLA-4+ TReg cells (CD4+CD25high T cells in subjects with HAM/TSP patients compared to healthy controls. Ki-67 expression was negatively correlated to the frequency of CTLA-4+ TReg cells in HAM/TSP only, although Ki-67 expression was inversely correlated with the percentage of CD127low TReg cells in healthy control subjects. Finally, the proportion of CD127low TReg cells correlated inversely with HTLV-1 proviral load. Conclusion Taken together, the results suggest that TReg cells may be subverted in HAM/TSP patients, which could explain the marked cellular activation, spontaneous cytokine production, and proliferation of CD4+ T cells, in particular those expressing the CD25highCD127low phenotype. TReg cells represent a potential target for therapeutic intervention for patients with HTLV-1-related neurological diseases.

  16. Stable cellular senescence is associated with persistent DDR activation.

    Directory of Open Access Journals (Sweden)

    Marzia Fumagalli

    Full Text Available The DNA damage response (DDR is activated upon DNA damage generation to promote DNA repair and inhibit cell cycle progression in the presence of a lesion. Cellular senescence is a permanent cell cycle arrest characterized by persistent DDR activation. However, some reports suggest that DDR activation is a feature only of early cellular senescence that is then lost with time. This challenges the hypothesis that cellular senescence is caused by persistent DDR activation. To address this issue, we studied DDR activation dynamics in senescent cells. Here we show that normal human fibroblasts retain DDR markers months after replicative senescence establishment. Consistently, human fibroblasts from healthy aged donors display markers of DDR activation even three years in culture after entry into replicative cellular senescence. However, by extending our analyses to different human cell strains, we also observed an apparent DDR loss with time following entry into cellular senescence. This though correlates with the inability of these cell strains to survive in culture upon replicative or irradiation-induced cellular senescence. We propose a model to reconcile these results. Cell strains not suffering the prolonged in vitro culture stress retain robust DDR activation that persists for years, indicating that under physiological conditions persistent DDR is causally involved in senescence establishment and maintenance. However, cell strains unable to maintain cell viability in vitro, due to their inability to cope with prolonged cell culture-associated stress, show an only-apparent reduction in DDR foci which is in fact due to selective loss of the most damaged cells.

  17. The impact of reproductive investment and early-life environmental conditions on senescence : Support for the disposable soma hypothesis

    NARCIS (Netherlands)

    Hammers, M.; Richardson, D. S.; Burke, T.; Komdeur, J.

    Several hypotheses have been put forward to explain the evolution of senescence. One of the leading hypotheses, the disposable soma hypothesis, predicts a trade-off, whereby early-life investment in reproduction leads to late-life declines in survival (survival senescence). Testing this hypothesis

  18. New agents that target senescent cells : The flavone, fisetin, and the BCL-X-L inhibitors, A1331852 and A1155463

    NARCIS (Netherlands)

    Zhu, Yi; Doornebal, Ewald J.; Pirtskhalava, Tamar; Giorgadze, Nino; Wentworth, Mark; Fuhrmann-Stroissnigg, Heike; Niedernhofer, Laura J.; Robbins, Paul D.; Tchkonia, Tamara; Kirkland, James L.

    2017-01-01

    Senescent cells accumulate with aging and at sites of pathology in multiple chronic diseases. Senolytics are drugs that selectively promote apoptosis of senescent cells by temporarily disabling the pro-survival pathways that enable senescent cells to resist the pro-apoptotic, pro-inflammatory

  19. Actuarial senescence in a long-lived orchid challenges our current understanding of ageing

    DEFF Research Database (Denmark)

    Dahlgren, Johan; Colchero, Fernando; Jones, Owen

    2016-01-01

    The dominant evolutionary theory of actuarial senescence – an increase in death rate with advancing age – is based on the concept of a germ cell line that is separated from the somatic cells early in life. However, such a separation is not clear in all organisms. This has been suggested to explain......, for individuals under two types of land-use, in two climatic regions. The mortality trajectory was best-approximated by a Weibull model, showing clear actuarial senescence. Rates of senescence in this model declined with advancing age, but were slightly higher in mown plots and in the more benign climatic region....... At older ages, senescence was evident only when accounting for a positive effect of reproductive investment on mortality. Our results demonstrate actuarial senescence as well as a survival-reproduction trade-off in plants, and indicate that environmental context may influence senescence rates...

  20. Density dependence triggers runaway selection of reduced senescence.

    Directory of Open Access Journals (Sweden)

    Robert M Seymour

    2007-12-01

    Full Text Available In the presence of exogenous mortality risks, future reproduction by an individual is worth less than present reproduction to its fitness. Senescent aging thus results inevitably from transferring net fertility into younger ages. Some long-lived organisms appear to defy theory, however, presenting negligible senescence (e.g., hydra and extended lifespans (e.g., Bristlecone Pine. Here, we investigate the possibility that the onset of vitality loss can be delayed indefinitely, even accepting the abundant evidence that reproduction is intrinsically costly to survival. For an environment with constant hazard, we establish that natural selection itself contributes to increasing density-dependent recruitment losses. We then develop a generalized model of accelerating vitality loss for analyzing fitness optima as a tradeoff between compression and spread in the age profile of net fertility. Across a realistic spectrum of senescent age profiles, density regulation of recruitment can trigger runaway selection for ever-reducing senescence. This novel prediction applies without requirement for special life-history characteristics such as indeterminate somatic growth or increasing fecundity with age. The evolution of nonsenescence from senescence is robust to the presence of exogenous adult mortality, which tends instead to increase the age-independent component of vitality loss. We simulate examples of runaway selection leading to negligible senescence and even intrinsic immortality.

  1. Cellular senescence in renal ageing and disease

    NARCIS (Netherlands)

    Sturmlechner, I.; Durik, M.; Sieben, C.J.; Baker, D.J.; Deursen, J.M.A. van

    2017-01-01

    The senescence programme is implicated in diverse biological processes, including embryogenesis, tissue regeneration and repair, tumorigenesis, and ageing. Although in vivo studies of senescence are in their infancy, evidence suggesting that senescent cells are a heterogeneous cell type is

  2. Cellular senescence in renal ageing and disease

    NARCIS (Netherlands)

    Sturmlechner, Ines; Durik, Matej; Sieben, Cynthia J.; Baker, Darren J.; van Deursen, Jan M.

    The senescence programme is implicated in diverse biological processes, including embryogenesis, tissue regeneration and repair, tumorigenesis, and ageing. Although in vivo studies of senescence are in their infancy, evidence suggesting that senescent cells are a heterogeneous cell type is

  3. Measuring senescence in human populations

    NARCIS (Netherlands)

    Koopman, Jacob Jan Egbert

    2015-01-01

    In this thesis, senescence is measured in human populations according to its definition of an increase in the risks of dysfunction, disease, and death with chronological age. Part I of this thesis investigates how a population’s senescence rate can be measured through the increase in mortality rate

  4. Biomarkers of replicative senescence revisited

    DEFF Research Database (Denmark)

    Nehlin, Jan

    2016-01-01

    Biomarkers of replicative senescence can be defined as those ultrastructural and physiological variations as well as molecules whose changes in expression, activity or function correlate with aging, as a result of the gradual exhaustion of replicative potential and a state of permanent cell cycle...... arrest. The biomarkers that characterize the path to an irreversible state of cell cycle arrest due to proliferative exhaustion may also be shared by other forms of senescence-inducing mechanisms. Validation of senescence markers is crucial in circumstances where quiescence or temporary growth arrest may...... be triggered or is thought to be induced. Pre-senescence biomarkers are also important to consider as their presence indicate that induction of aging processes is taking place. The bona fide pathway leading to replicative senescence that has been extensively characterized is a consequence of gradual reduction...

  5. Premature aging/senescence in cancer cells facing therapy: good or bad?

    Science.gov (United States)

    Gonzalez, Llilians Calvo; Ghadaouia, Sabrina; Martinez, Aurélie; Rodier, Francis

    2016-02-01

    Normal and cancer cells facing their demise following exposure to radio-chemotherapy can actively participate in choosing their subsequent fate. These programmed cell fate decisions include true cell death (apoptosis-necroptosis) and therapy-induced cellular senescence (TIS), a permanent "proliferative arrest" commonly portrayed as premature cellular aging. Despite a permanent loss of proliferative potential, senescent cells remain viable and are highly bioactive at the microenvironment level, resulting in a prolonged impact on tissue architecture and functions. Cellular senescence is primarily documented as a tumor suppression mechanism that prevents cellular transformation. In the context of normal tissues, cellular senescence also plays important roles in tissue repair, but contributes to age-associated tissue dysfunction when senescent cells accumulate. Theoretically, in multi-step cancer progression models, cancer cells have already bypassed cellular senescence during their immortalization step (see hallmarks of cancer). It is then perhaps surprising to find that cancer cells often retain the ability to undergo TIS, or premature aging. This occurs because cellular senescence results from multiple signalling pathways, some retained in cancer cells, aiming to prevent cell cycle progression in damaged cells. Since senescent cancer cells persist after therapy and secrete an array of cytokines and growth factors that can modulate the tumor microenvironment, these cells may have beneficial and detrimental effects regarding immune modulation and survival of remaining proliferation-competent cancer cells. Similarly, while normal cells undergoing senescence are believed to remain indefinitely growth arrested, whether this is true for senescent cancer cells remains unclear, raising the possibility that these cells may represent a reservoir for cancer recurrence after treatment. This review discusses our current knowledge on cancer cell senescence and highlight questions

  6. Markers of cellular senescence. Telomere shortening as a marker of cellular senescence.

    Science.gov (United States)

    Bernadotte, Alexandra; Mikhelson, Victor M; Spivak, Irina M

    2016-01-01

    The cellular senescence definition comes to the fact of cells irreversible proliferation disability. Besides the cell cycle arrest, senescent cells go through some morphological, biochemical, and functional changes which are the signs of cellular senescence. The senescent cells (including replicative senescence and stress-induced premature senescence) of all the tissues look alike. They are metabolically active and possess the set of characteristics in vitro and in vivo, which are known as biomarkers of aging and cellular senescence. Among biomarkers of cellular senescence telomere shortening is a rather elegant frequently used biomarker. Validity of telomere shortening as a marker for cellular senescence is based on theoretical and experimental data.

  7. NAC transcription factors in senescence

    DEFF Research Database (Denmark)

    Podzimska-Sroka, Dagmara; O'Shea, Charlotte; Gregersen, Per L.

    2015-01-01

    of these domains determine the interactions in gene regulatory networks. Emerging local NAC-centered gene regulatory networks reveal complex molecular mechanisms of stress- and hormone-regulated senescence and basic physiological steps of the senescence process. For example, through molecular interactions...... involving the hormone abscisic acid, Arabidopsis NAP promotes chlorophyll degradation, a hallmark of senescence. Furthermore, studies of the functional rice ortholog, OsNAP, suggest that NAC genes can be targeted to obtain specific changes in lifespan control and nutrient remobilization in crop plants...

  8. A senescent cell bystander effect: senescence‐induced senescence

    National Research Council Canada - National Science Library

    Nelson, Glyn; Wordsworth, James; Wang, Chunfang; Jurk, Diana; Lawless, Conor; Martin‐Ruiz, Carmen; von Zglinicki, Thomas

    2012-01-01

    ...‐degrading enzymes and reactive oxygen species (ROS). Thus, it has been proposed that senescent cells can damage their local environment, and a stimulatory effect on tumour cell growth and invasiveness has been documented...

  9. Physiological and pathological consequences of cellular senescence

    OpenAIRE

    Burton, Dominick G. A.; Krizhanovsky, Valery

    2014-01-01

    Cellular senescence, a permanent state of cell cycle arrest accompanied by a complex phenotype, is an essential mechanism that limits tumorigenesis and tissue damage. In physiological conditions, senescent cells can be removed by the immune system, facilitating tumor suppression and wound healing. However, as we age, senescent cells accumulate in tissues, either because an aging immune system fails to remove them, the rate of senescent cell formation is elevated, or both. If senescent cells p...

  10. Role of senescence and mitotic catastrophe in cancer therapy

    Directory of Open Access Journals (Sweden)

    Shukla Yogeshwer

    2010-01-01

    Full Text Available Abstract Senescence and mitotic catastrophe (MC are two distinct crucial non-apoptotic mechanisms, often triggered in cancer cells and tissues in response to anti-cancer drugs. Chemotherapeuticals and myriad other factors induce cell eradication via these routes. While senescence drives the cells to a state of quiescence, MC drives the cells towards death during the course of mitosis. The senescent phenotype distinguishes tumor cells that survived drug exposure but lost the ability to form colonies from those that recover and proliferate after treatment. Although senescent cells do not proliferate, they are metabolically active and may secrete proteins with potential tumor-promoting activities. The other anti-proliferative response of tumor cells is MC that is a form of cell death that results from abnormal mitosis and leads to the formation of interphase cells with multiple micronuclei. Different classes of cytotoxic agents induce MC, but the pathways of abnormal mitosis differ depending on the nature of the inducer and the status of cell-cycle checkpoints. In this review, we compare the two pathways and mention that they are activated to curb the growth of tumors. Altogether, we have highlighted the possibilities of the use of senescence targeting drugs, mitotic kinases and anti-mitotic agents in fabricating novel strategies in cancer control.

  11. MeCP2 mediated dysfunction in senescent EPCs

    Science.gov (United States)

    Wang, Chunli; Wang, Fei; Li, Zhen; Huang, Liya; Cao, Qing; Chen, Shuyan

    2017-01-01

    Aging endothelial progenitor cells (EPCs) exhibit functional impairment in terms of proliferation, migration and survival. SIRT1 plays an important role in improving EPCs function. MeCP2, another important epigenetic regulator, is involved in regulating many life-related activities such as cell growth, death and senescence. Here we aim to explore the effect of MeCP2 on the functional activities of senescent EPCs and the underlying mechanisms. By using western blot and real-time PCR, we found that the expression levels of MeCP2 were up-regulated and SIRT1 were down-regulated with replicative senescence and H2O2-induced senescence. Through transduction with adenoviral vectors, EPCs overexpressing MeCP2 had significantly reduced EPCs function, and silencing MeCP2 improved EPCs function. In addition, the protein and mRNA levels of SIRT1 were decreased with MeCP2 overexpression and increased with MeCP2 knockdown. Through co-transfection of EPCs with MeCP2 and SIRT1, we observed that SIRT1 could reverse the effects of MeCP2 on EPCs. In summary, our work demonstrated that MeCP2 inhibited SIRT1 in senescent EPCs. PMID:29108229

  12. Apoptosis during embryonic tissue remodeling is accompanied by cell senescence

    Science.gov (United States)

    Lorda-Diez, Carlos I.; Garcia-Riart, Beatriz; Montero, Juan A.; Rodriguez-León, Joaquín; Garcia-Porrero, Juan A; Hurle, Juan M.

    2015-01-01

    This study re-examined the dying process in the interdigital tissue during the formation of free digits in the developing limbs. We demonstrated that the interdigital dying process was associated with cell senescence, as deduced by induction of β-gal activity, mitotic arrest, and transcriptional up-regulation of p21 together with many components of the senescence-associated secretory phenotype. We also found overlapping domains of expression of members of the Btg/Tob gene family of antiproliferative factors in the regressing interdigits. Notably, Btg2 was up-regulated during interdigit remodeling in species with free digits but not in the webbed foot of the duck. We also demonstrate that oxidative stress promoted the expression of Btg2, and that FGF2 and IGF1 which are survival signals for embryonic limb mesenchyme inhibited Btg2 expression. Btg2 overexpression in vivo and in vitro induced all the observed changes during interdigit regression, including oxidative stress, arrest of cell cycle progression, transcriptional regulation of senescence markers, and caspase-mediated apoptosis. Consistent with the central role of p21 on cell senescence, the transcriptional effects induced by overexpression of Btg2 are attenuated by silencing p21. Our findings indicate that cell senescence and apoptosis are complementary processes in the regression of embryonic tissues and share common regulatory signals. PMID:26568417

  13. Individual variation in rates of senescence : natal origin effects and disposable soma in a wild bird population

    NARCIS (Netherlands)

    Bouwhuis, Sandra; Charmantier, Anne; Verhulst, Simon; Sheldon, Ben C.; Sandercock, Brett

    2010-01-01

    P>1. Longitudinal studies of various vertebrate populations have recently demonstrated senescent declines in reproductive performance and/or survival probability with age to be almost ubiquitous in nature. Little is known, however, about the extent to which rates of senescence vary between

  14. Identification of 30 protein species involved in replicative senescence and stress-induced premature senescence

    DEFF Research Database (Denmark)

    Dierick, Jean François; Kalume, Dário E; Wenders, Frédéric

    2002-01-01

    Exposure of human proliferative cells to subcytotoxic stress triggers stress-induced premature senescence (SIPS) which is characterized by many biomarkers of replicative senescence. Proteomic comparison of replicative senescence and stress-induced premature senescence indicates that, at the level...... of protein expression, stress-induced premature senescence and replicative senescence are different phenotypes sharing however similarities. In this study, we identified 30 proteins showing changes of expression level specific or common to replicative senescence and/or stress-induced premature senescence....... These changes affect different cell functions, including energy metabolism, defense systems, maintenance of the redox potential, cell morphology and transduction pathways....

  15. Cellular senescence and its effector programs

    Science.gov (United States)

    Salama, Rafik; Sadaie, Mahito; Hoare, Matthew; Narita, Masashi

    2014-01-01

    Cellular senescence is a stress response that accompanies stable exit from the cell cycle. Classically, senescence, particularly in human cells, involves the p53 and p16/Rb pathways, and often both of these tumor suppressor pathways need to be abrogated to bypass senescence. In parallel, a number of effector mechanisms of senescence have been identified and characterized. These studies suggest that senescence is a collective phenotype of these multiple effectors, and their intensity and combination can be different depending on triggers and cell types, conferring a complex and diverse nature to senescence. Series of studies on senescence-associated secretory phenotype (SASP) in particular have revealed various layers of functionality of senescent cells in vivo. Here we discuss some key features of senescence effectors and attempt to functionally link them when it is possible. PMID:24449267

  16. Overexpression of the novel senescence marker β-galactosidase (GLB1 in prostate cancer predicts reduced PSA recurrence.

    Directory of Open Access Journals (Sweden)

    Jennifer Wagner

    Full Text Available Senescence is a terminal growth arrest that functions as a tumor suppressor in aging and precancerous cells and is a response to selected anticancer compounds. Lysosomal-β-galactosidase (GLB1 hydrolyzes β-galactose from glycoconjugates and is the origin of senescence-associated β-gal activity (SA-β-gal. Using a new GLB1 antibody, senescence biology was investigated in prostate cancer (PCa tissues.In vitro characterization of GLB1 was determined in primary prostate epithelial cell cultures passaged to replicative senescence and in therapy-induced senescence in PCa lines using chemotherapeutic agents. FFPE tissue microarrays were subjected to immunofluorescent staining for GLB1, Ki67 and HP1γ and automated quantitative imaging initially using AQUA in exploratory samples and Vectra in a validation series.GLB1 expression accumulates in replicative and induced senescence and correlates with senescent morphology and P16 (CDKN2 expression. In tissue arrays, quantitative imaging detects increased GLB1 expression in high-grade prostatic intraepithelial neoplasia (HGPIN, known to contain senescent cells, and cancer compared to benign prostate tissues (p<0.01 and senescent cells contain low Ki67 and elevated HP1γ. Within primary tumors, elevated GLB1 associates with lower T stage (p=0.01, localized versus metastatic disease (p=0.0003 and improved PSA-free survival (p=0.03. Increased GLB1 stratifies better PSA-free survival in intermediate grade PCa (0.01. Tissues that elaborate higher GLB1 display increased uniformity of expression.Increased GLB1 is a valuable marker in formalin-fixed paraffin-embedded (FFPE tissues for the senescence-like phenotype and associates with improved cancer outcomes. This protein addresses a lack of senescence markers and should be applicable to study the biologic role of senescence in other cancers.

  17. Senescence (ageing @ 2011

    Directory of Open Access Journals (Sweden)

    Anjana Nigam

    2011-01-01

    Full Text Available Ageing, also called as senescence, is one of the most complex, intrinsic, biological processes of growing older and resulting into reduced functional ability of the organism. Telomerase, environment, low calorie diets, free radicals, etc., are all believed to affect this ageing process. A number of genetic components of ageing have been identified using model organisms. Genes, mainly the sirtuins, regulate the ageing speed by indirection and controlling organism resistance to damages by exogenous and endogenous stresses. In higher organisms, ageing is likely to be regulated, in part, through the insulin/insulin-like growth factor 1 pathway. Besides this, the induction of apoptosis in stem and progenitor cells, increased p53 activity, and autophagy is also thought to trigger premature organismal ageing. Ageing has also been shown to upregulate expression of inflammatory mediators in mouse adipose tissue. The understanding of pathophysiology of ageing over the past few years has posed tremendous challenges for the development of anti-ageing medicine for targeted therapy. Future research areas must include targeted role of systemic inflammatory markers such as C-reactive protein and interleukin 6 and other biochemical and genetic studies including gene signaling pathways, gene microarray analysis, gene modulation, gene therapy, and development of animal/human models for potential therapeutic measures and evaluations.

  18. Pleiotropic Effects of Tocotrienols and Quercetin on Cellular Senescence: Introducing the Perspective of Senolytic Effects of Phytochemicals.

    Science.gov (United States)

    Malavolta, Marco; Pierpaoli, Elisa; Giacconi, Robertina; Costarelli, Laura; Piacenza, Francesco; Basso, Andrea; Cardelli, Maurizio; Provinciali, Mauro

    2016-01-01

    The possibility to target cellular senescence with natural bioactive substances open interesting therapeutic perspective in cancer and aging. Engaging senescence response is suggested as a key component for therapeutic intervention in the eradication of cancer. At the same time, delaying senescence or even promote death of accumulating apoptosis-resistant senescent cells is proposed as a strategy to prevent age related diseases. Although these two desired outcome present an intrinsic dichotomy, there are examples of promising natural compounds that appear to satisfy all the requirements to develop senescence- targeted health promoting nutraceuticals. Tocotrienols (T3s) and quercetin (QUE), albeit belonging to different phytochemical classes, display similar and promising effects "in vitro" when tested in normal and cancer cells. Both compounds have been shown to induce senescence and promote apoptosis in a multitude of cancer lines. Conversely, they display senescence delaying activity in primary cells and rejuvenating effects in senescent cells. More recently, QUE has been shown to display senolytic effects in some primary senescent cells, likely as a consequence of its inhibitory effects on specific anti-apoptotic genes (i.e. PI3K and other kinases). Senolytic activity has not been tested for T3s but part of metabolic and apoptotic pathways affected by these compounds in cancer cells overlap with those of QUE. This suggests that the rejuvenating effects of T3s and QUE on pre-senescent and senescent primary cells might be the net results of a senolytic activity on senescent cells and a selective survival of a sub-population of non-senescent cells in the culture. The meaning of this hypothesis in the context of adjuvant therapy of cancer and preventive anti-aging strategies with QUE or T3s is discussed.

  19. Targeting cellular senescence prevents age-related bone loss in mice.

    Science.gov (United States)

    Farr, Joshua N; Xu, Ming; Weivoda, Megan M; Monroe, David G; Fraser, Daniel G; Onken, Jennifer L; Negley, Brittany A; Sfeir, Jad G; Ogrodnik, Mikolaj B; Hachfeld, Christine M; LeBrasseur, Nathan K; Drake, Matthew T; Pignolo, Robert J; Pirtskhalava, Tamar; Tchkonia, Tamara; Oursler, Merry Jo; Kirkland, James L; Khosla, Sundeep

    2017-09-01

    Aging is associated with increased cellular senescence, which is hypothesized to drive the eventual development of multiple comorbidities. Here we investigate a role for senescent cells in age-related bone loss through multiple approaches. In particular, we used either genetic (i.e., the INK-ATTAC 'suicide' transgene encoding an inducible caspase 8 expressed specifically in senescent cells) or pharmacological (i.e., 'senolytic' compounds) means to eliminate senescent cells. We also inhibited the production of the proinflammatory secretome of senescent cells using a JAK inhibitor (JAKi). In aged (20- to 22-month-old) mice with established bone loss, activation of the INK-ATTAC caspase 8 in senescent cells or treatment with senolytics or the JAKi for 2-4 months resulted in higher bone mass and strength and better bone microarchitecture than in vehicle-treated mice. The beneficial effects of targeting senescent cells were due to lower bone resorption with either maintained (trabecular) or higher (cortical) bone formation as compared to vehicle-treated mice. In vitro studies demonstrated that senescent-cell conditioned medium impaired osteoblast mineralization and enhanced osteoclast-progenitor survival, leading to increased osteoclastogenesis. Collectively, these data establish a causal role for senescent cells in bone loss with aging, and demonstrate that targeting these cells has both anti-resorptive and anabolic effects on bone. Given that eliminating senescent cells and/or inhibiting their proinflammatory secretome also improves cardiovascular function, enhances insulin sensitivity, and reduces frailty, targeting this fundamental mechanism to prevent age-related bone loss suggests a novel treatment strategy not only for osteoporosis, but also for multiple age-related comorbidities.

  20. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs

    Science.gov (United States)

    Zhu, Yi; Tchkonia, Tamara; Pirtskhalava, Tamar; Gower, Adam C; Ding, Husheng; Giorgadze, Nino; Palmer, Allyson K; Ikeno, Yuji; Hubbard, Gene B; Lenburg, Marc; O’Hara, Steven P; LaRusso, Nicholas F; Miller, Jordan D; Roos, Carolyn M; Verzosa, Grace C; LeBrasseur, Nathan K; Wren, Jonathan D; Farr, Joshua N; Khosla, Sundeep; Stout, Michael B; McGowan, Sara J; Fuhrmann-Stroissnigg, Heike; Gurkar, Aditi U; Zhao, Jing; Colangelo, Debora; Dorronsoro, Akaitz; Ling, Yuan Yuan; Barghouthy, Amira S; Navarro, Diana C; Sano, Tokio; Robbins, Paul D; Niedernhofer, Laura J; Kirkland, James L

    2015-01-01

    The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1−/Δ mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1−/Δ mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan. PMID:25754370

  1. The Achilles' heel of senescent cells: from transcriptome to senolytic drugs.

    Science.gov (United States)

    Zhu, Yi; Tchkonia, Tamara; Pirtskhalava, Tamar; Gower, Adam C; Ding, Husheng; Giorgadze, Nino; Palmer, Allyson K; Ikeno, Yuji; Hubbard, Gene B; Lenburg, Marc; O'Hara, Steven P; LaRusso, Nicholas F; Miller, Jordan D; Roos, Carolyn M; Verzosa, Grace C; LeBrasseur, Nathan K; Wren, Jonathan D; Farr, Joshua N; Khosla, Sundeep; Stout, Michael B; McGowan, Sara J; Fuhrmann-Stroissnigg, Heike; Gurkar, Aditi U; Zhao, Jing; Colangelo, Debora; Dorronsoro, Akaitz; Ling, Yuan Yuan; Barghouthy, Amira S; Navarro, Diana C; Sano, Tokio; Robbins, Paul D; Niedernhofer, Laura J; Kirkland, James L

    2015-08-01

    The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1(-/Δ) mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1(-/∆) mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  2. Palbociclib-induced autophagy and senescence in gastric cancer cells.

    Science.gov (United States)

    Valenzuela, Claudio A; Vargas, Leandro; Martinez, Valentina; Bravo, Sindy; Brown, Nelson E

    2017-11-15

    Targeting cyclin D-CDK4/6 kinase complexes has recently been shown to increase the survival of breast cancer patients with estrogen receptor positive breast tumors. Based on these outcomes, CDK4/6 inhibitors are currently being tested, alone o in combination with other drugs, in the treatment of other malignancies characterized by hyper-activation of cyclin D-CDK4/6 complexes. Nonetheless, a better understanding of the cellular processes that are implemented in response to CDK4/6 inhibition is necessary to expand the therapeutic window and confront the development of drug resistance. Herein, we show that, similar to mammary cells, gastric cancer cells are sensitive to the CDK4/6 inhibitor Palbociclib. Inhibition of CDK4/6 in gastric cancer cells leads to the implementation of cellular senescence. However, whether or not this response is accompanied by induction of autophagy seems to depend on both the pRB and p53 status. In cells retaining expression of both tumor suppressive proteins (AGS gastric cancer cells), exposure to Palbociclib induces senescence and autophagy. However, the simultaneous blockade of CDK4/6 and autophagy in these cells exacerbates the senescence phenotype, an indication that autophagy in these experimental settings represents an adaptive mechanism that promotes cell survival rather than being an effector mechanism of senescence. Interestingly, knocking down p53 resulted in senescence reduction and autophagy blockade, the latter apparently involving a disruption of the degradation of autophagosome cargo. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. CANCER Escape from senescence boosts tumour growth

    NARCIS (Netherlands)

    Medema, Jan Paul

    2018-01-01

    Some chemotherapies block cancer growth by driving tumour cells into a state of cell-division arrest termed senescence. It emerges that such cells have a boosted capacity to drive tumour growth if they exit senescence

  4. Role of Cell Senescence in Breast Cancer

    National Research Council Canada - National Science Library

    Krtolica, Ana

    2001-01-01

    .... In culture, the growth stimulation was evident when senescent cells comprised only 10% of the fibroblast population, and was equally robust whether senescence was induced by replicative exhaustion, oncogenic RAS, p14ARF or hydrogen peroxide...

  5. Role of galactose in cellular senescence.

    Science.gov (United States)

    Elzi, David J; Song, Meihua; Shiio, Yuzuru

    2016-01-01

    Cellular senescence has been proposed to play critical roles in tumor suppression and organismal aging, but the molecular mechanism of senescence remains incompletely understood. Here we report that a putative lysosomal carbohydrate efflux transporter, Spinster, induces cellular senescence in human primary fibroblasts. Administration of d-galactose synergistically enhanced Spinster-induced senescence and this synergism required the transporter activity of Spinster. Intracellular d-galactose is metabolized to galactose-1-phosphate by galactokinase. Galactokinase-deficient fibroblasts, which accumulate intracellular d-galactose, displayed increased baseline senescence. Senescence of galactokinase-deficient fibroblasts was further enhanced by d-galactose administration and was diminished by restoration of wild-type galactokinase expression. Silencing galactokinase in normal fibroblasts also induced senescence. These results suggest a role for intracellular galactose in the induction of cellular senescence. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Plants do not count… or do they? New perspectives on the universality of senescence

    Science.gov (United States)

    Salguero-Gómez, Roberto; Shefferson, Richard P; Hutchings, Michael J

    2013-01-01

    1. Senescence, the physiological decline that results in decreasing survival and/or reproduction with age, remains one of the most perplexing topics in biology. Most theories explaining the evolution of senescence (i.e. antagonistic pleiotropy, accumulation of mutations, disposable soma) were developed decades ago. Even though these theories have implicitly focused on unitary animals, they have also been used as the foundation from which the universality of senescence across the tree of life is assumed. 2. Surprisingly, little is known about the general patterns, causes and consequences of whole-individual senescence in the plant kingdom. There are important differences between plants and most animals, including modular architecture, the absence of early determination of cell lines between the soma and gametes, and cellular division that does not always shorten telomere length. These characteristics violate the basic assumptions of the classical theories of senescence and therefore call the generality of senescence theories into question. 3. This Special Feature contributes to the field of whole-individual plant senescence with five research articles addressing topics ranging from physiology to demographic modelling and comparative analyses. These articles critically examine the basic assumptions of senescence theories such as age-specific gene action, the evolution of senescence regardless of the organism's architecture and environmental filtering, and the role of abiotic agents on mortality trajectories. 4. Synthesis. Understanding the conditions under which senescence has evolved is of general importance across biology, ecology, evolution, conservation biology, medicine, gerontology, law and social sciences. The question ‘why is senescence universal or why is it not?’ naturally calls for an evolutionary perspective. Senescence is a puzzling phenomenon, and new insights will be gained by uniting methods, theories and observations from formal demography

  7. Predatory senescence in ageing wolves

    Science.gov (United States)

    MacNulty, D.R.; Smith, D.W.; Vucetich, J.A.; Mech, L.D.; Stahler, D.R.; Packer, C.

    2009-01-01

    It is well established that ageing handicaps the ability of prey to escape predators, yet surprisingly little is known about how ageing affects the ability of predators to catch prey. Research into long-lived predators has assumed that adults have uniform impacts on prey regardless of age. Here we use longitudinal data from repeated observations of individually-known wolves (Canis lupus) hunting elk (Cervus elaphus) in Yellowstone National Park to demonstrate that adult predatory performance declines with age and that an increasing ratio of senescent individuals in the wolf population depresses the rate of prey offtake. Because this ratio fluctuates independently of population size, predatory senescence may cause wolf populations of equal size but different age structure to have different impacts on prey populations. These findings suggest that predatory senescence is an important, though overlooked, factor affecting predator-prey dynamics. ?? 2009 Blackwell Publishing Ltd/CNRS.

  8. Predatory senescence in aging wolves

    Science.gov (United States)

    MacNulty, Daniel R.; Smith, Douglas W.; Vucetich, John A.; Mech, L. David; Stahler, Daniel R.; Packer, Craig

    2009-01-01

    It is well established that ageing handicaps the ability of prey to escape predators, yet surprisingly little is known about how ageing affects the ability of predators to catch prey. Research into long-lived predators has assumed that adults have uniform impacts on prey regardless of age. Here we use longitudinal data from repeated observations of individually-known wolves (Canis lupus) hunting elk (Cervus elaphus) in Yellowstone National Park to demonstrate that adult predatory performance declines with age and that an increasing ratio of senescent individuals in the wolf population depresses the rate of prey offtake. Because this ratio fluctuates independently of population size, predatory senescence may cause wolf populations of equal size but different age structure to have different impacts on prey populations. These findings suggest that predatory senescence is an important, though overlooked, factor affecting predator-prey dynamics.

  9. Aging, Cellular Senescence, and Cancer

    Science.gov (United States)

    Campisi, Judith

    2014-01-01

    For most species, aging promotes a host of degenerative pathologies that are characterized by debilitating losses of tissue or cellular function. However, especially among vertebrates, aging also promotes hyperplastic pathologies, the most deadly of which is cancer. In contrast to the loss of function that characterizes degenerating cells and tissues, malignant (cancerous) cells must acquire new (albeit aberrant) functions that allow them to develop into a lethal tumor. This review discusses the idea that, despite seemingly opposite characteristics, the degenerative and hyperplastic pathologies of aging are at least partly linked by a common biological phenomenon: a cellular stress response known as cellular senescence. The senescence response is widely recognized as a potent tumor suppressive mechanism. However, recent evidence strengthens the idea that it also drives both degenerative and hyper-plastic pathologies, most likely by promoting chronic inflammation. Thus, the senescence response may be the result of antagonistically pleiotropic gene action. PMID:23140366

  10. Selective insulin resistance in hepatocyte senescence

    Energy Technology Data Exchange (ETDEWEB)

    Aravinthan, Aloysious [Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge (United Kingdom); Challis, Benjamin [Institute of Metabolic Sciences, University of Cambridge, Cambridge (United Kingdom); Shannon, Nicholas [Cancer Research UK Cambridge Institute, Cambridge (United Kingdom); Hoare, Matthew [Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge (United Kingdom); Cancer Research UK Cambridge Institute, Cambridge (United Kingdom); Heaney, Judith [Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge (United Kingdom); Foundation for Liver Research, Institute of Hepatology, London (United Kingdom); Alexander, Graeme J.M., E-mail: gja1000@doctors.org.uk [Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge (United Kingdom)

    2015-02-01

    Insulin resistance has been described in association with chronic liver disease for decades. Hepatocyte senescence has been demonstrated in chronic liver disease and as many as 80% of hepatocytes show a senescent phenotype in advanced liver disease. The aim of this study was to understand the role of hepatocyte senescence in the development of insulin resistance. Senescence was induced in HepG2 cells via oxidative stress. The insulin metabolic pathway was studied in control and senescent cells following insulin stimulation. GLUT2 and GLUT4 expressions were studied in HepG2 cells and human liver tissue. Further, GLUT2 and GLUT4 expressions were studied in three independent chronic liver disease cohorts. Signalling impairment distal to Akt in phosphorylation of AS160 and FoxO1 was evident in senescent HepG2 cells. Persistent nuclear localisation of FoxO1 was demonstrated in senescent cells despite insulin stimulation. Increased GLUT4 and decreased GLUT2 expressions were evident in senescent cells, human cirrhotic liver tissue and publically available liver disease datasets. Changes in GLUT expressions were associated with a poor clinical prognosis. In conclusion, selective insulin resistance is evident in senescent HepG2 cells and changes in GLUT expressions can be used as surrogate markers of hepatocyte senescence. - Highlights: • Senescent hepatocytes demonstrate selective insulin resistance. • GLUT changes act as markers of hepatocyte senescence and have prognostic value. • Study offers insight into long noticed intimacy of cirrhosis and insulin resistance.

  11. Escherichia coli producing colibactin triggers premature and transmissible senescence in mammalian cells.

    Directory of Open Access Journals (Sweden)

    Thomas Secher

    Full Text Available Cellular senescence is an irreversible state of proliferation arrest evoked by a myriad of stresses including oncogene activation, telomere shortening/dysfunction and genotoxic insults. It has been associated with tumor activation, immune suppression and aging, owing to the secretion of proinflammatory mediators. The bacterial genotoxin colibactin, encoded by the pks genomic island is frequently harboured by Escherichia coli strains of the B2 phylogenetic group. Mammalian cells exposed to live pks+ bacteria exhibit DNA-double strand breaks (DSB and undergo cell-cycle arrest and death. Here we show that cells that survive the acute bacterial infection with pks+ E. coli display hallmarks of cellular senescence: chronic DSB, prolonged cell-cycle arrest, enhanced senescence-associated β-galactosidase (SA-β-Gal activity, expansion of promyelocytic leukemia nuclear foci and senescence-associated heterochromatin foci. This was accompanied by reactive oxygen species production and pro-inflammatory cytokines, chemokines and proteases secretion. These mediators were able to trigger DSB and enhanced SA-β-Gal activity in bystander recipient cells treated with conditioned medium from senescent cells. Furthermore, these senescent cells promoted the growth of human tumor cells. In conclusion, the present data demonstrated that the E. coli genotoxin colibactin induces cellular senescence and subsequently propel bystander genotoxic and oncogenic effects.

  12. Roscovitine modulates DNA repair and senescence: implications for combination chemotherapy.

    Science.gov (United States)

    Crescenzi, Elvira; Palumbo, Giuseppe; Brady, Hugh J M

    2005-11-15

    Treatment of tumor cells by chemotherapy activates a series of responses ranging from apoptosis to premature senescence and repair. Survival responses are characterized by inhibition of cyclin-dependent kinases. Because inhibition of cyclin-dependent kinases represents a distinctive feature of DNA damage-induced prosurvival responses, we investigated the possibility that the cyclin-dependent kinase inhibitor roscovitine modulates drug-induced responses in human adenocarcinoma cells, favoring cell survival. Sublethal concentrations of doxorubicin were used to induce premature senescence in human adenocarcinoma cells. The effect of the cyclin-dependent kinase inhibitor roscovitine on the doxorubicin-dependent cell cycle checkpoint activation and DNA repair pathways was evaluated. Roscovitine reinforces doxorubicin-dependent G(1) checkpoint in A549 and HEC1B cells leading to decreased frequency of double-strand breaks and to the preferential induction of senescence and enhanced clonogenic survival. However, in other tumor cell lines, such as HCT116 and H1299, combined treatment with doxorubicin and roscovitine increases the frequency of double-strand breaks and dramatically sensitizes to doxorubicin. This unexpected effect of roscovitine depends on a novel ability to inhibit DNA double-strand break repair processes and requires inactivation of the pRb pathway. Roscovitine, by hindering DNA repair processes, has the potential to inhibit recovery of mildly damaged tumor cells after doxorubicin treatment and to increase the susceptibility of tumor cells to chemotherapy. However, in some tumor cells, the cell cycle inhibitory function of roscovitine prevails over the DNA repair inhibitory activity, favoring premature senescence and clonogenic growth. These data indicate a novel mechanism underlying combined chemotherapy, which may have wide application in treatment of carcinomas.

  13. The Biochemistry of Human Senescence

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 11; Issue 2. The Biochemistry of Human Senescence. B Ramachandra Murty. General Article Volume 11 Issue 2 February 2006 pp 17-26. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/reso/011/02/0017-0026 ...

  14. Cellular senescence mediates fibrotic pulmonary disease.

    Science.gov (United States)

    Schafer, Marissa J; White, Thomas A; Iijima, Koji; Haak, Andrew J; Ligresti, Giovanni; Atkinson, Elizabeth J; Oberg, Ann L; Birch, Jodie; Salmonowicz, Hanna; Zhu, Yi; Mazula, Daniel L; Brooks, Robert W; Fuhrmann-Stroissnigg, Heike; Pirtskhalava, Tamar; Prakash, Y S; Tchkonia, Tamara; Robbins, Paul D; Aubry, Marie Christine; Passos, João F; Kirkland, James L; Tschumperlin, Daniel J; Kita, Hirohito; LeBrasseur, Nathan K

    2017-02-23

    Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by interstitial remodelling, leading to compromised lung function. Cellular senescence markers are detectable within IPF lung tissue and senescent cell deletion rejuvenates pulmonary health in aged mice. Whether and how senescent cells regulate IPF or if their removal may be an efficacious intervention strategy is unknown. Here we demonstrate elevated abundance of senescence biomarkers in IPF lung, with p16 expression increasing with disease severity. We show that the secretome of senescent fibroblasts, which are selectively killed by a senolytic cocktail, dasatinib plus quercetin (DQ), is fibrogenic. Leveraging the bleomycin-injury IPF model, we demonstrate that early-intervention suicide-gene-mediated senescent cell ablation improves pulmonary function and physical health, although lung fibrosis is visibly unaltered. DQ treatment replicates benefits of transgenic clearance. Thus, our findings establish that fibrotic lung disease is mediated, in part, by senescent cells, which can be targeted to improve health and function.

  15. Characterization of novel markers of senescence and their prognostic potential in cancer.

    Science.gov (United States)

    Althubiti, M; Lezina, L; Carrera, S; Jukes-Jones, R; Giblett, S M; Antonov, A; Barlev, N; Saldanha, G S; Pritchard, C A; Cain, K; Macip, S

    2014-11-20

    Cellular senescence is a terminal differentiation state that has been proposed to have a role in both tumour suppression and ageing. This view is supported by the fact that accumulation of senescent cells can be observed in response to oncogenic stress as well as a result of normal organismal ageing. Thus, identifying senescent cells in in vivo and in vitro has an important diagnostic and therapeutic potential. The molecular pathways involved in triggering and/or maintaining the senescent phenotype are not fully understood. As a consequence, the markers currently utilized to detect senescent cells are limited and lack specificity. In order to address this issue, we screened for plasma membrane-associated proteins that are preferentially expressed in senescent cells. We identified 107 proteins that could be potential markers of senescence and validated 10 of them (DEP1, NTAL, EBP50, STX4, VAMP3, ARMX3, B2MG, LANCL1, VPS26A and PLD3). We demonstrated that a combination of these proteins can be used to specifically recognize senescent cells in culture and in tissue samples and we developed a straightforward fluorescence-activated cell sorting-based detection approach using two of them (DEP1 and B2MG). Of note, we found that expression of several of these markers correlated with increased survival in different tumours, especially in breast cancer. Thus, our results could facilitate the study of senescence, define potential new effectors and modulators of this cellular mechanism and provide potential diagnostic and prognostic tools to be used clinically.

  16. Identification of novel senescence-associated genes in ionizing radiation-induced senescent carcinoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jae Seon; Kim, Bong Cho; Han, Na Kyung; Hong, Mi Na; Park, Su Min; Yoo, Hee Jung [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Chu, In Sun [Korea Research Institute of Bioscience and Biotechnology, Daejeon (Korea, Republic of); Lee, Sun Hee [Dong-A University, Busan (Korea, Republic of)

    2009-05-15

    Cellular senescence is considered as a defense mechanism to prevent tumorigenesis. Ionizing radiation (IR) induces stress-induced premature senescence as well as apoptosis in various cancer cells. Senescent cells undergo functional and morphological changes including large and flattened cell shape, senescence-associated {beta}-galactosidase (SA-{beta}Gal) activity, and altered gene expressions. Even with the recent findings of several gene expression profiles and supporting functional data, it is obscure that mechanism of IR-induced premature senescence in cancer cells. We performed microarray analysis to identify the common regulated genes in ionizing radiation-induced prematurely senescent human carcinoma cell lines.

  17. Exploiting tumor cell senescence in anticancer therapy

    Science.gov (United States)

    Lee, Minyoung; Lee, Jae-Seon

    2014-01-01

    Cellular senescence is a physiological process of irreversible cell-cycle arrest that contributes to various physiological and pathological processes of aging. Whereas replicative senescence is associated with telomere attrition after repeated cell division, stress-induced premature senescence occurs in response to aberrant oncogenic signaling, oxidative stress, and DNA damage which is independent of telomere dysfunction. Recent evidence indicates that cellular senescence provides a barrier to tumorigenesis and is a determinant of the outcome of cancer treatment. However, the senescence-associated secretory phenotype, which contributes to multiple facets of senescent cancer cells, may influence both cancer-inhibitory and cancer-promoting mechanisms of neighboring cells. Conventional treatments, such as chemo- and radiotherapies, preferentially induce premature senescence instead of apoptosis in the appropriate cellular context. In addition, treatment-induced premature senescence could compensate for resistance to apoptosis via alternative signaling pathways. Therefore, we believe that an intensive effort to understand cancer cell senescence could facilitate the development of novel therapeutic strategies for improving the efficacy of anticancer therapies. This review summarizes the current understanding of molecular mechanisms, functions, and clinical applications of cellular senescence for anticancer therapy. [BMB Reports 2014; 47(2): 51-59] PMID:24411464

  18. A comparison of oncogene-induced senescence and replicative senescence: implications for tumor suppression and aging.

    Science.gov (United States)

    Nelson, David M; McBryan, Tony; Jeyapalan, Jessie C; Sedivy, John M; Adams, Peter D

    2014-06-01

    Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway, the senescence-associated secretory phenotype. However, cellular senescence is initiated by diverse molecular triggers, such as activated oncogenes and shortened telomeres, and is associated with varied and complex physiological endpoints, such as tumor suppression and tissue aging. The extent to which distinct triggers activate divergent modes of senescence that might be associated with different physiological endpoints is largely unknown. To begin to address this, we performed gene expression profiling to compare the senescence programs associated with two different modes of senescence, oncogene-induced senescence (OIS) and replicative senescence (RS [in part caused by shortened telomeres]). While both OIS and RS are associated with many common changes in gene expression compared to control proliferating cells, they also exhibit substantial differences. These results are discussed in light of potential physiological consequences, tumor suppression and aging.

  19. Leaf Senescence by Magnesium Deficiency

    Directory of Open Access Journals (Sweden)

    Keitaro Tanoi

    2015-12-01

    Full Text Available Magnesium ions (Mg2+ are the second most abundant cations in living plant cells, and they are involved in various functions, including photosynthesis, enzyme catalysis, and nucleic acid synthesis. Low availability of Mg2+ in an agricultural field leads to a decrease in yield, which follows the appearance of Mg-deficient symptoms such as chlorosis, necrotic spots on the leaves, and droop. During the last decade, a variety of physiological and molecular responses to Mg2+ deficiency that potentially link to leaf senescence have been recognized, allowing us to reconsider the mechanisms of Mg2+ deficiency. This review focuses on the current knowledge about the physiological responses to Mg2+ deficiency including a decline in transpiration, accumulation of sugars and starch in source leaves, change in redox states, increased oxidative stress, metabolite alterations, and a decline in photosynthetic activity. In addition, we refer to the molecular responses that are thought to be related to leaf senescence. With these current data, we give an overview of leaf senescence induced by Mg deficiency.

  20. The oxidative hypothesis of senescence

    Directory of Open Access Journals (Sweden)

    Gilca M

    2007-01-01

    Full Text Available The oxidative hypothesis of senescence, since its origin in 1956, has garnered significant evidence and growing support among scientists for the notion that free radicals play an important role in ageing, either as "damaging" molecules or as signaling molecules. Age-increasing oxidative injuries induced by free radicals, higher susceptibility to oxidative stress in short-lived organisms, genetic manipulations that alter both oxidative resistance and longevity and the anti-ageing effect of caloric restriction and intermittent fasting are a few examples of accepted scientific facts that support the oxidative theory of senescence. Though not completely understood due to the complex "network" of redox regulatory systems, the implication of oxidative stress in the ageing process is now well documented. Moreover, it is compatible with other current ageing theories (e.g., those implicating the mitochondrial damage/mitochondrial-lysosomal axis, stress-induced premature senescence, biological "garbage" accumulation, etc. This review is intended to summarize and critically discuss the redox mechanisms involved during the ageing process: sources of oxidant agents in ageing (mitochondrial -electron transport chain, nitric oxide synthase reaction- and non-mitochondrial- Fenton reaction, microsomal cytochrome P450 enzymes, peroxisomal β -oxidation and respiratory burst of phagocytic cells, antioxidant changes in ageing (enzymatic- superoxide dismutase, glutathione-reductase, glutathion peroxidase, catalase- and non-enzymatic glutathione, ascorbate, urate, bilirubine, melatonin, tocopherols, carotenoids, ubiquinol, alteration of oxidative damage repairing mechanisms and the role of free radicals as signaling molecules in ageing.

  1. Assessing Cell and Organ Senescence Biomarkers

    Science.gov (United States)

    Bernardes de Jesus, Bruno; Blasco, Maria A.

    2015-01-01

    A major goal in cancer and aging research is to discriminate the biochemical modifications that happen locally that could account for the healthiness or malignancy of tissues. Senescence is one general antiproliferative cellular process that acts as a strong barrier for cancer progression, playing a crucial role in aging. Here, we focus on the current methods to assess cellular senescence, discriminating the advantages and disadvantages of several senescence biomarkers. PMID:22723221

  2. PPARgamma Deficiency Counteracts Thymic Senescence

    Directory of Open Access Journals (Sweden)

    David Ernszt

    2017-11-01

    Full Text Available Thymic senescence contributes to increased incidence of infection, cancer and autoimmunity at senior ages. This process manifests as adipose involution. As with other adipose tissues, thymic adipose involution is also controlled by PPARgamma. This is supported by observations reporting that systemic PPARgamma activation accelerates thymic adipose involution. Therefore, we hypothesized that decreased PPARgamma activity could prevent thymic adipose involution, although it may trigger metabolic adverse effects. We have confirmed that both human and murine thymic sections show marked staining for PPARgamma at senior ages. We have also tested the thymic lobes of PPARgamma haplo-insufficient and null mice. Supporting our working hypothesis both adult PPARgamma haplo-insufficient and null mice show delayed thymic senescence by thymus histology, thymocyte mouse T-cell recombination excision circle qPCR and peripheral blood naive T-cell ratio by flow-cytometry. Delayed senescence showed dose–response with respect to PPARgamma deficiency. Functional immune parameters were also evaluated at senior ages in PPARgamma haplo-insufficient mice (null mice do not reach senior ages due to metabolic adverse affects. As expected, sustained and elevated T-cell production conferred oral tolerance and enhanced vaccination efficiency in senior PPARgamma haplo-insufficient, but not in senior wild-type littermates according to ELISA IgG measurements. Of note, humans also show increased oral intolerance issues and decreased protection by vaccines at senior ages. Moreover, PPARgamma haplo-insufficiency also exists in human known as a rare disease (FPLD3 causing metabolic adverse effects, similar to the mouse. When compared to age- and metabolic disorder-matched other patient samples (FPLD2 not affecting PPARgamma activity, FPLD3 patients showed increased human Trec (hTrec values by qPCR (within healthy human range suggesting delayed thymic senescence, in accordance with

  3. An Extract from the Plant Deschampsia antarctica Protects Fibroblasts from Senescence Induced by Hydrogen Peroxide

    Science.gov (United States)

    Ortiz-Espín, Ana; Morel, Esther; Juarranz, Ángeles; Guerrero, Antonio; Jiménez, Ana

    2017-01-01

    The Antarctic plant Deschampsia antarctica (DA) is able to survive in extreme conditions thanks to its special mechanism of protection against environmental aggressions. In this work, we investigated whether an aqueous extract of the plant (EDA) retains some of its defensive properties and is able to protect our skin against common external oxidants. We evaluated EDA over young human fibroblasts and exposed to H2O2, and we measured cell proliferation, viability, and senescence-associated β-galactosidase (SA-β-Gal). We also tested the expression of several senescence-associated proteins including sirtuin1, lamin A/C, the replicative protein PCNA, and the redox protein thioredoxin 2. We found that EDA promoted per se cell proliferation and viability and increased the expression of anti-senescence-related markers. Then, we selected a dose of H2O2 as an inductor of senescence in human fibroblasts, and we found that an EDA treatment 24 h prior H2O2 exposure increased fibroblast proliferation. EDA significantly inhibited the increase in SA-β-Gal levels induced by H2O2 and promoted the expression of sirtuin 1 and lamin A/C proteins. Altogether, these results suggest that EDA protects human fibroblasts from cellular senescence induced by H2O2, pointing to this compound as a potential therapeutic agent to treat or prevent skin senescence. PMID:28894504

  4. An Extract from the Plant Deschampsia antarctica Protects Fibroblasts from Senescence Induced by Hydrogen Peroxide

    Directory of Open Access Journals (Sweden)

    Ana Ortiz-Espín

    2017-01-01

    Full Text Available The Antarctic plant Deschampsia antarctica (DA is able to survive in extreme conditions thanks to its special mechanism of protection against environmental aggressions. In this work, we investigated whether an aqueous extract of the plant (EDA retains some of its defensive properties and is able to protect our skin against common external oxidants. We evaluated EDA over young human fibroblasts and exposed to H2O2, and we measured cell proliferation, viability, and senescence-associated β-galactosidase (SA-β-Gal. We also tested the expression of several senescence-associated proteins including sirtuin1, lamin A/C, the replicative protein PCNA, and the redox protein thioredoxin 2. We found that EDA promoted per se cell proliferation and viability and increased the expression of anti-senescence-related markers. Then, we selected a dose of H2O2 as an inductor of senescence in human fibroblasts, and we found that an EDA treatment 24 h prior H2O2 exposure increased fibroblast proliferation. EDA significantly inhibited the increase in SA-β-Gal levels induced by H2O2 and promoted the expression of sirtuin 1 and lamin A/C proteins. Altogether, these results suggest that EDA protects human fibroblasts from cellular senescence induced by H2O2, pointing to this compound as a potential therapeutic agent to treat or prevent skin senescence.

  5. Senescence induction; a possible cancer therapy

    Directory of Open Access Journals (Sweden)

    Kondoh Hiroshi

    2009-01-01

    Full Text Available Abstract Cellular immortalization is a crucial step during the development of human cancer. Primary mammalian cells reach replicative exhaustion after several passages in vitro, a process called replicative senescence. During such a state of permanent growth arrest, senescent cells are refractory to physiological proliferation stimuli: they have altered cell morphology and gene expression patterns, although they remain viable with preserved metabolic activity. Interestingly, senescent cells have also been detected in vivo in human tumors, particularly in benign lesions. Senescence is a mechanism that limits cellular lifespan and constitutes a barrier against cellular immortalization. During immortalization, cells acquire genetic alterations that override senescence. Tumor suppressor genes and oncogenes are closely involved in senescence, as their knockdown and ectopic expression confer immortality and senescence induction, respectively. By using high throughput genetic screening to search for genes involved in senescence, several candidate oncogenes and putative tumor suppressor genes have been recently isolated, including subtypes of micro-RNAs. These findings offer new perspectives in the modulation of senescence and open new approaches for cancer therapy.

  6. Delayed animal aging through the recovery of stem cell senescence by platelet rich plasma.

    Science.gov (United States)

    Liu, Hen-Yu; Huang, Chiung-Fang; Lin, Tzu-Chieh; Tsai, Ching-Yu; Tina Chen, Szu-Yu; Liu, Alice; Chen, Wei-Hong; Wei, Hong-Jian; Wang, Ming-Fu; Williams, David F; Deng, Win-Ping

    2014-12-01

    Aging is related to loss of functional stem cell accompanying loss of tissue and organ regeneration potentials. Previously, we demonstrated that the life span of ovariectomy-senescence accelerated mice (OVX-SAMP8) was significantly prolonged and similar to that of the congenic senescence-resistant strain of mice after platelet rich plasma (PRP)/embryonic fibroblast transplantation. The aim of this study is to investigate the potential of PRP for recovering cellular potential from senescence and then delaying animal aging. We first examined whether stem cells would be senescent in aged mice compared to young mice. Primary adipose derived stem cells (ADSCs) and bone marrow derived stem cells (BMSCs) were harvested from young and aged mice, and found that cell senescence was strongly correlated to animal aging. Subsequently, we demonstrated that PRP could recover cell potential from senescence, such as promote cell growth (cell proliferation and colony formation), increase osteogenesis, decrease adipogenesis, restore cell senescence related markers and resist the oxidative stress in stem cells from aged mice. The results also showed that PRP treatment in aged mice could delay mice aging as indicated by survival, body weight and aging phenotypes (behavior and gross morphology) in term of recovering the cellular potential of their stem cells compared to the results on aged control mice. In conclusion these findings showed that PRP has potential to delay aging through the recovery of stem cell senescence and could be used as an alternative medicine for tissue regeneration and future rejuvenation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Androgen deprivation-induced senescence promotes outgrowth of androgen-refractory prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Dominick G A Burton

    Full Text Available Androgen deprivation (AD is an effective method for initially suppressing prostate cancer (PC progression. However, androgen-refractory PC cells inevitably emerge from the androgen-responsive tumor, leading to incurable disease. Recent studies have shown AD induces cellular senescence, a phenomenon that is cell-autonomously tumor-suppressive but which confers tumor-promoting adaptations that can facilitate the advent of senescence-resistant malignant cell populations. Because androgen-refractory PC cells emerge clonally from the originally androgen-responsive tumor, we sought to investigate whether AD-induced senescence (ADIS affects acquisition of androgen-refractory behavior in androgen-responsive LNCaP and LAPC4 prostate cancer cells. We find that repeated exposure of these androgen-responsive cells to senescence-inducing stimuli via cyclic AD leads to the rapid emergence of ADIS-resistant, androgen-refractory cells from the bulk senescent cell population. Our results show that the ADIS phenotype is associated with tumor-promoting traits, notably chemoresistance and enhanced pro-survival mechanisms such as inhibition of p53-mediated cell death, which encourage persistence of the senescent cells. We further find that pharmacologic enforcement of p53/Bax activation via Nutlin-3 prior to establishment of ADIS is required to overcome the associated pro-survival response and preferentially trigger pervasive cell death instead of senescence during AD. Thus our study demonstrates that ADIS promotes outgrowth of androgen-refractory PC cells and is consequently a suboptimal tumor-suppressor response to AD.

  8. Targeting senescence cells in pancreatic cancer | IDRC ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Targeting senescence cells in pancreatic cancer. Cellular senescence is a programmed response to oncogenic (tumour-causing) stress that aims to halt the expansion of cells with malignant potential. It does this by stopping the proliferation of pre-cancerous lesions and recruitment of the immune system for their elimination.

  9. Suppressing Cancer: The Importance of Being Senescent

    Energy Technology Data Exchange (ETDEWEB)

    Campisi, Judith

    2005-07-01

    Cellular senescence permanently arrests the cell division cycle, and has long been thought to prevent the growth of cells at risk for transformation into cancer cells. Four new papers now provide evidence that cellular senescence indeed limits the development of malignant cancers in mice and humans.

  10. IGF Binding Protein-5 Induces Cell Senescence

    Directory of Open Access Journals (Sweden)

    Fumihiro Sanada

    2018-02-01

    Full Text Available Cellular senescence is the complex process of deterioration that drives the aging of an organism, resulting in the progressive loss of organ function and eventually phenotypic aging. Senescent cells undergo irreversible growth arrest, usually by inducing telomere shortening. Alternatively, senescence may also occur prematurely in response to various stress stimuli, such as oxidative stress, DNA damage, or activated oncogenes. Recently, it has been shown that IGF binding protein-5 (IGFBP-5 with the induction of the tumor suppressor p53 is upregulated during cellular senescence. This mechanism mediates interleukin-6/gp130-induced premature senescence in human fibroblasts, irradiation-induced premature senescence in human endothelial cells (ECs, and replicative senescence in human ECs independent of insulin-like growth factor I (IGF-I and IGF-II. Additionally, a link between IGFBP-5, hyper-coagulation, and inflammation, which occur with age, has been implicated. Thus, IGFBP-5 seems to play decisive roles in controlling cell senescence and cell inflammation. In this review, we describe the accumulating evidence for this role of IGFBP-5 including our new finding.

  11. Unmasking Transcriptional Heterogeneity in Senescent Cells

    NARCIS (Netherlands)

    Hernandez-Segura, Alejandra; de Jong, Tristan V; Melov, Simon; Guryev, Victor; Campisi, Judith; Demaria, Marco

    2017-01-01

    Cellular senescence is a state of irreversibly arrested proliferation, often induced by genotoxic stress [1]. Senescent cells participate in a variety of physiological and pathological conditions, including tumor suppression [2], embryonic development [3, 4], tissue repair [5-8], and organismal

  12. Petal Senescence: New Concepts for Ageing Cells

    NARCIS (Netherlands)

    Woltering, E.J.; Doorn, van W.G.

    2009-01-01

    Senescence in flower petals can be regarded as a form of programmed cell death (PCD), being a process where cells or tissues are broken down in an orderly and predictable manner, whereby nutrients are re-used by other cells, tissues or plant parts. The process of petal senescence shows many

  13. Physiology and molecular biology of petal senescence

    NARCIS (Netherlands)

    Doorn, van W.G.; Woltering, E.J.

    2008-01-01

    Petal senescence is reviewed, with the main emphasis on gene expression in relation to physiological functions. Autophagy seems to be the major mechanism for large-scale degradation of macromolecules, but it is still unclear if it contributes to cell death. Depending on the species, petal senescence

  14. Possible Roles of Strigolactones during Leaf Senescence

    Directory of Open Access Journals (Sweden)

    Yusuke Yamada

    2015-09-01

    Full Text Available Leaf senescence is a complicated developmental process that involves degenerative changes and nutrient recycling. The progress of leaf senescence is controlled by various environmental cues and plant hormones, including ethylene, jasmonic acid, salicylic acid, abscisic acid, cytokinins, and strigolactones. The production of strigolactones is induced in response to nitrogen and phosphorous deficiency. Strigolactones also accelerate leaf senescence and regulate shoot branching and root architecture. Leaf senescence is actively promoted in a nutrient-poor soil environment, and nutrients are transported from old leaves to young tissues and seeds. Strigolactones might act as important signals in response to nutrient levels in the rhizosphere. In this review, we discuss the possible roles of strigolactones during leaf senescence.

  15. Piper betle L. Modulates Senescence-Associated Genes Expression in Replicative Senescent Human Diploid Fibroblasts

    Directory of Open Access Journals (Sweden)

    Lina Wati Durani

    2017-01-01

    Full Text Available Piper betle (PB is a traditional medicine that is widely used to treat different diseases around Asian region. The leaf extracts contain various bioactive compounds, which were reported to have antidiabetic, antibacterial, anti-inflammatory, antioxidant, and anticancer effects. In this study, the effect of PB aqueous extracts on replicative senescent human diploid fibroblasts (HDFs was investigated by determining the expressions of senescence-associated genes using quantitative PCR. Our results showed that PB extracts at 0.4 mg/ml can improve cell proliferation of young (143%, presenescent (127.3%, and senescent (157.3% HDFs. Increased expressions of PRDX6, TP53, CDKN2A, PAK2, and MAPK14 were observed in senescent HDFs compared to young and/or presenescent HDFs. Treatment with PB extracts modulates the transcriptional profile changes in senescent HDFs. By contrast, expressions of SOD1 increased, whereas GPX1, PRDX6, TP53, CDKN2A, PAK2, and MAPK14 were decreased in PB-treated senescent HDFs compared to untreated senescent HDFs. In conclusion, this study indicates the modulation of PB extracts on senescence-associated genes expression of replicative senescent HDFs. Further studies warrant determining the mechanism of PB in modulating replicative senescence of HDFs through these signaling pathways.

  16. Effects of bioactive compounds on senescence and components of senescence associated secretory phenotypes in vitro.

    Science.gov (United States)

    Mária, Janubová; Ingrid, Žitňanová

    2017-07-19

    Senescence is a permanent cell cycle arrest that is accompanied by changes in cell morphology and physiology occurring in vitro and in vivo. Senescence evolved as a beneficial response to damage promoting wound healing, limiting fibrosis, fighting against cancer and helping embryonic development. However, excessive accumulation of senescent cells is considered to play a substantial role in the development of aging-related diseases and other morphological and physiological changes associated with aging. Therefore, the aim of many researchers is to find out a way to eliminate senescent cells and improve the health condition of aging people. Bioactive compounds e.g. polyphenols, vitamins, phenols, carotenoids, ginsenosides, omega-3 fatty acids, and compounds isolated from algae (phloroglucinol, sargachromal) are known to affect important biological functions. Recent in vitro studies have revealed that they can protect different types of cells against stress induced senescence (SISP), delay replicative senescence, rejuvenate senescent cells and exert senolytic effects. This review summarizes how the biological compounds listed above affect cell morphology, cell proliferation, specific cell functions, the activity of senescence-associated β-galactosidase (SA-β-gal), the shortening of telomeres and reduction of telomerase activity, production of intracellular reactive oxygen species (ROS) and lipid peroxidation products, expression of antioxidant enzymes, expression of p53 and p21 - key effectors of cell cycle arrest leading to senescence - and expression of some key components of senescence associated secretory phenotype (SASP) in replicative senescence, stress induced senescence (SISP) and under conditions which may lead to the development of senescence such as UV-A and UV-B irradiation of cells and the production of matrix metalloproteinases (a component of the SASP) in cells. Finally, future perspectives of this research are discussed.

  17. Autocrine IL-6 mediates pituitary tumor senescence

    Science.gov (United States)

    Fuertes, Mariana; Ajler, Pablo; Carrizo, Guillermo; Cervio, Andrés; Sevlever, Gustavo; Stalla, Günter K.; Arzt, Eduardo

    2017-01-01

    Cellular senescence is a stable proliferative arrest state. Pituitary adenomas are frequent and mostly benign, but the mechanism for this remains unknown. IL-6 is involved in pituitary tumor progression and is produced by the tumoral cells. In a cell autonomous fashion, IL-6 participates in oncogene-induced senescence in transduced human melanocytes. Here we prove that autocrine IL-6 participates in pituitary tumor senescence. Endogenous IL-6 inhibition in somatotroph MtT/S shRNA stable clones results in decreased SA-β-gal activity and p16INK4a but increased pRb, proliferation and invasion. Nude mice injected with IL-6 silenced clones develop tumors contrary to MtT/S wild type that do not, demonstrating that clones that escape senescence are capable of becoming tumorigenic. When endogenous IL-6 is silenced, cell cultures derived from positive SA-β-gal human tumor samples decrease the expression of the senescence marker. Our results establish that IL-6 contributes to maintain senescence by its autocrine action, providing a natural model of IL-6 mediated benign adenoma senescence. PMID:27902467

  18. Bacterial Intoxication Evokes Cellular Senescence with Persistent DNA Damage and Cytokine Signaling

    DEFF Research Database (Denmark)

    Blazkova, Hana; Krejcikova, Katerina; Moudry, Pavel

    2009-01-01

    to such intoxication are mechanistically incompletely understood. Here we show that both normal and cancer cells (BJ, IMR-90 and WI-38 fibroblasts, HeLa and U2-OS cell lines) that survive the acute phase of intoxication by Haemophilus ducreyi CDT possess the hallmarks of cellular senescence. This characteristic...... features shared by cells undergoing replicative or premature cellular senescence. We conclude that analogous to oncogenic, oxidative and replicative stresses, bacterial intoxication represents another pathophysiological stimulus that induces premature senescence, an intrinsic cellular response that may......Cytolethal distending toxins (CDTs) are proteins produced and secreted by facultative pathogenic strains of Gram-negative bacteria with potentially genotoxic effects. Mammalian cells exposed to CDTs undergo cell type-dependent cell-cycle arrest or apoptosis; however the cell fate responses...

  19. Embryonic senescence and laminopathies in a progeroid zebrafish model.

    Science.gov (United States)

    Koshimizu, Eriko; Imamura, Shintaro; Qi, Jie; Toure, Jamal; Valdez, Delgado M; Carr, Christopher E; Hanai, Jun-ichi; Kishi, Shuji

    2011-03-30

    Mutations that disrupt the conversion of prelamin A to mature lamin A cause the rare genetic disorder Hutchinson-Gilford progeria syndrome and a group of laminopathies. Our understanding of how A-type lamins function in vivo during early vertebrate development through aging remains limited, and would benefit from a suitable experimental model. The zebrafish has proven to be a tractable model organism for studying both development and aging at the molecular genetic level. Zebrafish show an array of senescence symptoms resembling those in humans, which can be targeted to specific aging pathways conserved in vertebrates. However, no zebrafish models bearing human premature senescence currently exist. We describe the induction of embryonic senescence and laminopathies in zebrafish harboring disturbed expressions of the lamin A gene (LMNA). Impairments in these fish arise in the skin, muscle and adipose tissue, and sometimes in the cartilage. Reduced function of lamin A/C by translational blocking of the LMNA gene induced apoptosis, cell-cycle arrest, and craniofacial abnormalities/cartilage defects. By contrast, induced cryptic splicing of LMNA, which generates the deletion of 8 amino acid residues lamin A (zlamin A-Δ8), showed embryonic senescence and S-phase accumulation/arrest. Interestingly, the abnormal muscle and lipodystrophic phenotypes were common in both cases. Hence, both decrease-of-function of lamin A/C and gain-of-function of aberrant lamin A protein induced laminopathies that are associated with mesenchymal cell lineages during zebrafish early development. Visualization of individual cells expressing zebrafish progerin (zProgerin/zlamin A-Δ37) fused to green fluorescent protein further revealed misshapen nuclear membrane. A farnesyltransferase inhibitor reduced these nuclear abnormalities and significantly prevented embryonic senescence and muscle fiber damage induced by zProgerin. Importantly, the adult Progerin fish survived and remained fertile with

  20. Embryonic senescence and laminopathies in a progeroid zebrafish model.

    Directory of Open Access Journals (Sweden)

    Eriko Koshimizu

    Full Text Available BACKGROUND: Mutations that disrupt the conversion of prelamin A to mature lamin A cause the rare genetic disorder Hutchinson-Gilford progeria syndrome and a group of laminopathies. Our understanding of how A-type lamins function in vivo during early vertebrate development through aging remains limited, and would benefit from a suitable experimental model. The zebrafish has proven to be a tractable model organism for studying both development and aging at the molecular genetic level. Zebrafish show an array of senescence symptoms resembling those in humans, which can be targeted to specific aging pathways conserved in vertebrates. However, no zebrafish models bearing human premature senescence currently exist. PRINCIPAL FINDINGS: We describe the induction of embryonic senescence and laminopathies in zebrafish harboring disturbed expressions of the lamin A gene (LMNA. Impairments in these fish arise in the skin, muscle and adipose tissue, and sometimes in the cartilage. Reduced function of lamin A/C by translational blocking of the LMNA gene induced apoptosis, cell-cycle arrest, and craniofacial abnormalities/cartilage defects. By contrast, induced cryptic splicing of LMNA, which generates the deletion of 8 amino acid residues lamin A (zlamin A-Δ8, showed embryonic senescence and S-phase accumulation/arrest. Interestingly, the abnormal muscle and lipodystrophic phenotypes were common in both cases. Hence, both decrease-of-function of lamin A/C and gain-of-function of aberrant lamin A protein induced laminopathies that are associated with mesenchymal cell lineages during zebrafish early development. Visualization of individual cells expressing zebrafish progerin (zProgerin/zlamin A-Δ37 fused to green fluorescent protein further revealed misshapen nuclear membrane. A farnesyltransferase inhibitor reduced these nuclear abnormalities and significantly prevented embryonic senescence and muscle fiber damage induced by zProgerin. Importantly, the adult

  1. Neurons Generated in Senescence Maintain Capacity for Functional Integration

    Science.gov (United States)

    Marrone, Diano F.; Ramirez-Amaya, Victor; Barnes, Carol A.

    2012-01-01

    Adult-born neurons in the dentate gyrus (DG) can survive for long periods, are capable of integrating into neuronal networks, and are important for hippocampus-dependent learning. Neurogenesis is dramatically reduced during senescence, and it remains unknown whether those few neurons that are produced remain capable of network integration. The expression of Arc, a protein coupled to neuronal activity, was used to measure activity among granule cells that were labeled with BrdU four months earlier in young (9 months) and aged (25 months) Fischer344 rats. The results indicate that while fewer cells are generated in the senescent DG, those that survive are (a) more likely to respond to spatial processing by expressing Arc relative to the remainder of the granule cell population, and (b) equally responsive to spatial exploration as granule cells of the same age from young animals. These findings provide compelling evidence that newborn granule cells in the aged DG retain the capacity for participation in functional hippocampal networks. PMID:21695743

  2. Unbalanced Growth, Senescence and Aging.

    Science.gov (United States)

    Polymenis, Michael; Kennedy, Brian K

    2017-01-01

    Usually, cells balance their growth with their division. Coordinating growth inputs with cell division ensures the proper timing of division when sufficient cell material is available and affects the overall rate of cell proliferation. At a very fundamental level, cellular replicative lifespan-defined as the number of times a cell can divide, is a manifestation of cell cycle control. Hence, control of mitotic cell divisions, especially when the commitment is made to a new round of cell division, is intimately linked to replicative aging of cells. In this chapter, we review our current understanding, and its shortcomings, of how unbalanced growth and division, can dramatically influence the proliferative potential of cells, often leading to cellular and organismal aging phenotypes. The interplay between growth and division also underpins cellular senescence (i.e., inability to divide) and quiescence, when cells exit the cell cycle but still retain their ability to divide.

  3. The Lcn2-engineered HEK-293 cells show senescence under stressful condition

    Directory of Open Access Journals (Sweden)

    Bahareh Bahmani

    2015-05-01

    Full Text Available Objective(s: Lipocalin2 (Lcn2 gene is highly expressed in response to various types of cellular stresses. The precise role of Lcn2 has not been fully understood yet. However, it plays a key role in controlling vital cellular processes such as proliferation, apoptosis and metabolism. Recently it was shown that Lcn2 decreases senescence and increases proliferation of mesenchymal stem cells (MSC with finite life span under either normal or oxidative stress conditions. However, Lcn2 effects on immortal cell line with infinite proliferation are not defined completely.  Materials and Material and Methods: HEK-293 cells were transfected with recombinant pcDNA3.1 containing Lcn2 fragment (pcDNA3.1-Lcn2. Expression of lipocalin2 in transfected cells was evaluated by RT-PCR, real time RT-PCR, and ELISA. Different cell groups were treated with H2O2 and WST-1 assay was performed to determine their proliferation rate. Senescence was studied by β-galactosidase and gimsa staining methods as well as evaluation of the expression of senescence-related genes by real time RT-PCR. Results: Lcn2 increased cell proliferation under normal culture condition, while the proliferation slightly decreased under oxidative stress.  This decrease was further found to be attributed to senescence. Conclusion: Our findings indicated that under harmful conditions, Lcn2 gene is responsible for the regulation of cell survival through senescence.

  4. Three steps to the immortality of cancer cells: senescence, polyploidy and self-renewal.

    Science.gov (United States)

    Erenpreisa, Jekaterina; Cragg, Mark S

    2013-09-11

    Metastatic cancer is rarely cured by current DNA damaging treatments, apparently due to the development of resistance. However, recent data indicates that tumour cells can elicit the opposing processes of senescence and stemness in response to these treatments, the biological significance and molecular regulation of which is currently poorly understood. Although cellular senescence is typically considered a terminal cell fate, it was recently shown to be reversible in a small population of polyploid cancer cells induced after DNA damage. Overcoming genotoxic insults is associated with reversible polyploidy, which itself is associated with the induction of a stemness phenotype, thereby providing a framework linking these separate phenomena. In keeping with this suggestion, senescence and autophagy are clearly intimately involved in the emergence of self-renewal potential in the surviving cells that result from de-polyploidisation. Moreover, subsequent analysis indicates that senescence may paradoxically be actually required to rejuvenate cancer cells after genotoxic treatments. We propose that genotoxic resistance is thereby afforded through a programmed life-cycle-like process which intimately unites senescence, polyploidy and stemness.

  5. Quantitative identification of senescent cells in aging and disease.

    Science.gov (United States)

    Biran, Anat; Zada, Lior; Abou Karam, Paula; Vadai, Ezra; Roitman, Lior; Ovadya, Yossi; Porat, Ziv; Krizhanovsky, Valery

    2017-08-01

    Senescent cells are present in premalignant lesions and sites of tissue damage and accumulate in tissues with age. In vivo identification, quantification and characterization of senescent cells are challenging tasks that limit our understanding of the role of senescent cells in diseases and aging. Here, we present a new way to precisely quantify and identify senescent cells in tissues on a single-cell basis. The method combines a senescence-associated beta-galactosidase assay with staining of molecular markers for cellular senescence and of cellular identity. By utilizing technology that combines flow cytometry with high-content image analysis, we were able to quantify senescent cells in tumors, fibrotic tissues, and tissues of aged mice. Our approach also yielded the finding that senescent cells in tissues of aged mice are larger than nonsenescent cells. Thus, this method provides a basis for quantitative assessment of senescent cells and it offers proof of principle for combination of different markers of senescence. It paves the way for screening of senescent cells for identification of new senescence biomarkers, genes that bypass senescence or senolytic compounds that eliminate senescent cells, thus enabling a deeper understanding of the senescent state in vivo. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  6. Role of Cell Senescence in Breast Cancer

    National Research Council Canada - National Science Library

    Krtolica, Ana

    2000-01-01

    .... Here, we report that both mouse and human immortal pre-malignant breast epithelial cell lines increase 2 to 5 times their proliferation in the presence of senescent, compared to presenescent, human fibroblasts...

  7. Role of Cell Senescence in Breast Cancer

    National Research Council Canada - National Science Library

    Krtolica, Ana

    1999-01-01

    .... Here, we report that both mouse and human immortal pre-malignant breast epithelial cell lines show increased proliferation in the presence of senescent, compared to presenescent, human fibroblasts...

  8. Cellular senescence in aging and osteoarthritis.

    Science.gov (United States)

    Toh, Wei Seong; Brittberg, Mats; Farr, Jack; Foldager, Casper Bindzus; Gomoll, Andreas H; Hui, James Hoi Po; Richardson, James B; Roberts, Sally; Spector, Myron

    2016-12-01

    - It is well accepted that age is an important contributing factor to poor cartilage repair following injury, and to the development of osteoarthritis. Cellular senescence, the loss of the ability of cells to divide, has been noted as the major factor contributing to age-related changes in cartilage homeostasis, function, and response to injury. The underlying mechanisms of cellular senescence, while not fully understood, have been associated with telomere erosion, DNA damage, oxidative stress, and inflammation. In this review, we discuss the causes and consequences of cellular senescence, and the associated biological challenges in cartilage repair. In addition, we present novel strategies for modulation of cellular senescence that may help to improve cartilage regeneration in an aging population.

  9. Mitotic Stress Is an Integral Part of the Oncogene-Induced Senescence Program that Promotes Multinucleation and Cell Cycle Arrest

    Directory of Open Access Journals (Sweden)

    Dina Dikovskaya

    2015-09-01

    Full Text Available Oncogene-induced senescence (OIS is a tumor suppression mechanism that blocks cell proliferation in response to oncogenic signaling. OIS is frequently accompanied by multinucleation; however, the origin of this is unknown. Here, we show that multinucleate OIS cells originate mostly from failed mitosis. Prior to senescence, mutant H-RasV12 activation in primary human fibroblasts compromised mitosis, concordant with abnormal expression of mitotic genes functionally linked to the observed mitotic spindle and chromatin defects. Simultaneously, H-RasV12 activation enhanced survival of cells with damaged mitoses, culminating in extended mitotic arrest and aberrant exit from mitosis via mitotic slippage. ERK-dependent transcriptional upregulation of Mcl1 was, at least in part, responsible for enhanced survival and slippage of cells with mitotic defects. Importantly, mitotic slippage and oncogene signaling cooperatively induced senescence and key senescence effectors p21 and p16. In summary, activated Ras coordinately triggers mitotic disruption and enhanced cell survival to promote formation of multinucleate senescent cells.

  10. T CELL REPLICATIVE SENESCENCE IN HUMAN AGING

    Science.gov (United States)

    Chou, Jennifer P.; Effros, Rita B.

    2013-01-01

    The decline of the immune system appears to be an intractable consequence of aging, leading to increased susceptibility to infections, reduced effectiveness of vaccination and higher incidences of many diseases including osteoporosis and cancer in the elderly. These outcomes can be attributed, at least in part, to a phenomenon known as T cell replicative senescence, a terminal state characterized by dysregulated immune function, loss of the CD28 costimulatory molecule, shortened telomeres and elevated production of pro-inflammatory cytokines. Senescent CD8 T cells, which accumulate in the elderly, have been shown to frequently bear antigen specificity against cytomegalovirus (CMV), suggesting that this common and persistent infection may drive immune senescence and result in functional and phenotypic changes to the T cell repertoire. Senescent T cells have also been identified in patients with certain cancers, autoimmune diseases and chronic infections, such as HIV. This review discusses the in vivo and in vitro evidence for the contribution of CD8 T cell replicative senescence to a plethora of age-related pathologies and a few possible therapeutic avenues to delay or prevent this differentiative end-state in T cells. The age-associated remodeling of the immune system, through accumulation of senescent T cells has far-reaching consequences on the individual and society alike, for the current healthcare system needs to meet the urgent demands of the increasing proportions of the elderly in the US and abroad. PMID:23061726

  11. Cellular senescence and the aging brain.

    Science.gov (United States)

    Chinta, Shankar J; Woods, Georgia; Rane, Anand; Demaria, Marco; Campisi, Judith; Andersen, Julie K

    2015-08-01

    Cellular senescence is a potent anti-cancer mechanism that arrests the proliferation of mitotically competent cells to prevent malignant transformation. Senescent cells accumulate with age in a variety of human and mouse tissues where they express a complex 'senescence-associated secretory phenotype' (SASP). The SASP includes many pro-inflammatory cytokines, chemokines, growth factors and proteases that have the potential to cause or exacerbate age-related pathology, both degenerative and hyperplastic. While cellular senescence in peripheral tissues has recently been linked to a number of age-related pathologies, its involvement in brain aging is just beginning to be explored. Recent data generated by several laboratories suggest that both aging and age-related neurodegenerative diseases are accompanied by an increase in SASP-expressing senescent cells of non-neuronal origin in the brain. Moreover, this increase correlates with neurodegeneration. Senescent cells in the brain could therefore constitute novel therapeutic targets for treating age-related neuropathologies. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Astrocyte Senescence and Metabolic Changes in Response to HIV Antiretroviral Therapy Drugs

    Directory of Open Access Journals (Sweden)

    Justin Cohen

    2017-08-01

    Full Text Available With the advent of highly active antiretroviral therapy (HAART survival rates among patients infected by HIV have increased. However, even though survival has increased HIV-associated neurocognitive disorders (HAND still persist, suggesting that HAART-drugs may play a role in the neurocognitive impairment observed in HIV-infected patients. Given previous data demonstrating that astrocyte senescence plays a role in neurocognitive disorders such as Alzheimer’s disease (AD, we examined the role of HAART on markers of senescence in primary cultures of human astrocytes (HAs. Our results indicate HAART treatment induces cell cycle arrest, senescence-associated beta-galactosidase, and the cell cycle inhibitor p21. Highly active antiretroviral therapy treatment is also associated with the induction of reactive oxygen species and upregulation of mitochondrial oxygen consumption. These changes in mitochondria correlate with increased glycolysis in HAART drug treated astrocytes. Taken together these results indicate that HAART drugs induce the senescence program in HAs, which is associated with oxidative and metabolic changes that could play a role in the development of HAND.

  13. The Identification of Senescence-Specific Genes during the Induction of Senescence in Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Steven R. Schwarze

    2005-09-01

    Full Text Available Classic mechanisms of tumor response to chemotherapy include apoptosis, mitotic catastrophe. Recent studies have suggested that cellular senescence, a terminal proliferation arrest seen in vitro, may be invoked during the exposure of cancer cells to chemotherapeutic agents. To identify markers associated specifically with the cellular senescence phenotype, we utilized expression data from cDNA microarray experiments identifying transcripts whose expression levels increased as human prostate epithelial cells progressed to senescence. When screened against other growth-inhibitory conditions, including quiescence, apoptosis, many of these transcripts were also upregulated, indicating that similar pathways occur between apoptosis, senescence. A senescent-like phenotype was then induced in several prostate cancer cell lines using 5-aza-2′-deoxycytidine, doxorubicin, or Docetaxel. Treatment with these agents resulted in a significant increase in the induction of senescence-specific genes when compared to nonsenescent conditions. The performance of the panel was improved with fluorescence-activated cell sorting using PKH26 to isolate nonproliferating, viable, drug-treated populations, indicating that a heterogeneous response occurs with chemotherapy. We have defined an RNA-based gene panel that characterizes the senescent phenotype induced in cancer cells by drug treatment. These data also indicate that a panel of genes, rather than one marker, needs to be utilized to identify senescence.

  14. Is senescence-associated β-galactosidase a marker of neuronal senescence?

    Science.gov (United States)

    Piechota, Malgorzata; Sunderland, Piotr; Wysocka, Adrianna; Nalberczak, Maria; Sliwinska, Malgorzata A; Radwanska, Kasia; Sikora, Ewa

    2016-12-06

    One of the features of cellular senescence is the activity of senescence-associated- β-galactosidase (SA-β-gal). The main purpose of this study was to evaluate this marker of senescence in aging neurons. We found that cortical neurons exhibited noticeable SA-β-gal activity quite early in culture. Many SA-β-gal-positive neurons were negative for another canonical marker of senescence, namely, double-strand DNA breaks (DSBs). Moreover, DDR signalling triggered by low doses of doxorubicin did not accelerate the appearance of neuronal SA-β-gal. In vivo, we observed pronounced induction of SA-β-gal activity in the hippocampus of 24-month-old mice, which is consistent with previous findings and supports the view that at this advanced age neurons developed a senescence-like phenotype. Surprisingly however, relatively high SA-β-gal activity, probably unrelated to the senescence process, was also observed in much younger, 3-month-old mice. In conclusion, we propose that SA-β-gal activity in neurons cannot be attributed uniquely to cell senescence either in vitro or in vivo. Additionally, we showed induction of REST protein in aging neurons in long-term culture and we propose that REST could be a marker of neuronal senescence in vitro.

  15. A Micro-RNA Connection in BRafV600E-Mediated Premature Senescence of Human Melanocytes

    Directory of Open Access Journals (Sweden)

    Gang Ren

    2012-01-01

    Full Text Available Recent high-throughput-sequencing of the cancer genome has identified oncogenic mutations in BRaf genetic locus as one of the critical events in melanomagenesis. In normal cells, the activity of BRaf is tightly regulated. Gain-of-function mutations like those identified in melanoma frequently lead to enhanced cell-survival and unrestrained growth. The activating mutation of BRaf will also induce the cells to senesce. However, the mechanism by which the oncogenic BRaf induces the senescent barrier remains poorly defined. microRNAs have regulatory functions toward the expression of genes that are important in carcinogenesis. Here we show that expression of several microRNAs is altered when the oncogenic version of BRaf is introduced in cultured primary melanocytes and these cells undergo premature cellular senescence. These include eight microRNAs whose expression rates are significantly stimulated and three that are repressed. While most of the induced microRNAs have documented negative effects on cell cycle progression, one of the repressed microRNAs has proven oncogenic functions. Ectopic expression of some of these induced microRNAs increased the expression of senescence markers and induced growth arrest and senescence in primary melanocytes. Taken together, our results suggest that the change in microRNA expression rates may play a vital role in senescence induced by the oncogenic BRaf.

  16. New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463.

    Science.gov (United States)

    Zhu, Yi; Doornebal, Ewald J; Pirtskhalava, Tamar; Giorgadze, Nino; Wentworth, Mark; Fuhrmann-Stroissnigg, Heike; Niedernhofer, Laura J; Robbins, Paul D; Tchkonia, Tamara; Kirkland, James L

    2017-03-08

    Senescent cells accumulate with aging and at sites of pathology in multiple chronic diseases. Senolytics are drugs that selectively promote apoptosis of senescent cells by temporarily disabling the pro-survival pathways that enable senescent cells to resist the pro-apoptotic, pro-inflammatory factors that they themselves secrete. Reducing senescent cell burden by genetic approaches or by administering senolytics delays or alleviates multiple age- and disease-related adverse phenotypes in preclinical models. Reported senolytics include dasatinib, quercetin, navitoclax (ABT263), and piperlongumine. Here we report that fisetin, a naturally-occurring flavone with low toxicity, and A1331852 and A1155463, selective BCL-XL inhibitors that may have less hematological toxicity than the less specific BCL-2 family inhibitor navitoclax, are senolytic. Fisetin selectively induces apoptosis in senescent but not proliferating human umbilical vein endothelial cells (HUVECs). It is not senolytic in senescent IMR90 cells, a human lung fibroblast strain, or primary human preadipocytes. A1331852 and A1155463 are senolytic in HUVECs and IMR90 cells, but not preadipocytes. These agents may be better candidates for eventual translation into clinical interventions than some existing senolytics, such as navitoclax, which is associated with hematological toxicity.

  17. Ameliorating replicative senescence of human bone marrow stromal cells by PSMB5 overexpression

    Energy Technology Data Exchange (ETDEWEB)

    Lu, Li, E-mail: luli7300@126.com [Department of Anatomy, Shanxi Medical University, Taiyuan 030001 (China); Song, Hui-Fang; Wei, Jiao-Long; Liu, Xue-Qin [Department of Anatomy, Shanxi Medical University, Taiyuan 030001 (China); Song, Wen-Hui [Department of Orthopaedics, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan 030001 (China); Yan, Ba-Yi; Yang, Gui-Jiao [Department of Anatomy, Shanxi Medical University, Taiyuan 030001 (China); Li, Ang [Department of Medicine, University of Hong Kong Faculty of Medicine, Hong Kong (Hong Kong); Department of Anatomy, University of Hong Kong Faculty of Medicine, Hong Kong (Hong Kong); Yang, Wu-Lin, E-mail: wulinyoung@163.com [School of Biotechnology and Food Engineering, Hefei University of Technology, Hefei 230009 (China); Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium (SBIC), Agency for Science, Technology and Research - A*STAR (Singapore)

    2014-01-24

    Highlights: • PSMB5 overexpression restores the differentiation potential of aged hBMSCs. • PSMB5 overexpression enhances the proteasomal activity of late-stage hBMSCs. • PSMB5 overexpression inhibits replicative senescence and improved cell viability. • PSMB5 overexpression promotes cell growth by upregulating the Cyclin D1/CDK4 complex. - Abstract: Multipotent human bone marrow stromal cells (hBMSCs) potentially serve as a source for cell-based therapy in regenerative medicine. However, in vitro expansion was inescapably accompanied with cell senescence, characterized by inhibited proliferation and compromised pluripotency. We have previously demonstrated that this aging process is closely associated with reduced 20S proteasomal activity, with down-regulation of rate-limiting catalytic β-subunits particularly evident. In the present study, we confirmed that proteasomal activity directly contributes to senescence of hBMSCs, which could be reversed by overexpression of the β5-subunit (PSMB5). Knocking down PSMB5 led to decreased proteasomal activity concurrent with reduced cell proliferation in early-stage hBMSCs, which is similar to the senescent phenotype observed in late-stage cells. In contrast, overexpressing PSMB5 in late-stage cells efficiently restored the normal activity of 20S proteasomes and promoted cell growth, possibly via upregulating the Cyclin D1/CDK4 complex. Additionally, PSMB5 could enhance cell resistance to oxidative stress, as evidenced by the increased cell survival upon exposing senescent hBMSCs to hydrogen peroxide. Furthermore, PSMB5 overexpression retained the pluripotency of late-stage hBMSCs by facilitating their neural differentiation both in vitro and in vivo. Collectively, our work reveals a critical role of PSMB5 in 20S proteasome-mediated protection against replicative senescence, pointing to a possible strategy for maintaining the integrity of culture-expanded hBMSCs by manipulating the expression of PSMB5.

  18. Photo- and antioxidative protection during summer leaf senescence in Pistacia lentiscus L. grown under Mediterranean field conditions.

    Science.gov (United States)

    Munné-Bosch, S; Peñuelas, J

    2003-09-01

    Summer leaf senescence in Pistacia lentiscus L. plants serves to remobilize nutrients from the oldest leaves to the youngest ones, and therefore contributes to plant survival during the adverse climatic conditions typical of Mediterranean summers, i.e. water deficit superimposed on high solar radiation and high temperatures. To evaluate the extent of photo- and antioxidative protection during leaf senescence of this species, changes in carotenoids, including xanthophyll cycle pigments, and in the levels of ascorbate and alpha-tocopherol were measured prior to and during summer leaf senescence in 3-year-old plants grown under Mediterranean field conditions. Although a chlorophyll loss of approx. 20% was observed during the first stages of leaf senescence, no damage to the photosynthetic apparatus occurred as indicated by constant maximum efficiencies of photosystem II photochemistry. During this period the de-epoxidation state of the xanthophyll cycle, and lutein, neoxanthin and ascorbate levels were kept constant. At the same time beta-carotene and alpha-tocopherol levels increased by approx. 9 and 70%, respectively, presumably conferring photo- and antioxidative protection to the photosynthetic apparatus. By contrast, during the later stages of leaf senescence, characterized by severe chlorophyll loss, carotenoids were moderately degraded (neoxanthin by approx. 20%, and both lutein and beta-carotene by approx. 35%), ascorbate decreased by approx. 80% and alpha-tocopherol was not detected in senescing leaves. This study demonstrates that mechanisms of photo- and antioxidative protection may play a major role in maintaining chloroplast function during the first stages of leaf senescence, while antioxidant defences are lost during the latest stages of senescence.

  19. Transcriptional analyses of natural leaf senescence in maize.

    Directory of Open Access Journals (Sweden)

    Wei Yang Zhang

    Full Text Available Leaf senescence is an important biological process that contributes to grain yield in crops. To study the molecular mechanisms underlying natural leaf senescence, we harvested three different developmental ear leaves of maize, mature leaves (ML, early senescent leaves (ESL, and later senescent leaves (LSL, and analyzed transcriptional changes using RNA-sequencing. Three sets of data, ESL vs. ML, LSL vs. ML, and LSL vs. ESL, were compared, respectively. In total, 4,552 genes were identified as differentially expressed. Functional classification placed these genes into 18 categories including protein metabolism, transporters, and signal transduction. At the early stage of leaf senescence, genes involved in aromatic amino acids (AAAs biosynthetic process and transport, cellular polysaccharide biosynthetic process, and the cell wall macromolecule catabolic process, were up-regulated. Whereas, genes involved in amino acid metabolism, transport, apoptosis, and response to stimulus were up-regulated at the late stage of leaf senescence. Further analyses reveals that the transport-related genes at the early stage of leaf senescence potentially take part in enzyme and amino acid transport and the genes upregulated at the late stage are involved in sugar transport, indicating nutrient recycling mainly takes place at the late stage of leaf senescence. Comparison between the data of natural leaf senescence in this study and previously reported data for Arabidopsis implies that the mechanisms of leaf senescence in maize are basically similar to those in Arabidopsis. A comparison of natural and induced leaf senescence in maize was performed. Athough many basic biological processes involved in senescence occur in both types of leaf senescence, 78.07% of differentially expressed genes in natural leaf senescence were not identifiable in induced leaf senescence, suggesting that differences in gene regulatory network may exist between these two leaf senescence

  20. Senescence from glioma stem cell differentiation promotes tumor growth

    Energy Technology Data Exchange (ETDEWEB)

    Ouchi, Rie [Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Laboratory of Molecular Target Therapy of Cancer, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Okabe, Sachiko; Migita, Toshiro [Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Nakano, Ichiro [Department of Neurosurgery, Comprehensive Cancer Center, University of Alabama at Birmingham, 1824 6th Avenue South, Birmingham, AL 35233 (United States); Seimiya, Hiroyuki, E-mail: hseimiya@jfcr.or.jp [Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Laboratory of Molecular Target Therapy of Cancer, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan)

    2016-02-05

    Glioblastoma (GBM) is a lethal brain tumor composed of heterogeneous cellular populations including glioma stem cells (GSCs) and differentiated non-stem glioma cells (NSGCs). While GSCs are involved in tumor initiation and propagation, NSGCs' role remains elusive. Here, we demonstrate that NSGCs undergo senescence and secrete pro-angiogenic proteins, boosting the GSC-derived tumor formation in vivo. We used a GSC model that maintains stemness in neurospheres, but loses the stemness and differentiates into NSGCs upon serum stimulation. These NSGCs downregulated telomerase, shortened telomeres, and eventually became senescent. The senescent NSGCs released pro-angiogenic proteins, including vascular endothelial growth factors and senescence-associated interleukins, such as IL-6 and IL-8. Conditioned medium from senescent NSGCs promoted proliferation of brain microvascular endothelial cells, and mixed implantation of GSCs and senescent NSGCs into mice enhanced the tumorigenic potential of GSCs. The senescent NSGCs seem to be clinically relevant, because both clinical samples and xenografts of GBM contained tumor cells that expressed the senescence markers. Our data suggest that senescent NSGCs promote malignant progression of GBM in part via paracrine effects of the secreted proteins. - Highlights: • Non-stem glioma cells (NSGCs) lose telomerase and eventually become senescent. • Senescent NSGCs secrete pro-angiogenic proteins, such as VEGFs, IL-6, and IL-8. • Senescent NSGCs enhance the growth of brain microvascular endothelial cells. • Senescent NSGCs enhance the tumorigenic potential of glioma stem cells in vivo.

  1. Senescence and immortality in hepatocellular carcinoma.

    Science.gov (United States)

    Ozturk, Mehmet; Arslan-Ergul, Ayca; Bagislar, Sevgi; Senturk, Serif; Yuzugullu, Haluk

    2009-12-01

    Cellular senescence is a process leading to terminal growth arrest with characteristic morphological features. This process is mediated by telomere-dependent, oncogene-induced and ROS-induced pathways, but persistent DNA damage is the most common cause. Senescence arrest is mediated by p16(INK4a)- and p21(Cip1)-dependent pathways both leading to retinoblastoma protein (pRb) activation. p53 plays a relay role between DNA damage sensing and p21(Cip1) activation. pRb arrests the cell cycle by recruiting proliferation genes to facultative heterochromatin for permanent silencing. Replicative senescence that occurs in hepatocytes in culture and in liver cirrhosis is associated with lack of telomerase activity and results in telomere shortening. Hepatocellular carcinoma (HCC) cells display inactivating mutations of p53 and epigenetic silencing of p16(INK4a). Moreover, they re-express telomerase reverse transcriptase required for telomere maintenance. Thus, senescence bypass and cellular immortality is likely to contribute significantly to HCC development. Oncogene-induced senescence in premalignant lesions and reversible immortality of cancer cells including HCC offer new potentials for tumor prevention and treatment.

  2. Senescence-associated inflammatory responses: aging and cancer perspectives.

    Science.gov (United States)

    Lasry, Audrey; Ben-Neriah, Yinon

    2015-04-01

    Senescent cells, albeit not proliferating, are metabolically and transcriptionally active, thereby capable of affecting their microenvironment, notably via the production of inflammatory mediators. These mediators maintain and propagate the senescence process to neighboring cells, and then recruit immune cells for clearing senescent cells. Among the inflammatory cues are molecules with pronounced tumor-controlling properties, both growth and invasion factors and inhibitory factors, working directly or via recruited immune cells. These senescence-inflammatory effects also prevail within tumors, mediated by the senescent tumor cells and the senescent tumor stroma. Here, we review the course and impact of senescence-associated inflammatory responses in aging and cancer. We propose that controlling senescence-associated inflammation by targeting specific inflammatory mediators may have a beneficial therapeutic effect in treatment of cancer and aging-related diseases. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Epigenetic Basis of Cellular Senescence and Its Implications in Aging.

    Science.gov (United States)

    Nacarelli, Timothy; Liu, Pingyu; Zhang, Rugang

    2017-11-24

    Cellular senescence is a tumor suppressive response that has become recognized as a major contributor of tissue aging. Senescent cells undergo a stable proliferative arrest that protects against neoplastic transformation, but acquire a secretory phenotype that has long-term deleterious effects. Studies are still unraveling the effector mechanisms that underlie these senescence responses with the goal to identify therapeutic interventions. Such effector mechanisms have been linked to the dramatic remodeling in the epigenetic and chromatin landscape that accompany cellular senescence. We discuss these senescence-associated epigenetic changes and their impact on the senescence phenotypes, notably the proliferative arrest and senescence associated secretory phenotype (SASP). We also explore possible epigenetic targets to suppress the deleterious effects of senescent cells that contribute towards aging.

  4. Leaf senescence and nutrient remobilisation in barley and wheat

    DEFF Research Database (Denmark)

    Gregersen, P L; Holm, P B; Krupinska, K

    2008-01-01

    in degradative, metabolic and regulatory processes that could be used in future strategies aimed at modifying the senescence process. The breeding of crops for characters related to senescence processes, e.g. higher yields and better nutrient use efficiency, is complex. Such breeding has to cope with the dilemma...... that delayed senescence, which could lead to higher yields, is correlated with a decrease in nutrient use efficiency. Pinpointing regulatory genes involved in senescence might lead to tools that could effectively overcome this dilemma....

  5. Beryllium induces premature senescence in human fibroblasts.

    Science.gov (United States)

    Coates, Shannon S A; Lehnert, Bruce E; Sharma, Sunil; Kindell, Susan M; Gary, Ronald K

    2007-07-01

    After cells have completed a sufficient number of cell divisions, they exit the cell cycle and enter replicative senescence. Here, we report that beryllium causes proliferation arrest with premature expression of the principal markers of senescence. After young presenescent human fibroblasts were treated with 3 microM BeSO(4) for 24 h, p21 cyclin-dependent kinase inhibitor mRNA increased by >200%. Longer periods of exposure caused mRNA and protein levels to increase for both p21 and p16(Ink4a), a senescence regulator that prevents pRb-mediated cell cycle progression. BeSO(4) also caused dose-dependent induction of senescence-associated beta-galactosidase activity (SA-beta-gal). Untreated cells had 48 relative fluorescence units (RFU)/microg/h of SA-beta-gal, whereas 3 microM BeSO(4) caused activity to increase to 84 RFU/microg/h. In chromatin immunoprecipitation experiments, BeSO(4) caused p53 protein to associate with its DNA binding site in the promoter region of the p21 gene, indicating that p53 transcriptional activity is responsible for the large increase in p21 mRNA elicited by beryllium. Forced expression of human telomerase reverse transcriptase (hTERT) rendered HFL-1 cells incapable of normal replicative senescence. However, there was no difference in the responsiveness of normal HFL-1 fibroblasts (IC(50) = 1.9 microM) and hTERT-immortalized cells (IC(50) = 1.7 microM) to BeSO(4) in a 9-day proliferation assay. The effects of beryllium resemble those of histone deacetylase-inhibiting drugs, which also cause large increases in p21. However, beryllium produced no changes in histone acetylation, suggesting that Be(2+) acts as a novel and potent pharmacological inducer of premature senescence.

  6. HDACs and the senescent phenotype of WI-38 cells

    Directory of Open Access Journals (Sweden)

    Noonan Emily J

    2005-10-01

    Full Text Available Abstract Background Normal cells possess a limited proliferative life span after which they enter a state of irreversible growth arrest. This process, known as replicative senescence, is accompanied by changes in gene expression that give rise to a variety of senescence-associated phenotypes. It has been suggested that these gene expression changes result in part from alterations in the histone acetylation machinery. Here we examine the influence of HDAC inhibitors on the expression of senescent markers in pre- and post-senescent WI-38 cells. Results Pre- and post-senescent WI-38 cells were treated with the HDAC inhibitors butyrate or trichostatin A (TSA. Following HDAC inhibitor treatment, pre-senescent cells increased p21WAF1 and β-galactosidase expression, assumed a flattened senescence-associated morphology, and maintained a lower level of proteasome activity. These alterations also occurred during normal replicative senescence of WI-38 cells, but were not accentuated further by HDAC inhibitors. We also found that HDAC1 levels decline during normal replicative senescence. Conclusion Our findings indicate that HDACs impact numerous phenotypic changes associated with cellular senescence. Reduced HDAC1 expression levels in senescent cells may be an important event in mediating the transition to a senescent phenotype.

  7. Senescent cells: New target for an old treatment?

    Science.gov (United States)

    Demaria, Marco

    2017-01-01

    Many genotoxic chemotherapies have debilitating side effects and induce cellular senescence in normal tissues. Senescent cells acquire a pro-inflammatory phenotype which contributes to local and systemic inflammation. Eliminating senescent cells reduce several short- and long-term effects of the drugs, providing a new target to reduce the toxicity of anticancer treatments.

  8. The WRKY transcription factor family and senescence in switchgrass

    Science.gov (United States)

    Background: Early aerial senescence in switchgrass (Panicum virgatum) can significantly limit biomass yields. WRKY transcription factors that can regulate senescence could be used to reprogram senescence and enhance biomass yields. Methods: All potential WRKY genes present in the version 1.0 of the...

  9. Telomere Dynamics in Immune Senescence and Exhaustion Triggered by Chronic Viral Infection.

    Science.gov (United States)

    Bellon, Marcia; Nicot, Christophe

    2017-10-05

    The progressive loss of immunological memory during aging correlates with a reduced proliferative capacity and shortened telomeres of T cells. Growing evidence suggests that this phenotype is recapitulated during chronic viral infection. The antigenic volume imposed by persistent and latent viruses exposes the immune system to unique challenges that lead to host T-cell exhaustion, characterized by impaired T-cell functions. These dysfunctional memory T cells lack telomerase, the protein capable of extending and stabilizing chromosome ends, imposing constraints on telomere dynamics. A deleterious consequence of this excessive telomere shortening is the premature induction of replicative senescence of viral-specific CD8+ memory T cells. While senescent cells are unable to expand, they can survive for extended periods of time and are more resistant to apoptotic signals. This review takes a closer look at T-cell exhaustion in chronic viruses known to cause human disease: Epstein-Barr virus (EBV), Hepatitis B/C/D virus (HBV/HCV/HDV), human herpesvirus 8 (HHV-8), human immunodeficiency virus (HIV), human T-cell leukemia virus type I (HTLV-I), human papillomavirus (HPV), herpes simplex virus-1/2(HSV-1/2), and Varicella-Zoster virus (VZV). Current literature linking T-cell exhaustion with critical telomere lengths and immune senescence are discussed. The concept that enduring antigen stimulation leads to T-cell exhaustion that favors telomere attrition and a cell fate marked by enhanced T-cell senescence appears to be a common endpoint to chronic viral infections.

  10. Demographic analysis reveals gradual senescence in the flatworm Macrostomum lignano

    Directory of Open Access Journals (Sweden)

    Braeckman Bart P

    2009-07-01

    Full Text Available Abstract Free-living flatworms ("Turbellaria" are appropriate model organisms to gain better insight into the role of stem cells in ageing and rejuvenation. Ageing research in flatworms is, however, still scarce. This is partly due to culture difficulties and the lack of a complete set of demographic data, including parameters such as median lifespan and age-specific mortality rate. In this paper, we report on the first flatworm survival analysis. We used the species Macrostomum lignano, which is an emerging model for studying the reciprocal influence between stem cells, ageing and rejuvenation. This species has a median lifespan of 205 ± 13 days (average ± standard deviation [SD] and a 90th percentile lifespan of 373 ± 32 days. The maximum lifespan, however, is more than 745 days, and the average survival curve is characterised by a long tail because a small number of individuals lives twice as long as 90% of the population. Similar to earlier observations in a wide range of animals, in M. lignano the age-specific mortality rate increases exponentially, but levels off at the oldest ages. To compare the senescence of M. lignano with that of other ageing models, we determined the mortality rate doubling time, which is 0.20 ± 0.02 years. As a result, we can conclude that M. lignano shows gradual senescence at a rate similar to the vertebrate ageing models Rattus norvegicus and Mus musculus. We argue that M. lignano is a suitable model for ageing and rejuvenation research, and especially for the role of stem cells in these processes, due to its accessible stem cell system and regeneration capacity, and the possibility of combining stem cell studies with demographic analyses.

  11. Demographic analysis reveals gradual senescence in the flatworm Macrostomum lignano.

    Science.gov (United States)

    Mouton, Stijn; Willems, Maxime; Back, Patricia; Braeckman, Bart P; Borgonie, Gaetan

    2009-07-30

    Free-living flatworms ("Turbellaria") are appropriate model organisms to gain better insight into the role of stem cells in ageing and rejuvenation. Ageing research in flatworms is, however, still scarce. This is partly due to culture difficulties and the lack of a complete set of demographic data, including parameters such as median lifespan and age-specific mortality rate. In this paper, we report on the first flatworm survival analysis. We used the species Macrostomum lignano, which is an emerging model for studying the reciprocal influence between stem cells, ageing and rejuvenation. This species has a median lifespan of 205 +/- 13 days (average +/- standard deviation [SD]) and a 90th percentile lifespan of 373 +/- 32 days. The maximum lifespan, however, is more than 745 days, and the average survival curve is characterised by a long tail because a small number of individuals lives twice as long as 90% of the population. Similar to earlier observations in a wide range of animals, in M. lignano the age-specific mortality rate increases exponentially, but levels off at the oldest ages. To compare the senescence of M. lignano with that of other ageing models, we determined the mortality rate doubling time, which is 0.20 +/- 0.02 years. As a result, we can conclude that M. lignano shows gradual senescence at a rate similar to the vertebrate ageing models Rattus norvegicus and Mus musculus. We argue that M. lignano is a suitable model for ageing and rejuvenation research, and especially for the role of stem cells in these processes, due to its accessible stem cell system and regeneration capacity, and the possibility of combining stem cell studies with demographic analyses.

  12. Senescence in the aging process [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Richard GA Faragher

    2017-07-01

    Full Text Available The accumulation of ‘senescent’ cells has long been proposed to act as an ageing mechanism. These cells display a radically altered transcriptome and degenerative phenotype compared with their growing counterparts. Tremendous progress has been made in recent years both in understanding the molecular mechanisms controlling entry into the senescent state and in the direct demonstration that senescent cells act as causal agents of mammalian ageing. The challenges now are to gain a better understanding of how the senescent cell phenotype varies between different individuals and tissues, discover how senescence predisposes to organismal frailty, and develop mechanisms by which the deleterious effects of senescent cells can be ameliorated.

  13. biomedical challenges of human senescence: a review

    African Journals Online (AJOL)

    2002-12-12

    Dec 12, 2002 ... Conclusion: Biological and clinical studies over the past century clearly reflect a better understanding of the major factors ... Understanding the biology of human senescence is a major scientific challenge for both ...... Effect of dietary restriction of ageing-an update. Rev. Clin. Gerontol. I995; 5:247-258.

  14. Senescent Nephropathy: The New Renal Syndrome

    Directory of Open Access Journals (Sweden)

    Florencia Aiello

    2017-10-01

    Full Text Available Chronic kidney disease (CKD is a condition characterized by progressive and irreversible deterioration of renal function due to the reduction of nephron mass for a period of at least three months. The prevalence of CKD is roughly 10% in the general population but increases with age, affecting more than one-third of people older than 65. Frailty is a condition usually found in elderly people, characterized by weakness, motility, and balance issues, with a declined ability to resist stressors leading to increased risks of adverse health outcomes including falls, fracture, hospitalization, institutionalization, disability, dependence, dementia, poor quality of life, and death. There is interdependence between CKD and normal ageing whereby CKD makes ageing more accelerated and pronounced (senescence, whereas senescence accelerates chronic nephropathy’s progression. Frailty status catalyzes this spiral, with renal and systemic consequences, phenomenon which can be named senescent nephropathy. In conclusion, senescent nephropathy is a new renal syndrome that should be taken into account, and we must try to handle its appearance and progression not only by applying nephron prevention measurements but also by diagnosis and treating frailty in the CKD population.

  15. The role of senescent cells in ageing

    NARCIS (Netherlands)

    Deursen, J.M.A. van

    2014-01-01

    Cellular senescence has historically been viewed as an irreversible cell-cycle arrest mechanism that acts to protect against cancer, but recent discoveries have extended its known role to complex biological processes such as development, tissue repair, ageing and age-related disorders. New insights

  16. Evasion of cell senescence in SHH medulloblastoma.

    Science.gov (United States)

    Tamayo-Orrego, Lukas; Swikert, Shannon M; Charron, Frédéric

    2016-08-17

    The mechanisms leading to brain tumor formation are poorly understood. Using Ptch1+/- mice as a medulloblastoma model, sequential mutations were found to shape tumor evolution. Initially, medulloblastoma preneoplastic lesions display loss of heterozygosity of the Ptch1 wild-type allele, an event associated with cell senescence in preneoplasia. Subsequently, p53 mutations lead to senescence evasion and progression from preneoplasia to medulloblastoma. These findings are consistent with a model where high levels of Hedgehog signaling caused by the loss of the tumor suppressor Ptch1 lead to oncogene-induced senescence and drive p53 mutations. Thus, cell senescence is an important characteristic of a subset of SHH medulloblastoma and might explain the acquisition of somatic TP53 mutations in human medulloblastoma. This mode of medulloblastoma formation contrasts with the one characterizing Li-Fraumeni patients with medulloblastoma, where TP53 germ-line mutations cause chromothriptic genomic instability and lead to mutations in Hedgehog signaling genes, which drive medulloblastoma growth. Here we discuss in detail these 2 alternative mechanisms leading to medulloblastoma tumorigenesis.

  17. Mitochondria change dynamics and morphology during grapevine leaf senescence.

    Directory of Open Access Journals (Sweden)

    Cristina Ruberti

    Full Text Available Leaf senescence is the last stage of development of an organ and is aimed to its ordered disassembly and nutrient reallocation. Whereas chlorophyll gradually degrades during senescence in leaves, mitochondria need to maintain active to sustain the energy demands of senescing cells. Here we analysed the motility and morphology of mitochondria in different stages of senescence in leaves of grapevine (Vitis vinifera, by stably expressing a GFP (green fluorescent protein reporter targeted to these organelles. Results show that mitochondria were less dynamic and markedly changed morphology during senescence, passing from the elongated, branched structures found in mature leaves to enlarged and sparse organelles in senescent leaves. Progression of senescence in leaves was not synchronous, since changes in mitochondria from stomata were delayed. Mitochondrial morphology was also analysed in grapevine cell cultures. Mitochondria from cells at the end of their growth curve resembled those from senescing leaves, suggesting that cell cultures might represent a useful model system for senescence. Additionally, senescence-associated mitochondrial changes were observed in plants treated with high concentrations of cytokinins. Overall, morphology and dynamics of mitochondria might represent a reliable senescence marker for plant cells.

  18. Multiple climate drivers accelerate Arctic plant community senescence

    Science.gov (United States)

    Livensperger, C.; Steltzer, H.; Wallenstein, M. D.; Weintraub, M. N.

    2015-12-01

    Alteration of seasonal phenology cues due to climate change has led to changes in the onset and duration of the growing season. While photoperiod often acts as an ultimate control on phenological events, recent studies have shown that environmental cues such as temperature and soil water content can modify the direction and rate of senescence processes. Warmer temperatures have resulted in an observed trend towards delayed senescence across temperate latitudes. However, Arctic regions are characterized by extreme seasonality and rapidly decreasing photoperiod, and consequently senescence may not shift as climate warms. We monitored the timing of Arctic plant community senescence for three years under the framework of an experimental manipulation that altered seasonal phenological cues through warming and earlier snowmelt. Alternative models of senescence were tested to determine if microclimate (air temperature, soil temperature, and soil moisture) or start of season phenology affect the timing and rate of community senescence. We found that all three microclimate predictors contributed to explaining variation in timing of senescence, suggesting that photoperiod is not the sole control on timing of senescence in Arctic plant communities. Rather, increased air and soil temperatures along with drier soil conditions, led to acceleration in the onset of senescence at a community level. Our data suggest that (1) multiple climate drivers predict timing of plant community senescence, and (2) climate change could result in a shorter peak season due to earlier onset of senescence, which would decrease the potential carbon uptake in moist acidic tundra.

  19. Molecular bases of cellular senescence: Hayflick phenomenon 50 years later

    Directory of Open Access Journals (Sweden)

    Patrycja Sosińska

    2016-03-01

    Full Text Available Normal human somatic cells have strictly limited proliferative capacity and reach a state of senescence when it becomes exhausted. It is believed that senescence is a response to extensive and irreparable DNA injury, localized in telomeric and/or non-telomeric regions of the genome. Main cause of this damage is oxidative stress, increasing due to deteriorated function of mitochondria. Senescent cells accumulate in tissues during aging, which is causatively linked with the development of various pathologies in elderly individuals, including cancer. This paper, prepared exactly 50 years after Leonard Hayflick’s discovery of the relationship between cellular senescence and organismal aging is aimed at presenting the current knowledge about molecular determinants of senescence, with particular emphasis paid to the role of oxidative stress, effectors of senescence at the level of cell cycle, markers of this phenomenon, and the effect of senescent cells on the development of certain age-related diseases.

  20. Use of NAP gene to manipulate leaf senescence in plants

    Science.gov (United States)

    Gan, Susheng; Guo, Yongfeng

    2013-04-16

    The present invention discloses transgenic plants having an altered level of NAP protein compared to that of a non-transgenic plant, where the transgenic plants display an altered leaf senescence phenotype relative to a non-transgenic plant, as well as mutant plants comprising an inactivated NAP gene, where mutant plants display a delayed leaf senescence phenotype compared to that of a non-mutant plant. The present invention also discloses methods for delaying leaf senescence in a plant, as well as methods of making a mutant plant having a decreased level of NAP protein compared to that of a non-mutant plant, where the mutant plant displays a delayed leaf senescence phenotype relative to a non-mutant plant. Methods for causing precocious leaf senescence or promoting leaf senescence in a plant are also disclosed. Also disclosed are methods of identifying a candidate plant suitable for breeding that displays a delayed leaf senescence and/or enhanced yield phenotype.

  1. SIRT1 overexpression antagonizes cellular senescence with activated ERK/S6k1 signaling in human diploid fibroblasts.

    Directory of Open Access Journals (Sweden)

    Jing Huang

    Full Text Available Sir2, a NAD-dependent deacetylase, modulates lifespan in yeasts, worms and flies. The SIRT1, mammalian homologue of Sir2, regulates signaling for favoring survival in stress. But whether SIRT1 has the function to influence cell viability and senescence under non-stressed conditions in human diploid fibroblasts is far from unknown. Our data showed that enforced SIRT1 expression promoted cell proliferation and antagonized cellular senescence with the characteristic features of delayed Senescence-Associated beta-galactosidase (SA-beta-gal staining, reduced Senescence-Associated Heterochromatic Foci (SAHF formation and G1 phase arrest, increased cell growth rate and extended cellular lifespan in human fibroblasts, while dominant-negative SIRT1 allele (H363Y did not significantly affect cell growth and senescence but displayed a bit decreased lifespan. Western blot results showed that SIRT1 reduced the expression of p16(INK4A and promoted phosphorylation of Rb. Our data also exposed that overexpression of SIRT1 was accompanied by enhanced activation of ERK and S6K1 signaling. These effects were mimicked in both WI38 cells and 2BS cells by concentration-dependent resveratrol, a SIRT1 activator. It was noted that treatment of SIRT1-.transfected cells with Rapamycin, a mTOR inhibitor, reduced the phosphorylation of S6K1 and the expression of Id1, implying that SIRT1-induced phosphorylation of S6K1 may be partly for the decreased expression of p16(INK4A and promoted phosphorylation of Rb in 2BS. It was also observed that the expression of SIRT1 and phosphorylation of ERK and S6K1 was declined in senescent 2BS. These findings suggested that SIRT1-promoted cell proliferation and antagonized cellular senescence in human diploid fibroblasts may be, in part, via the activation of ERK/ S6K1 signaling.

  2. Sirtuins, Cell Senescence, and Vascular Aging.

    Science.gov (United States)

    Kida, Yujiro; Goligorsky, Michael S

    2016-05-01

    The sirtuins (SIRTs) constitute a class of proteins with nicotinamide adenine dinucleotide-dependent deacetylase or adenosine diphosphate-ribosyltransferase activity. Seven SIRT family members have been identified in mammals, from SIRT1, the best studied for its role in vascular aging, to SIRT7. SIRT1 and SIRT2 are localized in the nucleus and cytoplasm. SIRT3, SIRT4, and SIRT5 are mitochondrial, and SIRT6 and SIRT7 are nuclear. Extensive studies have clearly revealed that SIRT proteins regulate diverse cell functions and responses to stressors. Vascular aging involves the aging process (senescence) of endothelial and vascular smooth muscle cells. Two types of cell senescence have been identified: (1) replicative senescence with telomere attrition; and (2) stress-induced premature senescence without telomere involvement. Both types of senescence induce vascular cell growth arrest and loss of vascular homeostasis, and contribute to the initiation and progression of cardiovascular diseases. Previous mechanistic studies have revealed in detail that SIRT1, SIRT3, and SIRT6 show protective functions against vascular aging, and definite vascular function of other SIRTs is under investigation. Thus, direct SIRT modulation and nicotinamide adenine dinucleotide stimulation of SIRT are promising candidates for cardiovascular disease therapy. A small number of pilot studies have been conducted to assess SIRT modulation in humans. These clinical studies have not yet provided convincing evidence that SIRT proteins alleviate morbidity and mortality in patients with cardiovascular diseases. The outcomes of multiple ongoing clinical trials are awaited to define the efficacy of SIRT modulators and SIRT activators in cardiovascular diseases, along with the potential adverse effects of chronic SIRT modulation. Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

  3. Autolysosome biogenesis and developmental senescence are regulated by both Spns1 and v-ATPase.

    Science.gov (United States)

    Sasaki, Tomoyuki; Lian, Shanshan; Khan, Alam; Llop, Jesse R; Samuelson, Andrew V; Chen, Wenbiao; Klionsky, Daniel J; Kishi, Shuji

    2017-02-01

    Spns1 (Spinster homolog 1 [Drosophila]) in vertebrates, as well as Spin (Spinster) in Drosophila, is a hypothetical lysosomal H+-carbohydrate transporter, which functions at a late stage of macroautophagy (hereafter autophagy). The Spin/Spns1 defect induces aberrant autolysosome formation that leads to developmental senescence in the embryonic stage and premature aging symptoms in adulthood. However, the molecular mechanism by which loss of Spin/Spns1 leads to the specific pathogenesis remains to be elucidated. Using chemical, genetic and CRISPR/Cas9-mediated genome-editing approaches in zebrafish, we investigated and determined a mechanism that suppresses embryonic senescence as well as autolysosomal impairment mediated by Spns1 deficiency. Unexpectedly, we found that a concurrent disruption of the vacuolar-type H+-ATPase (v-ATPase) subunit gene, atp6v0ca (ATPase, H+ transporting, lysosomal, V0 subunit ca) led to suppression of the senescence induced by the Spns1 defect, whereas the sole loss of Atp6v0ca led to senescent embryos similar to the single spns1 mutation. Moreover, we discovered that the combined stable defect seen in the presence of both the spns1 and atp6v0ca mutant genes still subsequently induced premature autophagosome-lysosome fusion marked by insufficient acidity, while extending developmental life span, compared with the solely mutated spns1 defect. Our data suggest that Spns1 and the v-ATPase orchestrate proper autolysosomal biogenesis with optimal acidification that is critically linked to developmental senescence and survival.

  4. Stress-induced premature senescence or stress-induced senescence-like phenotype: one in vivo reality, two possible definitions?

    Science.gov (United States)

    Toussaint, Olivier; Dumont, Patrick; Remacle, José; Dierick, Jean-François; Pascal, Thierry; Frippiat, Christophe; Magalhaes, Joao Pedro; Zdanov, Stéphanie; Chainiaux, Florence

    2002-01-29

    No consensus exists so far on the definition of cellular senescence. The narrowest definition of senescence is irreversible growth arrest triggered by telomere shortening counting cell generations (definition 1). Other authors gave an enlarged functional definition encompassing any kind of irreversible arrest of proliferative cell types induced by damaging agents or cell cycle deregulations after overexpression of proto-oncogenes (definition 2). As stress increases, the proportion of cells in "stress-induced premature senescence-like phenotype" according to definition 1 or "stress-induced premature senescence," according to definition 2, should increase when a culture reaches growth arrest, and the proportion of cells that reached telomere-dependent replicative senescence due to the end-replication problem should decrease. Stress-induced premature senescence-like phenotype and telomere-dependent replicatively senescent cells share basic similarities such as irreversible growth arrest and resistance to apoptosis, which may appear through different pathways. Irreversible growth arrest after exposure to oxidative stress and generation of DNA damage could be as efficient in avoiding immortalisation as "telomere-dependent" replicative senescence. Probabilities are higher that the senescent cells (according to definition 2) appearing in vivo are in stress-induced premature senescence rather than in telomere-dependent replicative senescence. Examples are given suggesting these cells affect in vivo tissue (patho)physiology and aging.

  5. Hepatocellular carcinoma repression by TNFα-mediated synergistic lethal effect of mitosis defect-induced senescence and cell death sensitization.

    Science.gov (United States)

    Li, Dan; Fu, Jing; Du, Min; Zhang, Haibin; Li, Lu; Cen, Jin; Li, Weiyun; Chen, Xiaotao; Lin, Yunfei; Conway, Edward M; Pikarsky, Eli; Wang, Hongyan; Pan, Guoyu; Ji, Yuan; Wang, Hong-Yang; Hui, Lijian

    2016-10-01

    Hepatocellular carcinoma (HCC) is a cancer lacking effective therapies. Several measures have been proposed to treat HCCs, such as senescence induction, mitotic inhibition, and cell death promotion. However, data from other cancers suggest that single use of these approaches may not be effective. Here, by genetic targeting of Survivin, an inhibitor of apoptosis protein (IAP) that plays dual roles in mitosis and cell survival, we identified a tumor necrosis factor alpha (TNFα)-mediated synergistic lethal effect between senescence and apoptosis sensitization in malignant HCCs. Survivin deficiency results in mitosis defect-associated senescence in HCC cells, which triggers local inflammation and increased TNFα. Survivin inactivation also sensitizes HCC cells to TNFα-triggered cell death, which leads to marked HCC regression. Based on these findings, we designed a combination treatment using mitosis inhibitor and proapoptosis compounds. This treatment recapitulates the therapeutic effect of Survivin deletion and effectively eliminates HCCs, thus representing a potential strategy for HCC therapy. Survivin ablation dramatically suppresses human and mouse HCCs by triggering senescence-associated TNFα and sensitizing HCC cells to TNFα-induced cell death. Combined use of mitotic inhibitor and second mitochondrial-derived activator of caspases mimetic can induce senescence-associated TNFα and enhance TNFα-induced cell death and synergistically eliminate HCC. (Hepatology 2016;64:1105-1120). © 2016 The Authors. (Hepatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.

  6. Gene expression profiles deciphering leaf senescence variation between early- and late-senescence cotton lines.

    Directory of Open Access Journals (Sweden)

    Xiangqiang Kong

    Full Text Available Leaf senescence varies greatly among genotypes of cotton (Gossypium hirsutium L, possibly due to the different expression of senescence-related genes. To determine genes involved in leaf senescence, we performed genome-wide transcriptional profiling of the main-stem leaves of an early- (K1 and a late-senescence (K2 cotton line at 110 day after planting (DAP using the Solexa technology. The profiling analysis indicated that 1132 genes were up-regulated and 455 genes down-regulated in K1 compared with K2 at 110 DAP. The Solexa data were highly consistent with, and thus were validated by those from real-time quantitative PCR (RT-PCR. Most of the genes related to photosynthesis, anabolism of carbohydrates and other biomolecules were down-regulated, but those for catabolism of proteins, nucleic acids, lipids and nutrient recycling were mostly up-regulated in K1 compared with K2. Fifty-one differently expressed hormone-related genes were identified, of which 5 ethylene, 3 brassinosteroid (BR, 5 JA, 18 auxin, 8 GA and 1 ABA related genes were up-regulated in K1 compared with K2, indicating that these hormone-related genes might play crucial roles in early senescence of K1 leaves. Many differently expressed transcription factor (TF genes were identified and 11 NAC and 8 WRKY TF genes were up-regulated in K1 compared with K2, suggesting that TF genes, especially NAC and WRKY genes were involved in early senescence of K1 leaves. Genotypic variation in leaf senescence was attributed to differently expressed genes, particularly hormone-related and TF genes.

  7. Detection of Oncogene-Induced Senescence In Vivo.

    Science.gov (United States)

    Baek, Kwan-Hyuck; Ryeom, Sandra

    2017-01-01

    Oncogene-induced senescence or OIS is defined as a permanent state of proliferative arrest resulting from an activating oncogenic-lesion. OIS has been suggested to function as a cancer cell intrinsic mechanism to restrain tumor growth and has been implicated as a key mechanism preventing the progression of certain premalignant lesions in genetically engineered mouse models of cancer. The senescent phenotype can be defined by two criteria that include cell cycle arrest and resistance to mitogens and oncogenic transformation. While the phenotype and properties of senescent cells in vitro are well described, the morphological characteristics defining senescence in vivo have been controversial with no specific marker that definitively proves a senescent state. Indeed, many of the published in vivo markers to identify and characterize senescence in an organism are unreliable and often times have been found to be nonspecific. However, the use of multiple markers is accepted as confirmation of senescence in vivo. Here, we describe protocols for some of the most commonly used indicators of senescence in oncogenic Kras-induced lung adenomas including the detection of senescence-associated beta-galactosidase, expression of the tumor suppressor p19 ARF , the presence of senescence-associated heterochromatin foci, and in vivo BrdU uptake to confirm cell cycle arrest.

  8. Cellular senescence drives age-dependent hepatic steatosis.

    Science.gov (United States)

    Ogrodnik, Mikolaj; Miwa, Satomi; Tchkonia, Tamar; Tiniakos, Dina; Wilson, Caroline L; Lahat, Albert; Day, Christoper P; Burt, Alastair; Palmer, Allyson; Anstee, Quentin M; Grellscheid, Sushma Nagaraja; Hoeijmakers, Jan H J; Barnhoorn, Sander; Mann, Derek A; Bird, Thomas G; Vermeij, Wilbert P; Kirkland, James L; Passos, João F; von Zglinicki, Thomas; Jurk, Diana

    2017-06-13

    The incidence of non-alcoholic fatty liver disease (NAFLD) increases with age. Cellular senescence refers to a state of irreversible cell-cycle arrest combined with the secretion of proinflammatory cytokines and mitochondrial dysfunction. Senescent cells contribute to age-related tissue degeneration. Here we show that the accumulation of senescent cells promotes hepatic fat accumulation and steatosis. We report a close correlation between hepatic fat accumulation and markers of hepatocyte senescence. The elimination of senescent cells by suicide gene-meditated ablation of p16Ink4a-expressing senescent cells in INK-ATTAC mice or by treatment with a combination of the senolytic drugs dasatinib and quercetin (D+Q) reduces overall hepatic steatosis. Conversely, inducing hepatocyte senescence promotes fat accumulation in vitro and in vivo. Mechanistically, we show that mitochondria in senescent cells lose the ability to metabolize fatty acids efficiently. Our study demonstrates that cellular senescence drives hepatic steatosis and elimination of senescent cells may be a novel therapeutic strategy to reduce steatosis.

  9. The mitochondrial genome in aging and senescence.

    Science.gov (United States)

    Lauri, Andrea; Pompilio, Giulio; Capogrossi, Maurizio C

    2014-11-01

    Aging is characterized by a progressive decline in organism functions due to the impairment of all organs. The deterioration of both proliferative tissues in liver, skin and the vascular system, as well as of largely post-mitotic organs, such as the heart and brain could be attributed at least in part to cell senescence. In this review we examine the role of mitochondrial dysfunction and mtDNA mutations in cell aging and senescence. Specifically, we address how p53 and telomerase reverse transcriptase (TERT) activity switch their roles from cytoprotective to detrimental and also examine the role of microRNAs in cell aging. The proposed role of Reactive Oxygen Species (ROS), both as mutating agents and as signalling molecules, underlying these processes is also described. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Telomeres, replicative senescence and human ageing.

    Science.gov (United States)

    Kipling, D

    2001-02-28

    Ageing concerns the extracellular environment and cells that are either post-mitotic or capable of division during life. Primary human cells have a finite division capacity in culture before they enter a state of viable cell cycle arrest termed senescence. Cell division occurs during life in many tissues, either as part of normal tissue function or in response to tissue damage. The accumulation of cells at the end of their replicative lifespan in the elderly might contribute to aged tissue either because of a reduced ability to undergo proliferation or because of the known altered gene-expression patterns of senescent cells. This has been illustrated experimentally using a transgenic telomerase-negative mouse, which shows some premature ageing phenotypes. The mechanism whereby cells count divisions uses the gradual erosion of the ends of chromosomes (telomeres) with cell division caused by the repression of the telomere-maintenance enzyme telomerase in most human cells. Telomere erosion ultimately triggers replicative senescence in many cell types; this can be prevented experimentally by forcibly expressing telomerase. This extends the lifespan of normal human cells and those from progeroid syndromes such as Werner's. Telomere-driven senescence did not evolve to cause ageing, but is instead a by-product of a system devised to provide a tumour-suppression function, a concept that fits well with evolutionary arguments regarding trade-offs between somatic maintenance and reproduction. Work in the future will focus on the development of new animal models to critically address the quantitative significance of this ageing mechanism.

  11. Markers of T Cell Senescence in Humans

    Directory of Open Access Journals (Sweden)

    Weili Xu

    2017-08-01

    Full Text Available Many countries are facing the aging of their population, and many more will face a similar obstacle in the near future, which could be a burden to many healthcare systems. Increased susceptibility to infections, cardiovascular and neurodegenerative disease, cancer as well as reduced efficacy of vaccination are important matters for researchers in the field of aging. As older adults show higher prevalence for a variety of diseases, this also implies higher risk of complications, including nosocomial infections, slower recovery and sequels that may reduce the autonomy and overall quality of life of older adults. The age-related effects on the immune system termed as “immunosenescence” can be exemplified by the reported hypo-responsiveness to influenza vaccination of the elderly. T cells, which belong to the adaptive arm of the immune system, have been extensively studied and the knowledge gathered enables a better understanding of how the immune system may be affected after acute/chronic infections and how this matters in the long run. In this review, we will focus on T cells and discuss the surface and molecular markers that are associated with T cell senescence. We will also look at the implications that senescent T cells could have on human health and diseases. Finally, we will discuss the benefits of having these markers for investigators and the future work that is needed to advance the field of T cell senescence markers.

  12. Caveolin-1, cellular senescence and pulmonary emphysema

    Science.gov (United States)

    Volonte, Daniela; Galbiati, Ferruccio

    2009-01-01

    Caveolae are vesicular invaginations of the plasma membrane. Caveolin-1 is the structural protein component of caveolae. Caveolin-1 participates in signal transduction processes by acting as a scaffolding protein that concentrates, organizes and functional regulates signaling molecules within caveolar membranes. Cigarette smoke, a source of oxidants, is an environmental hazard that causes pulmonary emphysema. Recently, we reported that the development of cigarette smoking-induced pulmonary emphysema was inhibited in caveolin-1 null mice, which do not express caveolin-1. We demonstrated that lack of caveolin-1 expression in lung fibroblasts dramatically inhibited premature senescence induced by oxidants contained in cigarette smoke. Mechanistically, we uncovered that premature senescence of lung fibroblasts induced by oxidative stress occurred through activation of an ataxia telangiectasia-mutated (ATM)/p53-depedent pathway following sequestration of the catalytic subunit of protein phosphatase 2A (PP2A-C), an inhibitor of ATM, by caveolin-1 into caveolar membranes. We propose caveolin-1 as a key player of a novel signaling pathway that links cigarette smoke to premature senescence of lung fibroblasts and development of pulmonary emphysema. PMID:20157570

  13. Chronic induction of senescence marker in gamma-irradiation mice

    Energy Technology Data Exchange (ETDEWEB)

    Seol, Min A; Jung, U Hee; Eom, Hyeon Soo; Kim, Seol Hwa; Park, Hae Ran; Jo, Sung Kee [Korea Atomic Energy Research Institute, Jeongeup (Korea, Republic of)

    2011-10-15

    Aging or senescence occurs at organ level as well as cell level. Most senescent cells are characterized by morphological changes into large, flat, and multinucleated phenotypes. Also senescence cells show a stable and long-term loss of proliferative capacity although viability and metabolic activity are maintained. The in vivo senescence or aging has been studied using various animal models. However, until now, the mechanisms of senescence or aging in vivo. Ionizing radiation (IR) is a well-known inducer of oxidative stress and DNA damage, which is one of the important causes of aging process. Therefore, in this study, we wanted to find out whether IR can induce or accelerate aging process in mice by investigating the long-term effects of IR on the various senescence markers in the tissues

  14. Emerging roles of extracellular vesicles in cellular senescence and aging.

    Science.gov (United States)

    Takasugi, Masaki

    2018-02-01

    Cellular senescence is a cellular program that prevents the proliferation of cells at risk of neoplastic transformation. On the other hand, age-related accumulation of senescent cells promotes aging at least partially due to the senescence-associated secretory phenotype, whereby cells secrete high levels of inflammatory cytokines, chemokines, and matrix metalloproteinases. Emerging evidence, however, indicates that extracellular vesicles (EVs) are important mediators of the effects of senescent cells on their microenvironment. Senescent cells secrete more EphA2 and DNA via EVs, which can promote cancer cell proliferation and inflammation, respectively. Extracellular vesicles secreted from DNA-damaged cells can also affect telomere regulation. Furthermore, it has now become clear that EVs actually play important roles in many aspects of aging. This review is intended to summarize these recent progresses, with emphasis on relationships between cellular senescence and EVs. © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  15. Cellular senescence in normal and premature lung aging.

    Science.gov (United States)

    Bartling, B

    2013-10-01

    The incidence of chronic respiratory diseases (e.g., chronic obstructive pulmonary disease, COPD) and interstitial lung diseases (e.g., pneumonia and lung fibrosis) increases with age. In addition to immune senescence, the accumulation of senescent cells directly in lung tissue might play a critical role in the increased prevalence of these pulmonary diseases. In the last couple of years, detailed studies have identified the presence of senescent cells in the aging lung and in diseased lungs of patients with COPD and lung fibrosis. Cellular senescence has been shown for epithelial cells of bronchi and alveoli as well as mesenchymal and vascular cells. Known risk factors for pulmonary diseases (cigarette smoke, air pollutions, bacterial infections, etc.) were identified in experimental studies as being possible mediators in the development of cellular senescence. The present findings indicate the importance of cellular senescence in normal lung aging and in premature aging of the lung in patients with COPD, lung fibrosis, and probably other respiratory diseases.

  16. Contrasting patterns of cytokinins between years in senescing aspen leaves

    Czech Academy of Sciences Publication Activity Database

    Edlund, E.; Novák, Ondřej; Karady, M.; Ljung, K.; Jansson, S.

    2017-01-01

    Roč. 40, č. 5 (2017), s. 622-634 ISSN 0140-7791 R&D Projects: GA ČR GA14-34792S; GA MŠk(CZ) LO1204 Institutional support: RVO:61389030 Keywords : leaf senescence * arabidopsis-thaliana * autumn senescence * gene-expression * populus-trichocarpa * mass-spectrometry * tobacco plant s * translocation * biosynthesis * identification * autumn senescence * gene expression * metabolism * Populus tremula * profiling Subject RIV: CB - Analytical Chemistry, Separation Impact factor: 6.173, year: 2016

  17. Delayed leaf senescence induces extreme drought tolerance in crop plants

    OpenAIRE

    Rivero, Rosa; Peleg, Zvi; Szczerba, Mark; Tumimbang, Ellen; Jauregui, Rosa N; Liu, Li; Blumwald, Eduardo

    2009-01-01

    Drought, the most prominent threat to agricultural production worldwide, accelerates leaf senescence, leading to a decrease in canopy size, loss in photosynthesis and reduced yields. On the basis of the assumption that senescence is a type of cell death program that could be inappropriately activated during drought, we hypothesized that it may be possible to enhance drought tolerance by delaying drought-induced leaf senescence through the stress-induced synthesis of cytokinins. We generated m...

  18. Cellular senescence in the aging and diseased kidney.

    Science.gov (United States)

    Valentijn, F A; Falke, L L; Nguyen, T Q; Goldschmeding, Roel

    2017-12-19

    The program of cellular senescence is involved in both the G1 and G2 phase of the cell cycle, limiting G1/S and G2/M progression respectively, and resulting in prolonged cell cycle arrest. Cellular senescence is involved in normal wound healing. However, multiple organs display increased senescent cell numbers both during natural aging and after injury, suggesting that senescent cells can have beneficial as well as detrimental effects in organismal aging and disease. Also in the kidney, senescent cells accumulate in various compartments with advancing age and renal disease. In experimental studies, forced apoptosis induction through the clearance of senescent cells leads to better preservation of kidney function during aging. Recent groundbreaking studies demonstrate that senescent cell depletion through INK-ATTAC transgene-mediated or cell-penetrating FOXO4-DRI peptide induced forced apoptosis, reduced age-associated damage and dysfunction in multiple organs, in particular the kidney, and increased performance and lifespan. Senescence is also involved in oncology and therapeutic depletion of senescent cells by senolytic drugs has been studied in experimental and human cancers. Although studies with senolytic drugs in models of kidney injury are lacking, their dose limiting side effects on other organs suggest that targeted delivery might be needed for successful application of senolytic drugs for treatment of kidney disease. In this review, we discuss (i) current understanding of the mechanisms and associated pathways of senescence, (ii) evidence of senescence occurrence and causality with organ injury, and (iii) therapeutic strategies for senescence depletion (senotherapy) including targeting, all in the context of renal aging and disease.

  19. The WRKY transcription factor family and senescence in switchgrass.

    Science.gov (United States)

    Rinerson, Charles I; Scully, Erin D; Palmer, Nathan A; Donze-Reiner, Teresa; Rabara, Roel C; Tripathi, Prateek; Shen, Qingxi J; Sattler, Scott E; Rohila, Jai S; Sarath, Gautam; Rushton, Paul J

    2015-11-09

    Early aerial senescence in switchgrass (Panicum virgatum) can significantly limit biomass yields. WRKY transcription factors that can regulate senescence could be used to reprogram senescence and enhance biomass yields. All potential WRKY genes present in the version 1.0 of the switchgrass genome were identified and curated using manual and bioinformatic methods. Expression profiles of WRKY genes in switchgrass flag leaf RNA-Seq datasets were analyzed using clustering and network analyses tools to identify both WRKY and WRKY-associated gene co-expression networks during leaf development and senescence onset. We identified 240 switchgrass WRKY genes including members of the RW5 and RW6 families of resistance proteins. Weighted gene co-expression network analysis of the flag leaf transcriptomes across development readily separated clusters of co-expressed genes into thirteen modules. A visualization highlighted separation of modules associated with the early and senescence-onset phases of flag leaf growth. The senescence-associated module contained 3000 genes including 23 WRKYs. Putative promoter regions of senescence-associated WRKY genes contained several cis-element-like sequences suggestive of responsiveness to both senescence and stress signaling pathways. A phylogenetic comparison of senescence-associated WRKY genes from switchgrass flag leaf with senescence-associated WRKY genes from other plants revealed notable hotspots in Group I, IIb, and IIe of the phylogenetic tree. We have identified and named 240 WRKY genes in the switchgrass genome. Twenty three of these genes show elevated mRNA levels during the onset of flag leaf senescence. Eleven of the WRKY genes were found in hotspots of related senescence-associated genes from multiple species and thus represent promising targets for future switchgrass genetic improvement. Overall, individual WRKY gene expression profiles could be readily linked to developmental stages of flag leaves.

  20. Senescent cells: SASPected drivers of age-related pathologies.

    Science.gov (United States)

    Ovadya, Yossi; Krizhanovsky, Valery

    2014-12-01

    The progression of physiological ageing is driven by intracellular aberrations including telomere attrition, genomic instability, epigenetic alterations and loss of proteostasis. These in turn damage cells and compromise their functionality. Cellular senescence, a stable irreversible cell-cycle arrest, is elicited in damaged cells and prevents their propagation in the organism. Under normal conditions, senescent cells recruit the immune system which facilitates their removal from tissues. Nevertheless, during ageing, tissue-residing senescent cells tend to accumulate, and might negatively impact their microenvironment via profound secretory phenotype with pro-inflammatory characteristics, termed senescence-associated secretory phenotype (SASP). Indeed, senescent cells are mostly abundant at sites of age-related pathologies, including degenerative disorders and malignancies. Interestingly, studies on progeroid mice indicate that selective elimination of senescent cells can delay age-related deterioration. This suggests that chronic inflammation induced by senescent cells might be a main driver of these pathologies. Importantly, senescent cells accumulate as a result of deficient immune surveillance, and their removal is increased upon the use of immune stimulatory agents. Insights into mechanisms of senescence surveillance could be combined with current approaches for cancer immunotherapy to propose new preventive and therapeutic strategies for age-related diseases.

  1. Senescence rates in patients with end-stage renal disease

    DEFF Research Database (Denmark)

    Koopman, J J E; Rozing, M P; Kramer, Ada

    2011-01-01

    The most frequently used model to describe the exponential increase in mortality rate over age is the Gompertz equation. Logarithmically transformed, the equation conforms to a straight line, of which the slope has been interpreted as the rate of senescence. Earlier, we proposed the derivative...... function of the Gompertz equation as a superior descriptor of senescence rate. Here, we tested both measures of the rate of senescence in a population of patients with end-stage renal disease. It is clinical dogma that patients on dialysis experience accelerated senescence, whereas those with a functional...

  2. Senescent intervertebral disc cells exhibit perturbed matrix homeostasis phenotype.

    Science.gov (United States)

    Ngo, Kevin; Patil, Prashanti; McGowan, Sara J; Niedernhofer, Laura J; Robbins, Paul D; Kang, James; Sowa, Gwendolyn; Vo, Nam

    2017-09-01

    Aging greatly increases the risk for intervertebral disc degeneration (IDD) as a result of proteoglycan loss due to reduced synthesis and enhanced degradation of the disc matrix proteoglycan (PG). How disc matrix PG homeostasis becomes perturbed with age is not known. The goal of this study is to determine whether cellular senescence is a source of this perturbation. We demonstrated that disc cellular senescence is dramatically increased in the DNA repair-deficient Ercc1(-/Δ) mouse model of human progeria. In these accelerated aging mice, increased disc cellular senescence is closely associated with the rapid loss of disc PG. We also directly examine PG homeostasis in oxidative damage-induced senescent human cells using an in vitro cell culture model system. Senescence of human disc cells treated with hydrogen peroxide was confirmed by growth arrest, senescence-associated β-galactosidase activity, γH2AX foci, and acquisition of senescence-associated secretory phenotype. Senescent human disc cells also exhibited perturbed matrix PG homeostasis as evidenced by their decreased capacity to synthesize new matrix PG and enhanced degradation of aggrecan, a major matrix PG. of the disc. Our in vivo and in vitro findings altogether suggest that disc cellular senescence is an important driver of PG matrix homeostatic perturbation and PG loss. Published by Elsevier B.V.

  3. Transcriptome profiling of developmental leaf senescence in sorghum (Sorghum bicolor).

    Science.gov (United States)

    Wu, Xiao-Yuan; Hu, Wei-Juan; Luo, Hong; Xia, Yan; Zhao, Yi; Wang, Li-Dong; Zhang, Li-Min; Luo, Jing-Chu; Jing, Hai-Chun

    2016-11-01

    This piece of the submission is being sent via mail. Leaf senescence is essential for the nutrient economy of crops and is executed by so-called senescence-associated genes (SAGs). Here we explored the monocot C4 model crop Sorghum bicolor for a holistic picture of SAG profiles by RNA-seq. Leaf samples were collected at four stages during developmental senescence, and in total, 3396 SAGs were identified, predominantly enriched in GO categories of metabolic processes and catalytic activities. These genes were enriched in 13 KEGG pathways, wherein flavonoid and phenylpropanoid biosynthesis and phenylalanine metabolism were overrepresented. Seven regions on Chromosomes 1, 4, 5 and 7 contained SAG 'hotspots' of duplicated genes or members of cupin superfamily involved in manganese ion binding and nutrient reservoir activity. Forty-eight expression clusters were identified, and the candidate orthologues of the known important senescence transcription factors such as ORE1, EIN3 and WRKY53 showed "SAG" expression patterns, implicating their possible roles in regulating sorghum leaf senescence. Comparison of developmental senescence with salt- and dark- induced senescence allowed for the identification of 507 common SAGs, 1996 developmental specific SAGs as well as 176 potential markers for monitoring senescence in sorghum. Taken together, these data provide valuable resources for comparative genomics analyses of leaf senescence and potential targets for the manipulation of genetic improvement of Sorghum bicolor.

  4. The evolution of senescence in the tree of life

    DEFF Research Database (Denmark)

    Salguero-Gómez, Roberto

    The existing theories on the evolution of senescence assume that senescence is inevitable in all organisms. However, recent studies have shown that this is not necessarily true. A better understanding of senescence and its underlying mechanisms could have far-reaching consequences for conservation...... and eco-evolutionary research. This book is the first to offer interdisciplinary perspectives on the evolution of senescence in many species, setting the stage for further developments. It brings together new insights from a wide range of scientific fields and cutting-edge research done on a multitude...

  5. Senescence and apoptosis: dueling or complementary cell fates?

    Science.gov (United States)

    Childs, Bennett G; Baker, Darren J; Kirkland, James L; Campisi, Judith; van Deursen, Jan M

    2014-01-01

    In response to a variety of stresses, mammalian cells undergo a persistent proliferative arrest known as cellular senescence. Many senescence-inducing stressors are potentially oncogenic, strengthening the notion that senescence evolved alongside apoptosis to suppress tumorigenesis. In contrast to apoptosis, senescent cells are stably viable and have the potential to influence neighboring cells through secreted soluble factors, which are collectively known as the senescence-associated secretory phenotype (SASP). However, the SASP has been associated with structural and functional tissue and organ deterioration and may even have tumor-promoting effects, raising the interesting evolutionary question of why apoptosis failed to outcompete senescence as a superior cell fate option. Here, we discuss the advantages that the senescence program may have over apoptosis as a tumor protective mechanism, as well as non-neoplastic functions that may have contributed to its evolution. We also review emerging evidence for the idea that senescent cells are present transiently early in life and are largely beneficial for development, regeneration and homeostasis, and only in advanced age do senescent cells accumulate to an organism’s detriment. PMID:25312810

  6. Muscle fibers from senescent mice retain excitation-contraction coupling properties in culture.

    Science.gov (United States)

    Wang, Zhong-Min; Zheng, Zhenlin; Messi, María L; Delbono, Osvaldo

    2007-01-01

    In the present study, we test the hypothesis that mouse skeletal muscle in culture retains the fundamental properties of excitation-sarcoplasmic reticulum Ca(2+) release coupling reported for young-adult (3-4 mo) and senescent (22-23) mice. Dissociated flexor digitorum brevis (FDB) muscles from young-adult and senescent mice were cultured for 7 d in a serum-free medium. During this period, the overall morphology of cultured fibers resembled that exhibited by acutely dissociated cells. In addition, survival analysis revealed that more than 70% of the fibers from both young and old mice remained suitable for electrophysiological studies during this same culture period. Charge movement and intracellular Ca(2+) recordings in FDB fibers, voltage clamped in the whole cell configuration of the patch-clamp technique, reproduced the maximal values, and voltage dependence similarly displayed by acutely dissociated cells for both parameters in young-adult and senescent mice. The analysis of the dihydropyridine receptor by immunoblots confirmed, in the culture system, the age-dependent decrease in the expression of this protein. In conclusion, FDB fibers from young-adult and old mice retain the excitation-contraction coupling phenotype during the course of a week in serum-free medium culture.

  7. MicroRNA-22 increases senescence and activates cardiac fibroblasts in the aging heart.

    Science.gov (United States)

    Jazbutyte, Virginija; Fiedler, Jan; Kneitz, Susanne; Galuppo, Paolo; Just, Annette; Holzmann, Angelika; Bauersachs, Johann; Thum, Thomas

    2013-06-01

    MicroRNAs (miRs) are small non- coding RNA molecules controlling a plethora of biological processes such as development, cellular survival and senescence. We here determined miRs differentially regulated during cardiac postnatal development and aging. Cardiac function, morphology and miR expression profiles were determined in neonatal, 4 weeks, 6 months and 19 months old normotensive male healthy C57/Bl6N mice. MiR-22 was most prominently upregulated during cardiac aging. Cardiac expression of its bioinformatically predicted target mimecan (osteoglycin, OGN) was gradually decreased with advanced age. Luciferase reporter assays validated mimecan as a bona fide miR-22 target. Both, miR-22 and its target mimecan were co- expressed in cardiac fibroblasts and smooth muscle cells. Functionally, miR-22 overexpression induced cellular senescence and promoted migratory activity of cardiac fibroblasts. Small interference RNA-mediated silencing of mimecan in cardiac fibroblasts mimicked the miR-22-mediated effects. Rescue experiments revealed that the effects of miR-22 on cardiac fibroblasts were only partially mediated by mimecan. In conclusion, miR-22 upregulation in the aging heart contributed at least partly to accelerated cardiac fibroblast senescence and increased migratory activity. Our results suggest an involvement of miR-22 in age-associated cardiac changes, such as cardiac fibrosis.

  8. Age-related variation in reproductive traits in the wandering albatross: evidence for terminal improvement following senescence.

    Science.gov (United States)

    Froy, Hannah; Phillips, Richard A; Wood, Andrew G; Nussey, Daniel H; Lewis, Sue

    2013-05-01

    The processes driving age-related variation in demographic rates are central to understanding population and evolutionary ecology. An increasing number of studies in wild vertebrates find evidence for improvements in reproductive performance traits in early adulthood, followed by senescent declines in later life. However, life history theory predicts that reproductive investment should increase with age as future survival prospects diminish, and that raised reproductive investment may have associated survival costs. These non-mutually exclusive processes both predict an increase in breeding performance at the terminal breeding attempt. Here, we use a 30-year study of wandering albatrosses (Diomedea exulans) to disentangle the processes underpinning age-related variation in reproduction. Whilst highlighting the importance of breeding experience, we reveal senescent declines in performance are followed by a striking increase in breeding success and a key parental investment trait at the final breeding attempt. © 2013 Blackwell Publishing Ltd/CNRS.

  9. Strigolactone Regulates Leaf Senescence in Concert with Ethylene in Arabidopsis.

    Science.gov (United States)

    Ueda, Hiroaki; Kusaba, Makoto

    2015-09-01

    Leaf senescence is not a passive degenerative process; it represents a process of nutrient relocation, in which materials are salvaged for growth at a later stage or to produce the next generation. Leaf senescence is regulated by various factors, such as darkness, stress, aging, and phytohormones. Strigolactone is a recently identified phytohormone, and it has multiple functions in plant development, including repression of branching. Although strigolactone is implicated in the regulation of leaf senescence, little is known about its molecular mechanism of action. In this study, strigolactone biosynthesis mutant strains of Arabidopsis (Arabidopsis thaliana) showed a delayed senescence phenotype during dark incubation. The strigolactone biosynthesis genes MORE AXIALLY GROWTH3 (MAX3) and MAX4 were drastically induced during dark incubation and treatment with the senescence-promoting phytohormone ethylene, suggesting that strigolactone is synthesized in the leaf during leaf senescence. This hypothesis was confirmed by a grafting experiment using max4 as the stock and Columbia-0 as the scion, in which the leaves from the Columbia-0 scion senesced earlier than max4 stock leaves. Dark incubation induced the synthesis of ethylene independent of strigolactone. Strigolactone biosynthesis mutants showed a delayed senescence phenotype during ethylene treatment in the light. Furthermore, leaf senescence was strongly accelerated by the application of strigolactone in the presence of ethylene and not by strigolactone alone. These observations suggest that strigolactone promotes leaf senescence by enhancing the action of ethylene. Thus, dark-induced senescence is regulated by a two-step mechanism: induction of ethylene synthesis and consequent induction of strigolactone synthesis in the leaf. © 2015 American Society of Plant Biologists. All Rights Reserved.

  10. Dehydration induced loss of photosynthesis in Arabidopsis leaves during senescence is accompanied by the reversible enhancement in the activity of cell wall β-glucosidase.

    Science.gov (United States)

    Patro, Lichita; Mohapatra, Pranab Kishor; Biswal, Udaya Chand; Biswal, Basanti

    2014-08-01

    The physiology of loss of photosynthetic production of sugar and the consequent cellular sugar reprogramming during senescence of leaves experiencing environmental stress largely remains unclear. We have shown that leaf senescence in Arabidopsis thaliana causes a significant reduction in the rate of oxygen evolution and net photosynthetic rate (Pn). The decline in photosynthesis is further aggravated by dehydration. During dehydration, primary photochemical reaction of thylakoids and net photosynthesis decrease in parallel with the increase in water deficit. Senescence induced loss in photosynthesis is accompanied by a significant increase in the activity of cell wall hydrolyzing enzyme such as β-glucosidase associated with cell wall catabolism. The activity of this enzyme is further enhanced when the senescing leaves experience dehydration stress. It is possible that both senescence and stress separately or in combination result in the loss in photosynthesis which could be a signal for an enhancement in the activity of β-glucosidase that breaks down cell wall polysaccharides to sugar to sustain respiration for metabolic activities of plants experiencing stress. Thus dehydration response of cell wall hydrolases of senescing leaves is considered as plants' strategy to have cell wall polysaccharides as an alternative energy source for completion of energy requiring senescence process, stress survival and maintenance of recovery potential of energy deficit cells in the background of loss in photosynthesis. Withdrawal of stress (rehydration) distinctly exhibits recovery of photosynthesis and suppression of enzyme activity. Retention of the signaling for sugar reprogramming through breakdown of cell wall polysaccharides in the senescing leaves exposed to severe drought stress suggests that senescing leaves like mature ones possess potential for stress recovery. The precise mechanism of stress adaptation of senescing leaves is yet to be known. A significant

  11. Telomere Dynamics in Immune Senescence and Exhaustion Triggered by Chronic Viral Infection

    Directory of Open Access Journals (Sweden)

    Marcia Bellon

    2017-10-01

    Full Text Available The progressive loss of immunological memory during aging correlates with a reduced proliferative capacity and shortened telomeres of T cells. Growing evidence suggests that this phenotype is recapitulated during chronic viral infection. The antigenic volume imposed by persistent and latent viruses exposes the immune system to unique challenges that lead to host T-cell exhaustion, characterized by impaired T-cell functions. These dysfunctional memory T cells lack telomerase, the protein capable of extending and stabilizing chromosome ends, imposing constraints on telomere dynamics. A deleterious consequence of this excessive telomere shortening is the premature induction of replicative senescence of viral-specific CD8+ memory T cells. While senescent cells are unable to expand, they can survive for extended periods of time and are more resistant to apoptotic signals. This review takes a closer look at T-cell exhaustion in chronic viruses known to cause human disease: Epstein–Barr virus (EBV, Hepatitis B/C/D virus (HBV/HCV/HDV, human herpesvirus 8 (HHV-8, human immunodeficiency virus (HIV, human T-cell leukemia virus type I (HTLV-I, human papillomavirus (HPV, herpes simplex virus-1/2(HSV-1/2, and Varicella–Zoster virus (VZV. Current literature linking T-cell exhaustion with critical telomere lengths and immune senescence are discussed. The concept that enduring antigen stimulation leads to T-cell exhaustion that favors telomere attrition and a cell fate marked by enhanced T-cell senescence appears to be a common endpoint to chronic viral infections.

  12. Pathways of aging: comparative analysis of gene signatures in replicative senescence and stress induced premature senescence.

    Science.gov (United States)

    Kural, Kamil C; Tandon, Neetu; Skoblov, Mikhail; Kel-Margoulis, Olga V; Baranova, Ancha V

    2016-12-28

    In culturing normal diploid cells, senescence may either happen naturally, in the form of replicative senescence, or it may be a consequence of external challenges such as oxidative stress. Here we present a comparative analysis aimed at reconstruction of molecular cascades specific for replicative (RS) and stressinduced senescence (SIPS) in human fibroblasts. An involvement of caspase-3/keratin-18 pathway and serine/threonine kinase Aurora A/ MDM2 pathway was shared between RS and SIPS. Moreover, stromelysin/MMP3 and N-acetylglucosaminyltransferase enzyme MGAT1, which initiates the synthesis of hybrid and complex Nglycans, were identified as key orchestrating components in RS and SIPS, respectively. In RS only, Aurora-B driven cell cycle signaling was deregulated in concert with the suppression of anabolic branches of the fatty acids and estrogen metabolism. In SIPS, Aurora-B signaling is deprioritized, and the synthetic branches of cholesterol metabolism are upregulated, rather than downregulated. Moreover, in SIPS, proteasome/ubiquitin ligase pathways of protein degradation dominate the regulatory landscape. This picture indicates that SIPS proceeds in cells that are actively fighting stress which facilitates premature senescence while failing to completely activate the orderly program of RS. The promoters of genes differentially expressed in either RS or SIPS are unusually enriched by the binding sites for homeobox family proteins, with particular emphasis on HMX1, IRX2, HDX and HOXC13. Additionally, we identified Iroquois Homeobox 2 (IRX2) as a master regulator for the secretion of SPP1-encoded osteopontin, a stromal driver for tumor growth that is overexpressed by both RS and SIPS fibroblasts. The latter supports the hypothesis that senescence-specific de-repression of SPP1 aids in SIPS-dependent stromal activation. Reanalysis of previously published experimental data is cost-effective approach for extraction of additional insignts into the functioning of

  13. Cellular and molecular aspects of quinoa leaf senescence.

    Science.gov (United States)

    López-Fernández, María Paula; Burrieza, Hernán Pablo; Rizzo, Axel Joel; Martínez-Tosar, Leandro Julián; Maldonado, Sara

    2015-09-01

    During leaf senescence, degradation of chloroplasts precede to changes in nuclei and other cytoplasmic organelles, RuBisCO stability is progressively lost, grana lose their structure, plastidial DNA becomes distorted and degraded, the number of plastoglobuli increases and abundant senescence-associated vesicles containing electronically dense particles emerge from chloroplasts pouring their content into the central vacuole. This study examines quinoa leaf tissues during development and senescence using a range of well-established markers of programmed cell death (PCD), including: morphological changes in nuclei and chloroplasts, degradation of RuBisCO, changes in chlorophyll content, DNA degradation, variations in ploidy levels, and changes in nuclease profiles. TUNEL reaction and DNA electrophoresis demonstrated that DNA fragmentation in nuclei occurs at early senescence, which correlates with induction of specific nucleases. During senescence, metabolic activity is high and nuclei endoreduplicate, peaking at 4C. At this time, TEM images showed some healthy nuclei with condensed chromatin and nucleoli. We have found that DNA fragmentation, induction of senescence-associated nucleases and endoreduplication take place during leaf senescence. This provides a starting point for further research aiming to identify key genes involved in the senescence of quinoa leaves. Published by Elsevier Ireland Ltd.

  14. Global Reorganization of the Nuclear Landscape in Senescent Cells

    Directory of Open Access Journals (Sweden)

    Tamir Chandra

    2015-02-01

    Full Text Available Cellular senescence has been implicated in tumor suppression, development, and aging and is accompanied by large-scale chromatin rearrangements, forming senescence-associated heterochromatic foci (SAHF. However, how the chromatin is reorganized during SAHF formation is poorly understood. Furthermore, heterochromatin formation in senescence appears to contrast with loss of heterochromatin in Hutchinson-Gilford progeria. We mapped architectural changes in genome organization in cellular senescence using Hi-C. Unexpectedly, we find a dramatic sequence- and lamin-dependent loss of local interactions in heterochromatin. This change in local connectivity resolves the paradox of opposing chromatin changes in senescence and progeria. In addition, we observe a senescence-specific spatial clustering of heterochromatic regions, suggesting a unique second step required for SAHF formation. Comparison of embryonic stem cells (ESCs, somatic cells, and senescent cells shows a unidirectional loss in local chromatin connectivity, suggesting that senescence is an endpoint of the continuous nuclear remodelling process during differentiation.

  15. Senescence-associated intrinsic mechanisms of osteoblast dysfunctions

    DEFF Research Database (Denmark)

    Kassem, Moustapha; Trinquier, Anne Marie-Pierre Emilie

    2011-01-01

    factors, and intrinsic mechanisms caused by the osteoblast cellular senescence. The aim of this review is to provide a summary of the intrinsic senescence mechanisms affecting osteoblastic functions and how they can be targeted in order to abolish age-related osteoblastic dysfunction and bone loss...

  16. A role for p53 in selenium-induced senescence

    Science.gov (United States)

    The tumor suppressor p53 and the ataxia-telangiectasia mutated (ATM) kinase play important roles in the senescence response to oncogene activation and DNA damage. We have previously shown that selenium-containing compounds can activate an ATM-dependent senescence response in MRC-5 normal fibroblasts...

  17. Molecular and Biochemical Characterization of Postharvest Senescence in Broccoli

    Science.gov (United States)

    Page, Tania; Griffiths, Gareth; Buchanan-Wollaston, Vicky

    2001-01-01

    Postharvest senescence in broccoli (Brassica oleracea L. var Italica) florets results in phenotypic changes similar to those seen in developmental leaf senescence. To compare these two processes in more detail, we investigated molecular and biochemical changes in broccoli florets stored at two different temperatures after harvest. We found that storage at cooler temperatures delayed the symptoms of senescence at both the biochemical and gene expression levels. Changes in key biochemical components (lipids, protein, and chlorophyll) and in gene expression patterns occurred in the harvested tissue well before any visible signs of senescence were detected. Using previously identified senescence-enhanced genes and also newly isolated, differentially expressed genes, we found that the majority of these showed a similar enhancement of expression in postharvest broccoli as in developmental leaf senescence. At the biochemical level, a rapid loss of membrane fatty acids was detected after harvest, when stored at room temperature. However, there was no corresponding increase in levels of lipid peroxidation products. This, together with an increased expression of protective antioxidant genes, indicated that, in the initial stages of postharvest senescence, an orderly dismantling of the cellular constituents occurs, using the available lipid as an energy source. Postharvest changes in broccoli florets, therefore, show many similarities to the processes of developmental leaf senescence. PMID:11161029

  18. Exercise Prevents Diet-Induced Cellular Senescence in Adipose Tissue

    NARCIS (Netherlands)

    Schafer, M.J.; White, T.A.; Evans, G.; Tonne, J.M.; Verzosa, G.C.; Stout, M.B.; Mazula, D.L.; Palmer, A.K.; Baker, D.J.; Jensen, M.D.; Torbenson, M.S.; Miller, J.D.; Ikeda, Y.; Tchkonia, T.; Deursen, J.M.A. van; Kirkland, J.L.; LeBrasseur, N.K.

    2016-01-01

    Considerable evidence implicates cellular senescence in the biology of aging and chronic disease. Diet and exercise are determinants of healthy aging; however, the extent to which they affect the behavior and accretion of senescent cells within distinct tissues is not clear. Here we tested the

  19. Regulation of leaf senescence in Arabidopsis : isolation and characterisation

    NARCIS (Netherlands)

    Jing, Hai-Chun

    2005-01-01

    The effect of ethylene exposure time on leaf senescence was studied in Arabidopsis accessions Ler-0, Col-0 and Ws-0 and in several old (onset of leaf death) mutants representing different genetic loci. Leaf senescence was observed in 24-day-old plants exposed to ethylene for 3 to 16 days. For

  20. Therapeutic interventions for aging : The case of cellular senescence

    NARCIS (Netherlands)

    Soto-Gamez, Abel; Demaria, Marco

    Organismal aging is a multifactorial process characterized by the onset of degenerative conditions and cancer. One of the key drivers of aging is cellular senescence, a state of irreversible growth arrest induced by many pro-tumorigenic stresses. Senescent cells accumulate late in life and at sites

  1. Cellular senescence and tumor promotion : Is aging the key?

    NARCIS (Netherlands)

    Loaiza, Natalia; Demaria, Marco

    The senescence response is a potent tumor suppressor mechanism characterized by an irreversible growth arrest in response to potentially oncogenic signals to prevent the proliferation of damaged cells. Late in life, some of the features of senescent cells seem to mediate the development of

  2. Dissecting the metabolic role of mitochondria during developmental leaf senescence

    NARCIS (Netherlands)

    Chrobok, Daria; Law, Simon R.; Brouwer, Bas; Lindén, Pernilla; Ziolkowska, Agnieszka; Liebsch, Daniela; Narsai, Reena; Szal, Bozena; Moritz, Thomas; Rouhier, Nicolas; Whelan, James; Gardeström, Per; Keech, Olivier

    2016-01-01

    The functions of mitochondria during leaf senescence, a type of programmed cell death aimed at the massive retrieval of nutrients from the senescing organ to the rest of the plant, remain elusive. Here, combining experimental and analytical approaches, we showed that mitochondrial integrity in

  3. Leaf senescence in alstroemeria : regulation by phytochrome gibberellins and cytokinins

    NARCIS (Netherlands)

    Kappers, I.F.

    1998-01-01

    Leaf senescence in plants is a regulated process influenced by light as well as phytohormones. In the present study the putative role of the phytohormones cytokinins and gibberellins as mediators for the light signal on leaf senescence in alstroemeria was studied. It was found that low

  4. Cytokinin control of sequential leaf senescence in tobacco

    Energy Technology Data Exchange (ETDEWEB)

    Singh, S. (Univ. of Saskatchewan, Saskatoon (Canada)); Letham, D.S.; Parker, C.W. (Australian National Univ., Canberra (Australia))

    1990-05-01

    Exogenously applied cytokinins (especially dihydrozeatin) retarded senescence of leaf disks, detached and intact leaves of tobacco. The cytokinin complex in tobacco leaves of various maturities was characterized by radioimmunoassay. Zeatin was the major base whereas zeatin riboside was identified as the main riboside in both young (green) and senescing leaves. The basal, senescing leaves had lower levels of both cytokinin bases and ribosides. Exogenous applications of dihydrozeatin and zeatin to detached tobacco leaves delayed leaf senescence and elevated cytokinin base levels. These differences in endogenous levels of active cytokins in senescent and non-senescent leaves may be involved in the regulation of sequential leaf senescence in tobacco. There was no appreciable difference in either translocation or metabolism of xylem supplied tritium-labelled dihydrozeatin riboside between upper green and lower senescing leaves. The apical, green leaves (and not the basal, yellowing leaves) exhibited incorporation of ({sup 14}C)adenine into zeatin. The differing cytokinin levels in leaves of various maturity levels may be due to difference in cytokinin biosynthetic capacity.

  5. Cellular senescence drives age-dependent hepatic steatosis

    NARCIS (Netherlands)

    Ogrodnik, M. (Mikolaj); Miwa, S. (Satomi); Tchkonia, T. (Tamar); Tiniakos, D. (Dina); Wilson, C.L. (Caroline L.); Lahat, A. (Albert); Day, C.P. (Christoper P.); A.D. Burt (Alastair); Palmer, A. (Allyson); Anstee, Q.M. (Quentin M.); Grellscheid, S.N. (Sushma Nagaraja); J.H.J. Hoeijmakers; S. Barnhoorn (Sander); Mann, D.A. (Derek A.); Bird, T.G. (Thomas G.); W.P. Vermeij (Wilbert); Kirkland, J.L. (James L.); Passos, J.F. (João F.); Von Zglinicki, T. (Thomas); Jurk, D. (Diana)

    2017-01-01

    textabstractThe incidence of non-alcoholic fatty liver disease (NAFLD) increases with age. Cellular senescence refers to a state of irreversible cell-cycle arrest combined with the secretion of proinflammatory cytokines and mitochondrial dysfunction. Senescent cells contribute to age-related tissue

  6. Pathways from senescence to melanoma: focus on MITF sumoylation.

    Science.gov (United States)

    Leclerc, J; Ballotti, R; Bertolotto, C

    2017-11-30

    Cutaneous melanoma is a deadly skin cancer that originates from melanocytes. The development of cutaneous melanoma involves a complex interaction between environmental factors, mainly ultraviolet radiation from sunlight, and genetic alterations. Melanoma can also occur from a pre-existing nevus, a benign lesion formed from melanocytes harboring oncogenic mutations that trigger proliferative arrest and senescence entry. Senescence is a potent barrier against tumor progression. As such, the acquisition of mutations that suppress senescence and promote cell division is mandatory for cancer development. This topic appears central to melanoma development because, in humans, several somatic and germline mutations are related to the control of cellular senescence and proliferative activity. Consequently, primary melanoma can be viewed as a paradigm of senescence evasion. In support of this notion, a sumoylation-defective germline mutation in microphthalmia-associated transcription factor (MITF), a master regulator of melanocyte homeostasis, is associated with the development of melanoma. Interestingly, this MITF variant has also been recently reported to negatively impact the program of senescence. This article reviews the genetic alterations that have been shown to be involved in melanoma and that alter the process of senescence to favor melanoma development. Then, the transcription factor MITF and its sumoylation-defective mutant are described. How sumoylation misregulation can change MITF activity and impact the process of senescence is discussed. Finally, the contribution of such information to the development of anti-malignant melanoma strategies is evaluated.

  7. Proteomic responses of switchgrass and prairie cordgrass to senescence

    Science.gov (United States)

    Senescence in biofuel grasses is a critical issue because early senescence decreases potential biomass production by limiting aerial growth and development. 2-Dimensional,differential in-gel electrophoresis (2D-DIGE) followed by mass spectrometry of selected protein spots was used to evaluate differ...

  8. Cellular senescence and tumor promotion: Is aging the key?

    Science.gov (United States)

    Loaiza, Natalia; Demaria, Marco

    2016-04-01

    The senescence response is a potent tumor suppressor mechanism characterized by an irreversible growth arrest in response to potentially oncogenic signals to prevent the proliferation of damaged cells. Late in life, some of the features of senescent cells seem to mediate the development of age-related pathologies, including cancer. In the present review, we present a summary of the current knowledge regarding the causes, effector pathways and cellular features of senescence. We also discuss how the senescence response, initially a tumor suppressor mechanism, turns into a tumor promoter apparently as a consequence of aging. We argue that three age-related phenomena--senescence-associated secretory phenotype (SASP) dysregulation, decline in the immune system function and genomic instability--could contribute, independently or synergistically, to deteriorate the efficacy of the senescence response in stopping cancer. As a consequence, senescent cells could be considered premalignant cells, and targeting senescent cells could be a preventive and therapeutic strategy against cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Delay of Iris flower senescence by protease inhibitors

    NARCIS (Netherlands)

    Pak, C.; Doorn, van W.G.

    2005-01-01

    asterisk inside a circle sign Visible senescence of the flag tepals in Iris x hollandica (cv. Blue Magic) was preceded by a large increase in endoprotease activity. Just before visible senescence about half of total endoprotease activity was apparently due to cysteine proteases, somewhat less than

  10. To grow old: regulatory role of ethylene in senescence

    Science.gov (United States)

    Senescence is the final stage in the development of an organ or whole plant. It is a genetically programmed process controlled by both developmental and environmental signals. Age-related processes and signals underlie the onset of senescence in both organs (leaf, flower, and fruit) and the whole ...

  11. Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity

    Science.gov (United States)

    Palmer, Allyson K.; Tchkonia, Tamara; LeBrasseur, Nathan K.; Chini, Eduardo N.; Xu, Ming

    2015-01-01

    Cellular senescence is a fundamental aging mechanism that has been implicated in many age-related diseases and is a significant cause of tissue dysfunction. Accumulation of senescent cells occurs during aging and is also seen in the context of obesity and diabetes. Senescent cells may play a role in type 2 diabetes pathogenesis through direct impact on pancreatic β-cell function, senescence-associated secretory phenotype (SASP)-mediated tissue damage, and involvement in adipose tissue dysfunction. In turn, metabolic and signaling changes seen in diabetes, such as high circulating glucose, altered lipid metabolism, and growth hormone axis perturbations, can promote senescent cell formation. Thus, senescent cells might be part of a pathogenic loop in diabetes, as both a cause and consequence of metabolic changes and tissue damage. Therapeutic targeting of a basic aging mechanism such as cellular senescence may have a large impact on disease pathogenesis and could be more effective in preventing the progression of diabetes complications than currently available therapies that have limited impact on already existing tissue damage. Therefore, senescent cells and the SASP represent significant opportunities for advancement in the prevention and treatment of type 2 diabetes and its complications. PMID:26106186

  12. Roles of Apoptosis and Cellular Senescence in Cancer and Aging.

    Science.gov (United States)

    Cerella, Claudia; Grandjenette, Cindy; Dicato, Mario; Diederich, Marc

    2016-01-01

    Cancer and aging are two similar processes representing the final outcome of timedependent accumulation of various irreversible dysfunctions, mainly caused by stress-induced DNA and cellular damages. Apoptosis and senescence are two types of cellular response to damages that are altered in both cancer and aging, albeit through different mechanisms. Carcinogenesis is associated with a progressive reduction in the ability of the cells to trigger apoptosis and senescence. In contrast, in aging tissues, there is an increased accumulation of senescent cells, and the nature of apoptosis deregulation varies depending on the tissue. Thus, the prevailing model suggests that apoptosis and cellular senescence function as two essential tumor-suppressor mechanisms, ensuring the health of the individual during early and reproductive stages of life, but become detrimental and promote aging later in life. The recent discovery that various anticancer agents, including canonical inducers of apoptosis, act also as inducers of cellular senescence indicates that pro-senescence strategies may have applications in cancer prevention therapy. Therefore, dissection of the mechanisms mediating the delicate balance between apoptosis and cellular senescence will be beneficial in the therapeutic exploitation of both processes in the development of future anticancer and anti-aging strategies, including minimizing the side effects of such strategies. Here, we provide an overview of the roles of apoptosis and cellular senescence in cancer and aging.

  13. Senescence and programmed cell death : substance or semantics?

    NARCIS (Netherlands)

    Doorn, van W.G.; Woltering, E.J.

    2004-01-01

    The terms senescence and programmed cell death (PCD) have led to some confusion. Senescence as visibly observed in, for example, leaf yellowing and petal wilting, has often been taken to be synonymous with the programmed death of the constituent cells. PCD also obviously refers to cells, which show

  14. CLCA2 as a p53-Inducible Senescence Mediator

    Directory of Open Access Journals (Sweden)

    Chizu Tanikawa

    2012-02-01

    Full Text Available p53 is a tumor suppressor gene that is frequently mutated in multiple cancer tissues. Activated p53 protein regulates its downstream genes and subsequently inhibits malignant transformation by inducing cell cycle arrest, apoptosis, DNA repair, and senescence. However, genes involved in the p53-mediated senescence pathway are not yet fully elucidated. Through the screening of two genome-wide expression profile data sets, one for cells in which exogenous p53 was introduced and the other for senescent fibroblasts, we have identified chloride channel accessory 2 (CLCA2 as a p53-inducible senescence-associated gene. CLCA2 was remarkably induced by replicative senescence as well as oxidative stress in a p53-dependent manner. We also found that ectopically expressed CLCA2 induced cellular senescence, and the down-regulation of CLCA2 by small interfering RNA caused inhibition of oxidative stress-induced senescence. Interestingly, the reduced expression of CLCA2 was frequently observed in various kinds of cancers including prostate cancer, whereas its expression was not affected in precancerous prostatic intraepithelial neoplasia. Thus, our findings suggest a crucial role of p53/CLCA2-mediated senescence induction as a barrier for malignant transformation.

  15. Evasion of Cell Senescence Leads to Medulloblastoma Progression

    Directory of Open Access Journals (Sweden)

    Lukas Tamayo-Orrego

    2016-03-01

    Full Text Available How brain tumors progress from precancerous lesions to advanced cancers is not well understood. Using Ptch1+/− mice to study medulloblastoma progression, we found that Ptch1 loss of heterozygosity (LOH is an early event that is associated with high levels of cell senescence in preneoplasia. In contrast, advanced tumors have evaded senescence. Remarkably, we discovered that the majority of advanced medulloblastomas display either spontaneous, somatic p53 mutations or Cdkn2a locus inactivation. Consistent with senescence evasion, these p53 mutations are always subsequent to Ptch1 LOH. Introduction of a p53 mutation prevents senescence, accelerates tumor formation, and increases medulloblastoma incidence. Altogether, our results show that evasion of senescence associated with Ptch1 LOH allows progression to advanced tumors.

  16. Senescence and aging: Causes, consequences, and therapeutic avenues.

    Science.gov (United States)

    McHugh, Domhnall; Gil, Jesús

    2018-01-02

    Aging is the major risk factor for cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. Although we are far from understanding the biological basis of aging, research suggests that targeting the aging process itself could ameliorate many age-related pathologies. Senescence is a cellular response characterized by a stable growth arrest and other phenotypic alterations that include a proinflammatory secretome. Senescence plays roles in normal development, maintains tissue homeostasis, and limits tumor progression. However, senescence has also been implicated as a major cause of age-related disease. In this regard, recent experimental evidence has shown that the genetic or pharmacological ablation of senescent cells extends life span and improves health span. Here, we review the cellular and molecular links between cellular senescence and aging and discuss the novel therapeutic avenues that this connection opens. © 2018 McHugh and Gil.

  17. Secretome Analysis of Human Primary Fibroblasts Undergoing Senescence

    DEFF Research Database (Denmark)

    Rogowska-Wrzesinska, Adelina; Micutkova, Lucia; Diener, Thomas

    Introduction Cultures of diploid human fibroblasts can replicate only a finite number of times; rapid proliferation is followed by decline in replicative frequency and finally cells become senescent and are incapable of further proliferation. Senescencent cells display altered growth, morphology......-degrading. In this study we use proteomic tools to characterise the secretome of young and senescent fibroblasts.   Methods Three independent preparations of primary human foreskin fibroblasts were grown to senescence. Young, rapidly proliferating cells at passage 11 and cells from passage 28 displaying senescent...... spectrometry; peptide count was used to estimate protein abundance.   Results 2DGE based analysis of secretion profiles of young and senescent cells derived from the same cell lineage revealed a number of protein spots differentially expressed. We have observed an increased secretion of matrix...

  18. Emerging roles of lncRNAs in senescence

    DEFF Research Database (Denmark)

    Montes Resano, Marta; Lund, Anders H

    2016-01-01

    Cellular senescence is a complex stress response that leads to an irreversible state of cell growth arrest. Senescence may be induced by different stimuli such as telomere shortening, DNA damage or oncogenic insult among others. Senescent cells are metabolically highly active producing a wealth...... of cytokines and chemokines that depending on the context may have a beneficial or deleterious impact on the organism. Senescence is considered a tightly regulated stress response that is largely governed by the p53/p21 and p16/Rb pathways. Many molecules have been identified as regulators of these two...... networks, such as transcription factors, chromatin modifiers and recently, non-coding RNAs. The expression level of several long non-coding RNAs is affected during different types of senescence, however, which of these are important for the biological function remains poorly understood. We review here our...

  19. Senescence and aging: the critical roles of p53.

    Science.gov (United States)

    Rufini, A; Tucci, P; Celardo, I; Melino, G

    2013-10-24

    p53 functions as a transcription factor involved in cell-cycle control, DNA repair, apoptosis and cellular stress responses. However, besides inducing cell growth arrest and apoptosis, p53 activation also modulates cellular senescence and organismal aging. Senescence is an irreversible cell-cycle arrest that has a crucial role both in aging and as a robust physiological antitumor response, which counteracts oncogenic insults. Therefore, via the regulation of senescence, p53 contributes to tumor growth suppression, in a manner strictly dependent by its expression and cellular context. In this review, we focus on the recent advances on the contribution of p53 to cellular senescence and its implication for cancer therapy, and we will discuss p53's impact on animal lifespan. Moreover, we describe p53-mediated regulation of several physiological pathways that could mediate its role in both senescence and aging.

  20. Cell senescence: role in aging and age-related diseases.

    Science.gov (United States)

    Campisi, Judith; Robert, Ladislas

    2014-01-01

    Cell senescence is one of the major paradigms of aging research. It started with the demonstration by L. Hayflick of the limited number of divisions by normal, nontransformed cells, not shown by transformed malignant cells, this processes being largely regulated by the telomere-telomerase system. A complete renewal of this discipline came from the demonstration that cells can enter senescence at any time by an anti-oncogene-triggered pathway, enabling them to escape malignancy. The senescent cell became a major actor of the aging process, among others, by the acquisition of the senescence-associated secretory phenotype. This chapter is devoted to the regulatory process involved in the acquisition of the senescent cell phenotype and its role in organismal aging.

  1. Calculating the Rate of Senescence From Mortality Data

    DEFF Research Database (Denmark)

    Koopman, Jacob J E; Rozing, Maarten P; Kramer, Anneke

    2016-01-01

    The rate of senescence can be inferred from the acceleration by which mortality rates increase over age. Such a senescence rate is generally estimated from parameters of a mathematical model fitted to these mortality rates. However, such models have limitations and underlying assumptions. Notably......, they do not fit mortality rates at young and old ages. Therefore, we developed a method to calculate senescence rates from the acceleration of mortality directly without modeling the mortality rates. We applied the different methods to age group-specific mortality data from the European Renal Association......-European Dialysis and Transplant Association Registry, including patients with end-stage renal disease on dialysis, who are known to suffer from increased senescence rates (n = 302,455), and patients with a functioning kidney transplant (n = 74,490). From age 20 to 70, senescence rates were comparable when...

  2. Control of senescence in rumex leaf discs by gibberellic Acid.

    Science.gov (United States)

    Goldthwaite, J J; Laetsch, W M

    1968-11-01

    The kinetics of chlorophyll and protein decomposition and the effect of gibberellic acid (GA) were examined in senescing leaf discs of Rumex crispus and R. obtusifolius. Loss of Rumex total chlorophyll proceeds at a slow rate for about 2 days followed by a period of rapid logarithmic decline. Chlorophyll b is lost at a slightly faster rate than chlorophyll a during senescence in discs as well as in situ. GA causes a complete cessation of net chlorophyll and protein degradation for several days in Rumex, in contrast to the incomplete senescence inhibition generally observed with cytokinins. GA is fully effective even when added at the middle of the logarithmic phase of chlorophyll loss. Senescence inhibition by GA is apparently gradually reversed upon GA removal. The cytokinins, kinetin and 6-benzylaminopurine, were also effective in Rumex leaf discs, indicating that the senescence retarding effect was not restricted to the gibberellins.

  3. Type 1 interferons contribute to the clearance of senescent cell.

    Science.gov (United States)

    Katlinskaya, Yuliya V; Carbone, Christopher J; Yu, Qiujing; Fuchs, Serge Y

    2015-01-01

    The major known function of cytokines that belong to type I interferons (IFN, including IFNα and IFNβ) is to mount the defense against viruses. This function also protects the genetic information of host cells from alterations in the genome elicited by some of these viruses. Furthermore, recent studies demonstrated that IFN also restrict proliferation of damaged cells by inducing cell senescence. Here we investigated the subsequent role of IFN in elimination of the senescent cells. Our studies demonstrate that endogenous IFN produced by already senescent cells contribute to increased expression of the natural killer (NK) receptor ligands, including MIC-A and ULBP2. Furthermore, neutralization of endogenous IFN or genetic ablation of its receptor chain IFNAR1 compromises the recognition of senescent cells and their clearance in vitro and in vivo. We discuss the role of IFN in protecting the multi-cellular host from accumulation of damaged senescent cells and potential significance of this mechanism in human cancers.

  4. Arabidopsis CPR5 is a senescence-regulatory gene with pleiotropic functions as predicted by the evolutionary theory of senescence

    NARCIS (Netherlands)

    Jing, Hai-Chun; Anderson, Lisa; Sturre, Marcel J. G.; Hille, Jacques; Dijkwel, Paul P.

    2007-01-01

    Arabidopsis CPR5 is a senescence-regulatory gene with pleiotropic functions as predicted by the evolutionary theory of senescence Hai-Chun Jing1,2, Lisa Anderson3, Marcel J.G. Sturre1, Jacques Hille1 and Paul P. Dijkwel1,* 1Molecular Biology of Plants, Groningen Biomolecular Sciences and

  5. Senescent mouse cells fail to overtly regulate the HIRA histone chaperone and do not form robust Senescence Associated Heterochromatin Foci

    Directory of Open Access Journals (Sweden)

    Enders Greg H

    2010-06-01

    Full Text Available Abstract Background Cellular senescence is a permanent growth arrest that occurs in response to cellular stressors, such as telomere shortening or activation of oncogenes. Although the process of senescence growth arrest is somewhat conserved between mouse and human cells, there are some critical differences in the molecular pathways of senescence between these two species. Recent studies in human fibroblasts have defined a cell signaling pathway that is initiated by repression of a specific Wnt ligand, Wnt2. This, in turn, activates a histone chaperone HIRA, and culminates in formation of specialized punctate domains of facultative heterochromatin, called Senescence-Associated Heterochromatin Foci (SAHF, that are enriched in the histone variant, macroH2A. SAHF are thought to repress expression of proliferation-promoting genes, thereby contributing to senescence-associated proliferation arrest. We asked whether this Wnt2-HIRA-SAHF pathway is conserved in mouse fibroblasts. Results We show that mouse embryo fibroblasts (MEFs and mouse skin fibroblasts, do not form robust punctate SAHF in response to an activated Ras oncogene or shortened telomeres. However, senescent MEFs do exhibit elevated levels of macroH2A staining throughout the nucleus as a whole. Consistent with their failure to fully activate the SAHF assembly pathway, the Wnt2-HIRA signaling axis is not overtly regulated between proliferating and senescent mouse cells. Conclusions In addition to the previously defined differences between mouse and human cells in the mechanisms and phenotypes associated with senescence, we conclude that senescent mouse and human fibroblasts also differ at the level of chromatin and the signaling pathways used to regulate chromatin. These differences between human and mouse senescence may contribute to the increased propensity of mouse fibroblasts (and perhaps other mouse cell types to become immortalized and transformed, compared to human cells.

  6. Parallel evolution of senescence in annual fishes in response to extrinsic mortality.

    Science.gov (United States)

    Tozzini, Eva Terzibasi; Dorn, Alexander; Ng'oma, Enoch; Polačik, Matej; Blažek, Radim; Reichwald, Kathrin; Petzold, Andreas; Watters, Brian; Reichard, Martin; Cellerino, Alessandro

    2013-04-03

    Early evolutionary theories of aging predict that populations which experience low extrinsic mortality evolve a retarded onset of senescence. Experimental support for this theory in vertebrates is scarce, in part for the difficulty of quantifying extrinsic mortality and its condition- and density-dependent components that -when considered- can lead to predictions markedly different to those of the "classical" theories. Here, we study annual fish of the genus Nothobranchius whose maximum lifespan is dictated by the duration of the water bodies they inhabit. Different populations of annual fish do not experience different strengths of extrinsic mortality throughout their life span, but are subject to differential timing (and predictability) of a sudden habitat cessation. In this respect, our study allows testing how aging evolves in natural environments when populations vary in the prospect of survival, but condition-dependent survival has a limited effect. We use 10 Nothobranchius populations from seasonal pools that differ in their duration to test how this parameter affects longevity and aging in two independent clades of these annual fishes. We found that replicated populations from a dry region showed markedly shorter captive lifespan than populations from a humid region. Shorter lifespan correlated with accelerated accumulation of lipofuscin (an established age marker) in both clades. Analysis of wild individuals confirmed that fish from drier habitats accumulate lipofuscin faster also under natural conditions. This indicates faster physiological deterioration in shorter-lived populations. Our data provide a strong quantitative example of how extrinsic mortality can shape evolution of senescence in a vertebrate clade. Nothobranchius is emerging as a genomic model species. The characterization of pairs of closely related species with different longevities should provide a powerful paradigm for the identification of genetic variations responsible for evolution of

  7. Stress-induced senescence and plant tolerance to abiotic stress.

    Science.gov (United States)

    Sade, Nir; Del Mar Rubio-Wilhelmi, María; Umnajkitikorn, Kamolchanok; Blumwald, Eduardo

    2017-07-26

    Senescence is an age-dependent process, ultimately leading to plant death, that in annual crop plants overlaps with the reproductive stage of development. Research on the molecular and biochemical mechanisms of leaf senescence has revealed a multi-layered regulatory network operating to control age-dependent processes. Abiotic stress-induced senescence challenges source-sink relationships and results in significant reduction in crop yields. Although processes associated with plant senescence are well studied, the mechanisms regulating stress-induced senescence are not well known. Here, we discuss the effects of abiotic stress on crop productivity, mechanisms associated with stress-induced senescence, and the possible use of these mechanisms for the generation of plant stress tolerance. We emphasize the involvement of source strength and stability of the photosynthetic apparatus in this process, and suggest a possible role of a perennial plant life strategy for the amelioration of stress-induced senescence. © The Author 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  8. Senescence in intraductal papillary mucinous neoplasm of the pancreas.

    Science.gov (United States)

    Miyasaka, Yoshihiro; Nagai, Eishi; Ohuchida, Kenoki; Fujita, Hayato; Nakata, Kohei; Hayashi, Akifumi; Mizumoto, Kazuhiro; Tsuneyoshi, Masazumi; Tanaka, Masao

    2011-12-01

    Intraductal papillary mucinous neoplasm of the pancreas is attracting attention as a precursor lesion of the invasive ductal adenocarcinoma, whereas it has been reported that some intraductal papillary mucinous neoplasms do not display progression to malignancy and remain almost unchanged in size and morphology. Recent studies have reported that oncogene-induced senescence has been observed in neoplasms, especially in premalignant lesions, and that it can play an important role in preventing malignant progression. To clarify the presence of senescence in intraductal papillary mucinous neoplasms, we analyzed the expression of several markers of senescence. The intraductal papillary mucinous neoplasms evaluated in this study were classified into 4 groups according to the degree of dysplasia. Senescence-associated β-galactosidase activity and senescence-associated heterochromatin foci formation were investigated in 33 cases of intraductal papillary mucinous neoplasms and 6 normal controls. Immunohistochemical analysis of p16(INK4a) and p15(INK4b) was performed in 158 cases of intraductal papillary mucinous neoplasms and 10 normal controls. In the normal controls, neither senescence-associated β-galactosidase activity nor senescence-associated heterochromatin foci formation was observed. Most of the normal epithelia were negative for either p16(INK4a) or p15(INK4b). For all 4 markers, the percentages of positive cases reached a peak in intraductal papillary mucinous neoplasm with low-grade dysplasia and showed significant decreasing trends in the transition from intraductal papillary mucinous neoplasm with low-grade dysplasia to intraductal papillary mucinous neoplasm with an associated invasive carcinoma. Our results indicate that senescence is induced in the early stage of intraductal papillary mucinous neoplasm and gradually attenuated according to the progression. It is suggested that senescence plays a role in preventing malignant progression of intraductal

  9. Delay of iris flower senescence by cytokinins and jasmonates.

    Science.gov (United States)

    van Doorn, Wouter G; Çelikel, Fisun G; Pak, Caroline; Harkema, Harmannus

    2013-05-01

    It is not known whether tepal senescence in Iris flowers is regulated by hormones. We applied hormones and hormone inhibitors to cut flowers and isolated tepals of Iris × hollandica cv. Blue Magic. Treatments with ethylene or ethylene antagonists indicated lack of ethylene involvement. Auxins or auxin inhibitors also did not change the time to senescence. Abscisic acid (ABA) hastened senescence, but an inhibitor of ABA synthesis (norflurazon) had no effect. Gibberellic acid (GA3 ) slightly delayed senescence in some experiments, but in other experiments it was without effect, and gibberellin inhibitors [ancymidol or 4-hydroxy-5-isopropyl-2-methylphenyltrimethyl ammonium chloride-1-piperidine carboxylate (AMO-1618)] were ineffective as well. Salicylic acid (SA) also had no effect. Ethylene, auxins, GA3 and SA affected flower opening, therefore did reach the flower cells. Jasmonates delayed senescence by about 2.0 days. Similarly, cytokinins delayed senescence by about 1.5-2.0 days. Antagonists of the phosphatidylinositol signal transduction pathway (lithium), calcium channels (niguldipine and verapamil), calmodulin action [fluphenazine, trifluoroperazine, phenoxybenzamide and N-(6-aminohexyl)-5-chloro-1-naphtalenesulfonamide hydrochloride (W-7)] or protein kinase activity [1-(5-isoquinolinesulfonyl)-2-methylpiperazine hydrochloride (H-7), N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide hydrochloride (H-8) and N-(2-aminoethyl)-5-isoquinolinesulfonamide dihydrochloride (H-9)] had no effect on senescence, indicating no role of a few common signal transduction pathways relating to hormone effects on senescence. The results indicate that tepal senescence in Iris cv. Blue Magic is not regulated by endogenous ethylene, auxin, gibberellins or SA. A role of ABA can at present not be excluded. The data suggest the hypothesis that cytokinins and jasmonates are among the natural regulators. Copyright © Physiologia Plantarum 2012.

  10. ABA receptor PYL9 promotes drought resistance and leaf senescence

    Science.gov (United States)

    Zhao, Yang; Chan, Zhulong; Gao, Jinghui; Xing, Lu; Cao, Minjie; Yu, Chunmei; Hu, Yuanlei; You, Jun; Shi, Haitao; Zhu, Yingfang; Gong, Yuehua; Mu, Zixin; Wang, Haiqing; Deng, Xin; Wang, Pengcheng; Bressan, Ray A.; Zhu, Jian-Kang

    2016-01-01

    Drought stress is an important environmental factor limiting plant productivity. In this study, we screened drought-resistant transgenic plants from 65 promoter-pyrabactin resistance 1-like (PYL) abscisic acid (ABA) receptor gene combinations and discovered that pRD29A::PYL9 transgenic lines showed dramatically increased drought resistance and drought-induced leaf senescence in both Arabidopsis and rice. Previous studies suggested that ABA promotes senescence by causing ethylene production. However, we found that ABA promotes leaf senescence in an ethylene-independent manner by activating sucrose nonfermenting 1-related protein kinase 2s (SnRK2s), which subsequently phosphorylate ABA-responsive element-binding factors (ABFs) and Related to ABA-Insensitive 3/VP1 (RAV1) transcription factors. The phosphorylated ABFs and RAV1 up-regulate the expression of senescence-associated genes, partly by up-regulating the expression of Oresara 1. The pyl9 and ABA-insensitive 1-1 single mutants, pyl8-1pyl9 double mutant, and snrk2.2/3/6 triple mutant showed reduced ABA-induced leaf senescence relative to the WT, whereas pRD29A::PYL9 transgenic plants showed enhanced ABA-induced leaf senescence. We found that leaf senescence may benefit drought resistance by helping to generate an osmotic potential gradient, which is increased in pRD29A::PYL9 transgenic plants and causes water to preferentially flow to developing tissues. Our results uncover the molecular mechanism of ABA-induced leaf senescence and suggest an important role of PYL9 and leaf senescence in promoting resistance to extreme drought stress. PMID:26831097

  11. Senescence and quiescence in adipose-derived stromal cells

    DEFF Research Database (Denmark)

    Søndergaard, Rebekka Harary; Follin, Bjarke; Lund, Lisbeth Drozd

    2017-01-01

    serum (FBS) at normoxia. However, the low proliferation rates of FBS-expanded ASCs could be signs of senescence or quiescence. We aimed to determine the effects of hypoxia and hPL on the expansion of ASCs and whether FBS-expanded ASCs are senescent or quiescent. METHODS: ASCs expanded in FBS or h...... cycle regulation and expression of cyclins, p21 and p27. hPL rejuvenates FBS-expanded ASCs with regard to cell cycle regulation and expression of cyclins, p21 and p27. This indicates a reversible arrest. Therefore, we conclude that ASCs expanded until P7 are not senescent regardless of culture...

  12. B-Myb, Cancer, Senescence, and MicroRNAs

    OpenAIRE

    Martinez, Ivan; DiMaio, Daniel

    2011-01-01

    The transcription factor B-Myb plays a critical role in regulating gene expression and is implicated in controlling carcinogenesis and cellular senescence. Transcription of the B-Myb gene is regulated by retinoblastoma proteins acting directly on the B-Myb promoter. Recently, we found that microRNAs also control the abundance of B-Myb mRNA during senescence, adding another level of complexity to B-Myb regulation. This review focuses on the importance of B-Myb in cancer and senescence, with an...

  13. Loss of DLK expression in WI-38 human diploid fibroblasts induces a senescent-like proliferation arrest

    Energy Technology Data Exchange (ETDEWEB)

    Daviau, Alex; Couture, Jean-Philippe [Departement de Biologie, Faculte des Sciences, Universite de Sherbrooke, Sherbrooke, Quebec, Canada J1K 2R1 (Canada); Blouin, Richard, E-mail: Richard.Blouin@USherbrooke.ca [Departement de Biologie, Faculte des Sciences, Universite de Sherbrooke, Sherbrooke, Quebec, Canada J1K 2R1 (Canada)

    2011-09-23

    Highlights: {yields} Role of DLK in cell proliferation. {yields} Modulation of DLK expression during cell cycle progression. {yields} DLK knockdown induces proliferation arrest and senescence. {yields} DLK-depleted cells display loss of cyclin D1 and up-regulation of p21. {yields} DLK participates in cell proliferation by modulating cell cycle regulator expression. -- Abstract: DLK, a serine/threonine kinase that functions as an upstream activator of the mitogen-activated protein kinase (MAPK) pathways, has been shown to play a role in development, cell differentiation, apoptosis and neuronal response to injury. Interestingly, recent studies have shown that DLK may also be required for cell proliferation, although little is known about its specific functions. To start addressing this issue, we studied how DLK expression is modulated during cell cycle progression and what effect DLK depletion has on cell proliferation in WI-38 fibroblasts. Our results indicate that DLK protein levels are low in serum-starved cells, but that serum addition markedly stimulated it. Moreover, RNA interference experiments demonstrate that DLK is required for ERK activity, expression of the cell cycle regulator cyclin D1 and proliferation of WI-38 cells. DLK-depleted cells also show a senescent phenotype as revealed by senescence-associated galactosidase activity and up-regulation of the senescence pathway proteins p53 and p21. Consistent with a role for p53 in this response, inhibition of p53 expression by RNA interference significantly alleviated senescence induced by DLK knockdown. Together, these findings indicate that DLK participates in cell proliferation and/or survival, at least in part, by modulating the expression of cell cycle regulatory proteins.

  14. Senescing sexual ornaments recover after a sabbatical.

    Science.gov (United States)

    Velando, Alberto; Drummond, Hugh; Torres, Roxana

    2010-04-23

    Somatic deterioration in ageing animals may arise from allocation of resources to reproduction at the expense of repair and maintenance. Thus, accumulated reproductive effort is likely to progressively limit the expression of sexual ornaments at older ages. We analysed the effect of age and reproductive effort on the sexual attractiveness (foot colour) of male blue-footed boobies. Using a long-term dataset, we found that, as animals age and accumulate reproductive events, the expression of foot colour deteriorates. In addition, after non-breeding events males displayed more colourful feet compared with males that reproduced the year before, suggesting that sabbatical years facilitate recovery. Our results indirectly support the idea that allocation of resources to reproduction limits sexual attractiveness and that animals could cope with the negative effects of senescence on sexual ornaments by skipping some breeding events.

  15. Impact of senescence-associated secretory phenotype and its potential as a therapeutic target for senescence-associated diseases.

    Science.gov (United States)

    Watanabe, Sugiko; Kawamoto, Shimpei; Ohtani, Naoko; Hara, Eiji

    2017-04-01

    "Cellular senescence" is a state in which cells undergo irreversible cell cycle arrest in response to a variety of cellular stresses. Once cells senesce, they are strongly resistant to any mitogens, including oncogenic stimuli. Therefore, cellular senescence has been assumed to be a potent anticancer mechanism. Although irreversible cell-cycle arrest is traditionally considered the major characteristic of senescent cells, recent studies have revealed some additional functions. Most noteworthy is the increased secretion of various secretory proteins, such as inflammatory cytokines, chemokines, growth factors, and MMPs, into the surrounding extracellular fluid. These newly recognized senescent phenotypes, termed senescence-associated secretory phenotypes (SASPs), reportedly contribute to tumor suppression, wound healing, embryonic development, and even tumorigenesis promotion. Thus, SASPs appear to be beneficial or deleterious, depending on the biological context. As senescent cells are known to accumulate during the aging process in vivo, it is quite possible that their accumulation in aged tissues promotes age-associated functional decline and various diseases, including cancers, at least to some extent. Here, we focus on and discuss the functional and regulatory network of SASPs toward opening up new possibilities for controlling aging and aging-associated diseases. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  16. Transcriptional profile of genes involved in ascorbate glutathione cycle in senescing leaves for an early senescence leaf (esl) rice mutant.

    Science.gov (United States)

    Li, Zhaowei; Su, Da; Lei, Bingting; Wang, Fubiao; Geng, Wei; Pan, Gang; Cheng, Fangmin

    2015-03-15

    To clarify the complex relationship between ascorbate-glutathione (AsA-GSH) cycle and H2O2-induced leaf senescence, the genotype-dependent difference in some senescence-related physiological parameters and the transcript levels and the temporal patterns of genes involved in the AsA-GSH cycle during leaf senescence were investigated using two rice genotypes, namely, the early senescence leaf (esl) mutant and its wild type. Meanwhile, the triggering effect of exogenous H2O2 on the expression of OsAPX genes was examined using detached leaves. The results showed that the esl mutant had higher H2O2 level than its wild type at the initial stage of leaf senescence. At transcriptional level, the association of expression of various genes involved in the AsA-GSH cycle with leaf senescence was isoform dependent. For OsAPXs, the transcripts of two cytosolic OsAPX genes (OsAPX1 and OsAPX2), thylakoid-bound OsAPX8, chloroplastic OsAPX7 and peroxisomal OsAPX4 exhibited remarkable genotype-dependent variation in their expression levels and temporal patterns during leaf senescence, there were significantly increasing transcripts of OsAXP1 and OsAPX7, severely repressed transcripts of OsAPX4 and OsAPX8 for the esl rice at the initial leaf senescence. In contrast, the repressing transcript of OsAPX8 was highly sensitive to the increasing H2O2 level in the senescing rice leaves, while higher H2O2 concentration resulted in the enhancing transcripts of two cytosolic OsAPX genes, OsAPX7 transcript was greatly variable with different H2O2 concentrations and incubating duration, suggesting that the different OsAPXs isoforms played a complementary role in perceiving and scavenging H2O2 accumulation at various H2O2 concentrations during leaf senescence. Higher H2O2 level, increased AsA level, higher activities of APX and glutathione reductase (GR), and relatively stable GSH content during the entire sampling period in the leaves of esl mutant implied that a close interrelationship existed

  17. Senescent vs. non-senescent cells in the human annulus in vivo: Cell harvest with laser capture microdissection and gene expression studies with microarray analysis

    Directory of Open Access Journals (Sweden)

    Ingram Jane A

    2010-01-01

    Full Text Available Abstract Background Senescent cells are well-recognized in the aging/degenerating human disc. Senescent cells are viable, cannot divide, remain metabolically active and accumulate within the disc over time. Molecular analysis of senescent cells in tissue offers a special challenge since there are no cell surface markers for senescence which would let one use fluorescence-activated cell sorting as a method for separating out senescent cells. Methods We employed a novel laser capture microdissection (LCM design to selectively harvest senescent and non-senescent annulus cells in paraffin-embedded tissue, and compared their gene expression with microarray analysis. LCM was used to separately harvest senescent and non-senescent cells from 11 human annulus specimens. Results Microarray analysis revealed significant differences in expression levels in senescent cells vs non-senescent cells: 292 genes were upregulated, and 321 downregulated. Genes with established relationships to senescence were found to be significantly upregulated in senescent cells vs. non-senescent cells: p38 (MPAK14, RB-Associated KRAB zinc finger, Discoidin, CUB and LCCL domain, growth arrest and DNA-damage inducible beta, p28ING5, sphingosine-1-phosphate receptor 2 and somatostatin receptor 3; cyclin-dependent kinase 8 showed significant downregulation in senescent cells. Nitric oxidase synthase 1, and heat shock 70 kDa protein 6, both of which were significantly down-regulated in senescent cells, also showed significant changes. Additional genes related to cytokines, cell proliferation, and other processes were also identified. Conclusions Our LCM-microarray analyses identified a set of genes associated with senescence which were significantly upregulated in senescent vs non-senescent cells in the human annulus. These genes include p38 MAP kinase, discoidin, inhibitor of growth family member 5, and growth arrest and DNA-damage-inducible beta. Other genes, including genes

  18. Proteome data associated with the leaf senescence in Glycine max

    Directory of Open Access Journals (Sweden)

    Ravi Gupta

    2016-12-01

    Full Text Available The data presented in this article are associated with the article “Coupling of gel-based 2-DE and 1-DE shotgun proteomics approaches to dig deep into the leaf senescence proteome of Glycine max” (R. Gupta, S.J. Lee, C.W. Min, S.W. Kim, K.-H. Park, D.-W. Bae, et al., 2016 [1]. Leaf senescence is one of the important aspects of the life cycle of a plant that leads to the recycling of nutrients from source to sink cells. To understand the leaf senescence-associated proteins, we used a combination of gel-based 2-DE and 1-DE shotgun proteomic approaches. Here, we display the 2-DE, Mass spectrometry, and Gene ontology data related with the leaf senescence in soybean [1].

  19. Rapid induction of senescence in human cervical carcinoma cells

    Science.gov (United States)

    Goodwin, Edward C.; Yang, Eva; Lee, Chan-Jae; Lee, Han-Woong; Dimaio, Daniel; Hwang, Eun-Seong

    2000-09-01

    Expression of the bovine papillomavirus E2 regulatory protein in human cervical carcinoma cell lines repressed expression of the resident human papillomavirus E6 and E7 oncogenes and within a few days caused essentially all of the cells to synchronously display numerous phenotypic markers characteristic of cells undergoing replicative senescence. This process was accompanied by marked but in some cases transient alterations in the expression of cell cycle regulatory proteins and by decreased telomerase activity. We propose that the human papillomavirus E6 and E7 proteins actively prevent senescence from occurring in cervical carcinoma cells, and that once viral oncogene expression is extinguished, the senescence program is rapidly executed. Activation of endogenous senescence pathways in cancer cells may represent an alternative approach to treat human cancers.

  20. Redox control of senescence and age-related disease

    Directory of Open Access Journals (Sweden)

    Akshaya Chandrasekaran

    2017-04-01

    Full Text Available The signaling networks that drive the aging process, associated functional deterioration, and pathologies has captured the scientific community's attention for decades. While many theories exist to explain the aging process, the production of reactive oxygen species (ROS provides a signaling link between engagement of cellular senescence and several age-associated pathologies. Cellular senescence has evolved to restrict tumor progression but the accompanying senescence-associated secretory phenotype (SASP promotes pathogenic pathways. Here, we review known biological theories of aging and how ROS mechanistically control senescence and the aging process. We also describe the redox-regulated signaling networks controlling the SASP and its important role in driving age-related diseases. Finally, we discuss progress in designing therapeutic strategies that manipulate the cellular redox environment to restrict age-associated pathology.

  1. HIV-associated cellular senescence: A contributor to accelerated aging.

    Science.gov (United States)

    Cohen, Justin; Torres, Claudio

    2017-07-01

    Due to the advent of antiretroviral therapy HIV is no longer a terminal disease and the HIV infected patients are becoming increasingly older. While this is a major success, with increasing age comes an increased risk for disease. The age-related comorbidities that HIV infected patients experience suggest that they suffer from accelerated aging. One possible contributor to this accelerated aging is cellular senescence, an age-associated response that can occur prematurely in response to stress, and that is emerging as a contributor to disease and aging. HIV patients experience several stressors such as the virus itself, antiretroviral drugs and to a lesser extent, substance abuse that can induce cellular senescence. This review summarizes the current knowledge of senescence induction in response to these stressors and their relation to the comorbidities in HIV patients. Cellular senescence may be a possible therapeutic target for these comorbidities. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Redox control of senescence and age-related disease.

    Science.gov (United States)

    Chandrasekaran, Akshaya; Idelchik, Maria Del Pilar Sosa; Melendez, J Andrés

    2017-04-01

    The signaling networks that drive the aging process, associated functional deterioration, and pathologies has captured the scientific community's attention for decades. While many theories exist to explain the aging process, the production of reactive oxygen species (ROS) provides a signaling link between engagement of cellular senescence and several age-associated pathologies. Cellular senescence has evolved to restrict tumor progression but the accompanying senescence-associated secretory phenotype (SASP) promotes pathogenic pathways. Here, we review known biological theories of aging and how ROS mechanistically control senescence and the aging process. We also describe the redox-regulated signaling networks controlling the SASP and its important role in driving age-related diseases. Finally, we discuss progress in designing therapeutic strategies that manipulate the cellular redox environment to restrict age-associated pathology. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  3. Therapeutic interventions for aging: the case of cellular senescence.

    Science.gov (United States)

    Soto-Gamez, Abel; Demaria, Marco

    2017-05-01

    Organismal aging is a multifactorial process characterized by the onset of degenerative conditions and cancer. One of the key drivers of aging is cellular senescence, a state of irreversible growth arrest induced by many pro-tumorigenic stresses. Senescent cells accumulate late in life and at sites of age-related pathologies, where they contribute to disease onset and progression through complex cell and non-cell autonomous effects. Here, we summarize the mechanisms by which cellular senescence can promote aging, and we offer an extensive description of current potential pharmacological interventions for senescent cells, highlighting limitations and suggesting alternatives. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  4. The Pace and Shape of Senescence in Angiosperms

    DEFF Research Database (Denmark)

    Baudisch, Annette; Salguero-Gómez, Roberto; Jones, Owen

    2013-01-01

    1. Demographic senescence, the decay in fertility and increase in the risk of mortality with age, is one of the most striking phenomena in ecology and evolution. Comparative studies of senescence patterns of plants are scarce, and consequently, little is known about senescence and its determinants...... in the plant kingdom. 2. Senescence patterns of mortality can be classified by distinguishing between two metrics: pace and shape. The pace of mortality captures the speed at which life proceeds and can be measured by life expectancy, while the shape of mortality captures whether mortality increases...... (‘senescence’), decreases (‘negative senescence’) or remains constant over age (‘negligible senescence’). 3. We extract mortality trajectories from ComPADRe III, a data base that contains demographic information for several hundred plant species. We apply age-from-stage matrix decomposition methods to obtain...

  5. Interaction Mortality: Senescence May Have Evolved because It Increases Lifespan

    DEFF Research Database (Denmark)

    Wensink, M. J.; Wrycza, T. F.; Baudisch, A.

    2014-01-01

    Given an extrinsic challenge, an organism may die or not depending on how the threat interacts with the organism's physiological state. To date, such interaction mortality has been only a minor factor in theoretical modeling of senescence. We describe a model of interaction mortality that does...... not involve specific functions, making only modest assumptions. Our model distinguishes explicitly between the physiological state of an organism and potential extrinsic, age-independent threats. The resulting mortality may change with age, depending on whether the organism's state changes with age. We find...... that depending on the physiological constraints, any outcome, be it 'no senescence' or 'high rate of senescence', can be found in any environment; that the highest optimal rate of senescence emerges for an intermediate physiological constraint, i.e. intermediate strength of trade-off; and that the optimal rate...

  6. [Significance of senescence study on tree roots and its advances].

    Science.gov (United States)

    Wu, Chu; Wang, Zhengquan; Fan, Zhiqiang

    2004-07-01

    Root system is one of the important components of trees, and has some important physiological functions such as nutrient and water absorption, transport and storage, anchoring, and supporting. After tree root systems formed, roots often suffer from nutrient- and water-deficient stress, and thus, their absorption of nutrients and water appears more important. Soil nutrient and water have a great spatiotemporal heterogeneity. As the heterogeneity occurs, trees regulate carbon partitioning to roots, resulting in the senescence or death of some roots of the whole root system. In forestry, the senescence of tree roots is closely related to tree productivity, because there is a close relationship between the senescence of tree roots and the absorption of soil nutrient and water. At ecosystem and global scale, the senescence of tree roots influences the cycling of carbon and nutrients, because roots exhaust a great deal of carbon fixed by source leaves through photosynthesis, and there are great amounts of nutrients in tree roots. The senescence of tree roots is influenced by many environmental factors, biotic (e.g., fungi, bacteria, viruses, small edaphic animals) and abiotic (e.g., water, temperature, soil nutrients, heavy metals). These factors affect the senescence of tree roots by different mechanisms. Although we have much knowledge on the senescence of tree roots and some hypotheses have been proposed, some problems still remain to be resolved, and further experiments are needed to test these hypotheses. Interdisciplinary studies integrating cytology, biochemistry, soil science, and genetics are the prerequisite for rapid advances in understanding the essence of tree root senescence.

  7. CLCA2 as a p53-Inducible Senescence Mediator

    OpenAIRE

    Chizu Tanikawa; Hidewaki Nakagawa; Yoichi Furukawa; Yusuke Nakamura; Koichi Matsuda

    2012-01-01

    p53 is a tumor suppressor gene that is frequently mutated in multiple cancer tissues. Activated p53 protein regulates its downstream genes and subsequently inhibits malignant transformation by inducing cell cycle arrest, apoptosis, DNA repair, and senescence. However, genes involved in the p53-mediated senescence pathway are not yet fully elucidated. Through the screening of two genome-wide expression profile data sets, one for cells in which exogenous p53 was introduced and the other for sen...

  8. Biological Impact of Senescence Induction in Prostate Cancer

    Science.gov (United States)

    2010-01-01

    ionophore pyrithione induces oxidative stress.15 Both of these cellular stresses are associated with senescence induction. The mechanisms by which...mitochondrial function. The Zn2+ ionophore pyrithione is thought to generate oxidative stress, leading to growth arrest and senescence (39, 40...9): 1918-1922. 39. Magda, D, Lecane, P, Wang, Z, et al. Synthesis and anticancer properties of water-soluble zinc ionophores . Cancer Res, 2008; 68

  9. Apoptosis during embryonic tissue remodeling is accompanied by cell senescence

    OpenAIRE

    Lorda Diez, Carlos Ignacio; García-Riart Monzón, Beatriz Inmaculada; Montero Simón, Juan Antonio; Rodríguez León, J; García-Porrero Pérez, Juan Antonio; Hurlé González, Juan Mario

    2015-01-01

    This study re-examined the dying process in the interdigital tissue during the formation of free digits in the developing limbs. We demonstrated that the interdigital dying process was associated with cell senescence, as deduced by induction of β-gal activity, mitotic arrest, and transcriptional up-regulation of p21 together with many components of the senescence-associated secretory phenotype. We also found overlapping domains of expression of members of the Btg/Tob gene family of antiprolif...

  10. Morphologic aspects of the senescence processes in female genital system

    OpenAIRE

    Raluca Balan; Eduard Crauciuc; Vlad Gheorghita; Ovidiu Toma; Cornela Amalinei

    2008-01-01

    Senescence is characterized by a gradual loss of the stem cells activity and an atrophy of all cells and tissues which lead to the deterioration of the functional activity. The senescence processes manifest also in the female genital organs, producing different morphologic alterations. For the evidentiation of these aspects we retrospectively analyze 75 cases, from menopausal and postmenopausal women, investigating the histerectomy specimens, bioptic curettages and cervico-vaginal...

  11. Resveratrol Attenuates Copper-Induced Senescence by Improving Cellular Proteostasis

    Directory of Open Access Journals (Sweden)

    Liliana Matos

    2017-01-01

    Full Text Available Copper sulfate-induced premature senescence (CuSO4-SIPS consistently mimetized molecular mechanisms of replicative senescence, particularly at the endoplasmic reticulum proteostasis level. In fact, disruption of protein homeostasis has been associated to age-related cell/tissue dysfunction and human disorders susceptibility. Resveratrol is a polyphenolic compound with proved antiaging properties under particular conditions. In this setting, we aimed to evaluate resveratrol ability to attenuate cellular senescence induction and to unravel related molecular mechanisms. Using CuSO4-SIPS WI-38 fibroblasts, resveratrol is shown to attenuate typical senescence alterations on cell morphology, senescence-associated beta-galactosidase activity, and cell proliferation. The mechanisms implicated in this antisenescence effect seem to be independent of senescence-associated genes and proteins regulation but are reliant on cellular proteostasis improvement. In fact, resveratrol supplementation restores copper-induced increased protein content, attenuates BiP level, and reduces carbonylated and polyubiquitinated proteins by autophagy induction. Our data provide compelling evidence for the beneficial effects of resveratrol by mitigating CuSO4-SIPS stressful consequences by the modulation of protein quality control systems. These findings highlight the importance of a balanced cellular proteostasis and add further knowledge on molecular mechanisms mediating resveratrol antisenescence effects. Moreover, they contribute to identifying specific molecular targets whose modulation will prevent age-associated cell dysfunction and improve human healthspan.

  12. Onset of Phloem Export from Senescent Petals of Daylily.

    Science.gov (United States)

    Bieleski, R. L.

    1995-10-01

    During senescence, petals of attached daylily (Hemerocallis hybrid cv Cradle Song) flowers lost 95% sugar and 65% dry weight over the first 24 h, with 30% of dry weight loss coming from nonsugar components. Detaching flowers did not delay senescence, but halted loss of carbohydrate and amino acid, suggesting that loss in the intact state was due to phloem export. Petal autolysis occurred mainly in the interveinal parenchyma, causing vascular strands to begin separating from the petal mass. Such vascular strands still stained with tetrazolium and accumulated sucrose, indicating a retained viability. Their sucrose accumulation rates were high in comparison with those of other plant tissues, and the accumulated product was mainly sucrose. Sucrose synthesis took place in the senescent petal, and sucrose was the principal sugar in phloem exudate, whereas hydroxyproline and glutamine were the main transport amino acids. [14C]Sucrose applied to attached senescent flowers was rapidly translocated to other parts of the plant, particularly developing flower buds. Thus, onset of phloem export allowed most of the soluble carbohydrate and amino acid in the senescing flower to be retrieved by the plant. Additional salvaged material came from proteins and possibly from structural carbohydrate. Over a 12-h period, the flower switched from acting as a strong carbohydrate sink during expansion to become a strong source during senescence. This rapid reversal offers potential for phloem transport studies.

  13. Caveolin-1 deficiency induces premature senescence with mitochondrial dysfunction.

    Science.gov (United States)

    Yu, Dong-Min; Jung, Seung Hee; An, Hyoung-Tae; Lee, Sungsoo; Hong, Jin; Park, Jun Sub; Lee, Hyun; Lee, Hwayeon; Bahn, Myeong-Suk; Lee, Hyung Chul; Han, Na-Kyung; Ko, Jesang; Lee, Jae-Seon; Ko, Young-Gyu

    2017-08-01

    Paradoxical observations have been made regarding the role of caveolin-1 (Cav-1) during cellular senescence. For example, caveolin-1 deficiency prevents reactive oxygen species-induced cellular senescence despite mitochondrial dysfunction, which leads to senescence. To resolve this paradox, we re-addressed the role of caveolin-1 in cellular senescence in human diploid fibroblasts, A549, HCT116, and Cav-1(-/-) mouse embryonic fibroblasts. Cav-1 deficiency (knockout or knockdown) induced cellular senescence via a p53-p21-dependent pathway, downregulating the expression level of the cardiolipin biosynthesis enzymes and then reducing the content of cardiolipin, a critical lipid for mitochondrial respiration. Our results showed that Cav-1 deficiency decreased mitochondrial respiration, reduced the activity of oxidative phosphorylation complex I (CI), inactivated SIRT1, and decreased the NAD(+) /NADH ratio. From these results, we concluded that Cav-1 deficiency induces premature senescence via mitochondrial dysfunction and silent information regulator 2 homologue 1 (SIRT1) inactivation. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  14. Contrasting patterns of cytokinins between years in senescing aspen leaves.

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    Edlund, Erik; Novak, Ondrej; Karady, Michal; Ljung, Karin; Jansson, Stefan

    2017-05-01

    Cytokinins are plant hormones that typically block or delay leaf senescence. We profiled 34 different cytokinins/cytokinin metabolites (including precursors, conjugates and degradation products) in leaves of a free-growing mature aspen (Populus tremula) before and after the initiation of autumnal senescence over three consecutive years. The levels and profiles of individual cytokinin species, or classes/groups, varied greatly between years, despite the fact that the onset of autumn senescence was at the same time each year, and senescence was not associated with depletion of either active or total cytokinin levels. Levels of aromatic cytokinins (topolins) were low and changed little over the autumn period. Diurnal variations and weather-dependent variations in cytokinin content were relatively limited. We also followed the expression patterns of all aspen genes implicated as having roles in cytokinin metabolism or signalling, but neither the pattern of regulation of any group of genes nor the expression of any particular gene supported the notion that decreased cytokinin signalling could explain the onset of senescence. Based on the results from this tree, we therefore suggest that cytokinin depletion is unlikely to explain the onset of autumn leaf senescence in aspen. © 2017 The Authors Plant, Cell & Environment Published by John Wiley & Sons Ltd.

  15. Cellular Senescence and Lung Function during Aging. Yin and Yang.

    Science.gov (United States)

    Campisi, Judith

    2016-12-01

    Cellular senescence is a cell fate decision and stress response that entails a permanent arrest of cell proliferation coupled to a complex secretory phenotype. Senescent cells increase in number with age in most, if not all, mammalian tissues, including the airways and lungs. They also increase at greater than expected numbers, compared with age-matched controls, at sites of age-related pathologies such as chronic obstructive pulmonary disorder and emphysema. The senescence response is a double-edged sword. The proliferative arrest suppresses the development of cancer by preventing the propagation of stressed or damaged cells that are at risk for neoplastic transformation. However, this arrest can also curtail the proliferation of stem or progenitor cells and thus hamper tissue repair and regeneration. Similarly, the secretory phenotype can promote wound healing by transiently providing growth factors and the initial inflammatory stimulus that is required for tissue repair. However, when chronically present, the secretory phenotype of senescent cells can drive pathological inflammation, which contributes to a host of age-related pathologies, including cancer. There are now transgenes and prototype small molecules that can clear senescent cells, at least in mouse models, and thus improve health span and median life span. The next challenge will be to develop interventions and supplements that can abrogate the deleterious effects of senescent cells while preserving their beneficial effects.

  16. Gene pathways that delay Caenorhabditis elegans reproductive senescence.

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    Meng C Wang

    2014-12-01

    Full Text Available Reproductive senescence is a hallmark of aging. The molecular mechanisms regulating reproductive senescence and its association with the aging of somatic cells remain poorly understood. From a full genome RNA interference (RNAi screen, we identified 32 Caenorhabditis elegans gene inactivations that delay reproductive senescence and extend reproductive lifespan. We found that many of these gene inactivations interact with insulin/IGF-1 and/or TGF-β endocrine signaling pathways to regulate reproductive senescence, except nhx-2 and sgk-1 that modulate sodium reabsorption. Of these 32 gene inactivations, we also found that 19 increase reproductive lifespan through their effects on oocyte activities, 8 of them coordinate oocyte and sperm functions to extend reproductive lifespan, and 5 of them can induce sperm humoral response to promote reproductive longevity. Furthermore, we examined the effects of these reproductive aging regulators on somatic aging. We found that 5 of these gene inactivations prolong organismal lifespan, and 20 of them increase healthy life expectancy of an organism without altering total life span. These studies provide a systemic view on the genetic regulation of reproductive senescence and its intersection with organism longevity. The majority of these newly identified genes are conserved, and may provide new insights into age-associated reproductive senescence during human aging.

  17. Cellular senescence in aging and age-related disease: from mechanisms to therapy.

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    Childs, Bennett G; Durik, Matej; Baker, Darren J; van Deursen, Jan M

    2015-12-01

    Cellular senescence, a process that imposes permanent proliferative arrest on cells in response to various stressors, has emerged as a potentially important contributor to aging and age-related disease, and it is an attractive target for therapeutic exploitation. A wealth of information about senescence in cultured cells has been acquired over the past half century; however, senescence in living organisms is poorly understood, largely because of technical limitations relating to the identification and characterization of senescent cells in tissues and organs. Furthermore, newly recognized beneficial signaling functions of senescence suggest that indiscriminately targeting senescent cells or modulating their secretome for anti-aging therapy may have negative consequences. Here we discuss current progress and challenges in understanding the stressors that induce senescence in vivo, the cell types that are prone to senesce, and the autocrine and paracrine properties of senescent cells in the contexts of aging and age-related diseases as well as disease therapy.

  18. Skin melanocytes and fibroblasts show different changes in choline metabolism during cellular senescence.

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    Windler, Cordula; Gey, Claudia; Seeger, Karsten

    2017-06-01

    Unmodified cells undergo only a limited number of cell divisions until they enter a state termed cellular senescence. Other triggers like cytotoxic compounds can also induce cell senescence. Since cell senescence represents a major mechanism of tumor suppression this cellular state has attracted increasing attention. Different markers like senescence-associated β-galactosidase (SAβGal), senescence-associated heterochromatic foci (SAHF) or certain metabolic changes have been identified to be characteristic for senescent cells; however, data is often limited to fibroblasts - the cardinal model system for cellular senescence. In order to investigate whether metabolic changes during senescence are cell type independent, skin fibroblasts and skin melanocytes have been examined. Expression of the senescence marker p16 could be detected in skin fibroblasts but not in melanocytes of this specific donor, rendering the senescent phenotype not fully ascertained for the melanocytes. Metabolic profiles of senescent cells and controls have been determined using NMR spectroscopy. Changes in metabolism are different for fibroblasts and melanocytes. Senescent melanocytes showed lower levels of phosphocholine whereas for fibroblasts in accordance with literature, levels of glycerophosphocholine were increased during senescence. Although no general metabolic marker for cellular senescence exists, the same metabolic pathway seems to be affected for both cell types. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Prostaglandin E2 promotes features of replicative senescence in chronically activated human CD8+ T cells.

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    Jennifer P Chou

    Full Text Available Prostaglandin E2 (PGE2, a pleiotropic immunomodulatory molecule, and its free radical catalyzed isoform, iso-PGE2, are frequently elevated in the context of cancer and chronic infection. Previous studies have documented the effects of PGE2 on the various CD4+ T cell functions, but little is known about its impact on cytotoxic CD8+ T lymphocytes, the immune cells responsible for eliminating virally infected and tumor cells. Here we provide the first demonstration of the dramatic effects of PGE2 on the progression of human CD8+ T cells toward replicative senescence, a terminal dysfunctional state associated multiple pathologies during aging and chronic HIV-1 infection. Our data show that exposure of chronically activated CD8+ T cells to physiological levels of PGE2 and iso-PGE2 promotes accelerated acquisition of markers of senescence, including loss of CD28 expression, increased expression of p16 cell cycle inhibitor, reduced telomerase activity, telomere shortening and diminished production of key cytotoxic and survival cytokines. Moreover, the CD8+ T cells also produced higher levels of reactive oxygen species, suggesting that the resultant oxidative stress may have further enhanced telomere loss. Interestingly, we observed that even chronic activation per se resulted in increased CD8+ T cell production of PGE2, mediated by higher COX-2 activity, thus inducing a negative feedback loop that further inhibits effector function. Collectively, our data suggest that the elevated levels of PGE2 and iso-PGE2, seen in various cancers and HIV-1 infection, may accelerate progression of CD8+ T cells towards replicative senescence in vivo. Inhibition of COX-2 activity may, therefore, provide a strategy to counteract this effect.

  20. PTTG1 attenuates drug-induced cellular senescence.

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    Yunguang Tong

    Full Text Available As PTTG1 (pituitary tumor transforming gene abundance correlates with adverse outcomes in cancer treatment, we determined mechanisms underlying this observation by assessing the role of PTTG1 in regulating cell response to anti-neoplastic drugs. HCT116 cells devoid of PTTG1 (PTTG1(-/- exhibited enhanced drug sensitivity as assessed by measuring BrdU incorporation in vitro. Apoptosis, mitosis catastrophe or DNA damage were not detected, but features of senescence were observed using low doses of doxorubicin and TSA. The number of drug-induced PTTG1(-/- senescent cells increased ∼4 fold as compared to WT PTTG1-replete cells (p<0.001. p21, an important regulator of cell senescence, was induced ∼3 fold in HCT116 PTTG1(-/- cells upon doxorubicin or Trichostatin A treatment. Binding of Sp1, p53 and p300 to the p21 promoter was enhanced in PTTG1(-/- cells after treatment, suggesting transcriptional regulation of p21. p21 knock down abrogated the observed senescent effects of these drugs, indicating that PTTG1 likely suppresses p21 to regulate drug-induced senescence. PTTG1 also regulated SW620 colon cancer cells response to doxorubicin and TSA mediated by p21. Subcutaneously xenografted PTTG1(-/- HCT116 cells developed smaller tumors and exhibited enhanced responses to doxorubicin. PTTG1(-/- tumor tissue derived from excised tumors exhibited increased doxorubicin-induced senescence. As senescence is a determinant of cell responses to anti-neoplastic treatments, these findings suggest PTTG1 as a tumor cell marker to predict anti-neoplastic treatment outcomes.

  1. Cellular senescence and aging: the role of B-MYB.

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    Mowla, Sophia N; Lam, Eric W-F; Jat, Parmjit S

    2014-10-01

    Cellular senescence is a stable cell cycle arrest, caused by insults, such as: telomere erosion, oncogene activation, irradiation, DNA damage, oxidative stress, and viral infection. Extrinsic stimuli such as cell culture stress can also trigger this growth arrest. Senescence is thought to have evolved as an example of antagonistic pleiotropy, as it acts as a tumor suppressor mechanism during the reproductive age, but can promote organismal aging by disrupting tissue renewal, repair, and regeneration later in life. The mechanisms underlying the senescence growth arrest are broadly considered to involve p16(INK4A) -pRB and p53-p21(CIP1/WAF1/SDI1) tumor suppressor pathways; but it is not known what makes the senescence arrest stable and what the critical downstream targets are, as they are likely to be key to the establishment and maintenance of the senescent state. MYB-related protein B (B-MYB/MYBL2), a member of the myeloblastosis family of transcription factors, has recently emerged as a potential candidate for regulating entry into senescence. Here, we review the evidence which indicates that loss of B-MYB expression has an important role in causing senescence growth arrest. We discuss how B-MYB acts, as the gatekeeper, to coordinate transit through the cell cycle, in conjunction with the multivulval class B (MuvB) complex and FOXM1 transcription factors. We also evaluate the evidence connecting B-MYB to the mTOR nutrient signaling pathway and suggest that inhibition of this pathway leading to an extension of healthspan may involve activation of B-MYB. © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  2. Bioactive Peptides from Angelica sinensis Protein Hydrolyzate Delay Senescence in Caenorhabditis elegans through Antioxidant Activities

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    Qiangqiang Wang

    2016-01-01

    Full Text Available Since excessive reactive oxygen species (ROS is known to be associated with aging and age-related diseases, strategies modulating ROS level and antioxidant defense systems may contribute to the delay of senescence. Here we show that the protein hydrolyzate from Angelica sinensis was capable of increasing oxidative survival of the model animal Caenorhabditis elegans intoxicated by paraquat. The hydrolyzate was then fractionated by ultrafiltration, and the antioxidant fraction (<3 kDa was purified by gel filtration to obtain the antioxidant A. sinensis peptides (AsiPeps, which were mostly composed of peptides with <20 amino acid residues. Further studies demonstrate that AsiPeps were able to reduce the endogenous ROS level, increase the activities of the antioxidant enzymes superoxide dismutase and catalase, and decrease the content of the lipid peroxidation product malondialdehyde in nematodes treated with paraquat or undergoing senescence. AsiPeps were also shown to reduce age pigments accumulation and extend lifespan but did not affect the food-intake behavior of the nematodes. Taken together, our results demonstrate that A. sinensis peptides (AsiPeps are able to delay aging process in C. elegans through antioxidant activities independent of dietary restriction.

  3. Accelerated aging in HIV/AIDS: novel biomarkers of senescent human CD8+ T cells.

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    Jennifer P Chou

    Full Text Available Clinical evaluation of immune reconstitution and health status during HIV-1 infection and anti-retroviral therapy (ART is largely based on CD4+ T cell counts and viral load, measures that fail to take into account the CD8+ T cell subset, known to show features of accelerated aging in HIV disease. Here, we compare adenosine deaminase (ADA, glucose uptake receptor 1 (GLUT1, and leucine-rich repeat neuronal 3 (LRRN3 to CD38 expression and telomerase activity, two strong predictors of HIV disease progression. Our analysis revealed that reduced ADA, telomerase activity and LRRN3 gene expression were significantly associated with high CD38 and HLA-DR in CD8+ T cells, with % ADA+ cells being the most robust predictor of CD8+ T cell activation. Our results suggest that ADA, LRRN3 and telomerase activity in CD8+ T cells may serve as novel, clinically relevant biomarkers of immune status in HIV-1 infection, specifically by demonstrating the degree to which CD8+ T cells have progressed to the end stage of replicative senescence. Since chronological aging itself leads to the accumulation of senescent CD8+ T cells, the prolonged survival and resultant increased age of the HIV+ population may synergize with the chronic immune activation to exacerbate both immune decline and age-associated pathologies. The identification and future validation of these new biomarkers may lead to fresh immune-based HIV treatments.

  4. [Contribution to tumor escape and chemotherapy response: A choice between senescence and apoptosis in heterogeneous tumors].

    Science.gov (United States)

    Jonchère, Barbara; Vétillard, Alexandra; Toutain, Bertrand; Guette, Catherine; Coqueret, Olivier

    2016-01-01

    Understanding adaptive signaling pathways in response to chemotherapy is one of the main challenges of cancer treatment. Activated in response to DNA damage, cell cycle and mitotic checkpoints activate the p53-p21 and p16-Rb pathways and induce apoptosis or senescence. Since senescent cells survive and produce a secretome that influences neighbouring cells, it is not particularly clear whether these responses are equivalent and if tumor cells escape these two suppressive pathways to the same extent. Predicting escape is also complicated by the fact that cancer cells adapt to treatments by activating the epithelial-mesenchymal transition and by producing clones with cancer-initiating cells features. Dedifferentiation pathways used in stressful conditions reconstitute dividing and sometimes more aggressive populations in response to chemotherapy. These observations illustrate the importance of tumor heterogeneity and the adaptation capacities of different intra-tumoral subclones. Depending on their oncogenic profile, on their localisation within the tumor and on their interaction with stromal cells, these subclones are expected to have different responses and adaptation capacities to chemotherapy. A complete eradication will certainly rely on combination therapies that can kill at the same time the bulk of the sensitive tumor but can also prevent plasticity and the generation of persistent clones. Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  5. Bioactive Peptides from Angelica sinensis Protein Hydrolyzate Delay Senescence in Caenorhabditis elegans through Antioxidant Activities

    Science.gov (United States)

    Wang, Qiangqiang; Huang, Yunxuan; Qin, Chuixin; Liang, Ming; Mao, Xinliang; Li, Shuiming; Zou, Yongdong; Jia, Weizhang; Li, Haifeng; Ma, Chung Wah; Huang, Zebo

    2016-01-01

    Since excessive reactive oxygen species (ROS) is known to be associated with aging and age-related diseases, strategies modulating ROS level and antioxidant defense systems may contribute to the delay of senescence. Here we show that the protein hydrolyzate from Angelica sinensis was capable of increasing oxidative survival of the model animal Caenorhabditis elegans intoxicated by paraquat. The hydrolyzate was then fractionated by ultrafiltration, and the antioxidant fraction (<3 kDa) was purified by gel filtration to obtain the antioxidant A. sinensis peptides (AsiPeps), which were mostly composed of peptides with <20 amino acid residues. Further studies demonstrate that AsiPeps were able to reduce the endogenous ROS level, increase the activities of the antioxidant enzymes superoxide dismutase and catalase, and decrease the content of the lipid peroxidation product malondialdehyde in nematodes treated with paraquat or undergoing senescence. AsiPeps were also shown to reduce age pigments accumulation and extend lifespan but did not affect the food-intake behavior of the nematodes. Taken together, our results demonstrate that A. sinensis peptides (AsiPeps) are able to delay aging process in C. elegans through antioxidant activities independent of dietary restriction. PMID:26941890

  6. Stem cells, senescence, neosis and self-renewal in cancer

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    Rajaraman Murali M

    2006-11-01

    Full Text Available Abstract We describe the basic tenets of the current concepts of cancer biology, and review the recent advances on the suppressor role of senescence in tumor growth and the breakdown of this barrier during the origin of tumor growth. Senescence phenotype can be induced by (1 telomere attrition-induced senescence at the end of the cellular mitotic life span (MLS* and (2 also by replication history-independent, accelerated senescence due to inadvertent activation of oncogenes or by exposure of cells to genotoxins. Tumor suppressor genes p53/pRB/p16INK4A and related senescence checkpoints are involved in effecting the onset of senescence. However, senescence as a tumor suppressor mechanism is a leaky process and senescent cells with mutations or epimutations in these genes escape mitotic catastrophe-induced cell death by becoming polyploid cells. These polyploid giant cells, before they die, give rise to several cells with viable genomes via nuclear budding and asymmetric cytokinesis. This mode of cell division has been termed neosis and the immediate neotic offspring the Raju cells. The latter inherit genomic instability and transiently display stem cell properties in that they differentiate into tumor cells and display extended, but, limited MLS, at the end of which they enter senescent phase and can undergo secondary/tertiary neosis to produce the next generation of Raju cells. Neosis is repeated several times during tumor growth in a non-synchronized fashion, is the mode of origin of resistant tumor growth and contributes to tumor cell heterogeneity and continuity. The main event during neosis appears to be the production of mitotically viable daughter genome after epigenetic modulation from the non-viable polyploid genome of neosis mother cell (NMC. This leads to the growth of resistant tumor cells. Since during neosis, spindle checkpoint is not activated, this may give rise to aneuploidy. Thus, tumor cells also are destined to die due to

  7. Cellular Senescence as the Causal Nexus of Aging.

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    Bhatia-Dey, Naina; Kanherkar, Riya R; Stair, Susan E; Makarev, Evgeny O; Csoka, Antonei B

    2016-01-01

    In this paper we present cellular senescence as the ultimate driver of the aging process, as a "causal nexus" that bridges microscopic subcellular damage with the phenotypic, macroscopic effect of aging. It is important to understand how the various types of subcellular damage correlated with the aging process lead to the larger, visible effects of anatomical aging. While it has always been assumed that subcellular damage (cause) results in macroscopic aging (effect), the bridging link between the two has been hard to define. Here, we propose that this bridge, which we term the "causal nexus", is in fact cellular senescence. The subcellular damage itself does not directly cause the visible signs of aging, but rather, as the damage accumulates and reaches a critical mass, cells cease to proliferate and acquire the deleterious "senescence-associated secretory phenotype" (SASP) which then leads to the macroscopic consequences of tissue breakdown to create the physiologically aged phenotype. Thus senescence is a precondition for anatomical aging, and this explains why aging is a gradual process that remains largely invisible during most of its progression. The subcellular damage includes shortening of telomeres, damage to mitochondria, aneuploidy, and DNA double-strand breaks triggered by various genetic, epigenetic, and environmental factors. Damage pathways acting in isolation or in concert converge at the causal nexus of cellular senescence. In each species some types of damage can be more causative than in others and operate at a variable pace; for example, telomere erosion appears to be a primary cause in human cells, whereas activation of tumor suppressor genes is more causative in rodents. Such species-specific mechanisms indicate that despite different initial causes, most of aging is traced to a single convergent causal nexus: senescence. The exception is in some invertebrate species that escape senescence, and in non-dividing cells such as neurons, where

  8. Characterization of photosynthetic performance during senescence in stay-green and quick-leaf-senescence Zea mays L. inbred lines.

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    Zishan Zhang

    Full Text Available The net photosynthetic rate, chlorophyll content, chlorophyll fluorescence and 820 nm transmission were investigated to explore the behavior of the photosynthetic apparatus, including light absorption, energy transformation and the photoactivities of photosystem II (PSII and photosystem I (PSI during senescence in the stay-green inbred line of maize (Zea mays Q319 and the quick-leaf-senescence inbred line of maize HZ4. The relationship between the photosynthetic performance and the decrease in chlorophyll content in the two inbred lines was also studied. Both the field and laboratory data indicated that the chlorophyll content, net photosynthetic rate, and the photoactivities of PSII and PSI decreased later and slower in Q319 than in HZ4, indicating that Q319 is a functional stay-green inbred line. In order to avoid the influence of different development stages and environmental factors on senescence, age-matched detached leaf segments from the two inbred lines were treated with ethephon under controlled conditions to induce senescence. The net photosynthetic rate, light absorption, energy transformation, the activities of PSII acceptor side and donor side and the PSI activities decreased much slower in Q319 than in HZ4 during the ethephon-induced senescence. These results suggest that the retention of light absorption, energy transformation and activity of electron transfer contribute to the extended duration of active photosynthesis in Q319. Although the chlorophyll content decreased faster in HZ4, with decrease of chlorophyll content induced by ethephon, photosynthetic performance of Q319 deteriorated much more severely than that of HZ4, indicating that, compared with Q319, HZ4 has an advantage at maintaining higher photosynthetic activity with decrease of chlorophyll although HZ4 is a quick-leaf-senescence inbred line. We conclude that attention should be paid to two favorable characteristics in breeding long duration of active

  9. Characterization of photosynthetic performance during senescence in stay-green and quick-leaf-senescence Zea mays L. inbred lines.

    Science.gov (United States)

    Zhang, Zishan; Li, Geng; Gao, Huiyuan; Zhang, Litao; Yang, Cheng; Liu, Peng; Meng, Qingwei

    2012-01-01

    The net photosynthetic rate, chlorophyll content, chlorophyll fluorescence and 820 nm transmission were investigated to explore the behavior of the photosynthetic apparatus, including light absorption, energy transformation and the photoactivities of photosystem II (PSII) and photosystem I (PSI) during senescence in the stay-green inbred line of maize (Zea mays) Q319 and the quick-leaf-senescence inbred line of maize HZ4. The relationship between the photosynthetic performance and the decrease in chlorophyll content in the two inbred lines was also studied. Both the field and laboratory data indicated that the chlorophyll content, net photosynthetic rate, and the photoactivities of PSII and PSI decreased later and slower in Q319 than in HZ4, indicating that Q319 is a functional stay-green inbred line. In order to avoid the influence of different development stages and environmental factors on senescence, age-matched detached leaf segments from the two inbred lines were treated with ethephon under controlled conditions to induce senescence. The net photosynthetic rate, light absorption, energy transformation, the activities of PSII acceptor side and donor side and the PSI activities decreased much slower in Q319 than in HZ4 during the ethephon-induced senescence. These results suggest that the retention of light absorption, energy transformation and activity of electron transfer contribute to the extended duration of active photosynthesis in Q319. Although the chlorophyll content decreased faster in HZ4, with decrease of chlorophyll content induced by ethephon, photosynthetic performance of Q319 deteriorated much more severely than that of HZ4, indicating that, compared with Q319, HZ4 has an advantage at maintaining higher photosynthetic activity with decrease of chlorophyll although HZ4 is a quick-leaf-senescence inbred line. We conclude that attention should be paid to two favorable characteristics in breeding long duration of active photosynthesis hybrids: 1

  10. Losing grip: Senescent decline in physical strength in a small-bodied primate in captivity and in the wild.

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    Hämäläinen, Anni; Dammhahn, Melanie; Aujard, Fabienne; Kraus, Cornelia

    2015-01-01

    Muscle strength reflects physical functioning, declines at old age and predicts health and survival in humans and laboratory animals. Age-associated muscle deterioration causes loss of strength and may impair fitness of wild animals. However, the effects of age and life-history characteristics on muscle strength in wild animals are unknown. We investigated environment- and sex-specific patterns of physical functioning by measuring grip strength in wild and captive gray mouse lemurs. We expected more pronounced strength senescence in captivity due to condition-dependent, extrinsic mortality found in nature. Males were predicted to be stronger but potentially experience more severe senescence than females as predicted by life history theory. We found similar senescent declines in captive males and females as well as wild females, whereas wild males showed little decline, presumably due to their early mortality. Captive animals were generally weaker and showed earlier declines than wild animals. Unexpectedly, females tended to be stronger than males, especially in the reproductive season. Universal intrinsic mechanisms (e.g. sarcopenia) likely cause the similar patterns of strength loss across settings. The female advantage in muscle strength merits further study; it may follow higher reproductive investment by males, or be an adaptation associated with female social dominance. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Nutritional enhancement of leaves by a psyllid through senescence-like processes: insect manipulation or plant defence?

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    Steinbauer, M J; Burns, A E; Hall, A; Riegler, M; Taylor, G S

    2014-12-01

    Some herbivores can modify the physiology of plant modules to meet their nutritional requirements. Induction of premature leaf senescence could benefit herbivores since it is associated with the mobilisation of nutrients. We compared the effects of nymphal feeding by Cardiaspina near densitexta on Eucalyptus moluccana with endogenous processes associated with senescence to assess the relative merits of an insect manipulation or plant defence interpretation of responses. Evidence supporting insect manipulation included increased size of fourth and fifth instar nymphs (in the latter the effect was restricted to forewing pad length of females) on leaves supporting high numbers of conspecifics and feeding preventing leaf necrosis. Intra-specific competition negated greater performance at very high densities. High and very high abundances of nymphs were associated with increased concentrations of amino acid N but only very high abundances of nymphs tended to be associated with increased concentrations of six essential amino acids. Contrary to the insect manipulation interpretation, feeding by very high abundances of nymphs was associated with significant reductions in chlorophyll, carotenoids and anthocyanins. Evidence supporting plant defence included the severity of chlorosis increasing with the abundance of nymphs. Leaf reddening did not develop because ambient conditions associated with photoinhibition (high irradiance and low temperature) were not experienced by leaves with chlorotic lesions. Leaf reddening (from anthocyanins) alone is not expected to adversely affect nymphal survival; only leaf necrosis would kill nymphs. For senescence-inducing psyllids, nutritional enhancement does not fit neatly into either an insect manipulation or plant defence interpretation.

  12. Pummelo Protects Doxorubicin-Induced Cardiac Cell Death by Reducing Oxidative Stress, Modifying Glutathione Transferase Expression, and Preventing Cellular Senescence

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    L. Chularojmontri

    2013-01-01

    Full Text Available Citrus flavonoids have been shown to reduce cardiovascular disease (CVD risks prominently due to their antioxidant effects. Here we investigated the protective effect of pummelo (Citrus maxima, CM fruit juice in rat cardiac H9c2 cells against doxorubicin (DOX- induced cytotoxicity. Four antioxidant compositions (ascorbic acid, hesperidin, naringin, and gallic acid were determined by HPLC. CM significantly increased cardiac cell survival from DOX toxicity as evaluated by MTT assay. Reduction of cellular oxidative stress was monitored by the formation of DCF fluorescent product and total glutathione (GSH levels. The changes in glutathione-S-transferase (GST activity and expression were determined by enzyme activity assay and Western blot analysis, respectively. Influence of CM on senescence-associated β-galactosidase activity (SA-β-gal was also determined. The mechanisms of cytoprotection involved reduction of intracellular oxidative stress, maintaining GSH availability, and enhanced GST enzyme activity and expression. DOX-induced cellular senescence was also attenuated by long-term CM treatment. Thus, CM fruit juice can be promoted as functional fruit to protect cells from oxidative cell death, enhance the phase II GSTP enzyme activity, and decrease senescence phenotype population induced by cardiotoxic agent such as DOX.

  13. Stressing the cell cycle in senescence and aging.

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    Chandler, Hollie; Peters, Gordon

    2013-12-01

    Senescence represents a permanent exit from the cell cycle and its role in curtailing the proliferation of damaged and potentially oncogenic cells has relevance both as a front-line defense against cancer and as an underlying cause of aging. The retinoblastoma protein (RB) and p53 tumor suppressors are central to the process and the growth arrest is primarily implemented by the cyclin-dependent kinase (CDK) inhibitors, p16INK4a and p21CIP1. In contrast to terminal differentiation, senescence is a general response to a diverse range of cellular stresses and is typically accompanied by a characteristic set of phenotypic changes. Of particular note is a secretory program whose autocrine and paracrine effects can advertize the presence of senescent cells within a tissue and promote their clearance by the immune system. In this short review, we will highlight recent advances in understanding the relationship between senescence and aging and the distinction between senescence and terminal differentiation, from a cell cycle perspective. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Cellular Senescence and the Biology of Aging, Disease, and Frailty.

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    LeBrasseur, Nathan K; Tchkonia, Tamara; Kirkland, James L

    2015-01-01

    Population aging simultaneously highlights the remarkable advances in science, medicine, and public policy, and the formidable challenges facing society. Indeed, aging is the primary risk factor for many of the most common chronic diseases and frailty, which result in profound social and economic costs. Population aging also reveals an opportunity, i.e. interventions to disrupt the fundamental biology of aging could significantly delay the onset of age-related conditions as a group, and, as a result, extend the healthy life span, or health span. There is now considerable evidence that cellular senescence is an underlying mechanism of aging and age-related conditions. Cellular senescence is a process in which cells lose the ability to divide and damage neighboring cells by the factors they secrete, collectively referred to as the senescence-associated secretory phenotype (SASP). Herein, we discuss the concept of cellular senescence, review the evidence that implicates cellular senescence and SASP in age-related deterioration, hyperproliferation, and inflammation, and propose that this underlying mechanism of aging may play a fundamental role in the biology of frailty. © 2015 Nestec Ltd., Vevey/S. Karger AG, Basel.

  15. Role of plasminogen activator inhibitor-1 in senescence and aging.

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    Eren, Mesut; Boe, Amanda E; Klyachko, Ekaterina A; Vaughan, Douglas E

    2014-09-01

    The average age of the US population continues to increase. Age is the most important determinant of disease and disability in humans, but the fundamental mechanisms of aging remain largely unknown. Many age-related diseases are associated with an impaired fibrinolytic system. Elevated plasminogen activator inhibitor-1 (PAI-1) levels are reported in age-associated clinical conditions including cardiovascular diseases, type 2 diabetes, obesity and inflammation. PAI-1 levels are also elevated in animal models of aging. While the association of PAI-1 with physiological aging is well documented, it is only recently that its critical role in the regulation of aging and senescence has become evident. PAI-1 is synthesized and secreted in senescent cells and contributes directly to the development of senescence by acting downstream of p53 and upstream of insulin-like growth factor binding protein-3. Pharmacologic inhibition or genetic deficiency of PAI-1 was shown to be protective against senescence and the aging-like phenotypes in kl/kl and N(ω)-nitro-l-arginine methyl ester-treated wild-type mice. Further investigation into PAI-1's role in senescence and aging will likely contribute to the prevention and treatment of aging-related pathologies. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  16. Identification and functional characterization of a rice NAC gene involved in the regulation of leaf senescence

    National Research Council Canada - National Science Library

    Zhou, Yong; Huang, Weifeng; Liu, Li; Chen, Taiyu; Zhou, Fei; Lin, Yongjun

    2013-01-01

    ... during the process of leaf senescence. The results of qRT-PCR showed that the OsNAP transcripts were accumulated gradually in response to leaf senescence and treatment with methyl jasmonic acid (MeJA...

  17. Identification and Localization of Genes Which Restore Senescence in Breast Cancer Cells

    National Research Council Canada - National Science Library

    Reddy, Deepthi

    1999-01-01

    .... Continuous culture of the senescent cells in selection media gave rise to revertant cells which have parental cell growth phenotype and have lost the region of the introduced chromosome that harbors the senescence gene...

  18. Stromal-epithelial interactions in aging and cancer: Senescent fibroblasts alter epithelial cell differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Parrinello, Simona; Coppe, Jean-Philippe; Krtolica, Ana; Campisi, Judith

    2004-07-14

    Cellular senescence suppresses cancer by arresting cells at risk for malignant tumorigenesis. However, senescent cells also secrete molecules that can stimulate premalignant cells to proliferate and form tumors, suggesting the senescence response is antagonistically pleiotropic. We show that premalignant mammary epithelial cells exposed to senescent human fibroblasts in mice irreversibly lose differentiated properties, become invasive and undergo full malignant transformation. Moreover, using cultured mouse or human fibroblasts and non-malignant breast epithelial cells, we show that senescent fibroblasts disrupt epithelial alveolar morphogenesis, functional differentiation, and branching morphogenesis. Further, we identify MMP-3 as the major factor responsible for the effects of senescent fibroblasts on branching morphogenesis. Our findings support the idea that senescent cells contribute to age-related pathology, including cancer, and describe a new property of senescent fibroblasts--the ability to alter epithelial differentiation--that might also explain the loss of tissue function and organization that is a hallmark of aging.

  19. The emerging role of senescent cells in tissue homeostasis and pathophysiology

    OpenAIRE

    Tominaga, Kaoru

    2015-01-01

    Cellular senescence is a state of permanent growth arrest and is thought to play a pivotal role in tumor suppression. Cellular senescence may play an important role in tumor suppression, wound healing, and protection against tissue fibrosis in physiological conditions in vivo. However, accumulating evidence that senescent cells may have harmful effects in vivo and may contribute to tissue remodeling, organismal aging, and many age-related diseases also exists. Cellular senescence can be induc...

  20. Cell Senescence in Myxoid/Round Cell Liposarcoma

    Directory of Open Access Journals (Sweden)

    Christina Kåbjörn Gustafsson

    2014-01-01

    Full Text Available Myxoid/round cell liposarcoma (MLS/RCLS is the second most common liposarcoma type and characterized by the fusion oncogenes FUS-DDIT3 or EWSR1-DDIT3. Previous analysis of cell cycle regulatory proteins revealed a prominent expression of G1-cyclins, cyclin dependent kinases, and their inhibitors but very few cells progressing through the G1/S boundary. Here, we extend the investigation to proteins involved in cell senescence in an immunohistochemistry based study of 17 MLS/RCLS cases. Large subpopulations of tumor cells expressed the RBL2 pocket protein and senescence associated heterochromatin 1γ and IL8 receptor β. We conclude that MLS/RCLS tissues contain major populations of senescent tumor cells and this may explain the slow growth rate of this tumor type.

  1. Senescence and quiescence in adipose-derived stromal cells

    DEFF Research Database (Denmark)

    Søndergaard, Rebekka Harary; Follin, Bjarke; Lund, Lisbeth Drozd

    2017-01-01

    cycle regulation and expression of cyclins, p21 and p27. hPL rejuvenates FBS-expanded ASCs with regard to cell cycle regulation and expression of cyclins, p21 and p27. This indicates a reversible arrest. Therefore, we conclude that ASCs expanded until P7 are not senescent regardless of culture......Background aims. Adipose-derived stromal cells (ASCs) are attractive sources for cell-based therapies. The hypoxic niche of ASCs in vivo implies that cells will benefit from hypoxia during in vitro expansion. Human platelet lysate (hPL) enhances ASC proliferation rates, compared with fetal bovine...... serum (FBS) at normoxia. However, the low proliferation rates of FBS-expanded ASCs could be signs of senescence or quiescence. We aimed to determine the effects of hypoxia and hPL on the expansion of ASCs and whether FBS-expanded ASCs are senescent or quiescent. Methods. ASCs expanded in FBS or h...

  2. Fumarate induces redox-dependent senescence by modifying glutathione metabolism.

    Science.gov (United States)

    Zheng, Liang; Cardaci, Simone; Jerby, Livnat; MacKenzie, Elaine D; Sciacovelli, Marco; Johnson, T Isaac; Gaude, Edoardo; King, Ayala; Leach, Joshua D G; Edrada-Ebel, RuAngelie; Hedley, Ann; Morrice, Nicholas A; Kalna, Gabriela; Blyth, Karen; Ruppin, Eytan; Frezza, Christian; Gottlieb, Eyal

    2015-01-23

    Mutations in the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase (FH) are associated with a highly malignant form of renal cancer. We combined analytical chemistry and metabolic computational modelling to investigate the metabolic implications of FH loss in immortalized and primary mouse kidney cells. Here, we show that the accumulation of fumarate caused by the inactivation of FH leads to oxidative stress that is mediated by the formation of succinicGSH, a covalent adduct between fumarate and glutathione. Chronic succination of GSH, caused by the loss of FH, or by exogenous fumarate, leads to persistent oxidative stress and cellular senescence in vitro and in vivo. Importantly, the ablation of p21, a key mediator of senescence, in Fh1-deficient mice resulted in the transformation of benign renal cysts into a hyperplastic lesion, suggesting that fumarate-induced senescence needs to be bypassed for the initiation of renal cancers.

  3. The emerging role of alternative splicing in senescence and aging.

    Science.gov (United States)

    Deschênes, Mathieu; Chabot, Benoit

    2017-10-01

    Deregulation of precursor mRNA splicing is associated with many illnesses and has been linked to age-related chronic diseases. Here we review recent progress documenting how defects in the machinery that performs intron removal and controls splice site selection contribute to cellular senescence and organismal aging. We discuss the functional association linking p53, IGF-1, SIRT1, and ING-1 splice variants with senescence and aging, and review a selection of splicing defects occurring in accelerated aging (progeria), vascular aging, and Alzheimer's disease. Overall, it is becoming increasingly clear that changes in the activity of splicing factors and in the production of key splice variants can impact cellular senescence and the aging phenotype. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  4. Biliary Epithelial Apoptosis, Autophagy, and Senescence in Primary Biliary Cirrhosis

    Directory of Open Access Journals (Sweden)

    Motoko Sasaki

    2010-01-01

    Full Text Available Primary biliary cirrhosis (PBC is a chronic cholestatic liver disease characterized serologically by the high prevalence of anti-mitochondrial autoantibodies (AMAs and histologically by the cholangitis of small bile ducts, eventually followed by extensive loss of the small bile duct. An autoimmune pathogenesis is suggested by clinical and experimental studies, but there remain issues regarding the etiology, the significance of AMAs in the pathogenesis of bile duct lesions, and so on. The unique properties of apoptosis in biliary epithelial cells (BECs, in which there is exposure of autoantigen to the effectors of the immune system, are proposed to be a cause of bile duct lesions in PBC. Recent progress disclosed that cellular senescence and autophagy are involved in bile duct lesions in PBC. Senescent BECs may modulate the periductal microenvironment by expressing senescence-associated secretory phenotypes, including various chemokines, and contribute to the pathogenesis of bile duct lesions in PBC.

  5. Gene regulatory cascade of senescence-associated NAC transcription factors activated by ETHYLENE-INSENSITIVE2-mediated leaf senescence signalling in Arabidopsis.

    Science.gov (United States)

    Kim, Hyo Jung; Hong, Sung Hyun; Kim, You Wang; Lee, Il Hwan; Jun, Ji Hyung; Phee, Bong-Kwan; Rupak, Timilsina; Jeong, Hana; Lee, Yeonmi; Hong, Byoung Seok; Nam, Hong Gil; Woo, Hye Ryun; Lim, Pyung Ok

    2014-07-01

    Leaf senescence is a finely tuned and genetically programmed degeneration process, which is critical to maximize plant fitness by remobilizing nutrients from senescing leaves to newly developing organs. Leaf senescence is a complex process that is driven by extensive reprogramming of global gene expression in a highly coordinated manner. Understanding how gene regulatory networks involved in controlling leaf senescence are organized and operated is essential to decipher the mechanisms of leaf senescence. It was previously reported that the trifurcate feed-forward pathway involving EIN2, ORE1, and miR164 in Arabidopsis regulates age-dependent leaf senescence and cell death. Here, new components of this pathway have been identified, which enhances knowledge of the gene regulatory networks governing leaf senescence. Comparative gene expression analysis revealed six senescence-associated NAC transcription factors (TFs) (ANAC019, AtNAP, ANAC047, ANAC055, ORS1, and ORE1) as candidate downstream components of ETHYLENE-INSENSITIVE2 (EIN2). EIN3, a downstream signalling molecule of EIN2, directly bound the ORE1 and AtNAP promoters and induced their transcription. This suggests that EIN3 positively regulates leaf senescence by activating ORE1 and AtNAP, previously reported as key regulators of leaf senescence. Genetic and gene expression analyses in the ore1 atnap double mutant revealed that ORE1 and AtNAP act in distinct and overlapping signalling pathways. Transient transactivation assays further demonstrated that ORE1 and AtNAP could activate common as well as differential NAC TF targets. Collectively, the data provide insight into an EIN2-mediated senescence signalling pathway that coordinates global gene expression during leaf senescence via a gene regulatory network involving EIN3 and senescence-associated NAC TFs. © The Author 2014. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  6. Testosterone Antagonizes Doxorubicin-Induced Senescence of Cardiomyocytes.

    Science.gov (United States)

    Altieri, Paola; Barisione, Chiara; Lazzarini, Edoardo; Garuti, Anna; Bezante, Gian Paolo; Canepa, Marco; Spallarossa, Paolo; Tocchetti, Carlo Gabriele; Bollini, Sveva; Brunelli, Claudio; Ameri, Pietro

    2016-01-08

    Chronic cardiotoxicity is less common in male than in female patients receiving doxorubicin and other anthracyclines at puberty and adolescence. We hypothesized that this sex difference might be secondary to distinct activities of sex hormones on cardiomyocyte senescence, which is thought to be central to the development of long-term anthracycline cardiomyopathy. H9c2 cells and neonatal mouse cardiomyocytes were exposed to doxorubicin with or without prior incubation with testosterone or 17β-estradiol, the main androgen and estrogen, respectively. Testosterone, but not 17β-estradiol, counteracted doxorubicin-elicited senescence. Downregulation of telomere binding factor 2, which has been pinpointed previously as being pivotal to doxorubicin-induced senescence, was also prevented by testosterone, as were p53 phosphorylation and accumulation. Pretreatment with the androgen receptor antagonist flutamide, the phosphatidylinositol 3 kinase inhibitor LY294002, and the nitric oxide synthase inhibitor L-NG-nitroarginine methyl ester abrogated the reduction in senescence and the normalization of telomere binding factor 2 levels attained by testosterone. Consistently, testosterone enhanced the phosphorylation of AKT and nitric oxide synthase 3. In H9c2 cells, doxorubicin-stimulated senescence was still observed up to 21 days after treatment and increased further when cells were rechallenged with doxorubicin 14 days after the first exposure to mimic the schedule of anthracycline-containing chemotherapy. Remarkably, these effects were also inhibited by testosterone. Testosterone protects cardiomyocytes against senescence caused by doxorubicin at least in part by modulating telomere binding factor 2 via a pathway involving the androgen receptor, phosphatidylinositol 3 kinase, AKT, and nitric oxide synthase 3. This is a potential mechanism by which pubescent and adolescent boys are less prone to chronic anthracycline cardiotoxicity than girls. © 2016 The Authors. Published on

  7. Senescent T-Cells Promote Bone Loss in Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Johannes Fessler

    2018-02-01

    Full Text Available ObjectiveT-cells are critical players in the pathogenesis of osteoporosis in patients with rheumatoid arthritis (RA. Premature senescence of lymphocytes including the accumulation of senescent CD4+ T-cells is a hallmark feature of RA. Whether T-cell senescence is associated with bone loss in RA patients is elusive so far.MethodsThis includes a prospective study of consecutive patients with RA (n = 107, patients with primary osteopenia/-porosis (n = 75, and healthy individuals (n = 38. Bone mineral density (BMD was determined by dual-energy X-ray absorptiometry scan. Flow cytometry, magnetic-associated cell sorting, and cell culture experiments were performed to analyze the pro-osteoclastic phenotype and the function of senescent CD4+CD28− T-cells.ResultsPatients with osteopenia/-porosis yielded a higher prevalence of senescent CD4+CD28− T-cells than individuals with normal BMD, in the RA, as well as in the non-RA cohort. Receptor activator of nuclear factor kappa-B ligand (RANKL was expressed at higher levels on CD4+CD28− T-cells as compared to CD28+ T-cells. Stimulation with interleukin-15 led to an up-regulation of RANKL expression, particularly on CD28− T-cells. CD4+CD28− T-cells induced osteoclastogenesis more efficiently than CD28+ T-cells.ConclusionOur data indicate that senescent T-cells promote osteoclastogenesis more efficiently than conventional CD28+ T-cells, which might contribute to the pathogenesis of systemic bone loss in RA and primary osteoporosis.

  8. Senescent T-Cells Promote Bone Loss in Rheumatoid Arthritis.

    Science.gov (United States)

    Fessler, Johannes; Husic, Rusmir; Schwetz, Verena; Lerchbaum, Elisabeth; Aberer, Felix; Fasching, Patrizia; Ficjan, Anja; Obermayer-Pietsch, Barbara; Duftner, Christina; Graninger, Winfried; Stradner, Martin Helmut; Dejaco, Christian

    2018-01-01

    T-cells are critical players in the pathogenesis of osteoporosis in patients with rheumatoid arthritis (RA). Premature senescence of lymphocytes including the accumulation of senescent CD4 + T-cells is a hallmark feature of RA. Whether T-cell senescence is associated with bone loss in RA patients is elusive so far. This includes a prospective study of consecutive patients with RA ( n  = 107), patients with primary osteopenia/-porosis ( n  = 75), and healthy individuals ( n  = 38). Bone mineral density (BMD) was determined by dual-energy X-ray absorptiometry scan. Flow cytometry, magnetic-associated cell sorting, and cell culture experiments were performed to analyze the pro-osteoclastic phenotype and the function of senescent CD4 + CD28 - T-cells. Patients with osteopenia/-porosis yielded a higher prevalence of senescent CD4 + CD28 - T-cells than individuals with normal BMD, in the RA, as well as in the non-RA cohort. Receptor activator of nuclear factor kappa-B ligand (RANKL) was expressed at higher levels on CD4 + CD28 - T-cells as compared to CD28 + T-cells. Stimulation with interleukin-15 led to an up-regulation of RANKL expression, particularly on CD28 - T-cells. CD4 + CD28 - T-cells induced osteoclastogenesis more efficiently than CD28 + T-cells. Our data indicate that senescent T-cells promote osteoclastogenesis more efficiently than conventional CD28 + T-cells, which might contribute to the pathogenesis of systemic bone loss in RA and primary osteoporosis.

  9. Giant kelp vegetative propagation: Adventitious holdfast elements rejuvenate senescent individuals of the Macrocystis pyrifera "integrifolia" ecomorph.

    Science.gov (United States)

    Murúa, Pedro; Müller, Dieter G; Patiño, David J; Westermeier, Renato

    2017-02-01

    Recent findings on holdfast development in the giant kelp highlighted its key importance for Macrocystis vegetative propagation. We report here for the first time the development of adventitious holdfasts from Macrocystis stipes. Swellings emerge spontaneously from different areas of the stipes, especially in senescent or creeping individuals. After being manually fastened to solid substrata, these swellings elongated into haptera, which became strongly attached after 1 month. Within 4 months, new thalli increased in size and vitality, and developed reproductive fronds. Our results suggest the usage of these structures for auxiliary attachment techniques. These could act as a backup, when primary holdfasts are weak, and thus improve the survival rate of the giant kelp in natural beds. © 2016 Phycological Society of America.

  10. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA

    NARCIS (Netherlands)

    Demaria, Marco; Ohtani, Naoko; Youssef, Sameh A; Rodier, Francis; Toussaint, Wendy; Mitchell, James R; Laberge, Remi-Martin; Vijg, Jan; Van Steeg, Harry; Dollé, Martijn E T; Hoeijmakers, Jan H J; de Bruin, Alain; Hara, Eiji; Campisi, Judith

    2014-01-01

    Cellular senescence suppresses cancer by halting the growth of premalignant cells, yet the accumulation of senescent cells is thought to drive age-related pathology through a senescence-associated secretory phenotype (SASP), the function of which is unclear. To understand the physiological role(s)

  11. An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA

    NARCIS (Netherlands)

    Demaria, Marco; Ohtani, Naoko; Youssef Hassan, Sameh|info:eu-repo/dai/nl/374027080; Rodier, Francis; Toussaint, Wendy; Mitchell, James R; Laberge, Remi-Martin; Vijg, Jan; Van Steeg, Harry; Dollé, Martijn E T; Hoeijmakers, Jan H J; de Bruin, Alain|info:eu-repo/dai/nl/304837261; Hara, Eiji; Campisi, Judith

    2014-01-01

    Cellular senescence suppresses cancer by halting the growth of premalignant cells, yet the accumulation of senescent cells is thought to drive age-related pathology through a senescence-associated secretory phenotype (SASP), the function of which is unclear. To understand the physiological role(s)

  12. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA

    NARCIS (Netherlands)

    M. Demaria (Marco); N. Ohtani (Naoko); S. Youssef (SamehA.); F. Rodier (Francis); W. Toussaint (Wendy); J. Mitchell (JamesR.); R.-M. Laberge (Remi-Martin); J. Vijg (Jan); H. VanSteeg (Harry); M. Dollé (MartijnE.T.); J. Hoeijmakers (JanH.J.); A. deBruin (Alain); E. Hara (Eiji); J. Campisi (Judith)

    2014-01-01

    textabstractCellular senescence suppresses cancer by halting the growth of premalignant cells, yet the accumulation of senescent cells is thought to drive age-related pathology through a senescence-associated secretory phenotype (SASP), the function of which is unclear. To understand the

  13. Targeting Senescent Cells : Possible Implications for Delaying Skin Aging: A Mini-Review

    NARCIS (Netherlands)

    Velarde, Michael C.; Demaria, Marco

    2016-01-01

    Senescent cells are induced by a wide variety of stimuli. They accumulate in several tissues during aging, including the skin. Senescent cells secrete proinflammatory cytokines, chemokines, growth factors, and proteases, a phenomenon called senescence-associated secretory phenotype (SASP), which are

  14. Arabidopsis onset of leaf death mutants identify a regulatory pathway controlling leaf senescence

    NARCIS (Netherlands)

    Jing, Hai-Chun; Sturre, Marcel J.G.; Hille, Jacques; Dijkwel, Paul P.

    2002-01-01

    The onset of leaf senescence is controlled by leaf age and ethylene can promote leaf senescence within a specific age window. We exploited the interaction between leaf age and ethylene and isolated mutants with altered leaf senescence that are named as onset of leaf death (old) mutants. Early leaf

  15. [Impact of cellular senescence on organismal aging and age-related diseases].

    Science.gov (United States)

    Bielak-Zmijewska, Anna; Grabowska, Wioleta; Przybylska, Dorota

    2014-01-01

    Development of the civilization and medicine enables an even longer lifespan of people. To modulate the aging process it is necessary to discover its molecular mechanism and its causes. It has been known for almost 60 years that cells undergo senescence. A lot of markers of senescence have been described to distinguish senescent cells. Every year we can observe an increase in the number of data, supporting the thesis that the reason for aging of the whole organism is cellular senescence. We age because cells building tissues and organs undergo senescence. It is also believed that cellular senescence can increase the frequency of age-related diseases. The role of cellular senescence strictly depends on the age of the individual. In young ones it is essential for: protection against cancer and tissue regeneration. In old ones it causes tissues and organs dysfunctions and leads to age-related diseases. Slowing down aging could prevent age-related diseases and this seems to be more promising than curing them. To enrich our knowledge concerning aging it is important to understand signaling pathways leading to senescence. Recently a new role of cellular senescence has been discovered, namely during embryogenesis. This observation is very surprising and shows a new face of cellular senescence. It is possible that, similarly to the previously described role of apoptosis in embryogenesis, senescence is indispensable for proper organogenesis. Cellular senescence seems to be the universal and fundamental process, the role of which changes during the lifespan.

  16. ORE1 balances leaf senescence against maintenance by antagonizing G2-like-mediated transcription

    OpenAIRE

    Rauf, Mamoona; Arif, Muhammad; Dortay, Hakan; Matallana-Ramírez, Lilian P; Waters, Mark T.; Gil Nam, Hong; Lim, Pyung-Ok; Mueller-Roeber, Bernd; Balazadeh, Salma

    2013-01-01

    Transcription factor ORE1 is a key regulator of senescence in Arabidopsis thaliana. Here, it is shown to also inhibit the function of Golden2-like transcription factors, which antagonize senescence, revealing a new mechanism of ORE1-mediated senescence control.

  17. Life History Trade-Offs Modulate the Speed of Senescence

    DEFF Research Database (Denmark)

    Salguero-Gómez, Roberto; Jones, Owen

    2017-01-01

    The vast amount of scientific attention attracted by ageing research is, to a large extent, due to humanity’s desire to prolong life span and ‘health span’. Still, from a purely ecological and evolutionary point of view, the fact that such a large diversity of longevities exists is extremely...... examined how key life-history traits such as mean life expectancy, generation time and the length of life lived before maturity correlate with this measure of senescence, finding that iteroparous, slow-growing species are more likely to senesce slowly and thus attain long mature life spans. We further...

  18. A senescence-associated gene of Arabidopsis thaliana is distinctively regulated during natural and artificially induced leaf senescence.

    Science.gov (United States)

    Oh, S A; Lee, S Y; Chung, I K; Lee, C H; Nam, H G

    1996-02-01

    We have characterized the structure and expression of a senescence-associated gene (sen1) of Arabidopsis thaliana. The protein-coding region of the gene consists of 5 exons encoding 182 amino acids. The encoded peptide shows noticeable similarity to the bacterial sulfide dehydrogenase and 81% identity to the peptide encoded by the radish din1 gene. The 5'-upstream region contains sequence motifs resembling the heat-shock- and ABA-responsive elements and the TCA motif conserved among stress-inducible genes. Examination of the expression patterns of the sen1 gene under various senescing conditions along with measurements of photochemical efficiency and of chlorophyll content revealed that the sen1 gene expression is associated with Arabidopsis leaf senescence. During the normal growth phase, the gene is strongly induced in leaves at 25 days after germination when inflorescence stems are 2-3 cm high, and then the mRNA level is maintained at a comparable level in naturally senescing leaves. In addition, dark-induced senescence of detached leaves or of leaves in planta resulted in a high-level induction of the gene. Expression of the sen1 gene was also strongly induced in leaves subjected to senescence by 0.1mM abscisic acid or 1 mM ethephon treatment. The induced expression of the gene by dark treatment was not significantly repressed by treatment with 0.1 mM cytokinin or 50 mM CaCl2 which delayed loss of chlorophyll but not that of photochemical efficiency.

  19. effect of farmyard manure on senescence, nitrogen and protein ...

    African Journals Online (AJOL)

    DR. AMINU

    and days to total death of the plants occurred earlier in IT89KD – 288 than in Kanannado, while comparison between the treatments ... death, senescence in plants is a complex and highly regulated process that occurs as part of ... Africa, but are also grown in Asia, latin America and. North America (Rachie, 1985). In this ...

  20. Vascular Cell Senescence Contributes to Blood-Brain Barrier Breakdown

    NARCIS (Netherlands)

    Yamazaki, Y.; Baker, D.J.; Tachibana, M.; Liu, C.C.; Deursen, J.M.A. van; Brott, T.G.; Bu, G.; Kanekiyo, T.

    2016-01-01

    BACKGROUND AND PURPOSE: Age-related changes in the cerebrovasculature, including blood-brain barrier (BBB) disruption, are emerging as potential risks for diverse neurological conditions. Because the accumulation of senescent cells in tissues is increasingly recognized as a critical step leading to

  1. Senescence, Wound Healing and Cancer. The PAI-1 Connection

    NARCIS (Netherlands)

    Bernards, R.A.; Kortlever, R.M.

    2006-01-01

    Prolonged propagation of primary diploid fibroblasts in culture activates an ageing process known as replicative senescence, which is considered to provide a barrier against oncogenic transformation. Remarkably, both cell autonomous tumor‑suppressive and cell nonautonomous tumor‑promoting effects of

  2. Biological Impact of Senescence Induction in Prostate Cancer Therapy

    Science.gov (United States)

    2009-01-01

    1 mM Na3VO4 (wash buffer) before incubation in blocking buffer (wash buffer þ 10% fetal bovine serum þ 1% bovine serum albumin ) for 1 h at room...250nM AZQ for 3 days. Senescent cells become enlarged and flattened with a “fried egg ” appearance and blue SA-β-gal staining. Original image

  3. Daffodil flower delay senescence in cut Iris flowers

    NARCIS (Netherlands)

    Doorn, van W.G.; Sinz, A.; Tomassen, M.M.M.

    2004-01-01

    Visible symptoms of tepal senescence in cut Iris x hollandica (cv. Blue Magic) flowers were delayed by placing one cut daffodil flower (Narcissus pseudonarcissus, cv. Carlton) in the same vase. Addition of mucilage, exuded by daffodil stems, to the vase water had the same effect as the flowering

  4. Polyamines, peroxidase and proteins involved in the senescence ...

    African Journals Online (AJOL)

    ... the involvement of substances that may be related to senescence in plants, such as polyamines, peroxidase and proteins. These substances were related with the terminal stages of development of various plant organs (leaves, flowers, roots). Keywords: Flowers, putrescine, spermidine, spermine, reactive oxygen species

  5. Alkaline protease from senesced leaves of invasive weed Lantana ...

    African Journals Online (AJOL)

    STORAGESEVER

    2008-12-17

    Dec 17, 2008 ... The easy availability of the senesced leaves of this common weed makes it a cheaper ... generate new enzymes with altered properties (Rao et al., 1998). .... The activity of the enzyme was determined by incubating the reac- ..... Microbial alkaline proteases: from bio ... Phytochemistry, 49(3): 643-649.

  6. Oncogene-induced senescence: putting the brakes on tumor development

    National Research Council Canada - National Science Library

    Braig, Melanie; Schmitt, Clemens A

    2006-01-01

    ... an issue of debate over the years. A number of recent studies now show the effect of this acute and telomere-independent form of senescence as a tumor-protective, fail-safe mechanism in vivo that shares conceptual and possibly...

  7. Alkaline protease from senesced leaves of invasive weed | Gaur ...

    African Journals Online (AJOL)

    step procedure involving ammonium sulfate precipitation and Sephadex G-250 gel permeation chromatography. The Sephadex-G-250 fraction of senesced leaves of Lantana camara showed 28.31 fold with a yield of 6.19%. The enzyme was ...

  8. Testosterone supplementation restores vasopressin innervation in the senescent rat brain

    NARCIS (Netherlands)

    Goudsmit, E.; Fliers, E.; Swaab, D. F.

    1988-01-01

    The vasopressin (AVP) innervation in the male rat brain is decreased in senescence. This decrease is particularly pronounced in brain regions where AVP fiber density is dependent on plasma levels of sex steroids. Since plasma testosterone levels decrease progressively with age in the rat, the

  9. ATM Couples Replication Stress and Metabolic Reprogramming during Cellular Senescence

    Directory of Open Access Journals (Sweden)

    Katherine M. Aird

    2015-05-01

    Full Text Available Replication stress induced by nucleotide deficiency plays an important role in cancer initiation. Replication stress in primary cells typically activates the cellular senescence tumor-suppression mechanism. Senescence bypass correlates with development of cancer, a disease characterized by metabolic reprogramming. However, the role of metabolic reprogramming in the cellular response to replication stress has been little explored. Here, we report that ataxia telangiectasia mutated (ATM plays a central role in regulating the cellular response to replication stress by shifting cellular metabolism. ATM inactivation bypasses senescence induced by replication stress triggered by nucleotide deficiency. This was due to restoration of deoxyribonucleotide triphosphate (dNTP levels through both upregulation of the pentose phosphate pathway via increased glucose-6-phosphate dehydrogenase (G6PD activity and enhanced glucose and glutamine consumption. These phenotypes were mediated by a coordinated suppression of p53 and upregulation of c-MYC downstream of ATM inactivation. Our data indicate that ATM status couples replication stress and metabolic reprogramming during senescence.

  10. Delay of Iris flower senescence by cytokinins and jasmonates

    NARCIS (Netherlands)

    Doorn, van W.G.; Celikel, F.G.; Pak, C.; Harkema, H.

    2013-01-01

    It is not known whether tepal senescence in Iris flowers is regulated by hormones. We applied hormones and hormone inhibitors to cut flowers and isolated tepals of Iris x hollandica cv. Blue Magic. Treatments with ethylene or ethylene antagonists indicated lack of ethylene involvement. Auxins or

  11. Senescence sweetening of chip and fry processing potatoes

    Science.gov (United States)

    Potato storage makes the crop available over an extended time period, but increases financial risk to growers and end users. Senescence sweetening limits storage duration for chip and fry processing potatoes because it results in an unacceptable accumulation of reducing sugars that result in dark-co...

  12. Role of polyamines and ethylene as modulators of plant senescence

    Indian Academy of Sciences (India)

    Under optimal conditions of growth, senescence, a terminal phase of development, sets in after a certain physiological age. It is a dynamic and closely regulated developmental process which involves an array of changes at both physiological and biochemical levels including gene expression. A large number of biotic and ...

  13. Effect of farmyard manure on senescence, nitrogen and protein ...

    African Journals Online (AJOL)

    The effect of farmyard manure was studied on senescence, nitrogen and protein content of the leaves and grains of cowpea. The experimental site for this study was situated at the International Institute of Tropical Agriculture (IITA), Kano Station, Nigeria. The cowpea varieties used in this experiment were Kanannado a local ...

  14. Management practices to control premature senescence in bt cotton

    Science.gov (United States)

    Commercial cultivation of Bt cotton produced higher boll load which led to stiff inter-organal competition for photosynthates resulting in early cessation of growth (premature senescence) due to more availability of sink and less sources. To overcome this problem field experiment was conducted durin...

  15. Role of the ascorbate-glutathione cycle during senescence and ...

    African Journals Online (AJOL)

    Programmed cell death is an integral part of normal plant development including leaf senescence. This study investigated the response of some component of ascorbate-glutathione cycle, chlorophylls.a & b, protein content, and membrane leakage during the developmental stages of Phaseolus cotyledons from imbibition till ...

  16. Functional age as an indicator of reservoir senescence

    Science.gov (United States)

    Miranda, Leandro E.; Krogman, R. M.

    2015-01-01

    It has been conjectured that reservoirs differ in the rate at which they manifest senescence, but no attempt has been made to find an indicator of senescence that performs better than chronological age. We assembled an indicator of functional age by creating a multimetric scale consisting of 10 metrics descriptive of reservoir environments that were expected to change directionally with reservoir senescence. In a sample of 1,022 U.S. reservoirs, chronological age was not correlated with functional age. Functional age was directly related to percentage of cultivated land in the catchment and inversely related to reservoir depth. Moreover, aspects of reservoir fishing quality and fish population characteristics were related to functional age. A multimetric scale to indicate reservoir functional age presents the possibility for management intervention from multiple angles. If a reservoir is functionally aging at an accelerated rate, action may be taken to remedy the conditions contributing most to functional age. Intervention to reduce scores of selected metrics in the scale can potentially reduce the rate of senescence and increase the life expectancy of the reservoir. This leads to the intriguing implication that steps can be taken to reduce functional age and actually make the reservoir grow younger.

  17. Dynamics of senescence-related QTLs in potato

    NARCIS (Netherlands)

    Hurtado Lopez, P.X.; Schnabel, S.K.; Zaban, A.; Vetelainen, M.; Virtanen, E.; Eilers, P.; Eeuwijk, van F.A.; Visser, R.G.F.; Maliepaard, C.A.

    2012-01-01

    The study of quantitative trait’s expression over time helps to understand developmental processes which occur in the course of the growing season. Temperature and other environmental factors play an important role. The dynamics of haulm senescence was observed in a diploid potato mapping population

  18. Quantitative theory of telomere length regulation and cellular senescence.

    Science.gov (United States)

    Rodriguez-Brenes, Ignacio A; Peskin, Charles S

    2010-03-23

    In normal somatic cells, telomere length shortens with each cell replication. This progressive shortening is associated with cellular senescence and apoptosis. Germ cells, stem cells, and the majority of cancer cells express telomerase, an enzyme that extends telomere length and, when expressed at sufficient levels, can immortalize or extend the life span of a cell line. It is believed that telomeres switch between two states: capped and uncapped. The telomere state determines its accessibility to telomerase and also the onset of senescence. One hypothesis is that the t loop, a large lariat-like structure, represents the capped state. In this paper we model a telomere state on the basis of the biophysics of t-loop formation, allowing us to develop a single mathematical model that accounts for two processes: telomere length regulation for telomerase positive cells and cellular senescence in somatic cells. The model predicts the steady-state length distribution for telomerase positive cells, describes the time evolution of telomere length, and computes the life span of a cell line on the basis of the levels of TRF2 and telomerase expression. The model reproduces a wide range of experimental behavior and fits data from immortal cell lines (HeLa S3 and 293T) and somatic cells (human diploid fibroblasts) well. We conclude that the t loop as the capped state is a quantitatively reasonable model of telomere length regulation and cellular senescence.

  19. Role of p16INK4A in Replicative Senescence and DNA Damage-Induced Premature Senescence in p53-Deficient Human Cells

    Directory of Open Access Journals (Sweden)

    Razmik Mirzayans

    2012-01-01

    Full Text Available The p16INK4A (hereafter p16 tumor suppressor is encoded by the INK4A/ARF locus which is among the most commonly dysregulated sequences in human cancer. By inhibiting cyclin-dependent kinases, p16 activates the G1-S checkpoint, and this response is often considered to be critical for establishing a senescence-like growth arrest. Not all studies support a universal role for p16 in senescence. Single-cell analysis of noncancerous human fibroblast cultures undergoing senescence as a function of culture age (replicative senescence has revealed that p16 is not expressed in the majority (>90% of cells that exhibit features of senescence (e.g., flattened and enlarged morphology coupled with senescence-associated β-galactosidase expression, ruling out a requirement for p16 in this process. In addition, ionizing radiation triggers premature senescence in human cancer cell lines that do not express p16. These observations are made with cells that express wild-type p53, a key mediator of the DNA damage response. In this paper, we examine the growing evidence suggesting a negative regulatory relationship between p16 and p53 and discuss recent reports that implicate a role for p16 in replicative senescence and ionizing radiation-induced premature senescence in human cells that lack wild-type p53 function.

  20. Aging and atherosclerosis: mechanisms, functional consequences, and potential therapeutics for cellular senescence.

    Science.gov (United States)

    Wang, Julie C; Bennett, Martin

    2012-07-06

    Atherosclerosis is classed as a disease of aging, such that increasing age is an independent risk factor for the development of atherosclerosis. Atherosclerosis is also associated with premature biological aging, as atherosclerotic plaques show evidence of cellular senescence characterized by reduced cell proliferation, irreversible growth arrest and apoptosis, elevated DNA damage, epigenetic modifications, and telomere shortening and dysfunction. Not only is cellular senescence associated with atherosclerosis, there is growing evidence that cellular senescence promotes atherosclerosis. This review examines the pathology of normal vascular aging, the evidence for cellular senescence in atherosclerosis, the mechanisms underlying cellular senescence including reactive oxygen species, replication exhaustion and DNA damage, the functional consequences of vascular cell senescence, and the possibility that preventing accelerated cellular senescence is a therapeutic target in atherosclerosis.

  1. Stress induced premature senescence : a new culprit in ovarian tumorigenesis?

    Directory of Open Access Journals (Sweden)

    Gorantla Venkata Raghuram

    2014-01-01

    Full Text Available Stress induced premature senescence (SIPS is a relative extension to the concept of exogenous cellular insult. Besides persistent double strand (ds DNA breaks and increased β-galactosidase activity, biological significance of telomeric attrition in conjunction with senescence associated secretory phenotype (SASP has been highlighted in SIPS. To gain insight on the potential role of this unique phenomenon invoked upon environmental stress, we sequentially validated the molecular repercussions of this event in ovarian epithelial cells after exposure to methyl isocyanate, an elegant regulator of cellular biotransformation. Persistent accumulation of DNA damage response factors phospho-ATM/γ-H2AX, morphological changes with increased cell size and early yet incremental β-gal staining, imply the inception of premature senescence. Advent of SASP is attributed by prolonged secretion of pro-inflammatory cytokines along with untimely but significant G1/S cell cycle arrest. Telomeric dysfunction associated with premature senescence is indicative of early loss of TRF2 (telomeric repeat binding factor 2 protein and resultant multiple translocations. Induction of senescence-associated heterochromatic foci formation showcases the chromatin alterations in form of trimethylated H3K9me3 in conjunction with H4 hypoacetylation and altered miRNA expression. Anchorage-independent neoplastic growth observed in treated cells reaffirms the oncogenic transformation following the exposure. Collectively, we infer the possible role of SIPS, as a central phenomenon, to perturbed genomic integrity in ovarian surface epithelium, orchestrated through SASP and chromatin level alterations, a hitherto unknown molecular paradigm. Although translational utility of SIPS as a biomarker for estimating ovarian cancer risk seems evident, further investigations will be imperative to provide a tangible way for its precise validation in clinical settings.

  2. The ING tumor suppressors in cellular senescence and chromatin

    Directory of Open Access Journals (Sweden)

    Ludwig Susann

    2011-07-01

    Full Text Available Abstract The Inhibitor of Growth (ING proteins represent a type II tumor suppressor family comprising five conserved genes, ING1 to ING5. While ING1, ING2 and ING3 proteins are stable components of the mSIN3a-HDAC complexes, the association of ING1, ING4 and ING5 with HAT protein complexes was also reported. Among these the ING1 and ING2 have been analyzed more deeply. Similar to other tumor suppressor factors the ING proteins are also involved in many cellular pathways linked to cancer and cell proliferation such as cell cycle regulation, cellular senescence, DNA repair, apoptosis, inhibition of angiogenesis and modulation of chromatin. A common structural feature of ING factors is the conserved plant homeodomain (PHD, which can bind directly to the histone mark trimethylated lysine of histone H3 (H3K4me3. PHD mutants lose the ability to undergo cellular senescence linking chromatin mark recognition with cellular senescence. ING1 and ING2 are localized in the cell nucleus and associated with chromatin modifying enzymes, linking tumor suppression directly to chromatin regulation. In line with this, the expression of ING1 in tumors is aberrant or identified point mutations are mostly localized in the PHD finger and affect histone binding. Interestingly, ING1 protein levels increase in replicative senescent cells, latter representing an efficient pathway to inhibit cancer proliferation. In association with this, suppression of p33ING1 expression prolongs replicative life span and is also sufficient to bypass oncogene-induced senescence. Recent analyses of ING1- and ING2-deficient mice confirm a tumor suppressive role of ING1 and ING2 and also indicate an essential role of ING2 in meiosis. Here we summarize the activity of ING1 and ING2 as tumor suppressors, chromatin factors and in development.

  3. Depletion of HPV16 early genes induces autophagy and senescence in a cervical carcinogenesis model, regardless of viral physical state.

    Science.gov (United States)

    Hanning, Jennifer E; Saini, Harpreet K; Murray, Matthew J; Caffarel, Maria M; van Dongen, Stijn; Ward, Dawn; Barker, Emily M; Scarpini, Cinzia G; Groves, Ian J; Stanley, Margaret A; Enright, Anton J; Pett, Mark R; Coleman, Nicholas

    2013-11-01

    In cervical carcinomas, high-risk human papillomavirus (HR-HPV) may be integrated into host chromosomes or remain extra-chromosomal (episomal). We used the W12 cervical keratinocyte model to investigate the effects of HPV16 early gene depletion on in vitro cervical carcinogenesis pathways, particularly effects shared by cells with episomal versus integrated HPV16 DNA. Importantly, we were able to study the specific cellular consequences of viral gene depletion by using short interfering RNAs known not to cause phenotypic or transcriptional off-target effects in keratinocytes. We found that while cervical neoplastic progression in vitro was characterized by dynamic changes in HPV16 transcript levels, viral early gene expression was required for cell survival at all stages of carcinogenesis, regardless of viral physical state, levels of early gene expression or histology in organotypic tissue culture. Moreover, HPV16 early gene depletion induced changes in host gene expression that were common to both episome-containing and integrant-containing cells. In particular, we observed up-regulation of autophagy genes, associated with enrichment of senescence and innate immune-response pathways, including the senescence-associated secretory phenotype (SASP). In keeping with these observations, HPV16 early gene depletion induced autophagy in both episome-containing and integrant-containing W12 cells, as evidenced by the appearance of autophagosomes, punctate expression of the autophagy marker LC3, conversion of LC3B-I to LC3B-II, and reduced levels of the autophagy substrate p62. Consistent with the reported association between autophagy and senescence pathways, HPV16 early gene depletion induced expression of the senescence marker beta-galactosidase and increased secretion of the SASP-related protein IGFBP3. Together, these data indicate that depleting HR-HPV early genes would be of potential therapeutic benefit in all cervical carcinogenesis pathways, regardless of viral

  4. 17AAG Treatment Accelerates Doxorubicin Induced Cellular Senescence: Hsp90 Interferes with Enforced Senescence of Tumor Cells.

    NARCIS (Netherlands)

    Sarangi, U.; Paithankar, K.R.; Kumar, J.U.; Subramaniam, V.; Sreedhar, A.S.

    2012-01-01

    Hsp90 chaperone has been identified as an attractive pharmacological target to combat cancer. However, some metastatic tumors either fail to respond to Hsp90 inhibition or show recovery necessitating irreversible therapeutic strategies. In response to this enforced senescence has been proposed as an

  5. Mitochondrial pAL2-1 plasmid homologs are senescence factors in Podospora anserina independent of intrinsic senescence

    NARCIS (Netherlands)

    Diepeningen, van A.D.; Debets, A.J.M.; Slakhorst-Wandel, S.M.; Hoekstra, R.F.

    2008-01-01

    Since the first description of a linear mitochondrial plasmid in Podospora anserina, pAL2-1, and homologous plasmids have gone from being considered beneficial longevity plasmids, via neutral genetic elements, toward mutator plasmids causing senescence. The plasmid has an invertron structure, with

  6. Mitochondrial pAL2-1 plasmid homologs are senescence factors in Podospora anserina independent of intrinsic senescence

    NARCIS (Netherlands)

    van Diepeningen, Anne D; Debets, Alfons J M; Slakhorst, S Marijke; Hoekstra, Rolf F

    Since the first description of a linear mitochondrial plasmid in Podospora anserina, pAL2-1, and homologous plasmids have gone from being considered beneficial longevity plasmids, via neutral genetic elements, toward mutator plasmids causing senescence. The plasmid has an invertron structure, with

  7. Are reproductive and somatic senescence coupled in humans? Late, but not early, reproduction correlated with longevity in historical Sami women

    Science.gov (United States)

    Helle, Samuli; Lummaa, Virpi; Jokela, Jukka

    2005-01-01

    Evolutionary theory of senescence emphasizes the importance of intense selection on early reproduction owing to the declining force of natural selection with age that constrains lifespan. In humans, recent studies have, however, suggested that late-life mortality might be more closely related to late rather than early reproduction, although the role of late reproduction on fitness remains unclear. We examined the association between early and late reproduction with longevity in historical post-reproductive Sami women. We also estimated the strength of natural selection on early and late reproduction using path analysis, and the effect of reproductive timing on offspring survival to adulthood and maternal risk of dying at childbirth. We found that natural selection favoured both earlier start and later cessation of reproduction, and higher total fe cundity. Maternal age at childbirth was not related to offspring or maternal survival. Interestingly, females who produced their last offspring at advanced age also lived longest, while age at first reproduction and total fecundity were unrelated to female longevity. Our results thus suggest that reproductive and somatic senescence may have been coupled in these human populations, and that selection could have favoured late reproduction. We discuss alternative hypotheses for the mechanisms which might have promoted the association between late reproduction and longevity. PMID:15875567

  8. The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis.

    Science.gov (United States)

    Yang, Gong; Rosen, Daniel G; Zhang, Zhihong; Bast, Robert C; Mills, Gordon B; Colacino, Justin A; Mercado-Uribe, Imelda; Liu, Jinsong

    2006-10-31

    Epithelial-stromal interactions play a critical role in tumor initiation and progression; cancer-associated stroma, but not normal stroma, is known to be tumor-promoting. However, the molecular signal used by epithelial cancer cells to reprogram normal stroma to a tumorigenic stroma is not known. Here, we present evidence to suggest that the chemokine growth-regulated oncogene 1 (Gro-1) may be one such signaling molecule. We showed that the expression of Gro-1 is activated by RAS and is vital for cell survival and the malignant transformation of ovarian epithelial cells. Surprisingly, we found that Gro-1 is a potent inducer of senescence in stromal fibroblasts and that this effect depends on functional p53. Senescent fibroblasts induced by Gro-1 can promote tumor growth whereas abrogation of senescence through immortalization results in loss of such tumor promoting activity. We also demonstrated that stromal fibroblasts adjacent to epithelial cancer cells are senescent in human ovarian cancer specimens and in heterografts from RAS-transformed human ovarian epithelial cells and ovarian cancer cells. Moreover, Gro-1 was expressed at significantly higher amounts in ovarian cancer than in normal tissues and was higher in serum samples from women with ovarian cancer than in serum from women without ovarian cancer. These findings provide strong evidence that RAS-induced Gro-1 can reprogram the stromal microenvironment through the induction of senescence of fibroblasts and thus can promote tumorigenesis. Therefore, Gro-1 may be a therapeutic target as well as a diagnostic marker in ovarian cancer.

  9. Activation of Adenosine Receptor A2A Increases HSC Proliferation and Inhibits Death and Senescence by Down-regulation of p53 and Rb

    Directory of Open Access Journals (Sweden)

    Md. Kaimul eAhsan

    2014-04-01

    Full Text Available Background & Aims: During fibrosis hepatic stellate cells (HSC undergo activation, proliferation and senescence but the regulation of these important processes is poorly understood. The adenosine A2A receptor (A2A is known to be present on HSC, and its activation results in liver fibrosis. In this study, we tested if A2A has a role in the regulation of HSC proliferation, apoptosis, senescence, and the relevant molecular mechanism.Methods: The ability of adenosine to regulate p53 and Rb protein levels, proliferation, apoptosis and senescence was tested in the human HSC cell line LX-2 and rat primary HSC.Results: Adenosine receptor activation down-regulates p53 and Rb protein levels, increases BrdU incorporation and increases cell survival in LX-2 cells and in primary rat HSC. These effects of NECA were reproduced by an adenosine A2A receptor specific agonist (CGS21680 and blocked by a specific antagonist (ZM241385. By day twenty-one of culture primary rat HSC entered senescence and expressed -gal which was significantly inhibited by NECA. Furthermore, NECA induced down regulation of p53 and Rb and Rac1, and decreased phosphorylation of p44-42 MAP Kinase in LX-2 cells and primary rat HSC. These effects were reproduced by the cAMP analog 8-Bromo-cAMP, and the adenylyl cyclase activator forskolin, and were blocked by PKA inhibitors.Conclusions: These results demonstrate that A2A receptor regulates a number of HSC fate decisions and induces greater HSC proliferation, reduces apoptosis and senescence by decreasing p53 and Rb through cAMP-PKA/Rac1/p38 MAPK pathway. This provides a mechanism for adenosine induced HSC regulation and liver fibrosis.

  10. Knockdown of WHIRLY1 Affects Drought Stress-Induced Leaf Senescence and Histone Modifications of the Senescence-Associated Gene HvS40

    Directory of Open Access Journals (Sweden)

    Bianka Janack

    2016-09-01

    Full Text Available The plastid-nucleus located protein WHIRLY1 has been described as an upstream regulator of leaf senescence, binding to the promoter of senescence-associated genes like HvS40. To investigate the impact of WHIRLY1 on drought stress-induced, premature senescence, transgenic barley plants with an RNAi-mediated knockdown of the HvWHIRLY1 gene were grown under normal and drought stress conditions. The course of leaf senescence in these lines was monitored by physiological parameters and studies on the expression of senescence- and drought stress-related genes. Drought treatment accelerated leaf senescence in WT plants, whereas WHIRLY 1 knockdown lines (RNAi-W1 showed a stay-green phenotype. Expression of both senescence-associated and drought stress-responsive genes, was delayed in the transgenic plants. Notably, expression of transcription factors of the WRKY and NAC families, which are known to function in senescence- and stress-related signaling pathways, was affected in plants with impaired accumulation of WHIRLY1, indicating that WHIRLY1 acts as an upstream regulator of drought stress-induced senescence. To reveal the epigenetic indexing of HvS40 at the onset of drought-induced senescence in WT and RNAi-W1 lines, stress-responsive loading with histone modifications of promoter and coding sequences of HvS40 was analyzed by chromatin immunoprecipitation and quantified by qRT-PCR. In the wildtype, the euchromatic mark H3K9ac of the HvS40 gene was low under control conditions and was established in response to drought treatment, indicating the action of epigenetic mechanisms in response to drought stress. However, drought stress caused no significant increase in H3K9ac in plants impaired in accumulation of WHIRLY1. The results show that WHIRLY1 knockdown sets in motion a delay in senescence that involves all aspects of gene expression, including changes in chromatin structure.

  11. Analysis of Guard Cell Viability and Action in Senescing Leaves of Nicotiana glauca (Graham), Tree Tobacco.

    Science.gov (United States)

    Ozuna, R; Yera, R; Ortega, K; Tallman, G

    1985-09-01

    In an attempt to determine whether low epidermal conductances to water vapor diffusion of senescing leaves were caused by internal changes in guard cells or by factors external to guard cells, stomatal behavior was examined in intact senescing and nonsenescing leaves of Nicotiana glauca (Graham), tree tobacco, grown in the field or in an environmental chamber. Conductances of senescing leaves were 5 to 10% of the maximum conductances of nonsenescing leaves of the same plant, yet guard cell duplexes isolated from epidermal peels of senescing leaves developed full turgor in the light in solutions containing KCl, and sodium cobaltinitrite staining showed that K(+) accumulated as turgor developed. Ninety-five per cent of the guard cells isolated from senescing leaves concentrated neutral red and excluded trypan blue. Intercellular leaf CO(2) concentrations of senescing and nonsenescing leaves of chamber-grown plants were not significantly different (about 240 microliters per liter), but the potassium contents of adaxial and abaxial epidermes of senescing leaves taken from plants grown in the field were less than half those of nonsenescing leaves. We conclude that guard cells do not undergo the orderly senescence process that characteristically takes place in mesophyll tissue during whole-leaf senescence and that the reduced conductances of senescing leaves are produced by factors external to guard cells.

  12. The impact of cellular senescence in skin ageing: A notion of mosaic and therapeutic strategies.

    Science.gov (United States)

    Toutfaire, Marie; Bauwens, Emilie; Debacq-Chainiaux, Florence

    2017-10-15

    Cellular senescence is now recognized as one of the nine hallmarks of ageing. Recent data show the involvement of senescent cells in tissue ageing and some age-related diseases. Skin represents an ideal model for the study of ageing. Indeed, skin ageing varies between individuals depending on their chronological age but also on their exposure to various exogenous factors (mainly ultraviolet rays). If senescence traits can be detected with ageing in the skin, the senescent phenotype varies among the various skin cell types. Moreover, the origin of cellular senescence in the skin is still unknown, and multiple origins are possible. This reflects the mosaic of skin ageing. Senescent cells can interfere with their microenvironment, either via the direct secretion of factors (the senescence-associated secretory phenotype) or via other methods of communication, such as extracellular vesicles. Knowledge regarding the impact of cellular senescence on skin ageing could be integrated into dermatology research, especially to limit the appearance of senescent cells after photo(chemo)therapy or in age-related skin diseases. Therapeutic approaches include the clearance of senescent cells via the use of senolytics or via the cooperation with the immune system. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. MicroRNA-191 triggers keratinocytes senescence by SATB1 and CDK6 downregulation

    Energy Technology Data Exchange (ETDEWEB)

    Lena, A.M.; Mancini, M.; Rivetti di Val Cervo, P. [University of ' Tor Vergata' , Department of Experimental Medicine and Biochemical Sciences, Via Montpellier 1, Rome 00133 (Italy); Istituto Dermopatico dell' Immacolata-Istituto di Ricovero e Cura a Carattere Scientifico (IDI-IRCCS), Laboratory of Biochemistry c/o Department of Experimental Medicine and Biochemical Sciences, University of Rome ' Tor Vergata' , Rome 00133 (Italy); Saintigny, G.; Mahe, C. [CHANEL Parfums Beaute, 135 av. Charles de Gaulle, F 92521, Neuilly/Seine (France); Melino, G., E-mail: gerry.melino@uniroma2.it [University of ' Tor Vergata' , Department of Experimental Medicine and Biochemical Sciences, Via Montpellier 1, Rome 00133 (Italy); Istituto Dermopatico dell' Immacolata-Istituto di Ricovero e Cura a Carattere Scientifico (IDI-IRCCS), Laboratory of Biochemistry c/o Department of Experimental Medicine and Biochemical Sciences, University of Rome ' Tor Vergata' , Rome 00133 (Italy); Association Cell Death and Differentiation c/o Department of Experimental Medicine and Biochemical Sciences, University of Rome ' Tor Vergata' , Rome 00133 (Italy); and others

    2012-07-06

    Highlights: Black-Right-Pointing-Pointer miR-191 expression is upregulated in senescencent human epidermal keratinocytes. Black-Right-Pointing-Pointer miR-191 overexpression is sufficient per se to induce senescence in keratinocytes. Black-Right-Pointing-Pointer SATB1 and CDK6 are downregulated in senescence and are direct miR-191 targets. Black-Right-Pointing-Pointer SATB1 and CDK6 silencing by siRNA triggers senescence in HEKn cells. -- Abstract: Keratinocyte replicative senescence has an important role in time-dependent changes of the epidermis, a tissue with high turnover. Senescence encompasses growth arrest during which cells remain metabolically active but acquire a typical enlarged, vacuolar and flattened morphology. It is also accompanied by the expression of endogenous senescence-associated-{beta}-galactosidase and specific gene expression profiles. MicroRNAs levels have been shown to be modulated during keratinocytes senescence, playing key roles in inhibiting proliferation and in the acquisition of senescent markers. Here, we identify miR-191 as an anti-proliferative and replicative senescence-associated miRNA in primary human keratinocytes. Its overexpression is sufficient per se to induce senescence, as evaluated by induction of several senescence-associated markers. We show that SATB1 and CDK6 3 Prime UTRs are two miR-191 direct targets involved in this pathway. Cdk6 and Satb1 protein levels decrease during keratinocytes replicative senescence and their silencing by siRNA is able to induce a G1 block in cell cycle, accompanied by an increase in senescence-associated markers.

  14. In vivo inhibition of cysteine proteases provides evidence for the involvement of 'senescence-associated vacuoles' in chloroplast protein degradation during dark-induced senescence of tobacco leaves.

    Science.gov (United States)

    Carrión, Cristian A; Costa, María Lorenza; Martínez, Dana E; Mohr, Christina; Humbeck, Klaus; Guiamet, Juan J

    2013-11-01

    Breakdown of leaf proteins, particularly chloroplast proteins, is a massive process in senescing leaves. In spite of its importance in internal N recycling, the mechanism(s) and the enzymes involved are largely unknown. Senescence-associated vacuoles (SAVs) are small, acidic vacuoles with high cysteine peptidase activity. Chloroplast-targeted proteins re-localize to SAVs during senescence, suggesting that SAVs might be involved in chloroplast protein degradation. SAVs were undetectable in mature, non-senescent tobacco leaves. Their abundance, visualized either with the acidotropic marker Lysotracker Red or by green fluorescent protein (GFP) fluorescence in a line expressing the senescence-associated cysteine protease SAG12 fused to GFP, increased during senescence induction in darkness, and peaked after 2-4 d, when chloroplast dismantling was most intense. Increased abundance of SAVs correlated with higher levels of SAG12 mRNA. Activity labelling with a biotinylated derivative of the cysteine protease inhibitor E-64 was used to detect active cysteine proteases. The two apparently most abundant cysteine proteases of senescing leaves, of 40kDa and 33kDa were detected in isolated SAVs. Rubisco degradation in isolated SAVs was completely blocked by E-64. Treatment of leaf disks with E-64 in vivo substantially reduced degradation of Rubisco and leaf proteins. Overall, these results indicate that SAVs contain most of the cysteine protease activity of senescing cells, and that SAV cysteine proteases are at least partly responsible for the degradation of stromal proteins of the chloroplast.

  15. Members of the barley NAC transcription factor gene family show differential co-regulation with senescence-associated genes during senescence of flag leaves

    DEFF Research Database (Denmark)

    Christiansen, Michael W; Gregersen, Per L.

    2014-01-01

    The senescence process of plants is important for the completion of their life cycle, particularly for crop plants, it is essential for efficient nutrient remobilization during seed filling. It is a highly regulated process, and in order to address the regulatory aspect, the role of genes...... in the NAC transcription factor family during senescence of barley flag leaves was studied. Several members of the NAC transcription factor gene family were up-regulated during senescence in a microarray experiment, together with a large range of senescence-associated genes, reflecting the coordinated...... activation of degradation processes in senescing barley leaf tissues. This picture was confirmed in a detailed quantitative reverse transcription–PCR (qRT–PCR) experiment, which also showed distinct gene expression patterns for different members of the NAC gene family, suggesting a group of ~15 out of the 47...

  16. Stressed SIRT7: facing a crossroad of senescence and immortality.

    Science.gov (United States)

    Liu, Jun-Ping; Chen, Ruping

    2015-06-01

    SIRT7 with coenzyme NAD catalyzes protein de-acetylation. In stress response, SIRT7 regulates protein folding in mitochondria with unknown mechanisms. Decreases in SIRT7 entrain hematopoietic stem cell senescence, but increasing SIRT7 causes elevation of hematopoietic stem cell regenerative function. We discuss the recent findings on SIRT7 and its binding proteins, NRF1 and GABPβ1, in decision making between the choices of inducing cell aging and immortality. © 2015 Wiley Publishing Asia Pty Ltd.

  17. Changes in autophagy, proteasome activity and metabolism to determine a specific signature for acute and chronic senescent mesenchymal stromal cells.

    Science.gov (United States)

    Capasso, Stefania; Alessio, Nicola; Squillaro, Tiziana; Di Bernardo, Giovanni; Melone, Mariarosa A; Cipollaro, Marilena; Peluso, Gianfranco; Galderisi, Umberto

    2015-11-24

    A sharp definition of what a senescent cell is still lacking since we do not have in depth understanding of mechanisms that induce cellular senescence. In addition, senescent cells are heterogeneous, in that not all of them express the same genes and present the same phenotype. To further clarify the classification of senescent cells, hints may be derived by the study of cellular metabolism, autophagy and proteasome activity. In this scenario, we decided to study these biological features in senescence of Mesenchymal Stromal Cells (MSC). These cells contain a subpopulation of stem cells that are able to differentiate in mesodermal derivatives (adipocytes, chondrocytes, osteocytes). In addition, they can also contribute to the homeostatic maintenance of many organs, hence, their senescence could be very deleterious for human body functions. We induced MSC senescence by oxidative stress, doxorubicin treatment, X-ray irradiation and replicative exhaustion. The first three are considered inducers of acute senescence while extensive proliferation triggers replicative senescence also named as chronic senescence. In all conditions, but replicative and high IR dose senescence, we detected a reduction of the autophagic flux, while proteasome activity was impaired in peroxide-treated and irradiated cells. Differences were observed also in metabolic status. In general, all senescent cells evidenced metabolic inflexibility and prefer to use glucose as energy fuel. Irradiated cells with low dose of X-ray and replicative senescent cells show a residual capacity to use fatty acids and glutamine as alternative fuels, respectively. Our study may be useful to discriminate among different senescent phenotypes.

  18. Cytoplasmic chromatin triggers inflammation in senescence and cancer.

    Science.gov (United States)

    Dou, Zhixun; Ghosh, Kanad; Vizioli, Maria Grazia; Zhu, Jiajun; Sen, Payel; Wangensteen, Kirk J; Simithy, Johayra; Lan, Yemin; Lin, Yanping; Zhou, Zhuo; Capell, Brian C; Xu, Caiyue; Xu, Mingang; Kieckhaefer, Julia E; Jiang, Tianying; Shoshkes-Carmel, Michal; Tanim, K M Ahasan Al; Barber, Glen N; Seykora, John T; Millar, Sarah E; Kaestner, Klaus H; Garcia, Benjamin A; Adams, Peter D; Berger, Shelley L

    2017-10-19

    Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing. However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence, a form of terminal cell-cycle arrest associated with pro-inflammatory responses. The functional significance of chromatin in the cytoplasm is unclear. Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA-sensing cGAS-STING (cyclic GMP-AMP synthase linked to stimulator of interferon genes) pathway, leading both to short-term inflammation to restrain activated oncogenes and to chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin-cGAS-STING pathway promotes the senescence-associated secretory phenotype in primary human cells and in mice. Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders.

  19. Oxidative stress induces senescence in human mesenchymal stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Brandl, Anita [Department of Anesthesiology, University Medical Center Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg (Germany); Meyer, Matthias; Bechmann, Volker [Department of Trauma Surgery, University Medical Center Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg (Germany); Nerlich, Michael [Department of Anesthesiology, University Medical Center Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg (Germany); Angele, Peter, E-mail: Peter.Angele@klinik.uni-regensburg.de [Department of Trauma Surgery, University Medical Center Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg (Germany)

    2011-07-01

    Mesenchymal stem cells (MSCs) contribute to tissue repair in vivo and form an attractive cell source for tissue engineering. Their regenerative potential is impaired by cellular senescence. The effects of oxidative stress on MSCs are still unknown. Our studies were to investigate into the proliferation potential, cytological features and the telomere linked stress response system of MSCs, subject to acute or prolonged oxidant challenge with hydrogen peroxide. Telomere length was measured using the telomere restriction fragment assay, gene expression was determined by rtPCR. Sub-lethal doses of oxidative stress reduced proliferation rates and induced senescent-morphological features and senescence-associated {beta}-galactosidase positivity. Prolonged low dose treatment with hydrogen peroxide had no effects on cell proliferation or morphology. Sub-lethal and prolonged low doses of oxidative stress considerably accelerated telomere attrition. Following acute oxidant insult p21 was up-regulated prior to returning to initial levels. TRF1 was significantly reduced, TRF2 showed a slight up-regulation. SIRT1 and XRCC5 were up-regulated after oxidant insult and expression levels increased in aging cells. Compared to fibroblasts and chondrocytes, MSCs showed an increased tolerance to oxidative stress regarding proliferation, telomere biology and gene expression with an impaired stress tolerance in aged cells.

  20. Reduced PKC α Activity Induces Senescent Phenotype in Erythrocytes

    Directory of Open Access Journals (Sweden)

    Rukmini B. Govekar

    2012-01-01

    Full Text Available The molecular mechanism mediating expression of senescent cell antigen-aggregated or cleaved band 3 and externalized phosphatidylserine (PS on the surface of aged erythrocytes and their premature expression in certain anemias is not completely elucidated. The erythrocytes with these surface modifications undergo macrophage-mediated phagocytosis. In this study, the role of protein kinase C (PKC isoforms in the expression of these surface modifications was investigated. Inhibition of PKC α by 30 μM rottlerin (R30 and 2.3 nM Gö 6976 caused expression of both the senescent cell marker-externalized PS measured by FACS analysis and aggregated band 3 detected by western blotting. In contrast to this observation, but in keeping with literature, PKC activation by phorbol-12-myristate-13-acetate (PMA also led to the expression of senescence markers. We explain this antithesis by demonstrating that PMA-treated cells show reduction in the activity of PKC α, thereby simulating inhibition. The reduction in PKC α activity may be attributed to the known downregulation of PMA-activated PKC α, caused by its membrane translocation and proteolysis. We demonstrate membrane translocation of PKC α in PMA-treated cells to substantiate this inference. Thus loss of PKC α activity either by inhibition or downregulation can cause surface modifications which can trigger erythrophagocytosis.

  1. Sodium Valproate Induces Cell Senescence in Human Hepatocarcinoma Cells

    Directory of Open Access Journals (Sweden)

    Hong-Mei An

    2013-12-01

    Full Text Available Hepatocarcinogenesis is associated with epigenetic changes, including histone deacetylases (HDACs. Epigenetic modulation by HDAC inhibition is a potentially valuable approach for hepatocellular carcinoma treatment. In present study, we evaluated the anticancer effects of sodium valproate (SVP, a known HDAC inhibitor, in human hepatocarcinoma cells. The results showed SVP inhibited the proliferation of Bel-7402 cells in a dose-dependent manner. Low dose SVP treatment caused a large and flat morphology change, positive SA-β-gal staining, and G0/G1 phase cell cycle arrest in human hepatocarcinoma cells. Low dose SVP treatment also increased acetylation of histone H3 and H4 on p21 promoter, accompanied by up-regulation of p21 and down-regulation of RB phosphorylation. These observations suggested that a low dose of SVP could induce cell senescence in hepatocarcinoma cells, which might correlate with hyperacetylation of histone H3 and H4, up-regulation of p21, and inhibition of RB phosphorylation. Since the effective concentration inducing cell senescence in hepatocarcinoma cells is clinically available, whether a clinical dose of SVP could induce cell senescence in clinical hepatocarcinoma is worthy of further study.

  2. Altitudinal patterns for longevity, fecundity and senescence in Drosophila buzzatii.

    Science.gov (United States)

    Norry, F M; Sambucetti, P; Scannapieco, A C; Loeschcke, V

    2006-01-01

    We tested for variation in longevity, senescence rate and early fecundity of Drosophila buzzatii along an elevational transect in Argentina, using laboratory-reared flies in laboratory tests performed to avoid extrinsic mortality. At 25 degrees C, females from lowland populations lived longer and had a lower demographic rate of senescence than females from highland populations. Minimal instead of maximal temperature at the sites of origin of population best predicted this cline. A very different pattern was found at higher test temperature. At 29.5 degrees C, longevity of males increased with altitude of origin of population. No clinal trend was apparent for longevity of females at 29.5 degrees C. There was evidence for a trade-off between early fecundity and longevity at non-stressful temperature (25 degrees C) along the altitudinal gradient. This trait association is consistent with evolutionary theories of aging. Population-by-temperature and sex-by-temperature interactions indicate that senescence patterns are expressed in environment specific ways.

  3. The thorny path linking cellular senescence to organismalaging

    Energy Technology Data Exchange (ETDEWEB)

    Patil, Christopher K.; Mian, Saira; Campisi, Judith

    2005-08-09

    Half a century is fast approaching since Hayflick and colleagues formally described the limited ability of normal human cells to proliferate in culture (Hayflick and Moorhead, 1961). This finding--that normal somatic cells, in contrast to cancer cells, cannot divide indefinitely--challenged the prevailing idea that cells from mortal multicellular organisms were intrinsically ''immortal'' (Carrell, 1912). It also spawned two hypotheses, essential elements of which persist today. The first held that the restricted proliferation of normal cells, now termed cellular senescence, suppresses cancer (Hayflick, 1965; Sager, 1991; Campisi, 2001). The second hypothesis, as explained in the article by Lorenzini et al., suggested that the limited proliferation of cells in culture recapitulated aspects of organismal aging (Hayflick, 1965; Martin, 1993). How well have these hypotheses weathered the ensuing decades? Before answering this question, we first consider current insights into the causes and consequences of cellular senescence. Like Lorenzini et al., we limit our discussion to mammals. We also focus on fibroblasts, the cell type studied by Lorenzini et al., but consider other types as well. We suggest that replicative capacity in culture is not a straightforward assessment, and that it correlates poorly with both longevity and body mass. We speculate this is due to the malleable and variable nature of replicative capacity, which renders it an indirect metric of qualitative and quantitative differences among cells to undergo senescence, a response that directly alters cellular phenotype and might indirectly alter tissue structure and function.

  4. Insulin-like growth factor binding protein-6 delays replicative senescence of human fibroblasts

    DEFF Research Database (Denmark)

    Micutkova, Lucia; Diener, Thomas; Li, Chen

    2011-01-01

    extracellular proteins with significantly different abundance in conditioned media from young and senescent fibroblasts. Among these was insulin-like growth factor binding protein-6 (IGFBP-6), which was chosen for further analysis. When IGFBP-6 gene expression was downregulated, cell proliferation was inhibited...... and apoptotic cell death was increased. Furthermore, downregulation of IGFBP-6 led to premature entry into cellular senescence. Since IGFBP-6 overexpression increased cellular lifespan, the data suggest that IGFBP-6, in contrast to other IGF binding proteins, is a negative regulator of cellular senescence......Cellular senescence can be induced by a variety of mechanisms, and recent data suggest a key role for cytokine networks to maintain the senescent state. Here, we have used a proteomic LC-MS/MS approach to identify new extracellular regulators of senescence in human fibroblasts. We identified 26...

  5. From Ancient Pathways to Aging Cells-Connecting Metabolism and Cellular Senescence.

    Science.gov (United States)

    Wiley, Christopher D; Campisi, Judith

    2016-06-14

    Cellular senescence is a complex stress response that permanently arrests the proliferation of cells at risk for oncogenic transformation. However, senescent cells can also drive phenotypes associated with aging. Although the senescence-associated growth arrest prevents the development of cancer, and the metabolism of cancer cells has been studied in depth, the metabolic causes and consequences of cellular senescence were largely unexplored until recently. New findings reveal key roles for several aspects of cellular metabolism in the establishment and control of senescent phenotypes. These discoveries have important implications for both cancer and aging. In this review, we highlight some of the recent links between metabolism and phenotypes that are commonly associated with senescent cells. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Role of asparagine and asparagine synthetase genes in sunflower (Helianthus annuus) germination and natural senescence.

    Science.gov (United States)

    Herrera-Rodríguez, María Begoña; Maldonado, José María; Pérez-Vicente, Rafael

    2006-10-01

    Sunflower (Helianthus annuus) contains three active asparagine synthetase (EC 6.3.5.4, AS) genes: HAS1, HAS1.1 and HAS2. Asparagine content and AS gene expression were determined during germination and leaf and cotyledon natural senescence to assess the role of asparagine as well as the extent of participation of each AS gene in different nitrogen mobilizing processes. Asparagine accumulated in the dry seed and was the predominant amide throughout germination. During cotyledon senescence, the asparagine level was slightly higher than that of glutamine. The opposite was true for leaf senescence. According to transcript accumulation data, most of the asparagine newly synthesized for germination and cotyledon expansion was due to HAS2 activity, with little contribution of the other AS genes. However, all three genes work together to synthesize asparagine for leaf senescence. The absence of significant AS gene expression in cotyledon senescence differentiates leaf and cotyledon senescence, and suggests a cotyledon-specific regulation.

  7. Novel Approach to Bile Duct Damage in Primary Biliary Cirrhosis: Participation of Cellular Senescence and Autophagy

    Directory of Open Access Journals (Sweden)

    Motoko Sasaki

    2012-01-01

    Full Text Available Primary biliary cirrhosis (PBC is characterized by antimitochondrial autoantibodies (AMAs in patients' sera and histologically by chronic nonsuppurative destructive cholangitis in small bile ducts, eventually followed by extensive bile duct loss and biliary cirrhosis. The autoimmune-mediated pathogenesis of bile duct lesions, including the significance of AMAs, triggers of the autoimmune process, and so on remain unclear. We have reported that cellular senescence in biliary epithelial cells (BECs may be involved in bile duct lesions and that autophagy may precede the process of biliary epithelial senescence in PBC. Interestingly, BECs in damaged bile ducts show characteristicsof cellular senescence and autophagy in PBC. A suspected causative factor of biliary epithelial senescence is oxidative stress. Furthermore, senescent BECs may modulate the microenvironment around bile ducts by expressing various chemokines and cytokines called senescence-associated secretory phenotypes and contribute to the pathogenesis in PBC.

  8. Survival Analysis

    CERN Document Server

    Miller, Rupert G

    2011-01-01

    A concise summary of the statistical methods used in the analysis of survival data with censoring. Emphasizes recently developed nonparametric techniques. Outlines methods in detail and illustrates them with actual data. Discusses the theory behind each method. Includes numerous worked problems and numerical exercises.

  9. Modelling survival

    DEFF Research Database (Denmark)

    Ashauer, Roman; Albert, Carlo; Augustine, Starrlight

    2016-01-01

    well GUTS, calibrated with short-term survival data of Gammarus pulex exposed to four pesticides, can forecast effects of longer-term pulsed exposures. Thirdly, we tested the ability of GUTS to estimate 14-day median effect concentrations of malathion for a range of species and use these estimates...

  10. Inhibition of CIP2A attenuates tumor progression by inducing cell cycle arrest and promoting cellular senescence in hepatocellular carcinoma.

    Science.gov (United States)

    Yang, Xue; Qu, Kai; Tao, Jie; Yin, Guozhi; Han, Shaoshan; Liu, Qingguang; Sun, Hao

    2018-01-08

    CIP2A is a recent identified oncogene that inhibits protein phosphatase 2A (PP2A) and stabilizes c-Myc in cancer cells. To investigate the potential oncogenic role and prognostic value of CIP2A, we comprehensively analyzed the CIP2A expression levels in pan-cancer and observed high expression level of CIP2A in majority cancer types, including hepatocellular carcinoma (HCC). Based on a validation cohort including 60 HCC and 20 non-tumorous tissue samples, we further confirmed the high mRNA and protein expression levels of CIP2A in HCC, and found high CIP2A mRNA expression level was associated with unfavorable overall and recurrence-free survival in patients with HCC. Mechanistic investigations revealed that inhibition of CIP2A significantly attenuated cellular proliferation in vitro and tumourigenicity in vivo. Bioinformatic analysis suggested that CIP2A might be involved in regulating cell cycle. Our experimental data further confirmed CIP2A knockdown induced cell cycle arrest at G1 phase. We found accumulated cellular senescence in HCC cells with CIP2A knockdown, companying expression changes of senescence associated proteins (p21, CDK2, CDK4, cyclin D1, MCM7 and FoxM1). Mechanistically, CIP2A knockdown repressed FoxM1 expression and induced FoxM1 dephosphorylation. Moreover, inhibition of PP2A by phosphatase inhibitor rescued the repression of FoxM1. Taken together, our results showed that CIP2A was highly expressed in HCC. Inhibition of CIP2A induced cell cycle arrest and promoted cellular senescence via repressing FoxM1 transcriptional activity, suggesting a potential anti-cancer target for patients with HCC. Copyright © 2017. Published by Elsevier Inc.

  11. Characterization of sugarcane (Saccharum spp.) leaf senescence: implications for biofuel production.

    Science.gov (United States)

    Martins, Maria Thereza Bazzo; de Souza, Wagner Rodrigo; da Cunha, Bárbara Andrade Dias Brito; Basso, Marcos Fernando; de Oliveira, Nelson Geraldo; Vinecky, Felipe; Martins, Polyana Kelly; de Oliveira, Patrícia Abrão; Arenque-Musa, Bruna Cersózimo; de Souza, Amanda Pereira; Buckeridge, Marcos Silveira; Kobayashi, Adilson Kenji; Quirino, Betania Ferraz; Molinari, Hugo Bruno Correa

    2016-01-01

    Second-generation ethanol (2G-bioethanol) uses lignocellulosic feedstocks for ethanol production. Sugarcane is one among the most suitable crops for biofuel production. Its juice is extracted for sugar production, while sugarcane bagasse, straw, and senescing leaves are considered industrial waste. Senescence is the age-dependent deterioration of plant cells, ultimately leading to cell death and completion of the plant life cycle. Because senescing leaves may also be used for biofuel production, understanding the process of natural senescence, including remobilization of nutrients and its effect on cell walls can provide useful information for 2G-bioethanol production from sugarcane leaves. The natural senescence process in leaves of the commercial sugarcane cultivar RB867515 was investigated. Senescence was characterized by strong reduction in photosynthetic pigments content, remobilization of the nutrients N, P, K, B, Cu, Fe, and Zn, and accumulation of Ca, S, Mg, B, Mn, and Al. No significant changes in the cell-wall composition occurred, and only small changes in the expression of cell wall-related genes were observed, suggesting that cell walls are preserved during senescence. Senescence-marker genes, such as SAG12-like and XET-like genes, were also identified in sugarcane and found to be highly expressed. Our study on nutrient remobilization under senescence in a vigorous sugarcane cultivar can contribute to the understanding on how nutrient balance in a high-yielding crop is achieved. In general, neutral monosaccharide profile did not change significantly with leaf senescence, suggesting that senescing leaves of sugarcane can be as a feedstock for biofuel production using pretreatments established for non-senescing leaves without additional efforts. Based on our findings, the potential biotechnological applications for the improvement of sugarcane cultivars are discussed.

  12. MicroRNA-33 promotes the replicative senescence of mouse embryonic fibroblasts by suppressing CDK6

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Shun; Huang, Haijiao; Li, Nanhong; Zhang, Bing; Jia, Yubin; Yang, Yukun; Yuan, Yuan; Xiong, Xing-dong; Wang, Dengchuan; Zheng, Hui-ling [Institute of Aging Research, Guangdong Medical University, Dongguan (China); Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Dongguan (China); Institute of Biochemistry & Molecular Biology, Guangdong Medical University, Zhanjiang (China); Liu, Xinguang, E-mail: xgliu64@126.com [Institute of Aging Research, Guangdong Medical University, Dongguan (China); Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Dongguan (China); Institute of Biochemistry & Molecular Biology, Guangdong Medical University, Zhanjiang (China)

    2016-05-13

    MicroRNAs are a large class of tiny noncoding RNAs, which have emerged as critical regulators of gene expression, and thus are involved in multiple cellular processes, including cellular senescence. MicroRNA-33 has previously been established to exert crucial effect on cell proliferation, lipid metabolism and cholesterol metabolism. Nonetheless, the association between microRNA-33 and cellular senescence and its underlying molecular mechanism are far to be elucidated. The present study has attempted to probe into the effect of microRNA-33 on MEFs senescence. Our data unveiled that microRNA-33 was dramatically down-regulated in senescent MEFs compared to the young MEFs, and ectopic expression of microRNA-33 promoted MEFs senescence, while knock-down of microRNA-33 exhibited a protective effect against senescence phenotype. Moreover, we verified CDK6 as a direct target of microRNA-33 in mouse. Silencing of CDK6 induced the premature senescence phenotype of MEFs similarly as microRNA-33, while enforced expression of CDK6 significantly reverse the senescence-induction effect of microRNA-33. Taken together, our results suggested that microRNA-33 enhanced the replicative senescence of MEFs potentially by suppressing CDK6 expression. -- Highlights: •MicroRNA-33 was dramatically down-regulated in senescent MEF cells. •Altered expression of microRNA-33 exerted a critical role in MEFs senescence. •MicroRNA-33 promoted the replicative senescence of MEFs via targeting of CDK6.

  13. Transcriptional and metabolic analysis of senescence induced by preventing pollination in maize.

    Science.gov (United States)

    Sekhon, Rajandeep S; Childs, Kevin L; Santoro, Nicholas; Foster, Cliff E; Buell, C Robin; de Leon, Natalia; Kaeppler, Shawn M

    2012-08-01

    Transcriptional and metabolic changes were evaluated during senescence induced by preventing pollination in the B73 genotype of maize (Zea mays). Accumulation of free glucose and starch and loss of chlorophyll in leaf was manifested early at 12 d after anthesis (DAA), while global transcriptional and phenotypic changes were evident only at 24 DAA. Internodes exhibited major transcriptomic changes only at 30 DAA. Overlaying expression data onto metabolic pathways revealed involvement of many novel pathways, including those involved in cell wall biosynthesis. To investigate the overlap between induced and natural senescence, transcriptional data from induced senescence in maize was compared with that reported for Arabidopsis (Arabidopsis thaliana) undergoing natural and sugar-induced senescence. Notable similarities with natural senescence in Arabidopsis included up-regulation of senescence-associated genes (SAGs), ethylene and jasmonic acid biosynthetic genes, APETALA2, ethylene-responsive element binding protein, and no apical meristem transcription factors. However, differences from natural senescence were highlighted by unaltered expression of a subset of the SAGs, and cytokinin, abscisic acid, and salicylic acid biosynthesis genes. Key genes up-regulated during sugar-induced senescence in Arabidopsis, including a cysteine protease (SAG12) and three flavonoid biosynthesis genes (PRODUCTION OF ANTHOCYANIN PIGMENT1 (PAP1), PAP2, and LEUCOANTHOCYANIDIN DIOXYGENASE), were also induced, suggesting similarities in senescence induced by pollination prevention and sugar application. Coexpression analysis revealed networks involving known senescence-related genes and novel candidates; 82 of these were shared between leaf and internode networks, highlighting similarities in induced senescence in these tissues. Insights from this study will be valuable in systems biology of senescence in maize and other grasses.

  14. Sex differences in senescence: the role of intra-sexual competition in early adulthood

    OpenAIRE

    Beirne, Christopher; Delahay, Richard; Young, Andrew

    2015-01-01

    Males and females frequently differ in their rates of ageing, but the origins of these differences are poorly understood. Sex differences in senescence have been hypothesized to arise, because investment in intra-sexual reproductive competition entails costs to somatic maintenance, leaving the sex that experiences stronger reproductive competition showing higher rates of senescence. However, evidence that sex differences in senescence are attributable to downstream effects of the intensity of...

  15. Transcriptomic profiling of platelet senescence and platelet extracellular vesicles.

    Science.gov (United States)

    Pienimaeki-Roemer, Annika; Konovalova, Tatiana; Musri, Melina M; Sigruener, Alexander; Boettcher, Alfred; Meister, Gunter; Schmitz, Gerd

    2017-01-01

    Platelets (PLTs) are derived from megakaryocytes during PLT shedding. Senescent or activated PLTs are expanded in vascular and neurological diseases and release PLT extracellular vesicles (PL-EVs). A systematic analysis of regular messenger RNA (mRNA) and small RNA composition in PLTs and PL-EVs during in vitro PLT senescence has not yet been published. We isolated PLTs, total PL-EVs, and PL-EV subsets on Days 0 and 5 from human stored donor platelet concentrates. Isolated mRNA species and microRNA (miRNA) species were analyzed by microarrays and deep sequencing. Correlation of mRNA and miRNA species (miR) and miRNA target analyses were performed using bioinformatics. During in vitro PLT senescence, residual PLT mRNA species were decreased and partially converted to miRNA species. Residual mRNAs included encoded genes relevant for atherosclerosis, inflammation (matrix metallopeptidase 14 [MMP-14], granulin [GRN], angiopoietin like 2 [ANGPTL2]), and neurotransmission (dopamine receptor 2 [DRD2], γ-aminobutyric acid type A receptor ρ3 [GABRR3]). Compared with senescent PLTs, PL-EVs have up-regulated their miRNA species involved in "diabesity" and in vascular and metabolic disease (miR-144-3p, miR-486-5p, miR-142-5p, miR-451a, miR-25-3p, miR-145-5p, and let-7f-5p). The 100 highest expressed PL-EV miRNA species determined by microarrays were compared with the 100 highest expressed PL-EV miRNA species detected by deep sequencing. This approach resulted in 66 overlaps. The regulated miRNAs (assessed by both methods) were related to neurological disorders, including targets for Alzheimer's disease (e.g., β-site amyloid precursor protein APP-cleaving enzyme 1 [BACE1], translocase of outer mitochondrial membrane 40 homolog [TOMM40], neuron navigator 3 [NAV3]). During in vitro senescence, PLTs degrade large RNA species. Concomitantly, they up-regulate a distinct set of known small RNA species involved in atherosclerosis, inflammation, and neurodegeneration. PL-EVs enrich

  16. Major Cys protease activities are not essential for senescence in individually darkened Arabidopsis leaves.

    Science.gov (United States)

    Pružinská, Adriana; Shindo, Takayuki; Niessen, Sherry; Kaschani, Farnusch; Tóth, Réka; Millar, A Harvey; van der Hoorn, Renier A L

    2017-01-06

    Papain-like Cys Proteases (PLCPs) and Vacuolar Processing Enzymes (VPEs) are amongst the most highly expressed proteases during leaf senescence in Arabidopsis. Using activity-based protein profiling (ABPP), a method that enables detection of active enzymes within a complex sample using chemical probes, the activities of PLCPs and VPEs were investigated in individually darkened leaves of Arabidopsis, and their role in senescence was tested in null mutants. ABPP and mass spectrometry revealed an increased activity of several PLCPs, particularly RD21A and AALP. By contrast, despite increased VPE transcript levels, active VPE decreased in individually darkened leaves. Eight protease knock-out lines and two protease over expressing lines were subjected to senescence phenotype analysis to determine the importance of individual protease activities to senescence. Unexpectedly, despite the absence of dominating PLCP activities in these plants, the rubisco and chlorophyll decline in individually darkened leaves and the onset of whole plant senescence were unaltered. However, a significant delay in progression of whole plant senescence was observed in aalp-1 and rd21A-1/aalp-1 mutants, visible in the reduced number of senescent leaves. Major Cys protease activities are not essential for dark-induced and developmental senescence and only a knock out line lacking AALP shows a slight but significant delay in plant senescence.

  17. The emerging role of senescent cells in tissue homeostasis and pathophysiology

    Directory of Open Access Journals (Sweden)

    Kaoru Tominaga

    2015-05-01

    Full Text Available Cellular senescence is a state of permanent growth arrest and is thought to play a pivotal role in tumor suppression. Cellular senescence may play an important role in tumor suppression, wound healing, and protection against tissue fibrosis in physiological conditions in vivo. However, accumulating evidence that senescent cells may have harmful effects in vivo and may contribute to tissue remodeling, organismal aging, and many age-related diseases also exists. Cellular senescence can be induced by various intrinsic and extrinsic factors. Both p53/p21 and p16/RB pathways are important for irreversible growth arrest in senescent cells. Senescent cells secret numerous biologically active factors. This specific secretion phenotype by senescent cells may largely contribute to physiological and pathological consequences in organisms. Here I review the molecular basis of cell cycle arrest and the specific secretion phenotype in cellular senescence. I also summarize the current knowledge of the role of cellular senescence in vivo in physiological and pathological settings.

  18. Aberrant localization of lamin B receptor (LBR) in cellular senescence in human cells

    Energy Technology Data Exchange (ETDEWEB)

    Arai, Rumi; En, Atsuki; Ukekawa, Ryo [Graduate School of Nanobioscience, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027 (Japan); Miki, Kensuke [Graduate School of Nanobioscience, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027 (Japan); Ichiban Life Corporation, 1-1-7 Horai-cho, Naka-ku, Yokohama 231-0048 (Japan); Fujii, Michihiko, E-mail: mifuji@yokohama-cu.ac.jp [Graduate School of Nanobioscience, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027 (Japan); Ayusawa, Dai [Graduate School of Nanobioscience, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027 (Japan); Ichiban Life Corporation, 1-1-7 Horai-cho, Naka-ku, Yokohama 231-0048 (Japan)

    2016-05-13

    5-Bromodeoxyuridine (BrdU), a thymidine analogue, induces cellular senescence in mammalian cells. BrdU induces cellular senescence probably through the regulation of chromatin because BrdU destabilizes or disrupts nucleosome positioning and decondenses heterochromatin. Since heterochromatin is tethered to the nuclear periphery through the interaction with the nuclear envelope proteins, we examined the localization of the several nuclear envelope proteins such as lamins, lamin-interacting proteins, nuclear pore complex proteins, and nuclear transport proteins in senescent cells. We have shown here that lamin B receptor (LBR) showed a change in localization in both BrdU-induced and replicative senescent cells.

  19. Proteome oxidative carbonylation during oxidative stress-induced premature senescence of WI-38 human fibroblasts

    DEFF Research Database (Denmark)

    Le Boulch, Marine; Ahmed, Emad K; Rogowska-Wrzesinska, Adelina

    2017-01-01

    Accumulation of oxidatively damaged proteins is a hallmark of cellular and organismal ageing, and is also a phenotypic feature shared by both replicative senescence and stress-induced premature senescence of human fibroblasts. Moreover, proteins that are building up as oxidized (i.e. the "Oxi......-proteome") during ageing and age-related diseases represent a restricted set of cellular proteins, indicating that certain proteins are more prone to oxidative carbonylation and subsequent intracellular accumulation. The occurrence of specific carbonylated proteins upon oxidative stress induced premature senescence...... to belong to functional interaction networks pointing to signalling pathways that have been implicated in the oxidative stress response and subsequent premature senescence....

  20. To grow old: regulatory role of ethylene and jasmonic acid in senescence

    Science.gov (United States)

    Kim, Joonyup; Chang, Caren; Tucker, Mark L.

    2015-01-01

    Senescence, the final stage in the development of an organ or whole plant, is a genetically programmed process controlled by developmental and environmental signals. Age-related signals underlie the onset of senescence in specific organs (leaf, flower, and fruit) as well as the whole plant (monocarpic senescence). Rudimentary to most senescence processes is the plant hormone ethylene, a small gaseous molecule critical to diverse processes throughout the life of the plant. The role of ethylene in senescence was discovered almost 100 years ago, but the molecular mechanisms by which ethylene regulates senescence have been deciphered more recently primarily through genetic and molecular studies in Arabidopsis. Jasmonic acid (JA), another plant hormone, is emerging as a key player in the control of senescence. The regulatory network of ethylene and JA involves the integration of transcription factors, microRNAs, and other hormones. In this review, we summarize the current understanding of ethylene’s role in senescence, and discuss the interplay of ethylene with JA in the regulation of senescence. PMID:25688252

  1. Identification and characterization of secretory proteins during ionizing radiation-induced premature senescence

    Energy Technology Data Exchange (ETDEWEB)

    Han, Na Kyung; Hong, Mi Na; Jung, Seung Hee; Kang, Kyoung Ah; Lee, Jae Seon [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Chi, Seong Gil [Korea University, Seoul (Korea, Republic of)

    2011-05-15

    Cellular senescence was first described by Hayflick and Moorhead in 1961 who observed that cultures of normal human fibroblasts had a limited replicative potential and eventually became irreversibly arrest. The majority of senescent cells assume a characteristic flattened and enlarged morphological change, senescence associated {beta} alactosidase positivity. Recently a large number of molecular phenotypes such as changes in gene expression, protein processing and chromatin organization have been also described. In contrast to apoptosis, senescence does not destroy the cells but leaves them metabolically and synthetically active and therefore able to affect their microenvironment. In particular, senescent fibroblasts and some cancer cells were found to secrete proteins with known or putative tumor-promoting functions such as growth factors or proteolytic enzymes. However, the knowledge about secreted proteins from senescent tumor cells and their functions to surrounding cells is still lacking. In this study, changes of senescence associated secretory protein expression profile were observed in MCF7 human breast cancer cells exposed to gamma-ray radiation using two dimensional electrophoresis. Also, we identified up-regulated secretory proteins during ionizing radiation-induced cellular senescence. Here, we show that senescent human breast cancer MCF7 cells promote the proliferation, invasion and migration of neighboring cells

  2. The senescent bystander effect is caused by ROS-activated NF-κB signalling.

    Science.gov (United States)

    Nelson, Glyn; Kucheryavenko, Olena; Wordsworth, James; von Zglinicki, Thomas

    2017-08-25

    Cell senescence is an important driver of the ageing process. The accumulation of senescent cells in tissues is accelerated by stress signals from senescent cells that induce DNA damage and ultimately senescence in bystander cells. We examine here the interplay of senescence-associated mitochondrial dysfunction (SAMD)-driven production of reactive oxygen species (ROS) and senescence-associated secretory phenotype (SASP) in causing the bystander effect. We show that in various modes of fibroblast senescence ROS are necessary and sufficient to activate the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which facilitates a large part of the SASP. This ROS-NF-κB axis causes the DNA damage response in bystander cells. Cytokines IL-6 and IL-8 are major components of the pro-inflammatory SASP in senescent fibroblasts. However, their activation in senescence is only partially controlled by NF-κB, and they are thus not strong candidates as intercellular mediators of the bystander effect as mediated by the ROS-NF-κB axis. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  3. The Role of the S40 Gene Family in Leaf Senescence

    Directory of Open Access Journals (Sweden)

    Muhammad Jehanzeb

    2017-10-01

    Full Text Available Senescence affect different traits of plants, such as the ripening of fruit, number, quality and timing of seed maturation. While senescence is induced by age, growth hormones and different environmental stresses, a highly organized genetic mechanism related to substantial changes in gene expression regulates the process. Only a few genes associated to senescence have been identified in crop plants despite the vital significance of senescence for crop yield. The S40 gene family has been shown to play a role in leaf senescence. The barley HvS40 gene is one of the senescence marker genes which shows expression during age-dependent as well as dark-induced senescence. Like barley HvS40, the Arabidopsis AtS40-3 gene is also induced during natural senescence as well as in response to treatment with abscisic acid, salicylic acid, darkness and pathogen attack. It is speculated that rice OsS40 has a similar function in the leaf senescence of rice.

  4. Members of the barley NAC transcription factor gene family show differential co-regulation with senescence-associated genes during senescence of flag leaves.

    Science.gov (United States)

    Christiansen, Michael W; Gregersen, Per L

    2014-07-01

    The senescence process of plants is important for the completion of their life cycle, particularly for crop plants, it is essential for efficient nutrient remobilization during seed filling. It is a highly regulated process, and in order to address the regulatory aspect, the role of genes in the NAC transcription factor family during senescence of barley flag leaves was studied. Several members of the NAC transcription factor gene family were up-regulated during senescence in a microarray experiment, together with a large range of senescence-associated genes, reflecting the coordinated activation of degradation processes in senescing barley leaf tissues. This picture was confirmed in a detailed quantitative reverse transcription-PCR (qRT-PCR) experiment, which also showed distinct gene expression patterns for different members of the NAC gene family, suggesting a group of ~15 out of the 47 studied NAC genes to be important for signalling processes and for the execution of degradation processes during leaf senescence in barley. Seven models for DNA-binding motifs for NAC transcription factors were designed based on published motifs, and available promoter sequences of barley genes were screened for the motifs. Genes up-regulated during senescence showed a significant over-representation of the motifs, suggesting regulation by the NAC transcription factors. Furthermore, co-regulation studies showed that genes possessing the motifs in the promoter in general were highly co-expressed with members of the NAC gene family. In conclusion, a list of up to 15 NAC genes from barley that are strong candidates for being regulatory factors of importance for senescence and biotic stress-related traits affecting the productivity of cereal crop plants has been generated. Furthermore, a list of 71 senescence-associated genes that are potential target genes for these NAC transcription factors is presented. © The Author 2014. Published by Oxford University Press on behalf of the

  5. Replicatively senescent human fibroblasts reveal a distinct intracellular metabolic profile with alterations in NAD+ and nicotinamide metabolism.

    Science.gov (United States)

    James, Emma L; Lane, James A E; Michalek, Ryan D; Karoly, Edward D; Parkinson, E Kenneth

    2016-12-07

    Cellular senescence occurs by proliferative exhaustion (PEsen) or following multiple cellular stresses but had not previously been subject to detailed metabolomic analysis. Therefore, we compared PEsen fibroblasts with proliferating and transiently growth arrested controls using a combination of different mass spectroscopy techniques. PEsen cells showed many specific alterations in both the NAD+ de novo and salvage pathways including striking accumulations of nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) in the amidated salvage pathway despite no increase in nicotinamide phosphoribosyl transferase or in the NR transport protein, CD73. Extracellular nicotinate was depleted and metabolites of the deamidated salvage pathway were reduced but intracellular NAD+ and nicotinamide were nevertheless maintained. However, sirtuin 1 was downregulated and so the accumulation of NMN and NR was best explained by reduced flux through the amidated arm of the NAD+ salvage pathway due to reduced sirtuin activity. PEsen cells also showed evidence of increased redox homeostasis and upregulated pathways used to generate energy and cellular membranes; these included nucleotide catabolism, membrane lipid breakdown and increased creatine metabolism. Thus PEsen cells upregulate several different pathways to sustain their survival which may serve as pharmacological targets for the elimination of senescent cells in age-related disease.

  6. Sarcopenia, obesity, and natural killer cell immune senescence in aging: altered cytokine levels as a common mechanism.

    Science.gov (United States)

    Lutz, Charles T; Quinn, LeBris S

    2012-08-01

    Human aging is characterized by both physical and physiological frailty. A key feature of frailty, sarcopenia is the age-associated decline in skeletal muscle mass, strength, and endurance that characterize even the healthy elderly. Increases in adiposity, particularly in visceral adipose tissue, are almost universal in aging individuals and can contribute to sarcopenia and insulin resistance by increasing levels of inflammatory cytokines known collectively as adipokines. Aging also is associated with declines in adaptive and innate immunity, known as immune senescence, which are risk factors for cancer and all-cause mortality. The cytokine interleukin-15 (IL-15) is highly expressed in skeletal muscle tissue and declines in aging rodent models. IL-15 inhibits fat deposition and insulin resistance, is anabolic for skeletal muscle in certain situations, and is required for the development and survival of natural killer (NK) lymphocytes. We review the effect that adipokines and myokines have on NK cells, with special emphasis on IL-15. We posit that increased adipokine and decreased IL-15 levels during aging constitute a common mechanism for sarcopenia, obesity, and immune senescence.

  7. CD4+IL-21+T cells are correlated with regulatory T cells and IL-21 promotes regulatory T cells survival during HIV infection.

    Science.gov (United States)

    Zhang, Zi-Ning; Bai, Li-Xin; Fu, Ya-Jing; Jiang, Yong-Jun; Shang, Hong

    2017-03-01

    IL-21 enhances T and natural killer cells survival and antiviral functions without promoting T cell activation during HIV infection, which makes it a better adjuvant in anti-HIV immunotherapy. Due to the pleiotropy and redundancy of cytokines, it is vital to have a comprehensive knowledge of the role of IL-21 in the regulation of immune responses. Regulatory T cells (Tregs) play an important role in immune regulation and are a determinant of immune therapeutic efficacy in certain circumstances. In this study, we explored the direct effect of IL-21 on Tregs during HIV infection, which has not been addressed before. Thirty-four HIV treatment-naïve patients were enrolled and the relationship between CD4 + IL-21 + T cells and Tregs were studied. The effects of IL-21 on CD4 + CD25 + CD127 low Tregs' apoptosis, proliferation, and CTLA-4 and TGF-β expression in HIV-infected patients was investigated and compared with the effect of other common γ-chain cytokines. We found the percentage and absolute numbers of CD4 + IL-21 + T cells were positively related to the frequency or absolute numbers of CD4 + CD25 + or CD4 + CD25 + CD127 low Tregs. Compared with the media-alone control, IL-21, IL-7, and IL-15 could significantly reduce apoptosis of Tregs (pHIV infected patients. There were no significant differences of the fold induction of apoptosis, proliferation, or CTLA-4 and TGF-β expression by Tregs from HIV-infected patients and normal controls after IL-21 treatment. In vitro experiment showed that pretreatment with IL-21 significantly enhanced the suppressive effect of Tregs on CD8+ T cells' IFN-γ expression. We conclude that IL-21 promotes the survival and CTLA-4 expression of Tregs and enhanced the suppressive capacity of Tregs during HIV infection. These results broaden the understanding of HIV pathogenesis and provide critical information for HIV interventions. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Lithium Chloride Dependent Glycogen Synthase Kinase 3 Inactivation Links Oxidative DNA Damage, Hypertrophy and Senescence in Human Articular Chondrocytes and Reproduces Chondrocyte Phenotype of Obese Osteoarthritis Patients.

    Directory of Open Access Journals (Sweden)

    Serena Guidotti

    Full Text Available Recent evidence suggests that GSK3 activity is chondroprotective in osteoarthritis (OA, but at the same time, its inactivation has been proposed as an anti-inflammatory therapeutic option. Here we evaluated the extent of GSK3β inactivation in vivo in OA knee cartilage and the molecular events downstream GSK3β inactivation in vitro to assess their contribution to cell senescence and hypertrophy.In vivo level of phosphorylated GSK3β was analyzed in cartilage and oxidative damage was assessed by 8-oxo-deoxyguanosine staining. The in vitro effects of GSK3β inactivation (using either LiCl or SB216763 were evaluated on proliferating primary human chondrocytes by combined confocal microscopy analysis of Mitotracker staining and reactive oxygen species (ROS production (2',7'-dichlorofluorescin diacetate staining. Downstream effects on DNA damage and senescence were investigated by western blot (γH2AX, GADD45β and p21, flow cytometric analysis of cell cycle and light scattering properties, quantitative assessment of senescence associated β galactosidase activity, and PAS staining.In vivo chondrocytes from obese OA patients showed higher levels of phosphorylated GSK3β, oxidative damage and expression of GADD45β and p21, in comparison with chondrocytes of nonobese OA patients. LiCl mediated GSK3β inactivation in vitro resulted in increased mitochondrial ROS production, responsible for reduced cell proliferation, S phase transient arrest, and increase in cell senescence, size and granularity. Collectively, western blot data supported the occurrence of a DNA damage response leading to cellular senescence with increase in γH2AX, GADD45β and p21. Moreover, LiCl boosted 8-oxo-dG staining, expression of IKKα and MMP-10.In articular chondrocytes, GSK3β activity is required for the maintenance of proliferative potential and phenotype. Conversely, GSK3β inactivation, although preserving chondrocyte survival, results in functional impairment via

  9. Lithium Chloride Dependent Glycogen Synthase Kinase 3 Inactivation Links Oxidative DNA Damage, Hypertrophy and Senescence in Human Articular Chondrocytes and Reproduces Chondrocyte Phenotype of Obese Osteoarthritis Patients.

    Science.gov (United States)

    Guidotti, Serena; Minguzzi, Manuela; Platano, Daniela; Cattini, Luca; Trisolino, Giovanni; Mariani, Erminia; Borzì, Rosa Maria

    2015-01-01

    Recent evidence suggests that GSK3 activity is chondroprotective in osteoarthritis (OA), but at the same time, its inactivation has been proposed as an anti-inflammatory therapeutic option. Here we evaluated the extent of GSK3β inactivation in vivo in OA knee cartilage and the molecular events downstream GSK3β inactivation in vitro to assess their contribution to cell senescence and hypertrophy. In vivo level of phosphorylated GSK3β was analyzed in cartilage and oxidative damage was assessed by 8-oxo-deoxyguanosine staining. The in vitro effects of GSK3β inactivation (using either LiCl or SB216763) were evaluated on proliferating primary human chondrocytes by combined confocal microscopy analysis of Mitotracker staining and reactive oxygen species (ROS) production (2',7'-dichlorofluorescin diacetate staining). Downstream effects on DNA damage and senescence were investigated by western blot (γH2AX, GADD45β and p21), flow cytometric analysis of cell cycle and light scattering properties, quantitative assessment of senescence associated β galactosidase activity, and PAS staining. In vivo chondrocytes from obese OA patients showed higher levels of phosphorylated GSK3β, oxidative damage and expression of GADD45β and p21, in comparison with chondrocytes of nonobese OA patients. LiCl mediated GSK3β inactivation in vitro resulted in increased mitochondrial ROS production, responsible for reduced cell proliferation, S phase transient arrest, and increase in cell senescence, size and granularity. Collectively, western blot data supported the occurrence of a DNA damage response leading to cellular senescence with increase in γH2AX, GADD45β and p21. Moreover, LiCl boosted 8-oxo-dG staining, expression of IKKα and MMP-10. In articular chondrocytes, GSK3β activity is required for the maintenance of proliferative potential and phenotype. Conversely, GSK3β inactivation, although preserving chondrocyte survival, results in functional impairment via induction of

  10. Pentoxifylline sensitizes human cervical tumor cells to cisplatin-induced apoptosis by suppressing NF-kappa B and decreased cell senescence

    Directory of Open Access Journals (Sweden)

    Hernandez-Flores Georgina

    2011-11-01

    Full Text Available Abstract Background Worldwide, cervical cancer is the second most common causes of cancer in women and represents an important mortality rate. Cisplatin (CIS is a very important antitumoral agent and can lead tumor cells toward two important cellular states: apoptosis and senescence. In some types of cancers pentoxifylline (PTX sensitizes these cells to the toxic action of chemotherapeutics drugs such as adriamycin, inducing apoptosis. In the present work, we studied in vitro whether PTX alone or in combination with CIS induces apoptosis and/or senescence in cervix cancer HeLa and SiHa cell lines infected with HPV types 16 and 18, respectively, as well as in immortalized keratinocytyes HaCaT cells. Methods HeLa (HPV 18+, SiHa (HPV 16+ cervix cancer cells and non-tumorigenic immortalized HaCaT cells (control were treated with PTX, CIS or both. The cellular toxicity and survival fraction of PTX and CIS were determinate by WST-1 and clonogenic assays respectively. Apoptosis, caspase activation and phosphorylation of ERK1/2, p38, p65 (NF-κB, Bcl-2 and Bcl-XL anti-apoptotic proteins were determinated by flow cytometry. Senescence by microscopy. Phosphorylation of IκBα and IκB total were measured by ELISA. Pro-apoptotic, anti-apoptotic and senescence genes, as well as HPV-E6/7 mRNA expression, were detected by RT-PCR. Results Our results show that after 24 hours of incubation PTX per se is toxic for cancer cells affecting cell viability and inducing apoptosis. The toxicity in HaCaT cells was minimal. CIS induces apoptosis in HeLa and SiHa cells and its effect was significantly increases when the cells were treated with PTX + CIS. In all studies there was a direct correlation with levels of caspases (-3, -6, -7, -9 and -8 activity and apoptosis. CIS induces important levels of senescence and phosphorylation of ERK1/2, p38, p65/RELA, and IκBα, and decreased the expression of anti-apoptotic protein Bcl-XL. Surprisingly these levels were

  11. Genome-wide transcriptional reorganization associated with senescence-to-immortality switch during human hepatocellular carcinogenesis.

    Science.gov (United States)

    Yildiz, Gokhan; Arslan-Ergul, Ayca; Bagislar, Sevgi; Konu, Ozlen; Yuzugullu, Haluk; Gursoy-Yuzugullu, Ozge; Ozturk, Nuri; Ozen, Cigdem; Ozdag, Hilal; Erdal, Esra; Karademir, Sedat; Sagol, Ozgul; Mizrak, Dilsa; Bozkaya, Hakan; Ilk, Hakki Gokhan; Ilk, Ozlem; Bilen, Biter; Cetin-Atalay, Rengul; Akar, Nejat; Ozturk, Mehmet

    2013-01-01

    Senescence is a permanent proliferation arrest in response to cell stress such as DNA damage. It contributes strongly to tissue aging and serves as a major barrier against tumor development. Most tumor cells are believed to bypass the senescence barrier (become "immortal") by inactivating growth control genes such as TP53 and CDKN2A. They also reactivate telomerase reverse transcriptase. Senescence-to-immortality transition is accompanied by major phenotypic and biochemical changes mediated by genome-wide transcriptional modifications. This appears to happen during hepatocellular carcinoma (HCC) development in patients with liver cirrhosis, however, the accompanying transcriptional changes are virtually unknown. We investigated genome-wide transcriptional changes related to the senescence-to-immortality switch during hepatocellular carcinogenesis. Initially, we performed transcriptome analysis of senescent and immortal clones of Huh7 HCC cell line, and identified genes with significant differential expression to establish a senescence-related gene list. Through the analysis of senescence-related gene expression in different liver tissues we showed that cirrhosis and HCC display expression patterns compatible with senescent and immortal phenotypes, respectively; dysplasia being a transitional state. Gene set enrichment analysis revealed that cirrhosis/senescence-associated genes were preferentially expressed in non-tumor tissues, less malignant tumors, and differentiated or senescent cells. In contrast, HCC/immortality genes were up-regulated in tumor tissues, or more malignant tumors and progenitor cells. In HCC tumors and immortal cells genes involved in DNA repair, cell cycle, telomere extension and branched chain amino acid metabolism were up-regulated, whereas genes involved in cell signaling, as well as in drug, lipid, retinoid and glycolytic metabolism were down-regulated. Based on these distinctive gene expression features we developed a 15-gene

  12. Amyloid β Protein Aggravates Neuronal Senescence and Cognitive Deficits in 5XFAD Mouse Model of Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Zhen Wei

    2016-01-01

    Conclusions: oAβ-accelerated neuronal senescence may be associated with the cognitive impairment in 5XFAD mice. Senescence-associated marker p16 can serve as an indicator to estimate the cognitive prognosis for AD population.

  13. Sun Ginseng Protects Endothelial Progenitor Cells From Senescence Associated Apoptosis

    Science.gov (United States)

    Im, Wooseok; Chung, Jin-Young; Bhan, Jaejun; Lim, Jiyeon; Lee, Soon-Tae; Chu, Kon; Kim, Manho

    2012-01-01

    Endothelial progenitor cells (EPC) are a population of cells that circulate in the blood stream. They play a role in angiogenesis and, therefore, can be prognostic markers of vascular repair. Ginsenoside Rg3 prevents endothelial cell apoptosis through the inhibition of the mitochondrial caspase pathway. It also affects estrogen activity, which reduces EPC senescence. Sun ginseng (SG), which is heat-processed ginseng, has a high content of ginsenosides. The purpose of this study was to investigate the protective effects of SG on senescence-associated apoptosis in EPCs. In order to isolate EPCs, mononuclear cells of human blood buffy coats were cultured and characterized by their uptake of acetylated low-density lipoprotein (acLDL) and their binding of Ulex europaeus agglutinin I (ulex-lectin). Flow cytometry with annexin-V staining was performed in order to assess early and late apoptosis. Senescence was determined by β-galactosidase (β-gal) staining. Staining with 4′-6-Diamidino-2-phenylindole verified that most adherent cells (93±2.7%) were acLDL-positive and ulex-lectin-positive. The percentage of β-gal-positive EPCs was decreased from 93.8±2.0% to 62.5±3.6% by SG treatment. A fluorescence-activated cell sorter (FACS) analysis showed that 4.9% of EPCs were late apoptotic in controls. Sun ginseng decreased the apoptotic cell population by 39% in the late stage of apoptosis from control baseline levels. In conclusion, these results show antisenescent and antiapoptotic effects of SG in human-derived EPCs, indicating that SG can enhance EPC-mediated repair mechanisms. PMID:23717107

  14. Overexpression of the microRNA miR-433 promotes resistance to paclitaxel through the induction of cellular senescence in ovarian cancer cells

    Science.gov (United States)

    Weiner-Gorzel, Karolina; Dempsey, Eugene; Milewska, Malgorzata; McGoldrick, Aloysius; Toh, Valerie; Walsh, Aoibheann; Lindsay, Sinead; Gubbins, Luke; Cannon, Aoife; Sharpe, Daniel; O'Sullivan, Jacintha; Murphy, Madeline; Madden, Stephen F; Kell, Malcolm; McCann, Amanda; Furlong, Fiona

    2015-01-01

    Annually, ovarian cancer (OC) affects 240,000 women worldwide and is the most lethal gynecological malignancy. High-grade serous OC (HGSOC) is the most common and aggressive OC subtype, characterized by widespread genome changes and chromosomal instability and is consequently poorly responsive to chemotherapy treatment. The objective of this study was to investigate the role of the microRNA miR-433 in the cellular response of OC cells to paclitaxel treatment. We show that stable miR-433 expression in A2780 OC cells results in the induction of cellular senescence demonstrated by morphological changes, downregulation of phosphorylated retinoblastoma (p-Rb), and an increase in β-galactosidase activity. Furthermore, in silico analysis identified four possible miR-433 target genes associated with cellular senescence: cyclin-dependent kinase 6 (CDK6), MAPK14, E2F3, and CDKN2A. Mechanistically, we demonstrate that downregulation of p-Rb is attributable to a miR-433-dependent downregulation of CDK6, establishing it as a novel miR-433 associated gene. Interestingly, we show that high miR-433 expressing cells release miR-433 into the growth media via exosomes which in turn can induce a senescence bystander effect. Furthermore, in relation to a chemotherapeutic response, quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed that only PEO1 and PEO4 OC cells with the highest miR-433 expression survive paclitaxel treatment. Our data highlight how the aberrant expression of miR-433 can adversely affect intracellular signaling to mediate chemoresistance in OC cells by driving cellular senescence. PMID:25684390

  15. Platelet-Derived Growth Factor-BB Protects Mesenchymal Stem Cells (MSCs) Derived From Immune Thrombocytopenia Patients Against Apoptosis and Senescence and Maintains MSC-Mediated Immunosuppression.

    Science.gov (United States)

    Zhang, Jia-Min; Feng, Fei-Er; Wang, Qian-Ming; Zhu, Xiao-Lu; Fu, Hai-Xia; Xu, Lan-Ping; Liu, Kai-Yan; Huang, Xiao-Jun; Zhang, Xiao-Hui

    2016-12-01

    : Immune thrombocytopenia (ITP) is characterized by platelet destruction and megakaryocyte dysfunction. Mesenchymal stem cells (MSCs) from ITP patients (MSC-ITP) do not exhibit conventional proliferative abilities and thus exhibit defects in immunoregulation, suggesting that MSC impairment might be a mechanism involved in ITP. Platelet-derived growth factor (PDGF) improves growth and survival in various cell types. Moreover, PDGF promotes MSC proliferation. The aim of the present study was to analyze the effects of PDGF-BB on MSC-ITP. We showed that MSC-ITP expanded more slowly and appeared flattened and larger. MSC-ITP exhibited increased apoptosis and senescence compared with controls. Both the intrinsic and extrinsic pathways account for the enhanced apoptosis. P53 and p21 expression were upregulated in MSC-ITP, but inhibition of p53 with pifithrin-α markedly inhibited apoptosis and senescence. Furthermore, MSCs from ITP patients showed a lower capacity for inhibiting the proliferation of activated T cells inducing regulatory T cells (Tregs) and suppressing the synthesis of anti-glycoprotein (GP)IIb-IIIa antibodies. PDGF-BB treatment significantly decreased the expression of p53 and p21 and increased survivin expression in MSC-ITP. In addition, the apoptotic rate and number of senescent cells in ITP MSCs were reduced. Their impaired ability for inhibiting activated T cells, inducing Tregs, and suppressing the synthesis of anti-GPIIb-IIIa antibodies was restored after PDGF-BB treatment. In conclusion, we have demonstrated that PDGF-BB protects MSCs derived from ITP patients against apoptosis, senescence, and immunomodulatory defects. This protective effect of PDGF-BB is likely mediated via the p53/p21 pathway, thus potentially providing a new therapeutic approach for ITP. Immune thrombocytopenia (ITP) is characterized by platelet destruction and megakaryocyte dysfunction. Platelet-derived growth factor (PDGF) improves growth and survival in various cell types

  16. Role of p53 in Mammary Epithelial Cell Senescence

    Science.gov (United States)

    2009-05-01

    Cell Senescence 5b. GRANT NUMBER DAMD17-02-1-0509 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER Goberdhan P. Dimri, Ph.D 5e...Academy of Sciences, Vienna, Austria 2005: Mail Reviewer Pilot Research Projects for “Center for Genetics and Molecular...2006. HapMap -based study of the 17q21 ERBB.2 ampli- con in susceptibility to breast cancer. Br. J. Cancer, 95:1689–95. Breast Cancer Association, C

  17. TAp73 promotes anti-senescence-anabolism not proliferation.

    Science.gov (United States)

    Agostini, Massimiliano; Niklison-Chirou, Maria Victoria; Catani, Maria Valeria; Knight, Richard A; Melino, Gerry; Rufini, Alessandro

    2014-11-01

    TAp73, a member of the p53 family, has been traditionally considered a tumor suppressor gene, but a recent report has claimed that it can promote cellular proliferation. This assumption is based on biochemical evidence of activation of anabolic metabolism, with enhanced pentose phosphate shunt (PPP) and nucleotide biosynthesis. Here, while we confirm that TAp73 expression enhances anabolism, we also substantiate its role in inhibiting proliferation and promoting cell death. Hence, we would like to propose an alternative interpretation of the accumulating data linking p73 to cellular metabolism: we suggest that TAp73 promotes anabolism to counteract cellular senescence rather than to support proliferation.

  18. Biological age and rates of senescence of organism of students

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    Loshits'ka T.I.

    2010-07-01

    Full Text Available Correlations of biological and passport age of student young people are considered. In an experiment took part 25 students by age 17-19 years. The calculation of their biological age is conducted. The rates of senescence of organism of students are appraised. Indexes which have the strongest connection with the index of biological age are certain. The got results are compared to information of researchers of other regions of Ukraine. The prospects of health work are offered on physical education for adjustment of difference between biological and passport age.

  19. JNK inhibition sensitizes tumor cells to radiation-induced premature senescence via Bcl-2/ROS/DDR signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jae Seon; Lee, Je Jung [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2009-05-15

    Premature senescence is considered as a cellular defense mechanism to prevent tumorigenesis. Although recent evidences demonstrate that c-Jun N-terminal kinase (JNK) is involved in the senescence process, the target and exact mechanism of JNK signaling in the regulation of cell proliferation has yet to be defined. In this study, we investigated the role of JNK in premature senescence and demonstrated JNK inhibition sensitized tumor cells to radiation-induced premature senescence.

  20. Long noncoding RNA PANDA and scaffold-attachment-factor SAFA control senescence entry and exit.

    Science.gov (United States)

    Puvvula, Pavan Kumar; Desetty, Rohini Devi; Pineau, Pascal; Marchio, Agnés; Moon, Anne; Dejean, Anne; Bischof, Oliver

    2014-11-19

    Cellular senescence is a stable cell cycle arrest that limits the proliferation of pre-cancerous cells. Here we demonstrate that scaffold-attachment-factor A (SAFA) and the long noncoding RNA PANDA differentially interact with polycomb repressive complexes (PRC1 and PRC2) and the transcription factor NF-YA to either promote or suppress senescence. In proliferating cells, SAFA and PANDA recruit PRC complexes to repress the transcription of senescence-promoting genes. Conversely, the loss of SAFA-PANDA-PRC interactions allows expression of the senescence programme. Accordingly, we find that depleting either SAFA or PANDA in proliferating cells induces senescence. However, in senescent cells where PANDA sequesters transcription factor NF-YA and limits the expression of NF-YA-E2F-coregulated proliferation-promoting genes, PANDA depletion leads to an exit from senescence. Together, our results demonstrate that PANDA confines cells to their existing proliferative state and that modulating its level of expression can cause entry or exit from senescence.

  1. The splicing factor ASF/SF2 and intron retention as markers of endothelial senescence

    Directory of Open Access Journals (Sweden)

    Francisco Javier Blanco

    2012-03-01

    Full Text Available Aging is the major risk factor per se for the development of cardiovascular diseases. The senescence of endothelial cells, that line the lumen of blood vessels, is at the cellular basis of these age-dependent vascular pathologies, including atherosclerosis and hypertension. Along their lifespan, endothelial cells may reach the senescence stage by two different pathways, the replicative one derived from their finite number of divisions, and the one induced by stress stimuli. Also, certain physiological stimuli, such as TGF-β are able to modulate cellular senescence. Currently, the cellular aging process is being widely studied to identify novel molecular markers whose changes correlate with senescence. This review focuses on the regulation of alternative splicing mediated by the serine-arginine splicing factor 1 (SRSF1, or ASF/SF2 during endothelial senescence, a process that is associated with a differential subcellular localization of SRSF1, showing a scattered distribution throughout the cytoplasm. Based on its senescence-dependent involvement in alternative splicing, we postulate that SRSF1 is a key marker of endothelial cell senescence regulating the expression of alternative isoforms of target genes such as ENG, VEGFA, T3 or LMNA that integrate a common molecular senescence program.

  2. Reversal of Senescence in Mouse Fibroblasts through Lentiviral Suppression of p53

    NARCIS (Netherlands)

    Dirac, A.M.G.; Bernards, R.A.

    2003-01-01

    Senescence is generally defined as an irreversible state of G1 cell cycle arrest in which cells are refractory to growth factor stimulation. In mouse embryo fibroblasts (MEFs), induction of senescence requires the presence of p19ARF and p53, as genetic ablation of either of these genes allows escape

  3. Uncoupling the senescent phenotype from telomere shortening in hydrogen peroxide-treated fibroblasts

    NARCIS (Netherlands)

    Chen, QM; Prowse, KR; Tu, VC; Purdom, S; Linskens, MHK; Chen, Qin M.; Prowse, Karen R.; Tu, Victoria C.

    2001-01-01

    Normal human cells have a limited replicative potential and inevitably reach replicative senescence in culture. Replicatively senescent cells show multiple molecular changes, some of which are related to the irreversible growth arrest in culture, whereas others resemble the changes occurring during

  4. Senescent cells and their secretory phenotype as targets for cancer therapy

    NARCIS (Netherlands)

    Velarde, Michael C; Demaria, Marco; Campisi, Judith

    2013-01-01

    Cancer is a devastating disease that increases exponentially with age. Cancer arises from cells that proliferate in an unregulated manner, an attribute that is countered by cellular senescence. Cellular senescence is a potent tumor-suppressive process that halts the proliferation, essentially

  5. Involvement of papain and legumain proteinase in the senescence process of Medicago truncatula nodules.

    Science.gov (United States)

    Pierre, Olivier; Hopkins, Julie; Combier, Maud; Baldacci, Fabien; Engler, Gilbert; Brouquisse, Renaud; Hérouart, Didier; Boncompagni, Eric

    2014-05-01

    The symbiotic interaction between legumes and Rhizobiaceae leads to the formation of new root organs called nodules. Within the nodule, Rhizobiaceae differentiate into nitrogen-fixing bacteroids. However, this symbiotic interaction is time-limited as a result of the initiation of a senescence process, leading to a complete degradation of bacteroids and host plant cells. The increase in proteolytic activity is one of the key features of this process. In this study, we analysed the involvement of two different classes of cysteine proteinases, MtCP6 and MtVPE, in the senescence process of Medicago truncatula nodules. Spatiotemporal expression of MtCP6 and MtVPE was investigated using promoter- β-glucuronidase fusions. Corresponding gene inductions were observed during both developmental and stress-induced nodule senescence. Both MtCP6 and MtVPE proteolytic activities were increased during stress-induced senescence. Down-regulation of both proteinases mediated by RNAi in the senescence zone delayed nodule senescence and increased nitrogen fixation, while their early expression promoted nodule senescence. Using green fluorescent protein fusions, in vivo confocal imaging showed that both proteinases accumulated in the vacuole of uninfected cells or the symbiosomes of infected cells. These data enlighten the crucial role of MtCP6 and MtVPE in the onset of nodule senescence. © 2014 The Authors. New Phytologist © 2014 New Phytologist Trust.

  6. Gene expression in opening and senescing petals of morning glory (Ipomoea nil) flowers

    NARCIS (Netherlands)

    Yamada, T.; Ichimura, K.; Kanekatsu, M.; Doorn, van W.G.

    2007-01-01

    We isolated several senescence-associated genes (SAGs) from the petals of morning glory (Ipomoea nil) flowers, with the aim of furthering our understanding of programmed cell death. Samples were taken from the closed bud stage to advanced visible senescence. Actinomycin D, an inhibitor of

  7. p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes

    Science.gov (United States)

    Kawahara, Misako; Malhotra, Gautam K.; Schaum, Nicholas; Huang, Jiahao; Ved, Urvi; Beausejour, Christian M.; Coppe, Jean-Philippe; Rodier, Francis

    2013-01-01

    Cellular senescence irreversibly arrests proliferation in response to potentially oncogenic stress. Senescent cells also secrete inflammatory cytokines such as IL-6, which promote age-associated inflammation and pathology. HMGB1 (high mobility group box 1) modulates gene expression in the nucleus, but certain immune cells secrete HMGB1 as an extracellular Alarmin to signal tissue damage. We show that nuclear HMGB1 relocalized to the extracellular milieu in senescent human and mouse cells in culture and in vivo. In contrast to cytokine secretion, HMGB1 redistribution required the p53 tumor suppressor, but not its activator ATM. Moreover, altered HMGB1 expression induced a p53-dependent senescent growth arrest. Senescent fibroblasts secreted oxidized HMGB1, which stimulated cytokine secretion through TLR-4 signaling. HMGB1 depletion, HMGB1 blocking antibody, or TLR-4 inhibition attenuated senescence-associated IL-6 secretion, and exogenous HMGB1 stimulated NF-κB activity and restored IL-6 secretion to HMGB1-depleted cells. Our findings identify senescence as a novel biological setting in which HMGB1 functions and link HMGB1 redistribution to p53 activity and senescence-associated inflammation. PMID:23649808

  8. Senescent intimal foam cells are deleterious at all stages of atherosclerosis

    NARCIS (Netherlands)

    Childs, B.G.; Baker, D.J.; Wijshake, T.; Conover, C.A.; Campisi, J.; Deursen, J.M.A. van

    2016-01-01

    Advanced atherosclerotic lesions contain senescent cells, but the role of these cells in atherogenesis remains unclear. Using transgenic and pharmacological approaches to eliminate senescent cells in atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr-/-) mice, we show that these

  9. Senescent intimal foam cells are deleterious at all stages of atherosclerosis

    NARCIS (Netherlands)

    Childs, Bennett G.; Baker, Darren J.; Wijshake, Tobias; Conover, Cheryl A.; Campisi, Judith; van Deursen, Jan M.

    2016-01-01

    Advanced atherosclerotic lesions contain senescent cells, but the role of these cells in atherogenesis remains unclear. Using transgenic and pharmacological approaches to eliminate senescent cells in atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice, we show that

  10. Red wine extract protects against oxidative-stress-induced endothelial senescence

    NARCIS (Netherlands)

    I.P.G. Botden (Ilse); H. Oeseburg (Hisko); M. Durik (Matej); F.P.J. Leijten (Frank); L.C. van Vark-van der Zee (Leonie); U. Musterd-Bhaggoe (Usha); I.M. Garrelds (Ingrid); A.L.B. Seynhaeve (Ann); J.G. Langendonk (Janneke); E.J.G. Sijbrands (Eric); A.H.J. Danser (Jan); A.J.M. Roks (Anton)

    2012-01-01

    textabstractRed wine polyphenols may preserve endothelial function during aging. Endothelial cell senescence enhances age-related endothelial dysfunction. We investigated whether RWE (red wine extract) prevents oxidative-stress-induced senescence in HUVECs (human umbilical-vein endothelial cells).

  11. Early Autumn Senescence in Red Maple (Acer rubrum L. Is Associated with High Leaf Anthocyanin Content

    Directory of Open Access Journals (Sweden)

    Rachel Anderson

    2015-08-01

    Full Text Available Several theories exist about the role of anthocyanins in senescing leaves. To elucidate factors contributing to variation in autumn leaf anthocyanin contents among individual trees, we analysed anthocyanins and other leaf traits in 27 individuals of red maple (Acer rubrum L. over two growing seasons in the context of timing of leaf senescence. Red maple usually turns bright red in the autumn, but there is considerable variation among the trees. Leaf autumn anthocyanin contents were consistent between the two years of investigation. Autumn anthocyanin content strongly correlated with degree of chlorophyll degradation mid to late September, early senescing leaves having the highest concentrations of anthocyanins. It also correlated positively with leaf summer chlorophyll content and dry matter content, and negatively with specific leaf area. Time of leaf senescence and anthocyanin contents correlated with soil pH and with canopy openness. We conclude that the importance of anthocyanins in protection of leaf processes during senescence depends on the time of senescence. Rather than prolonging the growing season by enabling a delayed senescence, autumn anthocyanins in red maple in Ontario are important when senescence happens early, possibly due to the higher irradiance and greater danger of oxidative damage early in the season.

  12. The cell cycle regulator protein P16 and the cellular senescence of dental follicle cells.

    Science.gov (United States)

    Morsczeck, Christian; Hullmann, Markus; Reck, Anja; Reichert, Torsten E

    2017-08-02

    Cellular senescence is a restricting factor for regenerative therapies with somatic stem cells. We showed previously that the onset of cellular senescence inhibits the osteogenic differentiation in stem cells of the dental follicle (DFCs), although the mechanism remains elusive. Two different pathways are involved in the induction of the cellular senescence, which are driven either by the cell cycle protein P21 or by the cell cycle protein P16. In this study, we investigated the expression of cell cycle proteins in DFCs after the induction of cellular senescence. The induction of cellular senescence was proved by an increased expression of β-galactosidase and an increased population doubling time after a prolonged cell culture. Cellular senescence regulated the expression of cell cycle proteins. The expression of cell cycle protein P16 was up-regulated, which correlates with the induction of cellular senescence markers in DFCs. However, the expression of cyclin-dependent kinases (CDK)2 and 4 and the expression of the cell cycle protein P21 were successively decreased in DFCs. In conclusion, our data suggest that a P16-dependent pathway drives the induction of cellular senescence in DFCs.

  13. Delayed senescence in soybean: Terminology, research update, and survey results from growers

    Science.gov (United States)

    The terms used to describe symptoms of delayed senescence in soybean often are used inconsistently or interchangeably and do not adequately distinguish the observed symptoms in the field. Various causes have been proposed to explain the development of delayed senescence symptoms. In this article, we...

  14. Basal metabolic rate and the rate of senescence in the great tit

    NARCIS (Netherlands)

    Bouwhuis, Sandra; Sheldon, Ben C.; Verhulst, Simon; Koteja, Pawel

    1. Between-individual variation in rates of senescence has recently been found to relate to natal and early-life conditions in several natural populations. Mechanistic theories of senescence have predicted between-individual variation in basal metabolic rate (BMR) to also underlie such variation in

  15. Mechanism of Isoflavone Aglycone's Effect on Cognitive Performance of Senescence-Accelerated Mice

    Science.gov (United States)

    Yang, Hong; Jin, Guifang; Ren, Dongdong; Luo, Sijing; Zhou, Tianhong

    2011-01-01

    This study investigated the effect of isoflavone aglycone (IA) on the learning and memory performance of senescence-accelerated mice, and explored its neural protective mechanism. Results showed that SAM-P/8 senescence-accelerated mice treated with IA performed significantly better in the Y-maze cognitive test than the no treatment control (P less…

  16. Senescence in the wild : Insights from a long-term study on Seychelles warblers

    NARCIS (Netherlands)

    Hammers, Martijn; Kingma, Sjouke Anne; Bebbington, Kat; van de Crommenacker, Janske; Spurgin, Lewis; Richardson, DS; Burke, T; Dugdale, Hannah; Komdeur, Jan

    2015-01-01

    Senescence – the progressive age-dependent decline in performance – occurs in most organisms. There is considerable variation in the onset and rate of senescence between and within species. Yet the causes of this variation are still poorly understood, despite being central to understanding the

  17. Are there roles for brain cell senescence in aging and neurodegenerative disorders?

    Science.gov (United States)

    Tan, Florence C C; Hutchison, Emmette R; Eitan, Erez; Mattson, Mark P

    2014-12-01

    The term cellular senescence was introduced more than five decades ago to describe the state of growth arrest observed in aging cells. Since this initial discovery, the phenotypes associated with cellular senescence have expanded beyond growth arrest to include alterations in cellular metabolism, secreted cytokines, epigenetic regulation and protein expression. Recently, senescence has been shown to play an important role in vivo not only in relation to aging, but also during embryonic development. Thus, cellular senescence serves different purposes and comprises a wide range of distinct phenotypes across multiple cell types. Whether all cell types, including post-mitotic neurons, are capable of entering into a senescent state remains unclear. In this review we examine recent data that suggest that cellular senescence plays a role in brain aging and, notably, may not be limited to glia but also neurons. We suggest that there is a high level of similarity between some of the pathological changes that occur in the brain in Alzheimer's and Parkinson's diseases and those phenotypes observed in cellular senescence, leading us to propose that neurons and glia can exhibit hallmarks of senescence previously documented in peripheral tissues.

  18. Colony formation and colony size do not reflect the onset of replicative senescence in human fibroblasts

    NARCIS (Netherlands)

    Maier, Andrea B.; Maier, Ilko L.; Van Heemst, Diana; Westendorp, Rudi G.J.

    2008-01-01

    Replicative senescence of human fibroblasts in vitro has been used as a model for in vivo aging. The onset of replicative senescence varies between several months to years. A colony formation assay, critically dependent on growth speed, can be performed within weeks, and has been reported being an

  19. Identification of Secreted Proteins from Ionizing Radiation-Induced Senescent MCF7 Cells Using Comparative Proteomics

    Energy Technology Data Exchange (ETDEWEB)

    Han, Na Kyung; Kim, Han Na; Hong, Mi Na; Park, Su Min; Lee, Jae Seon [Korea Institue of Radiological and Medical Sciences, Seoul (Korea, Republic of); Chi, Seong Gil [Korea University, Seoul (Korea, Republic of)

    2010-05-15

    Cellular senescence was first described by Hayflick and Moorhead in 1961 who observed that cultures of normal human fibroblasts had a limited replicative potential and eventually became irreversibly arrest. The majority of senescent cells assume a characteristic flattened and enlarged morphological change, senescence associated beta-galactosidase positivity and over the years a large number of molecular phenotypes have been described, such as changes in gene expression, protein processing and chromatin organization. In contrast to apoptosis, senescence does not destroy the cells but leaves them metabolically and synthetically active and therefore able to affect their microenvironment. In particular, senescent fibroblasts and some cancer cells were found to secrete proteins with known or putative tumor-promoting functions such as growth factors or proteolytic enzymes. However, the knowledge about secreted proteins from senescent tumor cells and their functions to surrounding cells is still lacking. In this study, changes of senescence-associated secretory protein expression profile were observed in MCF7 human breast cancer cells exposed to gamma-ray radiation using two dimensional electrophoresis. Also, we identified up-regulated secretory proteins during ionizing radiation-induced cellular senescence

  20. Flower development and senescence in Narcissus tazetta ‘Kashmir Local’

    Directory of Open Access Journals (Sweden)

    Gul Fahima

    2015-12-01

    Full Text Available Flower development and senescence was studied in Narcissus tazetta ‘Kashmir Local’. Flower development was divided into six stages (I-VI, from the tight bud stage to the senescent stage. Flower fresh and dry weight increased as the flowers progressed from bud to bloom and then declined during senescence. Membrane permeability of tepal tissues increased as the flower progressed through various stages. The content of sugars (reducing and total increased during flower development and declined thereafter during senescence. The α-amino acid content registered an increase during flower development with a concomitant decrease in soluble protein content. The SDS-PAGE of protein extracts from tepal tissues revealed a general decrease in the expression of some high molecular weight proteins and an increase in low molecular weight proteins during flower development and senescence. It may be suggested that the flower senescence of N. tazetta may be linked to the protein turnover and sugar status of the perianth tissues and that these newly synthesized proteins may be involved in proteolysis. At this stage, it is not known whether these polypeptides play an important role in senescence but revealing the nature of these proteins can provide new insights into the pathways executing senescence in this flower system.

  1. Innovations’ Survival

    Directory of Open Access Journals (Sweden)

    Jakub Tabas

    2016-01-01

    Full Text Available Innovations currently represent a tool of maintaining the going concern of a business entity and its competitiveness. However, effects of innovations are not infinite and if an innovation should constantly preserve a life of business entity, it has to be a continual chain of innovations, i.e. continual process. Effective live of a single innovation is limited while the limitation is derived especially from industry. The paper provides the results of research on innovations effects in the financial performance of small and medium-sized enterprises in the Czech Republic. Objective of this paper is to determine the length and intensity of the effects of technical innovations in company’s financial performance. The economic effect of innovations has been measured at application of company’s gross production power while the Deviation Analysis has been applied for three years’ time series. Subsequently the Survival Analysis has been applied. The analyses are elaborated for three statistical samples of SMEs constructed in accordance to the industry. The results obtained show significant differences in innovations’ survival within these three samples of enterprises then. The results are quite specific for the industries, and are confronted and discussed with the results of authors’ former research on the issue.

  2. Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus

    DEFF Research Database (Denmark)

    Dietrich, Nikolaj; Bracken, Adrian P; Trinh, Emmanuelle

    2007-01-01

    -ARF, and that ectopic expression of CBX8 leads to repression of the Ink4a-Arf locus and bypass of senescence, leading to cellular immortalization. Gene expression and location analysis demonstrate that besides the INK4A-ARF locus, CBX8 also regulates a number of other genes important for cell growth and survival....... On the basis of these results, we conclude that CBX8 is an essential component of one of the PRC1 complexes, which directly regulate the expression of numerous target genes, including the INK4A-ARF locus, involved in cell-fate decisions....

  3. Epithelial cell senescence impairs repair process and exacerbates inflammation after airway injury

    Directory of Open Access Journals (Sweden)

    Nagai Atsushi

    2011-06-01

    Full Text Available Abstract Background Genotoxic stress, such as by exposure to bromodeoxyuridine (BrdU and cigarette smoke, induces premature cell senescence. Recent evidence indicates that cellular senescence of various types of cells is accelerated in COPD patients. However, whether the senescence of airway epithelial cells contributes to the development of airway diseases is unknown. The present study was designed to test the hypothesis that premature senescence of airway epithelial cells (Clara cells impairs repair processes and exacerbates inflammation after airway injury. Methods C57/BL6J mice were injected with the Clara-cell-specific toxicant naphthalene (NA on days 0, 7, and 14, and each NA injection was followed by a daily dose of BrdU on each of the following 3 days, during which regenerating cells were allowed to incorporate BrdU into their DNA and to senesce. The p38 MAPK inhibitor SB202190 was injected 30 minutes before each BrdU dose. Mice were sacrificed at different times until day 28 and lungs of mice were obtained to investigate whether Clara cell senescence impairs airway epithelial regeneration and exacerbates airway inflammation. NCI-H441 cells were induced to senesce by exposure to BrdU or the telomerase inhibitor MST-312. Human lung tissue samples were obtained from COPD patients, asymptomatic smokers, and nonsmokers to investigate whether Clara cell senescence is accelerated in the airways of COPD patients, and if so, whether it is accompanied by p38 MAPK activation. Results BrdU did not alter the intensity of the airway epithelial injury or inflammation after a single NA exposure. However, after repeated NA exposure, BrdU induced epithelial cell (Clara cell senescence, as demonstrated by a DNA damage response, p21 overexpression, increased senescence-associated β-galactosidase activity, and growth arrest, which resulted in impaired epithelial regeneration. The epithelial senescence was accompanied by p38 MAPK-dependent airway

  4. The nuclear lamina promotes telomere aggregation and centromere peripheral localization during senescence of human mesenchymal stem cells

    NARCIS (Netherlands)

    Raz, Vered; Vermolen, B.J.; Garini, Yuval; Onderwater, Jos J.M.; Mommaas-Kienhuis, Mieke A.; Koster, Abraham J.; Young, Ian T.; Tanke, Hans; Dirks, Roeland W.

    2008-01-01

    Ex vivo, human mesenchymal stem cells (hMSCs) undergo spontaneous cellular senescence after a limited number of cell divisions. Intranuclear structures of the nuclear lamina were formed in senescent hMSCs, which are identified by the presence of Hayflick-senescence-associated factors. Notably,

  5. A petunia homeodomain-leucine zipper protein, PhHD-Zip, plays an important role in flower senescence

    Science.gov (United States)

    Flower senescence is mediated in part by changes of plant hormones, such as ethylene, cytokinin and abscisic acid (ABA). Ethylene is known to control flower senescence in many species, especially ethylene sensitive flowers, like petunia, carnation and rose. During flower senescence in petunia and ot...

  6. Photosynthetic capacity of senescent leaves for a subtropical broadleaf deciduous tree species Liquidambar formosana Hance.

    Science.gov (United States)

    Luo, Zidong; Guan, Huade; Zhang, Xinping; Liu, Na

    2017-07-24

    Photosynthetic capacity and leaf life span generally determine how much carbon a plant assimilates during the growing season. Leaves of deciduous tree species start senescence in late season, but whether the senescent leaves still retain capacity of carbon assimilation remains a question. In this study, we investigated leaf phenology and photosynthesis of a subtropical broadleaf deciduous tree species Liquidambar formosana Hance in the central southern continental China. The results show that L. formosana has extended leaf senescence (more than 2 months) with a substantial number of red leaves persisting on the tree. Leaf photosynthetic capacity decreases over season, but the senescent red leaves still maintain relatively high photosynthetic capacity at 42%, 66% and 66% of the mature leaves for net photosynthesis rate, apparent quantum yield, and quantum yield at the light compensation point, respectively. These results indicate that L. formosana may still contribute to carbon sink during leaf senescence.

  7. Protein modification and replicative senescence of WI-38 human embryonic fibroblasts

    DEFF Research Database (Denmark)

    Ahmed, Emad K; Rogowska-Wrzesinska, Adelina; Roepstorff, Peter

    2010-01-01

    cellular senescence. Finally, in contrast to the proteasome, the activity of which is decreased in senescent fibroblasts, the mitochondrial matrix ATP-stimulated Lon-like proteolytic activity is increased in senescent cells but does not seem to be sufficient to cope with the increased load of modified......Summary Oxidized proteins as well as proteins modified by the lipid peroxidation product 4-hydroxy-2-nonenal (HNE) and by glycation (AGE) have been shown to accumulate with aging in vivo and during replicative senescence in vitro. To better understand the mechanisms by which these damaged proteins...... build up and potentially affect cellular function during replicative senescence of WI-38 fibroblasts, proteins targeted by these modifications have been identified using a bidimensional gel electrophoresis-based proteomic approach coupled with immunodetection of HNE-, AGE-modified and carbonylated...

  8. The Yin-Yang of DNA Damage Response: Roles in Tumorigenesis and Cellular Senescence

    Directory of Open Access Journals (Sweden)

    Sang Soo Kim

    2013-01-01

    Full Text Available Senescent cells are relatively stable, lacking proliferation capacity yet retaining metabolic activity. In contrast, cancer cells are rather invasive and devastating, with uncontrolled proliferative capacity and resistance to cell death signals. Although tumorigenesis and cellular senescence are seemingly opposite pathological events, they are actually driven by a unified mechanism: DNA damage. Integrity of the DNA damage response (DDR network can impose a tumorigenesis barrier by navigating abnormal cells to cellular senescence. Compromise of DDR, possibly due to the inactivation of DDR components, may prevent cellular senescence but at the expense of tumor formation. Here we provide an overview of the fundamental role of DDR in tumorigenesis and cellular senescence, under the light of the Yin-Yang concept of Chinese philosophy. Emphasis is placed on discussing DDR outcome in the light of in vivo models. This information is critical as it can help make better decisions for clinical treatments of cancer patients.

  9. Twist1 suppresses senescence programs and thereby accelerates and maintains mutant Kras-induced lung tumorigenesis

    DEFF Research Database (Denmark)

    Tran, Phuoc T; Shroff, Emelyn H; Burns, Timothy F

    2012-01-01

    overexpressed in primary human lung tumors. The suppression of TWIST1 in human lung cancer cells also induced cellular senescence. Hence, TWIST1 is a critical regulator of cellular senescence programs, and the suppression of TWIST1 in human tumors may be an effective example of pro-senescence therapy....... mouse model and in human lung tumors that the inhibition of Twist1 restores a senescence program inducing the loss of a neoplastic phenotype. The Twist1 gene encodes for a transcription factor that is essential during embryogenesis. Twist1 has been suggested to play an important role during tumor...... progression. However, there is no in vivo evidence that Twist1 plays a role in autochthonous tumorigenesis. Through two novel transgenic mouse models, we show that Twist1 cooperates with Kras(G12D) to markedly accelerate lung tumorigenesis by abrogating cellular senescence programs and promoting...

  10. Fatty acid and sterol contents during tulip leaf senescence induced by methyl jasmonate

    Directory of Open Access Journals (Sweden)

    Marian Saniewski

    2013-12-01

    Full Text Available It has been shown previously that methyl jasmonate (JA-Me applied in lanolin paste on the bottom surface of intact tulip leaves causes a rapid and intense its senescence. The aim of this work was to study the effect of JA-Me on free and bound fatty acid and sterol contents during tulip leaf senescence. The main free and bound fatty acids of tulip leaf, in decreasing order of their abundance, were linolenic, linoleic, palmitic, oleic, stearic and myristic acids. Only the content of free linolenic acid decreased after treatment with JA-Me during visible stage of senescence. ß-Sitosterol (highest concentration, campesterol, stigmasterol and cholesterol were identified in tulip leaf. Methyl jasmonate evidently increased the level of ß-sitosterol, campesterol and stigmasterol during induced senescence. It is suggested that the increase in sterol concentrations under the influence of methyl jasmonate induced changes in membrane fluidity and permeability, which may be responsible for senescence.

  11. Senescence of nickel-transformed cells by an X chromosome: possible epigenetic control.

    Science.gov (United States)

    Klein, C B; Conway, K; Wang, X W; Bhamra, R K; Lin, X H; Cohen, M D; Annab, L; Barrett, J C; Costa, M

    1991-02-15

    Transfer of a normal Chinese hamster X chromosome (carried in a mouse A9 donor cell line) to a nickel-transformed Chinese hamster cell line with an Xq chromosome deletion resulted in senescense of these previously immortal cells. At early passages of the A9/CX donor cells, the hamster X chromosome was highly active, inducing senescence in 100% of the colonies obtained after its transfer into the nickel-transformed cells. However, senescence was reduced to 50% when Chinese hamster X chromosomes were transferred from later passage A9 cells. Full senescing activity of the intact hamster X chromosome was restored by treatment of the donor mouse cells with 5-azacytidine, which induced demethylation of DNA. These results suggest that a senescence gene or genes, which may be located on the Chinese hamster X chromosome, can be regulated by DNA methylation, and that escape from senescence and possibly loss of tumor suppressor gene activity can occur by epigenetic mechanisms.

  12. Accumulation of α-Tocopherol in Senescing Organs as Related to Chlorophyll Degradation

    Science.gov (United States)

    Rise, Moshe; Cojocaru, Miriam; Gottlieb, Hugo E.; Goldschmidt, Eliezer E.

    1989-01-01

    α-Tocopherol (α-T) has been identified, using gas chromatography-mass spectroscopy and 1H- and 13C-nuclear magnetic resonance, in senescing leaves of Melia azedarach L. The content of α-T increased concomitantly with the breakdown of chlorophyll in senescing Vinca and Melia leaves. An increase in α-T was found also in detached Melia leaves, senescing in either light or darkness and in senescing, ethylene-treated orange leaves and fruit. The possibility that phytol, which is released from chlorophyll by chlorophyllase is utilized for the biosynthesis of α-T is discussed. Senescing leaves of the low chlorophyllase plants, parsley and tobacco, did not contain α-T in measureable amounts. PMID:16666657

  13. Senescent intimal foam cells are deleterious at all stages of atherosclerosis.

    Science.gov (United States)

    Childs, Bennett G; Baker, Darren J; Wijshake, Tobias; Conover, Cheryl A; Campisi, Judith; van Deursen, Jan M

    2016-10-28

    Advanced atherosclerotic lesions contain senescent cells, but the role of these cells in atherogenesis remains unclear. Using transgenic and pharmacological approaches to eliminate senescent cells in atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr-/-) mice, we show that these cells are detrimental throughout disease pathogenesis. We find that foamy macrophages with senescence markers accumulate in the subendothelial space at the onset of atherosclerosis, where they drive pathology by increasing expression of key atherogenic and inflammatory cytokines and chemokines. In advanced lesions, senescent cells promote features of plaque instability, including elastic fiber degradation and fibrous cap thinning, by heightening metalloprotease production. Together, these results demonstrate that senescent cells are key drivers of atheroma formation and maturation and suggest that selective clearance of these cells by senolytic agents holds promise for the treatment of atherosclerosis. Copyright © 2016, American Association for the Advancement of Science.

  14. Thrombospondin-1 signaling through CD47 inhibits cell cycle progression and induces senescence in endothelial cells.

    Science.gov (United States)

    Gao, Qi; Chen, Kexin; Gao, Lu; Zheng, Yang; Yang, Yong-Guang

    2016-09-08

    CD47 signaling in endothelial cells has been shown to suppress angiogenesis, but little is known about the link between CD47 and endothelial senescence. Herein, we demonstrate that the thrombospondin-1 (TSP1)-CD47 signaling pathway is a major mechanism for driving endothelial cell senescence. CD47 deficiency in endothelial cells significantly improved their angiogenic function and attenuated their replicative senescence. Lack of CD47 also suppresses activation of cell cycle inhibitors and upregulates the expression of cell cycle promoters, leading to increased cell cycle progression. Furthermore, TSP1 significantly accelerates replicative senescence and associated cell cycle arrest in a CD47-dependent manner. These findings demonstrate that TSP1-CD47 signaling is an important mechanism driving endothelial cell senescence. Thus, TSP1 and CD47 provide attractive molecular targets for treatment of aging-associated cardiovascular dysfunction and diseases involving endothelial dysregulation.

  15. NAC Transcription Factors of Barley (Hordeum vulgare L.) and their Involvement in Leaf Senescence

    DEFF Research Database (Denmark)

    Wagner, Michael

    yielding cereal crops are generated. In cereals, the process of leaf senescence is of utmost relevance when discussing yield. It is during the senescence process that all nutrients are transported from the withering leaf to the developing grains. Furthermore, the timing of senescence determines...... the photosynthetically productive period of the crop plant. Improving the process of senescence by genetic means rather than by increasing the amount of fertiliser is one potential approach towards a higher sustainable productivity. In several species of plants, the NAC transcription factors have been shown to regulate...... parts of the senescence process. The specific aims of this study were therefore (1) to establish and characterise the NAC transcription factors of the model cereal crop barley (Hordeum vulgare L.) (2) to identify and study putative barley NAC transcription factors involved in the regulation of leaf...

  16. Control of Senescence in Rumex Leaf Discs by Gibberellic Acid 1

    Science.gov (United States)

    Goldthwaite, Jonathan J.; Laetsch, W. M.

    1968-01-01

    The kinetics of chlorophyll and protein decomposition and the effect of gibberellic acid (GA) were examined in senescing leaf discs of Rumex crispus and R. obtusifolius. Loss of Rumex total chlorophyll proceeds at a slow rate for about 2 days followed by a period of rapid logarithmic decline. Chlorophyll b is lost at a slightly faster rate than chlorophyll a during senescence in discs as well as in situ. GA causes a complete cessation of net chlorophyll and protein degradation for several days in Rumex, in contrast to the incomplete senescence inhibition generally observed with cytokinins. GA is fully effective even when added at the middle of the logarithmic phase of chlorophyll loss. Senescence inhibition by GA is apparently gradually reversed upon GA removal. The cytokinins, kinetin and 6-benzylaminopurine, were also effective in Rumex leaf discs, indicating that the senescence retarding effect was not restricted to the gibberellins. PMID:16656979

  17. Williams's theory of the evolution of senescence: still useful at fifty.

    Science.gov (United States)

    Turke, Paul W

    2008-09-01

    George Williams indicated that he would not expect senescence to evolve in organisms that lack a distinction between germ line and soma. Escherichia coli--long assumed to lack even a hint of this distinction--is now known to senesce, posing what would seem to be a challenge to Williams's well-known theory of the evolution of senescence. However, in this review, I will show that cell division in E. coli produces a degree of germ-soma modularity sufficient to generate age structure and antagonistic pleiotropic effects, thereby satisfying the requirements of Williams's theory. From this perspective, senescence in E. coli is supportive and points the way to a better understanding of the pleiotropies that connect adaptive complexity and senescence. Sexual reproduction is but one of the complex adaptations illuminated by this approach.

  18. Neuroprotective role of intermittent fasting in senescence-accelerated mice P8 (SAMP8).

    Science.gov (United States)

    Tajes, M; Gutierrez-Cuesta, J; Folch, J; Ortuño-Sahagun, D; Verdaguer, E; Jiménez, A; Junyent, F; Lau, A; Camins, A; Pallàs, M

    2010-09-01

    Dietary interventions have been proposed as a way to increase lifespan and improve health. The senescence-accelerated prone 8 (SAMP8) mice have a shorter lifespan and show alterations in the central nervous system. Moreover, this mouse strain shows decreased sirtuin 1 protein expression and elevated expression of the acetylated targets NFkappaB and FoxO1, which are implicated in transcriptional control of key genes in cell proliferation and cell survival, in reference to control strain, SAMR1. After eight weeks of intermittent fasting, sirtuin 1 protein expression was recovered in SAMP8. This recovery was accompanied by a reduction in the two acetylated targets. Furthermore, SAMP8 showed a lower protein expression of BDNF and HSP70 while intermittent fasting re-established normal values. The activation of JNK and FoxO1 was also reduced in SAMP8 mice subjected to an IF regimen, compared with control SAMP8. Our findings provide new insights into the participation of sirtuin 1 in ageing and point to a potential novel application of this enzyme to prevent frailty due to ageing processes in the brain. Copyright 2010 Elsevier Inc. All rights reserved.

  19. Combining High-Content Imaging and Phenotypic Classification Analysis of Senescence-Associated Beta-Galactosidase Staining to Identify Regulators of Oncogene-Induced Senescence.

    Science.gov (United States)

    Chan, Keefe T; Paavolainen, Lassi; Hannan, Katherine M; George, Amee J; Hannan, Ross D; Simpson, Kaylene J; Horvath, Peter; Pearson, Richard B

    2016-09-01

    Hyperactivation of the PI3K/AKT/mTORC1 signaling pathway is a hallmark of the majority of sporadic human cancers. Paradoxically, chronic activation of this pathway in nontransformed cells promotes senescence, which acts as a significant barrier to malignant progression. Understanding how this oncogene-induced senescence is maintained in nontransformed cells and conversely how it is subverted in cancer cells will provide insight into cancer development and potentially identify novel therapeutic targets. High-throughput screening provides a powerful platform for target discovery. Here, we describe an approach to use RNAi transfection of a pre-established AKT-induced senescent cell population and subsequent high-content imaging to screen for senescence regulators. We have incorporated multiparametric readouts, including cell number, proliferation, and senescence-associated beta-galactosidase (SA-βGal) staining. Using machine learning and automated image analysis, we also describe methods to classify distinct phenotypes of cells with SA-βGal staining. These methods can be readily adaptable to high-throughput functional screens interrogating the mechanisms that maintain and prevent senescence in various contexts.

  20. A 'synthetic-sickness' screen for senescence re-engagement targets in mutant cancer backgrounds.

    Directory of Open Access Journals (Sweden)

    Claire J Cairney

    2017-08-01

    Full Text Available Senescence is a universal barrier to immortalisation and tumorigenesis. As such, interest in the use of senescence-induction in a therapeutic context has been gaining momentum in the past few years; however, senescence and immortalisation remain underserved areas for drug discovery owing to a lack of robust senescence inducing agents and an incomplete understanding of the signalling events underlying this complex process. In order to address this issue we undertook a large-scale morphological siRNA screen for inducers of senescence phenotypes in the human melanoma cell line A375P. Following rescreen and validation in a second cancer cell line, HCT116 colorectal carcinoma, a panel of 16 of the most robust hits were selected for further validation based on significance and the potential to be targeted by drug-like molecules. Using secondary assays for detection of senescence biomarkers p21, 53BP1 and senescence associated beta-galactosidase (SAβGal in a panel of HCT116 cell lines carrying cancer-relevant mutations, we show that partial senescence phenotypes can be induced to varying degrees in a context dependent manner, even in the absence of p21 or p53 expression. However, proliferation arrest varied among genetic backgrounds with predominantly toxic effects in p21 null cells, while cells lacking PI3K mutation failed to arrest. Furthermore, we show that the oncogene ECT2 induces partial senescence phenotypes in all mutant backgrounds tested, demonstrating a dependence on activating KRASG13D for growth suppression and a complete senescence response. These results suggest a potential mechanism to target mutant KRAS signalling through ECT2 in cancers that are reliant on activating KRAS mutations and remain refractory to current treatments.

  1. Cooperation between p21 and Akt is required for p53-dependent cellular senescence.

    Science.gov (United States)

    Kim, Young Yeon; Jee, Hye Jin; Um, Jee-Hyun; Kim, Young Mi; Bae, Sun Sik; Yun, Jeanho

    2017-10-01

    Cellular senescence has been implicated in normal aging, tissue homeostasis, and tumor suppression. Although p53 has been shown to be a central mediator of cellular senescence, the signaling pathway by which it induces senescence remains incompletely understood. In this study, we have shown that both Akt and p21 are required to induce cellular senescence in response to p53 expression. In a p53-induced senescence model, we found that Akt activation was essential for inducing a cellular senescence phenotype. Surprisingly, Akt inhibition did not abolish p53-induced cell cycle arrest, but it suppressed the increase in intracellular reactive oxygen species (ROS) levels. The results of the cell cycle and morphological analysis suggest that p53 induced quiescence, not senescence, following Akt inhibition. Conversely, the inhibition of p21 induction abolished cell cycle arrest but did not affect the p53-induced increase in ROS levels. Additionally, p21 and Akt separately controlled cell cycle arrest and ROS levels, respectively, during H-Ras-induced senescence in human normal fibroblasts. The mechanistic analysis revealed that Akt increased ROS levels through NOX4 induction, and increased Akt-dependent NF-κB binding to the NOX4 promoter is responsible for NOX4 induction upon p53 expression. We further showed that Akt activation upon p53 expression is mediated by mammalian target of rapamycin complex 2. In addition, p53-mediated IL6 and IL8 induction was abrogated by Akt inhibition, suggesting that Akt activation is also required for the senescence-associated secretory phenotype. Collectively, these results suggest that p53 simultaneously controls multiple pathways to induce cellular senescence through p21 and Akt. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  2. Pseudolaric acid B induced cell cycle arrest, autophagy and senescence in murine fibrosarcoma l929 cell.

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    Yu, Jing hua; Liu, Chun yu; Zheng, Gui bin; Zhang, Li Ying; Yan, Ming hui; Zhang, Wen yan; Meng, Xian ying; Yu, Xiao fang

    2013-01-01

    PAB induced various cancer cell apoptosis, cell cycle arrest and senescence. But in cell line murine fibrosarcoma L929, PAB did not induce apoptosis, but autophagy, therefore it was thought by us as a good model to research the relationship of cell cycle arrest, autophagy and senescence bypass apoptosis. Inhibitory ratio was assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis. Phase contrast microscopy visualized cell morphology. Hoechst 33258 staining for nuclear change, propidium iodode (PI) staining for cell cycle, monodansylcadaverine (MDC) staining for autophagy, and rodanmine 123 staining for mitochondrial membrane potential (MMP) were measured by fluorescence microscopy or flowcytometry. Apoptosis was determined by DNA ladder test. Protein kinase C (PKC) activity was detected by PKC assay kit. SA-β-galactosidase assay was used to detect senescence. Protein expression was examined by western blot. PAB inhibited L929 cell growth in time-and dose-dependent manner. At 12 h, 80 μmol/L PAB induced obvious mitotic arrest; at 24 h, PAB began to induce autophagy; at 36 h, cell-treated with PAB slip into G1 cell cycle; and 3 d PAB induced senescence. In time sequence PAB induced firstly cell cycle arrest, then autophagy, then slippage into G1 phase, lastly senescence. Senescent cells had high level of autophagy, inhibiting autophagy led to apoptosis, and no senescence. PAB activated PKC activity to induce cell cycle arrest, autophagy and senescence, inhibiting PKC activity suppressed cell cycle arrest, autophagy and senescence. PAB induced cell cycle arrest, autophagy and senescence in murine fibrosarcoma L929 cell through PKC.

  3. Histone Modifications in Senescence-Associated Resistance to Apoptosis by Oxidative Stress

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    Yan Y. Sanders

    2013-01-01

    Full Text Available Aging and age-related diseases are associated with cellular senescence that results in variable apoptosis susceptibility to oxidative stress. Although fibroblast senescence has been associated with apoptosis resistance, mechanisms for this have not been well defined. In this report, we studied epigenetic mechanisms involving histone modifications that confer apoptosis resistance to senescent human diploid fibroblasts (HDFs. HDFs that undergo replicative senescence display typical morphological features, express senescence-associated β-galactosidase, and increased levels of the tumor suppressor genes, p16, p21, and caveolin-1. Senescent HDFs are more resistant to oxidative stress (exogenous H2O2-induced apoptosis in comparison to non-senescent (control HDFs; this is associated with constitutively high levels of the anti-apoptotic gene, Bcl-2, and low expression of the pro-apoptotic gene, Bax. Cellular senescence is characterized by global increases in H4K20 trimethylation and decreases in H4K16 acetylation in association with increased activity of Suv420h2 histone methyltransferase (which targets H4K20, decreased activity of the histone acetyltransferase, Mof (which targets H4K16, as well as decreased total histone acetyltransferase activity. In contrast to Bax gene, chromatin immunoprecipitation studies demonstrate marked enrichment of the Bcl-2 gene with H4K16Ac, and depletion with H4K20Me3, predicting active transcription of this gene in senescent HDFs. These data indicate that both global and locus-specific histone modifications of chromatin regulate altered Bcl-2:Bax gene expression in senescent fibroblasts, contributing to its apoptosis-resistant phenotype.

  4. Cdk2 suppresses cellular senescence induced by the c-myc oncogene.

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    Campaner, Stefano; Doni, Mirko; Hydbring, Per; Verrecchia, Alessandro; Bianchi, Lucia; Sardella, Domenico; Schleker, Thomas; Perna, Daniele; Tronnersjö, Susanna; Murga, Matilde; Fernandez-Capetillo, Oscar; Barbacid, Mariano; Larsson, Lars-Gunnar; Amati, Bruno

    2010-01-01

    Activated oncogenes induce compensatory tumour-suppressive responses, such as cellular senescence or apoptosis, but the signals determining the main outcome remain to be fully understood. Here, we uncover a role for Cdk2 (cyclin-dependent kinase 2) in suppressing Myc-induced senescence. Short-term activation of Myc promoted cell-cycle progression in either wild-type or Cdk2 knockout mouse embryo fibroblasts (MEFs). In the knockout MEFs, however, the initial hyper-proliferative response was followed by cellular senescence. Loss of Cdk2 also caused sensitization to Myc-induced senescence in pancreatic beta-cells or splenic B-cells in vivo, correlating with delayed lymphoma onset in the latter. Cdk2-/- MEFs also senesced upon ectopic Wnt signalling or, without an oncogene, upon oxygen-induced culture shock. Myc also causes senescence in cells lacking the DNA repair protein Wrn. However, unlike loss of Wrn, loss of Cdk2 did not enhance Myc-induced replication stress, implying that these proteins suppress senescence through different routes. In MEFs, Myc-induced senescence was genetically dependent on the ARF-p53-p21Cip1 and p16INK4a-pRb pathways, p21Cip1 and p16INK4a being selectively induced in Cdk2-/- cells. Thus, although redundant for cell-cycle progression and development, Cdk2 has a unique role in suppressing oncogene- and/or stress-induced senescence. Pharmacological inhibition of Cdk2 induced Myc-dependent senescence in various cell types, including a p53-null human cancer cell line. Our data warrant re-assessment of Cdk2 as a therapeutic target in Myc- or Wnt-driven tumours.

  5. Sugar Maple Phenology: Anthocyanin Production During Leaf Senescence

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    Lindgren, E.; Rock, B.

    2007-12-01

    The Northeastern United States is known for its brilliant fall foliage colors. Foliage is responsible for a billion dollar tourism industry. Many comment that past years have not resulted in the amazing color displays seen historically. As sugar maple trees senesce they contribute bright red leaves to the mural of oranges, yellows, and greens. The pigment that produces the red color, anthocyanin, is synthesized in the fall as chlorophyll slowly degrades. Remote sensing data from LandSat during fall senescence can help investigate this event by quantifying color change and intensity. This data can then be compared to ground validation efforts in several study plots. The results will help answer the question, "Why do leaves turn red?" One hypothesis is that this pigment acts as a photoprotectant and screens leaves from UV light. It is possible that an increase in tropospheric ozone has negatively affected fall foliage due to the increased reflection of UV light before it reaches the trees; thereby reducing the leaves need to produce anthocyanin. Another hypothesis is that production of anthocyanin is linked to temperature, with maximum synthesis occurring during cold evenings and moderate days. Temperature changes caused by climate change could also be affecting anthocyanin. Through observing these changes by remote sensing and ground experiments, more can be learned about this phenological stage and why it happens.

  6. Unraveling the non-senescence phenomenon in Hydra.

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    Dańko, Maciej J; Kozłowski, Jan; Schaible, Ralf

    2015-10-07

    Unlike other metazoans, Hydra does not experience the distinctive rise in mortality with age known as senescence, which results from an increasing imbalance between cell damage and cell repair. We propose that the Hydra controls damage accumulation mainly through damage-dependent cell selection and cell sloughing. We examine our hypothesis with a model that combines cellular damage with stem cell renewal, differentiation, and elimination. The Hydra individual can be seen as a large single pool of three types of stem cells with some features of differentiated cells. This large stem cell community prevents "cellular damage drift," which is inevitable in complex conglomerate (differentiated) metazoans with numerous and generally isolated pools of stem cells. The process of cellular damage drift is based on changes in the distribution of damage among cells due to random events, and is thus similar to Muller's ratchet in asexual populations. Events in the model that are sources of randomness include budding, cellular death, and cellular damage and repair. Our results suggest that non-senescence is possible only in simple Hydra-like organisms which have a high proportion and number of stem cells, continuous cell divisions, an effective cell selection mechanism, and stem cells with the ability to undertake some roles of differentiated cells. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  7. Induction of leaf senescence by low nitrogen nutrition in sunflower (Helianthus annuus) plants.

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    Agüera, Eloísa; Cabello, Purificación; de la Haba, Purificación

    2010-03-01

    Different parameters which vary during the leaf development in sunflower plants grown with nitrate (2 or 20 mM) for a 42-day period have been determined. The plants grown with 20 mM nitrate (N+) showed greater leaf area and specific leaf mass than the plants grown with 2 mM nitrate (N-). The total chlorophyll content decreased with leaf senescence, like the photosynthetic rate. This decline of photosynthetic activity was greater in plants grown with low nitrogen level (N-), showing more pronounced senescence symptoms than with high nitrogen (N+). In both treatments, soluble sugars increased with aging, while starch content decreased. A significant increase of hexose to sucrose ratio was observed at the beginning of senescence, and this raise was higher in N- plants than in N+ plants. These results show that sugar senescence regulation is dependent on nitrogen, supporting the hypothesis that leaf senescence is regulated by the C/N balance. In N+ and N- plants, ammonium and free amino acid concentrations were high in young leaves and decreased progressively in the senescent leaves. In both treatments, asparagine, and in a lower extent glutamine, increased after senescence start. The drop in the (Glu+Asp)/(Gln+Asn) ratio associated with the leaf development level suggests a greater nitrogen mobilization. Besides, the decline in this ratio occurred earlier and more rapidly in N- plants than in N+ plants, suggesting that the N- remobilization rate correlates with leaf senescence severity. In both N+ and N- plants, an important oxidative stress was generated in vivo during sunflower leaf senescence, as revealed by lipid peroxidation and hydrogen peroxide accumulation. In senescent leaves, the increase in hydrogen peroxide levels occurred in parallel with a decline in the activity of antioxidant enzymes. In N+ plants, the activities of catalase and ascorbate peroxidase (APX) increased to reach their highest values at 28 days, and later decreased during senescence, whereas

  8. Macrophages, nitric oxide and microRNAs are associated with DNA damage response pathway and senescence in inflammatory bowel disease.

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    Jane J Sohn

    Full Text Available BACKGROUND: Cellular senescence can be a functional barrier to carcinogenesis. We hypothesized that inflammation modulates carcinogenesis through senescence and DNA damage response (DDR. We examined the association between senescence and DDR with macrophage levels in inflammatory bowel disease (IBD. In vitro experiments tested the ability of macrophages to induce senescence in primary cells. Inflammation modulating microRNAs were identified in senescence colon tissue for further investigation. METHODOLOGY/PRINCIPAL FINDINGS: Quantitative immunohistochemistry identified protein expression by colon cell type. Increased cellular senescence (HP1γ; P = 0.01 or DDR (γH2A.X; P = 0.031, phospho-Chk2, P = 0.014 was associated with high macrophage infiltration in UC. Co-culture with macrophages (ANA-1 induced senescence in >80% of primary cells (fibroblasts MRC5, WI38, illustrating that macrophages induce senescence. Interestingly, macrophage-induced senescence was partly dependent on nitric oxide synthase, and clinically relevant NO• levels alone induced senescence. NO• induced DDR in vitro, as detected by immunofluorescence. In contrast to UC, we noted in Crohn's disease (CD that senescence (HP1γ; P<0.001 and DDR (γH2A.X; P<0.05, phospho-Chk2; P<0.001 were higher, and macrophages were not associated with senescence. We hypothesize that nitric oxide may modulate senescence in CD; epithelial cells of CD had higher levels of NOS2 expression than in UC (P = 0.001. Microarrays and quantitative-PCR identified miR-21 expression associated with macrophage infiltration and NOS2 expression. CONCLUSIONS: Senescence was observed in IBD with senescence-associated β-galactosidase and HP1γ. Macrophages were associated with senescence and DDR in UC, and in vitro experiments with primary human cells showed that macrophages induce senescence, partly through NO•, and that NO• can induce DDR associated with senescence. Future experiments will investigate the

  9. Repeated summer drought and re-watering during the first growing year of oak (Quercus petraea delay autumn senescence and bud burst in the following spring

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    Kristine Vander Mijnsbrugge

    2016-03-01

    Full Text Available Climate change predicts harsher summer droughts for mid-latitudes in Europe. To enhance our understanding of the putative impacts on forest regeneration, we studied the response of oak seedlings (Quercus petraea to water deficit. Potted seedlings originating from three locally sourced provenances were subjected to two successive drought periods during the first growing season each followed by a plentiful re-watering. Here we describe survival and phenological responses after the second drought treatment, applying general linear mixed modelling. From the 441 drought treated seedlings 189 subsisted with higher chances of survival among smaller plants and among single plants per pot compared to doubles. Remarkably, survival was independent of the provenance, although relatively more plants had died off in two provenances compared to the third one with mean plant height being higher in one provenance and standard deviation of plant height being higher in the other. Timing of leaf senescence was clearly delayed after the severe drought treatment followed by re-watering, with two seedlings per pot showing a lesser retardation compared to single plants. This delay can be interpreted as a compensation time in which plants recover before entering the subsequent developmental process of leaf senescence, although it renders seedlings more vulnerable to early autumn frosts because of the delayed hardening of the shoots. Onset of bud flush in the subsequent spring still showed a significant but small delay in the drought treated group, independent of the number of seedlings per pot, and can be considered as an after effect of the delayed senescence. In both phenological models significant differences among the three provenances were detected independent from the treatment. The only provenance that is believed to be local of origin, displayed the earliest leaf senescence and the latest flushing, suggesting an adaptation to the local maritime climate. This

  10. RSK4 inhibition results in bypass of stress-induced and oncogene-induced senescence.

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    López-Vicente, Laura; Pons, Berta; Coch, Laura; Teixidó, Cristina; Hernández-Losa, Javier; Armengol, Gemma; Ramon Y Cajal, Santiago

    2011-04-01

    p90 Ribosomal S6 kinase (RSK) 4 is a serine-threonine kinase that belongs to the p90RSK family. RSK4 has been proposed as a tumor suppressor gene, related with anti-invasive activity, inhibition of the RAS-mitogen-activated protein kinase (MAPK) pathway and induction of senescence. Despite the related findings, little is known about RSK4 effectors. In human tumors, RSK4 is downregulated even in some benign lesions, such as colon adenomas and breast papillomas, indicating that RSK4 inhibition could be an early event in cellular transformation. For cells to achieve immortality and transformation, it is believed that they must override senescence. In the present study, we found that when RSK4 is inhibited in vitro using short hairpin RNA technology, cells can bypass stress-induced senescence and oncogene-induced senescence: normal human fibroblasts grew following oxidative stress, induction of DNA damage and KRAS(V12) or BRAF(E600) overexpression. To investigate the RSK4 effectors, we used short hairpin RNA or inhibitor molecules against major senescence mediators. We found that RSK4-induced senescence is mediated through p21, but is independent of p16, p38MAPKs and induction of reactive oxygen species, delimiting RSK4 signaling. These data support the importance of RSK4 for regulating senescence and indicate that downregulation of this kinase could be an important element in facilitating cell transformation.

  11. Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway

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    Valentina Rapisarda

    2017-03-01

    Full Text Available Cellular senescence is an important in vivo mechanism that prevents the propagation of damaged cells. However, the precise mechanisms regulating senescence are not well characterized. Here, we find that ITGB3 (integrin beta 3 or β3 is regulated by the Polycomb protein CBX7. β3 expression accelerates the onset of senescence in human primary fibroblasts by activating the transforming growth factor β (TGF-β pathway in a cell-autonomous and non-cell-autonomous manner. β3 levels are dynamically increased during oncogene-induced senescence (OIS through CBX7 Polycomb regulation, and downregulation of β3 levels overrides OIS and therapy-induced senescence (TIS, independently of its ligand-binding activity. Moreover, cilengitide, an αvβ3 antagonist, has the ability to block the senescence-associated secretory phenotype (SASP without affecting proliferation. Finally, we show an increase in β3 levels in a subset of tissues during aging. Altogether, our data show that integrin β3 subunit is a marker and regulator of senescence.

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

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    Kunieda, Takeshige; Minamino, Tohru; Katsuno, Taro; Tateno, Kaoru; Nishi, Jun-ichiro; Miyauchi, Hideyuki; Orimo, Masayuki; Okada, Sho; Komuro, Issei

    2006-03-03

    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.

  13. Androgen Depletion Induces Senescence in Prostate Cancer Cells through Down-regulation of Skp2

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    Zuzana Pernicová

    2011-06-01

    Full Text Available Although the induction of senescence in cancer cells is a potent mechanism of tumor suppression, senescent cells remain metabolically active and may secrete a broad spectrum of factors that promote tumorigenicity in neighboring malignant cells. Here we show that androgen deprivation therapy (ADT, a widely used treatment for advanced prostate cancer, induces a senescence-associated secretory phenotype in prostate cancer epithelial cells, indicated by increases in senescence-associated β-galactosidase activity, heterochromatin protein 1β foci, and expression of cathepsin B and insulin-like growth factor binding protein 3. Interestingly, ADT also induced high levels of vimentin expression in prostate cancer cell lines in vitro and in human prostate tumors in vivo. The induction of the senescence-associated secretory phenotype by androgen depletion was mediated, at least in part, by down-regulation of S-phase kinase-associated protein 2, whereas the neuroendocrine differentiation of prostate cancer cells was under separate control. These data demonstrate a previously unrecognized link between inhibition of androgen receptor signaling, down-regulation of S-phase kinase-associated protein 2, and the appearance of secretory, tumor-promoting senescent cells in prostate tumors. We propose that ADT may contribute to the development of androgen-independent prostate cancer through modulation of the tissue microenvironment by senescent cells.

  14. Oxidative Stress Induces Endothelial Cell Senescence via Downregulation of Sirt6

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    Rong Liu

    2014-01-01

    Full Text Available Accumulating evidence has shown that diabetes accelerates aging and endothelial cell senescence is involved in the pathogenesis of diabetic vascular complications, including diabetic retinopathy. Oxidative stress is recognized as a key factor in the induction of endothelial senescence and diabetic retinopathy. However, specific mechanisms involved in oxidative stress-induced endothelial senescence have not been elucidated. We hypothesized that Sirt6, which is a nuclear, chromatin-bound protein critically involved in many pathophysiologic processes such as aging and inflammation, may have a role in oxidative stress-induced vascular cell senescence. Measurement of Sirt6 expression in human endothelial cells revealed that H2O2 treatment significantly reduced Sirt6 protein. The loss of Sirt6 was associated with an induction of a senescence phenotype in endothelial cells, including decreased cell growth, proliferation and angiogenic ability, and increased expression of senescence-associated β-galactosidase activity. Additionally, H2O2 treatment reduced eNOS expression, enhanced p21 expression, and dephosphorylated (activated retinoblastoma (Rb protein. All of these alternations were attenuated by overexpression of Sirt6, while partial knockdown of Sirt6 expression by siRNA mimicked the effect of H2O2. In conclusion, these results suggest that Sirt6 is a critical regulator of endothelial senescence and oxidative stress-induced downregulation of Sirt6 is likely involved in the pathogenesis of diabetic retinopathy.

  15. Modulation of the Senescence-Associated Inflammatory Phenotype in Human Fibroblasts by Olive Phenols

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    Menicacci, Beatrice; Cipriani, Caterina; Margheri, Francesca

    2017-01-01

    Senescent cells display an increase in the secretion of growth factors, inflammatory cytokines and proteolytic enzymes, termed the “senescence-associated-secretory-phenotype” (SASP), playing a major role in many age-related diseases. The phenolic compounds present in extra-virgin olive oil are inhibitors of oxidative damage and have been reported to play a protective role in inflammation-related diseases. Particularly, hydroxytyrosol and oleuropein are the most abundant and more extensively studied. Pre-senescent human lung (MRC5) and neonatal human dermal (NHDF) fibroblasts were used as cellular model to evaluate the effect of chronic (4–6 weeks) treatment with 1 μM hydroxytyrosol (HT) or 10 μM oleuropein aglycone (OLE) on senescence/inflammation markers. Both phenols were effective in reducing β-galactosidase-positive cell number and p16 protein expression. In addition, senescence/inflammation markers such as IL-6 and metalloprotease secretion, and Ciclooxigenase type 2 (COX-2) and α-smooth-actin levels were reduced by phenol treatments. In NHDF, COX-2 expression, Nuclear Factor κ-light-chain-enhancer of activated B cells (NFκB) protein level and nuclear localization were augmented with culture senescence and decreased by OLE and HT treatment. Furthermore, the inflammatory effect of Tumor Necrosis Factor α (TNFα) exposure was almost completely abolished in OLE- and HT-pre-treated NHDF. Thus, the modulation of the senescence-associated inflammatory phenotype might be an important mechanism underlying the beneficial effects of olive oil phenols. PMID:29084133

  16. Roles of GSK3 in metabolic shift toward abnormal anabolism in cell senescence.

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    Kim, You-Mie; Seo, Yong-Hak; Park, Chan-Bae; Yoon, Soo-Han; Yoon, Gyesoon

    2010-07-01

    Diverse metabolic alterations, including mitochondrial dysfunction, have often been reported as characteristic phenotypes of senescent cells. However, the overall consequence of senescent metabolic features, how they develop, and how they are linked to other senescent phenotypes, such as enlarged cell volume, increased granularity, and oxidative stress, is not clear. We investigated the potential roles of glycogen synthase kinase 3 (GSK3), a multifunctional kinase, in the development of the metabolic phenotypes in cell senescence. The inactivation of GSK3 via phosphorylation is commonly observed in diverse cell senescences. Furthermore, subcytotoxic concentration of GSK3 inhibitor was sufficient to induce cellular senescence, accompanied by augmented anabolism, such as enhanced protein synthesis, and increased glycogenesis and lipogenesis, in addition to mitochondrial dysfunction. Anabolism was accomplished through glycogen synthase, eIF2B, and SREBP1. These metabolic features seem to contribute to an increase in cellular mass by increasing glycogen granules, protein mass, and organelles. Taken together, our results suggest that GSK3 is one of the key modulators of metabolic alteration, leading the cells to senescence.

  17. SIRT1 suppresses the senescence-associated secretory phenotype through epigenetic gene regulation.

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    Tomohisa Hayakawa

    Full Text Available Senescent cells develop a pro-inflammatory response termed the senescence-associated secretory phenotype (SASP. As many SASP components affect surrounding cells and alter their microenvironment, SASP may be a key phenomenon in linking cellular senesence with individual aging and age-related diseases. We herein demonstrated that the expression of Sirtuin1 (SIRT1 was decreased and the expression of SASP components was reciprocally increased during cellular senescence. The mRNAs and proteins of SASP components, such as IL-6 and IL-8, quickly accumulated in SIRT1-depleted cells, and the levels of these factors were also higher than those in control cells, indicating that SIRT1 negatively regulated the expression of SASP factors at the transcriptional level. SIRT1 bound to the promoter regions of IL-8 and IL-6, but dissociated from them during cellular senescence. The acetylation of Histone H3 (K9 and H4 (K16 of the IL-8 and IL-6 promoter regions gradually increased during cellular senescence. In SIRT1-depleted cells, the acetylation levels of these regions were already higher than those in control cells in the pre-senescent stage. Moreover, these acetylation levels in SIRT1-depleted cells were significantly higher than those in control cells during cellular senescence. These results suggest that SIRT1 repressed the expression of SASP factors through the deacetylation of histones in their promoter regions.

  18. Males do not senesce faster in large herbivores with highly seasonal rut.

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    Tidière, Morgane; Gaillard, Jean-Michel; Müller, Dennis W H; Lackey, Laurie Bingaman; Gimenez, Olivier; Clauss, Marcus; Lemaître, Jean-François

    2014-12-01

    Patterns of actuarial senescence vary among long-lived species. A proposed explanation of the evolution of species-specific senescence patterns is that increased levels of energy allocation to intra-male competition decrease the amount of energy available for somatic maintenance, leading to earlier or faster actuarial senescence. Previous studies did not provide support for such relationships, but did not focus on the intensity of allocation likely to shape inter-specific variation in actuarial senescence in males. Here, by analyzing data from 56 species of captive large herbivores, we tested whether actuarial senescence is more pronounced in species displaying a well-defined 'rut' period than in species with year-round reproduction. Using an original quantitative metric of the annual duration of reproductive activity, we demonstrated that the length of the mating season has no detectable effect on actuarial senescence. On the other hand, both diet and body mass are important factors shaping actuarial senescence patterns in male captive herbivores. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Sensitivity of neoplastic cells to senescence unveiled under standard cell culture conditions.

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    Zieba, Jolanta; Ksiazkiewcz, Magdalena; Janik, Karolina; Banaszczyk, Mateusz; Peciak, Joanna; Piaskowski, Sylwester; Lipinski, Marek; Olczak, Michal; Stoczynska-Fidelus, Ewelina; Rieske, Piotr

    2015-05-01

    Cancer cells are typically defined as infinitely proliferating, whereas normal cells (except stem cells) are considered as being programmed to become senescent. Our data show that this characterization is misleading. Multiplex Ligation-dependent Probe Amplification, TP53 sequencing, real-time polymerase chain reaction (PCR) for MUC1 and SCGB2A2 and immunocytochemistry, together with senescence detection assay and real-time microscopic observations were used to analyze primary neoplastic cells isolated from prostate, breast and colorectal tumors, as well as stable cancer cell lines (MCF7, MDA-MB-468, SW962, SK-MEL28, NCI-H1975 and NCI-H469). In all cases of primary cancer cell cultures, in vitro conditions rapidly revealed senescence in the majority of cells. Two out of six stable cancer cell lines did not exhibit any senescence-associated-β-Galactosidase-positive cells. Interestingly, four cell lines had small sub-populations of senescent cells (single SA-β-Gal-positive cells). Primary neoplastic cells from different types of cancer (prostate, breast, colon cancer) appear to be senescent in vitro. Apparently, cancer cell lines that have been used for many years in drug-testing analyses have constantly been misleading researchers in terms of the general sensitivity of cancer cells to senescence. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  20. Senescence in natural populations of animals: Widespread evidence and its implications for bio-gerontology

    Science.gov (United States)

    Nussey, Daniel H.; Froy, Hannah; Lemaitre, Jean-François; Gaillard, Jean-Michel; Austad, Steve N.

    2014-01-01

    That senescence is rarely, if ever, observed in natural populations is an oft-quoted fallacy within bio-gerontology. We identify the roots of this fallacy in the otherwise seminal works of Medawar and Comfort, and explain that under antagonistic pleiotropy or disposable soma explanations for the evolution of senescence there is no reason why senescence cannot evolve to be manifest within the life expectancies of wild organisms. The recent emergence of long-term field studies presents irrefutable evidence that senescence is commonly detected in nature. We found such evidence in 175 different animal species from 340 separate studies. Although the bulk of this evidence comes from birds and mammals, we also found evidence for senescence in other vertebrates and insects. We describe how high-quality longitudinal field data allow us to test evolutionary explanations for differences in senescence between the sexes and among traits and individuals. Recent studies indicate that genes, prior environment and investment in growth and reproduction influence aging rates in the wild. We argue that – with the fallacy that wild animals do not senesce finally dead and buried – collaborations between bio-gerontologists and field biologists can begin to test the ecological generality of purportedly ‘public’ mechanisms regulating aging in laboratory models. PMID:22884974

  1. Cellular Senescence Is Associated With Human Retinal Microaneurysm Formation During Aging.

    Science.gov (United States)

    López-Luppo, Mariana; Catita, Joana; Ramos, David; Navarro, Marc; Carretero, Ana; Mendes-Jorge, Luísa; Muñoz-Cánoves, Pura; Rodriguez-Baeza, Alfonso; Nacher, Victor; Ruberte, Jesus

    2017-06-01

    Microaneurysms are present in healthy old-age human retinas. However, to date, no age-related pathogenic mechanism has been implicated in their formation. Here, cellular senescence, a hallmark of aging and several age-related diseases, has been analyzed in the old-age human retina and in the retina of a progeric mouse. Retinas were obtained from 17 nondiabetic donors and from mice deficient in Bmi1. Cellular senescence was analyzed by immunohistochemistry, senescent-associated β-galactosidase activity assay, Sudan black B staining, conventional transmission electron microscopy, and immunoelectronmicroscopy. Neurons, but not neuroglia, and blood vessels undergo cellular senescence in the old-age human retina. The canonical senescence markers p16, p53, and p21 were up-regulated and coexisted with apoptosis in old-age human microaneurysms. Senescent endothelial cells were discontinuously covered by fibronectin, and p16 colocalized with the β1 subunit of fibronectin receptor α5β1 integrin under the endothelial cellular membrane, suggesting anoikis as a mechanism involved in endothelial cell apoptosis. In a progeric mouse model deficient in Bmi1, where p21 was overexpressed, the retinal blood vessels displayed an aging phenotype characterized by enlarged caveolae and lipofuscin accumulation. Although mouse retina is not prone to develop microaneurysms, Bmi1-deficient mice presented abundant retinal microaneurysms. Together, these results uncover cellular senescence as a player during the formation of microaneurysms in old-age human retinas.

  2. Induced senescence in HeLa cervical carcinoma cells containing elevated telomerase activity and extended telomeres.

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    Goodwin, E C; DiMaio, D

    2001-11-01

    Proliferation of normal somatic human cells in culture is limited by replicative senescence, a growth-arrested state that appears to be triggered by the erosion of telomeres. Tumor cells such as HeLa cervical carcinoma cells, which contain short telomeres, can be induced to undergo senescence by various manipulations including oncogene withdrawal. Repression of the human papillomavirus (HPV) type 18 E6/E7 genes in HeLa cells by the bovine papillomavirus E2 transcriptional regulatory protein results in reactivation of the dormant p53 and p105(Rb) tumor suppressor pathways in these cells, repression of telomerase, and profound growth arrest. Strikingly, the growth-arrested cells rapidly and synchronously acquired numerous characteristics of primary cells undergoing replicative senescence. To explore the role of telomerase and telomere length in induced senescence, we expressed an exogenous hTERT gene, which encodes the catalytic subunit of telomerase, to generate stable HeLa cell clones with elevated telomerase activity and extended telomeres. Expression of the E2 protein in these cells repressed HPV E6/E7 expression, activated tumor suppressor pathways, and induced senescence as assessed by growth arrest, morphological changes, senescence-associated beta-galactosidase expression, and increased autofluorescence. Cells carrying the hTERT gene and control cells displayed identical responses to E2 expression. Therefore, HeLa cell senescence induced by HPV repression is not triggered by short telomeres or low levels of telomerase activity.

  3. Comparison between various biomarkers of senescence in bone marrow-derived stromal cells in vitro and ex-vivo

    DEFF Research Database (Denmark)

    Nehlin, Jan; Kassem, Moustapha; Frary, Charles

    Senescent stem cells are classified as non-quiescent, irreversibly growth-arrested, non-terminally differentiated, apoptosis resistant multipotent stem cells that maintain an altered gene expression from their juvenescent precursors. Established markers of senescence such as senescent-associated β......-galactosidase, p16, and senescent-associated heterochromatic foci (SAHF) can only be analyzed through the use of cell toxic stains or fixatives while BOCS, biomarker of cellular senescence, along with certain morphological qualities can be visualized and quantified without inflicting any damage to cellular...... structures. Bone marrow-derived stromal cells were isolated from young and old healthy subjects and cultured to senescence. The senescent cells were compared to their passage 1 counterparts through fluorescent high-throughput examination of C12FDG, SAHF, p16, BOCS stainings and morphology. This analysis...

  4. Redox-Dependent Calcium-Mediated Signaling Networks that Control the Senescence-Associated Secretory Phenotype

    Science.gov (United States)

    Chandrasekaran, Akshaya

    Cellular senescence has evolved as a protective mechanism to arrest growth of cells with oncogenic potential. While senescent cells have lost the ability to divide, they remain metabolically active and adapt a deleterious senescence associated secretory phenotype (SASP) central to the progression of several age-associated disease pathologies. The SASP is mechanistically regulated by the pro-inflammatory cytokine interleukin-1 alpha (IL-1alpha) whose expression and activity is responsive to the senescence associated (SA) oxidant production and the accompanying disruption of calcium (Ca2+) homeostasis. Using primary IMR-90 human fetal lung fibroblasts as a model of replicative senescence, we explored the molecular underpinnings driving Ca2+ dysregulation in senescent cells. We establish that the redox-responsive Transient Receptor Potential TRPC6 channel is compromised due to desensitization owing to SA increases in steady state hydrogen peroxide (H2O2) production. SA dysregulation of Ca2+ is also accompanied by loss of response to H2O2-induced Ca2+ influx that can be rescued with catalase pre-treatments. Senescent cells are also insensitive to Ca2+ entry induced by hyperforin, a specific activator of TRPC6, that can be restored by catalase pre-treatments, further suggesting redox regulation of TRPC6 in senescence. Inhibition of TRPC6 channel activity restores the ability of senescent cells to respond to peroxide-induced Ca2+ in addition to suppressing SASP gene expression. Furthermore, mammalian target of rapamycin (mTOR) signaling regulates SASP by means of modulating TRPC6 channel expression. Together, our findings provide compelling evidence that redox and mTOR-mediated regulation of TRPC6 channel modulate SASP gene expression. Further, the gain-of-function mutation of TRPC6 has pathological implications in several chronic pathologies and renders it a viable target in age-associated diseases.

  5. Cellular senescence in naevi and immortalisation in melanoma: a role for p16?

    Science.gov (United States)

    Gray-Schopfer, V C; Cheong, S C; Chong, H; Chow, J; Moss, T; Abdel-Malek, Z A; Marais, R; Wynford-Thomas, D; Bennett, D C

    2006-08-21

    Cellular senescence, the irreversible proliferative arrest seen in somatic cells after a limited number of divisions, is considered a crucial barrier to cancer, but direct evidence for this in vivo was lacking until recently. The best-known form of human cell senescence is attributed to telomere shortening and a DNA-damage response through p53 and p21. There is also a more rapid form of senescence, dependent on the p16-retinoblastoma pathway. p16 (CDKN2A) is a known melanoma susceptibility gene. Here, we use retrovirally mediated gene transfer to confirm that the normal form of senescence in cultured human melanocytes involves p16, since disruption of the p16/retinoblastoma pathway is required as well as telomerase activation for immortalisation. Expression (immunostaining) patterns of senescence mediators and markers in melanocytic lesions provide strong evidence that cell senescence occurs in benign melanocytic naevi (moles) in vivo and does not involve p53 or p21 upregulation, although p16 is widely expressed. In comparison, dysplastic naevi and early (radial growth-phase, RGP) melanomas show less p16 and some p53 and p21 immunostaining. All RGP melanomas expressed p21, suggesting areas of p53-mediated senescence, while most areas of advanced (vertical growth-phase) melanomas lacked both p16 and p21, implying escape from both forms of senescence (immortalisation). Moreover, nuclear p16 but not p21 expression can be induced in human melanocytes by oncogenic BRAF, as found in around 80% of naevi. We conclude that cell senescence can form a barrier to melanoma development. This also provides a potential explanation of why p16 is a melanoma suppressor gene.

  6. Astrocytes in the aging brain express characteristics of senescence-associated secretory phenotype.

    Science.gov (United States)

    Salminen, Antero; Ojala, Johanna; Kaarniranta, Kai; Haapasalo, Annakaisa; Hiltunen, Mikko; Soininen, Hilkka

    2011-07-01

    Cellular stress increases progressively with aging in mammalian tissues. Chronic stress triggers several signaling cascades that can induce a condition called cellular senescence. Recent studies have demonstrated that senescent cells express a senescence-associated secretory phenotype (SASP). Emerging evidence indicates that the number of cells expressing biomarkers of cellular senescence increases in tissues with aging, which implies that cellular senescence is an important player in organismal aging. In the brain, the aging process is associated with degenerative changes, e.g. synaptic loss and white matter atrophy, which lead to progressive cognitive impairment. There is substantial evidence for the presence of oxidative, proteotoxic and metabolic stresses in aging brain. A low-level, chronic inflammatory process is also present in brain during aging. Astrocytes demonstrate age-related changes that resemble those of the SASP: (i) increased level of intermediate glial fibrillary acidic protein and vimentin filaments, (ii) increased expression of several cytokines and (iii) increased accumulation of proteotoxic aggregates. In addition, in vitro stress evokes a typical senescent phenotype in cultured astrocytes and, moreover, isolated astrocytes from aged brain display the proinflammatory phenotype. All of these observations indicate that astrocytes are capable of triggering the SASP and the astrocytes in aging brain display typical characteristics of cellular senescence. Bearing in mind the many functions of astrocytes, it is evident that the age-related senescence of astrocytes enhances the decline in functional capacity of the brain. We will review the astroglial changes occurring during aging and emphasize that senescent astrocytes can have an important role in age-related neuroinflammation and neuronal degeneration. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  7. Comparative analysis of gene expression data reveals novel targets of senescence-associated microRNAs.

    Directory of Open Access Journals (Sweden)

    Marco Napolitano

    Full Text Available In the last decades, cellular senescence is viewed as a complex mechanism involved in different processes, ranging from tumor suppression to induction of age-related degenerative alterations. Senescence-inducing stimuli are myriad and, recently, we and others have demonstrated the role exerted by microRNAs in the induction and maintenance of senescence, by the identification of a subset of Senescence-Associated microRNAs (SAmiRs up-regulated during replicative or stress-induced senescence and able to induce a premature senescent phenotype when over-expressed in human primary cells. With the intent to find novel direct targets of two specific SAmiRs, SAmiR-494 and -486-5p, and cellular pathways which they are involved in, we performed a comparative analysis of gene expression profiles available in literature to select genes down-regulated upon replicative senescence of human primary fibroblasts. Among them, we searched for SAmiR's candidate targets by analyzing with different target prediction algorithms their 3'UTR for the presence of SAmiR-binding sites. The expression profiles of selected candidates have been validated on replicative and stress-induced senescence and the targeting of the 3'UTRs was assessed by luciferase assay. Results allowed us to identify Cell Division Cycle Associated 2 (CDCA2 and Inhibitor of DNA binding/differentiation type 4 (ID4 as novel targets of SAmiR-494 and SAmiR-486-5p, respectively. Furthermore, we demonstrated that the over-expression of CDCA2 in human primary fibroblasts was able to partially counteract etoposide-induced senescence by mitigating the activation of DNA Damage Response.

  8. Deacetylation of H4-K16Ac and heterochromatin assembly in senescence

    Directory of Open Access Journals (Sweden)

    Contrepois Kévin

    2012-08-01

    Full Text Available Abstract Background Cellular senescence is a stress response of mammalian cells leading to a durable arrest of cell proliferation that has been implicated in tumor suppression, wound healing, and aging. The proliferative arrest is mediated by transcriptional repression of genes essential for cell division by the retinoblastoma protein family. This repression is accompanied by varying degrees of heterochromatin assembly, but little is known regarding the molecular mechanisms involved. Results We found that both deacetylation of H4-K16Ac and expression of HMGA1/2 can contribute to DNA compaction during senescence. SIRT2, an NAD-dependent class III histone deacetylase, contributes to H4-K16Ac deacetylation and DNA compaction in human fibroblast cell lines that assemble striking senescence-associated heterochromatin foci (SAHFs. Decreased H4-K16Ac was observed in both replicative and oncogene-induced senescence of these cells. In contrast, this mechanism was inoperative in a fibroblast cell line that did not assemble extensive heterochromatin during senescence. Treatment of senescent cells with trichostatin A, a class I/II histone deacetylase inhibitor, also induced rapid and reversible decondensation of SAHFs. Inhibition of DNA compaction did not significantly affect the stability of the senescent state. Conclusions Variable DNA compaction observed during senescence is explained in part by cell-type specific regulation of H4 deacetylation and HMGA1/2 expression. Deacetylation of H4-K16Ac during senescence may explain reported decreases in this mark during mammalian aging and in cancer cells.

  9. IGF-I enhances cellular senescence via the reactive oxygen species-p53 pathway

    Energy Technology Data Exchange (ETDEWEB)

    Handayaningsih, Anastasia-Evi; Takahashi, Michiko; Fukuoka, Hidenori; Iguchi, Genzo; Nishizawa, Hitoshi; Yamamoto, Masaaki; Suda, Kentaro [Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe (Japan); Takahashi, Yutaka, E-mail: takahash@med.kobe-u.ac.jp [Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe (Japan)

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer Cellular senescence plays an important role in tumorigenesis and aging process. Black-Right-Pointing-Pointer We demonstrated IGF-I enhanced cellular senescence in primary confluent cells. Black-Right-Pointing-Pointer IGF-I enhanced cellular senescence in the ROS and p53-dependent manner. Black-Right-Pointing-Pointer These results may explain the underlying mechanisms of IGF-I involvement in tumorigenesis and in regulation of aging. -- Abstract: Cellular senescence is characterized by growth arrest, enlarged and flattened cell morphology, the expression of senescence-associated {beta}-galactosidase (SA-{beta}-gal), and by activation of tumor suppressor networks. Insulin-like growth factor-I (IGF-I) plays a critical role in cellular growth, proliferation, tumorigenesis, and regulation of aging. In the present study, we show that IGF-I enhances cellular senescence in mouse, rat, and human primary cells in the confluent state. IGF-I induced expression of a DNA damage marker, {gamma}H2AX, the increased levels of p53 and p21 proteins, and activated SA-{beta}-gal. In the confluent state, an altered downstream signaling of IGF-I receptor was observed. Treatment with a reactive oxygen species (ROS) scavenger, N-acetylcystein (NAC) significantly suppressed induction of these markers, indicating that ROS are involved in the induction of cellular senescence by IGF-I. In p53-null mouse embryonic fibroblasts, the IGF-I-induced augmentation of SA-{beta}-gal and p21 was inhibited, demonstrating that p53 is required for cellular senescence induced by IGF-I. Thus, these data reveal a novel pathway whereby IGF-I enhances cellular senescence in the ROS and p53-dependent manner and may explain the underlying mechanisms of IGF-I involvement in tumorigenesis and in regulation of aging.

  10. A cytokinin receptor homologue is induced during root nodule organogenesis and senescence in Lupinus albus L.

    Science.gov (United States)

    Coba de la Peña, Teodoro; Cárcamo, Claudia B; Almonacid, Luis; Zaballos, Angel; Lucas, M Mercedes; Balomenos, Dimitrios; Pueyo, José J

    2008-02-01

    Here we report the isolation of a new cytokinin receptor homologue, LaHK1, from lupin (Lupinus albus) root nodules. LaHK1 transcript accumulation was detected in different plant organs, and expression was analyzed throughout nodule development. We observed notably higher expression in nodule primordia and young nodules compared to the root or to mature nodules. We also detected elevated transcript accumulation in naturally senescent nodules and in senescent nodules subjected to foliar dark stress. The results could be an indication of a putative role of this cytokinin receptor homologue in nodule development, from morphogenesis through senescence.

  11. Nucleases activities during French bean leaf aging and dark-induced senescence.

    Science.gov (United States)

    Lambert, Rocío; Quiles, Francisco Antonio; Gálvez-Valdivieso, Gregorio; Piedras, Pedro

    2017-11-01

    During leaf senescence resources are managed, with nutrients mobilized from older leaves to new sink tissues. The latter implies a dilemma in terms of resource utilization, the leaf senescence should increase seed quality whereas delay in senescence should improve the seed yield. Increased knowledge about nutrient recycling during leaf senescence could lead to advances in agriculture and improved seed quality. Macromolecules mobilized during leaf senescence include proteins and nucleic acids. Although nucleic acids have been less well studied than protein degradation, they are possible reservoirs of nitrogen and phosphorous. The present study investigated nuclease activities and gene expression patterns of five members of the S1/P1 family in French bean (Phaseolus vulgaris L. cv.)Page: 2 during leaf senescence. An in-gel assay was used to detect nuclease activity during natural and dark-induced senescence, with single-stranded DNA (ssDNA) used as a substrate. The results revealed two nucleases (glycoproteins), with molecular masses of 34 and 39kDa in the senescent leaves. The nuclease activities were higher at a neutral than at an acidic pH. EDTA treatment inhibited the activities of the nucleases, and the addition of zinc resulted in the recovery of these activities. Both the 34 and 39kDa nucleases were able to use RNA and double-stranded DNA (dsDNA) as substrates, although their activities were low when dsDNA was used as a substrate. In addition, two ribonucleases with molecular masses of 14 and 16kDa, both of which could only utilize RNA as a substrate, were detected in the senescent leaves. Two members of the S1/P1 family, PVN2 and PVN5, were expressed under the experimental conditions, suggesting that these two genes were involved in senescence. The nuclease activity of the glycoproteins and gene expression were similar under both natural senescence and dark-induced senescence conditions. Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights

  12. Changes in the abscisic acid content of oat leaves during senescence

    OpenAIRE

    Gepstein, Shimon; Thimann, Kenneth V.

    1980-01-01

    To investigate the possibility that experimental promotion of retardation of the senescence of oat leaves may be mediated by abscisic acid (AbA), determinations of AbA were made in leaves senescing under different conditions. The extracts were subjected to thin-layer chromatography, the spots were eluted and esterified, and the AbA was determined by gas chromatography (overall recovery, about 75%). In darkness, where the stomata are closed and senescence is rapid, the concentration of AbA inc...

  13. Moderate Autophagy Inhibits Vascular Smooth Muscle Cell Senescence to Stabilize Progressed Atherosclerotic Plaque via the mTORC1/ULK1/ATG13 Signal Pathway

    Directory of Open Access Journals (Sweden)

    Zhenli Luo

    2017-01-01

    Full Text Available In order to investigate the effects of autophagy induced by rapamycin in the development of atherosclerosis plaque we established murine atherosclerosis model which was induced in ApoE−/− mice by high fat and cholesterol diet (HFD for 16 weeks. Rapamycin and 3-Methyladenine (MA were used as autophagy inducer and inhibitor respectively. The plaque areas in aortic artery were detected with HE and Oil Red O staining. Immunohistochemical staining were applied to investigate content of plaque respectively. In contrast to control and 3-MA groups, rapamycin could inhibit atherosclerosis progression. Rapamycin was able to increase collagen content and a-SMA distribution relatively, as well as decrease necrotic core area. Then we used MOVAS and culture with ox-LDL for 72 h to induce smooth muscle-derived foam cell model in vitro. Rapamycin and 3-MA were cultured together respectively. Flow cytometry assay and SA-β-Gal staining experiments were performed to detect survival and senescence of VSMCs. Western blot analysis were utilized to analyze the levels of protein expression. We found that rapamycin could promote ox-LDL-induced VSMCs autophagy survival and alleviate cellular senescence, in comparison to control and 3-MA groups. Western blot analysis showed that rapamycin could upregulate ULK1, ATG13 and downregulate mTORC1 and p53 protein expression.

  14. NAC Transcription Factors in Stress Responses and Senescence

    DEFF Research Database (Denmark)

    O'Shea, Charlotte

    Plant-specific NAM/ATAF/CUC (NAC) transcription factors have recently received considerable attention due to their significant roles in plant development and stress signalling. This interest has resulted in a number of physiological, genetic and cell biological studies of their functions. Some...... low degree of average structure but different patterns of disorder/order and molecular recognition features (MoRFs). For example, senescence-associated ANAC046 has a simple pattern with just a single MoRF. Analysis in yeast and thermodynamic characterisation suggested that the 11-residue C-terminal Mo......RF is a functional hotspot for both transcriptional activity and interaction with the cellular hub protein Radical Induced Cell Death1 (RCD1). Specific amino acid residues essential for the interaction were identified. These studies and structural analysis suggested that RCD1-ANAC046 complex formation does...

  15. Aging and senescence of skin cells in culture

    DEFF Research Database (Denmark)

    Rattan, Suresh

    2015-01-01

    aging in vitro are dermal fibroblasts, epidermal keratinocytes, and melanocytes. Serial subcultivation of normal diploid skin cells can be performed only a limited number of times, and the emerging senescent phenotype can be categorized into structural, physiological, biochemical, and molecular......Studying age-related changes in the physiology, biochemistry, and molecular biology of isolated skin cell populations in culture has greatly expanded the understanding of the fundamental aspects of skin aging. The three main cell types that have been studied extensively with respect to cellular...... phenotypes, which can be used as biomarkers of cellular aging in vitro. The rate and phenotype of aging are different in different cell types. There are both common features and specific features of aging of skin fibroblasts, keratinocytes, melanocytes, and other cell types. A progressive accumulation...

  16. The Impact of Autophagy on Cardiovascular Senescence and Diseases.

    Science.gov (United States)

    Sasaki, Yuichi; Ikeda, Yoshiyuki; Iwabayashi, Masaaki; Akasaki, Yuichi; Ohishi, Mitsuru

    2017-10-21

    The risk of cardiovascular disease increases with age, causing chronic disability, morbidity, and mortality in the elderly. Cardiovascular aging and disease are characterized by heart failure, cardiac ischemia-reperfusion injury, cardiomyopathy, hypertension, arterial stiffness, and atherosclerosis. As a cell ages, damaged organelles and abnormal proteins accumulate. A system for removing these cytoplasmic substrates is essential for maintaining homeostasis. Autophagy assists tissue homeostasis by forming a pathway by which these substances are degraded. Growing evidence suggests that autophagy plays a role in age-related and disease states of the cardiovascular system, and it may even be effective in preventing or treating cardiovascular disease. On the other hand, overexpression of autophagy in the heart and arteries can produce detrimental effects. We summarize the current understanding of the close relationship between autophagy and cardiovascular senescence.

  17. Ageing and immunity: addressing immune senescence to ensure healthy ageing.

    Science.gov (United States)

    Boraschi, Diana; Del Giudice, Giuseppe; Dutel, Catherine; Ivanoff, Bernard; Rappuoli, Rino; Grubeck-Loebenstein, Beatrix

    2010-05-07

    Among the greatest achievements of the 20th century, prolongation of life expectancy has been the result of improved health conditions, decreased childhood mortality, lower incidence of infectious diseases. The consequence is the rapid ageing of the world population, with the elderly representing over 25% of the entire population by the year 2030, of which 75% living in less developed countries. Ageing thus represents one of the major public health challenges of the 21st century. Indeed, unhealthy ageing and frailty of the aged population has an important impact on the economic development and social costs of a country, a problem even more acute in less developed countries. A better knowledge of immune senescence and the design of customised vaccination strategies for the elderly are the immediate challenges posed to scientists and physicians. The conference "Ageing and immunity", recently held in Siena (Italy), has addressed these issues and defined the global strategic priorities for research and health policies aimed at ensuring healthy ageing.

  18. SOX2 and SOX2-MYC Reprogramming Process of Fibroblasts to the Neural Stem Cells Compromised by Senescence.

    Directory of Open Access Journals (Sweden)

    Marta Winiecka-Klimek

    Full Text Available Tumorigenic potential of induced pluripotent stem cells (iPSCs infiltrating population of induced neural stem cells (iNSCs generated from iPSCs may limit their medical applications. To overcome such a difficulty, direct reprogramming of adult somatic cells into iNSCs was proposed. The aim of this study was the systematic comparison of induced neural cells (iNc obtained with different methods-direct reprogramming of human adult fibroblasts with either SOX2 (SiNSc-like or SOX2 and c-MYC (SMiNSc-like and induced pluripotent stem cells differentiation to ebiNSc-in terms of gene expression profile, differentiation potential as well as proliferation properties. Immunocytochemistry and real-time PCR analyses were used to evaluate gene expression profile and differentiation potential of various iNc types. Bromodeoxyuridine (BrdU incorporation and senescence-associated beta-galactosidase (SA-β-gal assays were used to estimate proliferation potential. All three types of iNc were capable of neuronal differentiation; however, astrocytic differentiation was possible only in case of ebiNSc. Contrary to ebiNSc generation, the direct reprogramming was rarely a propitious process, despite 100% transduction efficiency. The potency of direct iNSCs-like cells generation was lower as compared to iNSCs obtained by iPSCs differentiation, and only slightly improved when c-MYC was added. Directly reprogrammed iNSCs-like cells were lacking the ability to differentiate into astrocytic cells and characterized by poor efficiency of neuronal cells formation. Such features indicated that these cells could not be fully reprogrammed, as confirmed mainly with senescence detection. Importantly, SiNSc-like and SMiNSc-like cells were unable to achieve the long-term survival and became senescent, which limits their possible therapeutic applicability. Our results suggest that iNSCs-like cells, generated in the direct reprogramming attempts, were either not fully reprogrammed or

  19. Identification and Localization of Genes Which Restore Senescence in Breast Cancer Cells

    National Research Council Canada - National Science Library

    Reddy, Deepthi

    1997-01-01

    .... Cell X cell hybridizations between breast tumor cells and normal cell lines containing gpt tagged human chromosomes 2, 3, 6 and 9 resulted in senesced hybrid clones whereas hybrid clones containing...

  20. The Senescence-Associated Secretory Phenotype: Critical Effector in Skin Cancer and Aging

    Science.gov (United States)

    Ghosh, Kanad; Capell, Brian C.

    2017-01-01

    Cellular senescence, a state of stable cell cycle arrest in response to cellular stress, is an indispensable mechanism to counter tumorigenesis by halting the proliferation of damaged cells. However, through the secretion of an array of diverse cytokines, chemokines, growth factors, and proteases known as the senescence-associated secretory phenotype (SASP), senescent cells can paradoxically promote carcinogenesis. Consistent with this, removal of senescent cells delays the onset of cancer and prolongs lifespan in vivo, potentially in part through SASP reduction. In this review, we consider the evidence for the SASP and “SASP-like” inflammation in driving skin carcinogenesis, emphasizing how further understanding of both the roles and mechanisms of SASP expression may offer new targets for skin cancer prevention and therapy. PMID:27543988

  1. The Senescence-Associated Secretory Phenotype: Critical Effector in Skin Cancer and Aging.

    Science.gov (United States)

    Ghosh, Kanad; Capell, Brian C

    2016-11-01

    Cellular senescence, a state of stable cell cycle arrest in response to cellular stress, is an indispensable mechanism to counter tumorigenesis by halting the proliferation of damaged cells. However, through the secretion of an array of diverse cytokines, chemokines, growth factors, and proteases known as the senescence-associated secretory phenotype (SASP), senescent cells can paradoxically promote carcinogenesis. Consistent with this, removal of senescent cells delays the onset of cancer and prolongs lifespan in vivo, potentially in part through SASP reduction. In this review, we consider the evidence for the SASP and "SASP-like" inflammation in driving skin carcinogenesis, emphasizing how further understanding of both the roles and mechanisms of SASP expression may offer new targets for skin cancer prevention and therapy. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  2. Ethylene Role in Plant Growth, Development and Senescence: Interaction with Other Phytohormones.

    Science.gov (United States)

    Iqbal, Noushina; Khan, Nafees A; Ferrante, Antonio; Trivellini, Alice; Francini, Alessandra; Khan, M I R

    2017-01-01

    The complex juvenile/maturity transition during a plant's life cycle includes growth, reproduction, and senescence of its fundamental organs: leaves, flowers, and fruits. Growth and senescence of leaves, flowers, and fruits involve several genetic networks where the phytohormone ethylene plays a key role, together with other hormones, integrating different signals and allowing the onset of conditions favorable for stage progression, reproductive success and organ longevity. Changes in ethylene level, its perception, and the hormonal crosstalk directly or indirectly regulate the lifespan of plants. The present review focused on ethylene's role in the development and senescence processes in leaves, flowers and fruits, paying special attention to the complex networks of ethylene crosstalk with other hormones. Moreover, aspects with limited information have been highlighted for future research, extending our understanding on the importance of ethylene during growth and senescence and boosting future research with the aim to improve the qualitative and quantitative traits of crops.

  3. Impaired metabolism of senescent muscle satellite cells is associated with oxidative modifications of glycolytic enzymes

    DEFF Research Database (Denmark)

    Baraibar, Martin; Hyzewicz, Janek; Rogowska-Wrzesinska, Adelina

    2014-01-01

    is assured by resident adult stem cells known as satellite cells. During senescence their replication and differentiation is compromised contributing to sarcopenia. In this study we have addressed the impact of oxidatively modified proteins in the impaired metabolism of senescent human satellite cells....... By using a targeted proteomics analysis we have found that proteins involved in protein quality control and glycolytic enzymes are the main targets of oxidation (carbonylation) and modification with advanced glycation/lipid peroxidation end products during replicative senescence of satellite cells....... Inactivation of the proteasome in aged cells appeared as a key contributor to the accumulation of such damaged proteins. Untargeted metabolomic profiling and functional analyses indicated glucose metabolism impairment in senescent cells, although mitochondrial respiration remained unaffected. A metabolic shift...

  4. Suppression of the vacuolar invertase gene delays senescent sweetening in chipping potatoes

    Science.gov (United States)

    Background: Potato chip processors require potato tubers that meet quality specifications for fried chip color, and color depends largely upon tuber sugar contents. At later times in storage, potatoes accumulate sucrose, glucose and fructose. This developmental process, senescent sweetening, manifes...

  5. NAC Transcription Factors in Senescence: From Molecular Structure to Function in Crops

    DEFF Research Database (Denmark)

    Podzimska, Dagmara Agata; O'Shea, Charlotte; Gregersen, Per L.

    2015-01-01

    as important regulators of the senescence process. The consensus DNA binding site of the NAC domain is used to predict NAC target genes, and protein interaction sites can be predicted for the intrinsically disordered transcription regulatory domains of NAC proteins. The molecular characteristics...... of these domains determine the interactions in gene regulatory networks. Emerging local NAC-centered gene regulatory networks reveal complex molecular mechanisms of stress- and hormone-regulated senescence and basic physiological steps of the senescence process. For example, through molecular interactions...... involving the hormone abscisic acid, Arabidopsis NAP promotes chlorophyll degradation, a hallmark of senescence. Furthermore, studies of the functional rice ortholog, OsNAP, suggest that NAC genes can be targeted to obtain specific changes in lifespan control and nutrient remobilization in crop plants...

  6. Aberrant localization of lamin B receptor (LBR) in cellular senescence in human cells.

    Science.gov (United States)

    Arai, Rumi; En, Atsuki; Ukekawa, Ryo; Miki, Kensuke; Fujii, Michihiko; Ayusawa, Dai

    2016-05-13

    5-Bromodeoxyuridine (BrdU), a thymidine analogue, induces cellular senescence in mammalian cells. BrdU induces cellular senescence probably through the regulation of chromatin because BrdU destabilizes or disrupts nucleosome positioning and decondenses heterochromatin. Since heterochromatin is tethered to the nuclear periphery through the interaction with the nuclear envelope proteins, we examined the localization of the several nuclear envelope proteins such as lamins, lamin-interacting proteins, nuclear pore complex proteins, and nuclear transport proteins in senescent cells. We have shown here that lamin B receptor (LBR) showed a change in localization in both BrdU-induced and replicative senescent cells. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. A Global Database of Carbon and Nutrient Concentrations of Green and Senesced Leaves

    Data.gov (United States)

    National Aeronautics and Space Administration — This data set provides carbon (C), nitrogen (N), phosphorus (P), potassium (K), calcium (Ca), and magnesium (Mg) concentrations in green and senesced leaves....

  8. A Global Database of Carbon and Nutrient Concentrations of Green and Senesced Leaves

    Data.gov (United States)

    National Aeronautics and Space Administration — ABSTRACT: This data set provides carbon (C), nitrogen (N), phosphorus (P), potassium (K), calcium (Ca), and magnesium (Mg) concentrations in green and senesced...

  9. Activation of nuclear factor-kappa B signalling promotes cellular senescence

    NARCIS (Netherlands)

    Rovillain, E.; Mansfield, L.; Caetano, C.; Alvarez-Fernandez, M.; Caballero, O. L.; Medema, R. H.; Hummerich, H.; Jat, P. S.

    Cellular senescence is a programme of irreversible cell cycle arrest that normal cells undergo in response to progressive shortening of telomeres, changes in telomeric structure, oncogene activation or oxidative stress. The underlying signalling pathways, of major clinicopathological relevance, are

  10. Nitric oxide prevents alveolar senescence and emphysema in a mouse model.

    Directory of Open Access Journals (Sweden)

    Amanda E Boe

    Full Text Available Nω-nitro-L-arginine methyl ester (L-NAME treatment induces arteriosclerosis and vascular senescence. Here, we report that the systemic inhibition of nitric oxide (NO production by L-NAME causes pulmonary emphysema. L-NAME-treated lungs exhibited both the structural (alveolar tissue destruction and functional (increased compliance and reduced elastance characteristics of emphysema development. Furthermore, we found that L-NAME-induced emphysema could be attenuated through both genetic deficiency and pharmacological inhibition of plasminogen activator inhibitor-1 (PAI-1. Because PAI-1 is an important contributor to the development of senescence both in vitro and in vivo, we investigated whether L-NAME-induced senescence led to the observed emphysematous changes. We found that L-NAME treatment was associated with molecular and cellular evidence of premature senescence in mice, and that PAI-1 inhibition attenuated these increases. These findings indicate that NO serves to protect and defend lung tissue from physiological aging.

  11. Analysis of Guard Cell Viability and Action in Senescing Leaves of Nicotiana glauca (Graham), Tree Tobacco 1

    Science.gov (United States)

    Ozuna, Richard; Yera, Ramon; Ortega, Kim; Tallman, Gary

    1985-01-01

    In an attempt to determine whether low epidermal conductances to water vapor diffusion of senescing leaves were caused by internal changes in guard cells or by factors external to guard cells, stomatal behavior was examined in intact senescing and nonsenescing leaves of Nicotiana glauca (Graham), tree tobacco, grown in the field or in an environmental chamber. Conductances of senescing leaves were 5 to 10% of the maximum conductances of nonsenescing leaves of the same plant, yet guard cell duplexes isolated from epidermal peels of senescing leaves developed full turgor in the light in solutions containing KCl, and sodium cobaltinitrite staining showed that K+ accumulated as turgor developed. Ninety-five per cent of the guard cells isolated from senescing leaves concentrated neutral red and excluded trypan blue. Intercellular leaf CO2 concentrations of senescing and nonsenescing leaves of chamber-grown plants were not significantly different (about 240 microliters per liter), but the potassium contents of adaxial and abaxial epidermes of senescing leaves taken from plants grown in the field were less than half those of nonsenescing leaves. We conclude that guard cells do not undergo the orderly senescence process that characteristically takes place in mesophyll tissue during whole-leaf senescence and that the reduced conductances of senescing leaves are produced by factors external to guard cells. PMID:16664404

  12. MiRNA profile associated with replicative senescence, extended cell culture, and ectopic telomerase expression in human foreskin fibroblasts.

    Directory of Open Access Journals (Sweden)

    Laura N Bonifacio

    Full Text Available Senescence is a highly regulated process that limits cellular replication by enforcing a G1 arrest in response to various stimuli. Replicative senescence occurs in response to telomeric DNA erosion, and telomerase expression can offset replicative senescence leading to immortalization of many human cells. Limited data exists regarding changes of microRNA (miRNA expression during senescence in human cells and no reports correlate telomerase expression with regulation of senescence-related miRNAs. We used miRNA microarrays to provide a detailed account of miRNA profiles for early passage and senescent human foreskin (BJ fibroblasts as well as early and late passage immortalized fibroblasts (BJ-hTERT that stably express the human telomerase reverse transcriptase subunit hTERT. Selected miRNAs that were differentially expressed in senescence were assayed for expression in quiescent cells to identify miRNAs that are specifically associated with senescence-associated growth arrest. From this group of senescence-associated miRNAs, we confirmed the ability of miR-143 to induce growth arrest after ectopic expression in young fibroblasts. Remarkably, miR-143 failed to induce growth arrest in BJ-hTERT cells. Importantly, the comparison of late passage immortalized fibroblasts to senescent wild type fibroblasts reveals that miR-146a, a miRNA with a validated role in regulating the senescence associated secretory pathway, is also regulated during extended cell culture independently of senescence. The discovery that miRNA expression is impacted by expression of ectopic hTERT as well as extended passaging in immortalized fibroblasts contributes to a comprehensive understanding of the connections between telomerase expression, senescence and processes of cellular aging.

  13. Bradykinin inhibits oxidative stress-induced cardiomyocytes senescence via regulating redox state.

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    Ruolan Dong

    Full Text Available BACKGROUND: Cell senescence is central to a large body of age related pathology, and accordingly, cardiomyocytes senescence is involved in many age related cardiovascular diseases. In consideration of that, delaying cardiomyocytes senescence is of great importance to control clinical cardiovascular diseases. Previous study indicated that bradykinin (BK protected endothelial cells from senescence induced by oxidative stress. However, the effects of bradykinin on cardiomyocytes senescence remain to be elucidated. In this study, we investigated the effect of bradykinin on H2O2-induced H9C2 cells senescence. METHODS AND RESULTS: Bradykinin pretreatment decreased the senescence induced by H2O2 in cultured H9C2 cells in a dose dependent manner. Interestingly, 1 nmol/L of BK almost completely inhibited the increase in senescent cell number and p21 expression induced by H2O2. Since H2O2 induces senescence through superoxide-induced DNA damage, we also observed the DNA damage by comet assay, and BK markedly reduced DNA damage induced by H2O2, and moreover, BK treatment significantly prevented reactive oxygen species (ROS production in H9C2 cells treated with H2O2. Importantly, when co-incubated with bradykinin B2 receptor antagonist HOE-140 or eNOS inhibitor N-methyl-L-arginine acetate salt (L-NAME, the protective effects of bradykinin on H9C2 senescence were totally blocked. Furthermore, BK administration significantly prevented the increase in nicotinamide adenine dinucleotide phosphate (NADPH oxidase activity characterized by increased ROS generation and gp91 expression and increased translocation of p47 and p67 to the membrane and the decrease in superoxide dismutase (SOD activity and expression induced by H2O2 in H9C2 cells, which was dependent on BK B2 receptor mediated nitric oxide (NO release. CONCLUSIONS: Bradykinin, acting through BK B2 receptor induced NO release, upregulated antioxidant Cu/Zn-SOD and Mn-SOD activity and expression while

  14. Comparable Senescence Induction in Three-dimensional Human Cartilage Model by Exposure to Therapeutic Doses of X-rays or C-ions

    Energy Technology Data Exchange (ETDEWEB)

    Hamdi, Dounia Houria; Chevalier, François [Laboratoire d' Accueil et de Recherche avec les Ions Accélérés (LARIA), Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), Direction de la Recherche Fondamentale - DRF, Commissariat à l' Energie Atomique et aux Energies Alternatives, Caen (France); Groetz, Jean-Emmanuel [UMR6249, Université de Franche-Comté, Besançon (France); Durantel, Florent [UMR6252, Centre de Recherche sur les Ions, les Matériaux et la Photonique (CIMAP), Direction de la Recherche Fondamentale (DRF), Commissariat à l' Energie Atomique et aux Energies Alternatives, Caen (France); Thuret, Jean-Yves; Mann, Carl [FRE3377, Service de Biologie Intégrative et Génétique Moléculaire SBIGeM, Institut de Biologie et de Technologies de Saclay (iBiTec-S), Direction de la Recherche Fondamentale (DRF), Commissariat à l' Energie Atomique et aux Energies Alternatives, Gif-sur-Yvette (France); Institut de Biologie Intégrative de la Cellule I2BC / Université Paris Saclay, Gif-sur-Yvette (France); and others

    2016-05-01

    Purpose: Particle therapy using carbon ions (C-ions) has been successfully used in the treatment of tumors resistant to conventional radiation therapy. However, the potential side effects to healthy cartilage exposed to lower linear energy transfer (LET) ions in the beam track before the tumor have not been evaluated. The aim of the present study was to assess the extent of damage after C-ion irradiation in a 3-dimensional (3D) cartilage model close to human homeostasis. Methods and Materials: Primary human articular chondrocytes from a healthy donor were cultured in a collagen scaffold to construct a physioxic 3D cartilage model. A 2-dimensional (2D) culture was used as a reference. The cells were irradiated with a single dose of a monoenergetic C-ion beam with a LET of approximatively 30 keV/μm. This LET corresponds to the entrance channel of C-ions in the shallow healthy tissues before the spread-out Bragg peak (∼100 keV/μm) during hadron therapy protocols. The same dose of X-rays was used as a reference. Survival, cell death, and senescence assays were performed. Results: As expected, in the 2D culture, C-ions were more efficient than X-rays in reducing cell survival with a relative biological effectiveness of 2.6. This correlated with stronger radiation-induced senescence (two-fold) but not with higher cell death induction. This differential effect was not reflected in the 3D culture. Both ionizing radiation types induced a comparable rate of senescence induction in the 3D model. Conclusions: The greater biological effectiveness of C-ions compared with low LET radiation when evaluated in treatment planning systems might be misevaluated using 2D culture experiments. Radiation-induced senescence is an important factor of potential cartilage attrition. The present data should encourage the scientific community to use relevant models and beams to improve the use of charged particles with better safety for patients.

  15. A distinct mechanism of senescence activation in amnion epithelial cells by infection, inflammation, and oxidative stress.

    Science.gov (United States)

    Dixon, Christopher Luke; Richardson, Lauren; Sheller-Miller, Samantha; Saade, George; Menon, Ramkumar

    2017-11-30

    We investigated p38MAPK activation-induced fetal membrane cell senescence in response to inflammation (tumour necrosis factor-alpha [TNF-α]) and infection (lipopolysaccharide [LPS]), factors associated with spontaneous preterm birth. Primary amnion epithelial cells (AECs) were exposed to TNF-α, 50 ng/mL and LPS, 100 ng/mL. Cigarette smoke extract (CSE), a known OS inducer, was used as positive control. AECs were cotreated with the antioxidant N-acetyl cysteine (NAC) and p38MAPK inhibitor SB203580 to determine the effect of OS and p38MAPK. Western blot analysis was performed for active (Phospho-p38MAPK) and total p38MAPK. Senescence was determined by flow cytometry, and culture supernatants were tested for IL-6 using ELISA. TNF-α, but not LPS, increased p38MAPK activation compared to untreated cells (P = .01). The number of senescent cells and senescence-associated IL-6 was higher in both TNF-α and LPS-treated cells compared to control (P = .001, P = .01, respectively). Antioxidant NAC inhibited p38MAPK activation by TNF-α. p38MAPK inhibitor SB203580 reduced the development of senescence and IL-6 by TNF-α and LPS. CSE treatment validated our current data. TNF-α caused OS-mediated p38MAPK induction, senescence, and IL-6 increase from AECs. LPS also induced senescence and IL-6 increase. Inflammatory and infectious factors may cause premature fetal cell senescence contributing to preterm birth pathophysiology. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Relationship between Photosynthesis and Chlorophyll Content during Leaf Senescence of Rice Seedlings

    OpenAIRE

    Mariko, Kura-Hotta; Kazuhiko, Satoh; Sakae, Katoh; Department of Pure and Applied Sciences, College of Arts and Sciences

    1987-01-01

    Photosynthetic oxygen evolution, chlorophyll contents and chlorophyll a/b ratios of 3rd to 6th leaves of rice seedlings were measured to examine whether or not inactivation of photosynthesis during senescence is related to loss of chlorophyll. Photosynthetic activity decreased more rapidly than chlorophyll content during leaf senescence; as a result, the lower the leaf position, the lower was the rate of oxygen evolution determined on the basis of chlorophyll. Chlorophyll a/b ratio also decre...

  17. Is Post-Traumatic Stress Disorder Associated with Premature Senescence? A Review of the Literature

    OpenAIRE

    Lohr, James B; Palmer, Barton W.; Eidt, Carolyn A.; Aailaboyina, Smitha; Mausbach, Brent T.; Wolkowitz, Owen M.; Thorp, Steven R.; Jeste, Dilip V.

    2015-01-01

    Post-Traumatic Stress Disorder (PTSD) has major public health significance. Evidence that PTSD may be associated with premature senescence (early or accelerated aging) would have major implications for quality of life and healthcare policy. We conducted a comprehensive review of published empirical studies relevant to early aging in PTSD. Our search included the PubMed, PsycINFO and PILOTS databases for empirical reports published since the year 2000 relevant to early senescence and PTSD, inc...

  18. Effects of oxygen, growth state, and senescence on the antioxidant responses of WI-38 fibroblasts.

    Science.gov (United States)

    Balin, Arthur K; Reimer, Richard J; Reenstra, Wende R; Lilie, Steven M; Leong, Ina; Sullivan, Katherine; Allen, Robert G

    2010-12-01

    Mitotically active, growth-arrested cells and proliferatively senescent cultures of human fetal lung fibroblasts (WI-38) were exposed to six different oxygen tensions for various lengths of time and then analyzed to determine the responses of their antioxidant defense system. Glutathione (GSH) concentration increased as a function of ambient oxygen tension in early passage cultures; the effect was larger in exponentially growing cultures than in those in a state of contact-inhibited growth arrest, but was absent in senescent cells. Conversely, the activity of glutathione disulfide reductase was greater in growth-arrested cultures than in mitotically active cells irrespective of oxygen tension. Glucose-6-phosphate dehydrogenase was lowest in log-phase cells exposed to different oxygen tensions for 24 h and in senescent cells. Both hypoxia and hyperoxia depressed selenium-dependent glutathione peroxidase activity in early passage cultures, while the activity of the enzyme progressively declined with increasing oxygen in senescent cells. The GSH S-transferase activity was unresponsive to changes in ambient oxygen tension in either young or senescent cultures. Manganese-containing superoxide dismutase (MnSOD) activity was unaffected by oxygen tension, but was elevated in young confluent cultures as compared with cultures in log-phase growth. MnSOD activity was significantly higher in senescent cultures than in early passage cultures and was also responsive to increased oxygen tension in senescent cultures. Copper-zinc-containing superoxide dismutases activity was not affected by oxygen tension or the passage of time, but it declined in senescent cultures.

  19. Cartilage oligomeric matrix protein prevents vascular aging and vascular smooth muscle cells senescence.

    Science.gov (United States)

    Wang, Meili; Fu, Yi; Gao, Cheng; Jia, Yiting; Huang, Yaqian; Liu, Limei; Wang, Xian; Wang, Wengong; Kong, Wei

    2016-09-16

    Aging-related vascular dysfunction contributes to cardiovascular morbidity and mortality. Cartilage oligomeric matrix protein (COMP), a vascular extracellular matrix protein, has been described as a negative regulatory factor for the vascular aging-related processes including atherosclerosis and vascular calcification. However, whether COMP is implicated in the process of vascular aging remains unclear. Here, we identified a novel function of COMP in preventing vascular aging and vascular smooth muscle cells (VSMCs) senescence. Firstly, vascular COMP expression was decreased in three different senescence-accelerated mouse models and was also declining with age. COMP(-/-) mice displayed elevated senescence-associated markers expression, including p53, p21 and p16, in the aortas compared with their wild type (WT) littermates. In accordance, COMP deficiency induced aging-related vascular dysfunction as evidenced by the significantly reduced phenylephrine-induced contraction and increased vascular stiffness as evaluated by pulse wave velocity. The aortic wall of COMP(-/-) mice was susceptible to senescence by displaying senescence-associated β-galactosidase (SA β-gal) activity induced by periadventitial application of CaCl2 to the abdominal aorta. In vitro, COMP knockdown by small interfering (si) RNA led to the elevation of p53, p21 and p16 as well as SA β-gal activity in VSMCs after H2O2 stimulation. VSMCs isolated from COMP(-/-) mice showed elevated senescence-associated markers expression and supplement of COMP adenovirus to COMP-deficient VSMCs greatly rescued cellular senescence. Taken together, these findings revealed the essential role of COMP in retarding the development of vascular aging and VSMC senescence. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Growth hormone is a cellular senescence target in pituitary and nonpituitary cells

    Science.gov (United States)

    Chesnokova, Vera; Zhou, Cuiqi; Ben-Shlomo, Anat; Zonis, Svetlana; Tani, Yuji; Ren, Song-Guang; Melmed, Shlomo

    2013-01-01

    Premature proliferative arrest in benign or early-stage tumors induced by oncoproteins, chromosomal instability, or DNA damage is associated with p53/p21 activation, culminating in either senescence or apoptosis, depending on cell context. Growth hormone (GH) elicits direct peripheral metabolic actions as well as growth effects mediated by insulin-like growth factor 1 (IGF1). Locally produced peripheral tissue GH, in contrast to circulating pituitary-derived endocrine GH, has been proposed to be both proapoptotic and prooncogenic. Pituitary adenomas expressing and secreting GH are invariably benign and exhibit DNA damage and a senescent phenotype. We therefore tested effects of nutlin-induced p53-mediated senescence in rat and human pituitary cells. We show that DNA damage senescence induced by nutlin triggers the p53/p21 senescent pathway, with subsequent marked induction of intracellular pituitary GH in vitro. In contrast, GH is not induced in cells devoid of p53. Furthermore we show that p53 binds specific GH promoter motifs and enhances GH transcription and secretion in senescent pituitary adenoma cells and also in nonpituitary (human breast and colon) cells. In vivo, treatment with nutlin results in up-regulation of both p53 and GH in the pituitary gland, as well as increased GH expression in nonpituitary tissues (lung and liver). Intracrine GH acts in pituitary cells as an apoptosis switch for p53-mediated senescence, likely protecting the pituitary adenoma from progression to malignancy. Unlike in the pituitary, in nonpituitary cells GH exerts antiapoptotic properties. Thus, the results show that GH is a direct p53 transcriptional target and fulfills criteria as a p53 target gene. Induced GH is a readily measurable cell marker for p53-mediated cellular senescence. PMID:23940366

  1. Effects of Controlled Release Fertilizer on the Flag Leaves Senescence in Dry-land Wheat

    OpenAIRE

    Dandan Liu; Yan Shi

    2013-01-01

    In order to select a reasonable controlled release fertilizer application method to slow down the senescence of flag leaf in dry-land wheat. The effects of controlled release fertilizer on soluble protein content, MDA content, the Catalase (CAT) activity, the Superoxide Dismutase (SOD) activity on the flag leaves senescence in dry-land wheat had been studied in the open field with the variety wheat Jimai22. The results indicated that, the combination application of controlled release fertiliz...

  2. Endothelial Senescence Contributes to Heart Failure With Preserved Ejection Fraction in an Aging Mouse Model.

    Science.gov (United States)

    Gevaert, Andreas B; Shakeri, Hadis; Leloup, Arthur J; Van Hove, Cor E; De Meyer, Guido R Y; Vrints, Christiaan J; Lemmens, Katrien; Van Craenenbroeck, Emeline M

    2017-06-01

    Because of global aging, the prevalence of heart failure with preserved ejection fraction (HFpEF) continues to rise. Although HFpEF pathophysiology remains incompletely understood, endothelial inflammation is stated to play a central role. Cellular senescence is a process of cellular growth arrest linked with aging and inflammation. We used mice with accelerated aging to investigate the role of cellular senescence in HFpEF development. Senescence-accelerated mice (SAM, n=18) and control mice with normal senescence (n=15) were fed normal chow or a high-fat, high-salt diet (WD). Vascular and cardiac function was assessed at 8, 16, and 24 weeks of age. At 24 weeks, both SAM on WD (SAM-WD) and SAM on regular diet displayed endothelial dysfunction, as evidenced by impaired acetylcholine-induced relaxation of aortic segments and reduced basal nitric oxide. At week 24, SAM-WD had developed HFpEF, characterized by diastolic dysfunction, left ventricular hypertrophy, left atrial dilatation, and interstitial fibrosis. Also, exercise capacity was reduced and lung weight increased. Cardiovascular inflammation and senescence were assessed by immunohistochemical and immunofluorescence staining of hearts and aortas. SAM-WD showed increased endothelial inflammation (intercellular adhesion molecule 1 expression) and increased endothelial senescence (acetyl-p53/CD31 costaining). The latter correlated with diastolic function and intercellular adhesion molecule 1 expression. SAM develop endothelial dysfunction. Adding a high-salt, high-fat diet accelerates endothelial senescence and instigates endothelial inflammation. This coincides with hemodynamic and structural changes typical of HFpEF. Targeting endothelial senescence could be a new therapeutic avenue in HFpEF. © 2017 American Heart Association, Inc.

  3. A Rice NAC Transcription Factor Promotes Leaf Senescence via ABA Biosynthesis.

    Science.gov (United States)

    Mao, Chanjuan; Lu, Songchong; Lv, Bo; Zhang, Bin; Shen, Jiabin; He, Jianmei; Luo, Liqiong; Xi, Dandan; Chen, Xu; Ming, Feng

    2017-07-01

    It is well known that abscisic acid (ABA)-induced leaf senescence and premature leaf senescence negatively affect the yield of rice (Oryza sativa). However, the molecular mechanism underlying this relationship, especially the upstream transcriptional network that modulates ABA level during leaf senescence, remains largely unknown. Here, we demonstrate a rice NAC transcription factor, OsNAC2, that participates in ABA-induced leaf senescence. Overexpression of OsNAC2 dramatically accelerated leaf senescence, whereas its knockdown lines showed a delay in leaf senescence. Chromatin immunoprecipitation-quantitative PCR, dual-luciferase, and yeast one-hybrid assays demonstrated that OsNAC2 directly activates expression of chlorophyll degradation genes, OsSGR and OsNYC3 Moreover, ectopic expression of OsNAC2 leads to an increase in ABA levels via directly up-regulating expression of ABA biosynthetic genes (OsNCED3 and OsZEP1) as well as down-regulating the ABA catabolic gene (OsABA8ox1). Interestingly, OsNAC2 is upregulated by a lower level of ABA but downregulated by a higher level of ABA, indicating a feedback repression of OsNAC2 by ABA. Additionally, reduced OsNAC2 expression leads to about 10% increase in the grain yield of RNAi lines. The novel ABA-NAC-SAGs regulatory module might provide a new insight into the molecular action of ABA to enhance leaf senescence and elucidates the transcriptional network of ABA production during leaf senescence in rice. © 2017 American Society of Plant Biologists. All Rights Reserved.

  4. Iscador Qu inhibits doxorubicin-induced senescence of MCF7 cells

    OpenAIRE

    Srdic-Rajic, T.; Santiba?ez, J. F.; Kanjer, K.; Tisma-Miletic, N.; Cavic, M.; Galun, D.; Jevric, M.; Kardum, N.; Konic-Ristic, A.; Zoranovic, T.

    2017-01-01

    Chemotherapy in patients with inoperable or advanced breast cancer inevitably results in low-dose exposure of tumor-cell subset and senescence. Metabolically active senescent cells secrete multiple tumor promoting factors making their elimination a therapeutic priority. Viscum album is one of the most widely used alternative anti-cancer medicines facilitating chemotherapy tolerance of breast cancer patients. The aim of this study was to model and investigate how Viscum album extracts execute ...

  5. Adaptation to altitude affects the senescence response to chilling in the perennial plant Arabis alpina

    Science.gov (United States)

    Wingler, Astrid; Juvany, Marta; Cuthbert, Caroline; Munné-Bosch, Sergi

    2015-01-01

    In annual plants with determinate growth, sugar accumulation signals high carbon availability once growth has ceased, resulting in senescence-dependent nutrient recycling to the seeds. However, this senescence-inducing effect of sugars is abolished at cold temperature, where sugar accumulation is important for protection. Here, natural variation was exploited to analyse the effect of chilling on interactions between leaf senescence, sugars, and phytohormones in Arabis alpina, a perennial plant with indeterminate growth. Eight accessions of A. alpina originating from between 2090 and 3090 m above sea level in the French Alps were used to identify heritable adaptations in senescence, stress response, sugars, and phytohormones to altitude. Accessions from high altitudes showed an enhanced capacity for sucrose accumulation and a diminished loss of chlorophyll in response to chilling. At warm temperature, sucrose content was negatively correlated with chlorophyll content, and sucrose treatment induced leaf senescence. Chilling resulted in lower indole-3-acetic acid, but higher zeatin and jasmonic acid contents. Interactions between sugar and phytohormones included a positive correlation between sucrose and jasmonic acid contents that may be involved in promoting the stress-dependent decline in chlorophyll. These findings reveal regulatory interactions that underlie adaptation in the senescence and stress response to chilling. PMID:25371506

  6. MicroRNA-22 Induces Endothelial Progenitor Cell Senescence by Targeting AKT3

    Directory of Open Access Journals (Sweden)

    Yue Zheng

    2014-10-01

    Full Text Available Objectives: Endothelial progenitor cells (EPCs play an important role in postnatal neovascularization. The number and function of EPCs declines as part of aging-associated senescence, thereby potentially contributing to vascular pathologies. Here, we investigated the significance and molecular mechanisms of microRNA-22 (miR-22 governing EPC senescence. Methods: EPCs were isolated from human circulating mononuclear cells from healthy young and aged volunteers. Cell senescence, proliferation, migration and tube formation ability were detected by SA-β-gal staining assay, MTT assay, transwell assay and Matrigel-based angiogenesis assay. Gene and protein expression were analyzed by qRT-PCR and Western blot respectively. Results: We found that miR-22 was upregulated in aged EPCs. Overexpression of miR-22 in young EPCs induced cell senescence, decreased proliferation and migration, and impaired angiogenesis in vitro. Conversely, silencing of endogenous miR-22 led to decreased cell senescence, increased proliferation and migration, and improved angiogenesis. AKT3 was identified as a direct target of miR-22, and restoration of AKT3 expression attenuated the effects of miR-22 in young EPCs. Conclusion: Our results indicate that miR-22 induces EPC senescence by downregulating AKT3 expression, providing a potential novel target for the reversal of EPC dysfunction in angiogenesis.

  7. p53-dependent translational control of senescence and transformation via 4E-BPs.

    Science.gov (United States)

    Petroulakis, Emmanuel; Parsyan, Armen; Dowling, Ryan J O; LeBacquer, Olivier; Martineau, Yvan; Bidinosti, Michael; Larsson, Ola; Alain, Tommy; Rong, Liwei; Mamane, Yaël; Paquet, Marilene; Furic, Luc; Topisirovic, Ivan; Shahbazian, David; Livingstone, Mark; Costa-Mattioli, Mauro; Teodoro, Jose G; Sonenberg, Nahum

    2009-11-06

    eIF4E, the mRNA 5' cap-binding translation initiation factor, is overexpressed in numerous cancers and is implicated in mechanisms underlying oncogenesis and senescence. 4E-BPs (eIF4E-binding proteins) inhibit eIF4E activity, and thereby act as suppressors of eIF4E-dependent pathways. Here, we show that tumorigenesis is increased in p53 knockout mice that lack 4E-BP1 and 4E-BP2. However, primary fibroblasts lacking 4E-BPs, but expressing p53, undergo premature senescence and resist oncogene-driven transformation. Thus, the p53 status governs 4E-BP-dependent senescence and transformation. Intriguingly, the 4E-BPs engage in senescence via translational control of the p53-stabilizing protein, Gas2. Our data demonstrate a role for 4E-BPs in senescence and tumorigenesis and highlight a p53-mediated mechanism of senescence through a 4E-BP-dependent pathway.

  8. Glucose Oxidase Induces Cellular Senescence in Immortal Renal Cells through ILK by Downregulating Klotho Gene Expression

    Science.gov (United States)

    Troyano-Suárez, Nuria; del Nogal-Avila, María; Mora, Inés; Sosa, Patricia; López-Ongil, Susana; Rodriguez-Puyol, Diego; Olmos, Gemma; Ruíz-Torres, María Piedad

    2015-01-01

    Cellular senescence can be prematurely induced by oxidative stress involved in aging. In this work, we were searching for novel intermediaries in oxidative stress-induced senescence, focusing our interest on integrin-linked kinase (ILK), a scaffold protein at cell-extracellular matrix (ECM) adhesion sites, and on the Klotho gene. Cultured renal cells were treated with glucose oxidase (GOx) for long time periods. GOx induced senescence, increasing senescence associated β-galactosidase activity and the expression of p16. In parallel, GOx increased ILK protein expression and activity. Ectopic overexpression of ILK in cells increased p16 expression, even in the absence of GOx, whereas downregulation of ILK inhibited the increase in p16 due to oxidative stress. Additionally, GOx reduced Klotho gene expression and cells overexpressing Klotho protein did not undergo senescence after GOx addition. We demonstrated a direct link between ILK and Klotho since silencing ILK expression in cells and mice increases Klotho expression and reduces p53 and p16 expression in renal cortex. In conclusion, oxidative stress induces cellular senescence in kidney cells by increasing ILK protein expression and activity, which in turn reduces Klotho expression. We hereby present ILK as a novel downregulator of Klotho gene expression. PMID:26583057

  9. Glucose Oxidase Induces Cellular Senescence in Immortal Renal Cells through ILK by Downregulating Klotho Gene Expression

    Directory of Open Access Journals (Sweden)

    Nuria Troyano-Suárez

    2015-01-01

    Full Text Available Cellular senescence can be prematurely induced by oxidative stress involved in aging. In this work, we were searching for novel intermediaries in oxidative stress-induced senescence, focusing our interest on integrin-linked kinase (ILK, a scaffold protein at cell-extracellular matrix (ECM adhesion sites, and on the Klotho gene. Cultured renal cells were treated with glucose oxidase (GOx for long time periods. GOx induced senescence, increasing senescence associated β-galactosidase activity and the expression of p16. In parallel, GOx increased ILK protein expression and activity. Ectopic overexpression of ILK in cells increased p16 expression, even in the absence of GOx, whereas downregulation of ILK inhibited the increase in p16 due to oxidative stress. Additionally, GOx reduced Klotho gene expression and cells overexpressing Klotho protein did not undergo senescence after GOx addition. We demonstrated a direct link between ILK and Klotho since silencing ILK expression in cells and mice increases Klotho expression and reduces p53 and p16 expression in renal cortex. In conclusion, oxidative stress induces cellular senescence in kidney cells by increasing ILK protein expression and activity, which in turn reduces Klotho expression. We hereby present ILK as a novel downregulator of Klotho gene expression.

  10. Arctigenin induced gallbladder cancer senescence through modulating epidermal growth factor receptor pathway.

    Science.gov (United States)

    Zhang, Mingdi; Cai, Shizhong; Zuo, Bin; Gong, Wei; Tang, Zhaohui; Zhou, Di; Weng, Mingzhe; Qin, Yiyu; Wang, Shouhua; Liu, Jun; Ma, Fei; Quan, Zhiwei

    2017-05-01

    Gallbladder cancer has poor prognosis and limited therapeutic options. Arctigenin, a representative dibenzylbutyrolactone lignan, occurs in a variety of plants. However, the molecular mechanisms involved in the antitumor effect of arctigenin on gallbladder cancer have not been fully elucidated. The expression levels of epidermal growth factor receptor were examined in 100 matched pairs of gallbladder cancer tissues. A positive correlation between high epidermal growth factor receptor expression levels and poor prognosis was observed in gallbladder cancer tissues. Pharmacological inhibition or inhibition via RNA interference of epidermal growth factor receptor induced cellular senescence in gallbladder cancer cells. The antitumor effect of arctigenin on gallbladder cancer cells was primarily achieved by inducing cellular senescence. In gallbladder cancer cells treated with arctigenin, the expression level of epidermal growth factor receptor significantly decreased. The analysis of the activity of the kinases downstream of epidermal growth factor receptor revealed that the RAF-MEK-ERK signaling pathway was significantly inhibited. Furthermore, the cellular senescence induced by arctigenin could be reverted by pcDNA-epidermal growth factor receptor. Arctigenin also potently inhibited the growth of tumor xenografts, which was accompanied by the downregulation of epidermal growth factor receptor and induction of senescence. This study demonstrates arctigenin could induce cellular senescence in gallbladder cancer through the modulation of epidermal growth factor receptor pathway. These data identify epidermal growth factor receptor as a key regulator in arctigenin-induced gallbladder cancer senescence.

  11. Telomerase prevents accelerated senescence in glucose-6-phosphate dehydrogenase (G6PD-deficient human fibroblasts

    Directory of Open Access Journals (Sweden)

    Wu Yi-Hsuan

    2009-02-01

    Full Text Available Abstract Fibroblasts derived from glucose-6-phosphate dehydrogenase (G6PD-deficient patients display retarded growth and accelerated cellular senescence that is attributable to increased accumulation of oxidative DNA damage and increased sensitivity to oxidant-induced senescence, but not to accelerated telomere attrition. Here, we show that ectopic expression of hTERT stimulates telomerase activity and prevents accelerated senescence in G6PD-deficient cells. Stable clones derived from hTERT-expressing normal and G6PD-deficient fibroblasts have normal karyotypes, and display no sign of senescence beyond 145 and 105 passages, respectively. Activation of telomerase, however, does not prevent telomere attrition in earlier-passage cells, but does stabilize telomere lengths at later passages. In addition, we provide evidence that ectopic expression of hTERT attenuates the increased sensitivity of G6PD-deficient fibroblasts to oxidant-induced senescence. These results suggest that ectopic expression of hTERT, in addition to acting in telomere length maintenance by activating telomerase, also functions in regulating senescence induction.

  12. miR-127 regulates cell proliferation and senescence by targeting BCL6.

    Directory of Open Access Journals (Sweden)

    Jingwen Chen

    Full Text Available Cellular senescence occurs as a response to extracellular and intracellular stresses and contributes to aging and age-related pathologies. Emerging evidence suggests that cellular senescence also acts as a potent tumor suppression mechanism that prevents the oncogenic transformation of primary human cells. Recent reports have indicated that miRNAsact as key modulators of cellular senescence by targeting critical regulators of the senescence pathways. We previously reported that miR-127 is up-regulated in senescent fibroblasts. In this report, we identified miR-127 as a novel regulator of cellular senescence that directly targets BCL6. We further showed that miR-127 is down-regulated in breast cancer tissues and that this down-regulation is associated with up-regulation of BCL6. Over-expression of miR-127 or depletion of BCL6 inhibits breast cancer cell proliferation. Our data suggest that miR-127 may function as a tumor suppressor that modulates the oncogene BCL6.

  13. ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age-Related Diseases

    Directory of Open Access Journals (Sweden)

    Pierpaola Davalli

    2016-01-01

    Full Text Available The aging process worsens the human body functions at multiple levels, thus causing its gradual decrease to resist stress, damage, and disease. Besides changes in gene expression and metabolic control, the aging rate has been associated with the production of high levels of Reactive Oxygen Species (ROS and/or Reactive Nitrosative Species (RNS. Specific increases of ROS level have been demonstrated as potentially critical for induction and maintenance of cell senescence process. Causal connection between ROS, aging, age-related pathologies, and cell senescence is studied intensely. Senescent cells have been proposed as a target for interventions to delay the aging and its related diseases or to improve the diseases treatment. Therapeutic interventions towards senescent cells might allow restoring the health and curing the diseases that share basal processes, rather than curing each disease in separate and symptomatic way. Here, we review observations on ROS ability of inducing cell senescence through novel mechanisms that underpin aging processes. Particular emphasis is addressed to the novel mechanisms of ROS involvement in epigenetic regulation of cell senescence and aging, with the aim to individuate specific pathways, which might promote healthy lifespan and improve aging.

  14. Perception of Arabidopsis AtPep peptides, but not bacterial elicitors, accelerates starvation-induced senescence

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    Kay eGully

    2015-01-01

    Full Text Available Members of the AtPep group of Arabidopsis endogenous peptides have frequently been reported to induce pattern-triggered immunity and to increase resistance to diverse pathogens by amplifying the innate immune response. Here, we made the surprising observation that dark-induced leaf senescence was accelerated by the presence of Peps. Adult leaves as well as leaf discs of Col-0 wild type plants showed a Pep-triggered early onset of chlorophyll breakdown and leaf yellowing whereas pepr1 pepr2 double mutant plants were insensitive. In addition, this response was dependent on ethylene signaling and inhibited by the addition of cytokinins. Notably, addition of the bacterial elicitors flg22 or elf18, both potent inducers of pattern-triggered immunity, did not provoke an early onset of leaf senescence.Continuous darkness leads to energy deprivation and starvation and therewith promotes leaf senescence. We found that continuous darkness also strongly induced PROPEP3 transcription. Moreover, Pep-perception led to a rapid induction of PAO, APG7 and APG8a, genes indispensable for chlorophyll degradation as well as autophagy, respectively, and all three hallmarks of starvation and senescence. Notably, addition of sucrose as a source of energy inhibited the Pep-triggered early onset of senescence. In conclusion, we report that Pep-perception accelerates dark/starvation-induced senescence via an early induction of chlorophyll degradation and autophagy. This represents a novel and unique characteristic of PEPR signaling, unrelated to pattern-triggered immunity.

  15. Post-meiotic intra-testicular sperm senescence in a wild vertebrate.

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    Attila Hettyey

    Full Text Available There is growing interest in sperm senescence, both in its underlying mechanisms and evolutionary consequences, because it can impact the evolution of numerous life history traits. Previous studies have documented various types of sperm senescence, but evidence of post-meiotic intra-testicular sperm senescence in wild animals is lacking. To assess such senescence, we studied within-season changes in sperm motility in the common toad (Bufo bufo, where males produce all sperm prior to the breeding season. We found that males exposed to experimentally induced re-hibernation at the start of the breeding season, that is to experimentally lowered metabolic rates, stored sperm of significantly higher motility than males that were kept under seminatural conditions without females throughout the breeding season. This finding indicates that re-hibernation slows normal rates of sperm ageing and constitutes the first evidence to our knowledge of post-meiotic intra-testicular sperm senescence in a wild vertebrate. We also found that in males kept in seminatural conditions, sperm motility was positively related to the number of matings a male achieved. Thus, our results suggest that post-meiotic intra-testicular sperm senescence does not have a genetically fixed rate and may be modulated by temperature and possibly by mating opportunities.

  16. Twist1 suppresses senescence programs and thereby accelerates and maintains mutant Kras-induced lung tumorigenesis.

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    Phuoc T Tran

    Full Text Available KRAS mutant lung cancers are generally refractory to chemotherapy as well targeted agents. To date, the identification of drugs to therapeutically inhibit K-RAS have been unsuccessful, suggesting that other approaches are required. We demonstrate in both a novel transgenic mutant Kras lung cancer mouse model and in human lung tumors that the inhibition of Twist1 restores a senescence program inducing the loss of a neoplastic phenotype. The Twist1 gene encodes for a transcription factor that is essential during embryogenesis. Twist1 has been suggested to play an important role during tumor progression. However, there is no in vivo evidence that Twist1 plays a role in autochthonous tumorigenesis. Through two novel transgenic mouse models, we show that Twist1 cooperates with Kras(G12D to markedly accelerate lung tumorigenesis by abrogating cellular senescence programs and promoting the progression from benign adenomas to adenocarcinomas. Moreover, the suppression of Twist1 to physiological levels is sufficient to cause Kras mutant lung tumors to undergo senescence and lose their neoplastic features. Finally, we analyzed more than 500 human tumors to demonstrate that TWIST1 is frequently overexpressed in primary human lung tumors. The suppression of TWIST1 in human lung cancer cells also induced cellular senescence. Hence, TWIST1 is a critical regulator of cellular senescence programs, and the suppression of TWIST1 in human tumors may be an effective example of pro-senescence therapy.

  17. Premature cellular senescence induced by pyocyanin, a redox-active Pseudomonas aeruginosa toxin.

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    Muller, Michael

    2006-12-01

    Pseudomonas aeruginosa is an important nosocomial pathogen that can cause acute and chronic infection, particularly of the respiratory system. Pyocyanin is a major P. aeruginosa virulence factor that displays redox activity and induces oxidative stress in cellular systems. The effect of pyocyanin on replicating human pulmonary epithelial (A549) cells was investigated. Cells were exposed to pyocyanin for 24 h and their subsequent growth and development were followed for 7 days. Pyocyanin (5-10 microM) arrested cell growth and resulted in the development of a morphological phenotype consistent with cellular senescence, that is, an enlarged and flattened appearance. The senescent nature of these cells was supported by positive staining for increased lysosomal content and senescence-associated beta-galactosidase activity. All cells treated with pyocyanin (10 microM) converted to the senescent phenotype, which remained stable for up to 7 days. Exposure to pyocyanin at 25 microM or greater resulted in cell death due to apoptosis. A549 cells exposed to pyocyanin generated hydrogen peroxide in a dose-dependent manner and the senescence-inducing effect of pyocyanin was inhibited by the antioxidant, glutathione, suggesting the involvement of reactive oxygen species. The induction of premature cellular senescence by redox-active bacterial toxins may be a hitherto unrecognized aspect of infection pathology and a limiting factor in the tissue repair response to infection.

  18. The WRKY70 transcription factor of Arabidopsis influences both the plant senescence and defense signaling pathways.

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    Ulker, Bekir; Shahid Mukhtar, M; Somssich, Imre E

    2007-06-01

    Regulatory proteins play critical roles in controlling the kinetics of various cellular processes during the entire life span of an organism. Leaf senescence, an integral part of the plant developmental program, is fine-tuned by a complex transcriptional regulatory network ensuring a successful switch to the terminal life phase. To expand our understanding on how transcriptional control coordinates leaf senescence, we characterized AtWRKY70, a gene encoding a WRKY transcription factor that functions as a negative regulator of developmental senescence. To gain insight into the interplay of senescence and plant defense signaling pathways, we employed a collection of mutants, allowing us to specifically define the role of AtWRKY70 in the salicylic acid-mediated signaling cascades and to further dissect the cross-talk of signal transduction pathways during the onset of senescence in Arabidopsis thaliana. Our results provide strong evidence that AtWRKY70 influences plant senescence and defense signaling pathways. These studies could form the basis for further unraveling of these two complex interlinked regulatory networks.

  19. Mussel oligopeptides protect human fibroblasts from hydrogen peroxide (H2O2)-induced premature senescence.

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    Zhou, Yue; Dong, Ying; Xu, Qing-Gang; Zhu, Shu-Yun; Tian, Shi-Lei; Huo, Jing-jing; Hao, Ting-Ting; Zhu, Bei-Wei

    2014-01-01

    Mussel bioactive peptides have been viewed as mediators to maximize the high quality of life. In this study, the anti-aging activities of mussel oligopeptides were evaluated using H2O2-induced prematurely senescent MRC-5 fibroblasts. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry displayed that exposure to H2O2 led to the loss of cell viability and cell cycle arrest. In addition, H2O2 caused the elevation of senescence-associated-β-galactosidase (SA-β-gal) activity and formation of senescence-associated heterochromatin foci (SAHF). It was found that pretreatment with mussel oligopeptides could significantly attenuate these properties associated with cellular senescence. Mussel oligopeptides also led to the increase of glutathione (GSH) level and mitochondrial transmembrane potential (Δψm) recovery. In addition, mussel oligopeptides resulted in an improvement in transcriptional activity of peroxiredoxin 1 (Prx1), nicotinamide phosphoribosyltransferase (NAMPT) and sirtuin 1 (SIRT1). This study revealed that mussel oligopeptides could protect against cellular senescence induced by H2O2, and the effects were closely associated with redox cycle modulating and potentiating the SIRT1 pathway. These findings provide new insights into the beneficial role of mussel bioactive peptides on retarding senescence process. Crown Copyright © 2013. Published by Elsevier Ireland Ltd. All rights reserved.

  20. Identification of Salvia haenkei as gerosuppressant agent by using an integrated senescence-screening assay

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    Matic, Ivana; Revandkar, Ajinkya; Chen, Jingjing; Bisio, Angela; Dall'Acqua, Stefano; Cocetta, Veronica; Brun, Paola; Mancino, Giorgio; Milanese, Martina; Mattei, Maurizio; Montopoli, Monica; Alimonti, Andrea

    2016-01-01

    Cellular senescence is a stable cell cycle arrest that is the causative process of aging. The PI3K/AKT/mTOR pathway is implicated in the control of cellular senescence and inhibitors of this pathway have been successfully used for life span prolongation experiments in mammals. PTEN is the major regulator of the PI3K/AKT/mTOR pathway and loss of PTEN promotes a senescence response termed PICS. Here we report a novel-screening assay, for the identification of compounds that block different types of senescence response. By testing a library of more than 3000 natural and chemical compounds in PTEN deficient cells we have found that an extract from Salvia haenkei (SH), a native plant of Bolivia is a potent inhibitor of PICS. SH also decreases replicative and UV-mediated senescence in human primary fibroblasts and in a model of in vitro reconstructed human epidermis. Mechanistically, SH treatment affects senescence driven by UV by interfering with IL1-ɑ signalling. Pre-clinical and clinical testing of this extract by performing toxicity and irritability evaluation in vitro also demonstrate the safety of SH extract for clinical use as anti-aging skin treatment. PMID:27922821