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Sample records for accelerates cellular senescence

  1. Absence of AMPKα2 accelerates cellular senescence via p16 induction in mouse embryonic fibroblasts.

    Science.gov (United States)

    Ding, Ye; Chen, Jie; Okon, Imoh Sunday; Zou, Ming-Hui; Song, Ping

    2016-02-01

    Emerging evidence suggests that activation of adenosine monophosphate-activated protein kinase (AMPK), an energy gauge and redox sensor, delays aging process. However, the molecular mechanisms by which AMPKα isoform regulates cellular senescence remain largely unknown. The aim of this study was to determine if AMPKα deletion contributes to the accelerated cell senescence by inducing p16(INK4A) (p16) expression thereby arresting cell cycle. The markers of cellular senescence, cell cycle proteins, and reactive oxygen species (ROS) were monitored in cultured mouse embryonic fibroblasts (MEFs) isolated from wild type (WT, C57BL/6J), AMPKα1, or AMPKα2 homozygous deficient (AMPKα1(-/-), AMPKα2(-/-)) mice by Western blot and cellular immunofluorescence staining, as well as immunohistochemistry (IHC) in skin tissue of young and aged mice. Deletion of AMPKα2, the minor isoform of AMPKα, but not AMPKα1 in high-passaged MEFs led to spontaneous cell senescence demonstrated by accumulation of senescence-associated-β-galactosidase (SA-β-gal) staining and foci formation of heterochromatin protein 1 homolog gamma (HP1γ). It was shown here that AMPKα2 deletion upregulates cyclin-dependent kinase (CDK) inhibitor, p16, which arrests cell cycle. Furthermore, AMPKα2 null cells exhibited elevated ROS production. Interestingly, knockdown of HMG box-containing protein 1 (HBP1) partially blocked the cellular senescence of AMPKα2-deleted MEFs via the reduction of p16. Finally, dermal cells senescence, including fibroblasts senescence evidenced by the staining of p16, HBP1, and Ki-67, in the skin of aged AMPKα2(-/-) mice was enhanced when compared with that in wild type mice. Taken together, our results suggest that AMPKα2 isoform plays a fundamental role in anti-oxidant stress and anti-senescence.

  2. Accelerated cellular senescence phenotype of GAPDH-depleted human lung carcinoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Phadke, Manali; Krynetskaia, Natalia [Temple University School of Pharmacy, Philadelphia, PA 19140 (United States); Mishra, Anurag [Jayne Haines Center for Pharmacogenomics, Temple University School of Pharmacy, Philadelphia, PA 19140 (United States); Krynetskiy, Evgeny, E-mail: ekrynets@temple.edu [Temple University School of Pharmacy, Philadelphia, PA 19140 (United States); Jayne Haines Center for Pharmacogenomics, Temple University School of Pharmacy, Philadelphia, PA 19140 (United States)

    2011-07-29

    Highlights: {yields} We examined the effect of glyceraldehyde 3-phosphate (GAPDH) depletion on proliferation of human carcinoma A549 cells. {yields} GAPDH depletion induces accelerated senescence in tumor cells via AMPK network, in the absence of DNA damage. {yields} Metabolic and genetic rescue experiments indicate that GAPDH has regulatory functions linking energy metabolism and cell cycle. {yields} Induction of senescence in LKB1-deficient lung cancer cells via GAPDH depletion suggests a novel strategy to control tumor cell proliferation. -- Abstract: Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a pivotal glycolytic enzyme, and a signaling molecule which acts at the interface between stress factors and the cellular apoptotic machinery. Earlier, we found that knockdown of GAPDH in human carcinoma cell lines resulted in cell proliferation arrest and chemoresistance to S phase-specific cytotoxic agents. To elucidate the mechanism by which GAPDH depletion arrests cell proliferation, we examined the effect of GAPDH knockdown on human carcinoma cells A549. Our results show that GAPDH-depleted cells establish senescence phenotype, as revealed by proliferation arrest, changes in morphology, SA-{beta}-galactosidase staining, and more than 2-fold up-regulation of senescence-associated genes DEC1 and GLB1. Accelerated senescence following GAPDH depletion results from compromised glycolysis and energy crisis leading to the sustained AMPK activation via phosphorylation of {alpha} subunit at Thr172. Our findings demonstrate that GAPDH depletion switches human tumor cells to senescent phenotype via AMPK network, in the absence of DNA damage. Rescue experiments using metabolic and genetic models confirmed that GAPDH has important regulatory functions linking the energy metabolism and the cell cycle networks. Induction of senescence in LKB1-deficient non-small cell lung cancer cells via GAPDH depletion suggests a novel strategy to control tumor cell proliferation.

  3. [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.

  4. Accelerated Telomere Shortening in Acromegaly; IGF-I Induces Telomere Shortening and Cellular Senescence

    Science.gov (United States)

    Matsumoto, Ryusaku; Fukuoka, Hidenori; Iguchi, Genzo; Odake, Yukiko; Yoshida, Kenichi; Bando, Hironori; Suda, Kentaro; Nishizawa, Hitoshi; Takahashi, Michiko; Yamada, Shozo; Ogawa, Wataru; Takahashi, Yutaka

    2015-01-01

    Objective Patients with acromegaly exhibit reduced life expectancy and increased prevalence of age-related diseases, such as diabetes, hypertension, and cardiovascular disease. However, the underlying mechanism has not been fully elucidated. Telomere shortening is reportedly associated with reduced life expectancy and increased prevalence of these age-related diseases. Methods We measured telomere length in patients with acromegaly using quantitative PCR method. The effect of GH and IGF-I on telomere length and cellular senescence was examined in human skin fibroblasts. Results Patients with acromegaly exhibited shorter telomere length than age-, sex-, smoking-, and diabetes-matched control patients with non-functioning pituitary adenoma (0.62 ± 0.23 vs. 0.75 ± 0.35, respectively, P = 0.047). In addition, telomere length in acromegaly was negatively correlated with the disease duration (R2 = 0.210, P = 0.003). In vitro analysis revealed that not GH but IGF-I induced telomere shortening in human skin fibroblasts. Furthermore, IGF-I-treated cells showed increased senescence-associated β-galactosidase activity and expression of p53 and p21 protein. IGF-I-treated cells reached the Hayflick limit earlier than GH- or vehicle-treated cells, indicating that IGF-I induces cellular senescence. Conclusion Shortened telomeres in acromegaly and cellular senescence induced by IGF-I can explain, in part, the underlying mechanisms by which acromegaly exhibits an increased morbidity and mortality in association with the excess secretion of IGF-I. PMID:26448623

  5. 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

  6. 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.

  7. Protein oxidation and aggregation in UVA-irradiated Escherichia coli cells as signs of accelerated cellular senescence.

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    Bosshard, Franziska; Riedel, Kathrin; Schneider, Thomas; Geiser, Carina; Bucheli, Margarete; Egli, Thomas

    2010-11-01

    Solar disinfection (SODIS) is a simple drinking water treatment method that improves microbiological water quality where other means are unavailable. It makes use of the deleterious effect of solar irradiation on pathogenic microbes and viruses. A positive impact on health has been documented in several epidemiological studies. However, the molecular mechanisms damaging cells during this simple treatment are not yet fully understood. Here we show that protein damage is crucial in the process of inactivation by sunlight. Protein damages in UVA-irradiated Escherichia coli cells have been evaluated by an immunoblot method for carbonylated proteins and an aggregation assay based on semi-quantitative proteomics. A wide spectrum of structural and enzymatic proteins within the cell is affected by carbonylation and aggregation. Vital cellular functions like the transcription and translation apparatus, transport systems, amino acid synthesis and degradation, respiration, ATP synthesis, glycolysis, the TCA cycle, chaperone functions and catalase are targeted by UVA irradiation. The protein damage pattern caused by SODIS strongly resembles the pattern caused by reactive oxygen stress. Hence, sunlight probably accelerates cellular senescence and leads to the inactivation and finally death of UVA-irradiated cells.

  8. ING proteins in cellular senescence.

    Science.gov (United States)

    Menéndez, Camino; Abad, María; Gómez-Cabello, Daniel; Moreno, Alberto; Palmero, Ignacio

    2009-05-01

    Cellular senescence is an effective anti-tumor barrier that acts by restraining the uncontrolled proliferation of cells carrying potentially oncogenic alterations. ING proteins are putative tumor suppressor proteins functionally linked to the p53 pathway and to chromatin regulation. ING proteins exert their tumor-protective action through different types of responses. Here, we review the evidence on the participation of ING proteins, mainly ING1 and ING2, in the implementation of the senescent response. The currently available data support an important role of ING proteins as regulators of senescence, in connection with the p53 pathway and chromatin organization.

  9. 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.

  10. 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.

    2017-01-01

    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. PMID:28230051

  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.

  12. Senescence-accelerated OXYS rats

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    Stefanova, Natalia A; Kozhevnikova, Oyuna S; Vitovtov, Anton O; Maksimova, Kseniya Yi; Logvinov, Sergey V; Rudnitskaya, Ekaterina A; Korbolina, Elena E; Muraleva, Natalia A; Kolosova, Nataliya G

    2014-01-01

    Senescence-accelerated OXYS rats are an experimental model of accelerated aging that was established from Wistar stock via selection for susceptibility to cataractogenic effects of a galactose-rich diet and via subsequent inbreeding of highly susceptible rats. Currently, we have the 102nd generation of OXYS rats with spontaneously developing cataract and accelerated senescence syndrome, which means early development of a phenotype similar to human geriatric disorders, including accelerated brain aging. In recent years, our group found strong evidence that OXYS rats are a promising model for studies of the mechanisms of brain aging and neurodegenerative processes similar to those seen in Alzheimer disease (AD). The manifestation of behavioral alterations and learning and memory deficits develop since the fourth week of age, i.e., simultaneously with first signs of neurodegeneration detectable on magnetic resonance imaging and under a light microscope. In addition, impaired long-term potentiation has been demonstrated in OXYS rats by the age of 3 months. With age, neurodegenerative changes in the brain of OXYS rats become amplified. We have shown that this deterioration happens against the background of overproduction of amyloid precursor protein (AβPP), accumulation of β-amyloid (Aβ), and hyperphosphorylation of the tau protein in the hippocampus and cortex. The development of AMD-like retinopathy in OXYS rats is also accompanied by increased accumulation of Aβ in the retina. These published data suggest that the OXYS strain may serve as a spontaneous rat model of AD-like pathology and could help to decipher the pathogenesis of AD. PMID:24552807

  13. 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.

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

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    Han, Ying-Hao; Kim, Hyun-Sun; Kim, Jin-Man; Kim, Sang-Keun; Yu, Dae-Yeul; Moon, Eun-Yi

    2005-08-29

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

  15. [Cellular senescence and chronic inflammation].

    Science.gov (United States)

    Ohtani, Naoko

    2014-01-01

    It has recently become apparent that obesity is associated with chronic inflammation and several common types of cancer development. Although several events were proposed to be involved in these pathologies, the precise mechanisms underlying obesity-associated inflammation and cancer largely remain unclear. Here, we show that senescence-associated secretory phenotype (SASP) plays crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice. Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of a bacterial metabolite that cause DNA damage. The enterohepatic circulation of the bacterial metabolites provokes SASP phenotype in hepatic stellate cells (HSCs), which in turn, secretes various inflammatory and tumour promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogen. Importantly, reducing gut bacteria efficiently prevents HCC development in obese mice. Similar results were also observed in mice lacking an SASP inducer or depleted of senescent HSCs, indicating that the induction of SASP by the gut bacterial metabolite in HSCs plays key roles in obesity-associated HCC development. Interestingly, moreover, signs of SASP were also observed in the HSCs in the area of HCC arising in patients with nonalcoholic steatohepatitis (NASH), implying that a similar pathway may contribute to at least certain aspects of obesity-associated HCC development in humans as well. These findings provide valuable new insights into the development of obesity-associated cancer.

  16. Cellular Senescence: Many Roads, One Final Destination

    Directory of Open Access Journals (Sweden)

    Raya Saab

    2010-01-01

    Full Text Available Cellular senescence is a tumor-suppressor mechanism that has been shown to occur in response to multiple signals, including oncogenic stress, DNA damage, oxidative stress, telomere shortening, and other tumor-promoting insults. Over the past decade, much has been uncovered regarding the phenotype of this tumor-suppressor response and the underlying pathways necessary for its establishment. However, we have also learned that the intricate details of signaling pathways underlying senescence as a tumor-suppressor response are very much context dependent. In addition, cross-talk among pathways, and negative and positive feedback loops, all complicate our understanding of this process. This short review attempts to summarize what is known to date regarding senescence in tumor suppression, both in vitro and in vivo. Further insights into pathways necessary for senescence will hopefully identify appropriate targets for interventions to not only induce senescence as a treatment of cancerous lesions, but also to maintain this state in premalignant lesions in an effort to prevent progression to cancer.

  17. [Research progress of cellular senescence and senescent secretary phenotype in intervertebral disc degeneration].

    Science.gov (United States)

    Wang, Feng; Zheng, Chenjingmei; Wu, Xiaotao

    2012-12-01

    To summarize the role of cellular senescence and senescent secretary phenotype in the intervertebral disc (IVD) degeneration. Relevant articles that discussed the roles of cellular senescence in the IVD degeneration were extensively reviewed, and retrospective and comprehensive analysis was performed. The senescent phenomenon during IVD degeneration, senescent secretary phenotype of the disc cells, senescent pathways within the IVD microenvironment, as well as the anti-senescent approaches for IVD regeneration were systematically reviewed. During aging and degeneration, IVD cells gradually and/or prematurely undergo senescence by activating p53-p21-retinoblastoma (RB) or p161NK4A-RB senescent pathways. The accumulation of senescent cells not only decreases the self-renewal ability of IVD, but also deteriorates the disc microenvironment by producing more inflammatory cytokines and matrix degrading enzymes. More specific senescent biomarkers are required to fully understand the phenotype change of senescent disc cells during IVD degeneration. Molecular analysis of the senescent disc cells and their intracellular signaling pathways are needed to get a safer and more efficient anti-senescence strategy for IVD regeneration. Cellular senescence is an important mechanism by which IVD cells decrease viability and degenerate biological behaviors, which provide a new thinking to understand the pathogenesis of IVD degeneration.

  18. YAP/TEAD-mediated transcription controls cellular senescence

    National Research Council Canada - National Science Library

    Xie, Qi; Chen, Jing; Feng, Han; Peng, Shengyi; Adams, Ursula; Bai, Yujie; Huang, Li; Li, Ji; Huang, Junjian; Meng, Songshu; Yuan, Zengqiang

    2013-01-01

    .... Silencing of YAP inhibits cell proliferation and induces premature senescence. In additional experiments, we observe that cellular senescence induced by YAP deficiency is TEAD- and Rb/p16/p53-dependent...

  19. Epigenetic clock analyses of cellular senescence and ageing.

    Science.gov (United States)

    Lowe, Donna; Horvath, Steve; Raj, Kenneth

    2016-02-23

    A confounding aspect of biological ageing is the nature and role of senescent cells. It is unclear whether the three major types of cellular senescence, namely replicative senescence, oncogene-induced senescence and DNA damage-induced senescence are descriptions of the same phenomenon instigated by different sources, or if each of these is distinct, and how they are associated with ageing. Recently, we devised an epigenetic clock with unprecedented accuracy and precision based on very specific DNA methylation changes that occur in function of age. Using primary cells, telomerase-expressing cells and oncogene-expressing cells of the same genetic background, we show that induction of replicative senescence (RS) and oncogene-induced senescence (OIS) are accompanied by ageing of the cell. However, senescence induced by DNA damage is not, even though RS and OIS activate the cellular DNA damage response pathway, highlighting the independence of senescence from cellular ageing. Consistent with this, we observed that telomerase-immortalised cells aged in culture without having been treated with any senescence inducers or DNA-damaging agents, re-affirming the independence of the process of ageing from telomeres and senescence. Collectively, our results reveal that cellular ageing is distinct from cellular senescence and independent of DNA damage response and telomere length.

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

    Science.gov (United States)

    Fumagalli, Marzia; Rossiello, Francesca; Mondello, Chiara; d'Adda di Fagagna, Fabrizio

    2014-01-01

    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.

  1. YAP/TEAD-mediated transcription controls cellular senescence.

    Science.gov (United States)

    Xie, Qi; Chen, Jing; Feng, Han; Peng, Shengyi; Adams, Ursula; Bai, Yujie; Huang, Li; Li, Ji; Huang, Junjian; Meng, Songshu; Yuan, Zengqiang

    2013-06-15

    Transcription coactivator Yes-associated protein (YAP) plays an important role in the regulation of cell proliferation and apoptosis. Here, we identify a new role of YAP in the regulation of cellular senescence. We find that the expression levels of YAP proteins decrease following the replication-induced cellular senescence in IMR90 cells. Silencing of YAP inhibits cell proliferation and induces premature senescence. In additional experiments, we observe that cellular senescence induced by YAP deficiency is TEAD- and Rb/p16/p53-dependent. Furthermore, we show that Cdk6 is a direct downstream target gene of YAP in the regulation of cellular senescence, and the expression of Cdk6 is through the YAP-TEAD complex. Ectopic expression of Cdk6 rescued YAP knockdown-induced senescence. Finally, we find that downregulation of YAP in tumor cells increases senescence in response to chemotherapeutic agents, and YAP or Cdk6 expression rescues cellular senescence. Taken together, our findings define the critical role of YAP in the regulation of cellular senescence and provide a novel insight into a potential chemotherapeutic avenue for tumor suppression. ©2013 AACR.

  2. Cellular senescence in normal and premature lung aging.

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    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.

  3. 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

  4. 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.

  5. Cellular senescence and tumor suppressor gene p16.

    Science.gov (United States)

    Rayess, Hani; Wang, Marilene B; Srivatsan, Eri S

    2012-04-15

    Cellular senescence is an irreversible arrest of cell growth. Biochemical and morphological changes occur during cellular senescence, including the formation of a unique cellular morphology such as flattened cytoplasm. Function of mitochondria, endoplasmic reticulum and lysosomes are affected resulting in the inhibition of lysosomal and proteosomal pathways. Cellular senescence can be triggered by a number of factors including, aging, DNA damage, oncogene activation and oxidative stress. While the molecular mechanism of senescence involves p16 and p53 tumor suppressor genes and telomere shortening, this review is focused on the mechanism of p16 control. The p16-mediated senescence acts through the retinoblastoma (Rb) pathway inhibiting the action of the cyclin dependant kinases leading to G1 cell cycle arrest. Rb is maintained in a hypophosphorylated state resulting in the inhibition of transcription factor E2F1. Regulation of p16 expression is complex and involves epigenetic control and multiple transcription factors. PRC1 (Pombe repressor complex (1) and PRC2 (Pombe repressor complex (2) proteins and histone deacetylases play an important role in the promoter hypermethylation for suppressing p16 expression. While transcription factors YY1 and Id1 suppress p16 expression, transcription factors CTCF, Sp1 and Ets family members activate p16 transcription. Senescence occurs with the inactivation of suppressor elements leading to the enhanced expression of p16. Copyright © 2011 UICC.

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

    Science.gov (United States)

    2017-01-01

    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. PMID:28280523

  7. 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.

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

    Science.gov (United States)

    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.

  9. Are microRNAs true sensors of ageing and cellular senescence?

    Science.gov (United States)

    Williams, Justin; Smith, Flint; Kumar, Subodh; Vijayan, Murali; Reddy, P Hemachandra

    2017-05-01

    All living beings are programmed to death due to aging and age-related processes. Aging is a normal process of every living species. While all cells are inevitably progressing towards death, many disease processes accelerate the aging process, leading to senescence. Pathologies such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, cardiovascular disease, cancer, and skin diseases have been associated with deregulated aging. Healthy aging can delay onset of all age-related diseases. Genetics and epigenetics are reported to play large roles in accelerating and/or delaying the onset of age-related diseases. Cellular mechanisms of aging and age-related diseases are not completely understood. However, recent molecular biology discoveries have revealed that microRNAs (miRNAs) are potential sensors of aging and cellular senescence. Due to miRNAs capability to bind to the 3' untranslated region (UTR) of mRNA of specific genes, miRNAs can prevent the translation of specific genes. The purpose of our article is to highlight recent advancements in miRNAs and their involvement in cellular changes in aging and senescence. Our article discusses the current understanding of cellular senescence, its interplay with miRNAs regulation, and how they both contribute to disease processes. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Telomerase prevents accelerated senescence in glucose-6-phosphate dehydrogenase (G6PD-deficient human fibroblasts

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    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.

  11. 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.

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

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    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.

  13. The ING tumor suppressors in cellular senescence and chromatin.

    Science.gov (United States)

    Ludwig, Susann; Klitzsch, Alexandra; Baniahmad, Aria

    2011-07-18

    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.

  14. Adiponectin corrects premature cellular senescence and normalizes antimicrobial peptide levels in senescent keratinocytes.

    Science.gov (United States)

    Jin, Taewon; Kim, Min Jeong; Heo, Won Il; Park, Kui Young; Choi, Sun Young; Lee, Mi-Kyung; Hong, Seung-Phil; Kim, Seong-Jin; Im, Myung; Moon, Nam Ju; Seo, Seong Jun

    2016-09-02

    Stress-induced premature senescence or aging causes dysfunction in the human somatic system. Adiponectin (Acrp30) plays a role in functional recovery, especially with adenosine 3',5'-monophosphate (AMP)-activated protein kinase (AMPK) and silent mating type information regulation 2 homolog 1 (SIRT1). Acrp30 stimulation reduced the premature senescence positive ratio induced by hydrogen peroxide (H2O2) and restituted human β-defensin 2 (hBD-2) levels in senescent keratinocytes. Acrp30 recovered AMPK activity in senescent keratinocytes and increased SIRT1 deacetylation activity. As a result, FoxO1 and FoxO3 transcription activity was recovered. Additionally, Acrp30 stimulation suppresses NFκB p65, which induces abnormal expression of hBD-2 induced by H2O2. In the present study, we have shown that Acrp30 reduces premature senescence and recovers cellular function in keratinocytes. These results suggest a role for Acrp30 as an anti-aging agent to improve impaired skin immune barriers. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Fat tissue, aging, and cellular senescence.

    NARCIS (Netherlands)

    Tchkonia, T.; Morbeck, D.E.; Zglinicki, T. von; Deursen, J.M.A. van; Lustgarten, J.; Scrable, H.; Khosla, S.; Jensen, M.D.; Kirkland, J.L.

    2010-01-01

    Fat tissue, frequently the largest organ in humans, is at the nexus of mechanisms involved in longevity and age-related metabolic dysfunction. Fat distribution and function change dramatically throughout life. Obesity is associated with accelerated onset of diseases common in old age, while fat abla

  16. REDOX REGULATION OF SIRT1 IN INFLAMMATION AND CELLULAR SENESCENCE

    Science.gov (United States)

    Hwang, Jae-woong; Yao, Hongwei; Caito, Samuel; Sundar, Isaac K.; Rahman, Irfan

    2013-01-01

    Sirtuin1 (SIRT1) regulates inflammation, aging (lifespan and healthspan), calorie restriction/energetics, mitochondrial biogenesis, stress resistance, cellular senescence, endothelial functions, apoptosis/autophagy, and circadian rhythms through deacetylation of transcription factors and histones. SIRT1 level and activity are decreased in chronic inflammatory conditions and aging where oxidative stress occurs. SIRT1 is regulated by a NAD+-dependent DNA repair enzyme poly(ADP-ribose)-polymerase-1 (PARP-1), and subsequent NAD+ depletion by oxidative stresses may have consequent effects on inflammatory and stress responses as well as cellular senescence. SIRT1 has been shown to undergo covalent oxidative modifications by cigarette smoke-derived oxidants/aldehydes, leading to post-translational modifications, inactivation, and protein degradation. Furthermore, oxidant/carbonyl stress-mediated reduction of SIRT1 leads to the loss of its control on acetylation of target proteins including p53, RelA/p65 and FOXO3, thereby enhancing the inflammatory, pro-senescent and apoptotic responses, as well as endothelial dysfunction. In this review, the mechanisms of cigarette smoke/oxidant-mediated redox post-translational modifications of SIRT1 and its role in PARP1, NF-κB activation, FOXO3 and eNOS regulation, as well as chromatin remodeling/histone modifications during inflammaging are discussed. Furthermore, we also discussed various novel ways to activate SIRT1 either directly or indirectly, which may have therapeutic potential in attenuating inflammation and premature senescence involved in chronic lung diseases. PMID:23542362

  17. 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.

  18. Apolipoprotein J/Clusterin is a novel structural component of human erythrocytes and a biomarker of cellular stress and senescence.

    Directory of Open Access Journals (Sweden)

    Marianna H Antonelou

    Full Text Available BACKGROUND: Secretory Apolipoprotein J/Clusterin (sCLU is a ubiquitously expressed chaperone that has been functionally implicated in several pathological conditions of increased oxidative injury, including aging. Nevertheless, the biological role of sCLU in red blood cells (RBCs remained largely unknown. In the current study we identified sCLU as a component of human RBCs and we undertook a detailed analysis of its cellular topology. Moreover, we studied the erythrocytic membrane sCLU content during organismal aging, in conditions of increased organismal stress and accelerated RBCs senescence, as well as during physiological in vivo cellular senescence. METHODOLOGY/PRINCIPAL FINDINGS: By using a combination of molecular, biochemical and high resolution microscopical methods we found that sCLU is a novel structural component of RBCs extra- and intracellular plasma membrane and cytosol. We observed that the RBCs membrane-associated sCLU decreases during organismal aging or exposure to acute stress (e.g. smoking, in patients with congenital hemolytic anemia, as well as during RBCs in vivo senescence. In all cases, sCLU reduction paralleled the expression of typical cellular senescence, redox imbalance and erythrophagocytosis markers which are also indicative of the senescence- and oxidative stress-mediated RBCs membrane vesiculation. CONCLUSIONS/SIGNIFICANCE: We propose that sCLU at the mature RBCs is not a silent remnant of the erythroid precursors, but an active component being functionally implicated in the signalling mechanisms of cellular senescence and oxidative stress-responses in both healthy and diseased organism. The reduced sCLU protein levels in the RBCs membrane following cell exposure to various endogenous or exogenous stressors closely correlates to the levels of cellular senescence and redox imbalance markers, suggesting the usefulness of sCLU as a sensitive biomarker of senescence and cellular stress.

  19. Redox regulation of SIRT1 in inflammation and cellular senescence.

    Science.gov (United States)

    Hwang, Jae-woong; Yao, Hongwei; Caito, Samuel; Sundar, Isaac K; Rahman, Irfan

    2013-08-01

    Sirtuin 1 (SIRT1) regulates inflammation, aging (life span and health span), calorie restriction/energetics, mitochondrial biogenesis, stress resistance, cellular senescence, endothelial functions, apoptosis/autophagy, and circadian rhythms through deacetylation of transcription factors and histones. SIRT1 level and activity are decreased in chronic inflammatory conditions and aging, in which oxidative stress occurs. SIRT1 is regulated by a NAD(+)-dependent DNA repair enzyme, poly(ADP-ribose) polymerase-1 (PARP1), and subsequent NAD(+) depletion by oxidative stress may have consequent effects on inflammatory and stress responses as well as cellular senescence. SIRT1 has been shown to undergo covalent oxidative modifications by cigarette smoke-derived oxidants/aldehydes, leading to posttranslational modifications, inactivation, and protein degradation. Furthermore, oxidant/carbonyl stress-mediated reduction of SIRT1 leads to the loss of its control on acetylation of target proteins including p53, RelA/p65, and FOXO3, thereby enhancing the inflammatory, prosenescent, and apoptotic responses, as well as endothelial dysfunction. In this review, the mechanisms of cigarette smoke/oxidant-mediated redox posttranslational modifications of SIRT1 and its roles in PARP1 and NF-κB activation, and FOXO3 and eNOS regulation, as well as chromatin remodeling/histone modifications during inflammaging, are discussed. Furthermore, we have also discussed various novel ways to activate SIRT1 either directly or indirectly, which may have therapeutic potential in attenuating inflammation and premature senescence involved in chronic lung diseases.

  20. Chronic treatment with N-acetyl-cystein delays cellular senescence in endothelial cells isolated from a subgroup of atherosclerotic patients.

    Science.gov (United States)

    Voghel, Guillaume; Thorin-Trescases, Nathalie; Farhat, Nada; Mamarbachi, Aida M; Villeneuve, Louis; Fortier, Annik; Perrault, Louis P; Carrier, Michel; Thorin, Eric

    2008-05-01

    Endothelial senescence may contribute to the pathogenesis of age-related vascular disorders. Furthermore, chronic exposure to risk factors for cardiovascular disease (CVD) accelerates the effects of chronological aging by generating stress-dependent damages, including oxidative stress, therefore promoting stress-induced premature senescence. Our objective was to determine whether a chronic treatment with an antioxidant (N-acetyl-cystein, NAC) could delay senescence of endothelial cells (EC) isolated and cultured from arterial segments of patients with severe coronary artery disease. If EC were considered as one population (n=26), chronic NAC treatment slightly shortened telomere attrition rate associated with senescence but did not significantly delay the onset of endothelial senescence. However, in a subgroup of NAC-treated EC (n=15) cellular senescence was significantly delayed, NAC decreased lipid peroxidation (HNE), activated the catalytic subunit of telomerase (hTERT) and inhibited telomere attrition. In contrast, in another subgroup of EC (n=11) characterized by initial short telomeres, no effect of NAC on HNE and high levels of DNA damages, the antioxidant was not beneficial on senescence, suggesting an irreversible stress-dependent damage. In conclusion, chronic exposure to NAC can delay senescence of diseased EC via hTERT activation and transient telomere stabilization, unless oxidative stress-associated cell damage has become irreversible.

  1. Identification of microRNAs dysregulated in cellular senescence driven by endogenous genotoxic stress

    Science.gov (United States)

    Nidadavolu, Lolita S.; Niedernhofer, Laura J.; Khan, Saleem A.

    2013-01-01

    XFE progeroid syndrome, a disease of accelerated aging caused by deficiency in the DNA repair endonuclease XPF-ERCC1, is modeled by Ercc1 knockout and hypomorphic mice. Tissues and primary cells from these mice senesce prematurely, offering a unique opportunity to identify factors that regulate senescence and aging. We compared microRNA (miRNA) expression in Ercc1−/− primary mouse embryonic fibroblasts (MEFs) and wild-type (WT) MEFs in different growth conditions to identify miRNAs that drive cellular senescence. Microarray analysis showed three differentially expressed miRNAs in passage 7 (P7) Ercc1−/− MEFs grown at 20% O2 compared to Ercc1−/− MEFs grown at 3% O2. Thirty-six differentially expressed miRNAs were identified in Ercc1−/− MEFs at P7 compared to early passage (P3) in 3% O2. Eight of these miRNAs (miR-449a, miR-455*, miR-128, miR-497, miR-543, miR-450b-3p, miR-872 and miR-10b) were similarly downregulated in the liver of progeroid Ercc1−/Δ and old WT mice compared to adult WT mice, a tissue that senesces with aging. Three miRNAs (miR-449a, miR-455* and miR-128) were also downregulated in Ercc1−/Δ and WT old mice kidneys compared to young WT mice. We also discovered that the miRNA expression regulator Dicer is significantly downregulated in tissues of old mice and late passage cells compared to young controls. Collectively these results support the conclusion that the miRNAs identified may play an important role in staving off cellular senescence and their altered expression could be indicative of aging. PMID:23852002

  2. Western diet consumption promotes vascular remodeling in non-senescent mice consistent with accelerated senescence, but does not modify vascular morphology in senescent ones.

    Science.gov (United States)

    Dantas, Ana Paula; Onetti, Yara; Oliveira, María Aparecida; Carvalho, Maria Helena; Heras, Magda; Vila, Elisabet; Jiménez-Altayó, Francesc

    2014-07-01

    Senescence accelerated mice (SAM) are susceptible to developing vascular dysfunction and remodeling. Food intake and type of diet have also been identified as determining factors in vascular remodeling. However, the interplay between senescence and diet in vascular remodeling is largely unknown. We aimed to analyze structure of large (aorta) and small (mesenteric; MA) arteries from seven-month-old SAM prone (SAMP8) and resistant (SAMR1) mice that received a Western-type high-fat diet (WD; 8weeks). Aortic structure was assessed by morphometric analysis of hematoxylin and eosin-stained cross sections, and collagen content by qRT-PCR, immunofluorescence and picrosirius red. In MAs, structural and mechanical properties were measured by pressure myography; elastin and collagen content by qRT-PCR and immunofluorescence; nuclei distribution by confocal microscopy; and apoptosis by qRT-PCR and TUNEL assay. In aorta, wall thickness (WT), but not cross-sectional area (CSA), was increased by senescence, and WD only increased WT in SAMR1. WD intake, but not senescence, was associated with increased collagen deposition. In MAs, senescence diminished WT and CSA, without altering collagen and elastin deposition, reduced the number of MA wall cells, and increased pro apoptotic activation. WD consumption promoted in SAMR1 the same remodeling observed with senescence, while in SAMP8 the senescence-associated changes remained unaffected. The mechanisms involved in WD-induced MA remodeling in SAMR1 mimicked those observed in senescence per se. Our study reveals qualitatively different remodeling in aortas and MAs from senescent mice. Consumption of a WD induced remodeling of the SAMR1 vasculature similar to that induced by senescence, while it did not promote any further alteration in the latter. Therefore, we propose that increased consumption of fat-enriched diets could promote accelerated senescence of the non-senescent vasculature, although it does not exacerbate vascular

  3. Attenuation of Replication Stress–Induced Premature Cellular Senescence to Assess Anti-Aging Modalities

    OpenAIRE

    Zhao, Hong; Darzynkiewicz, Zbigniew

    2014-01-01

    Described is an in vitro model of premature senescence in pulmonary adenocarcinoma A549 cells induced by persistent DNA replication stress in response to treatment with the DNA damaging drug mitoxantrone (Mxt). The degree of cellular senescence, based on characteristic changes in cell morphology, is measured by laser scanning cytometry. Specifically, the flattening of cells grown on slides (considered the hallmark of cellular senescence) is measured as the decline in local intensity of DNA-as...

  4. Conserved and novel functions of programmed cellular senescence during vertebrate development

    Science.gov (United States)

    Davaapil, Hongorzul; Brockes, Jeremy P.

    2017-01-01

    Cellular senescence, a form of stable cell cycle arrest that is traditionally associated with tumour suppression, has been recently found to occur during mammalian development. Here, we show that cell senescence is an intrinsic part of the developmental programme in amphibians. Programmed senescence occurs in specific structures during defined time windows during amphibian development. It contributes to the physiological degeneration of the amphibian pronephros and to the development of the cement gland and oral cavity. In both contexts, senescence depends on TGFβ but is independent of ERK/MAPK activation. Furthermore, elimination of senescent cells through temporary TGFβ inhibition leads to developmental defects. Our findings uncover conserved and new roles of senescence in vertebrate organogenesis and support the view that cellular senescence may have arisen in evolution as a developmental mechanism. PMID:27888193

  5. 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.

  6. 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.

  7. A small molecule inhibitor of PAI-1 protects against doxorubicin-induced cellular senescence.

    Science.gov (United States)

    Ghosh, Asish K; Rai, Rahul; Park, Kitae E; Eren, Mesut; Miyata, Toshio; Wilsbacher, Lisa D; Vaughan, Douglas E

    2016-11-08

    Doxorubicin, an anthracycline antibiotic, is a commonly used anticancer drug. In spite of its widespread usage, its therapeutic effect is limited by its cardiotoxicity. On the cellular level, Doxorubicin-induced cardiotoxicity manifests as stress induced premature senescence. Previously, we demonstrated that plasminogen activator inhibitor-1 (PAI-1), a potent inhibitor of serine proteases, is an important biomarker and regulator of cellular senescence and aging. Here, we tested the hypothesis that pharmacological inhibition of cellular PAI-1 protects against stress- and aging-induced cellular senescence and delineated the molecular basis of protective action of PAI-1 inhibition. Results show that TM5441, a potent small molecule inhibitor of PAI-1, effectively prevents Doxorubicin-induced senescence in cardiomyocytes, fibroblasts and endothelial cells. TM5441 exerts its inhibitory effect on Doxorubicin-induced cellular senescence by decreasing reactive oxygen species generation, induction of antioxidants like catalase and suppression of stress-induced senescence cadre p53, p21, p16, PAI-1 and IGFBP3. Importantly, TM5441 also reduces replicative senescence of fibroblasts. Together these results for the first time demonstrate the efficacy of PAI-1 inhibitor in prevention of Doxorubicin-induced and replicative senescence in normal cells. Thus PAI-1 inhibitor may form an important adjuvant component of chemotherapy regimens, limiting not only Doxorubicin-induced cardiac senescence but also ameliorating the prothrombotic profile.

  8. 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.

  9. The Yin-Yang of DNA Damage Response: Roles in Tumorigenesis and Cellular Senescence

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    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.

  10. 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.

  11. 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…

  12. 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.

  13. Senescence-associated heterochromatin foci are dispensable for cellular senescence, occur in a cell type- and insult-dependent manner and follow expression of p16

    National Research Council Canada - National Science Library

    Kosar, Martin; Bartkova, Jirina; Hubackova, Sona; Hodny, Zdenek; Lukas, Jiri; Bartek, Jiri

    2011-01-01

    Cellular senescence, an irreversible proliferation arrest evoked by stresses such as oncogene activation, telomere dysfunction, or diverse genotoxic insults, has been implicated in tumor suppression and aging...

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

    NARCIS (Netherlands)

    Childs, B.G.; Durik, M.; Baker, D.J.; Deursen, J.M.A. van

    2015-01-01

    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 senesc

  15. 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

  16. 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.

  17. 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

  18. 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.

    2011-01-01

    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

  19. Both Complexity and Location of DNA Damage Contribute to Cellular Senescence Induced by Ionizing Radiation.

    Directory of Open Access Journals (Sweden)

    Xurui Zhang

    Full Text Available Persistent DNA damage is considered as a main cause of cellular senescence induced by ionizing radiation. However, the molecular bases of the DNA damage and their contribution to cellular senescence are not completely clear. In this study, we found that both heavy ions and X-rays induced senescence in human uveal melanoma 92-1 cells. By measuring senescence associated-β-galactosidase and cell proliferation, we identified that heavy ions were more effective at inducing senescence than X-rays. We observed less efficient repair when DNA damage was induced by heavy ions compared with X-rays and most of the irreparable damage was complex of single strand breaks and double strand breaks, while DNA damage induced by X-rays was mostly repaired in 24 hours and the remained damage was preferentially associated with telomeric DNA. Our results suggest that DNA damage induced by heavy ion is often complex and difficult to repair, thus presents as persistent DNA damage and pushes the cell into senescence. In contrast, persistent DNA damage induced by X-rays is preferentially associated with telomeric DNA and the telomere-favored persistent DNA damage contributes to X-rays induced cellular senescence. These findings provide new insight into the understanding of high relative biological effectiveness of heavy ions relevant to cancer therapy and space radiation research.

  20. PTTG1 attenuates drug-induced cellular senescence.

    Directory of Open Access Journals (Sweden)

    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. Ionizing Radiation Induces Cellular Senescence of Articular Chondrocytes via Negative Regulation of SIRT1 by p38 Kinase

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Eun Hee; Hwang, Sang Gu [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2009-05-15

    Senescent cells exhibit irreversible growth arrest, large flat morphology, and up-regulated senescence-associated {beta}-galactosidase activity at pH 6.0. Several conditions, including oncogenic stress, oxidative stress, and DNA damage are associated with cellular senescence. Massive acute DNA double-strand breaks occurring as a result of mechanical and chemical stress can be repaired, but some DNA damage persists, eventually triggering premature senescence. Since ionizing radiation directly induces DBS, it is possible that cellular senescence is activated under these conditions. The biological events in chondrocytes following irradiation are poorly understood, and limited information is available on the molecular signal transduction mechanisms of cellular senescence at present. In this study, we identify SIRT1 as a target molecule of p38 kinase and demonstrate that the interactions between p38 kinase and SIRT1 protein play an important role in the regulation of cellular senescence in response to IR.

  2. Detection of cellular senescence within human invasive breast carcinomas distinguishes different breast tumor subtypes.

    Science.gov (United States)

    Cotarelo, Cristina L; Schad, Arno; Kirkpatrick, Charles James; Sleeman, Jonathan P; Springer, Erik; Schmidt, Marcus; Thaler, Sonja

    2016-11-15

    Oncogene-induced senescence is thought to act as a barrier to tumorigenesis by arresting cells at risk of malignant transformation. Nevertheless, numerous findings suggest that senescent cells may conversely promote tumor progression through the development of the senescence-associated secretome they produce. It is likely that the composition and the physiological consequences mediated by the senescence secretome are dependent on the oncogenes that trigger the senescence program. Breast cancer represents a heterogenous disease that can be divided into breast cancer subtypes due to different subsets of genetic and epigenetic abnormalities. As tumor initiation and progression of these breast cancer subtypes is triggered by diverse oncogenic stimuli, differences in the senescence secretomes within breast tumors might be responsible for tumor initiation, progression, metastasis and therapeutic response. Many studies have addressed the role of senescence as a barrier to tumor progression using murine xenograft models. However, few investigations have been performed to elucidate the degree to which senescent tumor cells are present within untreated human tumors, and if present, whether these senescent tumor cells may play a role in disease progression. In the present study we analysed the appearance of senescent cells within invasive breast cancers. Detection of cellular senescence by the use of SAβ-galactosidase (SAβ-gal) staining within invasive breast carcinoms from 129 untreated patients revealed differences in the amount of SAβ-gal+ tumor cells between breast cancer subtypes. The highest percentages of SAβ-gal+ tumor cells were found in HER2-positive and luminal A breast carcinomas whereas triple negative tumors showed either little or no positivity.

  3. The impact of MAO-A in cellular senescence

    OpenAIRE

    Sequeiros, Pedro Emanuel de Magalhães

    2014-01-01

    Dissertação de mestrado em Biologia Celular e Molecular , apresentada à Faculdade de Ciências e Tecnologia da Universidade de Coimbra. Senescência celular é um mecanismo de supressão tumoral e um contribuinte para a perda de função tecidual, a medida que envelhecemos, relacionado assim com o processo a que chamamos envelhecimento. Ele tem sido e caracterizado in vitro, como o resultado de uma resposta a danos no ADN em virtude de telómeros não disfuncionais. Senescência também pod...

  4. The role of cellular senescence during vascular calcification: a key paradigm in aging research.

    Science.gov (United States)

    Mackenzie, N C W; MacRae, V E

    2011-07-01

    Vascular calcification has severe clinical consequences and is considered an accurate predictor of future adverse cardiovascular events. Vascular calcification refers to the deposition of calcium phosphate mineral, most often hydroxyapatite, in arteries. Extensive calcification of the vascular system is a key characteristic of aging. In this article, we outline the mechanisms governing vascular calcification and highlight its association with cellular senescence. This review discusses the molecular mechanisms of cellular senescence and its affect on calcification of vascular cells, the relevance of phosphate regulation and the function of FGF23 and Klotho proteins. The association of vascular calcification and cellular senescence with the rare human aging disorder Hutchison-Gilford Progeria Syndrome (HGPS) is highlighted and the mouse models used to try to determine the underlying pathways are discussed. By understanding the pathways involved in these processes novel drug targets may be elucidated in an effort to reduce the effects of cellular aging as a risk factor in cardiovascular disease.

  5. Accelerated Telomere Shortening and Replicative Senescence in Human Fibroblasts Overexpressing Mutant and Wild Type Lamin A

    Science.gov (United States)

    Huang, Shurong; Risques, Rosa Ana; Martin, George M.; Rabinovitch, Peter S.; Oshima, Junko

    2008-01-01

    LMNA mutations are responsible for a variety of genetic disorders, including muscular dystrophy, lipodystrophy, and certain progeroid syndromes, notably Hutchinson-Gilford Progeria. Although a number of clinical features of these disorders are suggestive of accelerated aging, it is not known whether cells derived from these patients exhibit cellular phenotypes associated with accelerated aging. We examined a series of isogenic skin fibroblast lines transfected with LMNA constructs bearing known pathogenic point mutations or deletion mutations found in progeroid syndromes. Fibroblasts overexpressing mutant lamin A exhibited accelerated rates of loss of telomeres and shortened replicative lifespans, in addition to abnormal nuclear morphology. To our surprise, these abnormalities were also observed in lines overexpressing wild-type lamin A. Copy number variants are common in human populations; those involving LMNA, whether arising meiotically or mitotically, might lead to progeroid phenotypes. In an initial pilot study of 23 progeroid cases without detectible WRN or LMNA mutations, however, no cases of altered LMNA copy number were detected. Nevertheless, our findings raise a hypothesis that changes in lamina organization may cause accelerated telomere attrition, with different kinetics for overexpession of wild-type and mutant lamin A, which leads to rapid replicative senescence and progroid phenotypes. PMID:17870066

  6. Regulation of cellular senescence by the essential caveolar component PTRF/Cavin-1

    Institute of Scientific and Technical Information of China (English)

    Lin Bai; Xiaoli Deng; Juanjuan Li; Miao Wang; Qian Li; Wei An; Deli A; Yu-Sheng Cong

    2011-01-01

    Polymerase I and transcript release factor (PTRF, also known as Cavin-1) is an essential component in the biogenesis and function of caveolae. Here, we show that PTRF expression is increased in senescent human fibroblasts.Importantly, overexpression of PTRF induced features characteristic of cellular senescence, whereas reduced PTRF expression extended the cellular replicative lifespan. Interestingly, we found that PTRF localized primarily to the nuclei of young and quiescent WI-38 human fibroblasts, but translocated to the cytosol and plasma membrane during cellular senescence. Furthermore, electron microscopic analysis demonstrated an increased number of caveolar structures in senescent and PTRF-transfected WI-38 cells. Our data suggest that the role of PTRF in cellular senes cence is dependent on its targeting to caveolae and its interaction with caveolin-l, which appeared to be regulated by the phosphorylation of PTRF. Taken together, our findings identify PTRF as a novel regulator of cellular senescence that acts through the p53/p21 and caveolar pathways.

  7. Irreparable telomeric DNA damage and persistent DDR signalling as a shared causative mechanism of cellular senescence and ageing.

    Science.gov (United States)

    Rossiello, Francesca; Herbig, Utz; Longhese, Maria Pia; Fumagalli, Marzia; d'Adda di Fagagna, Fabrizio

    2014-06-01

    The DNA damage response (DDR) orchestrates DNA repair and halts cell cycle. If damage is not resolved, cells can enter into an irreversible state of proliferative arrest called cellular senescence. Organismal ageing in mammals is associated with accumulation of markers of cellular senescence and DDR persistence at telomeres. Since the vast majority of the cells in mammals are non-proliferating, how do they age? Are telomeres involved? Also oncogene activation causes cellular senescence due to altered DNA replication and DDR activation in particular at the telomeres. Is there a common mechanism shared among apparently distinct types of cellular senescence? And what is the role of telomeric DNA damage?

  8. Attenuation of Replication Stress–Induced Premature Cellular Senescence to Assess Anti-Aging Modalities

    Science.gov (United States)

    Zhao, Hong; Darzynkiewicz, Zbigniew

    2014-01-01

    Described is an in vitro model of premature senescence in pulmonary adenocarcinoma A549 cells induced by persistent DNA replication stress in response to treatment with the DNA damaging drug mitoxantrone (Mxt). The degree of cellular senescence, based on characteristic changes in cell morphology, is measured by laser scanning cytometry. Specifically, the flattening of cells grown on slides (considered the hallmark of cellular senescence) is measured as the decline in local intensity of DNA-associated DAPI fluorescence (represented by maximal pixels). This change is paralleled by an increase in nuclear area. Thus, the ratio of mean intensity of maximal pixels to nuclear area provides a very sensitive morphometric biomarker for the degree of senescence. This analysis is combined with immunocytochemical detection of senescence markers, such as overexpression of cyclin kinase inhibitors (e.g., p21WAF1) and phosphorylation of ribosomal protein S6 (rpS6), a key marker associated with aging/senescence that is detected using a phospho-specific antibody. These biomarker indices are presented in quantitative terms defined as a senescence index (SI), which is the fraction of the marker in test cultures relative to the same marker in exponentially growing control cultures. This system can be used to evaluate the anti-aging potential of test agents by assessing attenuation of maximal senescence. As an example, the inclusion of berberine, a natural alkaloid with reported anti-aging properties and a long history of use in traditional Chinese medicine, is shown to markedly attenuate the Mxt-induced SI and phosphorylation of rpS6. The multivariate analysis of senescence markers by laser scanning cytometry offers a promising tool to explore the potential anti-aging properties of a variety agents. PMID:24984966

  9. Attenuation of replication stress-induced premature cellular senescence to assess anti-aging modalities.

    Science.gov (United States)

    Zhao, Hong; Darzynkiewicz, Zbigniew

    2014-01-01

    Described is an in vitro model of premature senescence in pulmonary adenocarcinoma A549 cells induced by persistent DNA replication stress in response to treatment with the DNA damaging drug mitoxantrone (Mxt). The degree of cellular senescence, based on characteristic changes in cell morphology, is measured by laser scanning cytometry. Specifically, the flattening of cells grown on slides (considered the hallmark of cellular senescence) is measured as the decline in local intensity of DNA-associated DAPI fluorescence (represented by maximal pixels). This change is paralleled by an increase in nuclear area. Thus, the ratio of mean intensity of maximal pixels to nuclear area provides a very sensitive morphometric biomarker for the degree of senescence. This analysis is combined with immunocytochemical detection of senescence markers, such as overexpression of cyclin kinase inhibitors (e.g., p21(WAF1) ) and phosphorylation of ribosomal protein S6 (rpS6), a key marker associated with aging/senescence that is detected using a phospho-specific antibody. These biomarker indices are presented in quantitative terms defined as a senescence index (SI), which is the fraction of the marker in test cultures relative to the same marker in exponentially growing control cultures. This system can be used to evaluate the anti-aging potential of test agents by assessing attenuation of maximal senescence. As an example, the inclusion of berberine, a natural alkaloid with reported anti-aging properties and a long history of use in traditional Chinese medicine, is shown to markedly attenuate the Mxt-induced SI and phosphorylation of rpS6. The multivariate analysis of senescence markers by laser scanning cytometry offers a promising tool to explore the potential anti-aging properties of a variety agents.

  10. Quantitative model of cell cycle arrest and cellular senescence in primary human fibroblasts.

    Directory of Open Access Journals (Sweden)

    Sascha Schäuble

    Full Text Available Primary human fibroblasts in tissue culture undergo a limited number of cell divisions before entering a non-replicative "senescent" state. At early population doublings (PD, fibroblasts are proliferation-competent displaying exponential growth. During further cell passaging, an increasing number of cells become cell cycle arrested and finally senescent. This transition from proliferating to senescent cells is driven by a number of endogenous and exogenous stress factors. Here, we have developed a new quantitative model for the stepwise transition from proliferating human fibroblasts (P via reversibly cell cycle arrested (C to irreversibly arrested senescent cells (S. In this model, the transition from P to C and to S is driven by a stress function γ and a cellular stress response function F which describes the time-delayed cellular response to experimentally induced irradiation stress. The application of this model based on senescence marker quantification at the single-cell level allowed to discriminate between the cellular states P, C, and S and delivers the transition rates between the P, C and S states for different human fibroblast cell types. Model-derived quantification unexpectedly revealed significant differences in the stress response of different fibroblast cell lines. Evaluating marker specificity, we found that SA-β-Gal is a good quantitative marker for cellular senescence in WI-38 and BJ cells, however much less so in MRC-5 cells. Furthermore we found that WI-38 cells are more sensitive to stress than BJ and MRC-5 cells. Thus, the explicit separation of stress induction from the cellular stress response, and the differentiation between three cellular states P, C and S allows for the first time to quantitatively assess the response of primary human fibroblasts towards endogenous and exogenous stress during cellular ageing.

  11. Dysfunction of nucleus accumbens-1 activates cellular senescence and inhibits tumor cell proliferation and oncogenesis.

    Science.gov (United States)

    Zhang, Yi; Cheng, Yan; Ren, Xingcong; Hori, Tsukasa; Huber-Keener, Kathryn J; Zhang, Li; Yap, Kai Lee; Liu, David; Shantz, Lisa; Qin, Zheng-Hong; Zhang, Suping; Wang, Jianrong; Wang, Hong-Gang; Shih, Ie-Ming; Yang, Jin-Ming

    2012-08-15

    Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the BTB/POZ gene family, has emerging roles in cancer. We report here that NAC1 acts as a negative regulator of cellular senescence in transformed and nontransformed cells, and dysfunction of NAC1 induces senescence and inhibits its oncogenic potential. We show that NAC1 deficiency markedly activates senescence and inhibits proliferation in tumor cells treated with sublethal doses of γ-irradiation. In mouse embryonic fibroblasts from NAC1 knockout mice, following infection with a Ras virus, NAC1-/- cells undergo significantly more senescence and are either nontransformed or less transformed in vitro and less tumorigenic in vivo when compared with NAC1+/+ cells. Furthermore, we show that the NAC1-caused senescence blunting is mediated by ΔNp63, which exerts its effect on senescence through p21, and that NAC1 activates transcription of ΔNp63 under stressful conditions. Our results not only reveal a previously unrecognized function of NAC1, the molecular pathway involved and its impact on pathogenesis of tumor initiation and development, but also identify a novel senescence regulator that may be exploited as a potential target for cancer prevention and treatment.

  12. 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.

  13. Tissue depletion of taurine accelerates skeletal muscle senescence and leads to early death in mice.

    Directory of Open Access Journals (Sweden)

    Takashi Ito

    Full Text Available Taurine (2-aminoethanesulfonic acid is found in milimolar concentrations in mammalian tissues. One of its main functions is osmoregulation; however, it also exhibits cytoprotective activity by diminishing injury caused by stress and disease. Taurine depletion is associated with several defects, many of which are found in the aging animal, suggesting that taurine might exert anti-aging actions. Therefore, in the present study, we examined the hypothesis that taurine depletion accelerates aging by reducing longevity and accelerating aging-associated tissue damage. Tissue taurine depletion in taurine transporter knockout (TauTKO mouse was found to shorten lifespan and accelerate skeletal muscle histological and functional defects, including an increase in central nuclei containing myotubes, a reduction in mitochondrial complex 1 activity and an induction in an aging biomarker, Cyclin-dependent kinase 4 inhibitor A (p16INK4a. Tissue taurine depletion also enhances unfolded protein response (UPR, which may be associated with an improvement in protein folding by taurine. Our data reveal that tissue taurine depletion affects longevity and cellular senescence; an effect possibly linked to a disturbance in protein folding.

  14. Androgen receptor accelerates premature senescence of human dermal papilla cells in association with DNA damage.

    Directory of Open Access Journals (Sweden)

    Yi-Chien Yang

    Full Text Available The dermal papilla, located in the hair follicle, expresses androgen receptor and plays an important role in hair growth. Androgen/Androgen receptor actions have been implicated in the pathogenesis of androgenetic alopecia, but the exact mechanism is not well known. Recent studies suggest that balding dermal papilla cells exhibit premature senescence, upregulation of p16(INK4a, and nuclear expression of DNA damage markers. To investigate whether androgen/AR signaling influences the premature senescence of dermal papilla cells, we first compared frontal scalp dermal papilla cells of androgenetic alopecia patients with matched normal controls and observed that premature senescence is more prominent in the dermal papilla cells of androgenetic alopecia patients. Exposure of androgen induced premature senescence in dermal papilla cells from non-balding frontal and transitional zone of balding scalp follicles but not in beard follicles. Overexpression of the AR promoted androgen-induced premature senescence in association with p16(INK4a upregulation, whereas knockdown of the androgen receptor diminished the effects of androgen. An analysis of γ-H2AX expression in response to androgen/androgen receptor signaling suggested that DNA damage contributes to androgen/androgen receptor-accelerated premature senescence. These results define androgen/androgen receptor signaling as an accelerator of premature senescence in dermal papilla cells and suggest that the androgen/androgen receptor-mediated DNA damage-p16(INK4a axis is a potential therapeutic target in the treatment of androgenetic alopecia.

  15. CREG1 enhances p16(INK4a) -induced cellular senescence.

    Science.gov (United States)

    Moolmuang, Benchamart; Tainsky, Michael A

    2011-02-01

    Cellular senescence is an irreversible growth arrest that is activated in normal cells upon shortening of telomere and other cellular stresses. Bypassing cellular senescence is a necessary step for cells to become immortal during oncogenic transformation. During the spontaneous immortalization of Li-Fraumeni Syndrome (LFS) fibroblasts, we found that CREG1 (Cellular Repressor of E1A-stimulated Genes 1) expression was decreased during immortalization and increased in senescence. Moreover, we found that repression of CREG1 expression occurs via an epigenetic mechanism, promoter DNA methylation. Ectopic expression of CREG1 in the immortal LFS cell lines decreases cell proliferation but does not directly induce senescence. We confirmed this in osteosarcoma and fibrosarcoma cancer cell lines, cancers commonly seen in Li-Fraumeni Syndrome. In addition, we found that p16 (INK4a) is also downregulated in immortal cells and that coexpression of CREG1 and p16 (INK4a) , an inhibitor of CDK4/6 and Rb phosphorylation, has a greater effect than either CREG1 and p16 (INK4a) alone to reduce cell growth, induce cell cycle arrest and cellular senescence in immortal LFS fibroblasts, osteosarcoma and fibrosarcoma cell lines. Moreover, cooperation of CREG1 and p16 (INK4a) inhibits the expression of cyclin A and cyclin B by inhibiting promoter activity thereby decreasing mRNA and protein levels; these proteins are required for S-phase entry and G2/M transition. In conclusion, this is the first evidence to demonstrate that CREG1 enhances p16 (INK4a) -induced senescence by transcriptional repression of cell cycle-regulated genes.

  16. Irreversibility of cellular senescence: dual roles of p16INK4a/Rb-pathway in cell cycle control

    Directory of Open Access Journals (Sweden)

    Hara Eiji

    2007-03-01

    Full Text Available Abstract The retinoblastoma (Rb tumor suppressor gene product, pRb, has an established role in the implementation of cellular senescence, the state of irreversible G1 cell cycle arrest provoked by diverse oncogenic stresses. In murine cells, senescence cell cycle arrest can be reversed by subsequent inactivation of pRb, indicating that pRb is required not only for the onset of cellular senescence, but also for the maintenance of senescence program in murine cells. However, in human cells, once pRb is fully activated by p16INK4a, senescence cell cycle arrest becomes irreversible and is no longer revoked by subsequent inactivation of pRb, suggesting that p16INK4a/Rb-pathway activates an alternative mechanism to irreversibly block the cell cycle in human senescent cells. Here, we discuss the molecular mechanism underlying the irreversibility of senescence cell cycle arrest and its potential towards tumor suppression.

  17. Premature lung aging and cellular senescence in the pathogenesis of idiopathic pulmonary fibrosis and COPD/emphysema.

    Science.gov (United States)

    Chilosi, Marco; Carloni, Angelo; Rossi, Andrea; Poletti, Venerino

    2013-09-01

    Different anatomic and physiological changes occur in the lung of aging people that can affect pulmonary functions, and different pulmonary diseases, including deadly diseases such as chronic obstructive pulmonary disease (COPD)/emphysema and idiopathic pulmonary fibrosis (IPF), can be related to an acceleration of the aging process. The individual genetic background, as well as exposure to a variety of toxic substances (cigarette smoke in primis) can contribute significantly to accelerating pulmonary senescence. Premature aging can impair lung function by different ways: by interfering specifically with tissue repair mechanisms after damage, thus perturbing the correct crosstalk between mesenchymal and epithelial components; by inducing systemic and/or local alteration of the immune system, thus impairing the complex mechanisms of lung defense against infections; and by stimulating a local and/or systemic inflammatory condition (inflammaging). According to recently proposed pathogenic models in COPD and IPF, premature cellular senescence likely affects distinct progenitors cells (mesenchymal stem cells in COPD, alveolar epithelial precursors in IPF), leading to stem cell exhaustion. In this review, the large amount of data supporting this pathogenic view are discussed, with emphasis on the possible molecular and cellular mechanisms leading to the severe parenchymal remodeling that characterizes, in different ways, these deadly diseases.

  18. Effects of Longyanshen polysaccharides on free radical metabolism in senescence accelerated-prone mice

    Institute of Scientific and Technical Information of China (English)

    Zhongshi Huang; Haiyuan Xie; Shijun Zhang; Yang Jiao; Weizhe Jiang; Renbin Huang

    2008-01-01

    BACKGROUND: Along with aging, antioxidase activity decreases and oxygen-derived free radicals greatly accumulate, resulting in cellular senescence, or even cell death. This is manifested by hypomnesia and disordered metabolism of free radicals. Studies have reported that Longyanshen polysaccharidcs have the function of antioxidation and improved brain memory.OBJECTIVE: To observe the effects of Longyanshen polysaccharides on free radical metabolism in brain tissue to verify the anti-aging mechanisms in senescence accelerated-prime (SAMPS) mice. DESIGN, TIME AND SETTING: The randomized, controlled, biochemical experiment was performed in the Department of Pharmacology and Scientific Experimental Center of Guangxi Medical University (China) from September 2005 to January 2008.MATERIALS: Forty SAMP8 mice were randomized into four groups: SAMP8 control group, as well as low-, mid-, and high-dose polysaccharide, with 10 mice in each group. Ten senescence accelerated-resistant-prone (SAMR 1) mice served as the normal control group. Longyanshen polysaccharides, extracted from the medical plant Longyanshen, were supplied by the Department of Pharmacology, Guangxi Medical University. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malonaldehydc (MDA), nitric oxide (NO), and total protein test kitwere purchased from Nanjing Jiancheng Bioengineering Institute (China).METHODS: SAMP8 mice were used to establish a dementia animal model. SAMP8 and SAMRI control mice were administered 30 mL/kg saline. The low-, middle-, and high-dose polysaccharide groups were administered 45, 90, and 180 mg/kg Longyanshen polysaccharides, respectively. Each group was treated by intragastric administration, once daily, for 50 continuous days.MAIN OUTCOME MEASURES: One hour after the last administration, mouse brain tissues were collected, and retro orbital blood sampling was performed. Spectrophotometry was used to measure SOD and GSH-Px activity, as well as MDA and NO concentration

  19. 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...

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

    NARCIS (Netherlands)

    Childs, B.G.; Durik, M.; Baker, D.J.; Deursen, J.M.A. van

    2015-01-01

    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

  1. Chromatin remodeling of human subtelomeres and TERRA promoters upon cellular senescence

    Science.gov (United States)

    Thijssen, Peter E.; Tobi, Elmar W.; Balog, Judit; Schouten, Suzanne G.; Kremer, Dennis; El Bouazzaoui, Fatiha; Henneman, Peter; Putter, Hein; Eline Slagboom, P.; Heijmans, Bastiaan T.; Van der Maarel, Silvère M.

    2013-01-01

    Subtelomeres are patchworks of evolutionary conserved sequence blocks and harbor the transcriptional start sites for telomere repeat containing RNAs (TERRA). Recent studies suggest that the interplay between telomeres and subtelomeric chromatin is required for maintaining telomere function. To further characterize chromatin remodeling of subtelomeres in relation to telomere shortening and cellular senescence, we systematically quantified histone modifications and DNA methylation at the subtelomeres of chromosomes 7q and 11q in primary human WI-38 fibroblasts. Upon senescence, both subtelomeres were characterized by a decrease in markers of constitutive heterochromatin, suggesting relative chromatin relaxation. However, we did not find increased levels of markers of euchromatin or derepression of the 7q VIPR2 gene. The repressed state of the subtelomeres was maintained upon senescence, which could be attributed to a rise in levels of facultative heterochromatin markers at both subtelomeres. While senescence-induced subtelomeric chromatin remodeling was similar for both chromosomes, chromatin remodeling at TERRA promoters displayed chromosome-specific patterns. At the 7q TERRA promoter, chromatin structure was co-regulated with the more proximal subtelomere. In contrast, the 11q TERRA promoter, which was previously shown to be bound by CCCTC-binding factor CTCF, displayed lower levels of markers of constitutive heterochromatin that did not change upon senescence, whereas levels of markers of facultative heterochromatin decreased upon senescence. In line with the chromatin state data, transcription of 11q TERRA but not 7q TERRA was detected. Our study provides a detailed description of human subtelomeric chromatin dynamics and shows distinct regulation of the TERRA promoters of 7q and 11q upon cellular senescence. PMID:23644601

  2. Happily (never after: Aging in the context of oxidative stress, proteostasis loss and cellular senescence

    Directory of Open Access Journals (Sweden)

    Annika Höhn

    2017-04-01

    Full Text Available Aging is a complex phenomenon and its impact is becoming more relevant due to the rising life expectancy and because aging itself is the basis for the development of age-related diseases such as cancer, neurodegenerative diseases and type 2 diabetes. Recent years of scientific research have brought up different theories that attempt to explain the aging process. So far, there is no single theory that fully explains all facets of aging. The damage accumulation theory is one of the most accepted theories due to the large body of evidence found over the years. Damage accumulation is thought to be driven, among others, by oxidative stress. This condition results in an excess attack of oxidants on biomolecules, which lead to damage accumulation over time and contribute to the functional involution of cells, tissues and organisms. If oxidative stress persists, cellular senescence is a likely outcome and an important hallmark of aging. Therefore, it becomes crucial to understand how senescent cells function and how they contribute to the aging process. This review will cover cellular senescence features related to the protein pool such as morphological and molecular hallmarks, how oxidative stress promotes protein modifications, how senescent cells cope with them by proteostasis mechanisms, including antioxidant enzymes and proteolytic systems. We will also highlight the nutritional status of senescent cells and aged organisms (including human clinical studies by exploring trace elements and micronutrients and on their importance to develop strategies that might increase both, life and health span and postpone aging onset.

  3. Intermittent heterochronic plasma exchange as a modality for delaying cellular senescence-a hypothesis.

    Science.gov (United States)

    Kiprov, Dobri D

    2013-12-01

    The population of baby boomers (age 60-65) is rapidly increasing globally. The aging of the human body is associated with the decline of cellular function which leads to the development of a variety of diseases. The increased demand for health care for the aging population creates significant financial burden to any healthcare system. Developing strategies and health intervention methods to ameliorate this situation is paramount. Experiments utilizing heterochronic parabiosis in mice have demonstrated that replacing the aging cellular milieu with the plasma of a young experimental animal leads to reversal of cellular senescence. This article describes a hypothetical model of intermittent heterochronic plasma exchange in humans as a modality for heterochronic parabiosis in an attempt to delay cellular senescence. Copyright © 2013 Wiley Periodicals, Inc.

  4. The microtubule stabilizing agent discodermolide is a potent inducer of accelerated cell senescence.

    Science.gov (United States)

    Klein, Laura E; Freeze, B Scott; Smith, Amos B; Horwitz, Susan Band

    2005-03-01

    Discodermolide is a microtubule stabilizing agent that suppresses dynamic instability and blocks cells in mitosis. Selection of A549 nonsmall cell lung carcinoma cells with increasing concentrations of discodermolide yielded a clone that proliferated in 8 nM. When these cells were exposed to any concentration greater than 8 nM, replication ceased and the cells developed a flattened, enlarged, granular morphology. Accelerated senescence was demonstrated by a functional beta-galactosidase activity at pH 6. When parental A549 cells were treated with IC50-concentrations of doxorubicin, Taxol or discodermolide, the latter two drugs quickly produced aberrant mitosis. However, discodermolide, but not Taxol, also produced a large increase in senescence-associated beta-galactosidase activity and altered levels of known senescence markers. Although some of these differences between Taxol and discodermolide were dose dependent, only discodermolide produced a doxorubicin-like induction of a senescence phenotype, including a senescence-associated beta-galactosidase activity, up-regulation of PAI-1 and p66Shc, and a strong, sustained, Erk1/2 activation. This research provides insights into the mechanism of action of discodermolide and provides the first demonstration of a microtubule stabilizing agent that inhibits tumor cell growth with a powerful induction of accelerated senescence.

  5. Perception of Arabidopsis AtPep peptides, but not bacterial elicitors, accelerates starvation-induced senescence

    Directory of Open Access Journals (Sweden)

    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.

  6. NaDC3 Induces Premature Cellular Senescence by Promoting Transport of Krebs Cycle Intermediates, Increasing NADH, and Exacerbating Oxidative Damage.

    Science.gov (United States)

    Ma, Yuxiang; Bai, Xue-Yuan; Du, Xuan; Fu, Bo; Chen, Xiangmei

    2016-01-01

    High-affinity sodium-dependent dicarboxylate cotransporter 3 (NaDC3) is a key metabolism-regulating membrane protein responsible for transport of Krebs cycle intermediates. NaDC3 is upregulated as organs age, but knowledge regarding the underlying mechanisms by which NaDC3 modulates mammalian aging is limited. In this study, we showed that NaDC3 overexpression accelerated cellular senescence in young human diploid cells (MRC-5 and WI-38) and primary renal tubular cells, leading to cell cycle arrest in G1 phase and increased expression of senescent biomarkers, senescence-associated β-galactosidase and p16. Intracellular levels of reactive oxygen species, 8-hydroxy-2'-deoxyguanosine, malondialdehyde, and carbonyl were significantly enhanced, and activities of respiratory complexes I and III and ATP level were significantly decreased in NaDC3-infected cells. Stressful premature senescent phenotypes induced by NaDC3 were markedly ameliorated via treatment with the antioxidants Tiron and Tempol. High expression of NaDC3 caused a prominent increase in intracellular levels of Krebs cycle intermediates and NADH. Exogenous NADH and NAD(+) may aggravate and attenuate the aging phenotypes induced by NaDC3, respectively. These results suggest that NaDC3 can induce premature cellular senescence by promoting the transport of Krebs cycle intermediates, increasing generation of NADH and reactive oxygen species and leading to oxidative damage. Our results clarify the aging signaling pathway regulated by NaDC3.

  7. Aquatide Activation of SIRT1 Reduces Cellular Senescence through a SIRT1-FOXO1-Autophagy Axis.

    Science.gov (United States)

    Lim, Chae Jin; Lee, Yong-Moon; Kang, Seung Goo; Lim, Hyung W; Shin, Kyong-Oh; Jeong, Se Kyoo; Huh, Yang Hoon; Choi, Suin; Kor, Myungho; Seo, Ho Seong; Park, Byeong Deog; Park, Keedon; Ahn, Jeong Keun; Uchida, Yoshikazu; Park, Kyungho

    2017-09-01

    Ultraviolet (UV) irradiation is a relevant environment factor to induce cellular senescence and photoaging. Both autophagy- and silent information regulator T1 (SIRT1)-dependent pathways are critical cellular processes of not only maintaining normal cellular functions, but also protecting cellular senescence in skin exposed to UV irradiation. In the present studies, we investigated whether modulation of autophagy induction using a novel synthetic SIRT1 activator, heptasodium hexacarboxymethyl dipeptide-12 (named as Aquatide), suppresses the UVB irradiation-induced skin aging. Treatment with Aquatide directly activates SIRT1 and stimulates autophagy induction in cultured human dermal fibroblasts. Next, we found that Aquatide-mediated activation of SIRT1 increases autophagy induction via deacetylation of forkhead box class O (FOXO) 1. Finally, UVB irradiation-induced cellular senescence measured by SA-β-gal staining was significantly decreased in cells treated with Aquatide in parallel to occurring SIRT1 activation-dependent autophagy. Together, Aquatide modulates autophagy through SIRT1 activation, contributing to suppression of skin aging caused by UV irradiation.

  8. Phenylbutyric acid induces the cellular senescence through an Akt/p21{sup WAF1} signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hag Dong [Laboratory of Biochemistry, School of Life Sciences and Biotechnology, and BioInstitute, Korea University, Seoul 136-701 (Korea, Republic of); Jang, Chang-Young [Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women' s University, Seoul 140-742 (Korea, Republic of); Choe, Jeong Min [Laboratory of Biochemistry, School of Life Sciences and Biotechnology, and BioInstitute, Korea University, Seoul 136-701 (Korea, Republic of); Department of Biochemistry, Korea University College of Medicine, Seoul 136-705 (Korea, Republic of); Korean Institute of Molecular Medicine and Nutrition, Seoul 136-705 (Korea, Republic of); Sohn, Jeongwon, E-mail: biojs@korea.ac.kr [Department of Biochemistry, Korea University College of Medicine, Seoul 136-705 (Korea, Republic of); Korean Institute of Molecular Medicine and Nutrition, Seoul 136-705 (Korea, Republic of); Kim, Joon, E-mail: joonkim@korea.ac.kr [Laboratory of Biochemistry, School of Life Sciences and Biotechnology, and BioInstitute, Korea University, Seoul 136-701 (Korea, Republic of)

    2012-06-01

    Highlights: Black-Right-Pointing-Pointer Phenylbutyric acid induces cellular senescence. Black-Right-Pointing-Pointer Phenylbutyric acid activates Akt kinase. Black-Right-Pointing-Pointer The knockdown of PERK also can induce cellular senescence. Black-Right-Pointing-Pointer Akt/p21{sup WAF1} pathway activates in PERK knockdown induced cellular senescence. -- Abstract: It has been well known that three sentinel proteins - PERK, ATF6 and IRE1 - initiate the unfolded protein response (UPR) in the presence of misfolded or unfolded proteins in the ER. Recent studies have demonstrated that upregulation of UPR in cancer cells is required to survive and proliferate. Here, we showed that long exposure to 4-phenylbutyric acid (PBA), a chemical chaperone that can reduce retention of unfolded and misfolded proteins in ER, induced cellular senescence in cancer cells such as MCF7 and HT1080. In addition, we found that treatment with PBA activates Akt, which results in p21{sup WAF1} induction. Interestingly, the depletion of PERK but not ATF6 and IRE1 also induces cellular senescence, which was rescued by additional depletion of Akt. This suggests that Akt pathway is downstream of PERK in PBA induced cellular senescence. Taken together, these results show that PBA induces cellular senescence via activation of the Akt/p21{sup WAF1} pathway by PERK inhibition.

  9. Gamma-H2AX upregulation caused by Wip1 deficiency increases depression-related cellular senescence in hippocampus

    Science.gov (United States)

    He, Zhi-Yong; Wang, Wen-Yue; Hu, Wei-Yan; Yang, Lu; Li, Yan; Zhang, Wei-Yuan; Yang, Ya-Shu; Liu, Si-Cheng; Zhang, Feng-Lan; Mei, Rong; Xing, Da; Xiao, Zhi-Cheng; Zhang, Ming

    2016-01-01

    The PP2C family member Wild-type p53-induced phosphatase 1 (Wip1) critically regulates DNA damage response (DDR) under stressful situations. In the present study, we investigated whether Wip1 expression was involved in the regulation of DDR-induced and depression-related cellular senescence in mouse hippocampus. We found that Wip1 gene knockout (KO) mice showed aberrant elevation of hippocampal cellular senescence and of γ-H2AX activity, which is known as a biomarker of DDR and cellular senescence, indicating that the lack of Wip1-mediated γ-H2AX dephosphorylation facilitates cellular senescence in hippocampus. Administration of the antidepressant fluoxetine had no significant effects on the increased depression-like behaviors, enriched cellular senescence, and aberrantly upregulated hippocampal γ-H2AX activity in Wip1 KO mice. After wildtype C57BL/6 mice were exposed to the procedure of chronic unpredictable mild stress (CUMS), cellular senescence and γ-H2AX activity in hippocampus were also elevated, accompanied by the suppression of Wip1 expression in hippocampus when compared to the control group without CUMS experience. These CUMS-induced symptoms were effectively prevented following fluoxetine administration in wildtype C57BL/6 mice, with the normalization of depression-like behaviors. Our data demonstrate that Wip1-mediated γ-H2AX dephosphorylation may play an important role in the occurrence of depression-related cellular senescence. PMID:27686532

  10. Caveolin-1/PTRF upregulation constitutes a mechanism for mediating p53-induced cellular senescence: implications for evidence-based therapy of delayed wound healing in diabetes.

    Science.gov (United States)

    Bitar, Milad S; Abdel-Halim, Samy M; Al-Mulla, Fahd

    2013-10-15

    A heightened state of oxidative stress and senescence of fibroblasts constitute potential therapeutic targets in nonhealing diabetic wounds. Here, we studied the underlying mechanism mediating diabetes-induced cellular senescence using in vitro cultured dermal fibroblasts and in vivo circular wounds. Our results demonstrated that the total antioxidant capacity and mRNA levels of thioredoxinreductase and glucose-6-phosphate dehydrogenase as well as the ratio of NADPH/NADP were decreased markedly in fibroblasts from patients with type 2 diabetes (DFs). Consistent with this shift in favor of excessive reactive oxygen species, DFs also displayed a significant increase in senescence-associated β-galactosidase activity and phospho-γ-histone H2AX (pH2AX) level. Moreover, the ability of PDGF to promote cell proliferation/migration and regulate the phosphorylation-dependent activation of Akt and ERK1/2 appears to be attenuated as a function of diabetes. Mechanistically, we found that diabetes-induced oxidative stress upregulated caveolin-1 (Cav-1) and PTRF expression, which in turn sequestered Mdm2 away from p53. This process resulted in the activation of a p53/p21-dependent pathway and the induction of premature senescence in DFs. Most of the aforementioned oxidative stress and senescence-based features observed in DFs were recapitulated in a 10-day-old diabetic wound. Intriguingly, we confirmed that the targeted depletion of Cav-1 or PTRF using siRNA- or Vivo-Morpholino antisense-based gene therapy markedly inhibited diabetes/oxidative stress-induced premature senescence and also accelerated tissue repair in this disease state. Overall, our data illuminate Cav-1/PTRF-1 as a key player of a novel signaling pathway that may link a heightened state of oxidative stress to cellular senescence and impaired wound healing in diabetes.

  11. hnRNP A1 antagonizes cellular senescence and senescence-associated secretory phenotype via regulation of SIRT1 mRNA stability.

    Science.gov (United States)

    Wang, Hui; Han, Limin; Zhao, Ganye; Shen, Hong; Wang, Pengfeng; Sun, Zhaomeng; Xu, Chenzhong; Su, Yuanyuan; Li, Guodong; Tong, Tanjun; Chen, Jun

    2016-09-09

    Senescent cells display a senescence-associated secretory phenotype (SASP) which contributes to tumor suppression, aging, and cancer. However, the underlying mechanisms for SASP regulation are not fully elucidated. SIRT1, a nicotinamide adenosine dinucleotide-dependent deacetylase, plays multiple roles in metabolism, inflammatory response, and longevity, etc. However, its posttranscriptional regulation and its roles in cellular senescence and SASP regulation are still elusive. Here, we identify the RNA-binding protein hnRNP A1 as a posttranscriptional regulator of SIRT1, as well as cell senescence and SASP regulator. hnRNP A1 directly interacts with the 3' untranslated region of SIRT1 mRNA, promotes its stability, and increases SIRT1 expression. hnRNP A1 delays replicative cellular senescence and prevents from Ras OIS via upregulation of SIRT1 expression to deacetylate NF-κB, thus blunting its transcriptional activity and subsequent IL-6/IL-8 induction. hnRNP A1 overexpression promotes cell transformation and tumorigenesis in a SIRT1-dependent manner. Together, our findings unveil a novel posttranscriptional regulation of SIRT1 by hnRNP A1 and uncover a critical role of hnRNP A1-SIRT1-NF-κB pathway in regulating cellular senescence and SASP expression. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  12. Cellular senescence in livers from children with end stage liver disease.

    Directory of Open Access Journals (Sweden)

    Gabriela Gutierrez-Reyes

    Full Text Available BACKGROUND: Senescent cells occur in adults with cirrhotic livers independent of the etiology. AIM: Investigate the presence rate of cellular senescence and expression of cell cycle check points in livers from children with end stage disease. METHODOLOGY/PRINCIPAL FINDINGS: Livers of five children aged three years or less undergoing liver transplantation due to tyrosinemia (n = 1, biliary atresia (n = 2, or fulminant hepatitis (n = 2 were analyzed for senescence associated beta-galactosidase (SA-betagal activity and p16INK4a, p21cip1 and p53. All livers displayed positive cellular staining for SA-betagal in the canals of Hering and interlobular biliary ducts. In the presence of cirrhosis (3/5 cases SA-betagal was found at the cholangioles and hepatocytes surrounding the regenerative nodules. Children with fulminant hepatic failure without cirrhosis had significant ductular transformation with intense SA-betagal activity. No SA-betagal activity was evident in the fibrous septa. Staining for p53 had a similar distribution to that observed for SA-betagal. Staining for p16(INK4a and p21(cip1 was positive in the explanted liver of the patient with tyrosinemia, in the hepatocytes, the canals of Hering, cholangioles and interlobular bile ducts. In the livers with fulminant hepatitis, p21(cip1 staining occurred in the areas of ductular transformation and in the interlobular bile ducts. CONCLUSIONS/SIGNIFICANCE: Cellular senescence in livers of children with end stage disease is associated with damage rather than corresponding to an age dependent phenomenon. Further studies are needed to support the hypothesis that these senescence markers correlate with disease progression.

  13. Temporally distinct roles of ATM and ROS in genotoxic-stress-dependent induction and maintenance of cellular senescence.

    Science.gov (United States)

    Nair, Raji R; Bagheri, Meisam; Saini, Deepak Kumar

    2015-01-15

    Cells exposed to genotoxic stress induce cellular senescence through a DNA damage response (DDR) pathway regulated by ATM kinase and reactive oxygen species (ROS). Here, we show that the regulatory roles for ATM kinase and ROS differ during induction and maintenance of cellular senescence. Cells treated with different genotoxic agents were analyzed using specific pathway markers and inhibitors to determine that ATM kinase activation is directly proportional to the dose of the genotoxic stress and that senescence initiation is not dependent on ROS or the p53 status of cells. Cells in which ROS was quenched still activated ATM and initiated the DDR when insulted, and progressed normally to senescence. By contrast, maintenance of a viable senescent state required the presence of ROS as well as activated ATM. Inhibition or removal of either of the components caused cell death in senescent cells, through a deregulated ATM-ROS axis. Overall, our work demonstrates existence of an intricate temporal hierarchy between genotoxic stress, DDR and ROS in cellular senescence. Our model reports the existence of different stages of cellular senescence with distinct regulatory networks.

  14. JMJD2A Promotes Cellular Transformation by Blocking Cellular Senescence through Transcriptional Repression of the Tumor Suppressor CHD5

    Directory of Open Access Journals (Sweden)

    Frédérick A. Mallette

    2012-11-01

    Full Text Available Senescence is a cellular response preventing tumorigenesis. The Ras oncogene is frequently activated or mutated in human cancers, but Ras activation is insufficient to transform primary cells. In a search for cooperating oncogenes, we identify the lysine demethylase JMJD2A/KDM4A. We show that JMJD2A functions as a negative regulator of Ras-induced senescence and collaborates with oncogenic Ras to promote cellular transformation by negatively regulating the p53 pathway. We find CHD5, a known tumor suppressor regulating p53 activity, as a target of JMJD2A. The expression of JMJD2A inhibits Ras-mediated CHD5 induction leading to a reduced activity of the p53 pathway. In addition, we show that JMJD2A is overexpressed in mouse and human lung cancers. Depletion of JMJD2A in the human lung cancer cell line A549 bearing an activated K-Ras allele triggers senescence. We propose that JMJD2A is an oncogene that represents a target for Ras-expressing tumors.

  15. BAF180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21.

    Science.gov (United States)

    Lee, Hyemin; Dai, Fangyan; Zhuang, Li; Xiao, Zhen-Dong; Kim, Jongchan; Zhang, Yilei; Ma, Li; You, M James; Wang, Zhong; Gan, Boyi

    2016-04-12

    BAF180 (also called PBRM1), a subunit of the SWI/SNF complex, plays critical roles in the regulation of chromatin remodeling and gene transcription, and is frequently mutated in several human cancers. However, the role of mammalian BAF180 in tumor suppression and tissue maintenance in vivo remains largely unknown. Here, using a conditional somatic knockout approach, we explored the cellular and organismal functions of BAF180 in mouse. BAF180 deletion in primary mouse embryonic fibroblasts (MEFs) triggers profound cell cycle arrest, premature cellular senescence, without affecting DNA damage response or chromosomal integrity. While somatic deletion of BAF180 in adult mice does not provoke tumor development, BAF180 deficient mice exhibit defects in hematopoietic system characterized by progressive reduction of hematopoietic stem cells (HSCs), defective long-term repopulating potential, and hematopoietic lineage developmental aberrations. BAF180 deletion results in elevated p21 expression in both MEFs and HSCs. Mechanistically, we showed that BAF180 binds to p21 promoter, and BAF180 deletion enhances the binding of modified histones associated with transcriptional activation on p21 promoter. Deletion of p21 rescues cell cycle arrest and premature senescence in BAF180 deficient MEFs, and partially rescues hematopoietic defects in BAF180 deficient mice. Together, our study identifies BAF180 as a critical regulator of cellular senescence and HSC homeostasis, which is at least partially regulated through BAF180-mediated suppression of p21 expression. Our results also suggest that senescence triggered by BAF180 inactivation may serve as a failsafe mechanism to restrain BAF180 deficiency-associated tumor development, providing a conceptual framework to further understand BAF180 function in tumor biology.

  16. All-trans retinoic acid induces cellular senescence via upregulation of p16, p21, and p27.

    Science.gov (United States)

    Park, Sun-Hye; Lim, Joo Song; Jang, Kyung Lib

    2011-11-28

    We here present a new anti-tumor mechanism of all-trans retinoic acid (ATRA). ATRA induced several biomarkers of cellular senescence including irreversible G1 arrest, morphological changes, senescence-associated β-galactosidase, and heterochromatin foci in HepG2 cells. ATRA also upregulated levels of p16, p21, and p27 which lead to activation of Rb and subsequent inactivation of E2F1. These effects were abolished by the RNA interference-mediated silencing of p16, p21, and p27. Moreover, ATRA failed to induce cellular senescence in Huh7 and HCT116, in which p16, p21, and p27 were not upregulated by ATRA, confirming that ATRA induces cellular senescence via upregulation of p16, p21, and p27. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  17. Metformin and the ATM DNA damage response (DDR): accelerating the onset of stress-induced senescence to boost protection against cancer.

    Science.gov (United States)

    Menendez, Javier A; Cufí, Sílvia; Oliveras-Ferraros, Cristina; Martin-Castillo, Begoña; Joven, Jorge; Vellon, Luciano; Vazquez-Martin, Alejandro

    2011-11-01

    By activating the ataxia telangiectasia mutated (ATM)-mediated DNA Damage Response (DDR), the AMPK agonist metformin might sensitize cells against further damage, thus mimicking the precancerous stimulus that induces an intrinsic barrier against carcinogenesis. Herein, we present the new hypothesis that metformin might function as a tissue sweeper of pre-malignant cells before they gain stem cell/tumor initiating properties. Because enhanced glycolysis (the Warburg effect) plays a causal role in the gain of stem-like properties of tumor-initiating cells by protecting them from the pro-senescent effects of mitochondrial respiration-induced oxidative stress, metformin's ability to disrupt the glycolytic metabotype may generate a cellular phenotype that is metabolically protected against immortalization. The bioenergetic crisis imposed by metformin, which may involve enhanced mitochondrial biogenesis and oxidative stress, can lower the threshold for cellular senescence by pre-activating an ATM-dependent pseudo-DDR. This allows an accelerated onset of cellular senescence in response to additional oncogenic stresses. By pushing cancer cells to use oxidative phosphorylation instead of glycolysis, metformin can rescue cell surface major histocompatibility complex class I (MHC-I) expression that is downregulated by oncogenic transformation, a crucial adaptation of tumor cells to avoid the adaptive immune response by cytotoxic T-lymphocytes (CTLs). Aside from restoration of tumor immunosurveillance at the cell-autonomous level, metformin can activate a senescence-associated secretory phenotype (SASP) to reinforce senescence growth arrest, which might trigger an immune-mediated clearance of the senescent cells in a non-cell-autonomous manner. By diminishing the probability of escape from the senescence anti-tumor barrier, the net effect of metformin should be a significant decrease in the accumulation of dysfunctional, pre-malignant cells in tissues, including those with the

  18. Resveratrol sequentially induces replication and oxidative stresses to drive p53-CXCR2 mediated cellular senescence in cancer cells.

    Science.gov (United States)

    Li, Boxuan; Hou, Dong; Guo, Haiyang; Zhou, Haibin; Zhang, Shouji; Xu, Xiuhua; Liu, Qiao; Zhang, Xiyu; Zou, Yongxin; Gong, Yaoqin; Shao, Changshun

    2017-03-16

    Resveratrol (RSV) acts either as an antioxidant or a pro-oxidant depending on contexts. RSV-treated cancer cells may experience replication stress that can lead to cellular senescence or apoptosis. While both oxidative and replication stresses may mediate the anti-proliferation effect of RSV, to what extent each contributes to the impaired proliferation in response to RSV remains uncharacterized. We here report the study of the roles of replication and oxidative stresses in mediating cellular senescence in cancer cells treated with RSV. RSV induced S-phase arrest and cellular senescence in a dose-dependent manner in U2OS and A549 cancer cells as well as in normal human fibroblasts. We observed that nucleosides significantly alleviated RSV-induced replication stress and DNA damage response, and consequently attenuating cellular senescence. While the elevation of reactive oxygen species (ROS) also mediated the pro-senescent effect of RSV, it occurred after S-phase arrest. However, the induction of ROS by RSV was independent of S-phase arrest and actually reinforced the latter. We also demonstrated a critical role of the p53-CXCR2 axis in mediating RSV-induced senescence. Interestingly, CXCR2 also functioned as a barrier to apoptosis. Together, our results provided more insights into the biology of RSV-induced stress and its cellular consequences.

  19. Combinatorial effects of continuous protein synthesis, ERK-signaling, and reactive oxygen species on induction of cellular senescence.

    Science.gov (United States)

    Takauji, Yuki; En, Atsuki; Miki, Kensuke; Ayusawa, Dai; Fujii, Michihiko

    2016-07-15

    Mammalian cells, when treated with sub-lethal doses of genotoxic stresses, slow down DNA synthesis but continue protein synthesis. Thus, these cells show an accumulation of proteins and undergo unbalanced growth. In the previous studies, we have shown that HeLa cells treated with excess thymidine or camptothecin undergo unbalanced growth, and prolonged unbalanced growth causes induction of cellular senescence, which is suppressed by restriction of protein synthesis or inhibition of ERK-signaling. In this study, we found that restriction of protein synthesis, inhibition of ERK-signaling, and elimination of reactive oxygen species showed a combinatorial effect on suppression of cellular senescence induced by excess thymidine or camptothecin. Of these, restriction of protein synthesis most effectively suppressed cellular senescence. Importantly, a similar combinatorial effect was observed in replicative senescence in normal human diploid fibroblasts. Our findings suggested that various stresses were cumulatively involved in cellular senescence, and suppression of cellular senescence was improved by combining the treatments that reduce the stresses.

  20. DNA-damage response network at the crossroads of cell-cycle checkpoints,cellular senescence and apoptosis

    Institute of Scientific and Technical Information of China (English)

    SCHMITT Estelle; PAQUET Claudie; BEAUCHEMIN Myriam; BERTRAND Richard

    2007-01-01

    Tissue homeostasis requires a carefully-orchestrated balance between cell proliferation,cellular senescence and cell death.Cells proliferate through a cell cycle that is tightly regulated by cyclin-dependent kinase activities.Cellular senescence is a safeguard program limiting the proliferative competence of cells in living organisms.Apoptosis eliminates unwanted cells by the coordinated activity of gene products that regulate and effect cell death.The intimate link between the cell cycle,cellular senescence,apoptosis regulation,cancer development and tumor responses to cancer treatment has become eminently apparent.Extensive research on tumor suppressor genes,oncogenes,the cell cycle and apoptosis regulatory genes has revealed how the DNA damage-sensing and -signaling pathways,referred to as the DNA-damage response network,are tied to cell proliferation,cell-cycle arrest,cellular senescence and apoptosis.DNA-damage responses are complex,involving "sensor" proteins that sense the damage,and transmit signals to "transducer" proteins,which,in turn,convey the signals to numerous "effector" proteins implicated in specific cellular pathways,including DNA repair mechanisms,cell-cycle checkpoints,cellular senescence and apoptosis.The Bcl-2 family of proteins stands among the most crucial regulators of apoptosis and performs vital functions in deciding whether a cell will live or die after cancer chemotherapy and irradiation.In addition,several studies have now revealed that members of the Bcl-2 family also interface with the cell cycle,DNA repair/recombination and cellular senescence,effects that are generally distinct from their function in apoptosis.In this review,we report progress in understanding the molecular networks that regulate cell-cycle checkpoints,cellular senescence and apoptosis after DNA damage,and discuss the influence of some Bcl-2 family members on cell-cycle checkpoint regulation.

  1. Selenoprotein H suppresses cellular senescence through genome maintenance and redox regulation.

    Science.gov (United States)

    Wu, Ryan T Y; Cao, Lei; Chen, Benjamin P C; Cheng, Wen-Hsing

    2014-12-05

    Oxidative stress and persistent DNA damage response contribute to cellular senescence, a degeneration process critically involving ataxia telangiectasia-mutated (ATM) and p53. Selenoprotein H (SelH), a nuclear selenoprotein, is proposed to carry redox and transactivation domains. To determine the role of SelH in genome maintenance, shRNA knockdown was employed in human normal and immortalized cell lines. SelH shRNA MRC-5 diploid fibroblasts under ambient O2 displayed a distinct profile of senescence including β-galactosidase expression, autofluorescence, growth inhibition, and ATM pathway activation. Such senescence phenotypes were alleviated in the presence of ATM kinase inhibitors, by p53 shRNA knockdown, or by maintaining the cells under 3% O2. During the course of 5-day recovery, the induction of phospho-ATM on Ser-1981 and γH2AX by H2O2 treatment (20 μm) subsided in scrambled shRNA but exacerbated in SelH shRNA MRC-5 cells. Results from clonogenic assays demonstrated hypersensitivity of SelH shRNA HeLa cells to paraquat and H2O2, but not to hydroxyurea, neocarzinostatin, or camptothecin. While SelH mRNA expression was induced by H2O2 treatment, SelH-GFP did not mobilize to sites of oxidative DNA damage. The glutathione level was lower in SelH shRNA than scrambled shRNA HeLa cells, and the H2O2-induced cell death was rescued in the presence of N-acetylcysteine, a glutathione precursor. Altogether, SelH protects against cellular senescence to oxidative stress through a genome maintenance pathway involving ATM and p53.

  2. Mitochondrial dysfunction induced by frataxin deficiency is associated with cellular senescence and abnormal calcium metabolism

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    Arantxa eBolinches-Amorós

    2014-05-01

    Full Text Available Friedreich ataxia is considered a neurodegenerative disorder involving both the peripheral and central nervous systems. Dorsal root ganglia (DRG are the major target tissue structures. This neuropathy is caused by mutations in the FXN gene that encodes frataxin. Here, we investigated the mitochondrial and cell consequences of frataxin depletion in a cellular model based on frataxin silencing in SH-SY5Y human neuroblastoma cells, a cell line that has been used widely as in vitro models for studies on neurological diseases. We showed that the reduction of frataxin induced mitochondrial dysfunction due to a bioenergetic deficit and abnormal Ca2+ homeostasis in the mitochondria that were associated with oxidative and endoplasmic reticulum stresses. The depletion of frataxin did not cause cell death but increased autophagy, which may have a cytoprotective effect against cellular insults such as oxidative stress. Frataxin silencing provoked slow cell growth associated with cellular senescence, as demonstrated by increased SA-βgal activity and cell cycle arrest at the G1 phase. We postulate that cellular senescence might be related to a hypoplastic defect in the DRG during neurodevelopment, as suggested by necropsy studies.

  3. Co-targeting Deoxyribonucleic Acid–Dependent Protein Kinase and Poly(Adenosine Diphosphate-Ribose) Polymerase-1 Promotes Accelerated Senescence of Irradiated Cancer Cells

    Energy Technology Data Exchange (ETDEWEB)

    Azad, Arun, E-mail: arun.azad@bccancer.bc.ca [Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria (Australia); Department of Pathology, St. Vincent' s Hospital, University of Melbourne, Parkville, Victoria (Australia); Bukczynska, Patricia; Jackson, Susan [Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria (Australia); Haput, Ygal; Cullinane, Carleen [Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria (Australia); Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria (Australia); McArthur, Grant A.; Solomon, Benjamin [Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria (Australia); Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria (Australia); Department of Medicine, St. Vincent' s Hospital, University of Melbourne, Parkville, Victoria (Australia); Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria (Australia)

    2014-02-01

    Purpose: To examine the effects of combined blockade of DNA-dependent protein kinase (DNA-PK) and poly(adenosine diphosphate-ribose) polymerase-1 (PARP-1) on accelerated senescence in irradiated H460 and A549 non-small cell lung cancer cells. Methods and Materials: The effects of KU5788 and AG014699 (inhibitors of DNA-PK and PARP-1, respectively) on clonogenic survival, DNA double-strand breaks (DSBs), apoptosis, mitotic catastrophe, and accelerated senescence in irradiated cells were examined in vitro. For in vivo experiments, H460 xenografts established in athymic nude mice were treated with BEZ235 (a DNA-PK, ATM, and phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor) and AG014699 to determine effects on proliferation, DNA DSBs, and accelerated senescence after radiation. Results: Compared with either inhibitor alone, combination treatment with KU57788 and AG014699 reduced postradiation clonogenic survival and significantly increased persistence of Gamma-H2AX (γH2AX) foci in irradiated H460 and A549 cells. Notably, these effects coincided with the induction of accelerated senescence in irradiated cells as reflected by positive β-galactosidase staining, G2-M cell-cycle arrest, enlarged and flattened cellular morphology, increased p21 expression, and senescence-associated cytokine secretion. In irradiated H460 xenografts, concurrent therapy with BEZ235 and AG014699 resulted in sustained Gamma-H2AX (γH2AX) staining and prominent β-galactosidase activity. Conclusion: Combined DNA-PK and PARP-1 blockade increased tumor cell radiosensitivity and enhanced the prosenescent properties of ionizing radiation in vitro and in vivo. These data provide a rationale for further preclinical and clinical testing of this therapeutic combination.

  4. Melatonin can improve insulin resistance and aging-induced pancreas alterations in senescence-accelerated prone male mice (SAMP8)

    OpenAIRE

    Cuesta, Sara; Kireev, Roman; García, Cruz; Rancan, Lisa; Vara, Elena; Jesús A. F. Tresguerres

    2012-01-01

    The aim of the present study was to investigate the effect of aging on several parameters related to glucose homeostasis and insulin resistance in pancreas and how melatonin administration could affect these parameters. Pancreas samples were obtained from two types of male mice models: senescence-accelerated prone (SAMP8) and senescence-accelerated-resistant mice (SAMR1). Insulin levels in plasma were increased with aging in both SAMP8 and SAMR1 mice, whereas insulin content in pancreas was d...

  5. Evaluating the Role of p38 MAPK in the Accelerated Cell Senescence of Werner Syndrome Fibroblasts

    Directory of Open Access Journals (Sweden)

    Terence Davis

    2016-04-01

    Full Text Available Progeroid syndromes show features of accelerated ageing and are used as models for human ageing, of which Werner syndrome (WS is one of the most widely studied. WS fibroblasts show accelerated senescence that may result from p38 MAP kinase activation since it is prevented by the p38 inhibitor SB203580. Thus, small molecule inhibition of p38-signalling may be a therapeutic strategy for WS. To develop this approach issues such as the in vivo toxicity and kinase selectivity of existing p38 inhibitors need to be addressed, so as to strengthen the evidence that p38 itself plays a critical role in mediating the effect of SB203580, and to find an inhibitor suitable for in vivo use. In this work we used a panel of different p38 inhibitors selected for: (1 having been used successfully in vivo in either animal models or human clinical trials; (2 different modes of binding to p38; and (3 different off-target kinase specificity profiles, in order to critically address the role of p38 in the premature senescence seen in WS cells. Our findings confirmed the involvement of p38 in accelerated cell senescence and identified p38 inhibitors suitable for in vivo use in WS, with BIRB 796 the most effective.

  6. At the intersection of non-coding transcription, DNA repair, chromatin structure, and cellular senescence

    Directory of Open Access Journals (Sweden)

    Ryosuke eOhsawa

    2013-07-01

    Full Text Available It is well accepted that non-coding RNAs play a critical role in regulating gene expression. Recent paradigm-setting studies are now revealing that non-coding RNAs, other than microRNAs, also play intriguing roles in the maintenance of chromatin structure, in the DNA damage response, and in adult human stem cell aging. In this review, we will discuss the complex inter-dependent relationships among non-coding RNA transcription, maintenance of genomic stability, chromatin structure and adult stem cell senescence. DNA damage-induced non-coding RNAs transcribed in the vicinity of the DNA break regulate recruitment of the DNA damage machinery and DNA repair efficiency. We will discuss the correlation between non-coding RNAs and DNA damage repair efficiency and the potential role of changing chromatin structures around double-strand break sites. On the other hand, induction of non-coding RNA transcription from the repetitive Alu elements occurs during human stem cell aging and hinders efficient DNA repair causing entry into senescence. We will discuss how this fine balance between transcription and genomic instability may be regulated by the dramatic changes to chromatin structure that accompany cellular senescence.

  7. Autophagy and cellular senescence mediated by Sox2 suppress malignancy of cancer cells.

    Directory of Open Access Journals (Sweden)

    Yong-Yeon Cho

    Full Text Available Autophagy is a critical cellular process required for maintaining cellular homeostasis in health and disease states, but the molecular mechanisms and impact of autophagy on cancer is not fully understood. Here, we found that Sox2, a key transcription factor in the regulation of the "stemness" of embryonic stem cells and induced-pluripotent stem cells, strongly induced autophagic phenomena, including intracellular vacuole formation and lysosomal activation in colon cancer cells. The activation occurred through Sox2-mediated ATG10 gene expression and resulted in the inhibition of cell proliferation and anchorage-independent colony growth ex vivo and tumor growth in vivo. Further, we found that Sox2-induced-autophagy enhanced cellular senescence by up-regulating tumor suppressors or senescence factors, including p16(INK4a, p21 and phosphorylated p53 (Ser15. Notably, knockdown of ATG10 in Sox2-expressing colon cancer cells restored cancer cell properties. Taken together, our results demonstrated that regulation of autophagy mediated by Sox2 is a mechanism-driven novel strategy to treat human colon cancers.

  8. Resveratrol induces cellular senescence with attenuated mono-ubiquitination of histone H2B in glioma cells

    Energy Technology Data Exchange (ETDEWEB)

    Gao, Zhen; Xu, Michael S.; Barnett, Tamara L. [Nevada Cancer Institute, Las Vegas, NV 89135 (United States); Xu, C. Wilson, E-mail: wxu@nvcancer.org [Nevada Cancer Institute, Las Vegas, NV 89135 (United States)

    2011-04-08

    Research highlights: {yields} Resveratrol induces cellular senescence in glioma cell. {yields} Resveratrol inhibits mono-ubiquitination of histone H2B at K120. {yields} Depletion of RNF20, phenocopies the inhibitory effects of resveratrol. {yields} Mono-ubiquitination of histone H2B at K120 is a novel target of resveratrol. {yields} RNF20 inhibits cellular senescence in proliferating glioma cells. -- Abstract: Resveratrol (3,4',5-trihydroxy-trans-stilbene), a polyphenol naturally occurring in grapes and other plants, has cancer chemo-preventive effects and therapeutic potential. Although resveratrol modulates multiple pathways in tumor cells, how resveratrol or its affected pathways converge on chromatin to mediate its effects is not known. Using glioma cells as a model, we showed here that resveratrol inhibited cell proliferation and induced cellular hypertrophy by transforming spindle-shaped cells to enlarged, irregular and flatten-shaped ones. We further showed that resveratrol-induced hypertrophic cells expressed senescence-associated-{beta}-galactosidase, suggesting that resveratrol-induced cellular senescence in glioma cells. Consistent with these observations, we demonstrated that resveratrol inhibited clonogenic efficiencies in vitro and tumor growth in a xenograft model. Furthermore, we found that acute treatment of resveratrol inhibited mono-ubiquitination of histone H2B at K120 (uH2B) in breast, prostate, pancreatic, lung, brain tumor cells as well as primary human cells. Chronic treatment with low doses of resveratrol also inhibited uH2B in the resveratrol-induced senescent glioma cells. Moreover, we showed that depletion of RNF20, a ubiquitin ligase of histone H2B, inhibited uH2B and induced cellular senescence in glioma cells in vitro, thereby recapitulated the effects of resveratrol. Taken together, our results suggest that uH2B is a novel direct or indirect chromatin target of resveratrol and RNF20 plays an important role in inhibiting cellular

  9. Acute dyskerin depletion triggers cellular senescence and renders osteosarcoma cells resistant to genotoxic stress-induced apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Ping; Mobasher, Maral E.; Alawi, Faizan, E-mail: falawi@upenn.edu

    2014-04-18

    Highlights: • Dyskerin depletion triggers cellular senescence in U2OS osteosarcoma cells. • Dyskerin-depleted cells are resistant to apoptosis induced by genotoxic stress. • Chromatin relaxation sensitizes dyskerin-depleted cells to apoptosis. - Abstract: Dyskerin is a conserved, nucleolar RNA-binding protein implicated in an increasing array of fundamental cellular processes. Germline mutation in the dyskerin gene (DKC1) is the cause of X-linked dyskeratosis congenita (DC). Conversely, wild-type dyskerin is overexpressed in sporadic cancers, and high-levels may be associated with poor prognosis. It was previously reported that acute loss of dyskerin function via siRNA-mediated depletion slowed the proliferation of transformed cell lines. However, the mechanisms remained unclear. Using human U2OS osteosarcoma cells, we show that siRNA-mediated dyskerin depletion induced cellular senescence as evidenced by proliferative arrest, senescence-associated heterochromatinization and a senescence-associated molecular profile. Senescence can render cells resistant to apoptosis. Conversely, chromatin relaxation can reverse the repressive effects of senescence-associated heterochromatinization on apoptosis. To this end, genotoxic stress-induced apoptosis was suppressed in dyskerin-depleted cells. In contrast, agents that induce chromatin relaxation, including histone deacetylase inhibitors and the DNA intercalator chloroquine, sensitized dyskerin-depleted cells to apoptosis. Dyskerin is a core component of the telomerase complex and plays an important role in telomere homeostasis. Defective telomere maintenance resulting in premature senescence is thought to primarily underlie the pathogenesis of X-linked DC. Since U2OS cells are telomerase-negative, this leads us to conclude that loss of dyskerin function can also induce cellular senescence via mechanisms independent of telomere shortening.

  10. Cellular and Subcellular Localization of Endogenous Nitric Oxide in Young and Senescent Pea Plants12

    Science.gov (United States)

    Corpas, Francisco J.; Barroso, Juan B.; Carreras, Alfonso; Quirós, Miguel; León, Ana M.; Romero-Puertas, María C.; Esteban, Francisco J.; Valderrama, Raquel; Palma, José M.; Sandalio, Luisa M.; Gómez, Manuel; del Río, Luis A.

    2004-01-01

    The cellular and subcellular localization of endogenous nitric oxide (NO˙) in leaves from young and senescent pea (Pisum sativum) plants was studied. Confocal laser scanning microscopy analysis of pea leaf sections with the fluorescent probe 4,5-diaminofluorescein diacetate revealed that endogenous NO˙ was mainly present in vascular tissues (xylem and phloem). Green fluorescence spots were also detected in the epidermal cells, palisade and spongy mesophyll cells, and guard cells. In senescent leaves, NO˙ generation was clearly reduced in the vascular tissues. At the subcellular level, by electron paramagnetic resonance spectroscopy with the spin trap Fe(MGD)2 and fluorometric analysis with 4,5-diaminofluorescein diacetate, NO˙ was found to be an endogenous metabolite of peroxisomes. The characteristic three-line electron paramagnetic resonance spectrum of NO˙, with g = 2.05 and aN = 12.8 G, was detected in peroxisomes. By fluorometry, NO˙ was also found in these organelles, and the level measured of NO˙ was linearly dependent on the amount of peroxisomal protein. The enzymatic production of NO˙ from l-Arg (nitric oxide synthase [NOS]-like activity) was measured by ozone chemiluminiscence. The specific activity of peroxisomal NOS was 4.9 nmol NO˙ mg−1 protein min−1; was strictly dependent on NADPH, calmodulin, and BH4; and required calcium. In senescent pea leaves, the NOS-like activity of peroxisomes was down-regulated by 72%. It is proposed that peroxisomal NO˙ could be involved in the process of senescence of pea leaves. PMID:15347796

  11. Slow and Fast Neocortical Oscillations in the Senescence-Accelerated Mouse Model SAMP8

    Directory of Open Access Journals (Sweden)

    Patricia Castano-Prat

    2017-05-01

    Full Text Available The senescence-accelerated mouse prone 8 (SAMP8 model is characterized by accelerated, progressive cognitive decline as well as Alzheimer’s disease (AD-like neurodegenerative changes, and resembles the etiology of multicausal, sporadic late-onset/age-related AD in humans. Our aim was to find whether these AD-like pathological features, together with the cognitive deficits present in the SAMP8 strain, are accompanied by disturbances in cortical network activity with respect to control mice (SAM resistance 1, SAMR1 and, if so, how the alterations in cortical activity progress with age. For this purpose, we characterized the extracellular spontaneous oscillatory activity in different regions of the cerebral cortex of SAMP8 and SAMR1 mice under ketamine anesthesia at 5 and 7 months of age. Under these conditions, slow oscillations and fast rhythms generated in the cortical network were recorded and different parameters of these oscillations were quantified and compared between SAMP8 and their control, SAMR1 mice. The average frequency of slow oscillations in SAMP8 mice was decreased with respect to the control mice at both studied ages. An elongation of the silent periods or Down states was behind the decreased slow oscillatory frequency while the duration of active or Up states remained stable. SAMP8 mice also presented increased cycle variability and reduced high frequency components during Down states. During Up states, the power peak in the gamma range was displaced towards lower frequencies in all the cortical areas of SAMP8 with respect to control mice suggesting that the spectral profile of SAMP8 animals is shifted towards lower frequencies. This shift is reminiscent to one of the principal hallmarks of electroencephalography (EEG abnormalities in patients with Alzheimer’s disease, and adds evidence in support of the suitability of the SAMP8 mouse as a model of this disease. Although some of the differences between SAMP8 and control mice

  12. Rapamycin suppresses brain aging in senescence-accelerated OXYS rats.

    Science.gov (United States)

    Kolosova, Nataliya G; Vitovtov, Anton O; Muraleva, Natalia A; Akulov, Andrey E; Stefanova, Natalia A; Blagosklonny, Mikhail V

    2013-06-01

    Cellular and organismal aging are driven in part by the MTOR (mechanistic target of rapamycin) pathway and rapamycin extends life span inC elegans, Drosophila and mice. Herein, we investigated effects of rapamycin on brain aging in OXYS rats. Previously we found, in OXYS rats, an early development of age-associated pathological phenotypes similar to several geriatric disorders in humans, including cerebral dysfunctions. Behavioral alterations as well as learning and memory deficits develop by 3 months. Here we show that rapamycin treatment (0.1 or 0.5 mg/kg as a food mixture daily from the age of 1.5 to 3.5 months) decreased anxiety and improved locomotor and exploratory behavior in OXYS rats. In untreated OXYS rats, MRI revealed an increase of the area of hippocampus, substantial hydrocephalus and 2-fold increased area of the lateral ventricles. Rapamycin treatment prevented these abnormalities, erasing the difference between OXYS and Wister rats (used as control). All untreated OXYS rats showed signs of neurodegeneration, manifested by loci of demyelination. Rapamycin decreased the percentage of animals with demyelination and the number of loci. Levels of Tau and phospho-Tau (T181) were increased in OXYS rats (compared with Wistar). Rapamycin significantly decreased Tau and inhibited its phosphorylation in the hippocampus of OXYS and Wistar rats. Importantly, rapamycin treatment caused a compensatory increase in levels of S6 and correspondingly levels of phospo-S6 in the frontal cortex, indicating that some downstream events were compensatory preserved, explaining the lack of toxicity. We conclude that rapamycin in low chronic doses can suppress brain aging.

  13. Melatonin improves inflammation processes in liver of senescence-accelerated prone male mice (SAMP8).

    Science.gov (United States)

    Cuesta, Sara; Kireev, Roman; Forman, Katherine; García, Cruz; Escames, Germaine; Ariznavarreta, Carmen; Vara, Elena; Tresguerres, Jesús A F

    2010-12-01

    Aging is associated with an increase in oxidative stress and inflammation. The aim of this study was to investigate the effect of aging on various physiological parameters related to inflammation in livers obtained from two types of male mice models: Senescence-accelerated prone (SAMP8) and senescence-accelerated-resistant (SAMR1) mice, and to study the influence of the administration of melatonin (1mg/kg/day) for one month on old SAMP8 mice on these parameters. The parameters studied have been the mRNA expression of TNF-α, iNOS, IL-1β, HO-1, HO-2, MCP1, NFkB1, NFkB2, NFkB protein or NKAP and IL-10. All have been measured by real-time reverse transcription polymerase chain reaction RT-PCR. Furthermore we analyzed the protein expression of TNF-α, iNOS, IL-1β, HO-1, HO-2, and IL-10 by Western-blot. Aging increased oxidative stress and inflammation especially in the liver of SAMP8 mice. Treatment with melatonin decreased the mRNA expression of TNF-α, IL-1β, HO (HO-1 and HO-2), iNOS, MCP1, NFκB1, NFκB2 and NKAP in old male mice. The protein expression of TNF-α, IL-1β was also decreased and IL-10 increased with melatonin treatment and no significant differences were observed in the rest of parameters analyzed. The present study showed that aging was related to inflammation in livers obtained from old male senescence prone mice (SAMP8) and old male senescence resistant mice (SAMR1) being the alterations more evident in the former. Exogenous administration of melatonin was able to reduce inflammation. Copyright © 2010 Elsevier Inc. All rights reserved.

  14. SIRT6 Depletion Suppresses Tumor Growth by Promoting Cellular Senescence Induced by DNA Damage in HCC

    Science.gov (United States)

    Lee, Namgyu; Ryu, Hye Guk; Kwon, Jung-Hee; Kim, Dae-Kyum; Kim, Sae Rom; Wang, Hee Jung; Kim, Kyong-Tai; Choi, Kwan Yong

    2016-01-01

    The role of Sirtuin 6 (SIRT6) as a tumor suppressor or oncogene in liver cancer remains controversial. Thus, we identified the specific role of SIRT6 in the progression of hepatocellular carcinoma (HCC). SIRT6 expression was significantly higher in HCC cell lines and HCC tissues from 138 patients than in an immortalized hepatocyte cell line, THLE-2 and non-tumor tissues, respectively. SIRT6 knockdown by shRNA suppressed the growth of HCC cells and inhibited HCC tumor growth in vivo. In addition, SIRT6 silencing significantly prevented the growth of HCC cell lines by inducing cellular senescence in the p16/Rb- and p53/p21-pathway independent manners. Microarray analysis revealed that the expression of genes involved in nucleosome assembly was apparently altered in SIRT6-depleted Hep3B cells. SIRT6 knockdown promoted G2/M phase arrest and downregulation of genes encoding histone variants associated with nucleosome assembly, which could be attributed to DNA damage. Taken together, our findings suggest that SIRT6 acts as a tumor promoter by preventing DNA damage and cellular senescence, indicating that SIRT6 represents a potential therapeutic target for the treatment of HCC. PMID:27824900

  15. Dandelion Extracts Protect Human Skin Fibroblasts from UVB Damage and Cellular Senescence.

    Science.gov (United States)

    Yang, Yafan; Li, Shuangshuang

    2015-01-01

    Ultraviolet (UV) irradiation causes damage in skin by generating excessive reactive oxygen species (ROS) and induction of matrix metalloproteinases (MMPs), leading to skin photoageing. Dandelion extracts have long been used for traditional Chinese medicine and native American medicine to treat cancers, hepatitis, and digestive diseases; however, less is known on the effects of dandelion extracts in skin photoageing. Here we found that dandelion leaf and flower extracts significantly protect UVB irradiation-inhibited cell viability when added before UVB irradiation or promptly after irradiation. Dandelion leaf and flower extracts inhibited UVB irradiation-stimulated MMP activity and ROS generation. Dandelion root extracts showed less action on protecting HDFs from UVB irradiation-induced MMP activity, ROS generation, and cell death. Furthermore, dandelion leaf and flower but not root extracts stimulated glutathione generation and glutathione reductase mRNA expression in the presence or absence of UVB irradiation. We also found that dandelion leaf and flower extracts help absorb UVB irradiation. In addition, dandelion extracts significantly protected HDFs from H2O2-induced cellular senescence. In conclusion, dandelion extracts especially leaf and flower extracts are potent protective agents against UVB damage and H2O2-induced cellular senescence in HDFs by suppressing ROS generation and MMP activities and helping UVB absorption.

  16. Dandelion Extracts Protect Human Skin Fibroblasts from UVB Damage and Cellular Senescence

    Directory of Open Access Journals (Sweden)

    Yafan Yang

    2015-01-01

    Full Text Available Ultraviolet (UV irradiation causes damage in skin by generating excessive reactive oxygen species (ROS and induction of matrix metalloproteinases (MMPs, leading to skin photoageing. Dandelion extracts have long been used for traditional Chinese medicine and native American medicine to treat cancers, hepatitis, and digestive diseases; however, less is known on the effects of dandelion extracts in skin photoageing. Here we found that dandelion leaf and flower extracts significantly protect UVB irradiation-inhibited cell viability when added before UVB irradiation or promptly after irradiation. Dandelion leaf and flower extracts inhibited UVB irradiation-stimulated MMP activity and ROS generation. Dandelion root extracts showed less action on protecting HDFs from UVB irradiation-induced MMP activity, ROS generation, and cell death. Furthermore, dandelion leaf and flower but not root extracts stimulated glutathione generation and glutathione reductase mRNA expression in the presence or absence of UVB irradiation. We also found that dandelion leaf and flower extracts help absorb UVB irradiation. In addition, dandelion extracts significantly protected HDFs from H2O2-induced cellular senescence. In conclusion, dandelion extracts especially leaf and flower extracts are potent protective agents against UVB damage and H2O2-induced cellular senescence in HDFs by suppressing ROS generation and MMP activities and helping UVB absorption.

  17. Active Degradation Explains the Distribution of Nuclear Proteins during Cellular Senescence.

    Directory of Open Access Journals (Sweden)

    Enrico Giampieri

    Full Text Available The amount of cellular proteins is a crucial parameter that is known to vary between cells as a function of the replicative passages, and can be important during physiological aging. The process of protein degradation is known to be performed by a series of enzymatic reactions, ranging from an initial step of protein ubiquitination to their final fragmentation by the proteasome. In this paper we propose a stochastic dynamical model of nuclear proteins concentration resulting from a balance between a constant production of proteins and their degradation by a cooperative enzymatic reaction. The predictions of this model are compared with experimental data obtained by fluorescence measurements of the amount of nuclear proteins in murine tail fibroblast (MTF undergoing cellular senescence. Our model provides a three-parameter stationary distribution that is in good agreement with the experimental data even during the transition to the senescent state, where the nuclear protein concentration changes abruptly. The estimation of three parameters (cooperativity, saturation threshold, and maximal velocity of the reaction, and their evolution during replicative passages shows that only the maximal velocity varies significantly. Based on our modeling we speculate the reduction of functionality of the protein degradation mechanism as a possible competitive inhibition of the proteasome.

  18. Active Degradation Explains the Distribution of Nuclear Proteins during Cellular Senescence.

    Science.gov (United States)

    Giampieri, Enrico; De Cecco, Marco; Remondini, Daniel; Sedivy, John; Castellani, Gastone

    2015-01-01

    The amount of cellular proteins is a crucial parameter that is known to vary between cells as a function of the replicative passages, and can be important during physiological aging. The process of protein degradation is known to be performed by a series of enzymatic reactions, ranging from an initial step of protein ubiquitination to their final fragmentation by the proteasome. In this paper we propose a stochastic dynamical model of nuclear proteins concentration resulting from a balance between a constant production of proteins and their degradation by a cooperative enzymatic reaction. The predictions of this model are compared with experimental data obtained by fluorescence measurements of the amount of nuclear proteins in murine tail fibroblast (MTF) undergoing cellular senescence. Our model provides a three-parameter stationary distribution that is in good agreement with the experimental data even during the transition to the senescent state, where the nuclear protein concentration changes abruptly. The estimation of three parameters (cooperativity, saturation threshold, and maximal velocity of the reaction), and their evolution during replicative passages shows that only the maximal velocity varies significantly. Based on our modeling we speculate the reduction of functionality of the protein degradation mechanism as a possible competitive inhibition of the proteasome.

  19. Dandelion Extracts Protect Human Skin Fibroblasts from UVB Damage and Cellular Senescence

    Science.gov (United States)

    Yang, Yafan; Li, Shuangshuang

    2015-01-01

    Ultraviolet (UV) irradiation causes damage in skin by generating excessive reactive oxygen species (ROS) and induction of matrix metalloproteinases (MMPs), leading to skin photoageing. Dandelion extracts have long been used for traditional Chinese medicine and native American medicine to treat cancers, hepatitis, and digestive diseases; however, less is known on the effects of dandelion extracts in skin photoageing. Here we found that dandelion leaf and flower extracts significantly protect UVB irradiation-inhibited cell viability when added before UVB irradiation or promptly after irradiation. Dandelion leaf and flower extracts inhibited UVB irradiation-stimulated MMP activity and ROS generation. Dandelion root extracts showed less action on protecting HDFs from UVB irradiation-induced MMP activity, ROS generation, and cell death. Furthermore, dandelion leaf and flower but not root extracts stimulated glutathione generation and glutathione reductase mRNA expression in the presence or absence of UVB irradiation. We also found that dandelion leaf and flower extracts help absorb UVB irradiation. In addition, dandelion extracts significantly protected HDFs from H2O2-induced cellular senescence. In conclusion, dandelion extracts especially leaf and flower extracts are potent protective agents against UVB damage and H2O2-induced cellular senescence in HDFs by suppressing ROS generation and MMP activities and helping UVB absorption. PMID:26576225

  20. Novel roles of Skp2 E3 ligase in cellular senescence, cancer progression, and metastasis

    Institute of Scientific and Technical Information of China (English)

    Guocan Wang; Chia-Hsin Chan; Yuan Gao; Hui-Kuan Lin

    2012-01-01

    S-phase kinase-associated protein 2 (Skp2) belongs to the F-box protein family.It is a component of the SCF E3 ubiquitin ligase complex.Skp2 has been shown to regulate cellular proliferation by targeting several cell cycle-regulated proteins for ubiquitination and degradation,including cyclin-dependent kinase inhibitor p27.Skp2 has also been demonstrated to display an oncogenic function since its overexpression has been observed in many human cancers.This review discusses the recent discoveries on the novel roles of Skp2 in regulating cellular senescence,cancer progression,and metastasis,as well as the therapeutic potential of targeting Skp2 for human cancer treatment.

  1. Exome sequencing of senescence-accelerated mice (SAM) reveals deleterious mutations in degenerative disease-causing genes

    OpenAIRE

    2013-01-01

    Background Senescence-accelerated mice (SAM) are a series of mouse strains originally derived from unexpected crosses between AKR/J and unknown mice, from which phenotypically distinct senescence-prone (SAMP) and -resistant (SAMR) inbred strains were subsequently established. Although SAMP strains have been widely used for aging research focusing on their short life spans and various age-related phenotypes, such as immune dysfunction, osteoporosis, and brain atrophy, the responsible gene muta...

  2. Chronic stress impairs learning and hippocampal cell proliferation in senescence-accelerated prone mice.

    Science.gov (United States)

    Yan, Weihong; Zhang, Ting; Jia, Weiping; Sun, Xiaojiang; Liu, Xueyuan

    2011-02-25

    Chronic stress can induce cognitive impairment. It is unclear whether a higher susceptibility to chronic stress is associated with the progression of pathological brain aging. Senescence-accelerated prone mouse 8 (SAMP8) is a naturally occurring animal model of accelerated brain aging. Senescence-accelerated resistant mouse 1 (SAMR1) is usually used as the normal control. In this study, we examined the effects of chronic restraint stress (CRS) on learning in the Y-maze, hippocampal cell proliferation, and the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus of 4-month-old SAMP8 and SAMR1. The results showed that exposure to CRS impaired learning and hippocampal cell proliferation in SAMP8 and SAMR1 but to a much greater extent in SAMP8. Furthermore, CRS significantly decreased the expression of BDNF protein and mRNA in the hippocampus of SAMP8 and SAMR1. These data indicated that SAMP8 is more sensitive to the deleterious effects of CRS on learning than SAMR1. A greater decrease in hippocampal cell proliferation caused by chronic stress may be part of the underlying mechanism for the more severe learning deficit observed in SAMP8. In addition, our findings suggested a role of BDNF in the stress-induced impairment of learning and hippocampal cell proliferation in both strains.

  3. Growth under elevated atmospheric CO(2) concentration accelerates leaf senescence in sunflower (Helianthus annuus L.) plants.

    Science.gov (United States)

    de la Mata, Lourdes; Cabello, Purificación; de la Haba, Purificación; Agüera, Eloísa

    2012-09-15

    Some morphogenetic and metabolic processes were sensitive to a high atmospheric CO(2) concentration during sunflower primary leaf ontogeny. Young leaves of sunflower plants growing under elevated CO(2) concentration exhibited increased growth, as reflected by the high specific leaf mass referred to as dry weight in young leaves (16 days). The content of photosynthetic pigments decreased with leaf development, especially in plants grown under elevated CO(2) concentrations, suggesting that high CO(2) accelerates chlorophyll degradation, and also possibly leaf senescence. Elevated CO(2) concentration increased the oxidative stress in sunflower plants by increasing H(2)O(2) levels and decreasing activity of antioxidant enzymes such as catalase and ascorbate peroxidase. The loss of plant defenses probably increases the concentration of reactive oxygen species in the chloroplast, decreasing the photosynthetic pigment content as a result. Elevated CO(2) concentration was found to boost photosynthetic CO(2) fixation, especially in young leaves. High CO(2) also increased the starch and soluble sugar contents (glucose and fructose) and the C/N ratio during sunflower primary leaf development. At the beginning of senescence, we observed a strong increase in the hexoses to sucrose ratio that was especially marked at high CO(2) concentration. These results indicate that elevated CO(2) concentration could promote leaf senescence in sunflower plants by affecting the soluble sugar levels, the C/N ratio and the oxidative status during leaf ontogeny. It is likely that systemic signals produced in plants grown with elevated CO(2), lead to early senescence and a higher oxidation state of the cells of these plant leaves.

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

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    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.

  5. Changes and significance of SIRT3 expression in cellular senescence induced by high glucose

    Directory of Open Access Journals (Sweden)

    Bin ZHANG

    2011-09-01

    Full Text Available Objective To investigate the role of the silent information regulator 3(SIRT3 in the decrepitude process of human diploid fibroblasts(WI-38 induced by high glucose.Methods The WI-38 cells [population doublings(PDs,20-32] were cultured in media containing different concentrations of glucose as follows: low glucose(3.34mmol/L,LG,normal glucose(5.56mmol/L,NG,and high glucose(25mmol/L,HG.The protein expression levels of p21,p27,catalase,MnSOD,and SIRT3 were evaluated through Western blot.The double-label immunofluorescence assay was used to detect the location and expression of SIRT3,MnSOD,and senescence-associated heterochromatin foci(SAHF in the WI-38 cells.The ROS level was determined with fluorescent probe.Results The results from the Western blot showed that the protein expression of SIRT3,catalase,and MnSOD decreased significantly in the HG group compared with the LG and NG groups(P 0.05.SIRT3 and MnSOD were highly expressed in the cytoplasm.The ROS levels in the HG group were elevated compared with those in the LG and NG groups.Conclusion SIRT3 may play an important role in cellular senescence induced by high glucose in human diploid fibroblasts.

  6. Biology of cancer and aging: a complex association with cellular senescence.

    Science.gov (United States)

    Falandry, Claire; Bonnefoy, Marc; Freyer, Gilles; Gilson, Eric

    2014-08-20

    Over the last 50 years, major improvements have been made in our understanding of the driving forces, both parallel and opposing, that lead to aging and cancer. Many theories on aging first proposed in the 1950s, including those associated with telomere biology, senescence, and adult stem-cell regulation, have since gained support from cumulative experimental evidence. These views suggest that the accumulation of mutations might be a common driver of both aging and cancer. Moreover, some tumor suppressor pathways lead to aging in line with the theory of antagonist pleiotropy. According to the evolutionary-selected disposable soma theory, aging should affect primarily somatic cells. At the cellular level, both intrinsic and extrinsic pathways regulate aging and senescence. However, increasing lines of evidence support the hypothesis that these driving forces might be regulated by evolutionary-conserved pathways that modulate energy balance. According to the hyperfunction theory, aging is a quasi-program favoring both age-related diseases and cancer that could be inhibited by the regulation of longevity pathways. This review summarizes these hypotheses, as well as the experimental data that have accumulated over the last 60 years linking aging and cancer.

  7. CD9 monoclonal antibody-conjugated PEGylated liposomes for targeted delivery of rapamycin in the treatment of cellular senescence

    Science.gov (United States)

    Thuy Nguyen, Hanh; Thapa, Raj Kumar; Shin, Beom Soo; Jeong, Jee-Heon; Kim, Jae-Ryong; Yong, Chul Soon; Kim, Jong Oh

    2017-03-01

    Premature cellular senescence refers to the state of irreversible cell cycle arrest due to DNA damage or other stresses. In this study, CD9 monoclonal antibody (CD9mAb) was successfully conjugated to the surface of PEGylated liposomes for targeted delivery of rapamycin (LR-CD9mAb) to overcome senescence of CD9 receptor-overexpressing cells. LR-CD9mAb has a small particle size (143.3 ± 2.4 nm), narrow size distribution (polydispersity index: 0.220 ± 0.036), and negative zeta potential (‑14.6 ± 1.2 mV). The uptake of CD9-targeted liposomes by premature senescent human dermal fibroblasts (HDFs) was higher than that by young HDFs, as displayed by confocal microscopic images. The senescence might not be reversed by treatment with rapamycin; however, the drug promoted cell proliferation and reduced the number of cells that expressed the senescence-associated-β-galactosidase (SA-β-gal). These effects were further confirmed by cell viability, cell cycle, and Western blotting analyses. Moreover, CD9-targeted liposomes showed better anti-senescence activity, in comparison with free rapamycin or the conventional liposomal formulation, suggesting the potential application of this system in further in vivo studies.

  8. Influence of Electroacupuncture on COX Activity of Hippocampal Mitochondria in Senescence- accelerated Mouse Prone 8 Mice

    Institute of Scientific and Technical Information of China (English)

    Peng Jing; Zeng Fang; He Yu-heng; Tang Yong; Yin Hai-yan; Yu Shu-guang

    2014-01-01

    Objective: To observe the effect of electroacupuncture (EA) on cytochrome c oxidase (COX)activity of hippocampal mitochondria in senescence-accelerated mouse prone 8 (SAMP8) mice, and to explore the EA mechanism on Alzheimer disease (AD) in improving energy metabolic disorder. Methods: Twelve SAMP8 mice were randomly divided into a model group and an EA group, with six in each group. Six senescence-accelerated mouse resistance 1 (SAMR1) mice were prepared as blank group. Mice in the EA group received EA on Baihui (GV 20) and Yongquan (KI 1), once a day for 7 d as a course, altogether 3 courses with one day intervalbetween two courses. Mice in the model group and the blank group were manipulated and fixed as those in the EA group. After interventions, Morris water maze was employed to test spatial learning and memory ability to evaluate EA effect; spectrophotometry was used to detect the activity of hippocampal mitochondria COX. Results: Compared with the blank group, mean escape latenciesof the EA group and model group were prolonged significantly in Morris water maze tests (P Conclusion: It’s plausible that EA improves AD learning and memory ability by increasing mitochondria COX activity, protecting the structure and function, and improving energy metabolism.

  9. Relief of delayed oxidative stress by ascorbic acid can suppress radiation-induced cellular senescence in mammalian fibroblast cells.

    Science.gov (United States)

    Kobashigawa, Shinko; Kashino, Genro; Mori, Hiromu; Watanabe, Masami

    2015-03-01

    Ionizing radiation-induced cellular senescence is thought to be caused by nuclear DNA damage that cannot be repaired. However, here we found that radiation induces delayed increase of intracellular oxidative stress after irradiation. We investigated whether the relief of delayed oxidative stress by ascorbic acid would suppress the radiation-induced cellular senescence in Syrian golden hamster embryo (SHE) cells. We observed that the level of oxidative stress was drastically increased soon after irradiation, then declined to the level in non-irradiated cells, and increased again with a peak on day 3 after irradiation. We found that the inductions of cellular senescence after X-irradiation were reduced along with suppression of the delayed induction of oxidative stress by treatment with ascorbic acid, but not when oxidative stress occurred immediately after irradiation. Moreover, treatment of ascorbic acid inhibited p53 accumulation at 3 days after irradiation. Our data suggested a delayed increase of intracellular oxidative stress levels plays an important role in the process of radiation-induced cellular senescence by p53 accumulation.

  10. Icariin upregulates phosphorylated cyclic adenosine monophosphate response element binding protein levels in the hippocampus of the senescence- accelerated mouse

    Institute of Scientific and Technical Information of China (English)

    Zhanwei Zhang; Ting Zhang; Keli Dong

    2012-01-01

    At 8 weeks after intragastric administration of icariin to senescence-accelerated mice (P8 strain), Morris water maze results showed that escape latency was shortened, and the number of platform crossings was increased. Immunohistochemical staining and western blot assay detected signifi-cantly increased levels of cyclic adenosine monophosphate response element binding protein. These results suggest that icariin upregulates phosphorylated cyclic adenosine monophosphate response element binding protein levels and improves learning and memory functions in hippo-campus of the senescence-accelerated mouse.

  11. Carbamylated low-density lipoprotein induces oxidative stress and accelerated senescence in human endothelial progenitor cells.

    Science.gov (United States)

    Carracedo, Julia; Merino, Ana; Briceño, Carolina; Soriano, Sagrario; Buendía, Paula; Calleros, Laura; Rodriguez, Mariano; Martín-Malo, Alejandro; Aljama, Pedro; Ramírez, Rafael

    2011-04-01

    Carbamylated low-density lipoprotein (cLDL) plays a role in atherosclerosis. In this study we evaluate the effect of uremia on LDL carbamylation and the effect of cLDL and oxidized LDL (oxLDL; 200 μg/ml) on number, function, and genomic stability of endothelial progenitor cells (EPCs) obtained from healthy volunteers. cLDL was generated after incubation of native LDL (nLDL) with uremic serum from patients with chronic kidney disease (CKD) stages 2-4. Oxidative stress was measured by flow cytometry and fluorescent microscopy, mitochondrial depolarization by flow cytometry, senescence by β-galactosidase activity and telomere length, and DNA damage by phosphorylated histone H2AX (γH2AX). The percentage of cLDL by uremic serum was related to the severity of CKD. Compared with nLDL, cLDL induced an increase in oxidative stress (62±5 vs. 8±3%, P<0.001) and cells with mitochondrial depolarization (73±7 vs. 9±5%, P<0.001), and a decrease in EPC proliferation and angiogenesis. cLDL also induced accelerated senescence (73±16 vs. 12±9%, P<0.001), which was associated with a decrease in the expression of γH2AX (62±9 vs. 5±3%, P<0.001). The degree of injury induced by cLDL was comparable to that observed with oxLDL. This study supports the hypothesis that cLDL triggers genomic damage in EPCs, resulting in premature senescence. We can, therefore, hypothesize that EPCs injury by cLDL contributes to an increase in atherosclerotic disease in CKD.

  12. Autophagy: an adaptive physiological countermeasure to cellular senescence and ischaemia/reperfusion-associated cardiac arrhythmias.

    Science.gov (United States)

    Lekli, Istvan; Haines, David Donald; Balla, Gyorgy; Tosaki, Arpad

    2017-06-01

    Oxidative stress placed on tissues that involved in pathogenesis of a disease activates compensatory metabolic changes, such as DNA damage repair that in turn causes intracellular accumulation of detritus and 'proteotoxic stress', leading to emergence of 'senescent' cellular phenotypes, which express high levels of inflammatory mediators, resulting in degradation of tissue function. Proteotoxic stress resulting from hyperactive inflammation following reperfusion of ischaemic tissue causes accumulation of proteinaceous debris in cells of the heart in ways that cause potentially fatal arrhythmias, in particular ventricular fibrillation (VF). An adaptive response to VF is occurrence of autophagy, an intracellular bulk degradation of damaged macromolecules and organelles that may restore cellular and tissue homoeostasis, improving chances for recovery. Nevertheless, depending on the type and intensity of stressors and inflammatory responses, autophagy may become pathological, resulting in excessive cell death. The present review examines the multilayered defences that cells have evolved to reduce proteotoxic stress by degradation of potentially toxic material beginning with endoplasmic reticulum-associated degradation, and the unfolded protein response, which are mechanisms for removal from the endoplasmic reticulum of misfolded proteins, and then progressing through the stages of autophagy, including descriptions of autophagosomes and related vesicular structures which process material for degradation and autophagy-associated proteins including Beclin-1 and regulatory complexes. The physiological roles of each mode of proteotoxic defence will be examined along with consideration of how emerging understanding of autophagy, along with a newly discovered regulatory cell type called telocytes, may be used to augment existing strategies for the prevention and management of cardiovascular disease. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by

  13. P21-PARP-1 Pathway Is Involved in Cigarette Smoke-Induced Lung DNA Damage and Cellular Senescence

    Science.gov (United States)

    Yao, Hongwei; Sundar, Isaac K.; Gorbunova, Vera; Rahman, Irfan

    2013-01-01

    Persistent DNA damage triggers cellular senescence, which may play an important role in the pathogenesis of cigarette smoke (CS)-induced lung diseases. Both p21CDKN1A (p21) and poly(ADP-ribose) polymerase-1 (PARP-1) are involved in DNA damage and repair. However, the role of p21-PARP-1 axis in regulating CS-induced lung DNA damage and cellular senescence remains unknown. We hypothesized that CS causes DNA damage and cellular senescence through a p21-PARP-1 axis. To test this hypothesis, we determined the levels of γH2AX (a marker for DNA double-strand breaks) as well as non-homologous end joining proteins (Ku70 and Ku80) in lungs of mice exposed to CS. We found that the level of γH2AX was increased, whereas the level of Ku70 was reduced in lungs of CS-exposed mice. Furthermore, p21 deletion reduced the level of γH2AX, but augmented the levels of Ku70, Ku80, and PAR in lungs by CS. Administration of PARP-1 inhibitor 3-aminobenzamide increased CS-induced DNA damage, but lowered the levels of Ku70 and Ku80, in lungs of p21 knockout mice. Moreover, 3-aminobenzamide increased senescence-associated β-galactosidase activity, but decreased the expression of proliferating cell nuclear antigen in mouse lungs in response to CS. Interestingly, 3-aminobenzamide treatment had no effect on neutrophil influx into bronchoalveolar lavage fluid by CS. These results demonstrate that the p21-PARP-1 pathway is involved in CS-induced DNA damage and cellular senescence. PMID:24244594

  14. P21-PARP-1 pathway is involved in cigarette smoke-induced lung DNA damage and cellular senescence.

    Directory of Open Access Journals (Sweden)

    Hongwei Yao

    Full Text Available Persistent DNA damage triggers cellular senescence, which may play an important role in the pathogenesis of cigarette smoke (CS-induced lung diseases. Both p21(CDKN1A (p21 and poly(ADP-ribose polymerase-1 (PARP-1 are involved in DNA damage and repair. However, the role of p21-PARP-1 axis in regulating CS-induced lung DNA damage and cellular senescence remains unknown. We hypothesized that CS causes DNA damage and cellular senescence through a p21-PARP-1 axis. To test this hypothesis, we determined the levels of γH2AX (a marker for DNA double-strand breaks as well as non-homologous end joining proteins (Ku70 and Ku80 in lungs of mice exposed to CS. We found that the level of γH2AX was increased, whereas the level of Ku70 was reduced in lungs of CS-exposed mice. Furthermore, p21 deletion reduced the level of γH2AX, but augmented the levels of Ku70, Ku80, and PAR in lungs by CS. Administration of PARP-1 inhibitor 3-aminobenzamide increased CS-induced DNA damage, but lowered the levels of Ku70 and Ku80, in lungs of p21 knockout mice. Moreover, 3-aminobenzamide increased senescence-associated β-galactosidase activity, but decreased the expression of proliferating cell nuclear antigen in mouse lungs in response to CS. Interestingly, 3-aminobenzamide treatment had no effect on neutrophil influx into bronchoalveolar lavage fluid by CS. These results demonstrate that the p21-PARP-1 pathway is involved in CS-induced DNA damage and cellular senescence.

  15. Protective Effect of Garlic on Cellular Senescence in UVB-Exposed HaCaT Human Keratinocytes.

    Science.gov (United States)

    Kim, Hye Kyung

    2016-07-29

    Ultraviolet (UV) irradiation generates reactive oxygen species (ROS) in the cells, which induces the cellular senescence and photoaging. The present study investigated the protective effects of garlic on photo-damage and cellular senescence in UVB-exposed human keratinocytes, HaCaT cells. An in vitro cell free system was used to examine the scavenging activity of 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals and nitric oxide (NO). The effect of garlic extract on ROS formation, MMP-1 protein and mRNA expressions, cytokines such as interleukin (IL)-1β and IL-6, senescence associated-β-galactosidase (SA-β-gal) activity, and silent information regulator T1 (SIRT1) activity were determined in UVB-irradiated HaCaT cells. Garlic exhibited strong DPPH radical and NO scavenging activity in cell free system exhibiting IC50 values of 2.50 mg/mL and 4.38 mg/mL, respectively. Garlic pretreatment attenuated the production of UVB-induced intracellular ROS. MMP-1 level, which has been known to be induced by ROS, was dramatically elevated by UVB irradiation, and UVB-induced MMP-1 mRNA and protein expressions were significantly reduced by garlic treatment (50 µg/mL) comparable to those of UV-unexposed control cells. UV-induced pro-inflammatory cytokine productions (IL-6 and IL-1β) were significantly inhibited by pretreatment with garlic in a dose-dependent manner. SA-β-gal activity, a classical biomarker of cellular senescence, and SIRT1 activity, which has attracted attention as an anti-aging factor in recent years, were ameliorated by garlic treatment in UV-irradiated HaCaT cells. The present study provides the first evidence of garlic inhibiting UVB-induced photoaging as a result of augmentation of cellular senescence in HaCaT human keratinocytes.

  16. Cellular senescence induced by prolonged subculture adversely affects glutamate uptake in C6 lineage.

    Science.gov (United States)

    Pereira, Mery Stéfani Leivas; Zenki, Kamila; Cavalheiro, Marcela Mendonça; Thomé, Chairini Cássia; Filippi-Chiela, Eduardo Cremonese; Lenz, Guido; de Souza, Diogo Onofre Gomes; de Oliveira, Diogo Losch

    2014-05-01

    Several researchers have recently used C6 cells to evaluate functional properties of high-affinity glutamate transporters. However, it has been demonstrated that this lineage suffers several morphological and biochemical alterations according to the number of passages in culture. Currently, there are no reports showing whether functional properties of high-affinity glutamate transporters comply with these sub culturing-dependent modifications. The present study aimed to compare the functional properties of high-affinity glutamate transporters expressed in early (EPC6) and late (LPC6) passage C6 cells through a detailed pharmacological and biochemical characterization. Between 60-180 min of L-[(3)H]glu incubation, LPC6 presented an intracellular [(3)H] 55% lower than EPC6. Both cultures showed a time-dependent increase of intracellular [(3)H] reaching maximal levels at 120 min. Cultures incubated with D-[(3)H]asp showed a time-dependent increase of [(3)H] until 180 min. Moreover, LPC6 have a D-[(3)H]asp-derived intracellular [(3)H] 30-45% lower than EPC6 until 120 min. Only EAAT3 was immunodetected in cultures and its total content was equal between them. PMA-stimulated EAAT3 trafficking to membrane increased 50% of L-[(3)H]glu-derived intracellular [(3)H] in EPC6 and had no effect in LPC6. LPC6 displayed characteristics that resemble senescence, such as high β-Gal staining, cell enlargement and increase of large and regular nuclei. Our results demonstrated that LPC6 exhibited glutamate uptake impairment, which may have occurred due to its inability to mobilize EAAT3 to cell membrane. This profile might be related to senescent process observed in this culture. Our results suggest that LPC6 cells are an inappropriate glial cellular model to investigate the functional properties of high-affinity glutamate transporters.

  17. Roles of TP53 in determining therapeutic sensitivity, growth, cellular senescence, invasion and metastasis.

    Science.gov (United States)

    McCubrey, James A; Lertpiriyapong, Kvin; Fitzgerald, Timothy L; Martelli, Alberto M; Cocco, Lucio; Rakus, Dariusz; Gizak, Agnieszka; Libra, Massimo; Cervello, Melchiorre; Montalto, Guiseppe; Yang, Li V; Abrams, Stephen L; Steelman, Linda S

    2017-01-01

    TP53 is a critical tumor suppressor gene that regulates cell cycle progression, apoptosis, cellular senescence and many other properties critical for control of normal cellular growth and death. Due to the pleiotropic effects that TP53 has on gene expression and cellular physiology, mutations at this tumor suppressor gene result in diverse physiological effects. T53 mutations are frequently detected in numerous cancers. The expression of TP53 can be induced by various agents used to treat cancer patients such as chemotherapeutic drugs and ionizing radiation. Radiation will induce Ataxia telangiectasia mutated (ATM) and other kinases that results in the phosphorylation and activation of TP53. TP53 is also negatively regulated by other mechanisms, such as ubiquitination by ligases such as MDM2. While TP53 has been documented to control the expression of many "classical" genes (e.g., p21(Cip-1), PUMA, Bax) by transcriptional mechanisms for quite some time, more recently TP53 has been shown to regulate microRNA (miR) gene expression. Different miRs can promote oncogenesis (oncomiR) whereas others act to inhibit tumor progression (tumor suppressor miRs). Targeted therapies to stabilize TP53 have been developed by various approaches, MDM2/MDM4 inhibitors have been developed to stabilize TP53 in TP53-wild type (WT) tumors. In addition, small molecules have been isolated that will reactivate certain mutant TP53s. Both of these types of inhibitors are in clinical trials. Understanding the actions of TP53 may yield novel approaches to suppress cancer, aging and other health problems.

  18. Overexpression of HDAC1 induces cellular senescence by Sp1/PP2A/pRb pathway

    Energy Technology Data Exchange (ETDEWEB)

    Chuang, Jian-Ying [Department of Pharmacology, National Cheng-Kung University, Tainan 701, Taiwan (China); Hung, Jan-Jong, E-mail: petehung@mail.ncku.edu.tw [Department of Pharmacology, National Cheng-Kung University, Tainan 701, Taiwan (China); Institute of Bioinformatics and Biosignal Transduction, National Cheng-Kung University, Tainan 701, Taiwan (China)

    2011-04-15

    Highlights: {yields} Overexpression of HDAC1 induces Sp1 deacetylation and raises Sp1/p300 complex formation to bind to PP2Ac promoter. {yields} Overexpression of HDAC1 strongly inhibits the phosphorylation of pRb through up-regulation of PP2A. {yields} Overexpressed HDAC1 restrains cell proliferaction and induces cell senescence though a novel Sp1/PP2A/pRb pathway. -- Abstract: Senescence is associated with decreased activities of DNA replication, protein synthesis, and cellular division, which can result in deterioration of cellular functions. Herein, we report that the growth and division of tumor cells were significantly repressed by overexpression of histone deacetylase (HDAC) 1 with the Tet-off induced system or transient transfection. In addition, HDAC1 overexpression led to senescence through both an accumulation of hypophosphorylated active retinoblastoma protein (pRb) and an increase in the protein level of protein phosphatase 2A catalytic subunit (PP2Ac). HDAC1 overexpression also increased the level of Sp1 deacetylation and elevated the interaction between Sp1 and p300, and subsequently that Sp1/p300 complex bound to the promoter of PP2Ac, thus leading to induction of PP2Ac expression. Similar results were obtained in the HDAC1-Tet-off stable clone. Taken together, these results indicate that HDAC1 overexpression restrained cell proliferation and induced premature senescence in cervical cancer cells through a novel Sp1/PP2A/pRb pathway.

  19. Cellular senescence regulated by SWI/SNF complex subunits through p53/p21 and p16/pRB pathway.

    Science.gov (United States)

    He, Ling; Chen, Ying; Feng, Jianguo; Sun, Weichao; Li, Shun; Ou, Mengting; Tang, Liling

    2017-09-01

    SWI/SNF complex is an evolutionarily well-conserved chromatin-remodeling complex, which is implicated in the nucleosomes removing or sliding, impacting on the DNA repair, replication and genes expression regulation. The SWI/SNF complex consists up to 12 protein subunits. The catalytic subunits are BRG1 or BRM, which are exclusive ATPase subunits. BRG1 has been reported to play an important role in cellular senescence. However, The function of non-catalytic subunits involved in cellular senescence is rarely investigated. Therefore, we focused on the senescence regulation roles of SWI/SNF non-catalytic subunits in cellular senescent model induced by H2O2. H2O2 treatment was used to induce cellular senescence models in vitro. Screening the candidate subunits involved in this process by comparing the expression levels of SWI/SNF subunits with/without H2O2 treatment. Over-expression and knockdown the candidate subunits were utilized to investigate the functions and mechanism of the subunits involved in senescence regulation. The expressions of BAF57, BAF60a and SNF5 were changed significantly after H2O2 treatment. Overexpression of the three subunits separately induced cell growth arrest in both HaCaT and GLL19 cells, while knockdown of the subunits separately eased the senescence induced by H2O2 treatment. Results further showed that BAF57, BAF60a and SNF5 regulated cellular senescence via both p53/p21 and p16/pRB pathways, and the three subunits all had a directly interaction with p53. These results indicated that BAF57, BAF60a and SNF5 might act as novel pro-senescence factors in both normal and tumor human skin cells. Therefore, inhibiting expression of the three factors might delay the cellular senescence process. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Synthetic Resveratrol Analogue, 3,3',4,4',5,5'-Hexahydroxy-trans-Stilbene, Accelerates Senescence in Peritoneal Mesothelium and Promotes Senescence-Dependent Growth of Gastrointestinal Cancers

    Directory of Open Access Journals (Sweden)

    Krzysztof Książek

    2013-11-01

    Full Text Available 3,3',4,4',5,5'-Hexahydroxy-trans-stilbene (M8 is a synthetic resveratrol derivative, advertised as a candidate drug highly effective against numerous malignancies. Because multiple tumors prone to M8 frequently metastasize into the peritoneal cavity, this study was aimed at establishing the effect of M8 on the growth and senescence of human peritoneal mesothelial cells (HPMCs, the largest cell population within the peritoneum, actively involved in the intraperitoneal spread of cancer. The study showed that M8, used at the highest non-toxic dose of 10 μM, impairs proliferation and accelerates senescence in cultured HPMCs via an oxidative stress-dependent mechanism. At the same time, soluble factors released to the environment by HPMCs that senesced prematurely in response to M8 promoted growth of colorectal and pancreatic carcinomas in vitro. These findings indicate that M8 may indirectly—through the modification of normal (mesothelial cells phenotype—facilitate an expansion of cancer cells, which challenges the postulated value of this stilbene in chemotherapy.

  1. Cloning, expression and cellular localization of Daphnia pulex senescence-associated protein, DpSAP.

    Science.gov (United States)

    Liu, Ajing; Kong, Ling; Zhang, Mingqing; Wu, Donglei; Wang, Danli; Zhao, Yunlong

    2014-01-25

    Daphnia (water fleas) are small crustaceans that undergo an unusual switch from asexual to sexual reproduction that is dependent on environmental conditions. In this study, a senescence-associated protein (SAP) from the common freshwater species Daphnia pulex was cloned using primers based on homologous sequences and rapid amplification of cDNA ends (RACE). Real-time PCR was employed to quantify the expression of D. pulex SAP (DpSAP) in individual organisms. The role of DpSAP in the reproductive transformation was further investigated in both parthenogenetic and sexual females by using digoxin-labeled SAP RNA probes and RNA whole-mount in situ hybridization. DpSAP was more highly expressed in sexual females, indicating a role in growth and reproduction. Cellular localization studies using RNA whole-mount in situ hybridization showed specific expression in the second tentacle joints. These expression patterns suggest an important role for DpSAP in the reproductive transformation of D. pulex. Copyright © 2013 Elsevier B.V. All rights reserved.

  2. Happily (n)ever after: Aging in the context of oxidative stress, proteostasis loss and cellular senescence.

    Science.gov (United States)

    Höhn, Annika; Weber, Daniela; Jung, Tobias; Ott, Christiane; Hugo, Martin; Kochlik, Bastian; Kehm, Richard; König, Jeannette; Grune, Tilman; Castro, José Pedro

    2017-04-01

    Aging is a complex phenomenon and its impact is becoming more relevant due to the rising life expectancy and because aging itself is the basis for the development of age-related diseases such as cancer, neurodegenerative diseases and type 2 diabetes. Recent years of scientific research have brought up different theories that attempt to explain the aging process. So far, there is no single theory that fully explains all facets of aging. The damage accumulation theory is one of the most accepted theories due to the large body of evidence found over the years. Damage accumulation is thought to be driven, among others, by oxidative stress. This condition results in an excess attack of oxidants on biomolecules, which lead to damage accumulation over time and contribute to the functional involution of cells, tissues and organisms. If oxidative stress persists, cellular senescence is a likely outcome and an important hallmark of aging. Therefore, it becomes crucial to understand how senescent cells function and how they contribute to the aging process. This review will cover cellular senescence features related to the protein pool such as morphological and molecular hallmarks, how oxidative stress promotes protein modifications, how senescent cells cope with them by proteostasis mechanisms, including antioxidant enzymes and proteolytic systems. We will also highlight the nutritional status of senescent cells and aged organisms (including human clinical studies) by exploring trace elements and micronutrients and on their importance to develop strategies that might increase both, life and health span and postpone aging onset. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  3. IFI16, an amplifier of DNA-damage response: Role in cellular senescence and aging-associated inflammatory diseases.

    Science.gov (United States)

    Choubey, Divaker; Panchanathan, Ravichandran

    2016-07-01

    DNA-damage induces a DNA-damage response (DDR) in mammalian cells. The response, depending upon the cell-type and the extent of DNA-damage, ultimately results in cell death or cellular senescence. DDR-induced signaling in cells activates the ATM-p53 and ATM-IKKα/β-interferon (IFN)-β signaling pathways, thus leading to an induction of the p53 and IFN-inducible IFI16 gene. Further, upon DNA-damage, DNA accumulates in the cytoplasm, thereby inducing the IFI16 protein and STING-dependent IFN-β production and activation of the IFI16 inflammasome, resulting in the production of proinflammatory cytokines (e.g., IL-1β and IL-18). Increased expression of IFI16 protein in a variety of cell-types promotes cellular senescence. However, reduced expression of IFI16 in cells promotes cell proliferation. Because expression of the IFI16 gene is induced by activation of DNA-damage response in cells and increased levels of IFI16 protein in cells potentiate the p53-mediated transcriptional activation of genes and p53 and pRb-mediated cell cycle arrest, we discuss how an improved understanding of the role of IFI16 protein in cellular senescence and associated inflammatory secretory phenotype is likely to identify the molecular mechanisms that contribute to the development of aging-associated human inflammatory diseases and a failure to cancer therapy.

  4. Transfer of accelerated presbycusis by transplantation of bone marrow cells from senescence-accelerated mice.

    Science.gov (United States)

    Baba, Susumu; Iwai, Hiroshi; Inaba, Muneo; Kawamoto, Kohei; Omae, Mariko; Yamashita, Toshio; Ikehara, Susumu

    2006-11-20

    Until now, there has been no effective therapy for chronic sensorineural hearing impairment. This study investigated the role of bone marrow cells (BMCs) in cochlear dysfunction. BALB/c mice (2 months of age), a non-presbycusis-prone mouse strain, were lethally irradiated and then transplanted with BMCs from SAMP1 mice (2 months of age), a presbycusis-prone mouse strain. Acceleration of age-related hearing loss, early degeneration of spiral ganglion cells (SGCs) and impairment of immune function were observed in the recipient mice as well as in the SAMP1 mice. However, no spiral ganglion cells of donor (SAMP1) origin were detected in the recipient mice. These results indicated that accelerated presbycusis, cochlear pathology, and immune dysfunction of SAMP1 mice can be transferred to BALB/c recipient mice using allogeneic bone marrow transplantation (BMT). However, although the BMCs themselves cannot differentiate into the spiral ganglion cells (SGCs), they indirectly cause the degeneration of the SGCs. Further studies into the relationship between the inner ear cells and BMCs are required.

  5. Changes in the level and distribution of Ku proteins during cellular senescence

    Science.gov (United States)

    Seluanov, Andrei; Danek, Jacquelynn; Hause, Nola; Gorbunova, Vera

    2009-01-01

    Aging is associated with accumulation of genomic rearrangements consistent with aberrant repair of DNA breaks. We have shown previously that DNA repair by nonhomologous end joining (NHEJ) becomes less efficient and more error-prone in senescent cells. Here we show that the levels of Ku70 and Ku80 drop approximately two fold in replicatively senescent cells. Intracellular distribution of Ku also changes. In the young cells roughly half of Ku is located in the nucleus and half in the cytoplasm. In senescent cells the nuclear levels of Ku do not change, while the cytoplasmic Ku fraction disappears. Upon treatment with gamma-irradiation, in the young cells cytoplasmic Ku moved into the nuclear and membrane fractions, while no change in the Ku distribution occurred in senescent cells. Upon treatment with UVC Ku moved out of the nucleus in the young cells, while most Ku remained nuclear in senescent cells. This suggests that the nuclear Ku in senescent cells is unable to respond to DNA damage. We hypothesize that overall decline in Ku levels, changes in Ku intracellular distribution, and the loss of appropriate response of Ku to DNA damage in senescent cells contribute to the decline of NHEJ and to age-related genomic instability. PMID:17686666

  6. Preterm labor in the absence of acute histologic chorioamnionitis is characterized by cellular senescence of the chorioamniotic membranes.

    Science.gov (United States)

    Gomez-Lopez, Nardhy; Romero, Roberto; Plazyo, Olesya; Schwenkel, George; Garcia-Flores, Valeria; Unkel, Ronald; Xu, Yi; Leng, Yaozhu; Hassan, Sonia S; Panaitescu, Bogdan; Cha, Jeeyeon; Dey, Sudhansu K

    2017-08-25

    Decidual senescence has been considered a mechanism of disease for spontaneous preterm labor in the absence of severe acute inflammation. Yet, signs of cellular senescence have also been observed in the chorioamniotic membranes from women who underwent the physiological process of labor at term. We aimed to investigate whether, in the absence of acute histologic chorioamnionitis, the chorioamniotic membranes from women who underwent spontaneous preterm labor or labor at term exhibit markers of cellular senescence. Chorioamniotic membrane samples were collected from women who underwent spontaneous preterm labor or labor at term. Gestational age-matched nonlabor controls were also included. Senescence-associated genes/proteins were determined using reverse transcription quantitative polymerase chain reaction (n = 7-9 each for array; n = 26-28 each for validation), enzyme-linked immunosorbent assays (n = 7-9 each), immunoblotting (n = 6-7 each), and immunohistochemistry (n = 7-8 each). Senescence-associated β-galactosidase activity (n = 7-11 each) and telomere length (n = 15-22 each) were also evaluated. In the chorioamniotic membranes without acute histologic chorioamnionitis: (1) the expression profile of senescence-associated genes was different between the labor groups (term in labor and preterm in labor) and the nonlabor groups (term no labor and preterm no labor), yet, there were differences between the term in labor and preterm in labor groups; (2) most of the differentially expressed genes among the groups were closely related to the tumor suppressor protein 53 pathway; (3) the expression of TP53 was down-regulated in the term in labor and preterm in labor groups compared to their nonlabor counterparts; (4) the expression of CDKN1A (gene coding for p21) was up-regulated in the term in labor and preterm in labor groups compared to their nonlabor counterparts; (5) the expression of the cyclin kinase CDK2 and cyclins CCNA2, CCNB1, and CCNE1 was down

  7. Reed-Sternberg cells in Hodgkin's lymphoma present features of cellular senescence

    Science.gov (United States)

    Gopas, J; Stern, E; Zurgil, U; Ozer, J; Ben-Ari, A; Shubinsky, G; Braiman, A; Sinay, R; Ezratty, J; Dronov, V; Balachandran, S; Benharroch, D; Livneh, E

    2016-01-01

    Hodgkin's Lymphoma (HL) is one of the most prevailing malignancies in young adults. Reed–Sternberg (RS) cells in HL have distinctive large cell morphology, are characteristic of the disease and their presence is essential for diagnosis. Enlarged cells are one of the hallmarks of senescence, but whether RS cells are senescent has not been previously investigated. Here we show that RS cells have characteristics of senescent cells; RS cells in HL biopsies specifically express the senescence markers and cell cycle inhibitors p21Cip1 and p16INK4a and are negative for the proliferation marker Ki-67, suggesting that these cells have ceased to proliferate. Moreover, the RS-like cells in HL lines, stained specifically for senescence-associated β-galactosidase (SA-β-gal). Oxidative stress promoted senescence in these cells as demonstrated by their staining for p21Cip1, p16INK4a, p53 and γH2AX. Senescent cells produce copious amounts of inflammatory cytokines termed ‘senescence-associated secretory phenotype' (SASP), primarily regulated by Nuclear Factor κB (NF-κB). Indeed, we show that NF-κB activity and NF-κB-dependent cytokines production (e.g., IL-6, TNF-α, GM-CSF) were elevated in RS-like cells. Furthermore, NF-κB inhibitors, JSH-23 and curcumin reduced IL-6 secretion from RS-like cells. Thus, defining RS cells as senescent offers new insights on the origin of the proinflammatory microenvironment in HL. PMID:27831553

  8. Reed-Sternberg cells in Hodgkin's lymphoma present features of cellular senescence.

    Science.gov (United States)

    Gopas, J; Stern, E; Zurgil, U; Ozer, J; Ben-Ari, A; Shubinsky, G; Braiman, A; Sinay, R; Ezratty, J; Dronov, V; Balachandran, S; Benharroch, D; Livneh, E

    2016-11-10

    Hodgkin's Lymphoma (HL) is one of the most prevailing malignancies in young adults. Reed-Sternberg (RS) cells in HL have distinctive large cell morphology, are characteristic of the disease and their presence is essential for diagnosis. Enlarged cells are one of the hallmarks of senescence, but whether RS cells are senescent has not been previously investigated. Here we show that RS cells have characteristics of senescent cells; RS cells in HL biopsies specifically express the senescence markers and cell cycle inhibitors p21(Cip1) and p16(INK4a) and are negative for the proliferation marker Ki-67, suggesting that these cells have ceased to proliferate. Moreover, the RS-like cells in HL lines, stained specifically for senescence-associated β-galactosidase (SA-β-gal). Oxidative stress promoted senescence in these cells as demonstrated by their staining for p21(Cip1), p16(INK4a), p53 and γH2AX. Senescent cells produce copious amounts of inflammatory cytokines termed 'senescence-associated secretory phenotype' (SASP), primarily regulated by Nuclear Factor κB (NF-κB). Indeed, we show that NF-κB activity and NF-κB-dependent cytokines production (e.g., IL-6, TNF-α, GM-CSF) were elevated in RS-like cells. Furthermore, NF-κB inhibitors, JSH-23 and curcumin reduced IL-6 secretion from RS-like cells. Thus, defining RS cells as senescent offers new insights on the origin of the proinflammatory microenvironment in HL.

  9. Nanonized black soybean enhances immune response in senescence-accelerated mice

    Directory of Open Access Journals (Sweden)

    Yin-Ching Chan

    2009-02-01

    Full Text Available Yin-Ching Chan1,6, Chia-Chuan Wu1,6, Kung-Chi Chan1, Yo-Giao Lin1, Jiunn-Wang Liao3, Ming-Fu Wang1, Yung-Ho Chang1, Kee-Ching Jeng2,4,51Departments of Food and Nutrition and 2Applied Mathematics, Providence University, Taichung; 3Graduate Institutes of Veterinary Pathology and 4Medical Technology, National Chung Hsing University, Taichung, Taiwan; 5Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan; 6These authors have contributed equally to this workAbstract: Soy isoflavones may have applications in cancer prevention and anti-inflammation, therefore this study was conducted to investigate the effect of dietary supplementation with black soybean on the immune response in the senescence-accelerated-prone mice (SAMP8 and -resistant mice (SAMPR1, as controls. The mechanism of isoflavones was also investigated. Six-month-old male SAMP8 and SAMR1 mice were divided into the control groups and experimental groups supplemented with nanonized (Nano-soy or microparticled (Micro-soy black soybeans (n = 8/group, respectively for 12 weeks. Human peripheral blood mononuclear cells (PBMC and murine splenocytes were stimulated with mitogens and cytokines were determined by reverse transcriptase-polymerase chain reaction and/or ELISA. The results showed that body weight, food intake, and relative weights of organs did not differ among the SAMP8 control and experimental groups. Isoflavone (daidzin and genistin intake was higher in the Nano-soy group than the Micro-soy group. The lymphoproliferation and production of interleukin-2 (IL-2 and interferon-gamma (IFN-γ in the Nano-soy group had a significantly higher (P<0.05 than those in the control and Micro-soy groups. The Nano-soy supplemented mice reached these cytokine levels similar to SAMR1 mice. This result was consistent with the in vitro data that daidzein (a metabolite of daidzin, at a concentration of 10 μM, increased IL-2, IL-4, and IFN-γ production from

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

    Directory of Open Access Journals (Sweden)

    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.

  11. The telomeric protein AKTIP interacts with A- and B-type lamins and is involved in regulation of cellular senescence

    Science.gov (United States)

    Burla, Romina; Carcuro, Mariateresa; Torre, Mattia La; Fratini, Federica; Crescenzi, Marco; D'Apice, Maria Rosaria; Spitalieri, Paola; Raffa, Grazia Daniela; Astrologo, Letizia; Lattanzi, Giovanna; Cundari, Enrico; Raimondo, Domenico; Biroccio, Annamaria; Gatti, Maurizio

    2016-01-01

    AKTIP is a shelterin-interacting protein required for replication of telomeric DNA. Here, we show that AKTIP biochemically interacts with A- and B-type lamins and affects lamin A, but not lamin C or B, expression. In interphase cells, AKTIP localizes at the nuclear rim and in discrete regions of the nucleoplasm just like lamins. Double immunostaining revealed that AKTIP partially co-localizes with lamin B1 and lamin A/C in interphase cells, and that proper AKTIP localization requires functional lamin A. In mitotic cells, AKTIP is enriched at the spindle poles and at the midbody of late telophase cells similar to lamin B1. AKTIP-depleted cells show senescence-associated markers and recapitulate several aspects of the progeroid phenotype. Collectively, our results indicate that AKTIP is a new player in lamin-related processes, including those that govern nuclear architecture, telomere homeostasis and cellular senescence. PMID:27512140

  12. Immune Dysfunction Associated with Abnormal Bone Marrow-Derived Mesenchymal Stroma Cells in Senescence Accelerated Mice

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    Ming Li

    2016-01-01

    Full Text Available Senescence accelerated mice (SAM are a group of mice that show aging-related diseases, and SAM prone 10 (SAMP10 show spontaneous brain atrophy and defects in learning and memory. Our previous report showed that the thymus and the percentage of T lymphocytes are abnormal in the SAMP10, but it was unclear whether the bone marrow-derived mesenchymal stroma cells (BMMSCs were abnormal, and whether they played an important role in regenerative medicine. We thus compared BMMSCs from SAMP10 and their control, SAM-resistant (SAMR1, in terms of cell cycle, oxidative stress, and the expression of PI3K and mitogen-activated protein kinase (MAPK. Our cell cycle analysis showed that cell cycle arrest occurred in the G0/G1 phase in the SAMP10. We also found increased reactive oxygen stress and decreased PI3K and MAPK on the BMMSCs. These results suggested the BMMSCs were abnormal in SAMP10, and that this might be related to the immune system dysfunction in these mice.

  13. Limited impairments of associative learning in a mouse model of accelerated senescence.

    Science.gov (United States)

    Yang, Yi; Wu, Guang-yan; Li, Xuan; Huang, He; Hu, Bo; Yao, Juan; Wu, Bing; Sui, Jian-feng

    2013-11-15

    Research concerning impairment of associative learning during aging remains limited. The senescence-accelerated mice (SAM) prone/8 (P8) has been proposed as a useful model for the study of aging, and SAM resistant/1(SAMR1) is its control as a normal aging strain. Classical eyeblink conditioning has long been served as a model of associative learning. In order to explore the effects of aging on associative learning in SAM, the present study successively tested three paradigms of eyeblink conditioning in SAMP8 and SAMR1: classical single cue trace eyeblink conditioning (TEC), discriminative trace eyeblink conditioning and reversal learning of TEC. Behavioral performance indicated that SAMP8 could acquire limited single-cue trace eyeblink conditioning task and two-tone discrimination trace eyeblink conditioning with a relative lower acquisition rate compared to SAMR1. Both SAMP8 and SAMR1 failed to acquire reversal learning of discriminative TEC, and SAMP8' startle reflex to tone CS was lower than SAMR1. These results indicated that the impairments of aging on associative learning were incomplete in SAMP8.

  14. Changes of IgE production in senescence-accelerated mice SAMP8.

    Science.gov (United States)

    Oaki, K; Asano, K; Okamoto, K; Yoshida, T; Kuroiwa, Y

    1996-01-01

    The IgE production and proliferation activity of spleen B cells were studied in vivo in 2 approximately 3-month-old (designated as young) and 12 approximately 13-month-old (designated as old) senescence-accelerated mice (SAMP8) employing age-matched AKR mice, the origin of the SAM strain, as controls. After the secondary immunization with 2,4-dinitrophenylovalbumin conjugate (DNP-OVA) with aluminum hydroxide gel (alum) as an adjuvant, the serum IgE levels were significantly reduced in old SAMP8 compared to young SAMP8 mice, but there were no changes in AKR. However, old SAMP8 mice had a proliferative activity of spleen B cells comparable to that found in young SAMP8; proliferative activity was measured by 3H-thymidine incorporation into the spleen after stimulation with water extract from wood chips of coniferous splash pine (pine wood extract) as a mitogen. These data indicate that a decline in IgE production is a characteristic phenomenon of SAMP8 mice and was not due to the functional deficiency of B cells with aging.

  15. A specific group of genes respond to cold dehydration stress in cut Alstroemeria flowers whereas ambient dehydration stress accelerates developmental senescence expression patterns.

    Science.gov (United States)

    Wagstaff, Carol; Bramke, Irene; Breeze, Emily; Thornber, Sarah; Harrison, Elizabeth; Thomas, Brian; Buchanan-Wollaston, Vicky; Stead, Tony; Rogers, Hilary

    2010-06-01

    Petal development and senescence entails a normally irreversible process. It starts with petal expansion and pigment production, and ends with nutrient remobilization and ultimately cell death. In many species this is accompanied by petal abscission. Post-harvest stress is an important factor in limiting petal longevity in cut flowers and accelerates some of the processes of senescence such as petal wilting and abscission. However, some of the effects of moderate stress in young flowers are reversible with appropriate treatments. Transcriptomic studies have shown that distinct gene sets are expressed during petal development and senescence. Despite this, the overlap in gene expression between developmental and stress-induced senescence in petals has not been fully investigated in any species. Here a custom-made cDNA microarray from Alstroemeria petals was used to investigate the overlap in gene expression between developmental changes (bud to first sign of senescence) and typical post-harvest stress treatments. Young flowers were stressed by cold or ambient temperatures without water followed by a recovery and rehydration period. Stressed flowers were still at the bud stage after stress treatments. Microarray analysis showed that ambient dehydration stress accelerates many of the changes in gene expression patterns that would normally occur during developmental senescence. However, a higher proportion of gene expression changes in response to cold stress were specific to this stimulus and not senescence related. The expression of 21 transcription factors was characterized, showing that overlapping sets of regulatory genes are activated during developmental senescence and by different stresses.

  16. The interplay between p16 serine phosphorylation and arginine methylation determines its function in modulating cellular apoptosis and senescence

    OpenAIRE

    Lu, Yang; Ma, Wenlong; Li, Zhongwei; Lu, Jun; Wang, Xiuli

    2017-01-01

    Cyclin-dependent kinase inhibitor p16INK4a (p16) primarily functions as a negative regulator of the retinoblastoma protein (Rb) -E2F pathway, thus plays critical role in cell cycle progression, cellular senescence and apoptosis. In this study, we showed that the methylation of Arg 138 and the phosphorylation of Ser 140 on p16 were critical for the control of cell proliferation and apoptosis. Compared to wild type p16, mutant p16R138K possessed improved function in preventing cell proliferatio...

  17. The Impacts of Cellular Senescence in Elderly Pneumonia and in Age-Related Lung Diseases That Increase the Risk of Respiratory Infections.

    Science.gov (United States)

    Yanagi, Shigehisa; Tsubouchi, Hironobu; Miura, Ayako; Matsuo, Ayako; Matsumoto, Nobuhiro; Nakazato, Masamitsu

    2017-02-25

    Pneumonia generates considerable negative impacts on the elderly. Despite the widespread uses of vaccines and appropriate antibiotics, the morbidity and mortality of elderly pneumonia are significantly higher compared to the counterparts of young populations. The definitive mechanisms of high vulnerability in the elderly against pathogen threats are unclear. Age-associated, chronic low-grade inflammation augments the susceptibility and severity of pneumonia in the elderly. Cellular senescence, one of the hallmarks of aging, has its own characteristics, cell growth arrest and senescence-associated secretory phenotype (SASP). These properties are beneficial if the sequence of senescence-clearance-regeneration is transient in manner. However, persisting senescent cell accumulation and excessive SASP might induce sustained low-grade inflammation and disruption of normal tissue microenvironments in aged tissue. Emerging evidence indicates that cellular senescence is a key component in the pathogenesis of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), which are known to be age-related and increase the risk of pneumonia. In addition to their structural collapses, COPD and IPF might increase the vulnerability to pathogen insults through SASP. Here, we discuss the current advances in understanding of the impacts of cellular senescence in elderly pneumonia and in these chronic lung disorders that heighten the risk of respiratory infections.

  18. Beneficial effects of asiaticoside on cognitive deficits in senescence-accelerated mice.

    Science.gov (United States)

    Lin, Xing; Huang, Renbin; Zhang, Shijun; Wei, Ling; Zhuo, Lang; Wu, Xiaoyan; Tang, Aicun; Huang, Quanfang

    2013-06-01

    The effect of asiaticoside isolated from Hydrocotyle sibthorpioides (AHS) on the promotion of cognition in senescence-accelerated mice (SAMP) was evaluated. Six-month old male SAMP8 mice were orally administered 20, 40 or 80 mg/kg AHS daily for three months. SAMR1 mice were used as a "normal aging" control. The results showed that treatment with AHS significantly improved learning and memory abilities in behavioral tests. AHS-treated mice showed higher antioxidant enzyme activity and lower lipid oxidation in serum compared with untreated SAMP8 mice. Mechanistically, studies showed that AHS markedly reduced the content and deposition of β-amyloid peptide (Aβ) by inhibiting the expression of mRNA for amyloid protein precursor, β-site amyloid cleaving enzyme-1 and cathepsin B and promoting the expression of mRNA for neprilysin and insulin degrading enzyme. In addition, AHS significantly increased the expression of plasticity-related proteins including postsynaptic density-95, phosphor-N-methyl-D-aspartate receptor 1, phospho-calcium-calmodulin dependent kinase II, phospho-protein kinase A Catalyticβ subunit, protein kinase Cγ subunit, phospho-CREB and brain derived neurotrophic factor. Furthermore, AHS increased the levels of acetylcholine (Ach), but decreased cholinesterase (AchE) activity. These results demonstrated that AHS administration may prevent spatial learning and memory decline by scavenging free radicals, up-regulating the activity of antioxidant enzymes, decreasing the level of Aβ, ameliorating dysfunction in synaptic plasticity, and reversing abnormal changes in Ach level and AchE activity. Thus, AHS should be developed as a new drug to prevent age-related cognitive deficits.

  19. RESEARCH PROGRESS OF CELLULAR SENESCENCE AND SENESCENT SECRETARY PHENOTYPE IN INTERVERTEBRAL DISC DEGENERATION%细胞老化及老化表型改变在椎间盘退行性变中的研究进展

    Institute of Scientific and Technical Information of China (English)

    王锋; 郑陈静美; 吴小涛

    2012-01-01

    Objective To summarize the role of cellular senescence and senescent secretary phenotype in the intervertebral disc (IVD) degeneration. Methods Relevant articles that discussed the roles of cellular senescence in the IVD degeneration were extensively reviewed, and retrospective and comprehensive analysis was performed. The senescent phenomenon during IVD degeneration, senescent secretary phenotype of the disc cells, senescent pathways within the IVD microenvironment, as well as the anti-senescent approaches for IVD regeneration were systematically reviewed. Results During aging and degeneration, IVD cells gradually and/or prematurely undergo senescence by activating p53-p21-retinoblastoma (RB) or pl6INK4A-RB senescent pathways. The accumulation of senescent cells not only decreases the self-renewal ability of IVD, but also deteriorates the disc microenvironment by producing more inflammatory cytokines and matrix degrading enzymes. More specific senescent biomarkers are required to fully understand the phenotype change of senescent disc cells during IVD degeneration. Molecular analysis of the senescent disc cells and their intracellular signaling pathways are needed to get a safer and more efficient anti-senescence strategy for IVD regeneration. Conclusion Cellular senescence is an important mechanism by which IVD cells decrease viabil ity and degenerate biological behaviors, which provide a new thinking to understand the pathogenesis of IVD degeneration.%目的 综述细胞老化及老化表型改变在椎间盘退行性变中的研究进展. 方法 查阅椎间盘退行性变领域细胞老化相关的国内外文献并回顾分析,综述椎间盘细胞的老化现象、老化表型改变、老化信号激活与椎间盘退行性变的相互关系,评价抗老化治疗对椎间盘退行性变的修复作用. 结果 随着机体衰老与椎间盘退行性变,椎间盘细胞通过选择性地激活p53-p21-视网膜母细胞瘤(retinoblastoma,RB)或p16INK4A-RB信号

  20. El nucléolo como un regulador del envejecimiento celular The nucleolus as a regulator of cellular senescence

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    María Rosete

    2007-04-01

    Full Text Available El nucléolo, considerado únicamente como el sitio de síntesis de los ribosomas, actualmente representa una estructura nuclear dinámica que participa en la regulación de importantes procesos celulares. Numerosas evidencias han demostrado que el envejecimiento celular es una de las diversas funciones que son controladas por el nucléolo. Las mutaciones en las proteínas de localización nucleolar promueven el envejecimiento prematuro en levaduras y humanos. La carencia de represión en la transcripción de genes que codifican para el ARNr que se encuentran dañados, y las mutaciones en las helicasas del ADN encargadas de minimizar la formación de círculos extra-cromosómicos del ADN que codifica para el ARNr, provocan modificaciones en la estructura del nucléolo e inducen envejecimiento prematuro en levaduras. De igual manera, en los humanos la carencia de las helicasas del ADN localizadas en el nucléolo y que participan en el mantenimiento de la integridad genómica, favorecen el desarrollo de aquellas enfermedades asociadas con el envejecimiento acelerado. Además, la presencia de algunos componentes de la telomerasa en el nucléolo, indica que parte de la biosíntesis de esta enzima se realiza en esta estructura nuclear, sugiriendo una conexión entre el nucléolo y la síntesis de los telómeros en la regulación del envejecimiento celular. Por otra parte, el nucléolo secuestra proteínas para regular su actividad biológica durante el inicio o término de la vida replicativa celular.The nucleolus has been considered originally only as the site for the ribosome synthesis, but now it is well known that it represents a dynamic nuclear structure involved in important cellular processes. Several evidences have demonstrated that the nucleolus regulates the cellular senescence. Specific mutations on the DNAs codifying for nucleolar proteins induced premature senescence from yeast to human. The failure to repress the genes transcription

  1. The interplay between p16 serine phosphorylation and arginine methylation determines its function in modulating cellular apoptosis and senescence.

    Science.gov (United States)

    Lu, Yang; Ma, Wenlong; Li, Zhongwei; Lu, Jun; Wang, Xiuli

    2017-01-25

    Cyclin-dependent kinase inhibitor p16(INK4a) (p16) primarily functions as a negative regulator of the retinoblastoma protein (Rb) -E2F pathway, thus plays critical role in cell cycle progression, cellular senescence and apoptosis. In this study, we showed that the methylation of Arg 138 and the phosphorylation of Ser 140 on p16 were critical for the control of cell proliferation and apoptosis. Compared to wild type p16, mutant p16R138K possessed improved function in preventing cell proliferation and inducing apoptosis, while the Ser 140 mutation (p16S140A) exhibited the opposite alteration. We also demonstrated that H2O2 was able to induce the phosphorylation of p16, which facilitated the interaction between CDK4 (Cyclin-dependent protein kinase) and p16, in 293T (human emborynic kidney) cells. Furthermore, the elevated arginine methylation in p16S140A mutant and increased serine phosphorylation in p16R138K mutant suggest that a antagonizing mechanism coordinating Arg 138 methylation and Ser 140 phosphorylation to regulates p16 function as well as cellular apoptosis and senescence. These findings will therefore contribute to therapeutic treatment for p16-related gene therapy by providing theoretical and experimental evidence.

  2. Fibroblast growth factor-23 induces cellular senescence in human mesenchymal stem cells from skeletal muscle.

    Science.gov (United States)

    Sato, Chisato; Iso, Yoshitaka; Mizukami, Takuya; Otabe, Koji; Sasai, Masahiro; Kurata, Masaaki; Sanbe, Takeyuki; Sekiya, Ichiro; Miyazaki, Akira; Suzuki, Hiroshi

    2016-02-12

    Although muscle wasting and/or degeneration are prevalent in patients with chronic kidney disease, it remains unknown whether FGF-23 influences muscle homeostasis and regeneration. Mesenchymal stem cells (MSCs) in skeletal muscle are distinct from satellite cells and have a known association with muscle degeneration. In this study we sought to investigate the effects of FGF-23 on MSCs isolated from human skeletal muscle in vitro. The MSCs expressed FGF receptors (1 through 4) and angiotensin-II type 1 receptor, but no traces of the Klotho gene were detected. MSCs and satellite cells were treated with FGF-23 and angiotensin-II for 48 h. Treatment with FGF-23 significantly decreased the number of MSCs compared to controls, while treatment with angiotensin-II did not. FGF-23 and angiotensin-II both left the cell counts of the satellite cells unchanged. The FGF-23-treated MSCs exhibited the senescent phenotype, as judged by senescence-associated β-galactosidase assay, cell morphology, and increased expression of p53 and p21 in western blot analysis. FGF-23 also significantly altered the gene expression of oxidative stress regulators in the cells. In conclusion, FGF-23 induced premature senescence in MSCs from skeletal muscle via the p53/p21/oxidative-stress pathway. The interaction between the MSCs and FGF-23 may play a key role in the impaired muscle reparative mechanisms of chronic kidney disease.

  3. Expression of Senescence-Associated microRNAs and Target Genes in Cellular Aging and Modulation by Tocotrienol-Rich Fraction

    Directory of Open Access Journals (Sweden)

    Sharon Gwee Sian Khee

    2014-01-01

    Full Text Available Emerging evidences highlight the implication of microRNAs as a posttranscriptional regulator in aging. Several senescence-associated microRNAs (SA-miRNAs are found to be differentially expressed during cellular senescence. However, the role of dietary compounds on SA-miRNAs remains elusive. This study aimed to elucidate the modulatory role of tocotrienol-rich fraction (TRF on SA-miRNAs (miR-20a, miR-24, miR-34a, miR-106a, and miR-449a and established target genes of miR-34a (CCND1, CDK4, and SIRT1 during replicative senescence of human diploid fibroblasts (HDFs. Primary cultures of HDFs at young and senescent were incubated with TRF at 0.5 mg/mL. Taqman microRNA assay showed significant upregulation of miR-24 and miR-34a and downregulation of miR-20a and miR-449a in senescent HDFs (P<0.05. TRF reduced miR-34a expression in senescent HDFs and increased miR-20a expression in young HDFs and increased miR-449a expression in both young and senescent HDFs. Our results also demonstrated that ectopic expression of miR-34a reduced the expression of CDK4 significantly (P<0.05. TRF inhibited miR-34a expression thus relieved its inhibition on CDK4 gene expression. No significant change was observed on the expression of CCND1, SIRT1, and miR-34a upstream transcriptional regulator, TP53. In conclusion tocotrienol-rich fraction prevented cellular senescence of human diploid fibroblasts via modulation of SA-miRNAs and target genes expression.

  4. The Impacts of Cellular Senescence in Elderly Pneumonia and in Age-Related Lung Diseases That Increase the Risk of Respiratory Infections

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    Shigehisa Yanagi

    2017-02-01

    Full Text Available Pneumonia generates considerable negative impacts on the elderly. Despite the widespread uses of vaccines and appropriate antibiotics, the morbidity and mortality of elderly pneumonia are significantly higher compared to the counterparts of young populations. The definitive mechanisms of high vulnerability in the elderly against pathogen threats are unclear. Age-associated, chronic low-grade inflammation augments the susceptibility and severity of pneumonia in the elderly. Cellular senescence, one of the hallmarks of aging, has its own characteristics, cell growth arrest and senescence-associated secretory phenotype (SASP. These properties are beneficial if the sequence of senescence–clearance–regeneration is transient in manner. However, persisting senescent cell accumulation and excessive SASP might induce sustained low-grade inflammation and disruption of normal tissue microenvironments in aged tissue. Emerging evidence indicates that cellular senescence is a key component in the pathogenesis of chronic obstructive pulmonary disease (COPD and idiopathic pulmonary fibrosis (IPF, which are known to be age-related and increase the risk of pneumonia. In addition to their structural collapses, COPD and IPF might increase the vulnerability to pathogen insults through SASP. Here, we discuss the current advances in understanding of the impacts of cellular senescence in elderly pneumonia and in these chronic lung disorders that heighten the risk of respiratory infections.

  5. Feline chronic kidney disease is associated with shortened telomeres and increased cellular senescence.

    Science.gov (United States)

    Quimby, Jessica M; Maranon, David G; Battaglia, Christine L R; McLeland, Shannon M; Brock, William T; Bailey, Susan M

    2013-08-01

    Telomeres are protective structures at the ends of chromosomes that have important implications for aging. To address the question of whether telomeres contribute to feline chronic kidney disease (CKD), we evaluated kidney, liver, and skin samples from 12 cats with naturally occurring CKD, 12 young normal cats, and 6 old normal cats. Telomere length was assessed using standard telomere fluorescent in situ hybridization (TEL-FISH) combined with immunohistochemistry (TELI-FISH) to identify proximal (PTEC) and distal tubular epithelial cells (DTEC), whereas senescence-associated β-galactosidase (SABG) staining was used to evaluate senescence. Results revealed statistically significant decreases in the average telomere fluorescence intensity (TFI) of PTEC in CKD cats compared with young and geriatric normal cats, and in the DTEC of CKD cats compared with young normal cats. When histograms of individual TFI were compared, statistically significant decreases in the PTEC and DTEC of CKD cats were observed compared with young and geriatric normal cats. Concomitantly, a statistically significant increase in SABG staining was seen in CKD kidney samples compared with young normal cats. CKD cats tended to have increased SABG staining in the kidney compared with normal geriatric cats, but this did not reach statistical significance. No significant telomere shortening in liver or skin from any group was observed. Real-time quantitative telomeric repeat amplification protocol assessment of renal telomerase activity revealed comparable low levels of telomerase activity in all groups. Our results suggest that shortened telomeres and increased senescence in the kidneys of CKD cats may represent novel targets for interventional therapy.

  6. Human papillomavirus oncoprotein E7 targets the promyelocytic leukemia protein and circumvents cellular senescence via the Rb and p53 tumor suppressor pathways.

    Science.gov (United States)

    Bischof, Oliver; Nacerddine, Karim; Dejean, Anne

    2005-02-01

    Cellular senescence can be triggered by a variety of signals, including loss of telomeric integrity or intense oncogenic signaling, and is considered a potent, natural tumor suppressor mechanism. Previously, it was shown that the promyelocytic leukemia protein (PML) induces cellular senescence when overexpressed in primary human fibroblasts. The mechanism by which the PML IV isoform elicits this irreversible growth arrest is believed to involve activation of the tumor suppressor pathways p21/p53 and p16/Rb; however, a requirement for either pathway has not been demonstrated unequivocally. To investigate the individual contributions of p53 and Rb to PML-induced senescence, we used oncoproteins E6 and E7 from human papillomaviruses (HPVs), which predominantly target p53 and Rb. We show that E7, but not E6, circumvents PML-induced senescence. Using different E7 mutant proteins, dominant negative cyclin-dependent kinase 4, and p16 RNA interference, we demonstrate that Rb-related and Rb-independent mechanisms of E7 are necessary for subversion of PML-induced senescence and we identify PML as a novel target for E7. Interaction between E7 and a functional prosenescence complex composed of PML, p53, and CBP perturbs transcriptional activation of p53, thus highlighting a significant effect also on the p53 tumor suppressor pathway. Given the importance of HPV in the pathogenesis of cervical cancer, our results warrant a more detailed analyses of PML in HPV infections.

  7. Standardized Kaempferia parviflora Extract Inhibits Intrinsic Aging Process in Human Dermal Fibroblasts and Hairless Mice by Inhibiting Cellular Senescence and Mitochondrial Dysfunction

    Directory of Open Access Journals (Sweden)

    Ji-Eun Park

    2017-01-01

    Full Text Available Intrinsic skin aging is a complex biological phenomenon mainly caused by cellular senescence and mitochondrial dysfunction. This study evaluated the inhibitory effect of Kaempferia parviflora Wall ex. Baker ethanol extract (KPE on H2O2-stimulated cellular senescence and mitochondrial dysfunction both in vitro and in vivo. KPE significantly increased cell growth and suppressed senescence-associated β-galactosidase activation. KPE inhibited the expression of cell-cycle inhibitors (p53, p21, p16, and pRb and stimulated the expression of cell-cycle activators (E2F1 and E2F2. H2O2-induced hyperactivation of the phosphatidylinositol 3-kinase/protein kinase B (AKT signaling pathway was suppressed by KPE through regulated expression of forkhead box O3a (FoxO3a and mammalian target of rapamycin (mTOR. KPE attenuated inflammatory mediators (interleukin-6 (IL-6, IL-8, nuclear factor kappa B (NF-κB, and cyclooxygenase-2 (COX-2 and increased the mRNA expression of PGC-1α, ERRα, NRF1, and Tfam, which modulate mitochondrial biogenesis and function. Consequently, reduced ATP levels and increased ROS level were also reversed by KPE treatment. In hairless mice, KPE inhibited wrinkle formation, skin atrophy, and loss of elasticity by increasing the collagen and elastic fibers. The results indicate that KPE prevents intrinsic aging process in hairless mice by inhibiting cellular senescence and mitochondrial dysfunction, suggesting its potential as a natural antiaging agent.

  8. Standardized Kaempferia parviflora Extract Inhibits Intrinsic Aging Process in Human Dermal Fibroblasts and Hairless Mice by Inhibiting Cellular Senescence and Mitochondrial Dysfunction.

    Science.gov (United States)

    Park, Ji-Eun; Woo, Seon Wook; Kim, Mi-Bo; Kim, Changhee; Hwang, Jae-Kwan

    2017-01-01

    Intrinsic skin aging is a complex biological phenomenon mainly caused by cellular senescence and mitochondrial dysfunction. This study evaluated the inhibitory effect of Kaempferia parviflora Wall ex. Baker ethanol extract (KPE) on H2O2-stimulated cellular senescence and mitochondrial dysfunction both in vitro and in vivo. KPE significantly increased cell growth and suppressed senescence-associated β-galactosidase activation. KPE inhibited the expression of cell-cycle inhibitors (p53, p21, p16, and pRb) and stimulated the expression of cell-cycle activators (E2F1 and E2F2). H2O2-induced hyperactivation of the phosphatidylinositol 3-kinase/protein kinase B (AKT) signaling pathway was suppressed by KPE through regulated expression of forkhead box O3a (FoxO3a) and mammalian target of rapamycin (mTOR). KPE attenuated inflammatory mediators (interleukin-6 (IL-6), IL-8, nuclear factor kappa B (NF-κB), and cyclooxygenase-2 (COX-2)) and increased the mRNA expression of PGC-1α, ERRα, NRF1, and Tfam, which modulate mitochondrial biogenesis and function. Consequently, reduced ATP levels and increased ROS level were also reversed by KPE treatment. In hairless mice, KPE inhibited wrinkle formation, skin atrophy, and loss of elasticity by increasing the collagen and elastic fibers. The results indicate that KPE prevents intrinsic aging process in hairless mice by inhibiting cellular senescence and mitochondrial dysfunction, suggesting its potential as a natural antiaging agent.

  9. Photobiomodulation on senescence

    Science.gov (United States)

    Liu, Timon Cheng-Yi; Cheng, Lei; Rong, Dong-Liang; Xu, Xiao-Yang; Cui, Li-Ping; Lu, Jian; Deng, Xiao-Yuan; Liu, Song-Hao

    2006-09-01

    Photobiomodulation (PBM) is an effect oflow intensity monochromatic light or laser irradiation (LIL) on biological systems. which stimulates or inhibits biological functions but does not result in irreducible damage. It has been observed that PBM can suppress cellular senescence, reverse skin photoageing and improve fibromyalgia. In this paper, the biological information model of photobiomodulation (BIMP) is used to discuss its mechanism. Cellular senescence can result from short, dysfunctional telomeres, oxidative stress, or oncogene expression, and may contribute to aging so that it can be seen as a decline of cellular function in which cAMP plays an important role, which provide a foundation for PBM on senescence since cellular senescence is a reasonable model of senescence and PBM is a cellular rehabilitation in which cAMP also plays an important role according to BIMP. The PBM in reversing skin photoageing and improving fibromyalgia are then discussed in detail.

  10. Differential Roles for the Interferon-inducible IFI16 and AIM2 Innate Immune Sensors for Cytosolic DNA in Cellular Senescence of Human Fibroblasts

    Science.gov (United States)

    Duan, Xin; Ponomareva, Larissa; Veeranki, Sudhakar; Panchanathan, Ravichandran; Dickerson, Eric; Choubey, Divaker

    2011-01-01

    The interferon (IFN)-inducible IFI16 and AIM2 proteins act as innate immune sensors for cytosolic double-stranded DNA (dsDNA). Upon sensing dsDNA, the IFI16 protein induces the expression of IFN-β whereas the AIM2 protein forms an inflammasome, which promotes the secretion of IL-1β. Given that the knockdown of IFI16 expression in human diploid fibroblasts (HDFs) delays the onset of cellular senescence, we investigated the potential roles for the IFI16 and AIM2 proteins in cellular senescence. We found that increased IFI16 protein levels in old (versus young) HDFs were associated with the induction of IFN-β. In contrast, increased levels of the AIM2 protein in the senescent (versus old) HDFs were associated with increased production of IL-1β. The knockdown of type I IFN-receptor subunit-α, which reduced the basal levels of the IFI16, but not the AIM2, protein delayed the onset of cellular senescence. Accordingly, increased constitutive levels of IFI16 and AIM2 proteins in ataxia telangiectasia (AT) HDFs were associated with the activation of the IFN-signaling and increased levels of IL-1β. The IFN-β treatment of the young HDFs, which induced the expression of IFI16 and AIM2 proteins, activated a DNA-damage response and also increased basal levels of IL-1β. Interestingly, the knockdown of AIM2 expression in HDFs increased the basal levels of IFI16 protein and activated the IFN-signaling. In contrast, the knockdown of the IFI16 expression in HDFs decreased the basal and dsDNA-induced activation of the IFN-signaling. Collectively, our observations demonstrate differential roles for the IFI16 and AIM2 proteins in cellular senescence and associated secretory phenotype. PMID:21471287

  11. Induction of cellular senescence by doxorubicin is associated with upregulated miR-375 and induction of autophagy in K562 cells.

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    Ming-Yu Yang

    Full Text Available BACKGROUND: Cellular senescence is a specialized form of growth arrest that is generally irreversible. Upregulated p16, p53, and p21 expression and silencing of E2F target genes have been characterized to promote the establishment of senescence. It can be further aided by the transcriptional repression of proliferation-associated genes by the action of HP1γ, HMGA, and DNMT proteins to produce a repressive chromatin environment. Therefore, senescence has been suggested to functions as a natural brake for tumor development and plays a critical role in tumor suppression and aging. METHODOLOGY/PRINCIPAL FINDINGS: An in vitro senescence model has been established by using K562 cells treated with 50 nM doxorubicin (DOX. Since p53 and p16 are homozygously deleted in the K562 cells, the DOX-induced senescence in K562 cells ought to be independent of p53 and p16-pRb pathways. Indeed, no change in the expression of the typical senescence-associated premalignant cell markers in the DOX-induced senescent K562 cells was found. MicroRNA profiling revealed upregulated miR-375 in DOX-induced senescent K562 cells. Treatment with miR-375 inhibitor was able to reverse the proliferation ability suppressed by DOX (p<0.05 and overexpression of miR-375 suppressed the normal proliferation of K562 cells. Upregulated miR-375 expression was associated with downregulated expression of 14-3-3zeta and SP1 genes. Autophagy was also investigated since DOX treatment was able to induce cells entering senescence and eventually lead to cell death. Among the 24 human autophagy-related genes examined, a 12-fold increase of ATG9B at day 4 and a 20-fold increase of ATG18 at day 2 after DOX treatment were noted. CONCLUSIONS/SIGNIFICANCE: This study has demonstrated that in the absence of p53 and p16, the induction of senescence by DOX was associated with upregulation of miR-375 and autophagy initiation. The anti-proliferative function of miR-375 is possibly exerted, at least in part

  12. 细胞衰老与肿瘤发生%Cellular senescence and carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    胡兵; 安红梅; 沈克平

    2008-01-01

    细胞衰老(cell senescence)是指细胞在信号转导作用下不可逆地脱离细胞周期并丧失增殖能力后进入的一种相对稳定的状态.细胞衰老有增殖衰老与早熟衰老两种形式:增殖衰老由端粒缩短激发的信号转导激发,与TP53/CDKNla(p21WAF-1/cip1)/pRB/E2F信号通路密切相关;早熟衰老由细胞内在或外在急慢性应激信号引发,与TP53/CDKN1a(p21WAF-1/Cip1)/pRB/E2F或CDKN2a(p16ink4A)/pRB/E2F信号通路相关.日前研究已经证实早熟衰老是细胞在癌变过程中的天然屏障,是继DNA修复、细胞凋亡后的第三大细胞内在抗癌机制,在机体防止肿瘤形成中起重要作用.

  13. Elevated ozone reduces photosynthetic carbon gain by accelerating leaf senescence of inbred and hybrid maize in a genotype-specific manner

    Science.gov (United States)

    Exposure to elevated tropospheric ozone concentration ([O3]) accelerates leaf senescence in many C3 crops. However, the effects of elevated [O3] on C4 crops including maize (Zea mays L.) are poorly understood in terms of physiological mechanism and genetic variation in sensitivity. Using Free Air ga...

  14. Fusaric acid accelerates the senescence of leaf in banana when infected by Fusarium.

    Science.gov (United States)

    Dong, Xian; Xiong, Yinfeng; Ling, Ning; Shen, Qirong; Guo, Shiwei

    2014-04-01

    Fusarium oxysporum f.sp. cubense (FOC) is a causal agent of vascular wilt and leaf chlorosis of banana plants. Chloroses resulting from FOC occur first in the lowest leaves of banana seedlings and gradually progress upward. To investigate the responses of different leaf positions to FOC infection, hydroponic experiments with FOC inoculation were conducted in a greenhouse. Fusarium-infected seedlings exhibited a decrease in net photosynthesis rate, stomatal conductance, and transpiration rate of all leaves. The wilting process in Fusarium-infected seedlings varied with leaf position. Measurements of the maximum photochemical efficiency of photosystem II (F(V)/F(max) and visualization with transmission electron microscopy showed a positive correlation between chloroplast impairment and severity of disease symptoms. Furthermore, results of malondialdehyde content and relative membrane conductivity measurements demonstrated that the membrane system was damaged in infected leaves. Additionally, the activities of phenylalanine ammonia-lyase, peroxidase and polyphenol oxidase were increased and total soluble phenolic compounds were significantly accumulated in the leaves of infected plants. The structural and biochemical changes of infected plants was consistent with plant senescence. As the FOC was not detected in infected leaves, we proposed that the chloroplast and membrane could be damaged by fusaric acid produced by Fusarium. During the infection, fusaric acid was first accumulated in the lower leaves and water-soluble substances in the lower leaves could dramatically enhance fusaric acid production. Taken together, the senescence of infected banana plants was induced by Fusarium infection with fusaric acid production and the composition of different leaf positions largely contribute to the particular senescence process.

  15. Behaviour and cognitive changes correlated with hippocampal neuroinflammaging and neuronal markers in female SAMP8, a model of accelerated senescence.

    Science.gov (United States)

    Griñan-Ferré, Christian; Palomera-Ávalos, Verónica; Puigoriol-Illamola, Dolors; Camins, Antoni; Porquet, David; Plá, Virginia; Aguado, Fernando; Pallàs, Mercè

    2016-07-01

    Senescence accelerated mice P8 (SAMP8) is a phenotypic model of age, characterized by deficits in memory and altered behaviour. Here, we determined the effect of age in SAMP8, and compared with the resistant strain, SAMR1, in behaviour and learning parameters linking these disturbances with oxidative stress environment. We found impairment in emotional behaviour with regard to fear and anxiety in young SAMP8 vs. age-mated SAMR1. Differences were attenuated with age. In contrast, learning capabilities are worse in SAMP8, both in young and aged animals, with regard to SAMR1. These waves in behaviour and cognition were correlated with an excess of oxidative stress (OS) in SAMP8 at younger ages that diminished with age. In this manner, we found changes in the hippocampal expression of ALDH2, IL-6, HMOX1, COX2, CXCL10, iNOS, and MCP-1 with an altered amyloidogenic pathway by increasing the Amyloid beta precursor protein (APP) and BACE1, and reduced ADAM10 expression; in addition, astrogliosis and neuronal markers decreased. Moreover, Superoxide dismutase 1 (SOD1) and Nuclear factor-kappa beta (NF-kβ) expression and protein levels were higher in younger SAMP8 than in SAMR1. In conclusion, the accelerated senescence process present in SAMP8 can be linked with an initial deregulation in redox homeostasis, named neuroinflammaging, by inducing molecular changes that lead to neuroinflammation and the neurodegenerative process. These changes are reflected in the emotional and cognitive behaviour of SAMP8 that differs from that of SAMR1 and that highlighted the importance of earlier oxidative processes in the onset of neurodegeneration. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Melatonin can improve insulin resistance and aging-induced pancreas alterations in senescence-accelerated prone male mice (SAMP8).

    Science.gov (United States)

    Cuesta, Sara; Kireev, Roman; García, Cruz; Rancan, Lisa; Vara, Elena; Tresguerres, Jesús A F

    2013-06-01

    The aim of the present study was to investigate the effect of aging on several parameters related to glucose homeostasis and insulin resistance in pancreas and how melatonin administration could affect these parameters. Pancreas samples were obtained from two types of male mice models: senescence-accelerated prone (SAMP8) and senescence-accelerated-resistant mice (SAMR1). Insulin levels in plasma were increased with aging in both SAMP8 and SAMR1 mice, whereas insulin content in pancreas was decreased with aging in SAMP8 and increased in SAMR1 mice. Expressions of glucagon and GLUT2 messenger RNAs (mRNAs) were increased with aging in SAMP8 mice, and no differences were observed in somatostatin and insulin mRNA expressions. Furthermore, aging decreased also the expressions of Pdx-1, FoxO 1, FoxO 3A and Sirt1 in pancreatic SAMP8 samples. Pdx-1 was decreased in SAMR1 mice, but no differences were observed in the rest of parameters on these mice strains. Treatment with melatonin was able to decrease plasma insulin levels and to increase its pancreatic content in SAMP8 mice. In SAMR1, insulin pancreatic content and plasma levels were decreased. HOMA-IR was decreased with melatonin treatment in both strains of animals. On the other hand, in SAMP8 mice, treatment decreased the expression of glucagon, GLUT2, somatostatin and insulin mRNA. Furthermore, it was also able to increase the expression of Sirt1, Pdx-1 and FoxO 3A. According to these results, aging is associated with significant alterations in the relative expression of pancreatic genes associated to glucose metabolism. This has been especially observed in SAMP8 mice. Melatonin administration was able to improve pancreatic function in old SAMP8 mice and to reduce HOMA-IR improving their insulin physiology and glucose metabolism.

  17. Aging-associated oxidized albumin promotes cellular senescence and endothelial damage

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    Luna C

    2016-02-01

    Full Text Available Carlos Luna,1,* Matilde Alique,2,* Estefanía Navalmoral,2 Maria-Victoria Noci,3 Lourdes Bohorquez-Magro,2 Julia Carracedo,1 Rafael Ramírez2 1Nephrology Unit, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC, Reina Sofía University Hospital, Córdoba, Spain; 2Department of Systems Biology, Physiology Unit, Universidad de Alcalá, Madrid, Spain; 3Anesthesia Unit, Reina sofía University Hospital, Córdoba, Spain*These authors contributed equally to this work Abstract: Increased levels of oxidized proteins with aging have been considered a cardiovascular risk factor. However, it is unclear whether oxidized albumin, which is the most abundant serum protein, induces endothelial damage. The results of this study indicated that with aging processes, the levels of oxidized proteins as well as endothelial microparticles release increased, a novel marker of endothelial damage. Among these, oxidized albumin seems to play a principal role. Through in vitro studies, endothelial cells cultured with oxidized albumin exhibited an increment of endothelial damage markers such as adhesion molecules and apoptosis levels. In addition, albumin oxidation increased the amount of endothelial microparticles that were released. Moreover, endothelial cells with increased oxidative stress undergo senescence. In addition, endothelial cells cultured with oxidized albumin shown a reduction in endothelial cell migration measured by wound healing. As a result, we provide the first evidence that oxidized albumin induces endothelial injury which then contributes to the increase of cardiovascular disease in the elderly subjects.Keywords: elderly, oxidative stress, microparticles, vascular damage

  18. Protease activated receptor-1 regulates macrophage-mediated cellular senescence : a risk for idiopathic pulmonary fibrosis

    NARCIS (Netherlands)

    Lin, Cong; Rezaee, Farhad; Waasdorp, Maaike; Shi, Kun; van der Poll, Tom; Borensztajn, Keren; Spek, C. Arnold

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a destructive disease in part resulting from premature or mature cellular aging. Protease-activated receptor-1 (PAR-1) recently emerged as a critical component in the context of fibrotic lung diseases. Therefore, we aimed to study the role of macrophages in PAR

  19. Influence of long-term consumption of a Lactococcus lactis strain on the intestinal immunity and intestinal flora of the senescence-accelerated mouse.

    Science.gov (United States)

    Kimoto-Nira, Hiromi; Mizumachi, Koko; Okamoto, Takashi; Sasaki, Keisuke; Kurisaki, Jun-Ichi

    2009-07-01

    The senescence-accelerated mouse develops normally until 5-6 months of age and then displays rapid and irreversible advancement of senescence manifesting as clinical signs and gross lesions. To clarify the effect of lactic acid bacteria on the physiological changes with increasing age, heat-killed Lactococcus lactis G50 was administered to 1-month-old senescence-accelerated-prone mouse (SAMP)6 mice for 11 months, a senescence-accelerated mouse strain that develops senile osteoporosis. Mice fed G50 gained more weight than the control mice (not fed G50) during the feeding experiment. Faecal IgA levels in the mice fed G50 at 3 months were higher than those of the control mice but decreased to control levels with increasing age. The numbers of viable cells of Bacteroides sp., Lactobacillus sp., Staphylococcus sp., Enterococcus/Streptococcus sp. and Enterobacteriaceae sp. in faeces were similar for mice fed the G50 and control diets at any age, but strain G50 suppressed the intestinal growth of H2S-producing bacteria. Bone density of the thigh bone did not differ between aged G50 and control mice. Strain G50 would be a beneficial bacterium for the enhancement of intestinal immunity during youth and to suppress the growth of harmful intestinal bacteria. The applicability of strain G50 for the food and animal industries has been proposed in the present study.

  20. Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence

    Science.gov (United States)

    Revandkar, Ajinkya; Perciato, Maria Luna; Toso, Alberto; Alajati, Abdullah; Chen, Jingjing; Gerber, Hermeto; Dimitrov, Mitko; Rinaldi, Andrea; Delaleu, Nicolas; Pasquini, Emiliano; D'Antuono, Rocco; Pinton, Sandra; Losa, Marco; Gnetti, Letizia; Arribas, Alberto; Fraering, Patrick; Bertoni, Francesco; Nepveu, Alain; Alimonti, Andrea

    2016-01-01

    Activation of NOTCH signalling is associated with advanced prostate cancer and treatment resistance in prostate cancer patients. However, the mechanism that drives NOTCH activation in prostate cancer remains still elusive. Moreover, preclinical evidence of the therapeutic efficacy of NOTCH inhibitors in prostate cancer is lacking. Here, we provide evidence that PTEN loss in prostate tumours upregulates the expression of ADAM17, thereby activating NOTCH signalling. Using prostate conditional inactivation of both Pten and Notch1 along with preclinical trials carried out in Pten-null prostate conditional mouse models, we demonstrate that Pten-deficient prostate tumours are addicted to the NOTCH signalling. Importantly, we find that pharmacological inhibition of γ-secretase promotes growth arrest in both Pten-null and Pten/Trp53-null prostate tumours by triggering cellular senescence. Altogether, our findings describe a novel pro-tumorigenic network that links PTEN loss to ADAM17 and NOTCH signalling, thus providing the rational for the use of γ-secretase inhibitors in advanced prostate cancer patients. PMID:27941799

  1. Western-style diet modulates contractile responses to phenylephrine differently in mesenteric arteries from senescence-accelerated prone (SAMP8) and resistant (SAMR1) mice.

    Science.gov (United States)

    Jiménez-Altayó, Francesc; Onetti, Yara; Heras, Magda; Dantas, Ana P; Vila, Elisabet

    2013-08-01

    The influence of two known cardiovascular risk factors, aging and consumption of a high-fat diet, on vascular mesenteric artery reactivity was examined in a mouse model of accelerated senescence (SAM). Five-month-old SAM prone (SAMP8) and resistant (SAMR1) female mice were fed a Western-type high-fat diet (WD; 8 weeks). Mesenteric arteries were dissected, and vascular reactivity, protein and messenger RNA expression, superoxide anion (O 2 (·-) ) and hydrogen peroxide formation were evaluated by wire myography, immunofluorescence, RT-qPCR, ethidium fluorescence and ferric-xylenol orange, respectively. Contraction to KCl and relaxation to acetylcholine remained unchanged irrespective of senescence and diet. Although similar contractions to phenylephrine were observed in SAMR1 and SAMP8, accelerated senescence was associated with decreased eNOS and nNOS and increased O 2 (·-) synthesis. Senescence-related alterations were compensated, at least partly, by the contribution of NO derived from iNOS and the enhanced endogenous antioxidant capacity of superoxide dismutase 1 to maintain vasoconstriction. Administration of a WD induced qualitatively different alterations in phenylephrine contractions of mesenteric arteries from SAMR1 and SAMP8. SAMR1 showed increased contractions partly as a result of decreased NO availability generated by decreased eNOS and nNOS and enhanced O 2 (·-) formation. In contrast, WD feeding in SAMP8 resulted in reduced contractions due to, at least in part, the increased functional participation of iNOS-derived NO. In conclusion, senescence-dependent intrinsic alterations during early stages of vascular senescence may promote vascular adaptation and predispose to further changes in response to high-fat intake, which may lead to the progression of aging-related cardiovascular disease, whereas young subjects lack the capacity for this adaptation.

  2. Absolute leukocyte telomere length in HIV-infected and uninfected individuals: evidence of accelerated cell senescence in HIV-associated chronic obstructive pulmonary disease.

    Directory of Open Access Journals (Sweden)

    Joseph C Y Liu

    Full Text Available Combination antiretroviral therapy (cART has extended the longevity of human immunodeficiency virus (HIV-infected individuals. However, this has resulted in greater awareness of age-associated diseases such as chronic obstructive pulmonary disease (COPD. Accelerated cellular senescence may be responsible, but its magnitude as measured by leukocyte telomere length is unknown and its relationship to HIV-associated COPD has not yet been established. We measured absolute telomere length (aTL in peripheral leukocytes from 231 HIV-infected adults. Comparisons were made to 691 HIV-uninfected individuals from a population-based sample. Subject quartiles of aTL were assessed for relationships with measures of HIV disease severity, airflow obstruction, and emphysema severity on computed tomographic (CT imaging. Multivariable regression models identified factors associated with shortened aTL. Compared to HIV-uninfected subjects, the mean aTL in HIV-infected patients was markedly shorter by 27 kbp/genome (p<0.001; however, the slopes of aTL vs. age were not different (p=0.469. Patients with longer known durations of HIV infection (p=0.019 and lower nadir CD4 cell counts (p=0.023 had shorter aTL. Shorter aTL were also associated with older age (p=0.026, smoking (p=0.005, reduced forced expiratory volume in one second (p=0.030, and worse CT emphysema severity score (p=0.049. HIV-infected subjects demonstrate advanced cellular aging, yet in a cART-treated cohort, the relationship between aTL and age appears no different from that of HIV-uninfected subjects.

  3. PML, SUMOylation and senescence

    Directory of Open Access Journals (Sweden)

    Hugues eDe Thé

    2013-07-01

    Full Text Available Since its discovery, 25 years ago, PML has been an enigma. Implicated in the oncogenic PML/RARA fusion, forming elusive intranuclear domains, triggering cell death or senescence, controlled by and perhaps controlling SUMOylation... there are multiple PML-related issues. Here we review the reciprocal interactions between PML, senescence and SUMOylation, notably in the context of cellular transformation.

  4. Growth hormone can improve insulin resistance and differentiation in pancreas of senescence accelerated prone male mice (SAMP8).

    Science.gov (United States)

    Cuesta, Sara; Kireev, Roman; Forman, Katherine; García, Cruz; Acuña, Darío; Vara, Elena; Tresguerres, Jesús A F

    2011-04-01

    The aim of the present study was to investigate the effect of aging on several parameters related to glucose metabolism, proliferation and differentiation in the pancreas and how GH administration to old SAMP8 mice could affect these parameters. Pancreas samples were obtained from two types of male mice models: senescence-accelerated prone (SAMP8) and senescence-accelerated-resistant (SAMR1) mice SAMP8 and SAMR1 mice and the influence of exogenous administration of GH (2mgs.c./kg/day) on SAMP8 mice. RNA was isolated from pancreas samples of male mice using the kit RNeasy total RNA kit Ref. 50974104 (Qiagen). Insulin was measured in plasma by RIA kit and glucose was measured in plasma by an assay kit. Aging decreases the expression of differentiation in the pancreas of Pdx-1, FoxO 1 and FoxO 3A but not of Sirt 1 or of the expression of the proliferative genes PCNA and Sei1. The expression of glucagon and GLUT2 were increased with aging and no differences were observed in somatostatin and insulin expressions. Insulin levels in plasma were increased with aging in SAMP8 mice. IGF-1 expression was reduced with aging. The treatment with GH was able to increase the expression of Sirt 1, Pdx-1, FoxO 3A and IGF-1. On the other hand, the treatment decreased the expression of glucagon, GLUT2, somatostatin and insulin, furthermore GH was able to decrease the plasma levels of insulin in old male SAMP8 mice (p<0.0004). The present study has shown that aging is associated with significant alterations in the relative expression of pancreatic genes involved in insulin secretion as well as in the differentiation and in the intra islet glucose metabolism. According to our results, GH administration to old SAMP8 mice was able to improve the pancreatic function of the old SAMP8 mice and to decrease insulin and glucagon expressions in the pancreas improving instead insulin levels and glucose metabolism. Copyright © 2010 Growth Hormone Research Society. Published by Elsevier Ltd. All

  5. Melatonin decreases the expression of inflammation and apoptosis markers in the lung of a senescence-accelerated mice model.

    Science.gov (United States)

    Puig, Ángela; Rancan, Lisa; Paredes, Sergio D; Carrasco, Adrián; Escames, Germaine; Vara, Elena; Tresguerres, Jesús A F

    2016-03-01

    Aging is associated with an increase in oxidative stress and inflammation. The aging lung is particularly affected since it is continuously exposed to environmental oxidants while antioxidant machinery weakens with age. Melatonin, a free radical scavenger, counteracts inflammation and apoptosis in healthy cells from several tissues. Its effects on the aging lung are, however, not yet fully understood. This study aimed to investigate the effect of chronic administration of melatonin on the expression of inflammation markers (TNF-α, IL-1β, NFκB2, HO-1) and apoptosis parameters (BAD, BAX, AIF) in the lung tissue of male senescence-accelerated prone mice (SAMP8). In addition, RNA oxidative damage, as the formation of 8-hydroxyguanosine (8-OHG), was also evaluated. Young and old animals, aged 2 and 10 months respectively, were divided into 4 groups: untreated young, untreated old, old mice treated with 1mg/kg/day melatonin, and old animals treated with 10mg/kg/day melatonin. Untreated young and old male senescence accelerated resistant mice (SAMR1) were used as controls. After 30 days of treatment, animals were sacrificed. Lungs were collected and immediately frozen in liquid nitrogen. mRNA and protein expressions were measured by RT-PCR and Western blotting, respectively. Levels of 8-OHG were quantified by ELISA. Mean values were analyzed using ANOVA. Old nontreated SAMP8 animals showed increased (p<0.05) mRNA and protein levels of TNF-α, IL-1β, NFκB2, and HO-1 compared to young mice and SAMR1 mice. Melatonin treatment with either dose reversed the aging-derived inflammation (p<0.05). BAD, BAX and AIF expressions also rose with aging, the effect being counteracted with melatonin (p<0.05). Aging also caused a significant elevation (p<0.05) in SAMP8 8-OHG values. This increase was not observed in animals treated with melatonin (p<0.05). In conclusion, melatonin treatment was able to modulate the inflammatory and apoptosis status of the aging lungs, exerting a

  6. The essence of senescence

    National Research Council Canada - National Science Library

    Kuilman, Thomas; Michaloglou, Chrysiis; Mooi, Wolter J; Peeper, Daniel S

    2010-01-01

    Almost half a century after the first reports describing the limited replicative potential of primary cells in culture, there is now overwhelming evidence for the existence of "cellular senescence" in vivo...

  7. Accelerated senescence and enhanced disease resistance in hybrid chlorosis lines derived from interspecific crosses between tetraploid wheat and Aegilops tauschii.

    Science.gov (United States)

    Nakano, Hiroki; Mizuno, Nobuyuki; Tosa, Yukio; Yoshida, Kentaro; Park, Pyoyun; Takumi, Shigeo

    2015-01-01

    Hybrid chlorosis, a type of hybrid incompatibility, has frequently been reported in inter- and intraspecific crosses of allopolyploid wheat. In a previous study, we reported some types of growth abnormalities such as hybrid necrosis and observed hybrid chlorosis with mild or severe abnormalities in wheat triploids obtained in crosses between tetraploid wheat cultivar Langdon and four Ae. tauschii accessions and in their derived synthetic hexaploids. However, the molecular mechanisms underlying hybrid chlorosis are not well understood. Here, we compared cytology and gene expression in leaves to characterize the abnormal growth in wheat synthetics showing mild and severe chlorosis. In addition, we compared disease resistance to wheat blast fungus. In total 55 and 105 genes related to carbohydrate metabolism and 53 and 89 genes for defense responses were markedly up-regulated in the mild and severe chlorosis lines, respectively. Abnormal chloroplasts formed in the mesophyll cells before the leaves yellowed in the hybrid chlorosis lines. The plants with mild chlorosis showed increased resistance to wheat blast and powdery mildew fungi, although significant differences only in two, third internode length and maturation time, out of the examined agricultural traits were found between the wild type and plants showing mild chlorosis. These observations suggest that senescence might be accelerated in hybrid chlorosis lines of wheat synthetics. Moreover, in wheat synthetics showing mild chlorosis, the negative effects on biomass can be minimized, and they may show substantial fitness under pathogen-polluted conditions.

  8. Enzyme-treated Asparagus officinalis extract shows neuroprotective effects and attenuates cognitive impairment in senescence-accelerated mice.

    Science.gov (United States)

    Sakurai, Takuya; Ito, Tomohiro; Wakame, Koji; Kitadate, Kentaro; Arai, Takashi; Ogasawara, Junetsu; Kizaki, Takako; Sato, Shogo; Ishibashi, Yoshinaga; Fujiwara, Tomonori; Akagawa, Kimio; Ishida, Hitoshi; Ohno, Hideki

    2014-01-01

    Increases in the number of patients with dementia involving Alzheimer's disease (AD) are seen as a grave public health problem. In neurodegenerative disorders involving AD, biological stresses, such as oxidative and inflammatory stress, induce neural cell damage. Asparagus (Asparagus officinalis) is a popular vegetable, and an extract prepared from this reportedly possesses various beneficial biological activities. In the present study, we investigated the effects of enzyme-treated asparagus extract (ETAS) on neuronal cells and early cognitive impairment of senescence-accelerated mouse prone 8 (SAMP8) mice. The expression of mRNAs for factors that exert cytoprotective and anti-apoptotic functions, such as heat-shock protein 70 and heme oxygenase-1, was upregulated in NG108-15 neuronal cells by treatment with ETAS. Moreover, when release of lactate dehydrogenase from damaged NG108-15 cells was increased for cells cultured in medium containing either the nitric oxide donor sodium nitroprusside or the hypoxia mimic reagent cobalt chloride, ETAS significantly attenuated this cell damage. Also, when contextual fear memory, which is considered to be a hippocampus-dependent memory, was significantly impaired in SAMP8 mice, ETAS attenuated the cognitive impairment. These results suggest that ETAS produces cytoprotective effects in neuronal cells and attenuates the effects on the cognitive impairment of SAMP8 mice.

  9. Accelerated senescence and enhanced disease resistance in hybrid chlorosis lines derived from interspecific crosses between tetraploid wheat and Aegilops tauschii.

    Directory of Open Access Journals (Sweden)

    Hiroki Nakano

    Full Text Available Hybrid chlorosis, a type of hybrid incompatibility, has frequently been reported in inter- and intraspecific crosses of allopolyploid wheat. In a previous study, we reported some types of growth abnormalities such as hybrid necrosis and observed hybrid chlorosis with mild or severe abnormalities in wheat triploids obtained in crosses between tetraploid wheat cultivar Langdon and four Ae. tauschii accessions and in their derived synthetic hexaploids. However, the molecular mechanisms underlying hybrid chlorosis are not well understood. Here, we compared cytology and gene expression in leaves to characterize the abnormal growth in wheat synthetics showing mild and severe chlorosis. In addition, we compared disease resistance to wheat blast fungus. In total 55 and 105 genes related to carbohydrate metabolism and 53 and 89 genes for defense responses were markedly up-regulated in the mild and severe chlorosis lines, respectively. Abnormal chloroplasts formed in the mesophyll cells before the leaves yellowed in the hybrid chlorosis lines. The plants with mild chlorosis showed increased resistance to wheat blast and powdery mildew fungi, although significant differences only in two, third internode length and maturation time, out of the examined agricultural traits were found between the wild type and plants showing mild chlorosis. These observations suggest that senescence might be accelerated in hybrid chlorosis lines of wheat synthetics. Moreover, in wheat synthetics showing mild chlorosis, the negative effects on biomass can be minimized, and they may show substantial fitness under pathogen-polluted conditions.

  10. A diet enriched with plant sterols prevents the memory impairment induced by cholesterol loss in senescence-accelerated mice.

    Science.gov (United States)

    Pérez-Cañamás, Azucena; Sarroca, Sara; Melero-Jerez, Carolina; Porquet, David; Sansa, Joan; Knafo, Shira; Esteban, Jose A; Sanfeliu, Coral; Ledesma, Maria Dolores

    2016-12-01

    Cholesterol reduction at the neuronal plasma membrane has been related to age-dependent cognitive decline. We have used senescent-accelerated mice strain 8 (SAMP8), an animal model for aging, to examine the association between cholesterol loss and cognitive impairment and to test strategies to revert this process. We show that the hippocampus of SAMP8 mice presents reduced cholesterol levels and enhanced amount of its degrading enzyme Cyp46A1 (Cyp46) already at 6 months of age. Cholesterol loss accounts for the impaired long-term potentiation in these mice. Plant sterol (PSE)-enriched diet prevents long-term potentiation impairment and cognitive deficits in SAMP8 mice without altering cholesterol levels. PSE diet also reduces the abnormally high amyloid peptide levels in SAMP8 mice brains and restores membrane compartmentalization of presenilin1, the catalytic component of the amyloidogenic γ-secretase. These results highlight the influence of cholesterol loss in age-related cognitive decline and provide with a noninvasive strategy to counteract it. Our results suggest that PSE overtake cholesterol functions in the brain contributing to reduce deleterious consequences of cholesterol loss during aging. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Beneficial effect of melatonin treatment on inflammation, apoptosis and oxidative stress on pancreas of a senescence accelerated mice model.

    Science.gov (United States)

    Cuesta, Sara; Kireev, Roman; García, Cruz; Forman, Katherine; Escames, Germaine; Vara, Elena; Tresguerres, Jesús A F

    2011-01-01

    This study has investigated the effect of aging on parameters of inflammation, oxidative stress and apoptosis in pancreas obtained from two types of male mice models: senescence-accelerated prone (SAMP8) and resistant mice (SAMR1). Animals of 2 (young) and 10 months of age (old) were used (n = 64). The influence of the administration of melatonin in the drinking water for one month at two different dosages (1 and 10mg/(kg day) on old SAMP8 mice on these parameters was also studied. SAMP8 mice showed with age a significant increase in the relative expression of pancreatic genes involved in inflammation, oxidative stress and apoptosis. Furthermore the protein expression of several NFκB subunits was also enhanced. On the contrary aged SAMR1 mice did not show significant increases in these parameters. Melatonin administration to SAMP8 mice was able to reduce these age related alterations at the two used dosages. Copyright © 2011. Published by Elsevier Ireland Ltd.

  12. Senescence hypothesis for the pathogenetic mechanism of chronic obstructive pulmonary disease.

    Science.gov (United States)

    Aoshiba, Kazutetsu; Nagai, Atsushi

    2009-12-01

    We report herein that pulmonary emphysematous lesions appear to be a dynamic phenomenon that involves not only the gradual loss of alveolar structure but also apoptosis, cellular proliferation, and cellular senescence. Cellular proliferation compensates for increased alveolar cell apoptosis in patients with chronic obstructive pulmonary disease (COPD). However, smoking, age, and the increased cell cycle turnover that compensates for apoptosis accelerate alveolar cell senescence, thereby halting cellular proliferation and tipping the balance toward apoptosis, which, in turn, promotes the formation of emphysematous lesions. As a result, alveolar cells disappear and the emphysematous lesions progress. At the same time, cellular senescence is believed to induce inflammation. More specifically, senescent alveolar cells induce inflammation by producing various inflammatory cytokines in tissue. Lymphocytes and Clara cells may also age more rapidly in the lungs of patients with COPD. Lymphocyte senescence may induce an autoimmune reaction and increase susceptibility to infection, and Clara cell senescence may impair airway regeneration as well as sustain airway inflammation. Thus, cellular senescence may be involved in arrested tissue repair, chronic inflammation, and increased susceptibility to infection, which are the typical features of COPD.

  13. Cyanidin-3-O-galactoside and Blueberry Extracts Supplementation Improves Spatial Memory and Regulates Hippocampal ERK Expression in Senescence-accelerated Mice

    Institute of Scientific and Technical Information of China (English)

    TAN Long; YANG Hong Peng; PANG Wei; LU Hao; HU Yan Dan; LI Jing; LU Shi Jun; ZHANG Wan Qi; JIANG Yu Gang

    2014-01-01

    Objective To investigate whether the antioxidation and the regulation on the Extracellular Regulated Protein Kinases (ERK) signaling pathway are involved in the protective effects of blueberry on central nervous system. Methods 30 Senescence-accelerated mice prone 8 (SAMP8) mice were divided into three groups and treated with normal diet, blueberry extracts (200 mg/kg·bw/day) and cyaniding-3-O-galactoside (Cy-3-GAL) (50 mg/kg·bw/day) from blueberry for 8 weeks. 10 SAMR1 mice were set as control group. The capacity of spatial memory was assessed by Passive avoidance task and Morris water maze. Histological analyses on hippocampus were completed. Malondialdehyde (MDA) levels, Superoxide Dismutase (SOD) activity and the expression of ERK were detected. Results Both Cy-3-GAL and blueberry extracts were shown effective functions to relieve cellular injury, improve hippocampal neurons survival and inhibit the pyramidal cell layer damage. Cy-3-GAL and blueberry extracts also increased SOD activity and reduced MDA content in brain tissues and plasma, and increased hippocampal phosphorylated ERK (p-ERK) expression in SAMP8 mice. Further more, the passive avoidance task test showed that both the latency time and the number of errors were improved by Cy-3-GAL treatment, and the Morris Water Maze test showed significant decreases of latency were detected by Cy-3-GAL and blueberry extracts treatment on day 4. Conclusion Blueberry extracts may reverse the declines of cognitive and behavioral function in the ageing process through several pathways, including enhancing the capacity of antioxidation, altering stress signaling. Cy-3-GAL may be an important active ingredient for these biological effects.

  14. Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells

    DEFF Research Database (Denmark)

    Dokkedahl, Karin Stenderup; Justesen, Jeannette; Clausen, Christian

    2003-01-01

    donors were able to form similar amounts of mineralized matrix in vitro and of normal lamellar bone in vivo. In adipogenic medium similar numbers of adipocytes formed in cultures of young and old donors. In conclusion, aging is associated with decreased proliferative capacity of osteoprogenitor cells......Age-related decrease in bone formation is well described. However, the cellular causes are not known. Thus, we have established cultures of bone marrow stromal cells (MSC) from young (aged 18-29 years, n = 6) and old (aged 68-81 years, n = 5) donors. MSC were serially passaged until reaching......, suggesting that decreased osteoblastic cell number, and not function, leads to age-related decrease in bone formation....

  15. Revealing the cellular metabolism and microstructural changes in vivo in senescing Acer saccharum leaves using two-photon FLIM and full-field OCM

    Science.gov (United States)

    Chakraborty, Sandeep; Anna, Tulsi; Kuo, Wen-Chuan; Chiou, Arthur

    2016-10-01

    Seasonal as well as climate changes have immense effect on bud burst, leaf color and leaf abscission. Autumn phenology of leaves is clearly distinguishable in deciduous plant leaves where the leaf color changes from green to red (leaf senescence). In this work, two-photon fluorescence lifetime imaging microscopy (2P-FLIM) and full-field optical coherence microscopy (FF-OCM) were applied to study mitochondrial activity and microstructural changes, respectively, in the senescence of Acer saccharum (Sugar maple) leaves. Fluorescence lifetime of reduced nicotinamide adenine dinucleotide phosphate [NAD(P)H] was recorded using 2P-FLIM to quantify the cellular metabolic changes. Compared to the green leaves, the red leaves showed a 19% increase (P face sectional images at 0.8 μm axial resolutions of the green and the red color Acer saccharum leaves via FF-OCM using white light emitting diode (WLED) showed a well-defined microstructure of epicuticular waxy layer in green leaves as compared to red leaves where disintegrated microstructure was observed. Our approach can potentially be used to correlate mitochondrial activity with epicuticular microstructural changes in senescing leaves and other biological tissues.

  16. RNA methyltransferase NSUN2 promotes stress-induced HUVEC senescence.

    Science.gov (United States)

    Cai, Xiaoyu; Hu, Yuanyuan; Tang, Hao; Hu, Han; Pang, Lijun; Xing, Junyue; Liu, Zhenyun; Luo, Yuhong; Jiang, Bin; Liu, Te; Gorospe, Myriam; Chen, Chuan; Wang, Wengong

    2016-04-12

    The tRNA methyltransferase NSUN2 delays replicative senescence by regulating the translation of CDK1 and CDKN1B mRNAs. However, whether NSUN2 influences premature cellular senescence remains untested. Here we show that NSUN2 methylates SHC mRNA in vitro and in cells, thereby enhancing the translation of the three SHC proteins, p66SHC, p52SHC, and p46SHC. Our results further show that the elevation of SHC expression by NSUN2-mediated mRNA methylation increased the levels of ROS, activated p38MAPK, thereby accelerating oxidative stress- and high-glucose-induced senescence of human vascular endothelial cells (HUVEC). Our findings highlight the critical impact of NSUN2-mediated mRNA methylation in promoting premature senescence.

  17. Alpha fucosidase and beta galactosidase in serum of a Lyme disease patients as a possible marker of accelerated senescence - a preliminary study.

    Science.gov (United States)

    Wasiluk, Anna; Waszkiewicz, Napoleon; Szajda, Sławomir Dariusz; Wojewódzka-Żelezniakowicz, Marzena; Kępka, Alina; Minarowska, Alina; Zwierz, Zbigniew Wojciech; Pancewicz, Sławomir; Ładny, Jerzy Robert; Zwierz, Krzysztof

    2012-07-05

    Lyme disease (LD) is the most prevalent tick-borne disease in Europe. LD is caused by the spirochete Borrelia burgdorferi. LD is a chronic disease which can attack a number of organs: skin, heart, brain, joints. Chronic, low-grade inflammation involves general production of pro-inflammatory cytokines and inflammatory markers and is a typical feature of aging. So far, the best method of diagnosing LD is a time-consuming and expensive two-stage serological method. The aim of our study was to evaluate the activity of two lysosomal exoglycosidases: α-fucosidase (FUC) and β-galactosidase (GAL) in the serum of patients with Lyme disease, as potential markers of LD. Due to the increasing number of patients with Lyme disease and a number of false results, new ways to diagnose this disease are still being sought. As elevated level of β-galactosidase is a manifestation of residual lysosomal activity in senescent cells, the increase in its activity in serum during chronic Lyme disease might be a marker of a potentially accelerated senescence process. The study was performed on serum taken from cubital veins of 15 patients with Lyme disease and eight healthy subjects (control group). FUC and GAL activity was measured by the method of Chatterjee et al. as modified by Zwierz et al. In the serum of patients with Lyme disease, GAL activity significantly increased (p = 0.029), and the activity of FUC had a tendency to increase (p = 0.153), compared to the control group. A significant increase in GAL activity in the serum of patients with Lyme disease indicates an increased catabolism of glycoconjugates (glycoproteins, glycolipids, proteoglycans) and could be helpful in the diagnosis of Lyme disease, although this requires confirmation in a larger group of patients. As GAL is the most widely used assay for detection of senescent cells, an elevated level of β-galactosidase might be a manifestation of accelerated senescence process in the course of Lyme disease.

  18. Accelerating cellular automata simulations using AVX and CUDA

    CERN Document Server

    Szkoda, Sebastian; Tykierko, Mateusz

    2012-01-01

    We investigated various methods of parallelization of the Frish-Hasslacher-Pomeau (FHP) cellular automata algorithm for modeling fluid flow. These methods include SSE, AVX, and POSIX Threads for central processing units (CPUs) and CUDA for graphics processing units (GPUs). We present implementation details of the FHP algorithm based on AVX/SSE and CUDA technologies. We found that (a) using AVX or SSE is necessary to fully utilize the potential of modern CPUs; (b) CPUs and GPUs are comparable in terms of computational and economic efficiency only if the CPU code uses AVX or SSE instructions; (c) AVX does not offer any substantial improvement relative to SSE.

  19. Suppression of Transforming Growth Factor-β Signaling Delays Cellular Senescence and Preserves the Function of Endothelial Cells Derived From Human Pluripotent Stem Cells.

    Science.gov (United States)

    Bai, Hao; Gao, Yongxing; Hoyle, Dixie L; Cheng, Tao; Wang, Zack Z

    2016-09-20

    : Transplantation of vascular cells derived from human pluripotent stem cells (hPSCs) offers an attractive noninvasive method for repairing the ischemic tissues and for preventing the progression of vascular diseases. Here, we found that in a serum-free condition, the proliferation rate of hPSC-derived endothelial cells is quickly decreased, accompanied with an increased cellular senescence, resulting in impaired gene expression of endothelial nitric oxide synthase (eNOS) and impaired vessel forming capability in vitro and in vivo. To overcome the limited expansion of hPSC-derived endothelial cells, we screened small molecules for specific signaling pathways and found that inhibition of transforming growth factor-β (TGF-β) signaling significantly retarded cellular senescence and increased a proliferative index of hPSC-derived endothelial cells. Inhibition of TGF-β signaling extended the life span of hPSC-derived endothelial and improved endothelial functions, including vascular network formation on Matrigel, acetylated low-density lipoprotein uptake, and eNOS expression. Exogenous transforming growth factor-β1 increased the gene expression of cyclin-dependent kinase inhibitors, p15(Ink4b), p16(Ink4a), and p21(CIP1), in endothelial cells. Conversely, inhibition of TGF-β reduced the gene expression of p15(Ink4b), p16(Ink4a), and p21(CIP1). Our findings demonstrate that the senescence of newly generated endothelial cells from hPSCs is mediated by TGF-β signaling, and manipulation of TGF-β signaling offers a potential target to prevent vascular aging.

  20. The hemibiotroph Colletotrichum graminicola locally induces photosynthetically active green islands but globally accelerates senescence on aging maize leaves.

    Science.gov (United States)

    Behr, Michael; Humbeck, Klaus; Hause, Gerd; Deising, Holger B; Wirsel, Stefan G R

    2010-07-01

    Typically, pathogenesis of the hemibiotroph Colletotrichum graminicola and defense responses of its host, Zea mays, are studied on young leaves. Equivalent studies have not been performed with leaves undergoing senescence, a situation that is relevant in the field. We discovered that, in contrast to anthracnose symptoms formed on young and mature leaves, green islands reminiscent of those known from obligate biotrophs were formed on senescing leaves. Microscopy revealed that the fungus grew in both symptoms from the epidermis towards the bundle sheath. In green islands, tissues remained intact for an extended time period. Imaging PAM (pulse-amplitude-modulation) fluorescence analyses revealed that photosynthesis is transiently maintained at green islands but declined in tissue surrounding the infection. In younger leaves however, photosynthesis was reduced only at infection sites. Support for the local modification of host physiology came from quantitative reverse transcription-polymerase chain reaction analyzing gene expression at high spatial resolution. Decreased transcript levels of the senescence markers see1 and ccp1 corroborated a pathogen-induced delay of senescence. Expression of several genes encoding proteins involved in photosynthesis was strongly reduced by infection. In contrast, transcript levels of incw1, encoding a cell-wall invertase, were increased 70-fold at green islands, suggesting that C. graminicola induced carbon sinks in senescing tissue.

  1. Use of inductor agents GSE24.2 for producing pharmaceutical compositions for treating illnesses relating to cellular senescence

    OpenAIRE

    2010-01-01

    This invention relates to the use of an inductor or activator compound GSE24.2 for producing a medicament or a pharmaceutical composition for treating a preferably human illness or pathological situation caused by a senescence process. Said pharmaceutical composition can be useful for a treatment for regenerating tissues, for example of epithelial tissues or haematopoietic cells, and also for the immortalisation of eucaryotic cells in order to use of same in biotechnological investigation or ...

  2. Dysfunctional lipoproteins from young smokers exacerbate cellular senescence and atherogenesis with smaller particle size and severe oxidation and glycation.

    Science.gov (United States)

    Park, Ki-Hoon; Shin, Dong-Gu; Cho, Kyung-Hyun

    2014-07-01

    Until now, there has been limited information on the effects of smoking on atherogenesis and senescence in the context of lipoprotein parameters, particularly in young smokers who have smoked fewer than 10 cigarettes per day for 3 years. In this study, lipoprotein profiles and functions were compared between smoker (n = 21) and control groups (n = 20). In the smoking group, ferric ion reduction abilities of serum and high-density lipoprotein (HDL) fractions were significantly reduced, and low-density lipoprotein (LDL) was severely oxidized. All lipoprotein particles from the smoker group showed higher advanced glycated end products with more triglyceride (TG) content compared with the control group. Lipoproteins from smokers showed faster agarose gel electromobility as well as greater smear band intensity in SDS-PAGE due to oxidation and glycation. LDL from smokers was more sensitive to oxidation and promoted foam cell forma-tion in macrophages. Gel filtration column chromatography revealed that the protein and cholesterol peaks of VLDL and LDL were elevated in the smoker group, whereas those of HDL were reduced. Human dermal fibroblast cells from the smoker group showed severe senescence following treatment with HDL2 and HDL3. Although HDL from young smokers showed impaired antioxidant ability, smaller particle size, and increased TG content, cholesteryl ester transfer protein activities were greatly enhanced in the serum and HDL fractions of the smoker group. In conclusion, smoking can cause production of dysfunctional lipoproteins having a smaller particle size that exacerbate senescence and atherogenic progress due to oxidation and glycation.

  3. Defective ATM-Kap-1-mediated chromatin remodeling impairs DNA repair and accelerates senescence in progeria mouse model.

    Science.gov (United States)

    Liu, Baohua; Wang, Zimei; Ghosh, Shrestha; Zhou, Zhongjun

    2013-04-01

    ATM-mediated phosphorylation of KAP-1 triggers chromatin remodeling and facilitates the loading and retention of repair proteins at DNA lesions. Mouse embryonic fibroblasts (MEFs) derived from Zmpste24(-/-) mice undergo early senescence, attributable to delayed recruitment of DNA repair proteins. Here, we show that ATM-Kap-1 signaling is compromised in Zmpste24(-/-) MEFs, leading to defective DNA damage-induced chromatin remodeling. Knocking down Kap-1 rescues impaired chromatin remodeling, defective DNA repair and early senescence in Zmpste24(-/-) MEFs. Thus, ATM-Kap-1-mediated chromatin remodeling plays a critical role in premature aging, carrying significant implications for progeria therapy.

  4. Evolution of plant senescence

    Directory of Open Access Journals (Sweden)

    Young Mike

    2009-07-01

    characteristics of senescence-related genes allow a framework to be constructed of decisive events in the evolution of the senescence syndrome of modern land-plants. Combining phylogenetic, comparative sequence, gene expression and morphogenetic information leads to the conclusion that biochemical, cellular, integrative and adaptive systems were progressively added to the ancient primary core process of senescence as the evolving plant encountered new environmental and developmental contexts.

  5. Role of cellular senescence and apoptosis in kidney development%细胞衰老与凋亡在肾脏发育中的作用

    Institute of Scientific and Technical Information of China (English)

    李清刚; 谢院生; 陈香美

    2014-01-01

    Senescence is a normal process in the embryonic development,which is involved in embryonic tissue remodeling,tissue development,and morphogenesis,as a programmed aging mechanism during development.As different cellular processes,senescence and apoptosis are closely related to each other.Apoptosis plays an important role during the ureter development.Apoptosis in common nephric duct (CND)occurs normally during development to make the ureteral orifice separate from Wolffian duct (WD) and then fuse with the bladder epithelium,which leads to normal ureter development.%衰老是胚胎发育过程中的一种正常的程序,参与胚胎发育的组织重构、组织发育和形态上发生,属于发育程序性衰老机制。作为不同的细胞过程,衰老与凋亡密切相关。在输尿管发育过程中,凋亡具有重要作用,胚胎肾管(CND)发生正常凋亡使得输尿管口与中肾管(WD)分离并与膀胱上皮融合,维持正常输尿管发育以及与膀胱接口正常。

  6. Scoring of senescence signalling in multiple human tumour gene expression datasets, identification of a correlation between senescence score and drug toxicity in the NCI60 panel and a pro-inflammatory signature correlating with survival advantage in peritoneal mesothelioma

    Directory of Open Access Journals (Sweden)

    Burns Sharon

    2010-10-01

    Full Text Available Abstract Background Cellular senescence is a major barrier to tumour progression, though its role in pathogenesis of cancer and other diseases is poorly understood in vivo. Improved understanding of the degree to which latent senescence signalling persists in tumours might identify intervention strategies to provoke "accelerated senescence" responses as a therapeutic outcome. Senescence involves convergence of multiple pathways and requires ongoing dynamic signalling throughout its establishment and maintenance. Recent discovery of several new markers allows for an expression profiling approach to study specific senescence phenotypes in relevant tissue samples. We adopted a "senescence scoring" methodology based on expression profiles of multiple senescence markers to examine the degree to which signals of damage-associated or secretory senescence persist in various human tumours. Results We first show that scoring captures differential induction of damage or inflammatory pathways in a series of public datasets involving radiotherapy of colon adenocarcinoma, chemotherapy of breast cancer cells, replicative senescence of mesenchymal stem cells, and progression of melanoma. We extended these results to investigate correlations between senescence score and growth inhibition in response to ~1500 compounds in the NCI60 panel. Scoring of our own mesenchymal tumour dataset highlighted differential expression of secretory signalling pathways between distinct subgroups of MPNST, liposarcomas and peritoneal mesothelioma. Furthermore, a pro-inflammatory signature yielded by hierarchical clustering of secretory markers showed prognostic significance in mesothelioma. Conclusions We find that "senescence scoring" accurately reports senescence signalling in a variety of situations where senescence would be expected to occur and highlights differential expression of damage associated and secretory senescence pathways in a context-dependent manner.

  7. Alpha fucosidase and beta galactosidase in serum of a Lyme disease patients as a possible marker of accelerated senescence — a preliminary study

    Directory of Open Access Journals (Sweden)

    Anna Wasiluk

    2012-07-01

    Full Text Available Lyme disease (LD is the most prevalent tick-borne disease in Europe. LD is caused by the spirochete Borrelia burgdorferi. LD is a chronic disease which can attack a number of organs: skin, heart, brain, joints. Chronic, low-grade inflammation involves general production of pro-inflammatory cytokines and inflammatory markers and is a typical feature of aging. So far, the best method of diagnosing LD is a time-consuming and expensive two-stage serological method. The aim of our study was to evaluate the activity of two lysosomal exoglycosidases: α-fucosidase (FUC and β-galactosidase (GAL in the serum of patients with Lyme disease, as potential markers of LD. Due to the increasing number of patients with Lyme disease and a number of false results, new ways to diagnose this disease are still being sought. As elevated level of β-galactosidase is a manifestation of residual lysosomal activity in senescent cells, the increase in its activity in serum during chronic Lyme disease might be a marker of a potentially accelerated senescence process. The study was performed on serum taken from cubital veins of 15 patients with Lyme disease and eight healthy subjects (control group. FUC and GAL activity was measured by the method of Chatterjee et al. as modified by Zwierz et al. In the serum of patients with Lyme disease, GAL activity significantly increased (p = 0.029, and the activity of FUC had a tendency to increase (p = 0.153, compared to the control group. A significant increase in GAL activity in the serum of patients with Lyme disease indicates an increased catabolism of glycoconjugates (glycoproteins, glycolipids, proteoglycans and could be helpful in the diagnosis of Lyme disease, although this requires confirmation in a larger group of patients. As GAL is the most widely used assay for detection of senescent cells, an elevated level of β-galactosidase might be a manifestation of accelerated senescence process in the course of Lyme

  8. The anti-aging effects of LW-AFC via correcting immune dysfunctions in senescence accelerated mouse resistant 1 (SAMR1) strain.

    Science.gov (United States)

    Wang, Jianhui; Cheng, Xiaorui; Zhang, Xiaorui; Cheng, Junping; Xu, Yiran; Zeng, Ju; Zhou, Wenxia; Zhang, Yongxiang

    2016-05-10

    Although there were considerable advances in the anti-aging medical field, it is short of therapeutic drug for anti-aging. Mounting evidence indicates that the immunosenescence is the key physiopathological mechanism of aging. This study showed the treatment of LW-AFC, an herbal medicine, decreased the grading score of senescence, increased weight, prolonged average life span and ameliorated spatial memory impairment in 12- and 24-month-old senescence accelerated mouse resistant 1 (SAMR1) strain. And these anti-aging effects of LW-AFC were more excellent than melatonin. The administration of LW-AFC enhanced ConA- and LPS-induced splenocyte proliferation in aged SAMR1 mice. The treatment of LW-AFC not only reversed the decreased the proportions of helper T cells, suppressor T cells and B cells, the increased regulatory T cells in the peripheral blood of old SAMR1 mice, but also could modulate the abnormal secretion of IL-1β, IL-2, IL-6, IL-17, IL-23, GM-CSF, IFN-γ, TNF-α, TNF-β, RANTES, eotaxin, MCP-1, IL-4, IL-5, IL-10 and G-CSF. These data indicated that LW-AFC reversed the immunosenescence status by restoring immunodeficiency and decreasing chronic inflammation and suggested LW-AFC may be an effective anti-aging agent.

  9. 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

  10. Functional and RNA-sequencing analysis revealed expression of a novel stay-green gene from Zoysia japonica (ZjSGR caused chlorophyll degradation and accelerated senescence in Arabidopsis

    Directory of Open Access Journals (Sweden)

    Ke Teng

    2016-12-01

    Full Text Available Senescence is not only an important developmental process, but also a responsive regulation to abiotic and biotic stress for plants. Stay-green protein plays crucial roles in plant senescence and chlorophyll degradation. However, the underlying mechanisms were not well studied, particularly in non-model plants. In this study, a novel stay-green gene, ZjSGR, was isolated from Zoysia japonica. Subcellular localization result demonstrated that ZjSGR was localized in the chloroplasts. Quantitative real-time PCR results together with promoter activity determination using transgenic Arabidopsis confirmed that ZjSGR could be induced by darkness, ABA and MeJA. Its expression levels could also be up-regulated by natural senescence, but suppressed by SA treatments. Overexpression of ZjSGR in Arabidopsis resulted in a rapid yellowing phenotype; complementary experiments proved that ZjSGR was a functional homologue of AtNYE1 from Arabidopsis thaliana. Overexpression of ZjSGR accelerated chlorophyll degradation and impaired photosynthesis in Arabidopsis. Transmission electron microscopy observation revealed that overexpression of ZjSGR decomposed the chloroplasts structure. RNA sequencing analysis showed that ZjSGR could play multiple roles in senescence and chlorophyll degradation by regulating hormone signal transduction and the expression of a large number of senescence and environmental stress related genes. Our study provides a better understanding of the roles of SGRs, and new insight into the senescence and chlorophyll degradation mechanisms in plants.

  11. A Modified Cellular Automaton in Lagrange Form with Velocity Dependent Acceleration Rate

    Directory of Open Access Journals (Sweden)

    K. Rawat

    2011-07-01

    Full Text Available Road traffic micro simulations based on the individual motion of all the involvedvehicles are now recognized as an important tool to describe, understand and manage roadtraffic. With increasing computational power, simulating traffic in microscopic level bymeans of Cellular Automaton becomes a real possibility. Based on Nasch model of singlelane traffic flow, a modified Cellular Automaton traffic flow model is proposed to simulatehomogeneous and mixed type traffic flow. The model is developed with modified cell size,incorporating different acceleration characteristics depending upon the speed of eachindividual vehicle. Comparisons are made between Nasch model and modified model. It isobserved that slope of congested branch is changed for modified model as the vehicle thatare coming out of jam having dissimilar acceleration capabilities, therefore there is not asudden drop in throughput near critical density  c .

  12. Identification and Characterization of a Potent Activator of p53-Independent Cellular Senescence via a Small-Molecule Screen for Modifiers of the Integrated Stress Response

    Science.gov (United States)

    Sayers, Carly M.; Papandreou, Ioanna; Guttmann, David M.; Maas, Nancy L.; Diehl, J. Alan; Witze, Eric S.; Koong, Albert C.

    2013-01-01

    The Integrated Stress Response (ISR) is a signaling program that enables cellular adaptation to stressful conditions like hypoxia and nutrient deprivation in the tumor microenvironment. An important effector of the ISR is activating transcription factor 4 (ATF4), a transcription factor that regulates genes involved in redox homeostasis and amino acid metabolism and transport. Because both inhibition and overactivation of the ISR can induce tumor cell death, modulators of ATF4 expression could prove to be clinically useful. In this study, chemical libraries were screened for modulators of ATF4 expression. We identified one compound, E235 (N-(1-benzyl-piperidin-4-yl)-2-(4-fluoro-phenyl)-benzo[d]imidazo[2,1-b]thiazole-7-carboxamide), that activated the ISR and dose-dependently increased levels of ATF4 in transformed cells. A dose-dependent decrease in viability was observed in several mouse and human tumor cell lines, and knockdown of ATF4 significantly increased the antiproliferative effects of E235. Interestingly, low μM doses of E235 induced senescence in many cell types, including HT1080 human fibrosarcoma and B16F10 mouse melanoma cells. E235-mediated induction of senescence was not dependent on p21 or p53; however, p21 conferred protection against the growth inhibitory effects of E235. Treatment with E235 resulted in an increase in cells arrested at the G2/M phase with a concurrent decrease in S-phase cells. E235 also activated DNA damage response signaling, resulting in increased levels of Ser15-phosphorylated p53, γ-H2AX, and phosphorylated checkpoint kinase 2 (Chk2), although E235 does not appear to cause physical DNA damage. Induction of γ-H2AX was abrogated in ATF4 knockdown cells. Together, these results suggest that modulation of the ISR pathway with the small molecule E235 could be a promising antitumor strategy. PMID:23229510

  13. Behavioral and omics analyses study on potential involvement of dipeptide balenine through supplementation in diet of senescence-accelerated mouse prone 8

    Directory of Open Access Journals (Sweden)

    Nobuhiro Wada

    2016-12-01

    Full Text Available This study investigates effects of dipeptide balenine, as a major component of whale meat extract (hereafter, WME, supplementation on senescence-accelerated mouse prone 8 (SAMP8, an Alzheimer's disease (AD model at level of learning and memory formation and brain expression profiles genome-wide in brain. Mice fed experimental balenine (+WME supplemented diet for 26 weeks were subjected to four behavioral tests – open field, Y-maze, novel object recognition, and water-filled multiple T-maze – to examine effects on learning and memory. Brain transcriptome of SAMP8 mice-fed the WME diet over control low-safflower oil (LSO diet-fed mice was delineated on a 4 × 44 K mouse whole genome DNA microarray chip. Results revealed the WME diet not only induced improvements in the learning and memory formation but also positively modulated changes in the brain of the SAMP8 mouse; the gene inventories are publically available for analysis by the scientific community. Interestingly, the SAMP8 mouse model presented many genetic characteristics of AD, and numerous novel molecules (Slc2a5, Treh, Fbp1, Aldob, Ppp1r1a, DNase1, Agxt2l1, Cyp2e1, Acsm1, Acsm2, and Pah were revealed over the SAMR1 (senescence-accelerated mouse resistant 1 mouse, to be oppositely regulated/recovered under the balenine (+WME supplemented diet regime by DNA microarray and bioinformatics analyses. Our present study demonstrates an experimental strategy to understand the effects of dipeptide balenine, prominetly contained in meat diet, on SAMP8, providing new insight into whole brain transcriptome changes genome-wide. The gene expression data has been deposited into the Gene Expression Omnibus (GEO: GSE76459. The data will be a valuable resource in examining the effects of natural products, and which could also serve as a human model for further functional analysis and investigation.

  14. WNT16B is a new marker of cellular senescence that regulates p53 activity and the phosphoinositide 3-kinase/AKT pathway.

    Science.gov (United States)

    Binet, Romuald; Ythier, Damien; Robles, Ana I; Collado, Manuel; Larrieu, Delphine; Fonti, Claire; Brambilla, Elisabeth; Brambilla, Christian; Serrano, Manuel; Harris, Curtis C; Pedeux, Rémy

    2009-12-15

    Senescence is a tumor suppression mechanism that is induced by several stimuli, including oncogenic signaling and telomere shortening, and controlled by the p53/p21(WAF1) signaling pathway. Recently, a critical role for secreted factors has emerged, suggesting that extracellular signals are necessary for the onset and maintenance of senescence. Conversely, factors secreted by senescent cells may promote tumor growth. By using expression profiling techniques, we searched for secreted factors that were overexpressed in fibroblasts undergoing replicative senescence. We identified WNT16B, a member of the WNT family of secreted proteins. We found that WNT16B is overexpressed in cells undergoing stress-induced premature senescence and oncogene-induced senescence in both MRC5 cell line and the in vivo murine model of K-Ras(V12)-induced senescence. By small interfering RNA experiments, we observed that both p53 and WNT16B are necessary for the onset of replicative senescence. WNT16B expression is required for the full transcriptional activation of p21(WAF1). Moreover, WNT16B regulates activation of the phosphoinositide 3-kinase (PI3K)/AKT pathway. Overall, we identified WNT16B as a new marker of senescence that regulates p53 activity and the PI3K/AKT pathway and is necessary for the onset of replicative senescence.

  15. STIM1 accelerates cell senescence in a remodeled microenvironment but enhances the epithelial-to-mesenchymal transition in prostate cancer

    Science.gov (United States)

    Xu, Yingxi; Zhang, Shu; Niu, Haiying; Ye, Yujie; Hu, Fen; Chen, Si; Li, Xuefei; Luo, Xiaohe; Jiang, Shan; Liu, Yanhua; Chen, Yanan; Li, Junying; Xiang, Rong; Li, Na

    2015-01-01

    The importance of store-operated Ca2+ entry (SOCE) and the role of its key molecular regulators, STIM1 and ORAI1, in the development of cancer are emerging. Here, we report an unexpected dual function of SOCE in prostate cancer progression by revealing a decrease in the expression of STIM1 in human hyperplasia and tumor tissues of high histological grade and by demonstrating that STIM1 and ORAI1 inhibit cell growth by arresting the G0/G1 phase and enhancing cell senescence in human prostate cancer cells. In addition, STIM1 and ORAI1 inhibited NF-κB signaling and remodeled the tumor microenvironment by reducing the formation of M2 phenotype macrophages, possibly creating an unfavorable tumor microenvironment and inhibiting cancer development. However, STIM1 also promoted cell migration and the epithelial-to-mesenchymal transition by activating TGF-β, Snail and Wnt/β-Catenin pathways. Thus, our study revealed novel regulatory effects and the mechanisms by which STIM1 affects cell senescence, tumor migration and the tumor microenvironment, revealing that STIM1 has multiple functions in prostate cancer cells. PMID:26257076

  16. Ribosomal L1 domain and lysine-rich region are essential for CSIG/ RSL1D1 to regulate proliferation and senescence

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Liwei; Zhao, Wenting; Zheng, Quanhui; Chen, Tianda; Qi, Ji; Li, Guodong; Tong, Tanjun, E-mail: tztong@bjmu.edu.cn

    2016-01-15

    The expression change of cellular senescence-associated genes is underlying the genetic foundation of cellular senescence. Using a suppressive subtractive hybridization system, we identified CSIG (cellular senescence-inhibited gene protein; RSL1D1) as a novel senescence-associated gene. CSIG is implicated in various process including cell cycle regulation, apoptosis, and tumor metastasis. We previously showed that CSIG plays an important role in regulating cell proliferation and cellular senescence progression through inhibiting PTEN, however, which domain or region of CSIG contributes to this function? To clarify this question, we investigated the functional importance of ribosomal L1 domain and lysine (Lys) -rich region of CSIG. The data showed that expression of CSIG potently reduced PTEN expression, increased cell proliferation rates, and reduced the senescent phenotype (lower SA-β-gal activity). By contrast, neither the expression of CSIG N- terminal (NT) fragment containing the ribosomal L1 domain nor C-terminal (CT) fragment containing Lys-rich region could significantly altered the levels of PTEN; instead of promoting cell proliferation and delaying cellular senescence, expression of CSIG-NT or CSIG-CT inhibited cell proliferation and accelerated cell senescence (increased SA-β-gal activity) compared to either CSIG over-expressing or control (empty vector transfected) cells. The further immunofluorescence analysis showed that CSIG-CT and CSIG-NT truncated proteins exhibited different subcellular distribution with that of wild-type CSIG. Conclusively, both ribosomal L1 domain and Lys-rich region of CSIG are critical for CSIG to act as a regulator of cell proliferation and cellular senescence. - Highlights: • The ribosomal L1 domain and lysine-rich region of CSIG were expressed. • They are critical for CSIG to regulate proliferation and senescence. • CSIG and its domains exhibit different subcellular distribution.

  17. Early leaf senescence is associated with an altered cellular redox balance in Arabidopsis cpr5/old1 mutants

    NARCIS (Netherlands)

    Jing, H. -C.; Hebeler, R.; Oeljeklaus, S.; Sitek, B.; Stuehler, K.; Meyer, H. E.; Sturre, M. J. G.; Hille, J.; Warscheid, B.; Dijkwel, P. P.; Stühler, K.

    2008-01-01

    Reactive oxygen species (ROS) are the inevitable by-products of essential cellular metabolic and physiological activities. Plants have developed sophisticated gene networks of ROS generation and scavenging systems. However, ROS regulation is still poorly understood. Here, we report that mutations in

  18. Early leaf senescence is associated with an altered cellular redox balance in Arabidopsis cpr5/old1 mutants

    NARCIS (Netherlands)

    Jing, H. -C.; Hebeler, R.; Oeljeklaus, S.; Sitek, B.; Stuehler, K.; Meyer, H. E.; Sturre, M. J. G.; Hille, J.; Warscheid, B.; Dijkwel, P. P.; Stühler, K.

    Reactive oxygen species (ROS) are the inevitable by-products of essential cellular metabolic and physiological activities. Plants have developed sophisticated gene networks of ROS generation and scavenging systems. However, ROS regulation is still poorly understood. Here, we report that mutations in

  19. Germ line transmission of the Cdk4(R24C) mutation facilitates tumorigenesis and escape from cellular senescence.

    Science.gov (United States)

    Rane, Sushil G; Cosenza, Stephen C; Mettus, Richard V; Reddy, E Premkumar

    2002-01-01

    Mutations in CDK4 and its key kinase inhibitor p16(INK4a) have been implicated in the genesis and progression of familial human melanoma. The importance of the CDK4 locus in human cancer first became evident following the identification of a germ line CDK4-Arg24Cys (R24C) mutation, which abolishes the ability of CDK4 to bind to p16(INK4a). To determine the role of the Cdk4(R24C) germ line mutation in the genesis of other cancer types, we introduced the R24C mutation in the Cdk4 locus of mice by using Cre-loxP-mediated "knock-in" technology. Cdk4(R24C/R24C) mouse embryo fibroblasts (MEFs) displayed increased Cdk4 kinase activity resulting in hyperphosphorylation of all three members of the Rb family, pRb, p107, and p130. MEFs derived from Cdk4(R24C/R24C) mice displayed decreased doubling times, escape from replicative senescence, and escape sensitivity to contact-induced growth arrest. These MEFs also exhibited a high degree of susceptibility to oncogene-induced transformation, suggesting that the Cdk4(R24C) mutation can serve as a primary event in the progression towards a fully transformed phenotype. In agreement with the in vitro data, homozygous Cdk4(R24C/R24C) mice developed tumors of various etiology within 8 to 10 months of their life span. The majority of these tumors were found in the pancreas, pituitary, brain, mammary tissue, and skin. In addition, Cdk4(R24C/R24C) mice showed extraordinary susceptibility to carcinogens and developed papillomas within the first 8 to 10 weeks following cutaneous application of the carcinogens 9,10-di-methyl-1,2-benz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). This report formally establishes that the activation of Cdk4 is sufficient to promote cancer in many tissues. The observation that a wide variety of tumors develop in mice harboring the Cdk4(R24C) mutation offers a genetic proof that Cdk4 activation may constitute a central event in the genesis of many types of cancers in addition to melanoma.

  20. SM22{alpha}-induced activation of p16{sup INK4a}/retinoblastoma pathway promotes cellular senescence caused by a subclinical dose of {gamma}-radiation and doxorubicin in HepG2 cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Tae Rim; Lee, Hee Min; Lee, So Yong; Kim, Eun Jin; Kim, Kug Chan [Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of); Paik, Sang Gi [Department of Biology, School of Biosciences and Biotechnology, Chungnam National University, Daejeon (Korea, Republic of); Cho, Eun Wie, E-mail: ewcho@kribb.re.kr [Daejeon-KRIBB-FHCRC Cooperation Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon (Korea, Republic of); Kim, In Gyu, E-mail: igkim@kaeri.re.kr [Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2010-09-10

    Research highlights: {yields} SM22{alpha} overexpression in HepG2 cells leads cells to a growth arrest state, and the treatment of a subclinical dose of {gamma}-radiation or doxorubicin promotes cellular senescence. {yields} SM22{alpha} overexpression elevates p16{sup INK4a} followed by pRB activation, but there are no effects on p53/p21{sup WAF1/Cip1} pathway. {yields} SM22{alpha}-induced MT-1G activates p16{sup INK4a}/pRB pathway, which promotes cellular senescence by damaging agents. -- Abstract: Smooth muscle protein 22-alpha (SM22{alpha}) is known as a transformation- and shape change-sensitive actin cross-linking protein found in smooth muscle tissue and fibroblasts; however, its functional role remains uncertain. We reported previously that SM22{alpha} overexpression confers resistance against anti-cancer drugs or radiation via induction of metallothionein (MT) isozymes in HepG2 cells. In this study, we demonstrate that SM22{alpha} overexpression leads cells to a growth arrest state and promotes cellular senescence caused by treatment with a subclinical dose of {gamma}-radiation (0.05 and 0.1 Gy) or doxorubicin (0.01 and 0.05 {mu}g/ml), compared to control cells. Senescence growth arrest is known to be controlled by p53 phosphorylation/p21{sup WAF1/Cip1} induction or p16{sup INK4a}/retinoblastoma protein (pRB) activation. SM22{alpha} overexpression in HepG2 cells elevated p16{sup INK4a} followed by pRB activation, but did not activate the p53/p21{sup WAF1/Cip1} pathway. Moreover, MT-1G, which is induced by SM22{alpha} overexpression, was involved in the activation of the p16{sup INK4a}/pRB pathway, which led to a growth arrest state and promoted cellular senescence caused by damaging agents. Our findings provide the first demonstration that SM22{alpha} modulates cellular senescence caused by damaging agents via regulation of the p16{sup INK4a}/pRB pathway in HepG2 cells and that these effects of SM22{alpha} are partially mediated by MT-1G.

  1. The behavioral, pathological and therapeutic features of the senescence-accelerated mouse prone 8 strain as an Alzheimer's disease animal model.

    Science.gov (United States)

    Cheng, Xiao-rui; Zhou, Wen-xia; Zhang, Yong-xiang

    2014-01-01

    Alzheimer's disease (AD) is a widespread and devastating progressive neurodegenerative disease. Disease-modifying treatments remain beyond reach, and the etiology of the disease is uncertain. Animal model are essential for identifying disease mechanisms and developing effective therapeutic strategies. Research on AD is currently being carried out in rodent models. The most common transgenic mouse model mimics familial AD, which accounts for a small percentage of cases. The senescence-accelerated mouse prone 8 (SAMP8) strain is a spontaneous animal model of accelerated aging. Many studies indicate that SAMP8 mice harbor the behavioral and histopathological signatures of AD, namely AD-like cognitive and behavioral alterations, neuropathological phenotypes (neuron and dendrite spine loss, spongiosis, gliosis and cholinergic deficits in the forebrain), β-amyloid deposits resembling senile plaques, and aberrant hyperphosphorylation of Tau-like neurofibrillary tangles. SAMP8 mice are useful in the development of novel therapies, and many pharmacological agents and approaches are effective in SAMP8 mice. SAMP8 mice are considered a robust model for exploring the etiopathogenesis of sporadic AD and a plausible experimental model for developing preventative and therapeutic treatments for late-onset/age-related AD, which accounts for the vast majority of cases.

  2. Changes in expressions of proinflammatory cytokines IL-1beta, TNF-alpha and IL-6 in the brain of senescence accelerated mouse (SAM) P8.

    Science.gov (United States)

    Tha, K K; Okuma, Y; Miyazaki, H; Murayama, T; Uehara, T; Hatakeyama, R; Hayashi, Y; Nomura, Y

    2000-12-01

    The senescence-accelerated mouse (SAM) is known to be a murine model for accelerated aging. The SAMP8 strain shows age-related deterioration of learning and memory at an earlier age than control mice (SAMR1). In the present study, we investigated the changes in expressions of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in the brain of SAMP8. In the hippocampus of 10 months old SAMP8, the expression of IL-1 mRNA was significantly elevated in comparison with that of SAMR1. In both strains of SAMs, increases in IL-1beta protein in the brain were observed at 10 months of age compared with 2 and 5 months. The only differences found between the strain in protein levels were at 10 months and were elevations in IL-1beta in the hippocampus and hypothalamus, and in TNF-alpha and IL-6 in the cerebral cortex and the hippocampus in SAMP8 as compared with SAMR1. However, lipopolysaccharide-induced increases in the expression of these cytokines in brain did not differ between SAMP8 and SAMR1. Increases in expression of proinflammatory cytokines in the brain may be involved in the age-related neural dysfunction and/or learning deficiency in SAMP8.

  3. Effect of an Enhanced Nose-to-Brain Delivery of Insulin on Mild and Progressive Memory Loss in the Senescence-Accelerated Mouse.

    Science.gov (United States)

    Kamei, Noriyasu; Tanaka, Misa; Choi, Hayoung; Okada, Nobuyuki; Ikeda, Takamasa; Itokazu, Rei; Takeda-Morishita, Mariko

    2017-03-06

    Insulin is now considered to be a new drug candidate for treating dementias, such as Alzheimer's disease, whose pathologies are linked to insulin resistance in the brain. Our recent work has clarified that a noncovalent strategy involving cell-penetrating peptides (CPPs) can increase the direct transport of insulin from the nasal cavity into the brain parenchyma. The present study aimed to determine whether the brain insulin level increased by intranasal coadministration of insulin with the CPP penetratin has potential for treating dementia. The pharmacological actions of insulin were investigated at different stages of memory impairment using a senescence-accelerated mouse-prone 8 (SAMP8) model. The results of spatial learning tests suggested that chronic intranasal administration of insulin with l-penetratin to SAMP8 slowed the progression of memory loss in the early stage of memory impairment. However, contrary to expectations, this strategy using penetratin was ineffective in recovering the severe cognitive dysfunction in the progressive stage, which involves brain accumulation of amyloid β (Aβ). Immunohistological examination of hippocampal regions of samples from SAMP8 in the progressive stage suggested that accelerated nose-to-brain insulin delivery had a partial neuroprotective function but unexpectedly increased Aβ plaque deposition in the hippocampus. These findings suggest that the efficient nose-to-brain delivery of insulin combined with noncovalent CPP strategy has different effects on dementia during the mild and progressive stages of cognitive dysfunction.

  4. Modulation of Macrophage Polarization and HMGB1-TLR2/TLR4 Cascade Plays a Crucial Role for Cardiac Remodeling in Senescence-Accelerated Prone Mice

    Science.gov (United States)

    Arumugam, Somasundaram; Sreedhar, Remya; Palaniyandi, Suresh S.; Krishnamurthy, Prasanna; Quevedo, Joao; Watanabe, Kenichi; Konishi, Tetsuya; Thandavarayan, Rajarajan A.

    2016-01-01

    The aim of this study was to investigate the role of macrophage polarization in aging heart. Macrophage differentiation is pathogenically linked to many inflammatory and immune disorders. It is often preceded by myocardial inflammation, which is characterized by increased cardiac damage and pro-inflammatory cytokine levels. Therefore, we investigated the hypothesis that senescence accelerated-prone (SAMP8) mice cardiac tissue would develop macrophage polarization compared with senescence-resistant control (SAMR1) mice. Both SAMP8 and SAMR1 mice were sacrificed when they became six month old. We evaluated, histo-pathological changes and modifications in protein expression by Western blotting and immuno-histochemical staining for M1 and M2 macrophage markers, high mobility group protein (HMG)B1 and its cascade proteins, pro-inflammatory factors and inflammatory cytokines in cardiac tissue. We observed significant upregulation of HMGB1, toll-like receptor (TLR)2, TLR4, nuclear factor (NF)κB p65, tumor necrosis factor (TNF)α, cyclooxygenase (COX)2, interferon (IFN)γ, interleukin (IL)-1β, IL-6 and M1 like macrophage specific marker cluster of differentiation (CD)68 expressions in SAMP8 heart. In contrast, M2 macrophage specific marker CD36, and IL-10 expressions were down-regulated in SAMP8 mice. The results from the study demonstrated that, HMGB1-TLR2/TLR4 signaling cascade and induction of phenotypic switching to M1 macrophage polarization in SAMP8 mice heart would be one of the possible reasons behind the cardiac dysfunction and thus it could become an important therapeutic target to improve the age related cardiac dysfunction. PMID:27070323

  5. Chronic Psychological Stress Accelerates Vascular Senescence and Impairs Ischemia-Induced Neovascularization: The Role of Dipeptidyl Peptidase-4/Glucagon-Like Peptide-1-Adiponectin Axis.

    Science.gov (United States)

    Piao, Limei; Zhao, Guangxian; Zhu, Enbo; Inoue, Aiko; Shibata, Rei; Lei, Yanna; Hu, Lina; Yu, Chenglin; Yang, Guang; Wu, Hongxian; Xu, Wenhu; Okumura, Kenji; Ouchi, Noriyuki; Murohara, Toyoaki; Kuzuya, Masafumi; Cheng, Xian Wu

    2017-09-28

    Exposure to psychosocial stress is a risk factor for cardiovascular disease, including vascular aging and regeneration. Given that dipeptidyl peptidase-4 (DPP4) regulates several intracellular signaling pathways associated with the glucagon-like peptide-1 (GLP-1) metabolism, we investigated the role of DPP4/GLP-1 axis in vascular senescence and ischemia-induced neovascularization in mice under chronic stress, with a special focus on adiponectin -mediated peroxisome proliferator activated receptor-γ/its co-activator 1α (PGC-1α) activation. Seven-week-old mice subjected to restraint stress for 4 weeks underwent ischemic surgery and were kept under immobilization stress conditions. Mice that underwent ischemic surgery alone served as controls. We demonstrated that stress impaired the recovery of the ischemic/normal blood-flow ratio throughout the follow-up period and capillary formation. On postoperative day 4, stressed mice showed the following: increased levels of plasma and ischemic muscle DPP4 and decreased levels of GLP-1 and adiponectin in plasma and phospho-AMP-activated protein kinase α (p-AMPKα), vascular endothelial growth factor, peroxisome proliferator activated receptor-γ, PGC-1α, and Sirt1 proteins and insulin receptor 1 and glucose transporter 4 genes in the ischemic tissues, vessels, and/or adipose tissues and numbers of circulating endothelial CD31(+)/c-Kit(+) progenitor cells. Chronic stress accelerated aortic senescence and impaired aortic endothelial sprouting. DPP4 inhibition and GLP-1 receptor activation improved these changes; these benefits were abrogated by adiponectin blocking and genetic depletion. These results indicate that the DPP4/GLP-1-adiponectin axis is a novel therapeutic target for the treatment of vascular aging and cardiovascular disease under chronic stress conditions. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

  6. CHARACTERISTICS OF CELLULAR AND SERUM COMPONENTS OF MUCO-SALIVARY IMMUNE COMPARTMENT IN MATURE, AGED, AND SENESCENT PERSONS

    Directory of Open Access Journals (Sweden)

    E. D. Altman

    2011-01-01

    Full Text Available Аbstract. The objective of present study was to determine the immunological features of immune system aging in mucosa-associated lymphoid tissue (MALT in the patients at different ages (mature, aging and old observed at a dental unit. A study of cellular spectrum and humoral factors in salivary gland secretions has been performed in a group of 106 persons (35 to 90 years old. A number of age-dependent features of the immune profile were revealed for the mucous-salivary area, thus characterizing involution events within MALT structures. Among specific markers determining intensity of MALT-associated aging, a decreased percentage of viable immune cells (below 40%, along with the prevalence of the neutrophilic granulocytes in the salivary secretions (over 98% (with increased expression of β2-integrins; decreased counts of mononuclear cells, i.e., mononuclear cells with low expression of CD11β adhesion molecules, B-lymhocytes, and Th-lymphocytes have been revealed. Alterations in serum factors included a general decrease in complement system activity (СН50 and anaphylotoxines (С3а,С5а; elevated protein, mucine, and IgМ levels. The revealed specific features of cellular and humoral immunity within MALT-associated muco-salivary zone may be considered as a normal response connected with natural aging processes. (Med. Immunol., 2011, vol. 13, N 2-3, pp 167-174

  7. A cellular automata traffic flow model considering the heterogeneity of acceleration and delay probability

    Science.gov (United States)

    Li, Qi-Lang; Wong, S. C.; Min, Jie; Tian, Shuo; Wang, Bing-Hong

    2016-08-01

    This study examines the cellular automata traffic flow model, which considers the heterogeneity of vehicle acceleration and the delay probability of vehicles. Computer simulations are used to identify three typical phases in the model: free-flow, synchronized flow, and wide moving traffic jam. In the synchronized flow region of the fundamental diagram, the low and high velocity vehicles compete with each other and play an important role in the evolution of the system. The analysis shows that there are two types of bistable phases. However, in the original Nagel and Schreckenberg cellular automata traffic model, there are only two kinds of traffic conditions, namely, free-flow and traffic jams. The synchronized flow phase and bistable phase have not been found.

  8. Screening of microRNAs associated with Alzheimer's disease using oxidative stress cell model and different strains of senescence accelerated mice.

    Science.gov (United States)

    Zhang, Rui; Zhang, Qingfu; Niu, Jingya; Lu, Kang; Xie, Bing; Cui, Dongsheng; Xu, Shunjiang

    2014-03-15

    Oxidative stress plays a critical role in the etiology and pathogenesis of Alzheimer's disease (AD), and the molecular mechanisms that control the neuron response to oxidative stress have been extensively studied. However, the effects of oxidative stress on miRNA expression in hippocampal neurons has not been investigated, and little is known about the roles of ROS-modulated miRNAs in cell function as yet. In this study, miRNA microarray technology was used to analyze the expression of miRNAs in the oxidative stressed primary hippocampal neurons, hippocampus of senescence accelerated mouse prone 8 (SAMP8) and prone 10 (SAMP10). The targets of co-regulated microRNAs were also selected for computational prediction using miRWalk software and functional analysis by the DAVID software. In addition, the changes of co-regulated microRNA expression were validated by quantitative real-time PCR. The results of microarray analysis showed that miR-329, miR-193b, miR-20a, miR-296, and miR-130b were all upregulated in H2O2-induced primary hippocampal neurons and different strains of senescence accelerated mice. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that these co-regulated microRNAs may be involved in the regulation of cell growth, apoptosis, signal transmission and cancer development. In which, mitogen-activated protein kinase (MAPK) signaling pathway was one of the most significant pathways to be affected by 83 target genes of miR-329, miR-193b, miR-20a miR-296, and miR-130b. The quantitative real-time PCR data confirmed the alterations of the co-upregulated miRNAs. These results suggested that oxidative stress alters the miRNA expression profile of hippocampal neurons, and the deregulated miRNAs might play potential roles in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD). This study provided a strong basis for the future study aiming at contributions of miRNAs induced by oxidative stress in AD.

  9. 2, 3, 7, 8-Tetrachlorodibenzo-P-dioxin (TCDD induces premature senescence in human and rodent neuronal cells via ROS-dependent mechanisms.

    Directory of Open Access Journals (Sweden)

    Chunhua Wan

    Full Text Available The widespread environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD is a potent toxicant that causes significant neurotoxicity. However, the biological events that participate in this process remain largely elusive. In the present study, we demonstrated that TCDD exposure triggered apparent premature senescence in rat pheochromocytoma (PC12 and human neuroblastoma SH-SY5Y cells. Senescence-associated β-galactosidase (SA-β-Gal assay revealed that TCDD induced senescence in PC12 neuronal cells at doses as low as 10 nM. TCDD led to F-actin reorganization and the appearance of an alternative senescence marker, γ-H2AX foci, both of which are important features of cellular senescence. In addition, TCDD exposure altered the expression of senescence marker proteins, such as p16, p21 and p-Rb, in both dose- and time-dependent manners. Furthermore, we demonstrated that TCDD promotes mitochondrial dysfunction and the accumulation of cellular reactive oxygen species (ROS in PC12 cells, leading to the activation of signaling pathways that are involved in ROS metabolism and senescence. TCDD-induced ROS generation promoted significant oxidative DNA damage and lipid peroxidation. Notably, treatment with the ROS scavenger N-acetylcysteine (NAC markedly attenuated TCDD-induced ROS production, cellular oxidative damage and neuronal senescence. Moreover, we found that TCDD induced a similar ROS-mediated senescence response in human neuroblastoma SH-SY5Y cells. In sum, these results demonstrate for the first time that TCDD induces premature senescence in neuronal cells by promoting intracellular ROS production, supporting the idea that accelerating the onset of neuronal senescence may be an important mechanism underlying TCDD-induced neurotoxic effects.

  10. 2, 3, 7, 8-Tetrachlorodibenzo-P-dioxin (TCDD) induces premature senescence in human and rodent neuronal cells via ROS-dependent mechanisms.

    Science.gov (United States)

    Wan, Chunhua; Liu, Jiao; Nie, Xiaoke; Zhao, Jianya; Zhou, Songlin; Duan, Zhiqing; Tang, Cuiying; Liang, Lingwei; Xu, Guangfei

    2014-01-01

    The widespread environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent toxicant that causes significant neurotoxicity. However, the biological events that participate in this process remain largely elusive. In the present study, we demonstrated that TCDD exposure triggered apparent premature senescence in rat pheochromocytoma (PC12) and human neuroblastoma SH-SY5Y cells. Senescence-associated β-galactosidase (SA-β-Gal) assay revealed that TCDD induced senescence in PC12 neuronal cells at doses as low as 10 nM. TCDD led to F-actin reorganization and the appearance of an alternative senescence marker, γ-H2AX foci, both of which are important features of cellular senescence. In addition, TCDD exposure altered the expression of senescence marker proteins, such as p16, p21 and p-Rb, in both dose- and time-dependent manners. Furthermore, we demonstrated that TCDD promotes mitochondrial dysfunction and the accumulation of cellular reactive oxygen species (ROS) in PC12 cells, leading to the activation of signaling pathways that are involved in ROS metabolism and senescence. TCDD-induced ROS generation promoted significant oxidative DNA damage and lipid peroxidation. Notably, treatment with the ROS scavenger N-acetylcysteine (NAC) markedly attenuated TCDD-induced ROS production, cellular oxidative damage and neuronal senescence. Moreover, we found that TCDD induced a similar ROS-mediated senescence response in human neuroblastoma SH-SY5Y cells. In sum, these results demonstrate for the first time that TCDD induces premature senescence in neuronal cells by promoting intracellular ROS production, supporting the idea that accelerating the onset of neuronal senescence may be an important mechanism underlying TCDD-induced neurotoxic effects.

  11. Up-regulation of leucocytes genes implicated in telomere dysfunction and cellular senescence correlates with depression and anxiety severity scores.

    Directory of Open Access Journals (Sweden)

    Jean-Raymond Teyssier

    Full Text Available BACKGROUND: Major depressive disorder (MDD is frequently associated with chronic medical illness responsible of increased disability and mortality. Inflammation and oxidative stress are considered to be the major mediators of the allostatic load, and has been shown to correlate with telomere erosion in the leucocytes of MDD patients, leading to the model of accelerated aging. However, the significance of telomere length as an exclusive biomarker of aging has been questioned on both methodological and biological grounds. Furthermore, telomeres significantly shorten only in patients with long lasting MDD. Sensitive and dynamic functional biomarkers of aging would be clinically useful to evaluate the somatic impact of MDD. METHODOLOGY: To address this issue we have measured in the blood leucocytes of MDD patients (N=17 and controls (N=16 the expression of two genes identified as robust biomarkers of human aging and telomere dysfunction: p16(INK4a and STMN1. We have also quantified the transcripts of genes involved in the repair of oxidative DNA damage at telomeres (OGG1, telomere regulation and elongation (TERT, and in the response to biopsychological stress (FOS and DUSP1. RESULTS: The OGG1, p16(INK4a, and STMN1 gene were significantly up-regulated (25 to 100% in the leucocytes of MDD patients. Expression of p16(INK4a and STMN1 was directly correlated with anxiety scores in the depression group, and that of p16(INK4a, STMN and TERT with the depression and anxiety scores in the combined sample (MDD plus controls. Furthermore, we identified a unique correlative pattern of gene expression in the leucocytes of MDD subjects. CONCLUSIONS: Expression of p16(INK4 and STMN1 is a promising biomarker for future epidemiological assessment of the somatic impact of depressive and anxious symptoms, at both clinical and subclinical level in both depressive patients and general population.

  12. Cellular senescence and autophagy of myoepithelial cells are involved in the progression of in situ areas of carcinoma ex-pleomorphic adenoma to invasive carcinoma. An in vitro model.

    Science.gov (United States)

    Silva, Carolina Amália Barcellos; Martinez, Elizabeth Ferreira; Demasi, Ana Paula Dias; Altemani, Albina; da Silveira Bossonaro, Jeruza Pinheiro; Araújo, Ney Soares; de Araújo, Vera Cavalcanti

    2015-09-01

    During tumor invasion, benign myoepithelial cells of carcinoma ex-pleomorphic adenoma (CXPA) surround malignant epithelial cells and disappear. The mechanisms involved in the death and disappearance of these myoepithelial cells were investigated via analysis of the expression of regulatory proteins for apoptosis, autophagy and cellular senescence in an in situ in vitro model. Protein expression relating to apoptosis (Bax, Bcl-2, Survivin), autophagy (Beclin-1, LC3B) and cellular senescence (p21, p16) was evaluated using indirect immunofluorescence. β-galactosidase expression was assessed via histochemistry. Biopsies of CXPA (ex vivo) allowed immunhistochemical evaluation of p21 and p16, whilst LC3B, p21 and p16 protein expression was analyzed by western blotting. In the in vitro model, the myoepithelial cells were positive for LC3B (cytoplasm) and p21 (nucleus), whilst in vivo positivity for p21 and p16 was observed. In vitro, β-galactosidase activity increased in the myoepithelial cells over time. Western blotting analysis revealed an increased LC3B, p16 and p21 expression in the myoepithelial cells with previous contact with the malignant cells when compared with those without contact. The investigation of behavior of benign myoepithelial cells in ductal areas of CXAP revealed that the myoepithelial cells are involved in the autophagy-senescence phenotype that subsequently leads to their disappearance.

  13. Silencing SlELP2L, a tomato Elongator complex protein 2-like gene, inhibits leaf growth, accelerates leaf, sepal senescence, and produces dark-green fruit.

    Science.gov (United States)

    Zhu, Mingku; Li, Yali; Chen, Guoping; Ren, Lijun; Xie, Qiaoli; Zhao, Zhiping; Hu, Zongli

    2015-01-09

    The multi-subunit complex Elongator interacts with elongating RNA polymerase II (RNAPII) and is thought to facilitate transcription through histone acetylation. Elongator is highly conserved in eukaryotes, yet has multiple kingdom-specific functions in diverse organisms. Recent genetic studies performed in Arabidopsis have demonstrated that Elongator functions in plant growth and development, and in response to biotic and abiotic stress. However, little is known about its roles in other plant species. Here, we study the function of an Elongator complex protein 2-like gene in tomato, here designated as SlELP2L, through RNAi-mediated gene silencing. Silencing SlELP2L in tomato inhibits leaf growth, accelerates leaf and sepal senescence, and produces dark-green fruit with reduced GA and IAA contents in leaves, and increased chlorophyll accumulation in pericarps. Gene expression analysis indicated that SlELP2L-silenced plants had reduced transcript levels of ethylene- and ripening-related genes during fruit ripening with slightly decreased carotenoid content in fruits, while the expression of DNA methyltransferase genes was up-regulated, indicating that SlELP2L may modulate DNA methylation in tomato. Besides, silencing SlELP2L increases ABA sensitivity in inhibiting seedling growth. These results suggest that SlELP2L plays important roles in regulating plant growth and development, as well as in response to ABA in tomato.

  14. Suppression of the aging-associated decline in physical performance by a combination of resveratrol intake and habitual exercise in senescence-accelerated mice.

    Science.gov (United States)

    Murase, Takatoshi; Haramizu, Satoshi; Ota, Noriyasu; Hase, Tadashi

    2009-08-01

    The decline in physical performance with increasing age is a crucial problem in our aging society. We examined the effects of resveratrol, a natural polyphenolic compound present in grapes, in combination with habitual exercise on the aging-associated decline in physical performance in senescence-accelerated prone mice (SAMP1). The endurance capacity of SAMP1 mice undergoing an exercise regimen (SAMP1-Ex) decreased over 12 weeks whereas that of SAMP1 mice fed 0.2% (w/w) resveratrol along with exercise (SAMP1-ExRes) remained significantly higher. In the SAMP1-ExRes group, there was a significant increase in oxygen consumption and skeletal muscle mRNA levels of mitochondrial function-related enzymes. These results suggest that the intake of resveratrol, together with habitual exercise, is beneficial for suppressing the aging-related decline in physical performance and that these effects are attributable, at least in part, to improved mitochondrial function in skeletal muscle.

  15. Accelerated senescence prone mouse-8 shows early onset of deficits in spatial learning and memory in the radial six-arm water maze.

    Science.gov (United States)

    Chen, Gui-Hai; Wang, Yue-Ju; Wang, Xiao-Min; Zhou, Jiang-Ning

    2004-10-15

    Available data indicate that the senescence-accelerated prone mouse 8 (SAMP8) is an appropriate model of brain aging, with impairments in nonspatial learning and memory beginning as early as 2 months of age, and spatial learning and memory deficiencies not becoming apparent until after 4 months of age. However, with other strains (e.g., C57BL mice), the impairment in spatial memory was found earlier than that in nonspatial memory. We considered the possibility that the observed differences could be due to strain-specific differences in the training equipment. In the present study, a new optimized testing apparatus-the radial six-arm water maze (RAWM)-for detecting spatial learning and memory in mice, was employed, to determine whether there is impairment of spatial learning and memory in young SAMP8. The relationship between the spatial learning measures observed with the RAWM and the Morris maze, a classic spatial learning and memory testing apparatus, was also explored. It was found that, in the RAWM, rather than in the Morris maze, the impairment in spatial learning could be measured in SAMP8 mice as early as 3 months old, and the impairment in spatial memory in SAMP8 mice aged 5 months. These results suggested that the spatial learning and memory deficiencies could be found in early life of SAMP8 mice, and that RAWM and Morris maze each detect different aspects of spatial learning and memory.

  16. Ageing induced vascular smooth muscle cell senescence in atherosclerosis.

    Science.gov (United States)

    Uryga, Anna K; Bennett, Martin R

    2016-04-15

    Atherosclerosis is a disease of ageing in that its incidence and prevalence increase with age. However, atherosclerosis is also associated with biological ageing, manifest by a number of typical hallmarks of ageing in the atherosclerotic plaque. Thus, accelerated biological ageing may be superimposed on the effects of chronological ageing in atherosclerosis. Tissue ageing is seen in all cells that comprise the plaque, but particularly in vascular smooth muscle cells (VSMCs). Hallmarks of ageing include evidence of cell senescence, DNA damage (including telomere attrition), mitochondrial dysfunction, a pro-inflammatory secretory phenotype, defects in proteostasis, epigenetic changes, deregulated nutrient sensing, and exhaustion of progenitor cells. In this model, initial damage to DNA (genomic, telomeric, mitochondrial and epigenetic changes) results in a number of cellular responses (cellular senescence, deregulated nutrient sensing and defects in proteostasis). Ultimately, ongoing damage and attempts at repair by continued proliferation overwhelm reparative capacity, causing loss of specialised cell functions, cell death and inflammation. This review summarises the evidence for accelerated biological ageing in atherosclerosis, the functional consequences of cell ageing on cells comprising the plaque, and the causal role that VSMC senescence plays in atherogenesis. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

  17. 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.

  18. Senescence induction; a possible cancer therapy

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    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.

  19. Acceleration of leaf senescence is slowed down in transgenic barley plants deficient in the DNA/RNA-binding protein WHIRLY1

    Science.gov (United States)

    Kucharewicz, Weronika; Distelfeld, Assaf; Bilger, Wolfgang; Müller, Maren; Munné-Bosch, Sergi; Hensel, Götz

    2017-01-01

    Abstract WHIRLY1 in barley was isolated as a potential regulator of the senescence-associated gene HvS40. In order to investigate whether the plastid–nucleus-located DNA/RNA-binding protein WHIRLY1 plays a role in regulation of leaf senescence, primary foliage leaves from transgenic barley plants with an RNAi-mediated knockdown of the WHIRLY1 gene were characterized by typical senescence parameters, namely pigment contents, function and composition of the photosynthetic apparatus, as well as expression of selected genes known to be either down- or up-regulated during leaf senescence. When the plants were grown at low light intensity, senescence progression was similar between wild-type and RNAi-W1 plants. Likewise, dark-induced senescence of detached leaves was not affected by reduction of WHIRLY1. When plants were grown at high light intensity, however, senescence was induced prematurely in wild-type plants but was delayed in RNAi-W1 plants. This result suggests that WHIRLY1 plays a role in light sensing and/or stress communication between chloroplasts and the nucleus. PMID:28338757

  20. Accelerator Mass Spectrometry Allows for Cellular Quantification of Doxorubicin at Femtomolar Concentrations

    Energy Technology Data Exchange (ETDEWEB)

    DeGregorio, M W; Dingley, K H; Wurz, G T; Ubick, E; Turteltaub, K W

    2005-04-12

    Accelerator mass spectrometry (AMS) is a highly sensitive analytical methodology used to quantify the content of radioisotopes, such as {sup 14}C, in a sample. The primary goals of this work were to demonstrate the utility of AMS in determining cellular [{sup 14}C]doxorubicin (DOX) concentrations and to develop a sensitive assay that is superior to high performance liquid chromatography (HPLC) for the quantification of DOX at the tumor level. In order to validate the superior sensitivity of AMS versus HPLC with fluorescence detection, we performed three studies comparing the cellular accumulation of DOX: one in vitro cell line study, and two in vivo xenograft mouse studies. Using AMS, we quantified cellular DOX content up to 4 hours following in vitro exposure at concentrations ranging from 0.2 pg/ml (345 fM) to 2 {micro}g/ml (3.45 {micro}M) [{sup 14}C]DOX. The results of this study show that, compared to standard fluorescence-based HPLC, the AMS method was over five orders of magnitude more sensitive. Two in vivo studies compared the sensitivity of AMS to HPLC using a nude mouse xenograft model in which breast cancer cells were implanted subcutaneously. After sufficiently large tumors formed, DOX was administered intravenously at two dose levels. Additionally, we tested the AMS method in a nude mouse xenograft model of multidrug resistance (MDR) in which each mouse was implanted with both wild type and MDR+ cells on opposite flanks. The results of the second and third studies showed that DOX concentrations were significantly higher in the wild type tumors compared to the MDR+ tumors, consistent with the MDR model. The extreme sensitivity of AMS should facilitate similar studies in humans to establish target site drug delivery and to potentially determine the optimal treatment dose and regimen.

  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

    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. Oncogenic senescence: a multi-functional perspective

    NARCIS (Netherlands)

    Baker, D.J.; Alimirah, F.; Deursen, J.M.A. van; Campisi, J.; Hildesheim, J.

    2017-01-01

    Cellular senescence is defined as an irreversible growth arrest with the acquisition of a distinctive secretome. The growth arrest is a potent anticancer mechanism whereas the secretome facilitates wound healing, tissue repair, and development. The senescence response has also become increasingly

  3. Marcadores de senescencia celular en cáncer y precáncer oral Cellular senescence markers in oral cancer and precancer

    Directory of Open Access Journals (Sweden)

    J. Campo-Trapero

    2008-02-01

    Full Text Available Estudios recientes han demostrado la capacidad del organismo humano para detener el crecimiento de potenciales células cancerígenas y paralizarlas. Este mecanismo antitumoral, que actúa como freno del proceso maligno, se conocía ya en estudios de laboratorio "in vitro", pero se ha comprobado también su presencia en modelos "in vivo", tanto en ratones como en muestras de tejido de pacientes con cáncer. A este mecanismo se le denomina senescencia celular y se define como un sistema de defensa de emergencia de las células que están en camino de convertirse en cancerosas, una respuesta ante el estímulo de un oncogén. Se trataría pues de un freno a la progresión de las lesiones cancerizables, condenando a esas células a una "cadena perpetua celular". Este artículo de revisión se propone describir este mecanismo y poner al día la evidencia al respecto de este proceso, así como los marcadores de senescencia existentes en relación con el cáncer y precáncer oral.Recent studies have demonstrated the capacity of the human organism to prevent the growth of potentially carcinogenic cells, paralyzing them. This antitumor mechanism, which acts as a brake on the malignant process, was already known in lab studies "in vitro" but has now also been verified "in vivo" in mice and in tissue samples from cancer patients. This mechanism is known as cellular senescence and is defined as an emergency defense system for cells on the way to becoming cancerous, i.e., a response to the stimulation of an oncogene. These cells are sentenced to "life imprisonment", impeding the progression of premalignant lesions. This review aims to describe this mechanism and present an update of the evidence on this phenomenon in the setting of oral cancer and precancer.

  4. Simvastatin suppresses breast cancer cell proliferation induced by senescent cells

    NARCIS (Netherlands)

    Liu, Su; Uppal, Harpreet; Demaria, Marco; Desprez, Pierre-Yves; Campisi, Judith; Kapahi, Pankaj

    2015-01-01

    Cellular senescence suppresses cancer by preventing the proliferation of damaged cells, but senescent cells can also promote cancer though the pro-inflammatory senescence-associated secretory phenotype (SASP). Simvastatin, an HMG-coA reductase inhibitor, is known to attenuate inflammation and preven

  5. Mitochondrial DNA damage induces apoptosis in senescent cells

    NARCIS (Netherlands)

    Laberge, R-M; Adler, D; DeMaria, M; Mechtouf, N; Teachenor, R; Cardin, G B; Desprez, P-Y; Campisi, J; Rodier, F

    2013-01-01

    Senescence is a cellular response to damage and stress. The senescence response prevents cancer by suppressing the proliferation of cells with a compromised genome and contributes to optimal wound healing in normal tissues. Persistent senescent cells are also thought to drive aging and age-associate

  6. Limited Role of Murine ATM in Oncogene-Induced Senescence and p53-Dependent Tumor Suppression

    Science.gov (United States)

    Martinez-Pastor, Barbara; Ortega-Molina, Ana; Soria, Rebeca; Collado, Manuel; Fernandez-Capetillo, Oscar; Serrano, Manuel

    2009-01-01

    Recent studies in human fibroblasts have provided a new general paradigm of tumor suppression according to which oncogenic signaling produces DNA damage and this, in turn, results in ATM/p53-dependent cellular senescence. Here, we have tested this model in a variety of murine experimental systems. Overexpression of oncogenic Ras in murine fibroblasts efficiently induced senescence but this occurred in the absence of detectable DNA damage signaling, thus suggesting a fundamental difference between human and murine cells. Moreover, lung adenomas initiated by endogenous levels of oncogenic K-Ras presented abundant senescent cells, but undetectable DNA damage signaling. Accordingly, K-Ras-driven adenomas were also senescent in Atm-null mice, and the tumorigenic progression of these lesions was only modestly accelerated by Atm-deficiency. Finally, we have examined chemically-induced fibrosarcomas, which possess a persistently activated DNA damage response and are highly sensitive to the activity of p53. We found that the absence of Atm favored genomic instability in the resulting tumors, but did not affect the persistent DNA damage response and did not impair p53-dependent tumor suppression. All together, we conclude that oncogene-induced senescence in mice may occur in the absence of a detectable DNA damage response. Regarding murine Atm, our data suggest that it plays a minor role in oncogene-induced senescence or in p53-dependent tumor suppression, being its tumor suppressive activity probably limited to the maintenance of genomic stability. PMID:19421407

  7. Limited role of murine ATM in oncogene-induced senescence and p53-dependent tumor suppression.

    Directory of Open Access Journals (Sweden)

    Alejo Efeyan

    Full Text Available Recent studies in human fibroblasts have provided a new general paradigm of tumor suppression according to which oncogenic signaling produces DNA damage and this, in turn, results in ATM/p53-dependent cellular senescence. Here, we have tested this model in a variety of murine experimental systems. Overexpression of oncogenic Ras in murine fibroblasts efficiently induced senescence but this occurred in the absence of detectable DNA damage signaling, thus suggesting a fundamental difference between human and murine cells. Moreover, lung adenomas initiated by endogenous levels of oncogenic K-Ras presented abundant senescent cells, but undetectable DNA damage signaling. Accordingly, K-Ras-driven adenomas were also senescent in Atm-null mice, and the tumorigenic progression of these lesions was only modestly accelerated by Atm-deficiency. Finally, we have examined chemically-induced fibrosarcomas, which possess a persistently activated DNA damage response and are highly sensitive to the activity of p53. We found that the absence of Atm favored genomic instability in the resulting tumors, but did not affect the persistent DNA damage response and did not impair p53-dependent tumor suppression. All together, we conclude that oncogene-induced senescence in mice may occur in the absence of a detectable DNA damage response. Regarding murine Atm, our data suggest that it plays a minor role in oncogene-induced senescence or in p53-dependent tumor suppression, being its tumor suppressive activity probably limited to the maintenance of genomic stability.

  8. Eldecalcitol improves mechanical strength of cortical bones by stimulating the periosteal bone formation in the senescence-accelerated SAM/P6 mice - a comparison with alfacalcidol.

    Science.gov (United States)

    Shiraishi, Ayako; Sakai, Sadaoki; Saito, Hitoshi; Takahashi, Fumiaki

    2014-10-01

    Eldecalcitol (ELD), a 2β-hydroxypropyloxy derivative of 1α,25(OH)2D3, is a potent inhibitor of bone resorption that has demonstrated a greater effect at reducing the risk of fracture in osteoporotic patients than alfacalcidol (ALF). In the present study, we used the senescence-accelerated mouse strain P6 (SAM/P6), which has low bone mass caused by osteoblast dysfunction, to evaluate the effect of ELD on cortical bone in comparison with ALF. Four-month-old SAM/P6 mice were given either ELD (0.025 or 0.05μg/kg) or ALF (0.2 or 0.4μg/kg) by oral gavage 5 times/week for 6 weeks. Both ELD and ALF increased serum calcium (Ca) in a dose-dependent manner. Serum Ca levels in the ELD 0.05μg/kg group were comparable to those of the ALF 0.2μg/kg group. ELD 0.05μg/kg significantly improved the bone biomechanical properties of the femur compared with the vehicle control group (pBone histomorphometry revealed that in the femoral endocortical surface, the suppression of bone resorption parameters (N.Oc/BS) and bone formation parameters (MS/BS) by ELD (0.05μg/kg) was greater than that by ALF (0.2μg/kg). In contrast, in the femoral periosteal surface, ELD 0.05μg/kg significantly increased bone formation parameters (BFR/BS, MS/BS) compared with the vehicle control group (pbone not only by inhibiting endocortical bone resorption but also by stimulating the periosteal bone formation in SAM/P6 mice. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.

  9. Antisense directed against PS-1 gene decreases brain oxidative markers in aged senescence accelerated mice (SAMP8) and reverses learning and memory impairment: a proteomics study.

    Science.gov (United States)

    Fiorini, Ada; Sultana, Rukhsana; Förster, Sarah; Perluigi, Marzia; Cenini, Giovanna; Cini, Chiara; Cai, Jian; Klein, Jon B; Farr, Susan A; Niehoff, Michael L; Morley, John E; Kumar, Vijaya B; Allan Butterfield, D

    2013-12-01

    Amyloid β-peptide (Aβ) plays a central role in the pathophysiology of Alzheimer's disease (AD) through the induction of oxidative stress. This peptide is produced by proteolytic cleavage of amyloid precursor protein (APP) by the action of β- and γ-secretases. Previous studies demonstrated that reduction of Aβ, using an antisense oligonucleotide (AO) directed against the Aβ region of APP, reduced oxidative stress-mediated damage and prevented or reverted cognitive deficits in senescence-accelerated prone mice (SAMP8), a useful animal model for investigating the events related to Aβ pathology and possibly to the early phase of AD. In the current study, aged SAMP8 were treated by AO directed against PS-1, a component of the γ-secretase complex, and tested for learning and memory in T-maze foot shock avoidance and novel object recognition. Brain tissue was collected to identify the decrease of oxidative stress and to evaluate the proteins that are differently expressed and oxidized after the reduction in free radical levels induced by Aβ. We used both expression proteomics and redox proteomics approaches. In brain of AO-treated mice a decrease of oxidative stress markers was found, and the proteins identified by proteomics as expressed differently or nitrated are involved in processes known to be impaired in AD. Our results suggest that the treatment with AO directed against PS-1 in old SAMP8 mice reverses learning and memory deficits and reduces Aβ-mediated oxidative stress with restoration to the normal condition and identifies possible pharmacological targets to combat this devastating dementing disease. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor

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    Copp& #233; , Jean-Philippe; Patil, Christopher; Rodier, Francis; Sun, Yu; Munoz, Denise; Goldstein, Joshua; Nelson, Peter; Desprez, Pierre-Yves; Campisi, Judith

    2008-10-24

    Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays to provide a quantitative assessment of factors secreted by senescent cells. We show that human cells induced to senesce by genotoxic stress secrete myriad factors associated with inflammation and malignancy. This senescence-associated secretory phenotype (SASP) developed slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. Remarkably similar SASPs developed in normal fibroblasts, normal epithelial cells, and epithelial tumor cells after genotoxic stress in culture, and in epithelial tumor cells in vivo after treatment of prostate cancer patients with DNA-damaging chemotherapy. In cultured premalignant epithelial cells, SASPs induced an epithelial-mesenchyme transition and invasiveness, hallmarks of malignancy, by a paracrine mechanism that depended largely on the SASP factors interleukin (IL)-6 and IL-8. Strikingly, two manipulations markedly amplified, and accelerated development of, the SASPs: oncogenic RAS expression, which causes genotoxic stress and senescence in normal cells, and functional loss of the p53 tumor suppressor protein. Both loss of p53 and gain of oncogenic RAS also exacerbated the promalignant paracrine activities of the SASPs. Our findings define a central feature of genotoxic stress-induced senescence. Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment.

  11. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.

    Directory of Open Access Journals (Sweden)

    Jean-Philippe Coppé

    2008-12-01

    Full Text Available Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays to provide a quantitative assessment of factors secreted by senescent cells. We show that human cells induced to senesce by genotoxic stress secrete myriad factors associated with inflammation and malignancy. This senescence-associated secretory phenotype (SASP developed slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. Remarkably similar SASPs developed in normal fibroblasts, normal epithelial cells, and epithelial tumor cells after genotoxic stress in culture, and in epithelial tumor cells in vivo after treatment of prostate cancer patients with DNA-damaging chemotherapy. In cultured premalignant epithelial cells, SASPs induced an epithelial-mesenchyme transition and invasiveness, hallmarks of malignancy, by a paracrine mechanism that depended largely on the SASP factors interleukin (IL-6 and IL-8. Strikingly, two manipulations markedly amplified, and accelerated development of, the SASPs: oncogenic RAS expression, which causes genotoxic stress and senescence in normal cells, and functional loss of the p53 tumor suppressor protein. Both loss of p53 and gain of oncogenic RAS also exacerbated the promalignant paracrine activities of the SASPs. Our findings define a central feature of genotoxic stress-induced senescence. Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment.

  12. p53/p21 Pathway involved in mediating cellular senescence of bone marrow-derived mesenchymal stem cells from systemic lupus erythematosus patients.

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    Gu, Zhifeng; Jiang, Jinxia; Tan, Wei; Xia, Yunfei; Cao, Haixia; Meng, Yan; Da, Zhanyun; Liu, Hong; Cheng, Chun

    2013-01-01

    Our and other groups have found that bone marrow-derived mesenchymal stem cells (BM-MSCs) from systemic lupus erythematosus (SLE) patients exhibited senescent behavior and are involved in the pathogenesis of SLE. Numerous studies have shown that activation of the p53/p21 pathway inhibits the proliferation of BM-MSCs. The aim of this study was to determine whether p53/p21 pathway is involved in regulating the aging of BM-MSCs from SLE patients and the underlying mechanisms. We further confirmed that BM-MSCs from SLE patients showed characteristics of senescence. The expressions of p53 and p21 were significantly increased, whereas levels of Cyclin E, cyclin-dependent kinase-2, and phosphorylation of retinoblastoma protein were decreased in the BM-MSCs from SLE patients and knockdown of p21 expression reversed the senescent features of BM-MSCs from SLE patients. Our results demonstrated that p53/p21 pathway played an important role in the senescence process of BM-MSCs from SLE.

  13. p53/p21 Pathway Involved in Mediating Cellular Senescence of Bone Marrow-Derived Mesenchymal Stem Cells from Systemic Lupus Erythematosus Patients

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    Zhifeng Gu

    2013-01-01

    Full Text Available Our and other groups have found that bone marrow-derived mesenchymal stem cells (BM-MSCs from systemic lupus erythematosus (SLE patients exhibited senescent behavior and are involved in the pathogenesis of SLE. Numerous studies have shown that activation of the p53/p21 pathway inhibits the proliferation of BM-MSCs. The aim of this study was to determine whether p53/p21 pathway is involved in regulating the aging of BM-MSCs from SLE patients and the underlying mechanisms. We further confirmed that BM-MSCs from SLE patients showed characteristics of senescence. The expressions of p53 and p21 were significantly increased, whereas levels of Cyclin E, cyclin-dependent kinase-2, and phosphorylation of retinoblastoma protein were decreased in the BM-MSCs from SLE patients and knockdown of p21 expression reversed the senescent features of BM-MSCs from SLE patients. Our results demonstrated that p53/p21 pathway played an important role in the senescence process of BM-MSCs from SLE.

  14. Formate generated by cellular oxidation of formaldehyde accelerates the glycolytic flux in cultured astrocytes.

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    Tulpule, Ketki; Dringen, Ralf

    2012-04-01

    Formaldehyde is a neurotoxic compound that can be endogenously generated in the brain. Because astrocytes play a key role in metabolism and detoxification processes in brain, we have investigated the capacity of these cells to metabolize formaldehyde using primary astrocyte-rich cultures as a model system. Application of formaldehyde to these cultures resulted in the appearance of formate in cells and in a time-, concentration- and temperature-dependent disappearance of formaldehyde from the medium that was accompanied by a matching extracellular accumulation of formate. This formaldehyde-oxidizing capacity of astrocyte cultures is likely to be catalyzed by alcohol dehydrogenase 3 and aldehyde dehydrogenase 2, because the cells of the cultures contain the mRNAs of these formaldehyde-oxidizing enzymes. In addition, exposure to formaldehyde increased both glucose consumption and lactate production by the cells. Both the strong increase in the cellular formate content and the increase in glycolytic flux were only observed after application of formaldehyde to the cells, but not after treatment with exogenous methanol or formate. The accelerated lactate production was not additive to that obtained for azide, a known inhibitor of complex IV of the respiratory chain, and persisted after removal of formaldehyde after a formaldehyde exposure for 1.5 h. These data demonstrate that cultured astrocytes efficiently oxidize formaldehyde to formate, which subsequently enhances glycolytic flux, most likely by inhibition of mitochondrial respiration.

  15. Human endothelial senescence induced by IL-1α in vitro

    Institute of Scientific and Technical Information of China (English)

    YAO Aiyu; ZHOU Jianjun; LIU Yabing; FENG Meifu; ZHOU Rouli

    2004-01-01

    Interleukin 1(IL-1) is an important proinflammatory cytokine that causes pleiotropic effects. Vascular endothelial cells stimulated by IL-1α can lead to the inflammatory response. Reactive oxygen species (ROS) are also generated at the site of inflammation and serve as an important factor against foreign invader. Here we report that long-term stimulation of human vein endothelial cells with IL-1α can accelerate their senescence associated with β-galactosidase activity. The flow cytometric analyses showed that most of the induced cells entered G0-G1 phase. DNA damage was more severe in senescent cells by comet assay. The induced cells by IL-1α had higher levels of ROS and malonyldialdehyde (MDA), lower activity of antioxidant enzymes and lower capacity of total antioxidant systems than control, which led to cell damage and cell degeneration, that is to say, which contributed to cellular senescence. Our results gave a direct proof to a new hypothesis-"the inflammation hypothesis of aging" on cellular level, and also provided a basis for the study on anti-aging and aging-related diseases.

  16. Senescence from glioma stem cell differentiation promotes tumor growth

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    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.

  17. 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.

  18. Oxidative stress and leaf senescence

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    Sedigheh Hatami

    2011-11-01

    Full Text Available Abstract Background Senescence is an important developmental process that leads to the cell death through highly regulated genetically controlled processes in plants. Biotic and abiotic Oxidative stresses can also artificially induce senescence and increase the production of reactive oxygen species (ROS specifically in chloroplast. One of the important oxidative stresses is paraquat that induces deviation of electron from photosynthesis electron chain and lead to the production of more ROS in chloroplast. Plants have evolved special adoptive mechanism to reallocate nutrient to reproductive and juvenile organs in senescence and different oxidative stresses. Rubisco seems to be the most abundant protein in plants and is involved in many changes during senescence. Results In the present study, the effects of ROS on Rubisco during senescence and oxidative stresses were evaluated by measuring photosynthesis factors such as net photosynthesis rate (Pn, stomatal conductance (G, evaporation rate (E, intra cellular CO2 concentration (Ci, fluorescence and total protein during three stages of development. Our results showed that in paraquat treated plants, CO2 assimilation is the most effective factor that refers to Rubisco damages. The highest correlation and regression coefficient belonged to Ci, while correlation coefficient between photosynthesis rate and total protein was much smaller. Conclusion It appears in the early stage of oxidative stresses such as exposing to paraquat, ROS has the most effect on Rubisco activity that induces more susceptibility to Rubisco specific protease. Moreover, Rubisco deactivation acts as an initiative signal for Rubisco degradation.

  19. Oxidative stress induces senescence in human mesenchymal stem cells

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    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. PKCι depletion initiates mitotic slippage-induced senescence in glioblastoma.

    Science.gov (United States)

    Restall, Ian J; Parolin, Doris A E; Daneshmand, Manijeh; Hanson, Jennifer E L; Simard, Manon A; Fitzpatrick, Megan E; Kumar, Ritesh; Lavictoire, Sylvie J; Lorimer, Ian A J

    2015-01-01

    Cellular senescence is a tumor suppressor mechanism where cells enter a permanent growth arrest following cellular stress. Oncogene-induced senescence (OIS) is induced in non-malignant cells following the expression of an oncogene or inactivation of a tumor suppressor. Previously, we have shown that protein kinase C iota (PKCι) depletion induces cellular senescence in glioblastoma cells in the absence of a detectable DNA damage response. Here we demonstrate that senescent glioblastoma cells exhibit an aberrant centrosome morphology. This was observed in basal levels of senescence, in p21-induced senescence, and in PKCι depletion-induced senescence. In addition, senescent glioblastoma cells are polyploid, Ki-67 negative and arrest at the G1/S checkpoint, as determined by expression of cell cycle regulatory proteins. These markers are all consistent with cells that have undergone mitotic slippage. Failure of the spindle assembly checkpoint to function properly can lead to mitotic slippage, resulting in the premature exit of mitotic cells into the G1 phase of the cell cycle. Although in G1, these cells have the replicated DNA and centrosomal phenotype of a cell that has entered mitosis and failed to divide. Overall, we demonstrate that PKCι depletion initiates mitotic slippage-induced senescence in glioblastoma cells. To our knowledge, this is the first evidence of markers of mitotic slippage directly in senescent cells by co-staining for senescence-associated β-galactosidase and immunofluorescence markers in the same cell population. We suggest that markers of mitotic slippage be assessed in future studies of senescence to determine the extent of mitotic slippage in the induction of cellular senescence.

  1. 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.

  2. 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.

  3. A steroid like phytochemical Antcin M is an anti-aging reagent that eliminates hyperglycemia-accelerated premature senescence in dermal fibroblasts by direct activation of Nrf2 and SIRT-1.

    Science.gov (United States)

    Senthil, Kumar K J; Gokila, Vani M; Mau, Jeng-Leun; Lin, Chin-Chung; Chu, Fang-Hua; Wei, Chia-Cheng; Liao, Vivian Hsiu-Chuan; Wang, Sheng-Yang

    2016-09-27

    The present study revealed the anti-aging properties of antcin M (ANM) and elucidated the molecular mechanism underlying the effects. We found that exposure of human normal dermal fibroblasts (HNDFs) to high-glucose (HG, 30 mM) for 3 days, accelerated G0/G1 phase arrest and senescence. Indeed, co-treatment with ANM (10 µM) significantly attenuated HG-induced growth arrest and promoted cell proliferation. Further molecular analysis revealed that ANM blocked the HG-induced reduction in G1-S transition regulatory proteins such as cyclin D, cyclin E, CDK4, CDK6, CDK2 and protein retinoblastoma (pRb). In addition, treatment with ANM eliminated HG-induced reactive oxygen species (ROS) through the induction of anti-oxidant genes, HO-1 and NQO-1 via transcriptional activation of Nrf2. Moreover, treatment with ANM abolished HG-induced SIPS as evidenced by reduced senescence-associated β-galactosidase (SA-β-gal) activity. This effect was further confirmed by reduction in senescence-associated marker proteins including, p21CIP1, p16INK4A, and p53/FoxO1 acetylation. Also, the HG-induced decline in aging-related marker protein SMP30 was rescued by ANM. Furthermore, treatment with ANM increased SIRT-1 expression, and prevented SIRT-1 depletion. This protection was consistent with inhibition of SIRT-1 phosphorylation at Ser47 followed by blocking its upstream kinases, p38 MAPK and JNK/SAPK. Further analysis revealed that ANM partially protected HG-induced senescence in SIRT-1 silenced cells. A similar effect was also observed in Nrf2 silenced cells. However, a complete loss of protection was observed in both Nrf2 and SIRT-1 knockdown cells suggesting that both induction of Nrf2-mediated anti-oxidant defense and SIRT-1-mediated deacetylation activity contribute to the anti-aging properties of ANM in vitro. Result of in vivo studies shows that ANM-treated C. elegens exhibits an increased survival rate during HG-induced oxidative stress insult. Furthermore, ANM significantly

  4. Sp100 as a potent tumor suppressor: accelerated senescence and rapid malignant transformation of human fibroblasts through modulation of an embryonic stem cell program.

    Science.gov (United States)

    Negorev, Dmitri G; Vladimirova, Olga V; Kossenkov, Andrew V; Nikonova, Elena V; Demarest, Renee M; Capobianco, Anthony J; Showe, Michael K; Rauscher, Frank J; Showe, Louise C; Maul, Gerd G

    2010-12-01

    Identifying the functions of proteins, which associate with specific subnuclear structures, is critical to understanding eukaryotic nuclear dynamics. Sp100 is a prototypical protein of ND10/PML nuclear bodies, which colocalizes with Daxx and the proto-oncogenic PML. Sp100 isoforms contain SAND, PHD, Bromo, and HMG domains and are highly sumoylated, all characteristics suggestive of a role in chromatin-mediated gene regulation. A role for Sp100 in oncogenesis has not been defined previously. Using selective Sp100 isoform-knockdown approaches, we show that normal human diploid fibroblasts with reduced Sp100 levels rapidly senesce. Subsequently, small rapidly dividing Sp100 minus cells emerge from the senescing fibroblasts and are found to be highly tumorigenic in nude mice. The derivation of these tumorigenic cells from the parental fibroblasts is confirmed by microsatellite analysis. The small rapidly dividing Sp100 minus cells now also lack ND10/PML bodies, and exhibit genomic instability and p53 cytoplasmic sequestration. They have also activated MYC, RAS, and TERT pathways and express mesenchymal to epithelial transdifferentiation (MET) markers. Reintroduction of expression of only the Sp100A isoform is sufficient to maintain senescence and to inhibit emergence of the highly tumorigenic cells. Global transcriptome studies, quantitative PCR, and protein studies, as well as immunolocalization studies during the course of the transformation, reveal that a transient expression of stem cell markers precedes the malignant transformation. These results identify a role for Sp100 as a tumor suppressor in addition to its role in maintaining ND10/PML bodies and in the epigenetic regulation of gene expression.

  5. EIN3 and ORE1 Accelerate Degreening during Ethylene-Mediated Leaf Senescence by Directly Activating Chlorophyll Catabolic Genes in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Kai Qiu

    2015-07-01

    Full Text Available Degreening, caused by chlorophyll degradation, is the most obvious symptom of senescing leaves. Chlorophyll degradation can be triggered by endogenous and environmental cues, and ethylene is one of the major inducers. ETHYLENE INSENSITIVE3 (EIN3 is a key transcription factor in the ethylene signaling pathway. It was previously reported that EIN3, miR164, and a NAC (NAM, ATAF, and CUC transcription factor ORE1/NAC2 constitute a regulatory network mediating leaf senescence. However, how this network regulates chlorophyll degradation at molecular level is not yet elucidated. Here we report a feed-forward regulation of chlorophyll degradation that involves EIN3, ORE1, and chlorophyll catabolic genes (CCGs. Gene expression analysis showed that the induction of three major CCGs, NYE1, NYC1 and PAO, by ethylene was largely repressed in ein3 eil1 double mutant. Dual-luciferase assay revealed that EIN3 significantly enhanced the promoter activity of NYE1, NYC1 and PAO in Arabidopsis protoplasts. Furthermore, Electrophoretic mobility shift assay (EMSA indicated that EIN3 could directly bind to NYE1, NYC1 and PAO promoters. These results reveal that EIN3 functions as a positive regulator of CCG expression during ethylene-mediated chlorophyll degradation. Interestingly, ORE1, a senescence regulator which is a downstream target of EIN3, could also activate the expression of NYE1, NYC1 and PAO by directly binding to their promoters in EMSA and chromatin immunoprecipitation (ChIP assays. In addition, EIN3 and ORE1 promoted NYE1 and NYC1 transcriptions in an additive manner. These results suggest that ORE1 is also involved in the direct regulation of CCG transcription. Moreover, ORE1 activated the expression of ACS2, a major ethylene biosynthesis gene, and subsequently promoted ethylene production. Collectively, our work reveals that EIN3, ORE1 and CCGs constitute a coherent feed-forward loop involving in the robust regulation of ethylene-mediated chlorophyll

  6. Cytosolic malate dehydrogenase regulates senescence in human fibroblasts.

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    Lee, Seung-Min; Dho, So Hee; Ju, Sung-Kyu; Maeng, Jin-Soo; Kim, Jeong-Yoon; Kwon, Ki-Sun

    2012-10-01

    Carbohydrate metabolism changes during cellular senescence. Cytosolic malate dehydrogenase (MDH1) catalyzes the reversible reduction of oxaloacetate to malate at the expense of reduced nicotinamide adenine dinucleotide (NADH). Here, we show that MDH1 plays a critical role in the cellular senescence of human fibroblasts. We observed that the activity of MDH1 was reduced in old human dermal fibroblasts (HDFs) [population doublings (PD) 56], suggesting a link between decreased MDH1 protein levels and aging. Knockdown of MDH1 in young HDFs (PD 20) and the IMR90 human fibroblast cell line resulted in the appearance of significant cellular senescence features, including senescence-associated β-galactosidase staining, flattened and enlarged morphology, increased population doubling time, and elevated p16(INK4A) and p21(CIP1) protein levels. Cytosolic NAD/NADH ratios were decreased in old HDFs to the same extent as in MDH1 knockdown HDFs, suggesting that cytosolic NAD depletion is related to cellular senescence. We found that AMP-activated protein kinase, a sensor of cellular energy, was activated in MDH1 knockdown cells. We also found that sirtuin 1 (SIRT1) deacetylase, a controller of cellular senescence, was decreased in MDH1 knockdown cells. These results indicate that the decrease in MDH1 and subsequent reduction in NAD/NADH ratio, which causes SIRT1 inhibition, is a likely carbohydrate metabolism-controlled cellular senescence mechanism.

  7. Amyloid β Protein Aggravates Neuronal Senescence and Cognitive Deficits in 5XFAD Mouse Model of Alzheimer's Disease

    Institute of Scientific and Technical Information of China (English)

    Zhen Wei; Xiao-Chun Chen; Yue Song; Xiao-Dong Pan; Xiao-Man Dai; Jing Zhang; Xiao-Li Cui

    2016-01-01

    Background:Amyloid β (Aβ) has been established as a key factor for the pathological changes in the brains of patients with Alzheimer's disease (AD),and cellular senescence is closely associated with aging and cognitive impairment.However,it remains blurred whether,in the AD brains,Aβ accelerates the neuronal.senescence and whether this senescence,in turn,impairs the cognitive function.This study aimed to explore the expression of senescence-associated genes in the hippocampal tissue from young to aged 5XFAD mice and their age-matched wild type (WT) mice to determine whether senescent neurons are present in the transgenic AD mouse model.Methods:The 5XFAD mice and age-matched wild type mice,both raised from 1 to 18 months,were enrolled in the study.The senescence-associated genes in the hippocampus were analyzed and differentially expressed genes (DEGs) were screened by quantitative real-time polymerase chain reaction.Cognitive performance of the mice was evaluated by Y-maze and Morris water maze tests.Oligomeric Aβ (oAβ) (1-42) was applied to culture primary neurons to simulate the in vivo manifestation.Aging-related proteins were detected by Western blotting analysis and immunofluorescence.Results:In 5XFAD mice,of all the DEGs,the senescence-associated marker p 16 was most significantly increased,even at the early age.It was mainly localized in neurons,with a marginal expression in astrocytes (labeled as glutamine synthetase),nil expression in activated microglia (labeled as Iba1),and negatively correlated with the spatial cognitive impairments of 5XFAD mice.oAβ (1-42) induced the production of senescence-related protein p 16,but not p53 in vitro,which was in line with the in vivo manifestation.Conclusions:oAβ-accelerated neuronal senescence may be associated with the cognitive impairment in 5XFAD mice.Senescence-associated marker p 16 can serve as an indicator to estimate the cognitive prognosis for AD population.

  8. Jasmonates during senescence

    Science.gov (United States)

    Seltmann, Martin A; Hussels, Wiebke

    2010-01-01

    Jasmonic acid and derivatives are oxylipin signaling compounds derived from linolenic acid. Jasmonates accumulate during natural and dark-induced senescence but the increase in these compounds is not essential for the initiation or progression of these senescence processes. Here we report that during natural and dark-induced senescence the increase in jasmonate levels does not trigger jasmonate signaling. Furthermore we provide evidence that jasmonate production might result from membrane turnover during dark-induced senescence. PMID:21057217

  9. 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

  10. Mitochondria, telomeres and cell senescence: Implications for lung ageing and disease.

    Science.gov (United States)

    Birch, Jodie; Barnes, Peter J; Passos, Joao F

    2017-10-04

    Cellular senescence, the irreversible loss of replicative capacity in somatic cells, plays a causal role in the development of age-related pathology and in a number of age-related chronic inflammatory diseases. The ageing lung is marked by an increasing number of senescent cells, and evidence is mounting that senescence may directly contribute to a number of age-related respiratory diseases, including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Telomere dysfunction and alterations in mitochondrial homeostasis frequently occur in cellular senescence and are important to the development of the often detrimental senescence-associated secretory phenotype (SASP). The roles of telomeres, the mitochondria and cellular senescence in lung ageing and disease are discussed. Therapeutic interventions targeting cellular senescence are considered for delaying or potentially reversing age-related respiratory disease. Copyright © 2017. Published by Elsevier Inc.

  11. 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...

  12. Chronic Hepatitis B Virus Infection: The Relation between Hepatitis B Antigen Expression, Telomere Length, Senescence, Inflammation and Fibrosis.

    Directory of Open Access Journals (Sweden)

    Phaedra M Tachtatzis

    Full Text Available Chronic Hepatitis B virus (HBV infection can lead to the development of chronic hepatitis, cirrhosis and hepatocellular carcinoma. We hypothesized that HBV might accelerate hepatocyte ageing and investigated the effect of HBV on hepatocyte cell cycle state and biological age. We also investigated the relation between inflammation, fibrosis and cell cycle phase.Liver samples from patients with chronic HBV (n = 91, normal liver (n = 55 and regenerating liver (n = 15 were studied. Immunohistochemistry for cell cycle phase markers and HBV antigens was used to determine host cell cycle phase. Hepatocyte-specific telomere length was evaluated by quantitative fluorescent in-situ hybridization (Q-FISH in conjunction with hepatocyte nuclear area and HBV antigen expression. The effects of induced cell cycle arrest and induced cellular senescence on HBV production were assessed in vitro.13.7% hepatocytes in chronic HBV had entered cell cycle, but expression of markers for S, G2 and M phase was low compared with regenerating liver. Hepatocyte p21 expression was increased (10.9% in chronic HBV and correlated with liver fibrosis. Mean telomere length was reduced in chronic HBV compared to normal. However, within HBV-affected livers, hepatocytes expressing HBV antigens had longer telomeres. Telomere length declined and hepatocyte nuclear size increased as HBV core antigen (HBcAg expression shifted from the nucleus to cytoplasm. Nuclear co-expression of HBcAg and p21 was not observed. Cell cycle arrest induced in vitro was associated with increased HBV production, in contrast to in vitro induction of cellular senescence, which had no effect.Chronic HBV infection was associated with hepatocyte G1 cell cycle arrest and accelerated hepatocyte ageing, implying that HBV induced cellular senescence. However, HBV replication was confined to biologically younger hepatocytes. Changes in the cellular location of HBcAg may be related to the onset of cellular senescence.

  13. Stress-Induced Premature Senescence or Stress-Induced Senescence-Like Phenotype: One In Vivo Reality, Two Possible Definitions?

    Directory of Open Access Journals (Sweden)

    Olivier Toussaint

    2002-01-01

    Full Text Available 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 (pathophysiology and aging.

  14. 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)

  15. 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

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

    NARCIS (Netherlands)

    Demaria, Marco; Ohtani, Naoko; Youssef Hassan, Sameh; 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)

  17. The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4

    NARCIS (Netherlands)

    Kang, Chanhee; Xu, Qikai; Martin, Timothy D; Li, Mamie Z; Demaria, Marco; Aron, Liviu; Lu, Tao; Yankner, Bruce A; Campisi, Judith; Elledge, Stephen J

    2015-01-01

    Cellular senescence is a terminal stress-activated program controlled by the p53 and p16(INK4a) tumor suppressor proteins. A striking feature of senescence is the senescence-associated secretory phenotype (SASP), a pro-inflammatory response linked to tumor promotion and aging. We have identified the

  18. 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) o

  19. 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 physiologic

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

    NARCIS (Netherlands)

    Demaria, Marco; Ohtani, Naoko; Youssef Hassan, Sameh; 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) o

  1. Senescence and p130/Rb12: a new beginning to the end

    Institute of Scientific and Technical Information of China (English)

    Francesco P Fiorentino; Catherine E Symonds; Marcella Macaluso; Antonio Giordano

    2009-01-01

    Senescence is the process of cellular aging dependent on the normal physiological functions of non-immortalized cells. With increasing data being uncovered in this field, the complex molecular web regulating senescence is gradu-ally being unraveled. Recent studies have suggested two main phases of senescence, the triggering of senescence and the maintenance of senescence. Each has been supported by data implying precise roles for DNA methyltransferases, reactive oxygen species and other factors. We will first summarize the data supporting these claims and then high-light the specific role that we hypothesize that p130/Rb12 plays in the modulation of the senescence process.

  2. 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

    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...

  3. 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.

  4. Cellular and molecular effects for mutation induction in normal human cells irradiated with accelerated neon ions.

    Science.gov (United States)

    Suzuki, Masao; Tsuruoka, Chizuru; Kanai, Tatsuaki; Kato, Takeshi; Yatagai, Fumio; Watanabe, Masami

    2006-02-22

    We investigated the linear energy transfer (LET) dependence of mutation induction on the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus in normal human fibroblast-like cells irradiated with accelerated neon-ion beams. The cells were irradiated with neon-ion beams at various LETs ranging from 63 to 335 keV/microm. Neon-ion beams were accelerated by the Riken Ring Cyclotron at the Institute of Physical and Chemical Research in Japan. Mutation induction at the HPRT locus was detected to measure 6-thioguanine-resistant clones. The mutation spectrum of the deletion pattern of exons of mutants was analyzed using the multiplex polymerase chain reaction (PCR). The dose-response curves increased steeply up to 0.5 Gy and leveled off or decreased between 0.5 and 1.0 Gy, compared to the response to (137)Cs gamma-rays. The mutation frequency increased up to 105 keV/microm and then there was a downward trend with increasing LET values. The deletion pattern of exons was non-specific. About 75-100% of the mutants produced using LETs ranging from 63 to 335 keV/mum showed all or partial deletions of exons, while among gamma-ray-induced mutants 30% showed no deletions, 30% partial deletions and 40% complete deletions. These results suggested that the dose-response curves of neon-ion-induced mutations were dependent upon LET values, but the deletion pattern of DNA was not.

  5. Graphene oxide scaffold accelerates cellular proliferative response and alveolar bone healing of tooth extraction socket.

    Science.gov (United States)

    Nishida, Erika; Miyaji, Hirofumi; Kato, Akihito; Takita, Hiroko; Iwanaga, Toshihiko; Momose, Takehito; Ogawa, Kosuke; Murakami, Shusuke; Sugaya, Tsutomu; Kawanami, Masamitsu

    2016-01-01

    Graphene oxide (GO) consisting of a carbon monolayer has been widely investigated for tissue engineering platforms because of its unique properties. For this study, we fabricated a GO-applied scaffold and assessed the cellular and tissue behaviors in the scaffold. A preclinical test was conducted to ascertain whether the GO scaffold promoted bone induction in dog tooth extraction sockets. For this study, GO scaffolds were prepared by coating the surface of a collagen sponge scaffold with 0.1 and 1 µg/mL GO dispersion. Scaffolds were characterized using scanning electron microscopy (SEM), physical testing, cell seeding, and rat subcutaneous implant testing. Then a GO scaffold was implanted into a dog tooth extraction socket. Histological observations were made at 2 weeks postsurgery. SEM observations show that GO attached to the surface of collagen scaffold struts. The GO scaffold exhibited an interconnected structure resembling that of control subjects. GO application improved the physical strength, enzyme resistance, and adsorption of calcium and proteins. Cytocompatibility tests showed that GO application significantly increased osteoblastic MC3T3-E1 cell proliferation. In addition, an assessment of rat subcutaneous tissue response revealed that implantation of 1 µg/mL GO scaffold stimulated cellular ingrowth behavior, suggesting that the GO scaffold exhibited good biocompatibility. The tissue ingrowth area and DNA contents of 1 µg/mL GO scaffold were, respectively, approximately 2.5-fold and 1.4-fold greater than those of the control. Particularly, the infiltration of ED2-positive (M2) macrophages and blood vessels were prominent in the GO scaffold. Dog bone-formation tests showed that 1 µg/mL GO scaffold implantation enhanced bone formation. New bone formation following GO scaffold implantation was enhanced fivefold compared to that in control subjects. These results suggest that GO was biocompatible and had high bone-formation capability for the scaffold

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

    Science.gov (United States)

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

    2007-01-01

    Evolutionary theories of senescence predict that genes with pleiotropic functions are important for senescence regulation. In plants there is no direct molecular genetic test for the existence of such senescence-regulatory genes. Arabidopsis cpr5 mutants exhibit multiple phenotypes including hypersensitivity to various signalling molecules, constitutive expression of pathogen-related genes, abnormal trichome development, spontaneous lesion formation, and accelerated leaf senescence. These indicate that CPR5 is a beneficial gene which controls multiple facets of the Arabidopsis life cycle. Ectopic expression of CPR5 restored all the mutant phenotypes. However, in transgenic plants with increased CPR5 transcripts, accelerated leaf senescence was observed in detached leaves and at late development around 50 d after germination, as illustrated by the earlier onset of senescence-associated physiological and molecular markers. Thus, CPR5 has early-life beneficial effects by repressing cell death and insuring normal plant development, but late-life deleterious effects by promoting developmental senescence. As such, CPR5 appears to function as a typical senescence-regulatory gene as predicted by the evolutionary theories of senescence.

  7. Cancer stem cells display extremely large evolvability: alternating plastic and rigid networks as a potential Mechanism: network models, novel therapeutic target strategies, and the contributions of hypoxia, inflammation and cellular senescence.

    Science.gov (United States)

    Csermely, Peter; Hódsági, János; Korcsmáros, Tamás; Módos, Dezső; Perez-Lopez, Áron R; Szalay, Kristóf; Veres, Dániel V; Lenti, Katalin; Wu, Ling-Yun; Zhang, Xiang-Sun

    2015-02-01

    Cancer is increasingly perceived as a systems-level, network phenomenon. The major trend of malignant transformation can be described as a two-phase process, where an initial increase of network plasticity is followed by a decrease of plasticity at late stages of tumor development. The fluctuating intensity of stress factors, like hypoxia, inflammation and the either cooperative or hostile interactions of tumor inter-cellular networks, all increase the adaptation potential of cancer cells. This may lead to the bypass of cellular senescence, and to the development of cancer stem cells. We propose that the central tenet of cancer stem cell definition lies exactly in the indefinability of cancer stem cells. Actual properties of cancer stem cells depend on the individual "stress-history" of the given tumor. Cancer stem cells are characterized by an extremely large evolvability (i.e. a capacity to generate heritable phenotypic variation), which corresponds well with the defining hallmarks of cancer stem cells: the possession of the capacity to self-renew and to repeatedly re-build the heterogeneous lineages of cancer cells that comprise a tumor in new environments. Cancer stem cells represent a cell population, which is adapted to adapt. We argue that the high evolvability of cancer stem cells is helped by their repeated transitions between plastic (proliferative, symmetrically dividing) and rigid (quiescent, asymmetrically dividing, often more invasive) phenotypes having plastic and rigid networks. Thus, cancer stem cells reverse and replay cancer development multiple times. We describe network models potentially explaining cancer stem cell-like behavior. Finally, we propose novel strategies including combination therapies and multi-target drugs to overcome the Nietzschean dilemma of cancer stem cell targeting: "what does not kill me makes me stronger".

  8. Graphene oxide scaffold accelerates cellular proliferative response and alveolar bone healing of tooth extraction socket

    Directory of Open Access Journals (Sweden)

    Nishida E

    2016-05-01

    Full Text Available Erika Nishida,1 Hirofumi Miyaji,1 Akihito Kato,1 Hiroko Takita,2 Toshihiko Iwanaga,3 Takehito Momose,1 Kosuke Ogawa,1 Shusuke Murakami,1 Tsutomu Sugaya,1 Masamitsu Kawanami11Department of Periodontology and Endodontology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan; 2Support Section for Education and Research, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan; 3Laboratory of Histology and Cytology, Hokkaido University Graduate School of Medicine, Sapporo, JapanAbstract: Graphene oxide (GO consisting of a carbon monolayer has been widely investigated for tissue engineering platforms because of its unique properties. For this study, we fabricated a GO-applied scaffold and assessed the cellular and tissue behaviors in the scaffold. A preclinical test was conducted to ascertain whether the GO scaffold promoted bone induction in dog tooth extraction sockets. For this study, GO scaffolds were prepared by coating the surface of a collagen sponge scaffold with 0.1 and 1 µg/mL GO dispersion. Scaffolds were characterized using scanning electron microscopy (SEM, physical testing, cell seeding, and rat subcutaneous implant testing. Then a GO scaffold was implanted into a dog tooth extraction socket. Histological observations were made at 2 weeks postsurgery. SEM observations show that GO attached to the surface of collagen scaffold struts. The GO scaffold exhibited an interconnected structure resembling that of control subjects. GO application improved the physical strength, enzyme resistance, and adsorption of calcium and proteins. Cytocompatibility tests showed that GO application significantly increased osteoblastic MC3T3-E1 cell proliferation. In addition, an assessment of rat subcutaneous tissue response revealed that implantation of 1 µg/mL GO scaffold stimulated cellular ingrowth behavior, suggesting that the GO scaffold exhibited good biocompatibility. The tissue ingrowth area and DNA contents of 1

  9. Increased phytotoxic O3 dose accelerates autumn senescence in an O3-sensitive beech forest even under the present-level O3

    Science.gov (United States)

    Kitao, Mitsutoshi; Yasuda, Yukio; Kominami, Yuji; Yamanoi, Katsumi; Komatsu, Masabumi; Miyama, Takafumi; Mizoguchi, Yasuko; Kitaoka, Satoshi; Yazaki, Kenichi; Tobita, Hiroyuki; Yoshimura, Kenichi; Koike, Takayoshi; Izuta, Takeshi

    2016-09-01

    Ground-level ozone (O3) concentrations are expected to increase over the 21st century, especially in East Asia. However, the impact of O3 has not been directly assessed at the forest level in this region. We performed O3 flux-based risk assessments of carbon sequestration capacity in an old cool temperate deciduous forest, consisting of O3-sensitive Japanese beech (Fagus crenata), and in a warm temperate deciduous and evergreen forest dominated by O3-tolerant Konara oak (Quercus serrata) based on long-term CO2 flux observations. On the basis of a practical approach for a continuous estimation of canopy-level stomatal conductance (Gs), higher phytotoxic ozone dose above a threshold of 0 uptake (POD0) with higher Gs was observed in the beech forest than that in the oak forest. Light-saturated gross primary production, as a measure of carbon sequestration capacity of forest ecosystem, declined earlier in the late growth season with increasing POD0, suggesting an earlier autumn senescence, especially in the O3-sensitive beech forest, but not in the O3-tolerant oak forest.

  10. Senescence gives insights into the morphogenetic evolution of anamniotes

    Directory of Open Access Journals (Sweden)

    Éric Villiard

    2017-06-01

    Full Text Available Senescence represents a mechanism to avoid undesired cell proliferation that plays a role in tumor suppression, wound healing and embryonic development. In order to gain insight on the evolution of senescence, we looked at its presence in developing axolotls (urodele amphibians and in zebrafish (teleost fish, which are both anamniotes. Our data indicate that cellular senescence is present in various developing structures in axolotls (pronephros, olfactory epithelium of nerve fascicles, lateral organs, gums and in zebrafish (epithelium of the yolk sac and in the lower part of the gut. Senescence was particularly associated with transient structures (pronephros in axolotls and yolk sac in zebrafish suggesting that it may play a role in the elimination of these tissues. Our data supports the notion that cellular senescence evolved early in vertebrate evolution to influence embryonic development.

  11. Accelerating a three-dimensional eco-hydrological cellular automaton on GPGPU with OpenCL

    Science.gov (United States)

    Senatore, Alfonso; D'Ambrosio, Donato; De Rango, Alessio; Rongo, Rocco; Spataro, William; Straface, Salvatore; Mendicino, Giuseppe

    2016-10-01

    This work presents an effective implementation of a numerical model for complete eco-hydrological Cellular Automata modeling on Graphical Processing Units (GPU) with OpenCL (Open Computing Language) for heterogeneous computation (i.e., on CPUs and/or GPUs). Different types of parallel implementations were carried out (e.g., use of fast local memory, loop unrolling, etc), showing increasing performance improvements in terms of speedup, adopting also some original optimizations strategies. Moreover, numerical analysis of results (i.e., comparison of CPU and GPU outcomes in terms of rounding errors) have proven to be satisfactory. Experiments were carried out on a workstation with two CPUs (Intel Xeon E5440 at 2.83GHz), one GPU AMD R9 280X and one GPU nVIDIA Tesla K20c. Results have been extremely positive, but further testing should be performed to assess the functionality of the adopted strategies on other complete models and their ability to fruitfully exploit parallel systems resources.

  12. Exploring the link between depression and accelerated cellular aging: telomeres hold the key

    Directory of Open Access Journals (Sweden)

    Yu R

    2015-12-01

    Full Text Available Ruby Yu, Jean Woo Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, SAR, China Abstract: Accumulating evidence suggests that telomeres may be a marker for biological aging and telomere length may be affected by multifactorial influences, including cumulative exposure to depression. Associations with telomere length have been reported for major depressive disorder, lifetime duration of depression, higher depression severity, and history of depression. The exact underling mechanisms for these associations have yet to be fully elucidated; however, oxidative stress, chronic inflammation, dysregulated hypothalamus-pituitary-adrenal axis, and altered cortisol levels may be important biochemical mediators. These mediators could also be influenced by psychological stress, unhealthy lifestyle behaviors, or other potential factors, such as childhood abuse, post-traumatic stress disorder, and anxiety that are commonly associated with depression. As such, stress reduction and lifestyle interventions that may affect the telomere maintenance system should be considered for individuals with depression.Keywords: depression, telomere length, biomarkers, cellular ageing

  13. Chorioamniotic membrane senescence: a signal for parturition?

    Science.gov (United States)

    Behnia, Faranak; Taylor, Brandie D; Woodson, Michael; Kacerovsky, Marian; Hawkins, Hal; Fortunato, Stephen J; Saade, George R; Menon, Ramkumar

    2015-09-01

    Senescence is an important biological phenomenon involved in both physiologic and pathologic processes. We propose that chorioamniotic membrane senescence is a mechanism associated with human parturition. The present study was conducted to explore the association between senescence and normal term parturition by examining the morphologic and biochemical evidences in chorioamniotic membranes. Chorioamniotic membranes were collected from normal term deliveries; group 1: term labor and group 2: term, not in labor. Senescence-related morphologic changes were determined by transmission electron microscopy and biochemical changes were studied by senescence-associated (SA) β-galactosidase staining. Amniotic fluid samples collected from both term labor and term not in labor were analyzed for 14 SA secretory phenotype (SASP) markers. Morphologic evidence of cellular senescence (enlarged cells and organelles) and a higher number of SA β-galactosidase-stained amnion and chorion cells were observed in chorioamniotic membranes obtained from women in labor at term, when compared to term not in labor. The concentration of proinflammatory SASP markers (granulocyte macrophage colony-stimulating factor, interleukin-6 and -8) was significantly higher in the amniotic fluid of women in labor at term than women not in labor. In contrast, SASP factors that protect against cell death (eotaxin-1, soluble Fas ligand, osteoprotegerin, and intercellular adhesion molecule-1) were significantly lower in the amniotic fluid samples from term labor. Morphologic and biochemical features of senescence were more frequent in chorioamniotic membranes from women who experienced term labor. Senescence of chorioamniotic membranes were also associated with amniotic fluid SASP markers. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. 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.

  15. Long-term cilostazol administration ameliorates memory decline in senescence-accelerated mouse prone 8 (SAMP8) through a dual effect on cAMP and blood-brain barrier.

    Science.gov (United States)

    Yanai, Shuichi; Toyohara, Jun; Ishiwata, Kiichi; Ito, Hideki; Endo, Shogo

    2016-12-12

    Phosphodiesterases (PDEs), which hydrolyze and inactivate 3', 5'-cyclic adenosine monophosphate (cAMP) and 3', 5'-cyclic guanosine monophosphate (cGMP), play an important role in synaptic plasticity that underlies memory. Recently, several PDE inhibitors were assessed for their possible therapeutic efficacy in treating cognitive disorders. Here, we examined how cilostazol, a selective PDE3 inhibitor, affects brain functions in senescence-accelerated mouse prone 8 (SAMP8), an animal model of age-related cognitive impairment. Long-term administration of cilostazol restored the impaired context-dependent conditioned fear memory of SAMP8 to match that in normal aging control substrain SAMR1. Cilostazol also increased the number of cells containing phosphorylated cAMP-responsive element binding protein (CREB), a downstream component of the cAMP pathway. Finally, cilostazol improves blood-brain barrier (BBB) integrity, demonstrated by reduced extravasation of 2-deoxy-2-(18)F-fluoro-d-glucose and Evans Blue dye in the brains of SAMP8. This improvement in BBB integrity was associated with an increased amount of zona occludens protein 1 (ZO-1) and occludin proteins, components of tight junctions integral to the BBB. The results suggest that long-term administration of cilostazol exerts its beneficial effects on age-related cognitive impairment through a dual mechanism: by enhancing the cAMP system in the brain and by maintaining or improving BBB integrity.

  16. Construction of suppression subtracted cDNA library of hippocampus of senescence-accelerated mouse%快速老化小鼠海马抑制消减cDNA文库的构建

    Institute of Scientific and Technical Information of China (English)

    程肖蕊; 周文霞; 张永祥

    2004-01-01

    目的:构建快速老化小鼠(senescence-accelerated mouse, SAM)海马抑制消减cDNA文库.方法:以SAM快速老化亚系SAM-prone/8 (SAMP8)海马作为实验组,抗快速老化小鼠亚系SAM-resistance/1 (SAMR1)海马作为对照组,应用抑制消减杂交(SSH)技术,构建SAMP8海马特异表达cDNA抑制消减文库;用蓝白斑筛选,以PCR鉴定文库质量.结果:构建文库的阳性克隆率为96.18%,克隆中cDNA片段介于250~2?000?bp之间.结论:成功构建了SAMP8海马抑制消减文库.

  17. Global Reorganization of the Nuclear Landscape in Senescent Cells

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    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.

  18. Global reorganization of the nuclear landscape in senescent cells.

    Science.gov (United States)

    Chandra, Tamir; Ewels, Philip Andrew; Schoenfelder, Stefan; Furlan-Magaril, Mayra; Wingett, Steven William; Kirschner, Kristina; Thuret, Jean-Yves; Andrews, Simon; Fraser, Peter; Reik, Wolf

    2015-02-03

    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. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Role of endonuclease G in senescence-associated cell death of human endothelial cells

    OpenAIRE

    2011-01-01

    Mitotic cells in culture show a limited replicative potential and after extended subculturing undergo a terminal growth arrest termed cellular senescence. When cells reach the senescent phenotype, this is accompanied by a significant change in the cellular phenotype and massive changes in gene expression, including the upregulation of secreted factors. In human fibroblasts, senescent cells also acquire resistance to apoptosis. In contrary, in human endothelial cells, both replicative and stre...

  20. Redox control of senescence and age-related disease

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    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. Enrichment from birth accelerates the functional and cellular development of a motor control area in the mouse.

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    Teresa Simonetti

    Full Text Available BACKGROUND: There is strong evidence that sensory experience in early life has a profound influence on the development of sensory circuits. Very little is known, however, about the role of experience in the early development of striatal networks which regulate both motor and cognitive function. To address this, we have investigated the influence of early environmental enrichment on motor development. METHODOLOGY/PRINCIPAL FINDINGS: Mice were raised in standard or enriched housing from birth. For animals assessed as adults, half of the mice had their rearing condition reversed at weaning to enable the examination of the effects of pre- versus post-weaning enrichment. We found that exclusively pre-weaning enrichment significantly improved performance on the Morris water maze compared to non-enriched mice. The effects of early enrichment on the emergence of motor programs were assessed by performing behavioural tests at postnatal day 10. Enriched mice traversed a significantly larger region of the test arena in an open-field test and had improved swimming ability compared to non-enriched cohorts. A potential cellular correlate of these changes was investigated using Wisteria-floribunda agglutinin (WFA staining to mark chondroitin-sulfate proteoglycans (CSPGs. We found that the previously reported transition of CSPG staining from striosome-associated clouds to matrix-associated perineuronal nets (PNNs is accelerated in enriched mice. CONCLUSIONS/SIGNIFICANCE: This is the first demonstration that the early emergence of exploratory as well as coordinated movement is sensitive to experience. These behavioural changes are correlated with an acceleration of the emergence of striatal PNNs suggesting that they may consolidate the neural circuits underlying these behaviours. Finally, we confirm that pre-weaning experience can lead to life long changes in the learning ability of mice.

  2. 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.

  3. Senescence Meets Dedifferentiation

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    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.

  4. 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...... of biogerontology, it is clear that senescence is not inevitable....

  5. 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....

  6. 中波紫外线诱导的提前衰老成纤维细胞上清液对人真皮成纤维细胞增殖、老化及自噬的影响%Effects of conditioned medium of prematurely senescent fibroblasts induced by ultraviolet B on cellular proliferation, aging and autophagy of human dermal fibroblasts

    Institute of Scientific and Technical Information of China (English)

    王申; 周炳荣; 骆丹; 张家安; 刘娟; 张丽超; 易飞; 吴红巾; 栗丹

    2015-01-01

    by UVB radiation at 10 mJ/cm2 once daily for 5 consecutive days.Some fibroblasts were classified into two groups:an experimental group cultured in conditioned medium of UVB-induced prematurely senescent fibroblasts,and a control group cultured in conditioned medium of normal fibroblasts.After treatment for 20 consecutive days,cell counting kit-8 (CCK8) assay and 5-ethynyl-2'.-deoxyuridine (EDU) staining were performed to evaluate cellular proliferation,flow cytometry was conducted to estimate cell cycle,β-galactosidase staining to determine the percentage of senescent cells,accridine orange staining to detect the autophagy level,and Western blot and indirect immunofluorescence assay were carried out to determine the expression level of the autophagy-related protein LC3-B.Statistical analysis was done by using a two-sample t test with the Graphpad Prism 5 software.Results Compared with the control group,the proliferative activity of fibroblasts was significantly decreased (0.831 ± 0.017 vs.0.973 ± 0.017,t =5.850,P < 0.05),while EDU staining and flow cytometry both showed a significant increase in the percentage of S-phase cells (both P < 0.05),in the experimental group.The percentage of β-galactosidase-positive fibroblasts was significantly higher in the experimental group than in the control group (25.710% ± 0.304% vs.5.257% ± 1.023%,t =19.170,P < 0.05).Accridine orange staining revealed that the red fluorescence intensity of fibroblasts was significantly lower (14.287 ± 2.269 vs.29.614 ± 2.650,t =4.390,P < 0.05),while Western blot and indirect immunofluorescence assay both showed a significant elevation in the expression level of LC3-B (both P < 0.05),in the experimental group compared with the control group.Conclusions The conditioned medium of prematurely senescent fibroblasts induced by UVB can downregulate autophagy and proliferation of fibroblasts,but accelerate their aging.

  7. Chotosan (Diaoteng San-induced improvement of cognitive deficits in senescence-accelerated mouse (SAMP8 involves the amelioration of angiogenic/neurotrophic factors and neuroplasticity systems in the brain

    Directory of Open Access Journals (Sweden)

    Tanaka Ken

    2011-09-01

    Full Text Available Abstract Background Chotosan (CTS, Diaoteng San, a Kampo medicine (ie Chinese medicine formula, is reportedly effective in the treatment of patients with cerebral ischemic insults. This study aims to evaluate the therapeutic potential of CTS in cognitive deficits and investigates the effects and molecular mechanism(s of CTS on learning and memory deficits and emotional abnormality in an animal aging model, namely 20-week-old senescence-accelerated prone mice (SAMP8, with and without a transient ischemic insult (T2VO. Methods Age-matched senescence-resistant inbred strain mice (SAMR1 were used as control. SAMP8 received T2VO (T2VO-SAMP8 or sham operation (sham-SAMP8 at day 0. These SAMP8 groups were administered CTS (750 mg/kg, p.o. or water daily for three weeks from day 3. Results Compared with the control group, both sham-SAMP8 and T2VO-SAMP8 groups exhibited cognitive deficits in the object discrimination and water maze tests and emotional abnormality in the elevated plus maze test. T2VO significantly exacerbated spatial cognitive deficits of SAMP8 elucidated by the water maze test. CTS administration ameliorated the cognitive deficits and emotional abnormality of sham- and T2VO-SAMP8 groups. Western blotting and immunohistochemical studies revealed a marked decrease in the levels of phosphorylated forms of neuroplasticity-related proteins, N-methyl-D-aspartate receptor 1 (NMDAR1, Ca2+/calmodulin-dependent protein kinase II (CaMKII, cyclic AMP responsive element binding protein (CREB and brain-derived neurotrophic factor (BDNF in the frontal cortices of sham-SAMP8 and T2VO-SAMP8. Moreover, these animal groups showed significantly reduced levels of vasculogenesis/angiogenesis factors, vascular endothelial growth factor (VEGF, VEGF receptor type 2 (VEGFR2, platelet-derived growth factor-A (PDGF-A and PDGF receptor α (PDGFRα. CTS treatment reversed the expression levels of these factors down-regulated in the brains of sham- and T2VO-SAMP8

  8. 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

  9. A 181 GOPS AKAZE Accelerator Employing Discrete-Time Cellular Neural Networks for Real-Time Feature Extraction

    Directory of Open Access Journals (Sweden)

    Guangli Jiang

    2015-09-01

    Full Text Available This paper proposes a real-time feature extraction VLSI architecture for high-resolution images based on the accelerated KAZE algorithm. Firstly, a new system architecture is proposed. It increases the system throughput, provides flexibility in image resolution, and offers trade-offs between speed and scaling robustness. The architecture consists of a two-dimensional pipeline array that fully utilizes computational similarities in octaves. Secondly, a substructure (block-serial discrete-time cellular neural network that can realize a nonlinear filter is proposed. This structure decreases the memory demand through the removal of data dependency. Thirdly, a hardware-friendly descriptor is introduced in order to overcome the hardware design bottleneck through the polar sample pattern; a simplified method to realize rotation invariance is also presented. Finally, the proposed architecture is designed in TSMC 65 nm CMOS technology. The experimental results show a performance of 127 fps in full HD resolution at 200 MHz frequency. The peak performance reaches 181 GOPS and the throughput is double the speed of other state-of-the-art architectures.

  10. A 181 GOPS AKAZE Accelerator Employing Discrete-Time Cellular Neural Networks for Real-Time Feature Extraction.

    Science.gov (United States)

    Jiang, Guangli; Liu, Leibo; Zhu, Wenping; Yin, Shouyi; Wei, Shaojun

    2015-09-04

    This paper proposes a real-time feature extraction VLSI architecture for high-resolution images based on the accelerated KAZE algorithm. Firstly, a new system architecture is proposed. It increases the system throughput, provides flexibility in image resolution, and offers trade-offs between speed and scaling robustness. The architecture consists of a two-dimensional pipeline array that fully utilizes computational similarities in octaves. Secondly, a substructure (block-serial discrete-time cellular neural network) that can realize a nonlinear filter is proposed. This structure decreases the memory demand through the removal of data dependency. Thirdly, a hardware-friendly descriptor is introduced in order to overcome the hardware design bottleneck through the polar sample pattern; a simplified method to realize rotation invariance is also presented. Finally, the proposed architecture is designed in TSMC 65 nm CMOS technology. The experimental results show a performance of 127 fps in full HD resolution at 200 MHz frequency. The peak performance reaches 181 GOPS and the throughput is double the speed of other state-of-the-art architectures.

  11. 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.

  12. Drying Without Senescence in Resurrection Plants

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    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

  13. 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...

  14. The nuclear lamina promotes telomere aggregation and centromere peripheral localization during senescence of human mesenchymal stem cells

    NARCIS (Netherlands)

    Raz, Vered; Vermolen, Bart 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, spati

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

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    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.

  16. Myeloperoxidase-derived hypochlorous acid promotes ox-LDL-induced senescence of endothelial cells through a mechanism involving β-catenin signaling in hyperlipidemia.

    Science.gov (United States)

    Liu, Wei-Qi; Zhang, Yin-Zhuang; Wu, Yan; Zhang, Jie-Jie; Li, Tin-Bo; Jiang, Tian; Xiong, Xiao-Ming; Luo, Xiu-Ju; Ma, Qi-Lin; Peng, Jun

    2015-11-27

    Myeloperoxidase (MPO)-derived product hypochlorous acid (HOCl) is able to induce cellular senescence and MPO is also expressed in endothelial cells besides the well-recognized immune cells. This study aims to clarify the association of endothelium-derived MPO with endothelial senescence in hyperlipidemia. The rats were fed with high-fat diet for 8 weeks to establish a hyperlipidemic model, which showed an increase in plasma lipids, endothelium-derived MPO expression, endothelial senescence and endothelial dysfunction concomitant with a reduction in glycogen synthase kinase 3 beta (GSK-3β) activity and phosphorylated β-catenin (p-β-catenin) level as well as an increase in β-catenin and p53 levels within the endothelium. Next, human umbilical vein endothelial cells (HUVECs) were incubated with oxidized low density lipoprotein (ox-LDL, 100 μg/ml) for 24 h to establish a senescent cell model in vitro. Consistent with the finding in vivo, ox-LDL-induced MPO expression and HUVECs senescence, accompanied by a decrease in GSK-3β activity and p-β-catenin level as well as an increase in HOCl content, β-catenin and p53 levels; these phenomena were attenuated by MPO inhibitor. Replacement of ox-LDL with HOCl could also induce HUVECs senescence and activate the β-catenin/p53 pathway. Based on these observations, we conclude that endothelium-derived MPO is upregulated in hyperlipidemic rats, which may contribute to the accelerated vascular endothelial senescence through a mechanism involving the β-catenin/p53 pathway.

  17. Glycerophospholipid profile in oncogene-induced senescence.

    Science.gov (United States)

    Cadenas, Cristina; Vosbeck, Sonja; Hein, Eva-Maria; Hellwig, Birte; Langer, Alice; Hayen, Heiko; Franckenstein, Dennis; Büttner, Bettina; Hammad, Seddik; Marchan, Rosemarie; Hermes, Matthias; Selinski, Silvia; Rahnenführer, Jörg; Peksel, Begüm; Török, Zsolt; Vígh, László; Hengstler, Jan G

    2012-09-01

    Alterations in lipid metabolism and in the lipid composition of cellular membranes are linked to the pathology of numerous diseases including cancer. However, the influence of oncogene expression on cellular lipid profile is currently unknown. In this work we analyzed changes in lipid profiles that are induced in the course of ERBB2-expression mediated premature senescence. As a model system we used MCF-7 breast cancer cells with doxycycline-inducible expression of NeuT, an oncogenic ERBB2 variant. Affymetrix gene array data showed NeuT-induced alterations in the transcription of many enzymes involved in lipid metabolism, several of which (ACSL3, CHPT1, PLD1, LIPG, MGLL, LDL and NPC1) could be confirmed by quantitative realtime PCR. A study of the glycerophospholipid and lyso-glycerophospholipid profiles, obtained by high performance liquid chromatography coupled to Fourier-transform ion cyclotron resonance-mass spectrometry revealed senescence-associated changes in numerous lipid species, including mitochondrial lipids. The most prominent changes were found in PG(34:1), PG(36:1) (increased) and LPE(18:1), PG(40:7) and PI(36:1) (decreased). Statistical analysis revealed a general trend towards shortened phospholipid acyl chains in senescence and a significant trend to more saturated acyl chains in the class of phosphatidylglycerol. Additionally, the cellular cholesterol content was elevated and accumulated in vacuoles in senescent cells. These changes were accompanied by increased membrane fluidity. In mitochondria, loss of membrane potential along with altered intracellular distribution was observed. In conclusion, we present a comprehensive overview of altered cholesterol and glycerophospholipid patterns in senescence, showing that predominantly mitochondrial lipids are affected and lipid species less susceptible to peroxidation are increased.

  18. 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.

  19. Drying without senescence in resurrection plants.

    Science.gov (United States)

    Griffiths, Cara A; Gaff, Donald F; Neale, Alan D

    2014-01-01

    Research into extreme drought tolerance in resurrection plants using species such as Craterostigma plantagineum, C. 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. Extensive research on the molecular mechanism of leaf senescence in non-resurrection plants has revealed a multi-layered regulatory network operates to control programed cell death pathways. However, 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

  20. 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.

  1. Amyloid beta protein inhibits cellular MTT reduction not by suppression of mitochondrial succinate dehydrogenase but by acceleration of MTT formazan exocytosis in cultured rat cortical astrocytes.

    Science.gov (United States)

    Abe, K; Saito, H

    1998-08-01

    Alzheimer's disease amyloid beta protein (Abeta) inhibits cellular reduction of the dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Kaneko et al. have previously hypothesized that Abeta works by suppressing mitochondrial succinate dehydrogenase (SDH), but Liu and Schubert have recently demonstrated that Abeta decreases cellular MTT reduction by accelerating the exocytosis of MTT formazan in neuronal cells. To ask which is the case in astrocytes, we compared the effects of Abeta and 3-nitropropionic acid (3-NP), a specific SDH inhibitor, on MTT reduction in cultured rat cortical astrocytes. Treatment with 3-NP (10 mM) decreased cellular activity of MTT reduction, regardless of the time of incubation with MTT. On the other hand. Abeta-induced inhibition of cellular MTT reduction was dependent on the time of incubation with MTT. The cells treated with Abeta (0.1-1000 nM) exhibited normal capacity for MTT reduction at an early stage of incubation ( 1 h). Microscopic examination revealed that Abeta treatment accelerated the appearance of needle-like MTT formazan crystals at the cell surface. These observations support that Abeta accelerates the exocytosis of MTT formazan in astrocytes. In addition to inhibition of MTT reduction, Abeta is known to induce morphological changes in astrocytes. Following addition of Abeta (20 microM), polygonal astrocytes changed into process-bearing stellate cells. To explore a possible linkage between these two effects of Abeta, we tested if astrocyte stellation is induced by agents that mimic the effect of Abeta on MTT reduction. Cholesterol (5 5000 nM) and lysophosphatidic acid (0.2-20 microg/ml) were found to accelerate the exocytosis of MTT formazan in a similar manner to Abeta, but failed to induce astrocyte stellation. Therefore, Abeta-induced inhibition of MTT reduction is unlikely to be directly linked to its effect on astrocyte morphology.

  2. Perturbation of Ribosome Biogenesis Drives Cells into Senescence through 5S RNP-Mediated p53 Activation

    Directory of Open Access Journals (Sweden)

    Kazuho Nishimura

    2015-03-01

    Full Text Available The 5S ribonucleoprotein particle (RNP complex, consisting of RPL11, RPL5, and 5S rRNA, is implicated in p53 regulation under ribotoxic stress. Here, we show that the 5S RNP contributes to p53 activation and promotes cellular senescence in response to oncogenic or replicative stress. Oncogenic stress accelerates rRNA transcription and replicative stress delays rRNA processing, resulting in RPL11 and RPL5 accumulation in the ribosome-free fraction, where they bind MDM2. Experimental upregulation of rRNA transcription or downregulation of rRNA processing, mimicking the nucleolus under oncogenic or replicative stress, respectively, also induces RPL11-mediated p53 activation and cellular senescence. We demonstrate that exogenous expression of certain rRNA-processing factors rescues the processing defect, attenuates p53 accumulation, and increases replicative lifespan. To summarize, the nucleolar-5S RNP-p53 pathway functions as a senescence inducer in response to oncogenic and replicative stresses.

  3. Perturbation of ribosome biogenesis drives cells into senescence through 5S RNP-mediated p53 activation.

    Science.gov (United States)

    Nishimura, Kazuho; Kumazawa, Takuya; Kuroda, Takao; Katagiri, Naohiro; Tsuchiya, Mai; Goto, Natsuka; Furumai, Ryohei; Murayama, Akiko; Yanagisawa, Junn; Kimura, Keiji

    2015-03-03

    The 5S ribonucleoprotein particle (RNP) complex, consisting of RPL11, RPL5, and 5S rRNA, is implicated in p53 regulation under ribotoxic stress. Here, we show that the 5S RNP contributes to p53 activation and promotes cellular senescence in response to oncogenic or replicative stress. Oncogenic stress accelerates rRNA transcription and replicative stress delays rRNA processing, resulting in RPL11 and RPL5 accumulation in the ribosome-free fraction, where they bind MDM2. Experimental upregulation of rRNA transcription or downregulation of rRNA processing, mimicking the nucleolus under oncogenic or replicative stress, respectively, also induces RPL11-mediated p53 activation and cellular senescence. We demonstrate that exogenous expression of certain rRNA-processing factors rescues the processing defect, attenuates p53 accumulation, and increases replicative lifespan. To summarize, the nucleolar-5S RNP-p53 pathway functions as a senescence inducer in response to oncogenic and replicative stresses. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  4. Mesenchymal stem cells from rats with chronic kidney disease exhibit premature senescence and loss of regenerative potential.

    Directory of Open Access Journals (Sweden)

    Barbara Mara Klinkhammer

    Full Text Available Mesenchymal stem cell (MSC transplantation has the potential for organ repair. Nevertheless, some factors might lessen the regenerative potential of MSCs, e.g. donor age or systemic disease. It is thus important to carefully assess the patient's suitability for autologous MSC transplantation. Here we investigated the effects of chronic kidney disease (CKD on MSC function. We isolated bone marrow MSCs from remnant kidney rats (RK with CKD (CKD-RK-MSC and found signs of premature senescence: spontaneous adipogenesis, reduced proliferation capacity, active senescence-associated-β-galactosidase, accumulation of actin and a modulated secretion profile. The functionality of CKD-RK-MSCs in vivo was tested in rats with acute anti-Thy1.1-nephritis, where healthy MSCs have been shown to be beneficial. Rats received healthy MSCs, CKD-RK-MSC or medium by injection into the left renal artery. Kidneys receiving healthy MSCs exhibited accelerated healing of glomerular lesions, whereas CKD-RK-MSC or medium exerted no benefit. The negative influence of advanced CKD/uremia on MSCs was confirmed in a second model of CKD, adenine nephropathy (AD. MSCs from rats with adenine nephropathy (CKD-AD-MSC also exhibited cellular modifications and functional deficits in vivo. We conclude that CKD leads to a sustained loss of in vitro and in vivo functionality in MSCs, possibly due to premature cellular senescence. Considering autologous MSC therapy in human renal disease, studies identifying uremia-associated mechanisms that account for altered MSC function are urgently needed.

  5. Transcriptional networks in leaf senescence.

    Science.gov (United States)

    Schippers, Jos H M

    2015-10-01

    Plant senescence is a natural phenomenon known for the appearance of beautiful autumn colors and the ripening of cereals in the field. Senescence is a controlled process that plants utilize to remobilize nutrients from source leaves to developing tissues. While during the past decades, molecular components underlying the onset of senescence have been intensively studied, knowledge remains scarce on the age-dependent mechanisms that control the onset of senescence. Recent advances have uncovered transcriptional networks regulating the competence to senesce. Here, gene regulatory networks acting as internal timing mechanisms for the onset of senescence are highlighted, illustrating that early and late leaf developmental phases are highly connected.

  6. Recurrent turnover of senescent cells during regeneration of a complex structure.

    Science.gov (United States)

    Yun, Maximina H; Davaapil, Hongorzul; Brockes, Jeremy P

    2015-05-05

    Cellular senescence has been recently linked to the promotion of age-related pathologies, including a decline in regenerative capacity. While such capacity deteriorates with age in mammals, it remains intact in species such as salamanders, which have an extensive repertoire of regeneration and can undergo multiple episodes through their lifespan. Here we show that, surprisingly, there is a significant induction of cellular senescence during salamander limb regeneration, but that rapid and effective mechanisms of senescent cell clearance operate in normal and regenerating tissues. Furthermore, the number of senescent cells does not increase upon repetitive amputation or ageing, in contrast to mammals. Finally, we identify the macrophage as a critical player in this efficient senescent cell clearance mechanism. We propose that effective immunosurveillance of senescent cells in salamanders supports their ability to undergo regeneration throughout their lifespan.

  7. Delayed leaf senescence induces extreme drought tolerance in a flowering plant

    OpenAIRE

    Rivero, Rosa M.; Kojima, Mikiko; Gepstein, Amira; Sakakibara, Hitoshi; Mittler, Ron; Gepstein, Shimon; Blumwald, Eduardo

    2007-01-01

    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. We generated transgenic plants expressing an isopentenyltransfera...

  8. 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...

  9. Interactions Between Temperature and Sugars in the Regulation of Leaf Senescence in the Perennial Herb Arabis alpina L.

    Institute of Scientific and Technical Information of China (English)

    Astrid Wingler; Emma Josefine Stangberg; Triambak Saxena; Rupal Mistry

    2012-01-01

    Annual plants usually flower and set seed once before senescence results in the death of the whole plant (monocarpic senescence).Leaf senescence also occurs in polycarpic perennials; even in "evergreen" species individual leaves senesce.In the annual model Arabidopsis thaliana sugars accumulate in the senescent leaves and senescence is accelerated by high sugar availability.Similar to A.thaliana,sugar contents increased with leaf age in the perennial Arabis alpina grown under warm conditions (22 ℃day/18 night).At 5 ℃,sugar contents in non-senescent leaves were higher than at a warm temperature,but dependent on the accession,either sugars did not accumulate or their contents decreased in old leaves.In A.alpina plants grown in their natural habitat in the Alps,sugar contents declined with leaf age.Growth at a cold temperature slightly delayed senescence in A.alpina.In both warm and cold conditions,an external glucose supply accelerated senescence,but natural variation was found in this response.In conclusion,sugar accumulation under warm conditions could accelerate leaf senescence in A.alpina plants,but genotype-specific responses and interactions with growth temperature are likely to influence senescence under natural conditions.

  10. The sulfated polysaccharide fucoidan rescues senescence of endothelial colony-forming cells for ischemic repair.

    Science.gov (United States)

    Lee, Jun Hee; Lee, Sang Hun; Choi, Sung Hyun; Asahara, Takayuki; Kwon, Sang-Mo

    2015-06-01

    The efficacy of cell therapy using endothelial colony-forming cells (ECFCs) in the treatment of ischemia is limited by the replicative senescence of isolated ECFCs in vitro. Such senescence must therefore be overcome in order for such cell therapies to be clinically applicable. This study aimed to investigate the potential of sulfated polysaccharide fucoidan to rescue ECFCs from cellular senescence and to improve in vivo vascular repair by ECFCs. Fucoidan-preconditioning of senescent ECFCs was shown by flow cytometry to restore the expression of functional ECFC surface markers (CD34, c-Kit, VEGFR2, and CXCR4) and stimulate the in vitro tube formation capacity of ECFCs. Fucoidan also promoted the expression of cell cycle-associated proteins (cyclin E, Cdk2, cyclin D1, and Cdk4) in senescent ECFCs, significantly reversed cellular senescence, and increased the proliferation of ECFCs via the FAK, Akt, and ERK signaling pathways. Fucoidan was found to enhance the survival, proliferation, incorporation, and endothelial differentiation of senescent ECFCs transplanted in ischemic tissues in a murine hind limb ischemia model. Moreover, ECFC-induced functional recovery and limb salvage were markedly improved by fucoidan pretreatment of ECFCs. To our knowledge, the findings of our study are the first to demonstrate that fucoidan enhances the neovasculogenic potential of ECFCs by rescuing them from replicative cellular senescence. Pretreatment of ECFCs with fucoidan may thus provide a novel strategy for the application of senescent stem cells to therapeutic neovascularization.

  11. 白藜芦醇对快速老化鼠肝脏抗氧化能力的影响%Effect of resveratrol on antioxidant abilities of liver in senescence accelerated mice

    Institute of Scientific and Technical Information of China (English)

    刘贵珊; 杨博; 范艳丽; 张泽生; 贺伟

    2012-01-01

    To observe the effect of resveratrol on antioxidant abilities of liver in senescence accelerated mice. Four-month old SAMP/8 mice were divided into four groups randomly: The model group, resveratrol low- dose, moderate-dose and high-dose groups, and four-month old SAMR/1 mice were in normal control group. The normal control group and model group were given normal saline by garage, Res-treated mice were administered Res by garage at the daily doses of 25 mg/kg, 50 mg/kg and 100 mg/kg respectively. After medication for 8 weeks,superoxide dismutase (SOD), malondialdehyde (MDA) in the liver of mice were determined, histological changes in mice liver tissue were observed after HE stain. Resveratrol could significantly increase activities of SOD (P〈 0.01 ), decrease the content of MDA (P% 0.01 ) in liver tissue and ameliorate histological structure of liver tissue. Resveratrol could significantly improve antioxidant abilities of liver in SAMP/8 mice and have anti-aging effect.%分析白藜芦醇对快速老化鼠(SAMP/8)肝脏抗氧化能力的影响,将4月龄雄性SAMP/8鼠随机分为模型组和白藜芦醇低、中、高剂量纽,4月龄正常老化sAMR/1鼠为正常对照组.对照组及模型组用生理盐水灌胃,白藜芦醇治疗组给予25、50和100mg/kg白藜芦醇灌胃.连续给药8周,测定各组小鼠肝组织超氧化物歧化酶(SOD)、丙二醛(MDA)的含量,以HE染色进行肝组织形态学观察.结果表明:白藜芦醇各剂量组能提高sAMP/8鼠肝组织SOD活性(P〈0.01),降低MDA含量(P〈0.01),且能改善肝组织形态结构,尤以高剂量组效果显著.因此,白藜芦醇能显著提高SAMP/8鼠肝组织的抗氧化能力,具有一定的延缓衰老作用.

  12. 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...

  13. The case for negative senescence

    DEFF Research Database (Denmark)

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

    2004-01-01

    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...

  14. Identification of Senescent Cells in the Bone Microenvironment

    Science.gov (United States)

    Farr, Joshua N; Fraser, Daniel G; Wang, Haitao; Jaehn, Katharina; Ogrodnik, Mikolaj B; Weivoda, Megan M; Drake, Matthew T; Tchkonia, Tamara; LeBrasseur, Nathan K; Kirkland, James L; Bonewald, Lynda F; Pignolo, Robert J; Monroe, David G; Khosla, Sundeep

    2017-01-01

    Cellular senescence is a fundamental mechanism by which cells remain metabolically active yet cease dividing and undergo distinct phenotypic alterations, including upregulation of p16Ink4a, profound secretome changes, telomere shortening, and decondensation of pericentromeric satellite DNA. Because senescent cells accumulate in multiple tissues with aging, these cells and the dysfunctional factors they secrete, termed the senescence-associated secretory phenotype (SASP), are increasingly recognized as promising therapeutic targets to prevent age-related degenerative pathologies, including osteoporosis. However, the cell type(s) within the bone microenvironment that undergoes senescence with aging in vivo has remained poorly understood, largely because previous studies have focused on senescence in cultured cells. Thus in young (age 6 months) and old (age 24 months) mice, we measured senescence and SASP markers in vivo in highly enriched cell populations, all rapidly isolated from bone/marrow without in vitro culture. In both females and males, p16Ink4a expression by real-time quantitative polymerase chain reaction (rt-qPCR) was significantly higher with aging in B cells, T cells, myeloid cells, osteoblast progenitors, osteoblasts, and osteocytes. Further, in vivo quantification of senescence-associated distension of satellites (SADS), ie, large-scale unraveling of pericentromeric satellite DNA, revealed significantly more senescent osteocytes in old compared with young bone cortices (11% versus 2%, p < 0.001). In addition, primary osteocytes from old mice had sixfold more (p < 0.001) telomere dysfunction-induced foci (TIFs) than osteocytes from young mice. Corresponding with the age-associated accumulation of senescent osteocytes was significantly higher expression of multiple SASP markers in osteocytes from old versus young mice, several of which also showed dramatic age-associated upregulation in myeloid cells. These data show that with aging, a subset of cells

  15. Glucocorticoids suppress selected components of the senescence-associated secretory phenotype

    NARCIS (Netherlands)

    Laberge, Remi-Martin; Zhou, Lili; Sarantos, Melissa R; Rodier, Francis; Freund, Adam; de Keizer, Peter L J; Liu, Su; Demaria, Marco; Cong, Yu-Sheng; Kapahi, Pankaj; Desprez, Pierre-Yves; Hughes, Robert E; Campisi, Judith

    2012-01-01

    Cellular senescence suppresses cancer by arresting the proliferation of cells at risk for malignant transformation. Recently, senescent cells were shown to secrete numerous cytokines, growth factors, and proteases that can alter the tissue microenvironment and may promote age-related pathology. To i

  16. 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.

  17. Connective Tissue Growth Factor Promotes Pulmonary Epithelial Cell Senescence and Is Associated with COPD Severity.

    Science.gov (United States)

    Jang, Jun-Ho; Chand, Hitendra S; Bruse, Shannon; Doyle-Eisele, Melanie; Royer, Christopher; McDonald, Jacob; Qualls, Clifford; Klingelhutz, Aloysius J; Lin, Yong; Mallampalli, Rama; Tesfaigzi, Yohannes; Nyunoya, Toru

    2017-04-01

    The purpose of this study was to determine whether expression of connective tissue growth factor (CTGF) protein in chronic obstructive pulmonary disease (COPD) is consistent in humans and animal models of COPD and to investigate the role of this protein in lung epithelial cells. CTGF in lung epithelial cells of ex-smokers with COPD was compared with ex-smokers without COPD by immunofluorescence. A total of twenty C57Bl/6 mice and sixteen non-human primates (NHPs) were exposed to cigarette smoke (CS) for 4 weeks. Ten mice of these CS-exposed mice and eight of the CS-exposed NHPs were infected with H3N2 influenza A virus (IAV), while the remaining ten mice and eight NHPs were mock-infected with vehicle as control. Both mRNA and protein expression of CTGF in lung epithelial cells of mice and NHPs were determined. The effects of CTGF overexpression on cell proliferation, p16 protein, and senescence-associated β-galactosidase (SA-β-gal) activity were examined in cultured human bronchial epithelial cells (HBECs). In humans, CTGF expression increased with increasing COPD severity. We found that protein expression of CTGF was upregulated in lung epithelial cells in both mice and NHPs exposed to CS and infected with IAV compared to those exposed to CS only. When overexpressed in HBECs, CTGF accelerated cellular senescence accompanied by p16 accumulation. Both CTGF and p16 protein expression in lung epithelia are positively associated with the severity of COPD in ex-smokers. These findings show that CTGF is consistently expressed in epithelial cells of COPD lungs. By accelerating lung epithelial senescence, CTGF may block regeneration relative to epithelial cell loss and lead to emphysema.

  18. Sensitive detection and monitoring of senescence-associated secretory phenotype by SASP-RAP assay.

    Science.gov (United States)

    Gu, Liubao; Kitamura, Masanori

    2012-01-01

    Senescence-associated secretory phenotype (SASP) is characterized by abundant secretion of various proteins in senescent cells and implicated in tumor progression and inflammatory responses. However, the profile of secreted proteins in SASP is different from cell type to cell type, and currently, universal markers for SASP have not been reported. In the present investigation, we show that SASP-responsive alkaline phosphatase (SASP-RAP) serves as a sensitive, general and convenient marker for SASP. Etoposide-treated cells exhibited a senescent phenotype characterized by senile morphology, positive staining for senescence-associated β-galactosidase, growth arrest and induction of p53 and p21(WAF1/CIP1). In SASP-RAP-transfected cells, exposure to etoposide increased secretion of SASP-RAP time-dependently. The kinetics of secretion was closely correlated with that of activation of the p21(WAF1/CIP1) promoter and the p16(INK4a) promoter. The enhanced secretion of SASP-RAP by senescence was also observed in cells treated with other senescence inducers such as trichostatin A, doxorubicin and 4-phenylbutylic acid. The induction of SASP-RAP by senescence was similarly observed in natural replicative senescence. To confirm selectivity of the SASP-RAP response, cells were treated with senescence-related and -unrelated stimuli (IL-1β, LPS, TNF-α and TGF-β), and induction of senescence markers and activity of SASP-RAP were evaluated in parallel. Unlike etoposide, senescence-unrelated stimuli did not induce p53 and p21(WAF1/CIP1), and it was correlated with lack of induction of SASP-RAP. In contrast, senescence-unrelated stimuli up-regulated conventional indicators for SASP, e.g., MMP-3, IL-6 and TIMP, without induction of senescence. SASP-RAP thus serves as a selective, convenient and general marker for detection and monitoring of SASP during cellular senescence.

  19. A two-step model for senescence triggered by a single critically short telomere

    DEFF Research Database (Denmark)

    Abdallah, Pauline; Luciano, Pierre; Runge, Kurt W;

    2009-01-01

    Telomeres protect chromosome ends from fusion and degradation. In the absence of a specific telomere elongation mechanism, their DNA shortens progressively with every round of replication, leading to replicative senescence. Here, we show that telomerase-deficient cells bearing a single, very short...... telomere senesce earlier, demonstrating that the length of the shortest telomere is a major determinant of the onset of senescence. We further show that Mec1p-ATR specifically recognizes the single, very short telomere causing the accelerated senescence. Strikingly, before entering senescence, cells divide...... for several generations despite complete erosion of their shortened telomeres. This pre-senescence growth requires RAD52 (radiation sensitive) and MMS1 (methyl methane sulfonate sensitive), and there is no evidence for major inter-telomeric recombination. We propose that, in the absence of telomerase, a very...

  20. Chitosan Treatment Delays the Induction of Senescence in Human Foreskin Fibroblast Strains.

    Directory of Open Access Journals (Sweden)

    Ching-Wen Tsai

    Full Text Available Fibroblasts have been extensively used as a model to study cellular senescence. The purpose of this study was to investigate whether the human foreskin fibroblast aging process could be regulated by using the biomaterial chitosan. Fibroblasts cultured on commercial tissue culture polystyrene (TCPS entered senescence after 55-60 population doublings (PDs, and were accompanied by larger cell shape, higher senescence-associated β-galactosidase (SA β-gal activity, lower proliferation capacity, and upregulation of senescence-associated molecular markers p21, p53, retinoblastoma (pRB, and p16. Before senescence was reached, PD48 cells were collected from TCPS and seeded on chitosan for three days (PD48-Cd3 to form multicellular spheroids. The protein expression of senescence-associated secretory phenotypes (SASPs and senescence-associated molecular markers of these cells in PD48-Cd3 spheroids were downregulated significantly. Following chitosan treatment, fibroblasts reseeded on TCPS showed lower SA β-gal activity, increased cellular motility, and a higher proliferation ability of 70-75 PDs. These phenotypic changes were not accompanied by colonies forming in soft agar and a continuous decrease in the senescence-associated proteins p53 and pRB which act as a barrier to tumorigenesis. These results demonstrate that chitosan treatment could delay the induction of senescence which may be useful and safe for future tissue engineering applications.

  1. SIRT1 suppresses the senescence-associated secretory phenotype through epigenetic gene regulation.

    Directory of Open Access Journals (Sweden)

    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.

  2. Autophagy Protects Against Senescence and Apoptosis via the RAS-Mitochondria in High-Glucose-Induced Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Fei Chen

    2014-04-01

    Full Text Available Backgrounds: Autophagy is an important process in the pathogenesis of diabetes and plays a critical role in maintaining cellular homeostasis. However, the autophagic response and its mechanism in diabetic vascular endothelium remain unclear. Methods and Results: We studied high-glucose-induced renin-angiotensin system (RAS-mitochondrial damage and its effect on endothelial cells. With regard to therapeutics, we investigated the beneficial effect of angiotensin-converting enzyme inhibitors (ACEIs or angiotensin II type 1 receptor blockers (ARBs against high-glucose-induced endothelial responses. High glucose activated RAS, enhanced mitochondrial damage and increased senescence, apoptosis and autophagic-responses in endothelial cells, and these effects were mimicked by using angiotensin II (Ang. The use of an ACEI or ARB, however, inhibited the negative effects of high glucose. Direct mitochondrial injury caused by carbonyl cyanide 3-chlorophenylhydrazone (CCCP resulted in similar negative effects of high glucose or Ang and abrogated the protective effects of an ACEI or ARB. Additionally, by impairing autophagy, high-glucose-induced senescence and apoptosis were accelerated and the ACEI- or ARB-mediated beneficial effects were abolished. Furthermore, increases in FragEL™ DNA Fragmentation (TUNEL-positive cells, β-galactosidase activation and the expression of autophagic biomarkers were revealed in diabetic patients and rats, and the treatment with an ACEI or ARB decreased these responses. Conclusions: These data suggest that autophagy protects against senescence and apoptosis via RAS-mitochondria in high-glucose-induced endothelial cells.

  3. Mitochondrial bioenergetics in young, adult, middle-age and senescent brown Norway rats

    Science.gov (United States)

    Mitochondria are central regulators of energy homeostasis and may play a pivotal role in mechanisms of cellular senescence and age-related neurodegenerative and metabolic disorders. However, mitochondrial bioenergetic parameters have not been systematically evaluated under identi...

  4. 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.

  5. The inhibitory mechanism of Cordyceps sinensis on cigarette smoke extract-induced senescence in human bronchial epithelial cells.

    Science.gov (United States)

    Liu, Ailing; Wu, Jinxiang; Li, Aijun; Bi, Wenxiang; Liu, Tian; Cao, Liuzhao; Liu, Yahui; Dong, Liang

    2016-01-01

    Cellular senescence is a state of irreversible growth arrest induced either by telomere shortening (replicative senescence) or stress. The bronchial epithelial cell is often injured by inhaled toxic substances, such as cigarette smoke. In the present study, we investigated whether exposure to cigarette smoke extract (CSE) induces senescence of bronchial epithelial cells; and Cordyceps sinensis mechanism of inhibition of CSE-induced cellular senescence. Human bronchial epithelial cells (16HBE cells) cultured in vitro were treated with CSE and/or C. sinensis. p16, p21, and senescence-associated-galactosidase activity were used to detect cellular senescence with immunofluorescence, quantitative polymerase chain reaction, and Western blotting. Reactive oxygen species (ROS), PI3K/AKT/mTOR and their phosphorylated proteins were examined to testify the activation of signaling pathway by ROS fluorescent staining and Western blotting. Then, inhibitors of ROS and PI3K were used to further confirm the function of this pathway. Cellular senescence was upregulated by CSE treatment, and C. sinensis can decrease CSE-induced cellular senescence. Activation of ROS/PI3K/AKT/mTOR signaling pathway was enhanced by CSE treatment, and decreased when C. sinensis was added. Blocking ROS/PI3K/AKT/mTOR signaling pathway can attenuate CSE-induced cellular senescence. CSE can induce cellular senescence in human bronchial epithelial cells, and ROS/PI3K/AKT/mTOR signaling pathway may play an important role in this process. C. sinensis can inhibit the CSE-induced senescence.

  6. Effect of Naohuan Pills on Learning and Memory of Senescence Accelerated Mice%脑还丹对快速老化小鼠学习记忆能力的影响

    Institute of Scientific and Technical Information of China (English)

    陶彦谷; 黄启辉

    2011-01-01

    Objective To observe the effect of traditional Chinese medicine Naohuan Pills (NP) on learning and memory of senescence accelerated mice. Methods Thirty six-month old SAMP/8 mice were randomly divided into low- and high-dose NP groups and model group, and 10 six-month old SAMR/1 mice were in normal control group. After medication for 8 weeks, we analyzed the parameters of place navigation test and spatial probe test in Morris water maze. Results Learning and memory ability in SAMP/8 mice was significantly lower than SAMR/1 mice, manifesting as the prolongation of the escape latency from the second day, and the shortening of the time of staying on original platform quadrant. After treatment NP for 8 weeks, escape latency of SAMP/8 mice was shortened(P < 0.001-0.05) , the time of staying on original platform quadrant was prolonged(P < 0.001-0.05) , and the effect was in dose-dependent(P < 0.05 ). Conclusion NP can improve the learning ability in navigation and memory consolidation and reappearance in SAMP/8 mice%目的 观察脑还丹对快速老化( SAMP/8)小鼠学习记忆能力的影响.方法 用6月龄雄性SAMP/8小鼠随机等分为脑还丹高、低剂量组和模型组,6月龄正常老化(SAMR/1)小鼠为正常对照组.给药8周后,运用Morris水迷宫方法测试各组小鼠的定位航行和空间探索能力.结果 SAMP/8小鼠的学习记忆能力明显低于同月龄SAMR/1小鼠,表现为逃避潜伏期从第2天起显著延长,原平台象限停留时间缩短.给予脑还丹8周治疗,SAMP/8小鼠逃避潜伏期明显缩短(P<0.001~0.05).原平台象限停留时间明显延长(P<0.001~0.05),且有一定的量效关系(P<0.05).结论 脑还丹能显著改善SAMP/8小鼠方向辨别的学习能力及记忆巩固、再现能力.

  7. 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.

  8. A 181 GOPS AKAZE Accelerator Employing Discrete-Time Cellular Neural Networks for Real-Time Feature Extraction

    OpenAIRE

    Guangli Jiang; Leibo Liu; Wenping Zhu; Shouyi Yin; Shaojun Wei

    2015-01-01

    This paper proposes a real-time feature extraction VLSI architecture for high-resolution images based on the accelerated KAZE algorithm. Firstly, a new system architecture is proposed. It increases the system throughput, provides flexibility in image resolution, and offers trade-offs between speed and scaling robustness. The architecture consists of a two-dimensional pipeline array that fully utilizes computational similarities in octaves. Secondly, a substructure (block-serial discrete-time...

  9. Human endothelial senescence can be induced by TNF-α

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    TNF-α is one of the most important proinfiammatory cytokines in mediating multiple physio-pathological functions during immunological responses. Vascular endothelial cells, when stimulated by TNF-α2 can increase the expression of multiple cytokines and cellular adhesion molecules and, in turn, actively promote the inflammatory responses by recruiting and activating of leukocytes to the inflammatory site. In addition to endothelial death induced by TNF-α2 we found for the first time that TNF-α can also induce the human endothelial cells senescence. The induced senescent endothelial cells will display SA-β-Gal staining and they were arrested in G0-G1 phase. We found that Aψm would always be up-regulated in response to TNF-α stimulation at early time but when the cells become senescent, A ψmshows a tendency to decrease. It may reflect the sthenic function of mitochondria at early time in response to TNF-αstimulation and decay when the endothelial cells were induced senescent. ROS fluctuates at early time and also decreases when the endothelial cells become senescent. Our results show that the change of mitochondrial function may be related to the senescent process.``

  10. Western-type diet induces senescence, modifies vascular function in non-senescence mice and triggers adaptive mechanisms in senescent ones.

    Science.gov (United States)

    Onetti, Yara; Jiménez-Altayó, Francesc; Heras, Magda; Vila, Elisabet; Dantas, Ana Paula

    2013-12-01

    The effects of high-fat diet ingestion on senescence-induced modulation of contractile responses to phenylephrine (Phe) were determined in aortas of senescence-accelerated (SAMP8) and non-senescent (SAMR1) mice fed (8weeks) a Western-type high-fat diet (WD). Increased levels of senescence-associated β-galactosidase staining were found in aortas of SAMP8 and SAMR1 with WD. In SAMR1, WD did not modify Phe contraction in spite of inducing major changes in the mechanisms of regulation of contractile responses. Although WD increased NAD(P)H-oxidase-derived O2(-) and augmented peroxynitrite formation, we found an increase of inducible NOS (iNOS)-derived NO production which may contribute to maintain Phe contraction in SAMR1 WD. On SAMP8, WD significantly decreased Phe-induced contractions when compared with SAMP8 under normal chow. This response was not dependent on changes of NOS expression, but rather as consequence of increased antioxidant capacity by superoxide dismutase (SOD1). A similar constrictor influence from cyclooxygenase (COX) pathway on Phe responses was found in SAMR1 and SAMP8 ND. However, WD removed that influence on SAMR1, and produced a switch in the balance from a vasoconstrictor to a vasodilator component in SAMP8. These results were associated to the increased COX-2 expression, suggesting that a COX-2-derived vasodilator prostaglandin may contribute to the vascular adaptations after WD intake. Taken together, our data suggest that WD plays a detrimental role in the vasculature of non-senescent mice by increasing pro-inflammatory (iNOS) and pro-oxidative signaling pathways and may contribute to increase vascular senescence. In senescent vessels, however, WD triggers different intrinsic compensatory alterations which include increase of antioxidant activity by SOD1 and vasodilator prostaglandin production via COX-2. © 2013.

  11. 松果菊苷通过下调p53的表达抑制人成纤维细胞的衰老%Echinacoside suppresses cellular senescence of human fibroblastic cells by down-regulation of p53

    Institute of Scientific and Technical Information of China (English)

    朱慧; 成聪; 张弛; 王钊

    2011-01-01

    松果菊苷是一种从肉苁蓉中分离得到的苯乙醇苷类化合物,前期研究结果表明其有延缓人成纤维细胞衰老的作用.为了阐明松果菊苷抗衰老的机制,我们对相关基因p53,p16,p21及Rb的mRNA及蛋白水平的表达进行了检测,结果表明用松果菊苷处理后,衰老的人成纤维细胞(MRC-5) p53的表达被下调,且呈剂量依赖方式.进一步的研究显示可能和SIRTI蛋白的上调有关.分子对接模拟结果显示松果菊苷的作用可能优于另一公认的抗衰老剂白藜芦醇.松果菊苷可能是一种潜在的可以调控细胞衰老的化合物.%Echinacoside is one of the phenylethanoids isolated from the stems of Cistanches salsa.Our previous research showed that echinacoside has anti-senescence activity.To investigate the mechanism of echinacoside's anti-senescence activity,the expressions of p53,p21,p16 and Rb at the mRNA and protein levels were determined.Results showed that the expression of p53 was down-regulated significantly in a dose dependent manner after treatment with echinacoside.Further experiments suggested that the down-regulation of p53 may be correlated with the uprcgulation of SIRT1.In addition,echinacoside may exhibit considerable higher affinity towards SIRT1 than resveratrol,according to our molecular docking simulation.In conclusion,we expect that echinacoside might be a promising candidate for regulating cell senescence.

  12. 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.

  13. 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.

  14. The M-type receptor PLA2R regulates senescence through the p53 pathway.

    Science.gov (United States)

    Augert, Arnaud; Payré, Christine; de Launoit, Yvan; Gil, Jesus; Lambeau, Gérard; Bernard, David

    2009-03-01

    Senescence is a stable proliferative arrest induced by various stresses such as telomere erosion, oncogenic or oxidative stress. Compelling evidence suggests that it acts as a barrier against tumour development. Describing new mechanisms that favour an escape from senescence can thus reveal new insights into tumorigenesis. To identify new genes controlling the senescence programme, we performed a loss-of-function genetic screen in primary human fibroblasts. We report that knockdown of the M-type receptor PLA2R (phospholipase A2 receptor) prevents the onset of replicative senescence and diminishes stress-induced senescence. Interestingly, expression of PLA2R increases during replicative senescence, and its ectopic expression results in premature senescence. We show that PLA2R regulates senescence in a reactive oxygen species-DNA damage-p53-dependent manner. Taken together, our study identifies PLA2R as a potential new tumour suppressor gene crucial in the induction of cellular senescence through the activation of the p53 pathway.

  15. Senescence-associated intrinsic mechanisms of osteoblast dysfunctions

    DEFF Research Database (Denmark)

    Kassem, Moustapha; Trinquier, Anne Marie-Pierre Emilie

    2011-01-01

    -related osteoblast dysfunction is the main cause of age-related bone loss in both men and women beyond the fifth decade and results from two groups of pathogenic mechanisms: extrinsic mechanisms that are mediated by age-related changes in bone microenvironment including changes in levels of hormones and growth...... 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. 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

  17. 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.

  18. 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....... With the aim to enhance productivity, a number of functional stay-green cultivars have been selected by conventional breeding, in particular of sorghum and maize. In many cases, a positive correlation between leaf area duration and yield has been observed, although in a number of other cases, stay...... 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...

  19. Mitochondrial DNA deletion and impairment of mitochondrial biogenesis by reactive oxygen species in ionizing radiation-induced premature senescence

    Energy Technology Data Exchange (ETDEWEB)

    Eom, Hyeon Soo; Jung, U Hee; Jo, Sung Kee [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2011-10-15

    The aim of this study was to determine whether an increase of ROS level in cellular senescence induced by IR could mediate mtDNA deletion via impairment of mitochondria biogenesis in IMR-90 human lung fibroblast cells. Our results showed that IR induced cellular senescence, intracellular ROS, and mtDNA deletion, and in particular, suppressed the expression of mitochondrial biogenesis genes (NRF-1, TFAM). Furthermore, these IR-induced events were abolished using a potent antioxidant, NAC, which suggests that ROS is a key cause of mtDNA deletion in IR-induced cellular senescence, and that the alteration of mitochondrial biogenesis may mediate these processes

  20. MicroRNAs Regulate Key Effector Pathways of Senescence

    Directory of Open Access Journals (Sweden)

    Andrea Feliciano

    2011-01-01

    Full Text Available MicroRNAs (miRNAs are small (approximately 22 nt noncoding endogenous RNA molecules that regulate gene expression and protein coding by base pairing with the 3′ untranslated region (UTR of target mRNAs. miRNA expression is associated with cancer pathogenesis because miRNAs are intimately linked to cancer development. Senescence blocks cell proliferation, representing an important barrier that cells must bypass to reach malignancy. Importantly, certain miRNAs have been shown to have an important role during cellular senescence, which is also involved in human tumorigenesis. Therefore, therapeutic induction of senescence by drugs or miRNA-based therapies is a potential method to treat cancer by inducing a persistent growth arrest in tumors.

  1. 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.

  2. Interferon-γ induces senescence in normal human melanocytes.

    Directory of Open Access Journals (Sweden)

    Suiquan Wang

    Full Text Available BACKGROUND: Interferon-γ (IFN-γ plays an important role in the proceedings of vitiligo through recruiting lymphocytes to the lesional skin. However, the potential effects of IFN-γ on skin melanocytes and the subsequent contribution to the vitiligo pathogenesis are still unclear. OBJECTIVE: To investigate the effects of IFN-γ on viability and cellular functions of melanocytes. METHODS: Primary human melanocytes were treated with IFN-γ. Cell viability, apoptosis, cell cycle melanin content and intracellular reactive oxygen species (ROS level were measured. mRNA expression was examined by real-time PCR. The release of interleukin 6 (IL-6 and heat shock protein 70 (HSP-70 was monitored by ELISA. β-galactosidase staining was utilized to evaluate melanocyte senescence. RESULTS: Persistent IFN-γ treatment induced viability loss, apoptosis, cell cycle arrest and senescence in melanocytes. Melanocyte senescence was characterized as the changes in pigmentation and morphology, as well as the increase of β-galactosidase activity. Increase of p21Cip1/Waf1 protein was evident in melanocytes after IFN-γ treatment. IFN-γ induction of senescence was attenuated by siRNAs against p21, Janus kinase 2 (JAK2 or signal transducer and activator of transcription 1 (STAT1, but not by JAK1 siRNA nor by p53 inhibitor pifithrin-α. IFN-γ treatment increased the accumulation of intracellular ROS in melanocytes, while ROS scavenger N-acetyl cysteine (NAC effectively inhibited IFN-γ induced p21 expression and melanocyte senescence. IL-6 and HSP-70 release was significantly induced by IFN-γ treatment, which was largely inhibited by NAC. The increase of IL-6 and HSP-70 release could also be observed in senescent melanocytes. CONCLUSION: IFN-γ can induce senescence in melanocytes and consequently enhance their immuno-competency, leading to a vitiligo-prone milieu.

  3. Effect of Total Body Irradiation on Cellular Senescence Related Indexes of Bone Marrow Mesenchymal Stem Cells%全身照射对小鼠骨髓间充质干细胞细胞衰老相关指标的影响

    Institute of Scientific and Technical Information of China (English)

    马杰; 王宏兰; 李静; 史明霞; 李炳宗; 陈斌; 胡建立; 赵春华; 孙慧

    2008-01-01

    为了探讨小鼠骨髓间充质干细胞(bone marrow mesenchymal stem cells,BMMSCs)在放射损伤后细胞衰老(cellular senescence)的细胞和分子水平相关指标的变化,本研究采用全身照射(total body irradiation,TBI)小鼠模型,观察4 Gy TBI后4周内不同时间点小鼠BMMSCs的形态学和衰老相关β-半乳糖苷酶(senescence-associated β-galactosidase,SA-β-gal)的变化,用流式细胞术分析TBI对BMMSCs细胞周期分布的影响,用实时定量RT-PCR检测细胞衰老相关基因p16INK4a、p21Cipl/Wafl、p53和TGF-β1在TBI前后的表达变化.结果显示,4 Gy TBI后4周内小鼠BMMSC的形态和SA-β-gal的表达无明显变化,也未出现细胞衰老相关的细胞周期阻滞和衰老相关基因表达增高.结论:小鼠BMMSCs在4 Gy TBI后近期内未出现细胞衰老相关的分子水平的改变.

  4. 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.

  5. Calculating the Rate of Senescence From Mortality Data: An Analysis of Data From the ERA-EDTA Registry.

    Science.gov (United States)

    Koopman, Jacob J E; Rozing, Maarten P; Kramer, Anneke; Abad, José M; Finne, Patrik; Heaf, James G; Hoitsma, Andries J; De Meester, Johan M J; Palsson, Runolfur; Postorino, Maurizio; Ravani, Pietro; Wanner, Christoph; Jager, Kitty J; van Bodegom, David; Westendorp, Rudi G J

    2016-04-01

    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 calculated with or without a model. However, when using non-modeled mortality rates, senescence rates were yielded at young and old ages that remained concealed when using modeled mortality rates. At young ages senescence rates were negative, while senescence rates declined at old ages. In conclusion, the rate of senescence can be calculated directly from non-modeled mortality rates, overcoming the disadvantages of an indirect estimation based on modeled mortality rates.

  6. NAC transcription factors in senescence

    DEFF Research Database (Denmark)

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

    2015-01-01

    Within the last decade, NAC transcription factors have been shown to play essential roles in senescence, which is the focus of this review. Transcriptome analyses associate approximately one third of Arabidopsis NAC genes and many crop NAC genes with senescence, thereby implicating NAC genes...... 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...

  7. 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....... These changes affect different cell functions, including energy metabolism, defense systems, maintenance of the redox potential, cell morphology and transduction pathways.......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...

  8. Senescence in adipose-derived stem cells and its implications in nerve regeneration

    Institute of Scientific and Technical Information of China (English)

    Cristina Mantovani; Giorgio Terenghi; Valerio Magnaghi

    2014-01-01

    Adult mesenchymal stem cells, specifically adipose-derived stem cells have self-renewal and multiple differentiation potentials and have shown to be the ideal candidate for therapeutic applications in regenerative medicine, particularly in peripheral nerve regeneration. Adipose-de-rived stem cells are easily harvested, although they may show the effects of aging, hence their potential in nerve repair may be limited by cellular senescence or donor age. Cellular senescence is a complex process whereby stem cells grow old as consequence of intrinsic events (e.g., DNA damage) or environmental cues (e.g., stressful stimuli or diseases), which determine a permanent growth arrest. Several mechanisms are implicated in stem cell senescence, although no one is exclusive of the others. In this review we report some of the most important factors modulating the senescence process, which can inlfuence adipose-derived stem cell morphology and function, and compromise their clinical application for peripheral nerve regenerative cell therapy.

  9. p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes.

    Science.gov (United States)

    Davalos, Albert R; Kawahara, Misako; Malhotra, Gautam K; Schaum, Nicholas; Huang, Jiahao; Ved, Urvi; Beausejour, Christian M; Coppe, Jean-Philippe; Rodier, Francis; Campisi, Judith

    2013-05-13

    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.

  10. 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.

  11. 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

  12. Autophagy promotes radiation-induced senescence but inhibits bystander effects in human breast cancer cells.

    Science.gov (United States)

    Huang, Yao-Huei; Yang, Pei-Ming; Chuah, Qiu-Yu; Lee, Yi-Jang; Hsieh, Yi-Fen; Peng, Chih-Wen; Chiu, Shu-Jun

    2014-07-01

    Ionizing radiation induces cellular senescence to suppress cancer cell proliferation. However, it also induces deleterious bystander effects in the unirradiated neighboring cells through the release of senescence-associated secretory phenotypes (SASPs) that promote tumor progression. Although autophagy has been reported to promote senescence, its role is still unclear. We previously showed that radiation induces senescence in PTTG1-depleted cancer cells. In this study, we found that autophagy was required for the radiation-induced senescence in PTTG1-depleted breast cancer cells. Inhibition of autophagy caused the cells to switch from radiation-induced senescence to apoptosis. Senescent cancer cells exerted bystander effects by promoting the invasion and migration of unirradiated cells through the release of CSF2 and the subsequently activation of the JAK2-STAT3 and AKT pathways. However, the radiation-induced bystander effects were correlated with the inhibition of endogenous autophagy in bystander cells, which also resulted from the activation of the CSF2-JAK2 pathway. The induction of autophagy by rapamycin reduced the radiation-induced bystander effects. This study reveals, for the first time, the dual role of autophagy in radiation-induced senescence and bystander effects.

  13. Reinitiation of Growth in Senescent Mouse Mammary Epithelium in Response to Cholera Toxin

    Science.gov (United States)

    Daniel, Charles W.; Silberstein, Gary B.; Strickland, Phyllis

    1984-06-01

    Several lines of mouse mammary tissue that had been serially transplanted until mitotic senescence was reached were exposed in vivo to plastic implants that slowly released cholera toxin. Gland tissue surrounding the implants displayed new end buds, indicating reinitiation of growth and morphogenesis. The ability of cholera toxin, which elevates intracellular adenosine 3',5'-monophosphate, to temporarily reverse the senescent phenotype suggests that this mitotic dysfunction results not from generalized cellular deterioration but from specific changes in cell regulation.

  14. Phenotyping jasmonate regulation of senescence.

    Science.gov (United States)

    Seltmann, Martin A; Berger, Susanne

    2013-01-01

    Osmotic stress induces several senescence-like processes in leaves, such as specific changes in gene expression and yellowing. These processes are dependent on the accumulation of jasmonates and on intact jasmonate signaling. This chapter describes the treatment of Arabidopsis thaliana leaves with sorbitol as an osmotic stress agent and the determination of the elicited phenotypes encompassing chlorophyll loss, degradation of plastidial membrane lipids, and induction of genes regulated by senescence and jasmonate.

  15. SIRT1 ameliorates age-related senescence of mesenchymal stem cells via modulating telomere shelterin

    Directory of Open Access Journals (Sweden)

    Huiqiang eChen

    2014-06-01

    Full Text Available Age-related mesenchymal stem cells (MSCs senescence, which impairs its tissue repair capacity in vivo and hence compromises the effects of MSCs-based therapy in clinical applications, is closely related to aging and aging-related diseases. Here, we demonstrated the effect of SIRT1, a NAD+-dependent deacetylase, on age-related MSCs senescence. Knockdown of SIRT1 in young MSCs induces cellular senescence and inhibits cellular proliferation ability whereas overexpression of SIRT1 in aged MSCs reversed the cellular senescence and regained its proliferation capacity, suggesting that SIRT1 could modulate age-induced MSCs senescence. Aging-related proteins, P16 and P21, might be involved in SIRT1-mediated anti-aging effect on MSCs. SIRT1 could positively modulate age-related DNA damage in MSCs. In addition, SIRT1 could induce telomerase reverse transcriptase (TERT expression and consequently enhance telomerase activity, however, no significant change was observed in telomere length. Moreover, SIRT1 could positively regulate TPP1, an important member of telomere shelterin, expression. Together, these results demonstrate that SIRT1 dampens age-related MSCs senescence, which was correlated with the up-regulation of TPP1 expression, telomerase activity and down-regulation of DNA damage.

  16. NETRIN-4 protects glioblastoma cells FROM temozolomide induced senescence.

    Directory of Open Access Journals (Sweden)

    Li Li

    Full Text Available Glioblastoma multiforme is the most common primary tumor of the central nervous system. The drug temozolomide (TMZ prolongs lifespan in many glioblastoma patients. The sensitivity of glioblastoma cells to TMZ is interfered by many factors, such as the expression of O-6-methylguanine-DNA methyltransferase (MGMT and activation of AKT signaling. We have recently identified the interaction between netrin-4 (NTN4 and integrin beta-4 (ITGB4, which promotes glioblastoma cell proliferation via activating AKT-mTOR signaling pathway. In the current work we have explored the effect of NTN4/ITGB4 interaction on TMZ induced glioblastoma cell senescence. We report here that the suppression of either ITGB4 or NTN4 in glioblastoma cell lines significantly enhances cellular senescence. The sensitivity of GBM cells to TMZ was primarily determined by the expression of MGMT. To omit the effect of MGMT, we concentrated on the cell lines devoid of expression of MGMT. NTN4 partially inhibited TMZ induced cell senescence and rescued AKT from dephosphorylation in U251MG cells, a cell line bearing decent levels of ITGB4. However, addition of exogenous NTN4 displayed no significant effect on TMZ induced senescence rescue or AKT activation in U87MG cells, which expressed ITGB4 at low levels. Furthermore, overexpression of ITGB4 combined with exogenous NTN4 significantly attenuated U87MG cell senescence induced by TMZ. These data suggest that NTN4 protects glioblastoma cells from TMZ induced senescence, probably via rescuing TMZ triggered ITGB4 dependent AKT dephosphorylation. This suggests that interfering the interaction between NTN4 and ITGB4 or concomitant use of the inhibitors of the AKT pathway may improve the therapeutic efficiency of TMZ.

  17. NETRIN-4 protects glioblastoma cells FROM temozolomide induced senescence.

    Science.gov (United States)

    Li, Li; Hu, Yizhou; Ylivinkka, Irene; Li, Huini; Chen, Ping; Keski-Oja, Jorma; Hyytiäinen, Marko

    2013-01-01

    Glioblastoma multiforme is the most common primary tumor of the central nervous system. The drug temozolomide (TMZ) prolongs lifespan in many glioblastoma patients. The sensitivity of glioblastoma cells to TMZ is interfered by many factors, such as the expression of O-6-methylguanine-DNA methyltransferase (MGMT) and activation of AKT signaling. We have recently identified the interaction between netrin-4 (NTN4) and integrin beta-4 (ITGB4), which promotes glioblastoma cell proliferation via activating AKT-mTOR signaling pathway. In the current work we have explored the effect of NTN4/ITGB4 interaction on TMZ induced glioblastoma cell senescence. We report here that the suppression of either ITGB4 or NTN4 in glioblastoma cell lines significantly enhances cellular senescence. The sensitivity of GBM cells to TMZ was primarily determined by the expression of MGMT. To omit the effect of MGMT, we concentrated on the cell lines devoid of expression of MGMT. NTN4 partially inhibited TMZ induced cell senescence and rescued AKT from dephosphorylation in U251MG cells, a cell line bearing decent levels of ITGB4. However, addition of exogenous NTN4 displayed no significant effect on TMZ induced senescence rescue or AKT activation in U87MG cells, which expressed ITGB4 at low levels. Furthermore, overexpression of ITGB4 combined with exogenous NTN4 significantly attenuated U87MG cell senescence induced by TMZ. These data suggest that NTN4 protects glioblastoma cells from TMZ induced senescence, probably via rescuing TMZ triggered ITGB4 dependent AKT dephosphorylation. This suggests that interfering the interaction between NTN4 and ITGB4 or concomitant use of the inhibitors of the AKT pathway may improve the therapeutic efficiency of TMZ.

  18. Bisdemethoxycurcumin Increases Sirt1 to Antagonize t-BHP-Induced Premature Senescence in WI38 Fibroblast Cells

    Directory of Open Access Journals (Sweden)

    Ying-Bo Li

    2013-01-01

    Full Text Available Curcuminoids are well known for their capabilities to combat risk factors that are associated with ageing and cellular senescence. Recent reports have demonstrated that curcuminoids can extend the lifespan of model organisms. However, the underlying mechanisms by which these polyphenic compounds exert these beneficial effects remain unknown. In this study, t-BHP-induced premature senescence model in human fibroblasts was chosen to explore the protective effects of a curcuminoid, bisdemethoxycurcumin (BDMC, on cellular senescence. The results demonstrated that BDMC attenuated oxidative stress-induced senescence-like features which include the induction of an enlarged cellular appearance, higher frequency of senescence-associated β-galactosidase staining activity, appearance of senescence-associated heterochromatic foci in nuclei, decrease in proliferation capability, and alteration in related molecules such as p16 and retinoblastoma protein. Notably, we found that BDMC treatment activated Sirt1/AMPK signaling pathway. Moreover, downregulating Sirt1 by the pharmacological inhibitor nicotianamine or small interfering RNA blocked BDMC-mediated protection against t-BHP-mediated decrease in proliferation. These results suggested that BDMC prevented t-BHP-induced cellular senescence, and BDMC-induced Sirt1 may be a mechanism mediating its beneficial effects.

  19. Psychiatric Disorders, Morbidity, and Mortality: Tracing Mechanistic Pathways to Accelerated Aging.

    Science.gov (United States)

    Kiecolt-Glaser, Janice K; Wilson, Stephanie J

    2016-09-01

    A meta-analysis published in this issue of Psychosomatic Medicine provides convincing evidence that certain psychiatric populations have shorter telomeres than nonpsychiatric controls, in accord with the strong evidence linking psychiatric disorders with premature mortality. After addressing the clinical significance of shorter telomeres, this editorial describes mechanistic pathways that lead to telomere shortening. Additionally, two other novel methods for measuring biological markers of accelerated aging are briefly discussed: DNA methylation and cellular senescence based on p16. These innovative approaches could be used to confirm and extend our understanding of psychiatric patients' increased health and mortality risks.

  20. 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.

  1. Tissue formation and tissue engineering through host cell recruitment or a potential injectable cell-based biocomposite with replicative potential: Molecular mechanisms controlling cellular senescence and the involvement of controlled transient telomerase activation therapies.

    Science.gov (United States)

    Babizhayev, Mark A; Yegorov, Yegor E

    2015-12-01

    . Nuclear export is initiated by ROS-induced phosphorylation of tyrosine 707 within hTERT by the Src kinase family. It might be presumed that protection of mitochondria against oxidative stress is an important telomere length-independent function for telomerase in cell survival. Biotechnology companies are focused on development of therapeutic telomerase vaccines, telomerase inhibitors, and telomerase promoter-driven cell killing in oncology, have a telomerase antagonist in late preclinical studies. Anti-aging medicine-oriented groups have intervened on the market with products working on telomerase activation for a broad range of degenerative diseases in which replicative senescence or telomere dysfunction may play an important role. Since oxidative damage has been shown to shorten telomeres in tissue culture models, the adequate topical, transdermal, or systemic administration of antioxidants (such as, patented ocular administration of 1% N-acetylcarnosine lubricant eye drops in the treatment of cataracts) may be beneficial at preserving telomere lengths and delaying the onset or in treatment of disease in susceptible individuals. Therapeutic strategies toward controlled transient activation of telomerase are targeted to cells and replicative potential in cell-based therapies, tissue engineering and regenerative medicine.

  2. The inhibitory mechanism of Cordyceps sinensis on cigarette smoke extract-induced senescence in human bronchial epithelial cells

    Directory of Open Access Journals (Sweden)

    Liu AL

    2016-07-01

    Full Text Available Ailing Liu,1,2,* Jinxiang Wu,1,* Aijun Li,2 Wenxiang Bi,3 Tian Liu,1 Liuzhao Cao,1 Yahui Liu,1 Liang Dong1 1Department of Pulmonary Diseases, Qilu Hospital, Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Pulmonary Diseases, Weihai Municipal Hospital, Weihai, Shandong, People’s Republic of China; 3Institute of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China *These authors contributed equally to this work Objectives: Cellular senescence is a state of irreversible growth arrest induced either by telomere shortening (replicative senescence or stress. The bronchial epithelial cell is often injured by inhaled toxic substances, such as cigarette smoke. In the present study, we investigated whether exposure to cigarette smoke extract (CSE induces senescence of bronchial epithelial cells; and Cordyceps sinensis mechanism of inhibition of CSE-induced cellular senescence.Methods: Human bronchial epithelial cells (16HBE cells cultured in vitro were treated with CSE and/or C. sinensis. p16, p21, and senescence-associated-galactosidase activity were used to detect cellular senescence with immunofluorescence, quantitative polymerase chain reaction, and Western blotting. Reactive oxygen species (ROS, PI3K/AKT/mTOR and their phosphorylated proteins were examined to testify the activation of signaling pathway by ROS fluorescent staining and Western blotting. Then, inhibitors of ROS and PI3K were used to further confirm the function of this pathway.Results: Cellular senescence was upregulated by CSE treatment, and C. sinensis can decrease CSE-induced cellular senescence. Activation of ROS/PI3K/AKT/mTOR signaling pathway was enhanced by CSE treatment, and decreased when C. sinensis was added. Blocking ROS/PI3K/AKT/mTOR signaling pathway can attenuate CSE-induced cellular senescence.Conclusion: CSE can induce cellular senescence in human bronchial

  3. A Novel Protein RLS1 with NB-ARM Domains Is Involved in Chloroplast Degradation during Leaf Senescence in Rice

    Institute of Scientific and Technical Information of China (English)

    Bin-Bin Jiao; Jian-Jun Wang; Xu-Dong Zhu; Long-Jun Zeng; Qun Li; Zu-Hua He

    2012-01-01

    Leaf senescence,a type of programmed cell death (PCD) characterized by chlorophyll degradation,is important to plant growth and crop productivity.It emerges that autophagy is involved in chloroplast degradation during leaf senescence.However,the molecular mechanism(s) involved in the process is not well understood.In this study,the genetic and physiological characteristics of the rice rls1 (rapid leaf senescence 1) mutant were identified.The rls1 mutant developed small,yellow-brown lesions resembling disease scattered over the whole surfaces of leaves that displayed earlier senescence than those of wild-type plants.The rapid loss of chlorophyll content during senescence was the main cause of accelerated leaf senescence in rls1.Microscopic observation indicated that PCD was misregulated,probably resulting in the accelerated degradation of chloroplasts in rls1 leaves.Map-based cloning of the RLS1 gene revealed that it encodes a previously uncharacterized NB (nucleotide-binding site)-containing protein with an ARM (armadillo) domain at the carboxyl terminus.Consistent with its involvement in leaf senescence,RLS1 was up-regulated during dark-induced leaf senescence and down-regulated by cytokinin.Intriguingly,constitutive expression of RLS1 also slightly accelerated leaf senescence with decreased chlorophyll content in transgenic rice plants.Our study identified a previously uncharacterized NB-ARM protein involved in PCD during plant growth and development,providing a unique tool for dissecting possible autophagymediated PCD during senescence in plants.

  4. Differential senescence in feto-maternal tissues during mouse pregnancy.

    Science.gov (United States)

    Bonney, Elizabeth A; Krebs, Kendall; Saade, George; Kechichian, Talar; Trivedi, Jayshil; Huaizhi, Yin; Menon, Ramkumar

    2016-07-01

    Human studies show that fetal membranes have a limited lifespan and undergo telomere-dependent cellular senescence that is augmented by oxidative stress and mediated by p38 mitogen activated protein kinase (MAPK). Further, these studies suggest that fetal membranes are anatomically and physiologically positioned to transmit senescence signals that may initiate parturition at term. Longitudinal evaluation of feto-maternal tissues from mouse pregnancies was undertaken to determine the molecular progression of senescence during normal pregnancy. On days 10-18 of gestation, C57BL/6 mice were euthanized. Fetal membranes, placenta, and decidua/uterus were collected. Tissues were examined for Telomere length (TL) and the presence of Phosphorylated (P) p38MAPK and p53, p21 and senescence associated β-Galactosidase (SA- β-Gal). Linear regression modeling of observed telomere length as a function of gestational age revealed that beta (β), the slope of the linear regression was negative and significantly different from zero for each tissue (fetal membranes, β = -0.1901 ± 0.03125, p < 0.0001; placenta β = -0.09000 ± 0.03474, p = 0.0135; decidua/uterus β = -0.1317 ± 0.03264, p = 0.0003). Progressive activation p38MAPK was observed in all tissues from days 10 to day18, with the highest activation observed in fetal membranes. Activation of p53 was progressive in fetal membranes. In contrast, active p53 was constitutive in placenta and decidua/uterus throughout gestation. Detection of p21 indicated that pro-senescent change was higher in all compartments on day 18 as compared to other days. The number of SA-β-Gal positive cells increased in fetal membranes as gestation progressed. However, in placenta and uterus and decidua/uterus SA-β-Gal was seen only in days 15 and 18. Telomere dependent p38 and p53 mediated senescence progressed in mouse fetal membranes as gestation advanced. Although senescence is evident, telomere dependent events were not

  5. Evolution of maternal effect senescence.

    Science.gov (United States)

    Moorad, Jacob A; Nussey, Daniel H

    2016-01-12

    Increased maternal age at reproduction is often associated with decreased offspring performance in numerous species of plants and animals (including humans). Current evolutionary theory considers such maternal effect senescence as part of a unified process of reproductive senescence, which is under identical age-specific selective pressures to fertility. We offer a novel theoretical perspective by combining William Hamilton's evolutionary model for aging with a quantitative genetic model of indirect genetic effects. We demonstrate that fertility and maternal effect senescence are likely to experience different patterns of age-specific selection and thus can evolve to take divergent forms. Applied to neonatal survival, we find that selection for maternal effects is the product of age-specific fertility and Hamilton's age-specific force of selection for fertility. Population genetic models show that senescence for these maternal effects can evolve in the absence of reproductive or actuarial senescence; this implies that maternal effect aging is a fundamentally distinct demographic manifestation of the evolution of aging. However, brief periods of increasingly beneficial maternal effects can evolve when fertility increases with age faster than cumulative survival declines. This is most likely to occur early in life. Our integration of theory provides a general framework with which to model, measure, and compare the evolutionary determinants of the social manifestations of aging. Extension of our maternal effects model to other ecological and social contexts could provide important insights into the drivers of the astonishing diversity of lifespans and aging patterns observed among species.

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

    Indian Academy of Sciences (India)

    S Pandey; S A Ranade; P K Nagar; Nikhil Kumar

    2000-09-01

    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 abiotic factors accelerate the process. Convincing evidence suggests the involvement of polyamines (PAs) and ethylene in this process. Although the biosynthetic pathways of both PAs and ethylene are interrelated, S-adenosylmethionine (SAM) being a common precursor, their physiological functions are distinct and at times antagonistic, particularly during leaf and flower senescence and also during fruit ripening. This provides an effective means for regulation of their biosynthesis and also to understand the mechanism by which the balance between the two can be established for manipulating the senescence process. The present article deals with current advances in the knowledge of the interrelationship between ethylene and PAs during senescence which may open up new vistas of investigation for the future.

  7. Mitochondrial DNA Hypomethylation Is a Biomarker Associated with Induced Senescence in Human Fetal Heart Mesenchymal Stem Cells

    Directory of Open Access Journals (Sweden)

    Dehai Yu

    2017-01-01

    Full Text Available Background. Fetal heart can regenerate to restore its normal anatomy and function in response to injury, but this regenerative capacity is lost within the first week of postnatal life. Although the specific molecular mechanisms remain to be defined, it is presumed that aging of cardiac stem or progenitor cells may contribute to the loss of regenerative potential. Methods. To study this aging-related dysfunction, we cultured mesenchymal stem cells (MSCs from human fetal heart tissues. Senescence was induced by exposing cells to chronic oxidative stress/low serum. Mitochondrial DNA methylation was examined during the period of senescence. Results. Senescent MSCs exhibited flattened and enlarged morphology and were positive for the senescence-associated beta-galactosidase (SA-β-Gal. By scanning the entire mitochondrial genome, we found that four CpG islands were hypomethylated in close association with senescence in MSCs. The mitochondrial COX1 gene, which encodes the main subunit of the cytochrome c oxidase complex and contains the differentially methylated CpG island 4, was upregulated in MSCs in parallel with the onset of senescence. Knockdown of DNA methyltransferases (DNMT1, DNMT3a, and DNMT3B also upregulated COX1 expression and induced cellular senescence in MSCs. Conclusions. This study demonstrates that mitochondrial CpG hypomethylation may serve as a critical biomarker associated with cellular senescence induced by chronic oxidative stress.

  8. 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...... of WI-38 human fibroblasts and their follow-up identification have been addressed in this study. Indeed, it was expected that the identification of these proteins would give insights into the mechanisms by which oxidatively damaged proteins could affect cellular function. Among these proteins, some...

  9. Rescuing loading induced bone formation at senescence.

    Directory of Open Access Journals (Sweden)

    Sundar Srinivasan

    Full Text Available The increasing incidence of osteoporosis worldwide requires anabolic treatments that are safe, effective, and, critically, inexpensive given the prevailing overburdened health care systems. While vigorous skeletal loading is anabolic and holds promise, deficits in mechanotransduction accrued with age markedly diminish the efficacy of readily complied, exercise-based strategies to combat osteoporosis in the elderly. Our approach to explore and counteract these age-related deficits was guided by cellular signaling patterns across hierarchical scales and by the insight that cell responses initiated during transient, rare events hold potential to exert high-fidelity control over temporally and spatially distant tissue adaptation. Here, we present an agent-based model of real-time Ca(2+/NFAT signaling amongst bone cells that fully described periosteal bone formation induced by a wide variety of loading stimuli in young and aged animals. The model predicted age-related pathway alterations underlying the diminished bone formation at senescence, and hence identified critical deficits that were promising targets for therapy. Based upon model predictions, we implemented an in vivo intervention and show for the first time that supplementing mechanical stimuli with low-dose Cyclosporin A can completely rescue loading induced bone formation in the senescent skeleton. These pre-clinical data provide the rationale to consider this approved pharmaceutical alongside mild physical exercise as an inexpensive, yet potent therapy to augment bone mass in the elderly. Our analyses suggested that real-time cellular signaling strongly influences downstream bone adaptation to mechanical stimuli, and quantification of these otherwise inaccessible, transient events in silico yielded a novel intervention with clinical potential.

  10. Failure of cell cleavage induces senescence in tetraploid primary cells.

    Science.gov (United States)

    Panopoulos, Andreas; Pacios-Bras, Cristina; Choi, Justin; Yenjerla, Mythili; Sussman, Mark A; Fotedar, Rati; Margolis, Robert L

    2014-10-15

    Tetraploidy can arise from various mitotic or cleavage defects in mammalian cells, and inheritance of multiple centrosomes induces aneuploidy when tetraploid cells continue to cycle. Arrest of the tetraploid cell cycle is therefore potentially a critical cellular control. We report here that primary rat embryo fibroblasts (REF52) and human foreskin fibroblasts become senescent in tetraploid G1 after drug- or small interfering RNA (siRNA)-induced failure of cell cleavage. In contrast, T-antigen-transformed REF52 and p53+/+ HCT116 tumor cells rapidly become aneuploid by continuing to cycle after cleavage failure. Tetraploid primary cells quickly become quiescent, as determined by loss of the Ki-67 proliferation marker and of the fluorescent ubiquitination-based cell cycle indicator/late cell cycle marker geminin. Arrest is not due to DNA damage, as the γ-H2AX DNA damage marker remains at control levels after tetraploidy induction. Arrested tetraploid cells finally become senescent, as determined by SA-β-galactosidase activity. Tetraploid arrest is dependent on p16INK4a expression, as siRNA suppression of p16INK4a bypasses tetraploid arrest, permitting primary cells to become aneuploid. We conclude that tetraploid primary cells can become senescent without DNA damage and that induction of senescence is critical to tetraploidy arrest.

  11. Oxidative Stress Induces Endothelial Cell Senescence via Downregulation of Sirt6

    Directory of Open Access Journals (Sweden)

    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.

  12. HBP1-Mediated Transcriptional Regulation of DNA Methyltransferase 1 and Its Impact on Cell Senescence

    Science.gov (United States)

    Pan, Kewu; Chen, Yifan; Roth, Mendel; Wang, Weibin; Wang, Shuya; Yee, Amy S.

    2013-01-01

    The activity of DNA methyltransferase 1 (DNMT1) is associated with diverse biological activities, including cell proliferation, senescence, and cancer development. In this study, we demonstrated that the HMG box-containing protein 1 (HBP1) transcription factor is a new repressor of DNMT1 in a complex mechanism during senescence. The DNMT1 gene contains an HBP1-binding site at bp −115 to −134 from the transcriptional start site. HBP1 repressed the endogenous DNMT1 gene through sequence-specific binding, resulting in both gene-specific (e.g., p16INK4) and global DNA hypomethylation changes. The HBP1-mediated repression by DNMT1 contributed to replicative and premature senescence, the latter of which could be induced by Ras and HBP1 itself. A detailed investigation unexpectedly revealed that HBP1 has dual and complex transcriptional functions, both of which contribute to premature senescence. HBP1 both repressed the DNMT1 gene and activated the p16 gene in premature senescence. The opposite transcriptional functions proceeded through different DNA sequences and differential protein acetylation. While intricate, the reciprocal partnership between HBP1 and DNMT1 has exceptional importance, since its abrogation compromises senescence and promotes tumorigenesis. Together, our results suggest that the HBP1 transcription factor orchestrates a complex regulation of key genes during cellular senescence, with an impact on overall DNA methylation state. PMID:23249948

  13. miR-137 Modulates a Tumor Suppressor Network-Inducing Senescence in Pancreatic Cancer Cells

    Directory of Open Access Journals (Sweden)

    Mathieu Neault

    2016-03-01

    Full Text Available Activating K-Ras mutations occurs frequently in pancreatic cancers and is implicated in their development. Cancer-initiating events, such as oncogenic Ras activation, lead to the induction of cellular senescence, a tumor suppressor response. During senescence, the decreased levels of KDM4A lysine demethylase contribute to p53 activation, however, the mechanism by which KDM4A is downregulated is unknown. We show that miR-137 targets KDM4A mRNA during Ras-induced senescence and activates both p53 and retinoblastoma (pRb tumor suppressor pathways. Restoring the KDM4A expression contributed to bypass of miR-137-induced senescence and inhibition of endogenous miR-137 with an miRNA sponge-compromised Ras-induced senescence. miR-137 levels are significantly reduced in human pancreatic tumors, consistent with previous studies revealing a defective senescence response in this cancer type. Restoration of miR-137 expression inhibited proliferation and promoted senescence of pancreatic cancer cells. These results suggest that modulating levels of miR-137 may be important for triggering tumor suppressor networks in pancreatic cancer.

  14. Changes in the Transcriptome of Human Astrocytes Accompanying Oxidative Stress-Induced Senescence

    Science.gov (United States)

    Crowe, Elizabeth P.; Tuzer, Ferit; Gregory, Brian D.; Donahue, Greg; Gosai, Sager J.; Cohen, Justin; Leung, Yuk Y.; Yetkin, Emre; Nativio, Raffaella; Wang, Li-San; Sell, Christian; Bonini, Nancy M.; Berger, Shelley L.; Johnson, F. Brad; Torres, Claudio

    2016-01-01

    Aging is a major risk factor for many neurodegenerative disorders. A key feature of aging biology that may underlie these diseases is cellular senescence. Senescent cells accumulate in tissues with age, undergo widespread changes in gene expression, and typically demonstrate altered, pro-inflammatory profiles. Astrocyte senescence has been implicated in neurodegenerative disease, and to better understand senescence-associated changes in astrocytes, we investigated changes in their transcriptome using RNA sequencing. Senescence was induced in human fetal astrocytes by transient oxidative stress. Brain-expressed genes, including those involved in neuronal development and differentiation, were downregulated in senescent astrocytes. Remarkably, several genes indicative of astrocytic responses to injury were also downregulated, including glial fibrillary acidic protein and genes involved in the processing and presentation of antigens by major histocompatibility complex class II proteins, while pro-inflammatory genes were upregulated. Overall, our findings suggest that senescence-related changes in the function of astrocytes may impact the pathogenesis of age-related brain disorders. PMID:27630559

  15. Changes in the Transcriptome of Human Astrocytes Accompanying Oxidative Stress-induced Senescence

    Directory of Open Access Journals (Sweden)

    Elizabeth P. Crowe

    2016-08-01

    Full Text Available Aging is a major risk factor for many neurodegenerative disorders. A key feature of aging biology that may underlie these diseases is cellular senescence. Senescent cells accumulate in tissues with age, undergo widespread changes in gene expression, and typically demonstrate altered, pro-inflammatory profiles. Astrocyte senescence has been implicated in neurodegenerative disease, and to better understand senescence-associated changes in astrocytes, we investigated changes in their transcriptome using RNA sequencing. Senescence was induced in human fetal astrocytes by transient oxidative stress. Brain-expressed genes, including those involved in neuronal development and differentiation, were downregulated in senescent astrocytes. Remarkably, several genes indicative of astrocytic responses to injury were also downregulated, including GFAP and genes involved in the processing and presentation of antigens by major histocompatibility complex class II proteins, while pro-inflammatory genes were upregulated. Overall, our findings suggest that senescence-related changes in the function of astrocytes may impact the pathogenesis of age-related brain disorders.

  16. 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.

  17. The SETD8/PR-Set7 Methyltransferase Functions as a Barrier to Prevent Senescence-Associated Metabolic Remodeling

    Directory of Open Access Journals (Sweden)

    Hiroshi Tanaka

    2017-02-01

    Full Text Available Cellular senescence is an irreversible growth arrest that contributes to development, tumor suppression, and age-related conditions. Senescent cells show active metabolism compared with proliferating cells, but the underlying mechanisms remain unclear. Here we show that the SETD8/PR-Set7 methyltransferase, which catalyzes mono-methylation of histone H4 at lysine 20 (H4K20me1, suppresses nucleolar and mitochondrial activities to prevent cellular senescence. SETD8 protein was selectively downregulated in both oncogene-induced and replicative senescence. Inhibition of SETD8 alone was sufficient to trigger senescence. Under these states, the expression of genes encoding ribosomal proteins (RPs and ribosomal RNAs as well as the cyclin-dependent kinase (CDK inhibitor p16INK4A was increased, with a corresponding reduction of H4K20me1 at each locus. As a result, the loss of SETD8 concurrently stimulated nucleolar function and retinoblastoma protein-mediated mitochondrial metabolism. In conclusion, our data demonstrate that SETD8 acts as a barrier to prevent cellular senescence through chromatin-mediated regulation of senescence-associated metabolic remodeling.

  18. 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.

  19. p16(Ink4a)-induced senescence of pancreatic beta cells enhances insulin secretion.

    Science.gov (United States)

    Helman, Aharon; Klochendler, Agnes; Azazmeh, Narmen; Gabai, Yael; Horwitz, Elad; Anzi, Shira; Swisa, Avital; Condiotti, Reba; Granit, Roy Z; Nevo, Yuval; Fixler, Yaakov; Shreibman, Dorin; Zamir, Amit; Tornovsky-Babeay, Sharona; Dai, Chunhua; Glaser, Benjamin; Powers, Alvin C; Shapiro, A M James; Magnuson, Mark A; Dor, Yuval; Ben-Porath, Ittai

    2016-04-01

    Cellular senescence is thought to contribute to age-associated deterioration of tissue physiology. The senescence effector p16(Ink4a) is expressed in pancreatic beta cells during aging and limits their proliferative potential; however, its effects on beta cell function are poorly characterized. We found that beta cell-specific activation of p16(Ink4a) in transgenic mice enhances glucose-stimulated insulin secretion (GSIS). In mice with diabetes, this leads to improved glucose homeostasis, providing an unexpected functional benefit. Expression of p16(Ink4a) in beta cells induces hallmarks of senescence--including cell enlargement, and greater glucose uptake and mitochondrial activity--which promote increased insulin secretion. GSIS increases during the normal aging of mice and is driven by elevated p16(Ink4a) activity. We found that islets from human adults contain p16(Ink4a)-expressing senescent beta cells and that senescence induced by p16(Ink4a) in a human beta cell line increases insulin secretion in a manner dependent, in part, on the activity of the mechanistic target of rapamycin (mTOR) and the peroxisome proliferator-activated receptor (PPAR)-γ proteins. Our findings reveal a novel role for p16(Ink4a) and cellular senescence in promoting insulin secretion by beta cells and in regulating normal functional tissue maturation with age.

  20. 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.

  1. Induction of leaf senescence by low nitrogen nutrition in sunflower (Helianthus annuus) plants.

    Science.gov (United States)

    Agüera, Eloísa; Cabello, Purificación; de la Haba, Purificación

    2010-03-01

    in N- plants these activities started to decrease earlier, APX after 16 days and catalase after 22 days, suggesting that senescence is accelerated in N-leaves. It is probable that systemic signals, such as a deficit in amino acids or other metabolites associated with the nitrogen metabolism produced in plants grown with low nitrogen, lead to an early senescence and a higher oxidation state of the cells of these plant leaves.

  2. DNA Hypomethylation and Histone Variant macroH2A1 Synergistically Attenuate Chemotherapy-Induced Senescence to Promote Hepatocellular Carcinoma Progression

    NARCIS (Netherlands)

    Borghesan, Michela; Fusilli, Caterina; Rappa, Francesca; Panebianco, Concetta; Rizzo, Giovanni; Oben, Jude A.; Mazzoccoli, Gianluigi; Faulkes, Chris; Pata, Illar; Agodi, Antonella; Rezaee, Farhad; Minogue, Shane; Warren, Alessandra; Peterson, Abigail; Sedivy, John M.; Douet, Julien; Buschbeck, Marcus; Cappello, Francesco; Mazza, Tommaso; Pazienza, Valerio; Vinciguerra, Manlio

    2016-01-01

    Aging is a major risk factor for progression of liver diseases to hepatocellular carcinoma (HCC). Cellular senescence contributes to age-related tissue dysfunction, but the epigenetic basis underlying drug-induced senescence remains unclear. macroH2A1, a variant of histone H2A, is a marker of

  3. Glucagon-Like Peptide 1 Prevents Reactive Oxygen Species-Induced Endothelial Cell Senescence Through the Activation of Protein Kinase A

    NARCIS (Netherlands)

    Oeseburg, Hisko; de Boer, Rudolf A.; Buikema, Hendrik; van der Harst, Pim; van Gilst, Wiek H.; Sillje, Herman H. W.

    2010-01-01

    Objective-Endothelial cell senescence is an important contributor to vascular aging and is increased under diabetic conditions. Here we investigated whether the antidiabetic hormone glucagon-like peptide 1 (GLP-1) could prevent oxidative stress-induced cellular senescence in endothelial cells. Metho

  4. A Petunia homeodomain-leucine zipper protein, PhHD-Zip, plays an important role in flower senescence.

    Directory of Open Access Journals (Sweden)

    Xiaoxiao Chang

    Full Text Available Flower senescence is initiated by developmental and environmental signals, and regulated by gene transcription. A homeodomain-leucine zipper transcription factor, PhHD-Zip, is up-regulated during petunia flower senescence. Virus-induced gene silencing of PhHD-Zip extended flower life by 20% both in unpollinated and pollinated flowers. Silencing PhHD-Zip also dramatically reduced ethylene production and the abundance of transcripts of genes involved in ethylene (ACS, ACO, and ABA (NCED biosynthesis. Abundance of transcripts of senescence-related genes (SAG12, SAG29 was also dramatically reduced in the silenced flowers. Over-expression of PhHD-Zip accelerated petunia flower senescence. Furthermore, PhHD-Zip transcript abundance in petunia flowers was increased by application of hormones (ethylene, ABA and abiotic stresses (dehydration, NaCl and cold. Our results suggest that PhHD-Zip plays an important role in regulating petunia flower senescence.

  5. AMPK induces vascular smooth muscle cell senescence via LKB1 dependent pathway

    Energy Technology Data Exchange (ETDEWEB)

    Sung, Jin Young; Woo, Chang-Hoon [Department of Pharmacology, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of); Aging-associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of); Kang, Young Jin; Lee, Kwang Youn [Department of Pharmacology, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of); Choi, Hyoung Chul, E-mail: hcchoi@med.yu.ac.kr [Department of Pharmacology, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of); Aging-associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of)

    2011-09-16

    Highlights: {yields} An aging model was established by stimulating VSMC with adriamycin. {yields} Adriamycin increased p-LKB1, p-AMPK, p53 and p21 expressions. {yields} Inhibition of AMPK diminished SA-{beta}-gal staining and restored VSMC proliferation. {yields} p53 and p21 siRNA attenuated adriamycin-induced SA-{beta}-gal staining in VSMC. {yields} p53-p21 pathway is a mediator of LKB1/AMPK induced VSMC senescence. -- Abstract: Vascular cells have a limited lifespan with limited cell proliferation and undergo cellular senescence. The functional changes associated with cellular senescence are thought to contribute to age-related vascular disorders. AMP-activated protein kinase (AMPK) has been discussed in terms of beneficial or harmful effects for aging-related diseases. However, the detailed functional mechanisms of AMPK are largely unclear. An aging model was established by stimulating vascular smooth muscle cell (VSMC) with adriamycin. Adriamycin progressively increased the mRNA and protein expressions of AMPK. The phosphorylation levels of LKB1 and acetyl-CoA carboxylase (ACC), the upstream and downstream of AMPK, were dramatically increased by adriamycin stimulation. The expressions of p53 and p21, which contribute to vascular senescence, were also increased. Inhibition of AMPK diminished senescence-associated {beta}-galactosidase (SA-{beta}-gal) staining, and restored VSMC proliferation. Cytosolic translocation of LKB1 by adriamycin could be a mechanism for AMPK activation in senescence. Furthermore, p53 siRNA and p21 siRNA transfection attenuated adriamycin-induced SA-{beta}-gal staining. These results suggest that LKB1 dependent AMPK activation elicits VSMC senescence and p53-p21 pathway is a mediator of LKB1/AMPK-induced senescence.

  6. Mortalin sensitizes human cancer cells to MKT-077-induced senescence.

    Science.gov (United States)

    Deocaris, Custer C; Widodo, Nashi; Shrestha, Bhupal G; Kaur, Kamaljit; Ohtaka, Manami; Yamasaki, Kazuhiko; Kaul, Sunil C; Wadhwa, Renu

    2007-07-18

    Mortalin is a chaperone protein that functions in many cellular processes such as mitochondrial biogenesis, intracellular trafficking, cell proliferation and signaling. Its upregulation in many human cancers makes it a candidate target for therapeutic intervention by small molecule drugs. In continuation to our earlier studies showing mortalin as a cellular target of MKT-077, a mitochondrion-seeking delocalized cationic dye that causes selective death of cancer cells, in this work, we report that MKT-077 binds to the nucleotide-binding domain of mortalin, causes tertiary structural changes in the protein, inactivates its chaperone function, and induces senescence in human tumor cell lines. Interestingly, in tumor cells with elevated level of mortalin expression, fairly low drug doses were sufficient to induce senescence. Guided by molecular screening for mortalin in tumor cells, our results led to the idea that working at low doses of the drug could be an alternative senescence-inducing cancer therapeutic strategy that could, in theory, avoid renal toxicities responsible for the abortion of MKT-077 clinical trials. Our work may likely translate to a re-appraisal of the therapeutic benefits of low doses of several classes of anti-tumor drugs, even of those that had been discontinued due to adverse effects.

  7. CELLULAR RESPONSES TO DNA DAMAGE AND ONCOGENESIS BY THE p53 AND pRb/E2F PATHWAYS

    Directory of Open Access Journals (Sweden)

    Elza Ibrahim Auerkari

    2015-07-01

    Full Text Available Cellular responses to stress including DNA damage, show multiple options involving the mechanisms of growth arrest. DNA repair and programmed cell death or apoptosis. Failures in these mechanisms can result in oncogenesis or accelerated senescence. Much of the response is coordinated by p53, a nuclear phosphoprotein with a central role in the defences against physical, chemical and pathogenic agents which challenge the DNA integrity. The p53 pathways for mobilising the cellular defences are linked to the pRB/E2D pathways regulating the cell cycle progression. This paper aims to review the current understanding on the networks and main molecular machinery of these processes. In addition, the implications on cellular decision making for the defences as well as revolutionary aspects of these mechanisms are discussed in brief.

  8. Regulation of Senescence in Carnation (Dianthus caryophyllus): Effect of Abscisic Acid and Carbon Dioxide on Ethylene Production.

    Science.gov (United States)

    Mayak, S; Dilley, D R

    1976-11-01

    Abscisic acid hastened senescence of carnation flowers and this was preceded by stimulation of accelerated ethylene production. Carbon dioxide delayed the onset of autocatalytic ethylene production in flowers regardless of treatment with abscisic acid. Flowers exhibited a low and transient climacteric of ethylene production without wilting while in 4% carbon dioxide and underwent accelerated ethylene production culminating in wilting when removed from carbon dioxide. Hypobaric ventilation, which lowers ethylene to hyponormal levels within tissues, extended flower longevity and largely negated enhancement of senescence by abscisic acid. Supplementing hypobarically ventilated flowers with ethylene hastened senescence irrespective of abscisic acid treatment. Collectively, the data indicate that abscisic acid hastens senescence of carnations largely as a result of advancing the onset of autocatalytic ethylene production.

  9. Investigation of protective effects of naloxone on aluminium trichloride-induced memory impairment of senescence-accelerated mice and its mechanism%纳洛酮对三氯化铝致急性衰老小鼠记忆障碍的保护作用及其机制

    Institute of Scientific and Technical Information of China (English)

    顾饶胜; 沈楠; 王艳春; 刘微; 任旷

    2005-01-01

    BACKGROUND: The content of aluminium generally increases in the cerebral cells of patients with senile dementia. Aluminium poisoning in brain has inner link with senile dementia. Naloxone is the specific antagonist of opioid receptor, which can be applied in the treatment of senile dementia according to foreign reports.OBJECTIVE: To investigate protective effects of naloxone on aluminium trichloride-induced memory impairment of senescence-accelerated mice and its mechanism.DESIGN: Randomized controlled trial.SETTING: Jilin Medical College.MATERIALS: The experiment was completed in Laboratory of Pharmacology of Jilin Medical College (formerly the Jilin Military Medical College) from February 2001 to February 2003. A total of 100 healthy adult Kunming mice were selected and randomly divided into 5 groups: control group, model group, naloxone 0.1 mg/kg group, naloxone 0.3 mg/kg group and naloxone 0.9 mg/kg group, with 20 in each group. Except the control group, subcutaneous injection with 70 mg/kg aluminium trichloride was given to the mouse in each group once a day for continuous 7 days; besides this, intraperitoneal injection with 0.1, 0.3, 0.9 mg/kg naloxone was given to the mouse in naloxone groups and the same amount of physiological saline was given to the mouse in the control group.METHODS: The methods of jumping stand and escaping dark were conducted to detect learning ability and memory of mice. Meanwhile, the content of malondialdhehyde in liver and mono-amine oxidase B in brain of mice were also detect.MAIN OUTCOME MEASURES: ① Results of jumping stand experiment of aluminium trichloride-induced model of senescence. ② Results of escaping dark experiment of aluminium trichloride-induced model of senescence. ③ Comparison of malondialdhehyde and mono-amine oxidase B among each group.RESULTS: ① Results of jumping stand experiment of aluminium trichloride-induced model of senescence: Compared withmodel group, the frequency of electric shocks suffered by

  10. Raman and infrared spectroscopy differentiate senescent from proliferating cells in a human dermal fibroblast 3D skin model.

    Science.gov (United States)

    Eberhardt, Katharina; Matthäus, Christian; Winter, Doreen; Wiegand, Cornelia; Hipler, Uta-Christina; Diekmann, Stephan; Popp, Jürgen

    2017-08-15

    Senescent cells contribute to tissue aging and dysfunction. Therefore, detecting senescent cells in skin is of interest for skin tumor diagnostics and therapy. Here, we studied the transition into senescence of human dermal fibroblasts (HDFs) in a three-dimensional (3D) human fibroblast-derived matrix (FDM). Senescent and proliferating cells were imaged by Raman spectroscopy (RS) and Fourier transform infrared (FTIR) spectroscopy. The obtained averaged spectra were analyzed using PLS-LDA. For these 3D cultured cells, RS and FTIR could clearly distinguish senescent from proliferating cells. For both techniques, we detected senescence-associated alterations in almost all cellular macromolecules. Furthermore, we identified different biochemical properties of 3D compared to two-dimensional (2D) cultured cells, indicating that cells in their natural, skin-like 3D environment act differently than in (2D) cell cultivations in vitro. Compared to 2D cultured cells, cells grown in 3D models displayed a sharper contrast between the proliferating and senescent state, also affecting the abundance of biomolecules including nucleic acids. The training accuracies of both vibrational spectroscopic techniques were >96%, demonstrating the suitability of these label-free measurements for detecting these cellular states in 3D skin models.

  11. Structural Changes in Senescing Oilseed Rape Leaves at Tissue and Subcellular Levels Monitored by Nuclear Magnetic Resonance Relaxometry through Water Status

    National Research Council Canada - National Science Library

    Maja Musse; Loriane De Franceschi; Mireille Cambert; Clément Sorin; Françoise Le Caherec; Agnès Burel; Alain Bouchereau; François Mariette; Laurent Leport

    2013-01-01

    ... and the associated senescence processes. In this study, nuclear magnetic resonance (NMR) relaxometry was used to describe water distribution and status at the cellular level in different leaf ranks of well-watered plants...

  12. Quantitative digital in situ senescence-associated β-galactosidase assay

    Directory of Open Access Journals (Sweden)

    Yehezkel Shiran

    2011-04-01

    Full Text Available Abstract Background Cellular senescence plays important roles in the aging process of complex organisms, in tumor suppression and in response to stress. Several markers can be used to identify senescent cells, of which the most widely used is the senescence-associated β-galactosidase (SABG activity. The main advantage of SABG activity over other markers is the simplicity of the detection assay and the capacity to identify in situ a senescent cell in a heterogeneous cell population. Several approaches have been introduced to render the SABG assay quantitative. However none of these approaches to date has proven particularly amenable to quantitative analysis of SABG activity in situ. Furthermore the role of cellular senescence (CS in vivo remains unclear mainly due to the ambiguity of current cellular markers in identifying CS of individual cells in tissues. Results In the current study we applied a digital image analysis technique to the staining generated using the original SABG assay, and demonstrate that this analysis is highly reproducible and sensitive to subtle differences in staining intensities resulting from diverse cellular senescence pathways in culture. We have further validated our method on mouse kidney samples with and without diabetes mellitus, and show that a more accurate quantitative SABG activity with a wider range of values can be achieved at a pH lower than that used in the conventional SABG assay. Conclusions We conclude that quantitative in situ SABG assay, is feasible and reproducible and that the pH at which the reaction is performed should be tailored and chosen, depending on the research question and experimental system of interest.

  13. Knockin mice expressing a chimeric p53 protein reveal mechanistic differences in how p53 triggers apoptosis and senescence

    OpenAIRE

    2008-01-01

    The contribution of transcriptional activation to the p53 effector functions critical for tumor suppression, apoptosis and cellular senescence, remains unclear because of p53's ability to regulate diverse cellular processes in a transactivation-independent manner. Dissociating the importance of transactivation from other p53 functions, including regulating transcriptional repression, DNA replication, homologous recombination, centrosome duplication, and mitochondrial function, has been diffic...

  14. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.

    Science.gov (United States)

    Baar, Marjolein P; Brandt, Renata M C; Putavet, Diana A; Klein, Julian D D; Derks, Kasper W J; Bourgeois, Benjamin R M; Stryeck, Sarah; Rijksen, Yvonne; van Willigenburg, Hester; Feijtel, Danny A; van der Pluijm, Ingrid; Essers, Jeroen; van Cappellen, Wiggert A; van IJcken, Wilfred F; Houtsmuller, Adriaan B; Pothof, Joris; de Bruin, Ron W F; Madl, Tobias; Hoeijmakers, Jan H J; Campisi, Judith; de Keizer, Peter L J

    2017-03-23

    The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability. We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur density, and renal function in both fast aging Xpd(TTD/TTD) and naturally aged mice. Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. High concentrations of NaCl induce cell swelling leading to senescence in human cells.

    Science.gov (United States)

    Yamakami, Yoshimi; Yonekura, Ryuzo; Matsumoto, Yuko; Takauji, Yuki; Miki, Kensuke; Fujii, Michihiko; Ayusawa, Dai

    2016-01-01

    Cell swelling and retardation in DNA replication are always observed in senescent cells. When DNA replication is slowed down with RNA and protein syntheses unchanged in proliferating cells, it causes a phenomenon known as unbalanced growth. The purpose of this study is to assess the role of cell swelling in unbalanced growth in terms of senescence and investigate the mechanism underlying this phenomenon. We tried to induce cell swelling with minimum damage to cells in this study. We perturbed the osmoregulatory functions to induce cell swelling under hypotonic and hypertonic conditions in normal human fibroblasts. Addition of excess NaCl was found to induce significant cell and nuclear swelling in dose- and time-dependent manners. Excess NaCl immediately retarded DNA replication, accumulated cells at G1 phase of the cell cycle, and eventually deprived division potential of the cells. Such cells showed typical senescent cell shape followed by expression of the typical senescence-associated genes. Excess NaCl also activated ERK1/2, p38, and JNK of the mitogen activated protein kinase family. Addition of U0126, an inhibitor of ERK1/2, prevented appearance of senescent features induced by excess NaCl. These results suggest that hypertonic conditions induce cell swelling due to unbalanced growth, thereby leading to cellular senescence.

  16. Induction of Extracellular Matrix-Remodeling Genes by the Senescence-Associated Protein APA-1

    Science.gov (United States)

    Benanti, Jennifer A.; Williams, Dawnnica K.; Robinson, Kristin L.; Ozer, Harvey L.; Galloway, Denise A.

    2002-01-01

    Human fibroblasts undergo cellular senescence after a finite number of divisions, in response to the erosion of telomeres. In addition to being terminally arrested in the cell cycle, senescent fibroblasts express genes that are normally induced upon wounding, including genes that remodel the extracellular matrix. We have identified the novel zinc finger protein APA-1, whose expression increased in senescent human fibroblasts independent of telomere shortening. Extended passage, telomerase-immortalized fibroblasts had increased levels of APA-1 as well as the cyclin-dependent kinase inhibitor p16. In fibroblasts, APA-1 was modified by the ubiquitin-like protein SUMO-1, which increased APA-1 half-life, possibly by blocking ubiquitin-mediated degradation. Overexpression of APA-1 did not cause cell cycle arrest; but, it induced transcription of the extracellular matrix-remodeling genes MMP1 and PAI2, which are associated with fibroblast senescence. MMP1 and PAI2 transcript levels also increased in telomerase-immortalized fibroblasts that had high levels of APA-1, demonstrating that the matrix-remodeling phenotype of senescent fibroblasts was not induced by telomere attrition alone. APA-1 was able to transactivate and bind to the MMP1 promoter, suggesting that APA-1 is a transcription factor that regulates expression of matrix-remodeling genes during fibroblast senescence. PMID:12370286

  17. 自愿运动对快速老化小鼠学习记忆能力和海马生长相关蛋白43的影响%Effects of voluntary exercise on learning ability, memory and hippocampus growth-associated protein 43 expression in senescence-accelerated prone mouse

    Institute of Scientific and Technical Information of China (English)

    苑振云; 姜向明; 王铭维; 顾平; 杨秀芬; 苏冠丽; 杨涛; 李斌

    2012-01-01

    Objective To observe the effects of voluntary exercise on the learning ability, memory and hippocampus growth-associated protein 43 (GAP43) expression in senescence-accelerated prone mouse (SAMP8), so as to explore the possible mechanism of exercises on improving the cognitive ability and delaying aging. Methods A total of 60 three-month old female SAMP8 mice were evenly assigned to running cage environment (RCE) group and standard environment (SE) group at random. After three months, Morris water maze test was used to test the platform-seeking latency and search strategy. Then 10 mice were sacrificed in each group for RT-PCR analysis of hippocampus GAP43 mRNA expression, 10 for Western blotting analysis of hippocampus GAP43 protein expression, and 10 for immunohistochemistry staining of hippocampus GAP43 expression. Results Morris water maze test showed that RCE mice had a significant shorter platform-seeking latency than SE mice(P<0. 01, P<0. 05) , and RCE mice had a significant longer time in the first quadrant (P<0. 01) and a shorter time in the fourth quadrant (P<0. 05) compared with SE mice. RCE mice had a significantly higher GAP43 expression in the hippocampus compared with SE mice (P<0. 01). Conclusion Voluntary exercise can improve the learning ability and memory of SAMP8, which might be associated with the increase of GAP43 in the hippocampus.%目的 观察自愿运动对快速老化小鼠(senescence-accelerated mouse prone 8,SA MP8)学习记忆能力和海马生长相关蛋白43(growth-associated protein-43,GAP43)表达的影响,探讨运动提高认知能力延缓衰老的机制.方法 60只3个月龄雌性SAMP8小鼠随机平均分为跑笼环境组(RCE组)和标准环境组(SE组).饲养3个月后,用Morris水迷宫测试小鼠的寻找平台潜伏期及搜索策略.行为学测试后,各组分别取10只小鼠的鼠脑用RT-PCR法检测海马GAP43 mRNA的表达;取10只小鼠的鼠脑用免疫印迹实验检测海马GAP43蛋白的表达;剩余10

  18. Immune response to RB1-regulated senescence limits radiation-induced osteosarcoma formation

    Science.gov (United States)

    Kansara, Maya; Leong, Huei San; Lin, Dan Mei; Popkiss, Sophie; Pang, Puiyi; Garsed, Dale W.; Walkley, Carl R.; Cullinane, Carleen; Ellul, Jason; Haynes, Nicole M.; Hicks, Rod; Kuijjer, Marieke L.; Cleton-Jansen, Anne-Marie; Hinds, Philip W.; Smyth, Mark J.; Thomas, David M.

    2013-01-01

    Ionizing radiation (IR) and germline mutations in the retinoblastoma tumor suppressor gene (RB1) are the strongest risk factors for developing osteosarcoma. Recapitulating the human predisposition, we found that Rb1+/– mice exhibited accelerated development of IR-induced osteosarcoma, with a latency of 39 weeks. Initial exposure of osteoblasts to carcinogenic doses of IR in vitro and in vivo induced RB1-dependent senescence and the expression of a panel of proteins known as senescence-associated secretory phenotype (SASP), dominated by IL-6. RB1 expression closely correlated with that of the SASP cassette in human osteosarcomas, and low expression of both RB1 and the SASP genes was associated with poor prognosis. In vivo, IL-6 was required for IR-induced senescence, which elicited NKT cell infiltration and a host inflammatory response. Mice lacking IL-6 or NKT cells had accelerated development of IR-induced osteosarcomas. These data elucidate an important link between senescence, which is a cell-autonomous tumor suppressor response, and the activation of host-dependent cancer immunosurveillance. Our findings indicate that overcoming the immune response to senescence is a rate-limiting step in the formation of IR-induced osteosarcoma. PMID:24231354

  19. 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...... with their chronological age and present health status, help define their current rate of aging and contribute to establish personalized therapy plans to reduce, counteract or even avoid the appearance of aging biomarkers....

  20. The oxidative hypothesis of senescence.

    Science.gov (United States)

    Gilca, M; Stoian, I; Atanasiu, V; Virgolici, B

    2007-01-01

    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 beta -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. 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.

  2. Mitochondrial fission and fusion in astrocytes: a new pathway towards senescence

    Directory of Open Access Journals (Sweden)

    Sonia Luz Albarracin

    2015-02-01

    Full Text Available Astrocytes are highly specialized cells that can maintain the integrity of the synapse, facilitate nutrition and trophic support to neurons, and regulate metabolic coupling between neurons and glia. However, astrocytes are involved in resolving different types of injuries and in aging processes in the brain. Senescence has also been reported in the brain, and senescence-associated loss of astrocyte function is linked to neuronal dysfunction in age-related neurodegenerative diseases such as Alzheimer’s disease and Parkinson's disease. For example, astrocyte senescence per se inhibits synapse maturation and affects synaptic transmission. In response to the cell’s bio-energetic state, mitochondria continuously undergo structural remodeling through fission and fusion processes. These tightly regulated events are believed to be involved in many cellular events such as apoptosis, senescence, and age-related diseases. Although, little is known about the age-related changes that occur in astrocytes and if these cells are able to generate a senescent phenotype mediated by mitochondria, in the present study we evaluated the involvement of mitochondrial remodeling in the senescence process of rat astrocytes in vitro. The results obtained showed that when comparing cells at population doubling two (PD2 with cells at population doubling ten (PD10 there is a significant increase in the activity of the senescence-associated β-galactosidase marker in PD10 cells. In addition, PD10 cells had increased mitochondrial volume, decreased superoxide production, and decreased mitochondrial membrane potential. Protein characterization evidenced changes in the balance between mitochondrial fission and fusion proteins. Collectively, our results demonstrated a senescent-astrocyte phenotype at PD10, which is associated with metabolic and mitochondrial phenotype changes.

  3. Influence of aging and growth hormone on different members of the NFkB family and IkB expression in the heart from a murine model of senescence-accelerated aging.

    Science.gov (United States)

    Forman, K; Vara, E; García, C; Kireev, R; Cuesta, S; Acuña-Castroviejo, D; Tresguerres, J A F

    2016-01-01

    Inflammation is related to several pathological processes. The aim of this study was to investigate the protein expression of the different subunits of the nuclear factor Kappa b (NFkBp65, p50, p105, p52, p100) and the protein expressions of IkB beta and alpha in the hearts from a murine model of accelerated aging (SAM model) by Western blot. In addition, the translocation of some isoforms of NFkB from cytosol to nuclei (NFkBp65, p50, p52) and ATP level content was studied. In addition we investigated the effect of the chronic administration of growth hormone (GH) on these age-related parameters. SAMP8 and SAMR1 mice of 2 and 10 months of age were used (n = 30). Animals were divided into five experimental groups: 2 old untreated (SAMP8/SAMR1), 2 young control (SAMP8/SAMR1) and one GH treated-old groups (SAMP8). Age-related changes were found in the studied parameters. We were able to see decreases of ATP level contents and the translocation of the nuclear factor kappa B p50, p52 and p65 from cytosol to nuclei in old SAMP8 mice together with a decrease of IKB proteins. However p100 and p105 did not show differences with aging. No significant changes were recorded in SAMR1 animals. GH treatment showed beneficial effects in old SAMP8 mice inducing an increase in ATP levels and inhibiting the translocation of some NFkB subunits such as p52. Our results supported the relation of NFkB activation with enhanced apoptosis and pro-inflammatory status in old SAMP8 mice and suggested a selective beneficial effect of the GH treatment, which was able to partially reduce the incidence of some deleterious changes in the heart of those mice.

  4. Ablation of XP-V gene causes adipose tissue senescence and metabolic abnormalities.

    Science.gov (United States)

    Chen, Yih-Wen; Harris, Robert A; Hatahet, Zafer; Chou, Kai-ming

    2015-08-18

    Obesity and the metabolic syndrome have evolved to be major health issues throughout the world. Whether loss of genome integrity contributes to this epidemic is an open question. DNA polymerase η (pol η), encoded by the xeroderma pigmentosum (XP-V) gene, plays an essential role in preventing cutaneous cancer caused by UV radiation-induced DNA damage. Herein, we demonstrate that pol η deficiency in mice (pol η(-/-)) causes obesity with visceral fat accumulation, hepatic steatosis, hyperleptinemia, hyperinsulinemia, and glucose intolerance. In comparison to WT mice, adipose tissue from pol η(-/-) mice exhibits increased DNA damage and a greater DNA damage response, indicated by up-regulation and/or phosphorylation of ataxia telangiectasia mutated (ATM), phosphorylated H2AX (γH2AX), and poly[ADP-ribose] polymerase 1 (PARP-1). Concomitantly, increased cellular senescence in the adipose tissue from pol η(-/-) mice was observed and measured by up-regulation of senescence markers, including p53, p16(Ink4a), p21, senescence-associated (SA) β-gal activity, and SA secretion of proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) as early as 4 wk of age. Treatment of pol η(-/-) mice with a p53 inhibitor, pifithrin-α, reduced adipocyte senescence and attenuated the metabolic abnormalities. Furthermore, elevation of adipocyte DNA damage with a high-fat diet or sodium arsenite exacerbated adipocyte senescence and metabolic abnormalities in pol η(-/-) mice. In contrast, reduction of adipose DNA damage with N-acetylcysteine or metformin ameliorated cellular senescence and metabolic abnormalities. These studies indicate that elevated DNA damage is a root cause of adipocyte senescence, which plays a determining role in the development of obesity and insulin resistance.

  5. YUCCA6 over-expression demonstrates auxin function in delaying leaf senescence in Arabidopsis thaliana

    KAUST Repository

    Kim, Jeong Im

    2011-04-21

    The Arabidopsis thaliana YUCCA family of flavin monooxygenase proteins catalyses a rate-limiting step in de novo auxin biosynthesis. A YUCCA6 activation mutant, yuc6-1D, has been shown to contain an elevated free IAA level and to display typical high-auxin phenotypes. It is reported here that Arabidopsis plants over-expressing YUCCA6, such as the yuc6-1D activation mutant and 35S:YUC6 transgenic plants, displayed dramatic longevity. In addition, plants over-expressing YUCCA6 exhibited classical, delayed dark-induced and hormone-induced senescence in assays using detached rosette leaves. However, plants over-expressing an allele of YUCCA6, that carries mutations in the NADPH cofactor binding site, exhibited neither delayed leaf senescence phenotypes nor phenotypes typical of auxin overproduction. When the level of free IAA was reduced in yuc6-1D by conjugation to lysine, yuc6-1D leaves senesced at a rate similar to the wild-type leaves. Dark-induced senescence in detached leaves was accompanied by a decrease in their free IAA content, by the reduced expression of auxin biosynthesis enzymes such as YUCCA1 and YUCCA6 that increase cellular free IAA levels, and by the increased expression of auxin-conjugating enzymes encoded by the GH3 genes that reduce the cellular free auxin levels. Reduced transcript abundances of SAG12, NAC1, and NAC6 during senescence in yuc6-1D compared with the wild type suggested that auxin delays senescence by directly or indirectly regulating the expression of senescence-associated genes. 2011 The Author(s).

  6. Hyperosmolarity induced by high glucose promotes senescence in human glomerular mesangial cells.

    Science.gov (United States)

    del Nogal, Maria; Troyano, Nuria; Calleros, Laura; Griera, Mercedes; Rodriguez-Puyol, Manuel; Rodriguez-Puyol, Diego; Ruiz-Torres, María P

    2014-09-01

    Hyperglycemia is involved in the diabetic complication of different organs and can elevate serum osmolarity. Here, we tested whether hyperosmolarity promoted by high glucose levels induces cellular senescence in renal cells. We treated Wistar rats with streptozotocin to induce diabetes or with consecutive daily injections of mannitol to increase serum osmolarity and analyzed p53 and p16 genes in renal cortex by immunohistochemistry. Both diabetic and mannitol treated rats showed a significant increase in serum osmolarity, without significant signs of renal dysfunction, but associated with increased staining for p53 and p16 in the renal cortex. An increase in p53 and p16 expression was also found in renal cortex slices and glomeruli isolated from healthy rats, which were later treated with 30 mM glucose or mannitol. Intracellular mechanisms involved were analyzed in cultured human glomerular mesangial cells treated with 30 mM glucose or mannitol. After treatments, cells showed increased p53, p21 and p16 expression and elevated senescence-associated β-galactosidase activity. Senescence was prevented when myo-inositol was added before treatment. High glucose or mannitol induced constitutive activation of Ras and ERK pathways which, in turn, were activated by oxidative stress. In summary, hyperosmolarity induced renal senescence, particularly in glomerular mesangial cells, increasing oxidative stress, which constitutively activated Ras-ERK 1/2 pathway. Cellular senescence could contribute to the organ dysfunction associated with diabetes.

  7. Low zinc environment induces stress signaling, senescence and mixed cell death modalities in colon cancer cells.

    Science.gov (United States)

    Rudolf, Emil; Rudolf, Kamil

    2015-12-01

    Currently it is not clear what type of the final cellular response (i.e. cell death modality or senescence) is induced upon chronic intracellular zinc depletion in colon cancer cells. To address this question, isogenic colon cancer lines SW480 and SW620 exposed to low zinc environment were studied over the period of 6 weeks. Low zinc environment reduced total as well as free intracellular zinc content in both cell lines. Decreased intracellular zinc content resulted in changes in cellular proliferation, cell cycle distribution and activation of stress signaling. In addition, colonocytes with low zinc content displayed increased levels of oxidative stress, changes in mitochondrial activity but in the absence of significant DNA damage. Towards the end of treatment (4th-6th week), exposed cells started to change morphologically, and typical markers of senescence as well as cell death appeared. Of two examined colon cancer cell lines, SW480 cells proved to activate predominantly senescent phenotype, with frequent form of demise being necrosis and mixed cell death modality but not apoptosis. Conversely, SW620 cells activated mostly cell death, with relatively equal distribution of apoptosis and mixed types, while senescent phenotypes and necrosis were present only in a small fraction of cell populations. Addition of zinc at the beginning of 4th week of treatment significantly suppressed cell death phenotypes in both cell lines but had no significant effect on senescence. In conclusion, presented results demonstrate variability of responses to chronic zinc depletion in colon cancer as modeled in vitro.

  8. 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.

  9. Senescing cells share common features with dedifferentiating cells.

    Science.gov (United States)

    Damri, Meytal; Granot, Gila; Ben-Meir, Hagit; Avivi, Yigal; Plaschkes, Inbar; Chalifa-Caspi, Vered; Wolfson, Marina; Fraifeld, Vadim; Grafi, Gideon

    2009-12-01

    Dedifferentiation signifies the capacity of somatic cells to acquire stem cell-like properties. This process can be induced during normal development and as a response to various stimuli, such as pathogen infection and wounding. Dedifferentiation also characterizes the transition of differentiated leaf cells into protoplasts (plant cells devoid of cell walls), a transition accompanied by widespread chromatin decondensation. Transcriptome profiling of dedifferentiating protoplast cells revealed striking similarities with senescing cells; both display a large increase in the expression of genes of specific transcription factor (TF) families, including ANAC, WRKY, bZIP, and C2H2. Further analysis showed that leaves induced to senesce by exposure to dark display characteristic features of dedifferentiating cells, including chromatin decondensation, disruption of the nucleolus, and condensation of rRNA genes. Considering that premature senescence can be induced by various stress conditions both in plant and animal cells, our results suggest that the response of plant and also animal cells to certain stresses converges on cellular dedifferentiation whereby cells first acquire stem cell-like state prior to acquisition of a new cell fate (e.g., reentry into the cell cycle or death).

  10. RhHB1 mediates the antagonism of gibberellins to ABA and ethylene during rose (Rosa hybrida) petal senescence.

    Science.gov (United States)

    Lü, Peitao; Zhang, Changqing; Liu, Jitao; Liu, Xiaowei; Jiang, Guimei; Jiang, Xinqiang; Khan, Muhammad Ali; Wang, Liangsheng; Hong, Bo; Gao, Junping

    2014-05-01

    Rose (Rosa hybrida) is one of the most important ornamental plants worldwide; however, senescence of its petals terminates the ornamental value of the flower, resulting in major economic loss. It is known that the hormones abscisic acid (ABA) and ethylene promote petal senescence, while gibberellins (GAs) delay the process. However, the molecular mechanisms underlying the antagonistic effects amongst plant hormones during petal senescence are still unclear. Here we isolated RhHB1, a homeodomain-leucine zipper I transcription factor gene, from rose flowers. Quantitative RT-PCR and GUS reporter analyses showed that RhHB1 was strongly expressed in senescing petals, and its expression was induced by ABA or ethylene in petals. ABA or ethylene treatment clearly accelerated rose petal senescence, while application of the gibberellin GA3 delayed the process. However, silencing of RhHB1 delayed the ABA- or ethylene-mediated senescence, and resulted in higher petal anthocyanin levels and lower expression of RhSAG12. Moreover, treatment with paclobutrazol, an inhibitor of GA biosynthesis, repressed these delays. In addition, silencing of RhHB1 blocked the ABA- or ethylene-induced reduction in expression of the GA20 oxidase encoded by RhGA20ox1, a gene in the GA biosynthetic pathway. Furthermore, RhHB1 directly binds to the RhGA20ox1 promoter, and silencing of RhGA20ox1 promoted petal senescence. Eight senescence-related genes showed substantial differences in expression in petals after treatment with GA3 or paclobutrazol. These results suggest that RhHB1 mediates the antagonistic effect of GAs on ABA and ethylene during rose petal senescence, and that the promotion of petal senescence by ABA or ethylene operates through an RhHB1-RhGA20ox1 regulatory checkpoint.

  11. Biomolecular bases of the senescence process and cancer. A new approach to oncological treatment linked to ageing.

    Science.gov (United States)

    Badiola, Iker; Santaolalla, Francisco; Garcia-Gallastegui, Patricia; Ana, Sánchez-Del Rey; Unda, Fernando; Ibarretxe, Gaskon

    2015-09-01

    Human ageing is associated with a gradual decline in the physiological functions of the body at multiple levels and it is a key risk factor for many diseases, including cancer. Ageing process is intimately related to widespread cellular senescence, characterised by an irreversible loss of proliferative capacity and altered functioning associated with telomere attrition, accumulation of DNA damage and compromised mitochondrial and metabolic function. Tumour and senescent cells may be generated in response to the same stimuli, where either cellular senescence or transformation would constitute two opposite outcomes of the same degenerative process. This paper aims to review the state of knowledge on the biomolecular relationship between cellular senescence, ageing and cancer. Importantly, many of the cell signalling pathways that are found to be altered during both cellular senescence and tumourigenesis are regulated through shared epigenetic mechanisms and, therefore, they are potentially reversible. MicroRNAs are emerging as pivotal players linking ageing and cancer. These small RNA molecules have generated great interest from the point of view of future clinical therapy for cancer because successful experimental results have been obtained in animal models. Micro-RNA therapies for cancer are already being tested in clinical phase trials. These findings have potential importance in cancer treatment in aged people although further research-based knowledge is needed to convert them into an effective molecular therapies for cancer linked to ageing. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Simvastatin rises reactive oxygen species levels and induces senescence in human melanoma cells by activation of p53/p21 pathway

    Energy Technology Data Exchange (ETDEWEB)

    Guterres, Fernanda Augusta de Lima Barbosa; Martinez, Glaucia Regina; Rocha, Maria Eliane Merlin; Winnischofer, Sheila Maria Brochado, E-mail: sheilambw@ufpr.br

    2013-11-15

    Recent studies demonstrated that simvastatin has antitumor properties in several types of cancer cells, mainly by inducing apoptosis and inhibiting growth. The arrest of proliferation is a feature of cellular senescence; however, the occurrence of senescence in melanoma cells upon simvastatin treatment has not been investigated until now. Our results demonstrated that exposure of human metastatic melanoma cells (WM9) to simvastatin induces a senescent phenotype, characterized by G1 arrest, positive staining for senescence-associated β-galactosidase assay, and morphological changes. Also, the main pathways leading to cell senescence were examined in simvastatin-treated human melanoma cells, and the expression levels of phospho-p53 and p21 were upregulated by simvastatin, suggesting that cell cycle regulators and DNA damage pathways are involved in the onset of senescence. Since simvastatin can act as a pro-oxidant agent, and oxidative stress may be related to senescence, we measured the intracellular ROS levels in WM9 cells upon simvastatin treatment. Interestingly, we found an increased amount of intracellular ROS in these cells, which was accompanied by elevated expression of catalase and peroxiredoxin-1. Collectively, our results demonstrated that simvastatin can induce senescence in human melanoma cells by activation of p53/p21 pathway, and that oxidative stress may be related to this process. - Highlights: • Lower concentrations of simvastatin can induce senescent phenotype in melanoma cells. • Simvastatin induces senescence in human melanoma cells via p53/p21 pathway. • Senescent phenotype is related with increased intracellular ROS. • Partial detoxification of ROS by catalase/peroxiredoxin-1 could lead cells to senescence rather than apoptosis.

  13. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation

    Science.gov (United States)

    Laberge, Remi-Martin; Sun, Yu; Orjalo, Arturo V.; Patil, Christopher K.; Freund, Adam; Zhou, Lili; Curran, Samuel C.; Davalos, Albert R.; Wilson-Edell, Kathleen A.; Liu, Su; Limbad, Chandani; Demaria, Marco; Li, Patrick; Hubbard, Gene B.; Ikeno, Yuji; Javors, Martin; Desprez, Pierre-Yves; Benz, Christopher C.; Kapahi, Pankaj; Nelson, Peter S.; Campisi, Judith

    2015-01-01

    The TOR (target of rapamycin) kinase limits longevity by poorly understood mechanisms. Rapamycin suppresses the mammalian TORC1 complex, which regulates translation, and extends lifespan in diverse species, including mice. We show that rapamycin selectively blunts the pro-inflammatory phenotype of senescent cells. Cellular senescence suppresses cancer by preventing cell proliferation. However, as senescent cells accumulate with age, the senescence-associated secretory phenotype (SASP) can disrupt tissues and contribute to age-related pathologies, including cancer. MTOR inhibition suppressed the secretion of inflammatory cytokines by senescent cells. Rapamycin reduced IL6 and other cytokine mRNA levels, but selectively suppressed translation of the membrane-bound cytokine IL1A. Reduced IL1A diminished NF-κB transcriptional activity, which controls much of the SASP; exogenous IL1A restored IL6 secretion to rapamycin-treated cells. Importantly, rapamycin suppressed the ability of senescent fibroblasts to stimulate prostate tumour growth in mice. Thus, rapamycin might ameliorate age-related pathologies, including late-life cancer, by suppressing senescence-associated inflammation. PMID:26147250

  14. 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

  15. 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

  16. 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

  17. Resistance to discodermolide, a microtubule-stabilizing agent and senescence inducer, is 4E-BP1–dependent

    OpenAIRE

    Chao, Suzan K.; Lin, Juan; Brouwer-Visser, Jurriaan; Smith, Amos B.; Horwitz, Susan Band; McDaid, Hayley M.

    2010-01-01

    Discodermolide is a microtubule-stabilizing agent that induces accelerated cell senescence. A discodermolide-resistant cell line, AD32, was generated from the human lung cancer cell line A549. We hypothesize that the major resistance mechanism in these cells is escape from accelerated senescence. AD32 cells have decreased levels of 4E-BP1 mRNA and protein, relative to the parental discodermolide-sensitive A549 cells. Lentiviral-mediated re-expression of wild-type 4E-BP1 in AD32 cells increase...

  18. A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen.

    Directory of Open Access Journals (Sweden)

    Jean-Philippe Coppé

    Full Text Available Cellular senescence irreversibly arrests cell proliferation in response to oncogenic stimuli. Human cells develop a senescence-associated secretory phenotype (SASP, which increases the secretion of cytokines and other factors that alter the behavior of neighboring cells. We show here that "senescent" mouse fibroblasts, which arrested growth after repeated passage under standard culture conditions (20% oxygen, do not express a human-like SASP, and differ from similarly cultured human cells in other respects. However, when cultured in physiological (3% oxygen and induced to senesce by radiation, mouse cells more closely resemble human cells, including expression of a robust SASP. We describe two new aspects of the human and mouse SASPs. First, cells from both species upregulated the expression and secretion of several matrix metalloproteinases, which comprise a conserved genomic cluster. Second, for both species, the ability to promote the growth of premalignant epithelial cells was due primarily to the conserved SASP factor CXCL-1/KC/GRO-alpha. Further, mouse fibroblasts made senescent in 3%, but not 20%, oxygen promoted epithelial tumorigenesis in mouse xenographs. Our findings underscore critical mouse-human differences in oxygen sensitivity, identify conditions to use mouse cells to model human cellular senescence, and reveal novel conserved features of the SASP.

  19. TGFβ-dependent gene expression shows that senescence correlates with abortive differentiation along several lineages in Myc-induced lymphomas.

    Science.gov (United States)

    Müller, Judith; Samans, Birgit; van Riggelen, Jan; Fagà, Giovanni; Peh K N, Raquel; Wei, Chia-Lin; Müller, Heiko; Amati, Bruno; Felsher, Dean; Eilers, Martin

    2010-12-01

    Deregulated expression of Myc under the control of an immunoglobulin enhancer induces lymphoma formation in mice. The development of lymphomas is limited by TGFβ-dependent senescence and high levels of Myc expression are continuously required to antagonize senescence. The biological processes underlying senescence are not fully resolved. We report here a comprehensive analysis of TGFβ-dependent alterations in gene expression when the Myc transgene is switched off. Our data show that Myc-induced target genes are downregulated in a TGFβ-independent manner. In contrast, TGFβ is required to upregulate a broad spectrum of genes that are characteristic of different T-cell lineages when Myc is turned off. The analysis reveals a significant overlap between these Myc-repressed genes with genes that are targets of polycomb repressive complexes in embryonic stem cells. Therefore, TGFβ-dependent senescence is associated with gene expression patterns indicative of abortive cellular differentiation along several lineages.

  20. SIRT1 and AMPK in regulating mammalian senescence: a critical review and a working model.

    Science.gov (United States)

    Wang, Yu; Liang, Yan; Vanhoutte, Paul M

    2011-04-06

    Ageing in mammals remains an unsolved mystery. Anti-ageing is a recurring topic in the history of scientific research. Lifespan extension evoked by Sir2 protein in lower organisms has attracted a large amount of interests in the last decade. This review summarizes recent evidence supporting the role of a Sir2 mammalian homologue, SIRT1 (Silent information regulator T1), in regulating ageing and cellular senescence. The various signaling networks responsible for the anti-ageing and anti-senescence activity of SIRT1 have been discussed. In particular, a counter-balancing model involving the cross-talks between SIRT1 and AMP-activated protein kinase (AMPK), another stress and energy sensor, is suggested for controlling the senescence program in mammalian cells.

  1. Suppressor of Overexpression of CO 1 Negatively Regulates Dark-Induced Leaf Degreening and Senescence by Directly Repressing Pheophytinase and Other Senescence-Associated Genes in Arabidopsis.

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    Chen, Junyi; Zhu, Xiaoyu; Ren, Jun; Qiu, Kai; Li, Zhongpeng; Xie, Zuokun; Gao, Jiong; Zhou, Xin; Kuai, Benke

    2017-03-01

    Although the biochemical pathway of chlorophyll (Chl) degradation has been largely elucidated, how Chl is rapidly yet coordinately degraded during leaf senescence remains elusive. Pheophytinase (PPH) is the enzyme for catalyzing the removal of the phytol group from pheophytin a, and PPH expression is significantly induced during leaf senescence. To elucidate the transcriptional regulation of PPH, we used a yeast (Saccharomyces cerevisiae) one-hybrid system to screen for its trans-regulators. SUPPRESSOR OF OVEREXPRESSION OF CO 1 (SOC1), a key flowering pathway integrator, was initially identified as one of the putative trans-regulators of PPH After dark treatment, leaves of an SOC1 knockdown mutant (soc1-6) showed an accelerated yellowing phenotype, whereas those of SOC1-overexpressing lines exhibited a partial stay-green phenotype. SOC1 and PPH expression showed a negative correlation during leaf senescence. Substantially, SOC1 protein could bind specifically to the CArG box of the PPH promoter in vitro and in vivo, and overexpression of SOC1 significantly inhibited the transcriptional activity of the PPH promoter in Arabidopsis (Arabidopsis thaliana) protoplasts. Importantly, soc1-6 pph-1 (a PPH knockout mutant) double mutant displayed a stay-green phenotype similar to that of pph-1 during dark treatment. These results demonstrated that SOC1 inhibits Chl degradation via negatively regulating PPH expression. In addition, measurement of the Chl content and the maximum photochemical efficiency of photosystem II of soc1-6 and SOC1-OE leaves after dark treatment suggested that SOC1 also negatively regulates the general senescence process. Seven SENESCENCE-ASSOCIATED GENES (SAGs) were thereafter identified as its potential target genes, and NONYELLOWING1 and SAG113 were experimentally confirmed. Together, we reveal that SOC1 represses dark-induced leaf Chl degradation and senescence in general in Arabidopsis.

  2. Ghd2, a CONSTANS-like gene, confers drought sensitivity through regulation of senescence in rice

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    Liu, Juhong; Shen, Jianqiang; Xu, Yan; Li, Xianghua; Xiao, Jinghua; Xiong, Lizhong

    2016-01-01

    CONSTANS (CO)-like genes have been intensively investigated for their roles in the regulation of photoperiodic flowering, but very limited information has been reported on their functions in other biological processes. Here, we found that a CO-like gene, Ghd2 (Grain number, plant height, and heading date2), which can increase the yield potential under normal growth condition just like its homologue Ghd7, is involved in the regulation of leaf senescence and drought resistance. Ghd2 is expressed mainly in the rice (Oryza sativa) leaf with the highest level detected at the grain-filling stage, and it is down-regulated by drought stress conditions. Overexpression of Ghd2 resulted in significantly reduced drought resistance, while its knockout mutant showed the opposite phenotype. The earlier senescence symptoms and the transcript up-regulation of many senescence-associated genes (SAGs) in Ghd2-overexpressing transgenic rice plants under drought stress conditions indicate that Ghd2 plays essential roles in accelerating drought-induced leaf senescence in rice. Moreover, developmental and dark-induced leaf senescence was accelerated in the Ghd2-overexpressing rice and delayed in the ghd2 mutant. Several SAGs were confirmed to be regulated by Ghd2 using a transient expression system in rice protoplasts. Ghd2 interacted with several regulatory proteins, including OsARID3, OsPURα, and three 14-3-3 proteins. OsARID3 and OsPURα showed expression patterns similar to Ghd2 in rice leaves, with the highest levels at the grain-filling stage, whereas OsARID3 and the 14-3-3 genes responded differently to drought stress conditions. These results indicate that Ghd2 functions as a regulator by integrating environmental signals with the senescence process into a developmental programme through interaction with different proteins. PMID:27638689

  3. Role of the gynoecium in natural senescence of carnation (Dianthus caryophyllus L.) flowers.

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    Shibuya, K; Yoshioka, T; Hashiba, T; Satoh, S

    2000-12-01

    Although the role of the gynoecium in natural senescence of the carnation flower has long been suggested, it has remained a matter of dispute because petal senescence in the cut carnation flower was not delayed by the removal of gynoecium. In this study, the gynoecium was snapped off by hand, in contrast to previous investigations where removal was achieved by forceps or scissors. The removal of the gynoecium by hand prevented the onset of ethylene production and prolonged the vase life of the flower, demonstrating a decisive role of the gynoecium in controlling natural senescence of the carnation flower. Abscisic acid (ABA) and indole-3-acetic acid (IAA), which induced ethylene production and accelerated petal senescence in carnation flowers, did not stimulate ethylene production in the flowers with gynoecia removed (-Gyn flowers). Application of 1-aminocyclopropane-1-carboxylate (ACC), the ethylene precursor, induced substantial ethylene production and petal wilting in the flowers with gynoecia left intact, but was less effective at stimulating ethylene production in the -Gyn flowers and negligible petal in-rolling was observed. Exogenous ethylene induced autocatalytic production of the gas and petal wilting in the -Gyn flowers. These results indicated that ethylene generated in the gynoecium triggers the onset of ethylene production in the petals of carnation during natural senescence.

  4. Daily Feeding of Fructooligosaccharide or Glucomannan Delays Onset of Senescence in SAMP8 Mice

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    Sadako Nakamura

    2014-01-01

    Full Text Available We hypothesized that daily intake of nondigestible saccharides delays senescence onset through the improvement of intestinal microflora. Here, we raised senescence accelerated mice prone 8 (SAMP8 on the AIN93 diet (CONT, with sucrose being substituted for 5% of fructooligosaccharide (FOS or 5% of glucomannan (GM, 15 mice per group. Ten SAMR1 were raised as reference of normal aging with control diet. Grading of senescence was conducted using the method developed by Hosokawa, and body weight, dietary intake, and drinking water intake were measured on alternate days. Following 38 weeks of these diets we evaluated learning and memory abilities using a passive avoidance apparatus and investigated effects on the intestinal microflora, measured oxidative stress markers, and inflammatory cytokines. Continuous intake of FOS and GM significantly enhanced learning and memory ability and decelerated senescence development when compared with the CONT group. Bifidobacterium levels were significantly increased in FOS and GM-fed mice. Urinary 8OHdG, 15-isoprostane, serum TNF-α, and IL-6 were also lower in FOS-fed mice, while IL-10 in FOS and GM groups was higher than in CONT group. These findings suggest that daily intake of nondigestible saccharides delays the onset of senescence via improvement of intestinal microflora.

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

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    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.

  6. Rejuvenation of MPTP-induced human neural precursor cell senescence by activating autophagy

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    Zhu, Liang [East Hospital, Tongji University School of Medicine, Shanghai (China); Dong, Chuanming [East Hospital, Tongji University School of Medicine, Shanghai (China); Department of Anatomy and Neurobiology, The Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong (China); Sun, Chenxi; Ma, Rongjie; Yang, Danjing [East Hospital, Tongji University School of Medicine, Shanghai (China); Zhu, Hongwen, E-mail: hongwen_zhu@hotmail.com [Tianjin Hospital, Tianjin Academy of Integrative Medicine, Tianjin (China); Xu, Jun, E-mail: xunymc2000@yahoo.com [East Hospital, Tongji University School of Medicine, Shanghai (China)

    2015-08-21

    Aging of neural stem cell, which can affect brain homeostasis, may be caused by many cellular mechanisms. Autophagy dysfunction was found in aged and neurodegenerative brains. However, little is known about the relationship between autophagy and human neural stem cell (hNSC) aging. The present study used 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) to treat neural precursor cells (NPCs) derived from human embryonic stem cell (hESC) line H9 and investigate related molecular mechanisms involved in this process. MPTP-treated NPCs were found to undergo premature senescence [determined by increased senescence-associated-β-galactosidase (SA-β-gal) activity, elevated intracellular reactive oxygen species level, and decreased proliferation] and were associated with impaired autophagy. Additionally, the cellular senescence phenotypes were manifested at the molecular level by a significant increase in p21 and p53 expression, a decrease in SOD2 expression, and a decrease in expression of some key autophagy-related genes such as Atg5, Atg7, Atg12, and Beclin 1. Furthermore, we found that the senescence-like phenotype of MPTP-treated hNPCs was rejuvenated through treatment with a well-known autophagy enhancer rapamycin, which was blocked by suppression of essential autophagy gene Beclin 1. Taken together, these findings reveal the critical role of autophagy in the process of hNSC aging, and this process can be reversed by activating autophagy. - Highlights: • We successfully establish hESC-derived neural precursor cells. • MPTP treatment induced senescence-like state in hESC-derived NPCs. • MPTP treatment induced impaired autophagy of hESC-derived NPCs. • MPTP-induced hESC-derived NPC senescence was rejuvenated by activating autophagy.

  7. Aging and senescence of skin cells in culture

    DEFF Research Database (Denmark)

    Rattan, Suresh

    2015-01-01

    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...... 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...... 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...

  8. BRAF Mutation Is Associated With a Specific Cell Type With Features Suggestive of Senescence in Ovarian Serous Borderline (Atypical Proliferative) Tumors

    DEFF Research Database (Denmark)

    Zeppernick, Felix; Ardighieri, Laura; Hannibal, Charlotte G

    2014-01-01

    . Immunohistochemistry showed that the EC cells always expressed p16, a senescence-associated marker, and had a significantly lower Ki-67 labeling index than adjacent cuboidal and columnar cells (P=0.02). In vitro studies supported the interpretation that these cells were undergoing senescence, as the same morphologic...... features could be reproduced in cultured epithelial cells by ectopic expression of BRAF(V600E). Senescence was further established by markers such as SA-β-gal staining, expression of p16 and p21, and reduction in DNA synthesis. In conclusion, this study sheds light on the pathogenesis of this unique group...... of ovarian tumors by showing that BRAF mutation is associated with cellular senescence and the presence of a specific cell type characterized by abundant EC. This "oncogene-induced senescence" phenotype may represent a mechanism that impedes progression of APSTs to LGSC....

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

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    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.

  10. Induction of senescence and identification of differentially expressed genes in tomato in response to monoterpene.

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    Sumit Ghosh

    Full Text Available Monoterpenes, which are among the major components of plant essential oils, are known for their ecological roles as well for pharmaceutical properties. Geraniol, an acyclic monoterpene induces cell cycle arrest and apoptosis/senescence in various cancer cells and plants; however, the genes involved in the process and the underlying molecular mechanisms are not well understood. In this study, we demonstrate that treatment of tomato plants with geraniol results in induction of senescence due to a substantial alteration in transcriptome. We have identified several geraniol-responsive protein encoding genes in tomato using suppression subtractive hybridization (SSH approach. These genes comprise of various components of signal transduction, cellular metabolism, reactive oxygen species (ROS, ethylene signalling, apoptosis and DNA damage response. Upregulation of NADPH oxidase and antioxidant genes, and increase in ROS level after geraniol treatment point towards the involvement of ROS in geraniol-mediated senescence. The delayed onset of seedling death and induced expression of geraniol-responsive genes in geraniol-treated ethylene receptor mutant (Nr suggest that geraniol-mediated senescence involves both ethylene dependent and independent pathways. Moreover, expression analysis during tomato ripening revealed that geraniol-responsive genes are also associated with the natural organ senescence process.

  11. Adiponectin Suppresses UVB-Induced Premature Senescence and hBD2 Overexpression in Human Keratinocytes.

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    Kim, MinJeong; Park, Kui Young; Lee, Mi-Kyung; Jin, Taewon; Seo, Seong Jun

    2016-01-01

    Recent studies have revealed that adiponectin can suppress cellular inflammatory signaling pathways. This study aimed to elucidate the effect of adiponectin on the unregulated production of hBD2 in UVB-induced premature senescent keratinocytes. We constructed an in vitro model of premature senescent keratinocytes through repeated exposure to low energy UVB. After repeated low energy UVB exposure, there was significant generation of reactive oxygen species (ROS) and induction of senescence-associated markers, including senescence associated beta-galactosidase activity and expression of p16INK4a and histone H2AX. In addition, the present clinical study showed higher expression of hBD2 in sun-exposed skin of elderly group, and the overexpression of hBD2 was observed by c-Fos activation in vitro. Adiponectin has the ability to scavenge ROS and consequently inhibit MAPKs and SA-markers in UVB-exposed keratinocytes. An inhibitor study demonstrated that adiponectin downregulated hBD2 mRNA expression through suppression of the AP-1 transcription factor components c-Fos via inactivation of p38 MAPK. Collectively, the dysregulated production of hBD2 by the induction of oxidative stress was attenuated by adiponectin through the suppression of p38 and JNK/SAPK MAPK signaling in UVB-mediated premature senescent inducible conditions. These results suggest the feasibility of adiponectin as an anti-photoaging and anti-inflammatory agent in the skin.

  12. Human Dermal Stem/Progenitor Cell-Derived Conditioned Medium Improves Senescent Human Dermal Fibroblasts

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    Ji-Yong Jung

    2015-08-01

    Full Text Available Adult skin stem cells are recognized as potential therapeutics to rejuvenate aged skin. We previously demonstrated that human dermal stem/progenitor cells (hDSPCs with multipotent capacity could be enriched from human dermal fibroblasts using collagen type IV. However, the effects of hDSPCs on cellular senescence remain to be elucidated. In the present study, we investigated whether conditioned medium (CM collected from hDSPC cultures (hDSPC-CM exhibits beneficial effects on senescent fibroblasts. We found that hDSPC-CM promoted proliferation and decreased the expression level of senescence-associated β-galactosidase in sene