tag:blogger.com,1999:blog-83106965848118174942024-03-14T05:30:50.461+00:00cellular senescence blogA blog for those interested in the physiological and pathological impact of senescent cells. Anonymoushttp://www.blogger.com/profile/05125651385504239005noreply@blogger.comBlogger96125tag:blogger.com,1999:blog-8310696584811817494.post-70637677576373258512018-02-09T15:13:00.001+00:002018-02-09T15:21:46.178+00:00Beyond Senolytics: immunotherapy targeting senescent cells<div>
<span style="background-color: white; color: #2e2e2e; font-family: "arial" , "helvetica" , "lucida sans unicode" , "microsoft sans serif" , "segoe ui symbol" , "stixgeneral" , "cambria math" , "arial unicode ms" , sans-serif; font-size: 16px; word-spacing: -1.24453px;">Taken from: </span><span style="color: red; font-family: "arial" , "helvetica" , "lucida sans unicode" , "microsoft sans serif" , "segoe ui symbol" , "stixgeneral" , "cambria math" , "arial unicode ms" , sans-serif;"><b style="background-color: white;"><a href="https://www.sciencedirect.com/science/article/pii/S1568163718300114" target="_blank">Cellular senescence: immunosurveillance and future immunotherapy</a></b></span></div>
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<span style="background-color: white;"><span style="color: #2e2e2e;"><span style="word-spacing: -1.24453px;">"Immunotherapeutic strategies already in development for combating cancer may one day be repurposed for targeting senescent cells for the alleviation of age-related diseases (see Fig. 3). Discussed in detail elsewhere (Burton and Krizhanovsky, 2014; Childs et al., 2015; Muñoz-Espín and Serrano, 2014; van Deursen, 2014), such age-related diseases include diabetes, Alzheimer’s, pulmonary fibrosis, cardiovascular disease and osteoporosis. In addition, identifying further molecular changes associated with senescent cells, especially cell-type specific alterations, would be advantageous for developing therapeutic approaches for targeting senescent cells. However, since senescent cells can also be beneficial, the elimination of acute senescent cells could be problematic. Therefore, the identification of therapeutic targets specific to chronic senescent which are absent in acute senescent cells would be highly desirable.</span></span></span><br />
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<span style="background-color: white;"><span style="color: #2e2e2e;"><span style="word-spacing: -1.24453px;">A recent study identified the expression of CD26/dipeptidyl peptidase 4 (DPP4) on the membrane surface of senescent fibroblasts which have undergone replicative senescence (Kim et al., 2017). This study assessed the potential use of DPP4 as a membrane target for promoting antibody-dependent cell-mediated cytotoxicity (ADCC) against senescent cells. ADCC is a natural mechanism of cell-mediated immune defence involving the activation NK cells by antibodies which has been adapted to promote NK cell-mediated ADCC in cancer immunotherapy (Wang et al., 2015). Kim et al. demonstrated that targeting DPP4 via an ADCC assay in vitro preferentially sensitised senescent, but not proliferating cells to cytotoxicity by NK cells. These finding highlight a potential immunotherapeutic strategy for targeting senescent cells.</span></span></span></div>
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<span style="background-color: white;"><span style="color: #2e2e2e;"><span style="word-spacing: -1.24453px;">As stated previously, one of the mechanisms by which NK cells specifically recognise and kill senescent cells is via the surface expression of NKG2D ligands (Sagiv et al., 2016). Since many tumour cells also express NKG2D ligands, such ligands have been suggested to be a useful target for immunotherapeutic approaches in cancer (Spear et al., 2013), and so could be adapted for senescent cell clearance. For example, the use of engineered immune cells such as chimeric antigen receptor (CAR) T cells to target specific molecules on cancer cells has great potential as an anti-cancer therapy (Yu et al., 2017). As such, it may be possible to target senescent cells by engineering T cells to express a NKG2D CAR which recognise NKG2D ligands on the surface of senescent cells.</span></span></span></div>
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<span style="background-color: white;"><span style="color: #2e2e2e;"><span style="word-spacing: -1.24453px;">An adaption of cancer vaccines could also be considered for boosting immune clearance of senescent cells. Although a universal biomarker of cell senescence has not been identified, the exposure of senescent cell membranes to immune cells may evoke an immune response to antigens not yet identified. In one approach, senescence vaccines would involve the isolation of senescence specific antigens (SSAs) which are then exposed to dendritic cells, professional antigen presenting cells. In response to SSA uptake, dendritic cells process and express these antigens on their cell surface which can then be recognised by T cells. T cell interaction with these antigens promotes T cell activation, differentiation and ultimately killing of target cells.</span></span></span></div>
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<span style="background-color: white;"><span style="color: #2e2e2e;"><span style="word-spacing: -1.24453px;">As discussed previously, the senescence program can also be activated in immune cells, which likely contributes towards impaired immune function, contributing to senescent cell accumulation. In addition to impaired immune cell function, the persistence of senescent immune cells would likely take up valuable immunological space required for expansion of functionally competent immune cells. T cells for example undergo rapid expansion in response to antigenic stimuli followed by cell-mediated apoptosis (Chou and Effros, 2013), a process that may be prevented if senescent T cells are present. As such, another strategy for promoting the elimination of non-immune senescent cells may be the removal of senescent immune cells with the anticipation that such an approach would enhance immune function.</span></span></span></div>
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<span style="background-color: white;"><span style="color: #2e2e2e;"><span style="word-spacing: -1.24453px;">One possibility could be to filter the blood of the unwanted senescent immune cells, maybe through the use of antibodies linked to magnetic nanoparticles/beads (Chen et al., 2017; Rebo et al., 2010). Another strategy may be the use of senolytic drugs to specifically kill senescent immune cells or senescent hematopoietic stem cells (HSCs) which give rise to immune cells. Senolytic targeting of senescent HSCs in mice leading to rejuvenation of aged tissue stem cells has already provided promising results (Chang et al., 2015). Rather than eliminating senescent immune cells, it may one day be possible to rejuvenate senescent immune cells, reversing their detrimental phenotype to improve immune function. For example, inhibition of p38 signalling in CD8+ T cells which exhibit features of cell senescence, increased proliferation, telomerase activity, mitochondria biogenesis and fitness (Henson et al., 2014). Small molecules based on resveratrol have also been reported to rescue cells from cell senescence (Latorre et al., 2017).</span></span></span></div>
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<span style="background-color: white;"><span style="color: #2e2e2e;"><span style="word-spacing: -1.24453px;">The ability of immune cells to migrate and kill target cells can become compromised with age, suggesting that therapeutically boosting these responses may be beneficial for promoting senescent cell clearance. One approach that can be adapted within immune cells is the engineering of cells that recognise specific components of the senescent secretome. As proof of principle, Qudrat et al. generated cells with a chimeric IL-6 receptor (IL6Rchi) that generates a Ca2+ signal in response to IL-6, a component of the senescent secretome (Qudrat et al., 2017). When IL6Rchi was expressed with an engineered Ca2+-activated RhoA (CaRQ), it enabled directed migration to IL-6 in cells which normally have no such function. Furthermore, the expression of vesicular stomatitis virus glycoprotein G (VSVG) and herpes simplex virus type 1 thymidine kinase (TK) in these IL-6 seeking cells allowed cell-cell fusion to occur with target cells and consequently cell death upon administration of ganciclovir, an anti-viral drug."</span></span></span></div>
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</script>Anonymoushttp://www.blogger.com/profile/05125651385504239005noreply@blogger.com0tag:blogger.com,1999:blog-8310696584811817494.post-45631618494066371382017-06-13T18:30:00.000+01:002017-06-13T18:30:33.937+01:00Lipids and Cellular Senescence<div style="text-align: justify;">
Taken From: <a href="https://link.springer.com/article/10.1007/s10522-017-9710-z" target="_blank">Lipid (per) oxidation in mitochondria: an emerging target in the ageing process?</a></div>
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Mitochondrial dysfunction, increased lipid peroxidation and altered catabolism will affect the cellular lipidome during cell senescence. Alterations in lipid metabolism and the generation of oxidised lipids may be beneficial for the senescent program during the early stages of senescence induction, possibly through modulating inflammatory and immune responses (Lawrence et al. 2002; van Diepen et al. 2013; Yaqoob 2003). However, if senescent cells persist in tissues, changes in lipid composition can result in cell dysfunction, altered rates of fatty acid oxidation that can induce inflammation and increased lipid peroxidation that can promote damage to neighbouring cells. These factors may contribute to ageing and age-related diseases. Research focused on altered lipid metabolism during cellular senescence, particularly regarding mitochondrial lipids, is in its infancy. However, in recent years, several studies have made progress in evaluating the senescent lipidome of fibroblasts.</div>
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One group investigated the alterations in a number of metabolites associated with the extracellular metabolome of fibroblasts induced to senesce via proliferative exhaustion or via γ-irradiation (James et al. 2015). They reported that a number of fatty acids and their precursors such as eicosapentaenoate, malonate, 7-alpha-hydroxy-3-oxo-4-cholestenoate and 1-stearoylglycerophosphoinositol were elevated during fibroblast senescence when compared with proliferating and quiescent cells, whereas linoleate, dihomo-linoleate, 10-heptadecenoate were depleted. Also amongst the secretory lipidome from senescent fibroblasts was an accumulation of monohydroxy fatty acids (2-hydroxypalmitate, 2-hydroxystearate, 3-hydroxydecanoate, 3-hydroxyoctanoate) and a phospholipid catabolite (glycerophosphorylcholine). It was suggested that whilst some of these changes may be due to oxidative stress, other observed increases may be a response to increased biomass commonly observed amongst senescent cells.</div>
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Maeda et al. (2009) investigated the regulation of fatty acid synthesis and ∆9-desaturation during cell senescence in human fibroblasts (Maeda et al. 2009). They found that the levels of fatty acid synthase and stearoyl-CoA desaturase-1 were decreased in senescent fibroblasts compared to proliferating fibroblasts, consequently leading to a decrease in monounsaturated fatty acids. In addition, reduced de novo synthesis of phospholipids with an associated increase in the formation of cholesterol in senescent cells was also observed and exogenous fatty acids were shown to be preferentially incorporated into the triacylglycerol pool of senescent cells.</div>
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In another study, the metabolic alterations associated with oncogene-induced senescence (OIS), using Ras-induced senescent human fibroblasts as a model were investigated (Quijano et al. 2012). Through the profiling of ~300 different intracellular metabolites, these authors showed that cells that have undergone OIS develop a metabolic signature which is distinct from cells which have undergone replicative senescence in response to extended in vitro cell culture. In the latter, a switch towards glycolysis has been observed that precedes the onset of senescence (Bittles and Harper 1984). In OIS, an increase in certain intracellular long chain fatty acids, including eicosanoate, dihomo-linoleate, mead acid and docosadienoate were observed. This altered metabolome was shown to associate with a decline in lipid synthesis and increases in fatty acid oxidation. Interestingly, the pro-inflammatory activity of the senescent secretome was reduced by inhibition of carnitine palmitoyltransferase 1, the rate limiting step in mitochondrial fatty acid oxidation, suggesting that alterations in lipid metabolism during OIS may play a role in regulating the pro-inflammatory senescent secretome. Although the mechanism underlying the increase in fatty acid levels during OIS were not fully explored, it may be due to promyelocytic leukemia (PML) activation of the fatty acid oxidation pathway through PPAR signalling (Aird and Zhang 2014). The differences between replicative senescence and OIS are intriguing; they may relate to the physiological need in preventing cancer to switch away from glycolysis as a rapid source of energy that is harnessed by cancer cells to enable them to proliferate rapidly versus the increasing insulin resistance that is seen in ageing and which associates with impaired oxidative metabolism (Burkart et al. 2016). However, while this and other studies have indicated an increase in glucose uptake during OIS, a number of other studies have observed either no change or a significant decrease in glucose uptake. This may relate to the timing of senescence induction, the cell type or the oncogene responsible.</div>
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A further study compared global lipid profiles and associated mRNA levels of proliferating and replicative senescent BJ fibroblasts; 19 specific polyunsaturated triacylglycerol species were identified as undergoing significant changes in lipid composition during cell senescence (Lizardo et al. 2017). In addition, significant changes in the expression of genes involved in specific lipid-related pathways, including glycerolipid metabolism, glycerophospholipid metabolism, unsaturated fatty acid synthesis and sphingolipid metabolism were observed during cell senescence. Based on these lipidomic and transcriptomic analysis, the authors postulated that activation of CD36-mediated fatty acid uptake and alteration to glycerolipid biosynthesis may contribute to the accumulation of triacylglycerols during cell senescence. It was suggested that these changes may be a mechanism to prevent lipotoxicity during elevated oxidative stress conditions during cell senescence.</div>
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In addition to an altered lipidome during cellular senescence, elevated ROS, likely from uncoupled mitochondria, can promote lipid peroxidation which potentiates cellular damage at distant sites. For example, stable aldehydes can diffuse from their site of generation and form adducts at distant locations, thereby propagating the responses and injury initiated by ROS (Ramana et al. 2013), including the induction of cell senescence in neighbouring cells. Flor and Kron observed an accumulation of lipid-derived aldehydes such as 4-hydroxy-2-nonenal (4-HNE) during accelerated senescence (Flor and Kron 2016). Whereas, the treatment of cells with either 4-HNE or low (5 Gy) γ-irradiation only generated low levels of cell senescence, combining both 4-HNE and 5 Gy γ-irradiation significantly elevated the senescence response. Furthermore, the use of the aldehyde-sequestering drug hydralazine blocked cell senescence induction by 25 Gy and etoposide treatment, demonstrating the potential importance of lipid peroxidation during therapy-induced senescence (Flor et al. 2016). Despite the highly damaging and pro-ageing potential of senescence-derived lipid peroxidation, little research has been conducted in this area and this requires further study.</div>
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Research on cell senescence has primarily been undertaken on fibroblasts and more research is required to explore whether the same phenomena are observed in cell-types linked to age-related disease such as in senescent adipocytes, pancreatic beta cells, renal proximal tubular epithelial cells and vascular endothelial cells. Whilst different types of senescent cells may share similarities in lipid metabolism, there may also be differences that are cell type-dependent or due to the mechanism of senescence induction and these require further study to better assess the role of altered lipid metabolism during ageing and disease. Finally, an important question to contemplate is whether the alterations in ROS, lipid metabolism and mitochondrial lipids observed during ageing and diseases are due solely to the presence of senescent cells or whether lipidomic changes can occur in absence of senescent cell accumulation.</div>
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Anonymoushttp://www.blogger.com/profile/05125651385504239005noreply@blogger.com0tag:blogger.com,1999:blog-8310696584811817494.post-81424684948487479162017-04-13T13:29:00.000+01:002017-04-13T13:29:01.573+01:00"Cell Senescence" verses "Cell Ageing": What is the Difference?<div class="separator" style="clear: both; text-align: center;">
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<span style="font-size: 18px;">First published @ <a href="https://cellsen.wixsite.com/senescentcell" target="_blank">Senescent CELL blog</a></span></div>
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<span style="font-size: 18px;">In recent times, scientific findings on cellular senescence have made headlines. The majority of these highly publicized articles are concerned with the potential health benefits of removing senescent cells from our bodies. Destroying senescent cells in mice can reverse aspects of <span style="font-weight: bold;"><a dataquery="#txtMedia23zf" href="https://www.blogger.com/null"><span style="color: #213f92;">ageing</span></a></span> and prevent side effects in response to <span style="font-weight: bold;"><a dataquery="#txtMedia10hw" href="https://www.blogger.com/null"><span style="color: #213f92;">chemotherapy</span></a></span>. </span></div>
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In an attempt to simplify the term "cell senescence" for public consumption, the media incorrectly use words such as "old", "aged" and "elderly" to describe such cells. This is understandable since "senescence" means "to grow old". </div>
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The term "<span style="font-weight: bold;"><a dataquery="#txtMedia17jd" href="https://www.blogger.com/null"><span style="color: #213f92;">senescence</span></a></span>" regarding cells was first used over fifty years ago to describe cells that could no longer proliferate after extended time in culture. Without our current understandings, this inability to proliferate was thought to be due to processes related to cell ageing and so such cells were labelled as "senescent". Although now inaccurate, this labeling is still in use today.</div>
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<span style="font-weight: bold;"><span style="font-size: 18px;">So what is the difference between cell "ageing" and cell "senescence"? </span></span></div>
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<span style="font-size: 18px;">Cell ageing results from the accumulation of random damage leading to impairment in cell function with time. Cell ageing may result from the build up of damage to cellular lipids (i.e. peroxidation), damage to proteins leading to altered protein folding and aggregation, damage to the mitochondria resulting in abnormal metabolic processes and changes (epigenetic) to DNA causing alterations in gene expression. </span></div>
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<span style="font-size: 18px;">In contrast to cell ageing, cell senescence is a programmed change in cell state often initiated by persistent damage to DNA. </span></div>
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<span style="font-size: 18px;">Although the initial factors which trigger DNA damage in cells may itself be random, the accompanying cellular changes associated with cell senescence are not random. In an <span style="font-weight: bold;"><a dataquery="#txtMedia1pib" href="https://www.blogger.com/null"><span style="color: #213f92;">orchestrated response</span></a></span><a dataquery="#txtMedia1pib" href="https://www.blogger.com/null">,</a><span style="font-weight: bold;"><a dataquery="#txtMedia1pib" href="https://www.blogger.com/null"><span style="color: #213f92;"> </span></a></span>cells permanently stop dividing, they secrete molecules that can attract immune cells and express immune proteins on their cell surface. As such, cell senescence can be considered as a mechanism to eliminate unwanted cells by the immune system.</span></div>
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<span style="font-size: 18px;">Part of the reason why senescent cells stay in our bodies and promote ageing may be due to a failure in the ability of an aged immune system to kill senescent cells. The molecules that were once beneficial in attracting immune cells now become destructive over time.</span></div>
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Further scientific evidence demonstrating that senescent cells are not "aged" cells but rather a programmed change in cell state, comes from studies on embryonic development. </div>
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<span data-reactid=".0.$SITE_ROOT.$desktop_siteRoot.$PAGES_CONTAINER.1.1.$SITE_PAGES.$cjds.1.$ppPrt7-8uz.0.0.$child.$0.1.$1.$5.$0.0.p.0" style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Two </span><span data-reactid=".0.$SITE_ROOT.$desktop_siteRoot.$PAGES_CONTAINER.1.1.$SITE_PAGES.$cjds.1.$ppPrt7-8uz.0.0.$child.$0.1.$1.$5.$0.0.p.1" style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; font-weight: bold; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><a data-content="http://www.cell.com/abstract/S0092-8674(13)01295-6" data-reactid=".0.$SITE_ROOT.$desktop_siteRoot.$PAGES_CONTAINER.1.1.$SITE_PAGES.$cjds.1.$ppPrt7-8uz.0.0.$child.$0.1.$1.$5.$0.0.p.1.0" data-type="external" href="http://www.cell.com/abstract/S0092-8674(13)01295-6" style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; cursor: pointer; margin: 0px; outline: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" target="_blank"><span data-reactid=".0.$SITE_ROOT.$desktop_siteRoot.$PAGES_CONTAINER.1.1.$SITE_PAGES.$cjds.1.$ppPrt7-8uz.0.0.$child.$0.1.$1.$5.$0.0.p.1.0.0" style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; color: #213f92; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">back</span></a></span><span data-reactid=".0.$SITE_ROOT.$desktop_siteRoot.$PAGES_CONTAINER.1.1.$SITE_PAGES.$cjds.1.$ppPrt7-8uz.0.0.$child.$0.1.$1.$5.$0.0.p.2" style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"> to </span><span data-reactid=".0.$SITE_ROOT.$desktop_siteRoot.$PAGES_CONTAINER.1.1.$SITE_PAGES.$cjds.1.$ppPrt7-8uz.0.0.$child.$0.1.$1.$5.$0.0.p.3" style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; font-weight: bold; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><a data-content="http://www.cell.com/cell/fulltext/S0092-8674(13)01359-7" data-reactid=".0.$SITE_ROOT.$desktop_siteRoot.$PAGES_CONTAINER.1.1.$SITE_PAGES.$cjds.1.$ppPrt7-8uz.0.0.$child.$0.1.$1.$5.$0.0.p.3.0" data-type="external" href="http://www.cell.com/cell/fulltext/S0092-8674(13)01359-7" style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; cursor: pointer; margin: 0px; outline: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" target="_blank"><span data-reactid=".0.$SITE_ROOT.$desktop_siteRoot.$PAGES_CONTAINER.1.1.$SITE_PAGES.$cjds.1.$ppPrt7-8uz.0.0.$child.$0.1.$1.$5.$0.0.p.3.0.0" style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; color: #213f92; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">back</span></a></span><span data-reactid=".0.$SITE_ROOT.$desktop_siteRoot.$PAGES_CONTAINER.1.1.$SITE_PAGES.$cjds.1.$ppPrt7-8uz.0.0.$child.$0.1.$1.$5.$0.0.p.4" style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"> publications in Cell from 2013 demonstrated that the change in cell state associated with senescent cells may be beneficial during embryonic development. If this indeed the case, it is highly unlikely that such cells suddenly become "aged" or "old" to carry out their function. Embryonic development is highly a regulated process. What is more likely is that such senescent cells are indeed programmed and like </span><span data-reactid=".0.$SITE_ROOT.$desktop_siteRoot.$PAGES_CONTAINER.1.1.$SITE_PAGES.$cjds.1.$ppPrt7-8uz.0.0.$child.$0.1.$1.$5.$0.0.p.5" style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; font-weight: bold; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><a data-content="http://www.cell.com/cell/fulltext/S0092-8674(11)01283-9" data-reactid=".0.$SITE_ROOT.$desktop_siteRoot.$PAGES_CONTAINER.1.1.$SITE_PAGES.$cjds.1.$ppPrt7-8uz.0.0.$child.$0.1.$1.$5.$0.0.p.5.0" data-type="external" href="http://www.cell.com/cell/fulltext/S0092-8674(11)01283-9" style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; cursor: pointer; margin: 0px; outline: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" target="_blank"><span data-reactid=".0.$SITE_ROOT.$desktop_siteRoot.$PAGES_CONTAINER.1.1.$SITE_PAGES.$cjds.1.$ppPrt7-8uz.0.0.$child.$0.1.$1.$5.$0.0.p.5.0.0" style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; color: #213f92; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">programmed cell death </span></a></span><span data-reactid=".0.$SITE_ROOT.$desktop_siteRoot.$PAGES_CONTAINER.1.1.$SITE_PAGES.$cjds.1.$ppPrt7-8uz.0.0.$child.$0.1.$1.$5.$0.0.p.6" style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">(apoptosis), play an important role in tissue remodeling during embryonic development. </span></div>
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<span data-reactid=".0.$SITE_ROOT.$desktop_siteRoot.$PAGES_CONTAINER.1.1.$SITE_PAGES.$cjds.1.$ppPrt7-8uz.0.0.$child.$0.1.$1.$5.$0.0.r.0" style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><span data-reactid=".0.$SITE_ROOT.$desktop_siteRoot.$PAGES_CONTAINER.1.1.$SITE_PAGES.$cjds.1.$ppPrt7-8uz.0.0.$child.$0.1.$1.$5.$0.0.r.0.0" style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; font-weight: bold; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Telomere shortening: adding further to the confusion</span></span></div>
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The vast majority of the early studies on cell senescence were focused on cells which stopped dividing after extended proliferation in culture. This was later shown to be due to telomere shortening.</div>
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Every time a cell divides it loses a portion of DNA at the end of its chromosomes called telomeres- long repeats of non-coding DNA. Telomeres protect the ends of our DNA, but when they become too short, they can no longer perform this task. This causes the cell to recognize unprotected DNA-ends as damage. A result of this DNA damage signal is induction of cell senescence. </div>
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Throughout our lives, cells divide and our telomeres gradually become shorter. There have been numerous studies investigating the correlation between telomere length and chronological age. In parallel to telomere shortening, gradual random alterations associated with cell ageing will also occur.</div>
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This relationship between age, telomere length and cell senescence is likely another explanation for why senescent cells are often thought of as "aged" or "old" cells. But even in this instance, cell senescence does not occur gradually over time like ageing cells, but suddenly in response to a very short telomere. </div>
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<div class="font_8" data-reactid=".0.$SITE_ROOT.$desktop_siteRoot.$PAGES_CONTAINER.1.1.$SITE_PAGES.$cjds.1.$ppPrt7-8uz.0.0.$child.$0.1.$1.$5.$0.0.14" style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; color: #030303; font-family: helvetica-w01-light, helvetica-w02-light, sans-serif; font-size: 18px; font-stretch: normal; line-height: normal; outline: 0px; padding: 0px; vertical-align: baseline;">
<span data-reactid=".0.$SITE_ROOT.$desktop_siteRoot.$PAGES_CONTAINER.1.1.$SITE_PAGES.$cjds.1.$ppPrt7-8uz.0.0.$child.$0.1.$1.$5.$0.0.14.0" style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">There is little or no evidence suggesting that telomere shortening </span><span data-reactid=".0.$SITE_ROOT.$desktop_siteRoot.$PAGES_CONTAINER.1.1.$SITE_PAGES.$cjds.1.$ppPrt7-8uz.0.0.$child.$0.1.$1.$5.$0.0.14.1" style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; font-style: italic; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">per se </span><span data-reactid=".0.$SITE_ROOT.$desktop_siteRoot.$PAGES_CONTAINER.1.1.$SITE_PAGES.$cjds.1.$ppPrt7-8uz.0.0.$child.$0.1.$1.$5.$0.0.14.2" style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">causes ageing. Cells likely function perfectly well with progressively shorter telomeres. Problems only arise when a telomere eventually becomes too short. As such, telomere shortening increases our risk of age-related conditions as cells are more likely to become senescent. </span></div>
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Drugs which could extend the length of telomeres by activating an enzyme called telomerase (which adds lost telomeres back to DNA) could prevent cells from becoming senescent and help prevent ageing. </div>
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In summary, cell ageing can be considered as a unprogrammed, random process leading to a gradual decline in cell function. Cell ageing is detrimental to the function of normal biological processes. Cell senescence can be induced randomly, but is a programmed change in cell state that can occur independent of age. Cell senescence can be both detrimental and beneficial depending on the biological context. </div>
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<img alt="Image 20170316 10913 xvyi5c" height="215" src="https://cdn.theconversation.com/files/161150/width754/image-20170316-10913-xvyi5c.jpg" width="400" /></h1>
<br />
<a href="https://theconversation.com/profiles/dominick-burton-345961">Dominick Burton</a>, Research Fellow, <em><a href="http://theconversation.com/institutions/aston-university-1107">Aston University</a></em><br />
<br />
This article was originally published on <a href="http://theconversation.com/">The Conversation</a>. Read the <a href="https://theconversation.com/killing-zombie-cells-to-improve-health-in-old-age-74557">original article</a>.<br />
<br />
<br />
Imagine a world where you could take just a single pill for the treatment or prevention of several age-related diseases. Although still in the realms of science fiction, accumulating scientific data now suggests that despite their biological differences a variety of these diseases share a common cause: senescent cells. This has led scientists to find drugs that can destroy these cells.<br />
<br />
When cells become damaged, they either self-destruct (apoptosis) or they lose their ability to grow and remain stuck within the body. These are the non-growing senescent cells that no longer carry out their tasks properly. They spew out chemicals that cause damage to cells nearby, sometimes turning them into “zombies” – hence why they are sometimes referred to as “zombie cells”. Eventually, the damage builds up so much that the function of bodily organs and tissues, such as skin and muscle, becomes impaired. At this point, we identify the changes as disease. <br />
<br />
Depending on where these senescent cells gather within the body will determine which disease will develop. Senescent cells have now been shown to be linked to <a href="http://www.nature.com/nrm/journal/v15/n7/full/nrm3823.html">several diseases</a>, including <a href="http://science.sciencemag.org/content/354/6311/472.long">cardiovascular disease</a>, <a href="http://diabetes.diabetesjournals.org/content/64/7/2289">type 2 diabetes</a>, <a href="https://academic.oup.com/biomedgerontology/article/doi/10.1093/gerona/glw154/2630057/Transplanted-Senescent-Cells-Induce-an">osteoarthritis</a> and <a href="http://www.sciencedirect.com/science/article/pii/S0092867407008902">cancer</a>. <br />
<br />
In <a href="http://www.nature.com/nature/journal/v479/n7372/full/nature10600.html">2011</a> and in <a href="http://www.nature.com/nature/journal/v530/n7589/full/nature16932.html">2016</a>, researchers at the Mayo Clinic in the US showed, through the use of genetically engineered (transgenic) mice, that the removal of senescent cells reduced cancer formation, delayed ageing and protected the mice against age-related diseases. The mice also lived 25% longer, on average. A similar result in humans would mean an increase in life expectancy from 80 years to 100 years. It was proof-of-principle studies like these that laid the groundwork and inspired other researchers to build on these findings. <br />
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<figure class="align-center "></figure><br /><br />
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<img alt="" height="251" src="https://cdn.theconversation.com/files/161154/width754/image-20170316-10911-16e230q.jpg" width="400" /><br />
<span class="caption">I’ll live how much longer?</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/521838493?src=tIuAXDhnqJIM4IqQWoWpYQ-1-4&size=medium_jpg">Kirill Kurashov/Shutterstock.com</a></span><br />
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<h2>
Killing a few to save the many</h2>
<br />
It is not known how many senescent cells need to be present to cause damage to the body, but the harmful effects of the chemicals they release can spread quickly. A few zombie cells may have a huge impact. Drugs for specifically killing senescent cells in order to extinguish their destructive force have recently been revealed and tested on mice. The collective term for these drugs is “senolytics”. <br />
<br />
In 2016, two research groups independently published findings on the discovery of two new senolytic drugs which target proteins responsible for protecting senescent cells from cell death. Research lead by scientists from the University of Arkansas, US, <a href="http://www.nature.com/nm/journal/v22/n1/full/nm.4010.html">showed</a> that the drug ABT-263 (Navitoclax) could selectively kill senescent cells in mice, making aged tissues young again. And scientists from the <a href="http://www.nature.com/articles/ncomms11190">Weizmann Institute of Science</a> in Israel used the drug ABT-737 to kill senescent cells in the lungs and skin of mice. <br />
<br />
There has also been a lot of interest in the role of senescent cells in pulmonary diseases caused by damage to the lungs. Among the risk factors, smoking is known to speed up lung ageing and disease, partly by attacking healthy cells with toxic chemicals from <a href="http://www.atsjournals.org/doi/abs/10.1165/rcmb.2006-0169OC">cigarette smoke</a> which can result in cells becoming senescent. <br />
<br />
In late 2016, <a href="https://insight.jci.org/articles/view/87732">Japanese scientists</a> showed that the removal of senescent cells using genetically engineered mice greatly restored lung function in old mice. A more recent <a href="http://www.nature.com/articles/ncomms14532?WT.feed_name=subjects_biological-sciences">study</a>, lead by scientists at the Mayo Clinic in the US, showed that <a href="http://www.nhs.uk/Conditions/pulmonary-fibrosis/Pages/introduction.aspx">idiopathic pulmonary fibrosis</a> (scarring of the lungs) was linked to an increase in the number of senescent cells and the damaging effects of the chemicals they release. The killing of senescent cells using genetically engineered mice again greatly improved lung function. In the same study, this group also reported the possible use of a combination of drugs, dasatinib and quercetin, to destroy senescent cells. <br />
<br />
A <a href="http://www.sciencedirect.com/science/article/pii/S0360301617306314">study</a> published earlier this month from the University of Arkansas, extended their previous findings on the drug ABT-263 to pulmonary fibrosis. They found that ABT-263 treatment reduced the problems caused by senescent cells and reversed the disease in mice. <br />
<br />
<h2>
There’s money in senolytics</h2>
<br />
In light of these accumulating and highly promising findings, a number of start-up biotechnology companies have been created to exploit the health benefits of targeting senescent cells. Probably the most well funded is Unity Biotechnology in the US which <a href="http://www.prnewswire.com/news-releases/unity-biotechnology-announces-116-million-series-b-financing-300352831.html">raised US$116m</a> for research and development.<br />
<br />
It will likely be several years before we see senolytic drugs being tested on humans. If you can’t wait that long, exercise may be the answer. A study published in <a href="http://diabetes.diabetesjournals.org/content/65/6/1606">March 2016</a> by the Mayo Clinic showed that exercise prevented the accumulation of senescent cells caused by a high-fat diet in mice. So if the regular health benefits of exercise were not enough to get you off the sofa, maybe the anti-ageing benefits will be.<br />
<br />
<div>
Original Article: <a href="https://theconversation.com/killing-zombie-cells-to-improve-health-in-old-age-74557" target="_blank">The Conversation</a></div>
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<span style="font-size: 12.0pt; line-height: 107%;">Cellular senescence is an altered cell state associated with permanent
cell cycle arrest and an immunogenic, pro-inflammatory secretome that can
contribute to the development and progression of age-related diseases. Because cellular senescence can occur in
different cell types (i.e. pancreatic beta cells, vascular smooth muscle cells,
astrocytes) that undertake different biological functions, then their
appearance can manifest differently and we refer to these manifestations as
different diseases. These include, diabetes,
cardiovascular disease, COPD and cancer.
The mechanisms by which senescent cells can cause disease include:<o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-size: 12.0pt; line-height: 107%;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-size: 12pt; line-height: 107%; text-indent: -18pt;"> (1)<span style="font-size: 7pt; font-stretch: normal; font-variant-numeric: normal; line-height: normal;"> </span></span><span style="font-size: 12pt; line-height: 107%; text-indent: -18pt;">Loss
of cellular regenerative capacity.</span><span style="font-size: 12pt; line-height: 107%; text-indent: -18pt;"><span style="font-size: 7pt; font-stretch: normal; font-variant-numeric: normal; line-height: normal;"> </span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-size: 12pt; line-height: 107%; text-indent: -18pt;"> (2) Loss
of normal cell function.</span><span style="font-size: 12pt; line-height: 107%; text-indent: -18pt;"><span style="font-size: 7pt; font-stretch: normal; font-variant-numeric: normal; line-height: normal;"> </span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-size: 12pt; line-height: 107%; text-indent: -18pt;"> (3) Persistent
pro-inflammatory tissue damage.</span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-size: 12pt; text-indent: -18pt;"> (4) Altering
the behaviour of neighbouring cells.</span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-size: 12pt; text-indent: -18pt;"> (5) Protease-mediated
degradation of extracellular structural proteins.</span></div>
<div class="MsoListParagraphCxSpLast" style="mso-list: l1 level1 lfo1; text-align: justify; text-indent: -18.0pt;">
<span style="font-size: 12.0pt; line-height: 107%;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-size: 12.0pt; line-height: 107%;">Although scientists researching cell senescence have long
suspected that senescent cells play an important role in ageing and age-related
disease, convincing evidence had not been provided until 2011 when Scientists
from the Mayo Clinic in the US published their findings on the elimination of
senescent cells in mice. The
elimination of senescent cells using transgenic (genetically engineered) mice
delayed the onset of disease, thereby increasing healthspan. However, likely owing to the use of an accelerated
ageing mouse model, no life extension was observed in this instance. However, a follow-up study by the same group
using naturally aged mice lead to delayed tumorigenesis and reduced age-related
decline leading to significant increase (up to 35%) in lifespan. Studies like these thus provide a convincing
rationale for developing therapeutic approaches for targeting senescent cells, so-called
“senotherapeutics”. These may include:<o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-size: 12.0pt; line-height: 107%;"><br /></span></div>
<div class="MsoListParagraphCxSpFirst" style="text-align: justify; text-indent: -18pt;">
</div>
<ol>
<li> <span style="font-size: 12pt; line-height: 107%; text-indent: -18pt;">Specifically
inducing cell death in senescent cells (i.e. small-molecule compounds).</span></li>
<li> <span style="font-size: 12pt; line-height: 107%; text-indent: -18pt;">Inhibiting
the senescent secretome (i.e. inhibitors of inflammation).</span></li>
<li> <span style="font-size: 12pt; line-height: 107%; text-indent: -18pt;">Preventing
senescence induction (i.e. telomerase activators, geroprotectors).</span></li>
<li> <span style="font-size: 12pt; line-height: 107%; text-indent: -18pt;">Boost
immune response towards senescent cells (i.e. immunotherapy).</span></li>
</ol>
<!--[if !supportLists]--><br />
<div class="MsoListParagraphCxSpLast" style="mso-list: l0 level1 lfo2; text-align: justify; text-indent: -18.0pt;">
<span style="font-size: 12.0pt; line-height: 107%;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-size: 12.0pt; line-height: 107%;">A few recent studies have published findings regarding the
elimination of senescent cells by small-molecule compounds. Wang et al (2016) identified the compound
ABT-263 as a potent inducer of cell death in senescent cells leading to
rejuvenation of aged tissue stem cells.
In another study, Yosef et al (2016) identified ABT-737 which through
the elimination of senescent cells from the epidermis of the skin of mice lead
to increased hair-follicle stem cell proliferation. Both ABT-263 and ABT-737 inhibit proteins
(BCL-2 family) known to play a role in cell survival. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-size: 12.0pt; line-height: 107%;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-size: 12.0pt; line-height: 107%;">Studies focused on the elimination of senescent cells are
only beginning to emerge and will no doubt gain momentum as they show
tremendous potential for improving health and wellbeing. One intriguing notion that may arise from
this research is concerned with the question of whether it may one day be
possible to treat many diseases with a single drug. If senescent cells play a role in the
development of many different diseases, then a drug that can eliminate
senescent cells in all cell types could act as both a preventative and a
treatment for many diseases. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-size: 12.0pt; line-height: 107%;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-size: 12.0pt; line-height: 107%;">One of the obstacles preventing research into
senotherapeutics from advancing and ultimately becoming translational to help increase
healthspan of individuals within the general public, is funding. However, this has not discouraged some
researchers who were determined enough to acquire funding through the help of
crowdfunding. The Major Mouse Testing
Programme (MMTP) raised over $50,000 towards research focused on eliminating
senescent cells and is still ongoing (<a href="https://www.lifespan.io/campaigns/the-major-mouse-testing-program/" target="_blank">Click Here</a>). <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-size: 12.0pt; line-height: 107%;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-size: 12.0pt; line-height: 107%;">A new start-up company, CellAge (<a href="http://www.cellage.org/" target="_blank">click here</a>) is also
interested in targeting senescent cells and has recently announced a
crowdfunding campaign (<a href="https://www.lifespan.io/campaigns/cellage-targeting-senescent-cells-with-synthetic-biology/" target="_blank">click here</a>) to raise funds for their ongoing
research. CellAge aims are to “<i>Increase human healthspan and reduce the
incidence of age-related diseases by helping the human body eliminate senescent
cells. Our breakthrough technology
concept harvests the promise of synthetic biology and recent findings in ageing
research to deliver novel products and therapies to enable people to live
healthier longer lives”</i><o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-size: 12.0pt; line-height: 107%;"><i><br /></i></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-size: 12.0pt; line-height: 107%;">So if you are interested in stimulating research in this field for the benefit of all, then please make a donation </span><span style="font-size: 16px;">(</span><a href="https://www.lifespan.io/campaigns/cellage-targeting-senescent-cells-with-synthetic-biology/" style="font-size: 16px;" target="_blank">link here</a><span style="font-size: 16px;">).</span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-size: 12.0pt; line-height: 107%;"><br /></span></div>
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<span style="font-size: 12.0pt; line-height: 107%;"><br /></span></div>
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Abstract</h4>
<div style="background-color: white; border: 0px; color: #333333; font-family: Verdana, arial, Helvetica, sans-serif; font-size: 13.31px; font-weight: bold; line-height: 16.94px; margin-right: 30px; padding: 0px; text-align: justify;">
Cellular senescence is a stress response mechanism that limits tumorigenesis and tissue damage. Induction of cellular senescence commonly coincides with an immunogenic phenotype that promotes self-elimination by components of the immune system, thereby facilitating tumor suppression and limiting excess fibrosis during wound repair. The mechanisms by which senescent cells regulate their immune surveillance are not completely understood. Here we show that ligands of an activating Natural Killer (NK) cell receptor (NKG2D), MICA and ULBP2 are consistently up-regulated following induction of replicative senescence, oncogene-induced senescence and DNA damage - induced senescence. MICA and ULBP2 proteins are necessary for efficient NK-mediated cytotoxicity towards senescent fibroblasts. The mechanisms regulating the initial expression of NKG2D ligands in senescent cells are dependent on a DNA damage response, whilst continuous expression of these ligands is regulated by the ERK signaling pathway. In liver fibrosis, the accumulation of senescent activated stellate cells is increased in mice lacking NKG2D receptor leading to increased fibrosis. Overall, our results provide new insights into the mechanisms regulating the expression of immune ligands in senescent cells and reveal the importance of NKG2D receptor-ligand interaction in protecting against liver fibrosis.</div>
<div style="background-color: white; border: 0px; color: #333333; font-family: Verdana, arial, Helvetica, sans-serif; font-size: 13.31px; font-weight: bold; line-height: 16.94px; margin-right: 30px; padding: 0px; text-align: justify;">
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<div style="background-color: white; border: 0px; color: #333333; font-family: Verdana, arial, Helvetica, sans-serif; font-size: 13.31px; font-weight: bold; line-height: 16.94px; margin-right: 30px; padding: 0px; text-align: justify;">
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<div style="background-color: white; border: 0px; color: #333333; font-family: Verdana, arial, Helvetica, sans-serif; font-size: 13.31px; font-weight: bold; line-height: 16.94px; margin-right: 30px; padding: 0px; text-align: justify;">
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Link: <a href="http://impactaging.com/papers/v8/n2/full/100897.html">http://impactaging.com/papers/v8/n2/full/100897.html</a></div>
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Abstract</h2>
<div id="p-3" style="background-color: white; border: 0px; color: #403838; font-family: 'Lucida Sans Unicode', Arial, 'Lucida Grande', Tahoma, Verdana, Helvetica, sans-serif; font-size: 12.8000001907349px; line-height: 1.5; margin-bottom: 15px; margin-top: 15px; outline-style: none; padding: 0px; text-align: justify; vertical-align: baseline; word-wrap: break-word;">
Mammalian cells mostly rely on extracellular molecules to transfer signals to other cells. However, in stress conditions, more robust mechanisms might be necessary to facilitate cell–cell communications. Cellular senescence, a stress response associated with permanent exit from the cell cycle and the development of an immunogenic phenotype, limits both tumorigenesis and tissue damage. Paradoxically, the long-term presence of senescent cells can promote tissue damage and aging within their microenvironment. Soluble factors secreted from senescent cells mediate some of these cell-nonautonomous effects. However, it is unknown whether senescent cells impact neighboring cells by other mechanisms. Here we show that senescent cells directly transfer proteins to neighboring cells and that this process facilitates immune surveillance of senescent cells by natural killer (NK) cells. We found that transfer of proteins to NK and T cells is increased in the murine preneoplastic pancreas, a site where senescent cells are present in vivo. Proteomic analysis and functional studies of the transferred proteins revealed that the transfer is strictly dependent on cell–cell contact and CDC42-regulated actin polymerization and is mediated at least partially by cytoplasmic bridges. These findings reveal a novel mode of intercellular communication by which senescent cells regulate their immune surveillance and might impact tumorigenesis and tissue aging.</div>
<div id="p-3" style="background-color: white; border: 0px; margin-bottom: 15px; margin-top: 15px; outline-style: none; padding: 0px; text-align: justify; vertical-align: baseline; word-wrap: break-word;">
<div style="text-align: left;">
<span style="color: #003366; font-family: Lucida Sans Unicode, Arial, Lucida Grande, Tahoma, Verdana, Helvetica, sans-serif;"><span style="font-size: 12.8000001907349px; line-height: 17.4545459747314px;"><a href="http://genesdev.cshlp.org/content/early/2015/04/03/gad.259341.115.abstract">http://genesdev.cshlp.org/content/early/2015/04/03/gad.259341.115.abstract</a></span></span><br />
<span style="color: #003366; font-family: Lucida Sans Unicode, Arial, Lucida Grande, Tahoma, Verdana, Helvetica, sans-serif;"><br /></span>
<span style="color: #003366; font-family: Lucida Sans Unicode, Arial, Lucida Grande, Tahoma, Verdana, Helvetica, sans-serif;">.</span></div>
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Senescent cells are often associated with changes in gene expression that appear to occur independent of the regulated gene expression linked to aspects of the senescent phenotype such as cell cycle arrest, the secretory response and apoptosis resistance. This phenomenon has been termed promiscuous gene expression (pGE) (Burton and Krizhanovsky, 2014) and can be more specifically defined as gene expression that is uncoupled from tissue or developmental regulation. </div>
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<div style="text-align: justify;">
pGE can be observed in microarray analysis by comparing the gene expression profiles of different senescent cell types and lines. Zhang et al (2003) has demonstrated that the up-regulation of genes in senescent fibroblasts was associated with gene clustering (150 of the 376 gene up-regulated), whereas the down-regulation of genes (313) was not. 48.1% of the up-regulated genes were designated as membrane-associated proteins, 10.5% related to apoptosis and 15.8% to transport, whereas 17.9% of the down-regulated genes are involved in cell cycle regulation. Gene expression changes in senescent human mammary epithelial cells (HMECs) were shown to be drastically different than that of the fibroblasts, despite both undergoing senescence induced by telomere attrition. Only five genes up-regulated and seven genes down-regulated in HMECs showed similar regulation in fibroblasts. However, like senescent fibroblasts, HMECs also demonstrated gene clustering associated with up-regulated genes only. Zhang et al postulated at the time, that if senescence is a response to DNA damage, then the observed differences in gene expression between senescent fibroblasts and HMECs imply that the effects of DNA damage must vary according to cell type and line. This study also suggested that processes occurring during senescence may lead to localized alteration in chromatin and the consequent up-regulation of groups of genes within “opened” domains. </div>
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Shelton et al (1999) also demonstrated that senescence-mediated gene expression between different cell lineages varies greatly. BJ fibroblasts, HUVECs and retinal pigment epithelial cells (RPE340) that underwent replicative senescence demonstrated substantial variation in gene expression. A genomic comparison of three different senescent fibroblasts strains also demonstrated significant differences in gene expression, but also shared trends were apparent. If indeed pGE is uncoupled from tissue or developmental regulation, then stochastic processes that alter chromatin structure could be at play and the different response between cell types and cell strains could reflect differences in cell-specific chromatin architecture important for cell-specific gene expression. Elevated levels of oxidative stress, a feature of senescent cells could be one such stochastic process. </div>
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Bahar et al demonstrated that although gene expression levels varied among cardiomyocytes taken from hearts of young mice, the heterogeneity is elevated with age (Bahar et al. 2006). This increased stochastic gene expression with age was suggested to be the result of genomic damage, as mouse embryonic fibroblasts treated with hydrogen peroxide in culture resulted in significant cell-cell variation in gene expression in conjunction with these cells showing morphological signs of cellular senescence (Bahar et al. 2006). </div>
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So how could DNA damage induced by oxidative stress result in stochastic changes in gene expression? When cells sustain DNA damage, chromatin undergoes remodeling to facilitate DNA repair (Price and D’Andrea, 2013, House et al. 2014). This remodeling or “opening” of tightly packed DNA could allow transcription factors access to previously inaccessible genes. Therefore, persistent DNA damage and consequently continuous chromatin remodeling may facilitate pGE. While the induction of DNA damage is likely a stochastic process, the sites of DNA damage may not be completely random, as certain areas of the genome may be more or less prone to genomic insults (Ma et al. 2012). The clustering phenomenon reported by Zhang et al may be the result of these DNA damage prone sites (Zhang et al. 2003). If this were indeed the case, while there may be substantial differences in gene expression at a cell-cell comparison, an overall comparison between cell cultures would likely demonstrate consistent gene alterations resulting from an average expression of all cells within a culture. </div>
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In addition to oxidative stress, a number of other possible mechanisms may exist for generating pGE. Senescent fibroblasts are known to undergo methylation changes (Cruickshanks et al. 2013) and these alterations may lead to epigenetic alterations that promote stochastic changes in gene expression. Alternatively, it has been suggested that DNA damage may modulate gene expression by altering the binding capacity of transcription factors (Rose et al. 2012). </div>
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Interestingly, the reprogramming of fibroblasts into induced pluripotent stem cells (iPSCs) via the addition of OCT4, SOX2, KLF4 and MYC (OSKM) requires a long stochastic phase of gene activation associated with changes in histone modifications at somatic genes and activation of DNA repair and RNA processing (Buganim et al. 2013). This stochastic gene expression may be the result of “promiscuous binding” by OCT4, SOX2 and KLF4, where they occupy accessible chromatin and bind to promoters of genes that are active or repressed (Buganim et al. 2013). It is possible that pGE in senescent cells partly mimics stochastic gene activation associated with cellular reprogramming. However, whether pGE in senescent cells is associated with factors that can undergo “promiscuous binding” has yet to be determined. </div>
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Whether pGE plays a functional role in cell senescence has yet to be determined. However, it can be speculated that pGE may function to generate an array of tissue-restricted proteins that can subsequently be processed into peptides by autophagic proteases for presentation on MHC molecules (Dengjel et al. 2005). Similar to the presentation of tumour-associated antigens (Reuschenbach et al. 2009), senescent cells may also present antigens that can be recognized by immune cells, thereby becoming antigen-presenting cells (APCs). Although the up-regulation of MHC molecules on senescent cells have yet to be fully evaluated, the up-regulation of MHC class I but not MHC class II in response to DNA damage in fibroblasts has been reported (Tang et al. 2014). It remains to be determined whether pGE is a component of immunogenic conversion.</div>
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<b style="background-color: #fefdfa; font-family: 'Times New Roman'; font-size: 13px; line-height: 19.5px;">Taken from:<a href="http://link.springer.com/article/10.1007/s11357-015-9764-2" style="color: #602512; text-decoration: none;" target="_blank"><span style="color: #602512;"> </span><span style="color: red; text-decoration: none;">Cellular Senescence: From Growth Arrest to Immunogenic Conversion</span></a> </b></div>
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</script>Anonymoushttp://www.blogger.com/profile/05125651385504239005noreply@blogger.com0tag:blogger.com,1999:blog-8310696584811817494.post-40330567609500160572015-04-02T11:58:00.000+01:002015-04-02T11:58:37.964+01:00Atypical senescent states: Experimental induction of cyclin-dependent kinase inhibitors (e.g. p16, p21)
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<span lang="EN-US" style="font-family: "Times New Roman"; font-size: 10.0pt; line-height: 150%;">For many researchers, irreversible cell cycle
arrest is the canonical trait of senescent cells. Such growth arrest can be induced
experimentally by the up-regulation or over-expression of cyclin dependent
kinase inhibitors (CDKi). Thus valuable
models are, at least potentially, available in which to study the physiological
effect of growth arrest distinct from the DDR or any other upstream response. Unfortunately there has been little
characterization of the phenotype of cells rendered ‘senescent’ by this means.<o:p></o:p></span></div>
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<br /></div>
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<span lang="EN-US" style="font-family: "Times New Roman"; font-size: 10.0pt; line-height: 150%;">Blagosklonny and co-workers (Korotchkina <i>et al. </i>2009) used an
isopropyl-thio-galactosidase (IPTG)-inducible p21 expression construct to
induce a senescence-like state in an HT1080-derived cell line (HT-p21-9). Characterisation of the phenotype of these
cells does not appear to have been attempted beyond observing irreversible
growth arrest and the presence of increased SA-</span><span lang="EN-US" style="font-family: "MS 明朝"; font-size: 10.0pt; line-height: 150%; mso-ascii-font-family: "Times New Roman"; mso-hansi-font-family: "Times New Roman";">β</span><span lang="EN-US" style="font-family: "Times New Roman"; font-size: 10.0pt; line-height: 150%;">-Gal
activity. Given that HT1080 is a highly
tumorigenic fibrosarcoma carrying an activated N-ras oncogene (Benedict <i>et al.</i> 1984), it probably represents a
poor genetic background in which to assess whether markers of immunogenic
conversion or resistance to cell death can be induced by CDKi overexpression
alone. However, the basic principle of using
such a construct for that purpose is sound.<o:p></o:p></span></div>
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<br /></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "Times New Roman"; font-size: 10.0pt; line-height: 150%;">Tokarsky-Amiel <i>et al</i> (2013) showed that overexpression of p14<sup>ARF</sup> in the
epidermis of the skin of mice (using a tetracyclin-inducible construct) resulted
in mass apoptosis and cell cycle arrest.
As measured by SA-</span><span lang="EN-US" style="font-family: "MS 明朝"; font-size: 10.0pt; line-height: 150%; mso-ascii-font-family: "Times New Roman"; mso-hansi-font-family: "Times New Roman";">β</span><span lang="EN-US" style="font-family: "Times New Roman"; font-size: 10.0pt; line-height: 150%;">-Gal
activity, the p14<sup>ARF</sup> transgene drove senescence in up to 8% of the
surviving cells in the epithelium by a p53-dependent mechanism (demonstrated by
ablation of p53 through co-expression of a specific shRNA directed against it). These senescent cells were viable within the
epidermis for several weeks consistent with lack of clearance. Unfortunately, minimal analysis of their
phenotype was conducted (beyond assessment of the message levels for the
senescence-associated genes Pai-1 and Dcr2).
Thus, the immune state of the p14<sup>ARF</sup>-senescent cells is currently
unclear and the picture is complicated by the fact that senescent rodent cells
do not display a senescent secretome under some conditions. However, given that alopecia and follical
stem cell dysfunction were observed in the animals, it is clear that cells
rendered ‘senescent’ in this manner can exert phenotypic effects. Thus, there is some evidence that cell cycle
arrest alone may be sufficient to cause problems in highly mitotic tissues such
as the epidermis, but large amounts of work remain to be done. <o:p></o:p></span></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<br /></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "Times New Roman"; font-size: 10.0pt; line-height: 150%;">CDKi overexpression systems clearly have the
potential to be valuable tools. However the
extent to which these are physiologically reflective can legitimately be challenged. This can be understood in two ways (i) the
mechanism by which the growth arrest is induced has not been reported <i>in vivo</i> and (ii) cells do not become
senescent <i>en mass </i>but gradually as a
result of tissue turnover throughout life.
Thus, findings made with these systems could be considered ‘artefactual’<o:p></o:p></span></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<br /></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "Times New Roman"; font-size: 10.0pt; line-height: 150%;">By way of addressing these concerns, it is worth
remembering that for many years replicative senescence was dismissed as a
‘tissue culture artefact’ because senescent cells had not been observed <i>in vivo </i>(evidence for their existence in
tissue remained severely limited until the late 1990s). By the same token, elevation of CDKi alone in
cells <i>in vivo </i>is not impossible. Absence of evidence is never evidence of
absence. Similarly, many
over-expression systems model systems can be said to be non-physiological. However, valuable data is routinely gathered
using them and in this instance could allow researchers to gage the maximum
physiological impact that irreversible growth arrest can have on tissue
function. Thus, if these limits are
recognized, such models are potentially utile, especially when combined with
detailed analysis of phenotypes known to exist in other ‘senescent cells’ (e.g.
apoptosis resistance, immune ligand presentation and the secretory response) <o:p></o:p></span></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "Times New Roman"; font-size: 10.0pt; line-height: 150%;"><br /></span></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "Times New Roman"; font-size: 10.0pt; line-height: 150%;"><b style="background-color: #fefdfa; font-size: 13px; line-height: 19.5px;">Taken from:<a href="http://link.springer.com/article/10.1007/s11357-015-9764-2" style="color: #602512; text-decoration: none;" target="_blank"><span style="color: #602512;"> </span><span style="color: red; text-decoration: none;">Cellular Senescence: From Growth Arrest to Immunogenic Conversion</span></a></b></span></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "Times New Roman"; font-size: 10.0pt; line-height: 150%;"><br /></span></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "Times New Roman"; font-size: 10.0pt; line-height: 150%;"><br /></span></div>
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</script>Anonymoushttp://www.blogger.com/profile/05125651385504239005noreply@blogger.com0tag:blogger.com,1999:blog-8310696584811817494.post-91019728823305314442015-03-29T15:31:00.000+01:002015-03-29T15:31:04.814+01:00Atypical senescent states: Endoplasmic Reticulum stress induced senescence
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<span lang="EN-US" style="font-family: "Times New Roman"; font-size: 10.0pt; line-height: 150%;">Endoplasmic reticulum (ER) stress may also
promote a senescent-like response. The
accumulation of unfolded proteins in the ER triggers a stress-signaling pathway
that can result in cell cycle arrest mediated by p27 (Han <i>et al</i>. 2013) and the p53/47 isoform (Bourougaa <i>et al.</i> 2010). Furthermore,
ER stress has also been shown to induce an inflammatory response via NFkB
activation (Garg <i>et al</i>. 2012) and
induce cytokines such as MCP-1, IL-6 and IL-8 (Schroder, 2008), which are
capable of attracting and activating immune cells (Sagiv and Krizhanovsky, 2013).
ER stress has also been shown to promote cell survival, another feature of cell
senescence (Raciti <i>et al</i>. 2012). Interestingly, a senescent state via
activation of ER stress-dependent p21 signaling has been reported in proximal
tubular epithelial cells, triggered by receptors for advanced glycation
end-products (RAGE) (Liu <i>et al</i>. 2014). Although, ER stress-induced senescence has
the potential induce an immunogenic phenotype in the absence of DNA damage, a full
evaluation of the phenotype is required to determine if this is so.<o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "Times New Roman"; font-size: 10.0pt; line-height: 150%;">Metabolic stress, defined here as a combination
of aerobic glycolysis and mitochondria dysfunction can potentially trigger a senescent
state. All organisms that use aerobic
glycolysis form reactive acyclic </span><span lang="EN-US" style="font-family: "MS 明朝"; font-size: 10.0pt; line-height: 150%; mso-ascii-font-family: "Times New Roman"; mso-hansi-font-family: "Times New Roman";">α</span><span lang="EN-US" style="font-family: "Times New Roman"; font-size: 10.0pt; line-height: 150%;">-oxoaldehydes
(e.g. methylglyoxal and glyoxal) spontaneously from triosephosphates and by a
wide variety of other routes (Thornalley, 2009). These dicarbonyl compounds are highly
reactive and damage proteins through non-enzymatic modification producing a
wide variety of covalent adducts (AGEs).
Elevated levels of methylglyoxal and glyoxal are known to be cytotoxic
and although the mechanism of action remains imprecisely defined, it can be
blocked by ROS scavengers, suggesting that oxidative stress mediates at least
some of the deleterious effects (Shangari and O’Brian, 2004).<o:p></o:p></span></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "Times New Roman"; font-size: 10.0pt; line-height: 150%;"><br /></span></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: 'Times New Roman'; font-size: 10pt; line-height: 150%;">Cytosolic and mitochondrial protection from dicarbonly
damage is primarily mediated through the action of the glyoxalase system that
consists of two enzymes, glyoxalase I and II.
However, in cultures of WI38 fibroblasts a significant reduction in the
activity of glyoxalase-I occurs with serial passage (Ahmed <i>et al</i>. 2010). Treatment of cultures
of ASF2 human adult dermal fibroblasts with micro or millimolar concentrations of
glyoxal or methylglyoxal renders them senescent within 72 hours. This was defined by the presence of typical
senescent morphology, irreversible growth arrest and increased SA-</span><span lang="EN-US" style="font-family: 'MS 明朝'; font-size: 10pt; line-height: 150%;">β</span><span lang="EN-US" style="font-family: 'Times New Roman'; font-size: 10pt; line-height: 150%;">-Gal
activity (Sejersen & Rattan, 2009). Further
studies (Larsen <i>et al. </i>2012) extended
these observations to immortalized human mesenchymal stem cells (MSCs) and demonstrated
that treatment with physiologically reflective (Han <i>et al.</i> 2007) concentrations of glyoxal for 72 hours led to
senescence without significant cell death (although massive cell death occurred
at higher glyoxal concentrations). Elevated
levels of SA-</span><span lang="EN-US" style="font-family: 'MS 明朝'; font-size: 10pt; line-height: 150%;">β</span><span lang="EN-US" style="font-family: 'Times New Roman'; font-size: 10pt; line-height: 150%;">-Gal, p16 and DNA damage (as measured by
COMET) accompanied the growth arrest. Interestingly,
a profound reduction in the ability of these senescent MSCs to differentiate
into functional osteoblasts (as determined by alkaline phosphatase and
mineralization assays) was also observed.
Given the imbalances in glucose metabolism that accompany mammalian
ageing (and diabetes), the authors proposed that this type of metabolic stress
might underlie age-related changes in bone function. Unfortunately, no markers of immunogenic
conversion have yet been measured in this system and whilst the presence of DNA
damage could indicate the likelihood of a secretory response, this cannot be
assumed. Thus, the propensity of
senescence human MSCs to be cleared by the immune system remains unknown and is
of considerable physiological significance.</span></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<br /></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<b style="background-color: #fefdfa; font-family: 'Times New Roman'; font-size: 13px; line-height: 19.5px;">Taken from:<a href="http://link.springer.com/article/10.1007/s11357-015-9764-2" style="color: #602512; text-decoration: none;" target="_blank"> <span style="color: red;">Cellular Senescence: From Growth Arrest to Immunogenic Conversion</span></a></b></div>
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</script>Anonymoushttp://www.blogger.com/profile/05125651385504239005noreply@blogger.com0tag:blogger.com,1999:blog-8310696584811817494.post-29259219748729828552015-03-25T09:12:00.000+00:002015-03-25T09:13:52.753+00:00Atypical senescent states: TGFβ-induced senescence and Developmentally programmed senescence<div style="text-align: justify;">
<span style="font-family: Arial, Helvetica, sans-serif;"><b>TGFβ-induced senescence:</b> A growing body of evidence suggests that the members of the transforming growth factor beta (TGF- β) family can induce a senescence-like state. Experimentally, senescence has been predominantly, but not exclusively, characterized by the presence of senescence-associated beta galactosidase (SA-β-Gal) staining and the up-regulation of cyclin dependent kinase inhibitors (CDKi) (see below). Human prostate basal cells treated with TGF-β1/2/3 show increased SA-β-Gal activity, which is associated with the flattened, and enlarged cell morphology typical of adherent senescent cells in vitro (Untergasser et al. 2003). Similarly TGF-β1 has been reported to induce a senescent state in bone marrow mesenchymal stem cells as a result of increased mitochondria ROS production (Wu et al. 2014). These cells also showed SA-β-Gal staining and an increased expression of p16. Yu et al. (2010) demonstrated that TGF-β2 could induce a senescent-like state in human trabecular meshwork cells. Again, this was associated with SA-β-Gal staining, increased levels of p16 at both the message and protein level and a reduction in the level of pRB protein. No impact on p21 mRNA or protein expression was observed in response to TGF-β2 exposure. Other groups have also reported a role for TGF-β signaling in inducing a senescent state (Senturk et al. 2010, Minagawa et al. 2011, Acosta et al. 2013). </span></div>
<div style="text-align: justify;">
<span style="font-family: Arial, Helvetica, sans-serif;"><br /></span></div>
<div style="text-align: justify;">
<span style="font-family: Arial, Helvetica, sans-serif;">It is generally accepted that SA-β-Gal staining should be used in conjunction with several other senescent markers, as it does not appear to detect senescent cells specifically (Severino et al, 2000). However, other than the expression of CDKi, it appears that the phenotypes of cells induced to enter senescence by exposure to TGF-βs have been poorly characterized, especially in regard to immunogenic conversion. Some cell types that become senescent via this route may be cleared by the immune system in a manner analogous to those undergoing developmentally programmed senescence. Others may not and this area represents a fruitful field for further investigation.</span></div>
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<span style="font-family: Arial, Helvetica, sans-serif;"><b>Developmentally programmed senescence:</b> Cells sharing features of senescence have been reported within the mesonephros and the endolymphatic sac of the inner ear in human and mouse embryos; as well as the neural roof plate and apical ectodermal ridge in rodents (Munoz-Espin et al. 2013, Storer et al. 2013). The authors hypothesize that this “developmental senescence” (DS) is a programmed part of normal embryonic development. DS was demonstrated experimentally by the presence of SA-β-Gal activity and senescence associated heterochromatin (Munoz-Espin et al. 2013). These cells seem to lack detectable DNA damage and appear to have become senescent independent of p53 and p16 and have gene expression patterns that significantly overlap with those of IMR90 fibroblasts in a state of oncogene-induced senescence. Arrest in this instance is dependent instead upon p21, regulated via the TGF-β/SMAD and PI3K/FOXO pathways (thus showing some affinity with other TGF-β induced senescent states). Interestingly, DS cells are removed during normal embryonic development by macrophages in a manner related to immune clearance of senescent cells in the mature organism (or by apoptosis should senescence fail) contributing to the formation of normal tissue architecture. Thus, the long-recognized distinction between programmed cell death in development and apoptosis in the mature organism appears to be mirrored in DS. Given that the expression of p21 in developing embryos is often attributed to ‘terminal differentiation’ (Vasey et al. 2011), it will be interesting to determine how many of these p21 positive cells are senescent cells and have undergone immunogenic conversion.</span><br />
<span style="font-family: Arial, Helvetica, sans-serif;"><br /></span>
<b style="background-color: #fefdfa; font-family: 'Times New Roman'; line-height: 19.5px;">Taken from:<a href="http://link.springer.com/article/10.1007/s11357-015-9764-2" style="color: #602512; text-decoration: none;" target="_blank"> <span style="color: red;">Cellular Senescence: From Growth Arrest to Immunogenic Conversion</span></a></b></div>
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<span lang="EN-US" style="font-family: "Times New Roman"; font-size: 10.0pt; line-height: 150%;">In addition to secreting soluble factors for the
attraction of immune cells, senescent cells can also become immunogenic through
the up-regulation of ligands that can specifically be recognized by immune
cells. While research into the
recognition and interaction of immune cells with senescent cells is at its
infancy, a number of studies have reported the up-regulation of the Natural
Killer Group 2D (NKG2D) ligands in senescent cells that can be recognized by
receptors on Natural Killer (NK) cells and CD8+ T-cells. Since NKG2D ligands are not widely expressed
on healthy cells, this would allow for specific recognition, interaction and
elimination of senescent cells by immune cells.
As with the senescent secretome, this response is likely not exclusive
to cell senescence as the same mechanism functions in immunosurveillance of
tumour cells (López-Soto <i>et al</i>. 2014). The human NKG2D ligands primarily consist of
MICA, MICB, ULBP1, ULBP2, ULBP3, ULBP4, ULBP5 and ULBP6. The transcriptional up-regulation of MICA and
ULBP2 during cell senescence have been reported in senescent activated hepatic
stellate cells, replicative senescent fibroblasts and HUVECs, etoposide-induced
senescent fibroblasts, fusion-induced senescent fibroblasts and
chemotherapy-induced senescent multiple myeloma cells (<span style="background: white;">Krizhanovsky, <i>et al</i>. 2008, Kim
<i>et al. </i>2008 Chuprin <i>et al</i>. 2013, Soriani <i>et al</i>. 2014, Lackner <i>et al</i>, 2014). In addition to MICA and ULBP2, microarray
analysis of replicative senescent fibroblasts demonstrated an increase in the
expression of ULBP1 (2.75 fold) compared to growing cells, in addition to the
up-regulation of HLA-E (2 fold) (Lackner <i>et
al</i>. 2014). HLA-E is a non-classical
MHC class I molecule that plays a role in cell recognition by NK cells. However,
replicative senescent vascular smooth muscle cells do not appear to up-regulate
MICA, ULBP2 or ULBP1, at least not greater than 2 fold as assessed by microarray
analysis (Burton <i>et al</i>. 2009). Therefore, it should not be assumed that all
senescent cell types up regulate NKG2D ligands and this should be evaluated in
underexplored senescent cell types. Mechanisms involved in the interaction of
senescent cells with T-cells is less understood, but it appears that major
histocompatibility complex class II (MHCII) expression is required for killing
of pre-malignant senescent hepatocytes by T-cells (Kang <i>et al</i>. 2011). Mice with
liver specific MHCII deficiency resulted in impaired immunosurveillance of
senescent cells. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<br /></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="background: white; font-family: "Times New Roman"; font-size: 10.0pt; line-height: 150%;">At the mechanistic level, </span><span lang="EN-US" style="font-family: "Times New Roman"; font-size: 10.0pt; line-height: 150%;">little
is currently known about the regulation of NKG2D ligand expression in senescent
cells. Nonetheless, some extrapolation
from others models is possible. For
example, MICA and MICB have been reported to be regulated by endogenous miRNAs
in tumours and as a result of infection with cytomegalovirus (Stern-Ginossar <i>et al</i>. 2008). Since miRNAs appear to play a role in
regulating cellular senescence (Feliciano <i>et
al</i>. 2011, Liu <i>et al. </i>2012
Benhamad <i>et al</i>. 2012) and their
expression is altered in response to DNA damage (Dolezalova <i>et al.</i> 2012, Wang and Taniguchi, 2013), it
is possible that changes in miRNA expression also regulate the expression of
immune ligands in senescent cells. <o:p></o:p></span></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<br /></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "Times New Roman"; font-size: 10.0pt; line-height: 150%;">Soriani <i>et
al</i> demonstrated that the up-regulation of MICA in senescent multiple
myeloma cells was dependent upon the DDR (<span style="background: white;">Soriani
<i>et al</i>. 2014). </span> In other systems, NKG2D ligands have also
been shown to be up-regulated in response to DNA damage and Ras activation via
ATM and ATR (Gasser <i>et al</i>. 2005,
Cerboni <i>et al</i>. 2014). Inhibition of the ATM or ATR pathways
prevented the up-regulation of immune ligands.
<o:p></o:p></span></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<br /></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "Times New Roman"; font-size: 10.0pt; line-height: 150%;">It is also possible that the up-regulation of
immune ligands on senescent cells is mediated via the secretory response. In addition to activating and attracting
immune cells, the senescent secretome may serve to up-regulate immune ligands in
an autocrine or paracrine manner. It has
been shown for example, that TNF</span><span lang="EN-US" style="font-family: "MS 明朝"; font-size: 10.0pt; line-height: 150%; mso-ascii-font-family: "Times New Roman"; mso-hansi-font-family: "Times New Roman";">α</span><span lang="EN-US" style="font-family: "Times New Roman"; font-size: 10.0pt; line-height: 150%;"> can
up-regulate MICA on human endothelial cells and that the addition of exogenous
MICA seems to induce senescence in HUVECs (Lin <i>et al</i>. 2011), but the extent to which this occurs under more
physiologically reflective situations remains unclear. <o:p></o:p></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "Times New Roman"; font-size: 10.0pt; line-height: 150%;">Immune ligands can also be up-regulated in
response to various other forms of cell stress such as heat shock, metabolic
stress and endoplasmic reticulum (ER) stress (Cerwenka, 2009, Valés-Gómez <i>et al</i>. 2008). Thus, as with the secretory response, mechanisms
exists that can up-regulate immune ligands independent of DNA damage. Given that this is an important aspect of
senescent cell clearance and the number of cell types in which the up-regulation
of immune ligands has been shown is limited, a more detailed study of this
aspect of immunogenic conversion seems warranted. <o:p></o:p></span></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<br /></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "Times New Roman"; font-size: 10.0pt; line-height: 150%;">While senescent cells are likely eliminated by
the immune system during normal physiological processes, it has been speculated
that the accumulation of senescent cells with age could be due to inefficient
elimination by an ageing immune system (Burton, 2009). In fact, immune cells may themselves undergo
cellular senescence, a process that requires further investigations (Effros <i>et al</i>. 2005, Rajagopalan <i>et al</i>. 2012). As such, induction of cell
senescence in immune cells may represent one aspect of immunosenescence, the
gradual deterioration of the immune system, which consequently leads to
impaired immunosurveillance of non-immune senescent cells. It can be speculated that impaired
immunosurveillance may result from altered expression of surface receptors on
immune cells that impair recognition and interaction with target senescent
cells (and cancer cells). In addition,
it is possible that aged or senescent immune cells do not respond as efficiently
to chemoattractants secreted by senescent cells. In order to understand the mechanisms
associated with age-related changes resulting in impaired immunosurveillance of
senescent cells, we must first fully understand the normal processes governing
immune clearance of senescent cells.
However, evaluating the hypothesis that aged or senescent immune cells display
a reduced capacity to target senescent cells and the physiological impact of
this decline can still be assessed. If
this were indeed found to be the case, the rejuvenation of an ageing immune
system would represent an attractive approach for promoting health span.<o:p></o:p></span></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<br /></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<b style="background-color: #fefdfa; font-family: 'Times New Roman'; line-height: 19.5px;">Taken from:<a href="http://link.springer.com/article/10.1007/s11357-015-9764-2" style="text-decoration: none;" target="_blank"><span style="color: #602512;"> </span><span style="color: red;">Cellular Senescence: From Growth Arrest to Immunogenic Conversion</span></a></b></div>
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</script>Anonymoushttp://www.blogger.com/profile/05125651385504239005noreply@blogger.com0tag:blogger.com,1999:blog-8310696584811817494.post-67721008772308343132015-03-22T09:54:00.001+00:002017-06-13T18:37:56.934+01:00Apoptosis Resistance in Senescent cells<!--[if gte mso 9]><xml>
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<b style="font-family: "times new roman";">Taken from:<a href="http://link.springer.com/article/10.1007/s11357-015-9764-2" target="_blank"> <span style="color: red;">Cellular Senescence: From Growth Arrest to Immunogenic Conversion</span></a></b><br />
<b><span style="font-family: "arial" , "helvetica" , sans-serif;"><span lang="EN-US" style="line-height: 150%;"><br /></span></span></b>
<b><span style="font-family: "arial" , "helvetica" , sans-serif;"><span lang="EN-US" style="line-height: 150%;">In order to develop senotherapeutic drugs </span><span style="line-height: 20px;">(<a href="http://ageing-research.blogspot.co.il/2009/06/removal-of-senescent-cells-using.html" target="_blank">targeting cellular senescence</a>)</span></span><span style="line-height: 150%;"><span style="font-family: "arial" , "helvetica" , sans-serif;">, it is important to understand the molecular mechanisms governing the pro-survival phenotype of senescent cells.</span> </span></b><br />
<span lang="EN-US" style="font-family: "times new roman"; font-size: 10.0pt; line-height: 150%;"><br /></span>
<span lang="EN-US" style="font-family: "times new roman"; font-size: 10.0pt; line-height: 150%;">Senescent cells are frequently referred to as
‘apoptosis resistant’. This apparent resistance
to an apoptotic stimulus <i>in vitro</i> was
originally reported by Wang (1995) who observed that late passage (58
population doubling) WI38 fibroblasts were resistant to death caused by serum
withdrawal compared to WI38 cultures at less than 15 or approximately 38
population doublings. All of these human
cell populations were dramatically more resistant to death by growth factor
deprivation than Swiss 3T3 fibroblasts.
This death resistant phenotype was linked to maintenance of Bcl2 protein
levels in senescent WI38 cells.
Subsequent studies extended the resistance phenotype to treatment with
both UV light (120mJ) and staurosporin (35nM) and linked it to reduced
expression of caspase 3 (Marcotte <i>et al.</i>
2004). Subsequent work (Ryu <i>et al. </i>2007) using human dermal
fibroblasts confirmed resistance to staurosporin-induced cell death and
demonstrated significant resistance to thapsigargin (up to 700nM). The enhanced survival of senescent dermal
fibroblasts under these conditions was attributed to a failure to down regulate
Bcl2 under conditions of cellular stress.
<o:p></o:p></span></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<br /></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "times new roman"; font-size: 10.0pt; line-height: 150%;">It has been proposed that resistance to
apoptotic cell death is a feature of the senescent phenotype that may promote
their persistence <i>in vivo, </i>thereby<i> </i>favoring immune clearance over cell
death. However, key questions around this phenotypic aspect remain and may be
summarized as (i) what are the primary molecular players driving apoptosis
resistance in senescent human dermal and lung fibroblasts? (ii) is this
phenomenon a general one across tissues and between species?<o:p></o:p></span></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<br /></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "times new roman"; font-size: 10.0pt; line-height: 150%;">It is possible that the pro-survival response observed
in fibroblasts normally facilitates DNA repair, but is maintained when
persistent DNA damage activates the senescent program. For example, when low levels of DSBs are
present, ATM and ATR can result in ERK/NFkB pro-survival signaling (Khalil <i>et al</i>. 2010, Hawkins <i>et al</i>. 2011, Janssens and Tschopp, 2006)
that has been associated with the induction of senescent cells by various
triggers. Paradoxically ATM-deficient
human fibroblasts are significantly more resistant to cell death triggered by
exposure to doxorubicin or low dose ionizing radiation than wild type controls
(Park <i>et al.</i> 2012). However, the population doublings levels of
the wild type and mutant cultures were not reported. If significantly different, this has the
potential to confound studies of this type (since normal fibroblast cultures
are mixtures of senescent and proliferating cells, the proportions of which
alter as the culture is passaged).<o:p></o:p></span></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<br /></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "times new roman"; font-size: 10.0pt; line-height: 150%;">In addition to activating cell cycle arrest in
response to DNA damage, the p53/p21 pathway can also initiate a pro-survival
response. In some studies, p21 has been
shown to play a role in cell survival through its cytoplasmic localization,
rather than its nuclear localization associated with cell cycle arrest (Gartel
and Tyner, 2002, Piccolo and Crispi 2012, Kreis et al. 2014). Interestingly, p21 has been reported to be a negative
regulator of p53-mediated apoptosis (Gartel and Tyner, 2002), a known response
reported in senescent fibroblasts (Seluanov <i>et
al. </i>2001). p21 has also been
reported to promote cell survival in response to oxidative stress by
integrating the DDR with endoplasmic reticulum (ER) stress signaling (Vitiello <i>et al</i>. 2009). However, the up-regulation of p21 may also be
required for cells to enter and maintain quiescence (Perucca <i>et al</i>. 2009), suggesting a pro-survival
response may occur independent of DNA damage, but dependent upon growth
state. <o:p></o:p></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "times new roman"; font-size: 10.0pt; line-height: 150%;">Autophagy is another feature of senescent cells which
can also be initiated by DNA damage and promote cell survival (Rodriguez-Rocha <i>et al</i>. 2011, Singh <i>et al</i>. 2012). Autophagy
promotes cell survival by the degradation of damaged cellular components (Codogno
and Meijer, 2005), probably as a result of elevated ROS (Scherz-Shouval and
Elazar, 2011) in the case of cell senescence.
Interestingly, there is crosstalk between autophagy and apoptosis
pathways (Zhou <i>et al</i>. 2011, Xu <i>et al</i>. 2013, Lindqvist and Vaux, 2014),
with particular emphasis on the anti-apoptotic Bcl2 protein family. <o:p></o:p></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "times new roman"; font-size: 10.0pt; line-height: 150%;">It has long been recognized that cytokines and
their binding proteins can act to modulate cell survival (Lotem and Sachs, 1999). Given the altered secretory phenotype of some
senescent cells, it would be unsurprising if this did not contribute to altered
death dynamics, but the mechanisms by which this could occur are potentially
highly complex. For example Interleukin-6
(secreted by senescent cells) has been shown to promote cell survival in
transformed cells (Biroccio <i>et al</i>.
2013), and its secretion by cancer-associated fibroblasts protects luminal
breast cancer cells from tamoxifen treatment (Sun <i>et al.</i> 2014). Whilst inhibition
of insulin-like growth factor-1 (IGF-1) has been shown to induce apoptosis in senescent
fibroblasts (Luo <i>et al</i>. 2014), the
alteration of IGF-1 binding proteins are just as likely to influence cell
survival. For example,</span><span lang="EN-US" style="font-family: "times new roman"; font-size: 10.0pt; line-height: 150%;"> insulin-like growth factor binding protein 3
(IGFBP-3) is both transcriptionally up-regulated and secreted in elevated amounts
by senescent human fibroblasts (Hampel <i>et
al</i>. 2005). IGFBP-3 triggers enhance
apoptotic cell death in tumor cells when internalized and translocated to the
nucleus, where it targets intracellular regulators of apoptosis (Hampel <i>et al</i>. 2005). Endocytotic uptake of
IGFBP-3 in senescent human fibroblasts did not occur. This has the potential to</span><span lang="EN-US" style="font-family: "times new roman"; font-size: 10.0pt; line-height: 150%;">
render them apoptosis resistant and capable of promoting apoptosis in cells
nearby. It could be speculated that in a
microenvironment characterized by high cell turnover, both senescent and
precancerous cells could be in close proximity. Elevated local IGFBP-3
generated by senescent cells could thus act as a paracrine tumour suppression
mechanism. This idea remains untested.<o:p></o:p></span></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<br /></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "times new roman"; font-size: 10.0pt; line-height: 150%;">It seems doubtful that global apoptosis
resistance is a general feature of senescent cells. For example, early work by one of us (RGAF)
failed to show any elevation in spontaneous apoptosis rates in HUVECs cultured
to senescence (although baseline apoptosis rates as measured by TUNEL were significantly
higher than those seen in fibroblasts) (Kalashnik <i>et al.</i> 2000). Later studies (Hoffman
<i>et al.</i> 2001) demonstrated that late
passage HUVECs were more sensitive to apoptosis induced by oxidized LDL or TNF</span><span lang="EN-US" style="font-family: "lucida grande"; font-size: 8pt; line-height: 150%;">α </span><span lang="EN-US" style="font-family: "times new roman"; font-size: 10.0pt; line-height: 150%;">compared to early passage cells. Jeon and Boo (2013) have recently shown that up-regulation
of the Fas receptor at both the mRNA and protein level in senescent HUVECs
probably underlies their enhanced potential to undergo programmed cell death. Perhaps most compellingly, Hample<i> et al.</i> (2004) demonstrated in parallel
culture experiments that whilst senescent human dermal fibroblasts were more resistant
to cell death induced by exposure to ceramide than early passage cells,
senescent HUVECs were significantly more apoptosis prone.<o:p></o:p></span></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<br /></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "times new roman"; font-size: 10.0pt; line-height: 150%;">It is interesting that minimal changes in
baseline apoptosis rates could be detected in senescent HUVEC populations
despite their increased sensitivity to Fas or ceramide-induced killing. However Wang <i>et al.</i> (2004) reported an analogous phenomenon in senescent human
keratinocytes. This study demonstrated
that spontaneous apoptosis rates did not alter in cultures of senescent human
keratinocytes (duplicating an earlier report by Norsgaard <i>et al.</i> 1996). Nonetheless,
levels of Fas and related apoptotic effectors (e.g. FLICE) increased whilst Bcl2
declined significantly (as measured by ELISA).
The authors showed that antibody-mediated Fas activation or medium
exhaustion increased the apoptotic fraction from 3-5% to 30% in senescent
keratinocytes, whilst leaving apoptosis levels unchanged in early passage
cultures.<o:p></o:p></span></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<br /></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "times new roman"; font-size: 10.0pt; line-height: 150%;">Interestingly, Crescenzi <i>et al. </i>(2011) have recently shown that induction of premature
senescence in human cancer cell lines also induces Fas expression, and
concomitant susceptibility to Fas-induced apoptosis. Fibroblasts rendered senescent by serial
passage are also susceptible to Fas-mediated killing (Tepper <i>et al</i>. 2000). Thus it is possible that at senescence, human
cell types differ in their resistance to apoptosis induced by stressors, but
show a common susceptibility to Fas/TNF</span><span lang="EN-US" style="font-family: "lucida grande"; font-size: 8pt; line-height: 150%;">α</span><span lang="EN-US" style="font-family: "times new roman"; font-size: 8.0pt; line-height: 150%;">
</span><span lang="EN-US" style="font-family: "times new roman"; font-size: 10.0pt; line-height: 150%;">mediated killing.</span><span lang="EN-US" style="font-family: "times new roman"; font-size: 8.0pt; line-height: 150%;"> </span><span lang="EN-US" style="font-family: "times new roman"; font-size: 10.0pt; line-height: 150%;">If immunogenic
conversion were a key hallmark of senescence, then this would seem
plausible. It does however require
significant additional experimental study.<o:p></o:p></span></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<br /></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "times new roman"; font-size: 10.0pt; line-height: 150%;">As with the secretory response, it should not be
assumed that an “apoptosis resistant” phenotype is conserved across
species. For example Mayogora <i>et al.</i> (2004) demonstrated that cultures
of cardiac fibroblasts from Sprague-Dawley rats were more resistant to apoptosis
induced by serum withdrawal or staurosporin, than dermal fibroblast cultures initiated
from the same animals. Dermal
fibroblasts from this species apparently lacked Bcl2 protein as measured by
Western blot (although it remained readily detectable in cardiac
fibroblasts). This is a clear species
difference and suggests that researchers working in other systems should not
assume that the features observed in human cells are duplicated across the
animal kingdom.<o:p></o:p></span></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "times new roman"; font-size: 10.0pt; line-height: 150%;"><br /></span></div>
<div class="MsoNormal" style="line-height: 150%; text-align: justify; text-justify: inter-ideograph;">
<br /></div>
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<span style="font-size: large;">Abstract</span></h2>
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<div class="a-plus-plus" style="border-image-outset: initial; border-image-repeat: initial; border-image-slice: initial; border-image-source: initial; border-image-width: initial; border: 0px; color: #333333; font-family: inherit; font-size: inherit; font-stretch: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: 1.6; outline: 0px; padding: 0px; text-align: justify; vertical-align: baseline;">
Cellular senescence was first reported in human fibroblasts as a state of stable in vitro growth arrest following extended culture. Since that initial observation, a variety of other phenotypic characteristics have been shown to co-associate with irreversible cell cycle exit in senescent fibroblasts. These include (1) a pro-inflammatory secretory response, (2) the up-regulation of immune ligands, (3) altered responses to apoptotic stimuli and (4) promiscuous gene expression (stochastic activation of genes possibly as a result of chromatin remodeling). Many features associated with senescent fibroblasts appear to promote conversion to an immunogenic phenotype that facilitates self-elimination by the immune system. Pro-inflammatory cytokines can attract and activate immune cells, the presentation of membrane bound immune ligands allows for specific recognition and promiscuous gene expression may function to generate an array of tissue restricted proteins that could subsequently be processed into peptides for presentation via <a class="reference-link webtrekk-track" gaaction="reference keyword" gacategory="Internal link" galabel="MHC molecules" href="http://link.springer.com/search?dc.title=MHC+molecules&facet-content-type=ReferenceWorkEntry&sortOrder=relevance" style="border: 0px; color: #0176c3; font-family: inherit; font-size: inherit; font-stretch: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;">MHC molecules</a>. However, the phenotypes of senescent cells from different tissues and species are often assumed to be broadly similar to those seen in senescent human fibroblasts, but the data show a more complex picture in which the growth arrest mechanism, tissue of origin and species can all radically modulate this basic pattern. Furthermore, well-established triggers of cell senescence are often associated with a DNA damage response (DDR), but this may not be a universal feature of senescent cells. As such, we discuss the role of DNA damage in regulating an immunogenic response in senescent cells, in addition to discussing less established “atypical” senescent states that may occur independent of DNA damage.</div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhOEvjPBQVMoKezAiCyZLFB4nI4B7WqUQY4E3lwVuYKtTxEcb-m_KOkdZskeU8xjMCjo29HvHVlB1iWkwiTn6ETyhf8vSn67oIhkAkiAY-W9afp22Dvg_CH6OQfFiFaKyTzLPFttDR4F6mG/s1600/Burton+Faragher+Cellular+Senescence.tif" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhOEvjPBQVMoKezAiCyZLFB4nI4B7WqUQY4E3lwVuYKtTxEcb-m_KOkdZskeU8xjMCjo29HvHVlB1iWkwiTn6ETyhf8vSn67oIhkAkiAY-W9afp22Dvg_CH6OQfFiFaKyTzLPFttDR4F6mG/s1600/Burton+Faragher+Cellular+Senescence.tif" height="301" width="400" /></a></div>
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<b><span style="color: #333333;">Link: </span><a href="http://link.springer.com/article/10.1007/s11357-015-9764-2" target="_blank"><span style="color: red;">Burton and Faragher (2015) Cellular senescence: from growth arrest to immunogenic conversion. AGE. </span></a></b><b style="font-family: inherit; font-size: inherit; font-style: inherit; font-variant: inherit; line-height: 1.6;"><a href="http://link.springer.com/article/10.1007/s11357-015-9764-2" target="_blank"><span style="color: red;"><span style="line-height: 19.5px;">DOI </span><span style="line-height: 19.5px;">10.1007/s11357-015-9764-2</span></span></a></b></div>
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<span style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><span style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; font-weight: bold; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Cell Senescence: From Physiology to Pathology</span></span></div>
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<span style="color: #060605; font-family: Spinnaker, sans-serif;"><span style="font-size: 30px;"><a href="http://cellsenescence.wix.com/icsa2015">http://cellsenescence.wix.com/icsa2015</a></span></span><a href="http://cellsenescence.wix.com/icsa2015" style="color: #060605; font-family: Spinnaker, sans-serif; font-size: 30px;" target="_blank"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgyFl2FK0J0qIj86_AZXItRttIsxF2jnw1iJ-kZIBkefH8pf7ZYEAOfO9aSUeaypZ_ycwqOyrnX6e2DFI1eNNzXe25zQDtsFCA-MW6EROAw_twGBulGBe7ykadWy6BsAOtXcnKGm4UqfpvZ/s1600/ICSA+2015+poster.jpg" height="640" width="480" /></a></div>
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<span style="font-size: 16px;">It is clear that investment in fundamental biological research will help ensure that the ageing population worldwide can remain healthy, and avoid frailty and decline.</span></div>
<div class="rtejustify" style="background-color: white; margin-bottom: 0.8em; margin-top: 0.4em; text-align: justify;">
<span style="color: #444444; font-family: 'Helvetica neue', Helvetica, Arial, Verdana, sans-serif; font-size: 16px; line-height: 18px;">The British Society for Research on Ageing has announced that it will henceforth support crucial research on the biology of ageing in the UK. The Glenn Foundation has generously kick-started our funds by awarding BSRA £70,000 towards the initial aim of generating £700,000 to support research into biogerontology. If you would like to help support this research with a donation visit...</span></div>
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<span style="background-color: transparent; line-height: 18px;"><span style="color: #444444; font-family: Helvetica neue, Helvetica, Arial, Verdana, sans-serif; font-size: large;"><a href="http://bsra.org.uk/node/838">http://bsra.org.uk/node/838</a></span></span></div>
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<div class="MsoNormal" style="line-height: 200%; margin-bottom: .0001pt; margin-bottom: 0cm; margin-left: 6.0pt; margin-right: 2.95pt; margin-top: 0cm; text-align: justify;">
<span lang="EN-US" style="font-family: Garamond; font-size: 12.0pt; line-height: 200%; mso-bidi-font-family: Garamond; mso-fareast-font-family: Garamond;">In
addition to their tumor suppression function, senescent cells also play a
beneficial role in<span style="letter-spacing: 2.2pt;"> </span>non-cancer<span style="letter-spacing: 2.2pt;"> </span>pathology<span style="letter-spacing: 2.2pt;">
</span>by<span style="letter-spacing: 2.2pt;"> </span>limiting<span style="letter-spacing: 2.2pt;"> </span>tissue<span style="letter-spacing: 2.2pt;"> </span>fibrosis.
<span style="letter-spacing: 1.45pt;"> </span>For<span style="letter-spacing: 2.2pt;"> </span>instance,<span style="letter-spacing: 2.2pt;"> </span>tissue<span style="letter-spacing: 2.2pt;"> </span>damage
within the liver stimulates the activation of hepatic stellate cells (HSCs),
which hyper- proliferate<span style="letter-spacing: 1.1pt;"> </span>and<span style="letter-spacing: 1.1pt;"> </span>secrete<span style="letter-spacing: 1.1pt;">
</span>extracellular<span style="letter-spacing: 1.1pt;"> </span>matrix<span style="letter-spacing: 1.1pt;"> </span>components<span style="letter-spacing: 1.1pt;"> </span>to<span style="letter-spacing: 1.1pt;"> </span>form<span style="letter-spacing: 1.1pt;"> </span>a<span style="letter-spacing: 1.1pt;"> </span>fibrotic<span style="letter-spacing: 1.1pt;"> </span>scar. <span style="letter-spacing: 2.15pt;"> </span>Hyper- proliferation of HSCs induces
cell senescence leading to a reduction in the secretion of ECM proteins and
enhanced secretion of ECM degrading proteins, thereby limiting fibrosis. <span style="letter-spacing: .05pt;"> </span>Senescent
HSCs are then<span style="letter-spacing: .05pt;"> </span>eliminated in a timely
manner by immune cells such as natural killer (NK) cells. <span style="letter-spacing: .3pt;"> </span>When
the mechanisms leading to NK cell mediated elimination are<span style="letter-spacing: 1.1pt;"> </span>disabled,<span style="letter-spacing: 1.1pt;">
</span>fibrosis<span style="letter-spacing: 1.1pt;"> </span>is<span style="letter-spacing: 1.1pt;"> </span>increased. <span style="letter-spacing: 2.15pt;"> </span>In<span style="letter-spacing: 1.1pt;"> </span>mice<span style="letter-spacing: 1.1pt;"> </span>lacking<span style="letter-spacing: 1.1pt;">
</span>molecular<span style="letter-spacing: 1.1pt;"> </span>components<span style="letter-spacing: 1.1pt;"> </span>required for induction of cell senesce<span style="letter-spacing: .05pt;">n</span>ce, HSCs continue to proliferate,
depositing ECM components and elevating the fibrotic response. <span style="letter-spacing: .15pt;"> </span>Therefore,
induction of senescence in<span style="letter-spacing: .55pt;"> </span>HSCs<span style="letter-spacing: .55pt;"> </span>prevents<span style="letter-spacing: .55pt;">
</span>short-term<span style="letter-spacing: .55pt;"> </span>tissue<span style="letter-spacing: .55pt;"> </span>damage<span style="letter-spacing: .55pt;"> </span>by<span style="letter-spacing: .55pt;"> </span>limiting<span style="letter-spacing: .55pt;">
</span>fibrosis. <span style="letter-spacing: 1.1pt;"> </span>In<span style="letter-spacing: .55pt;"> </span>addition<span style="letter-spacing: .55pt;"> </span>to<span style="letter-spacing: .55pt;"> </span>the<span style="letter-spacing: .55pt;"> </span>liver, a<span style="letter-spacing: .05pt;">
</span>similar<span style="letter-spacing: .05pt;"> </span>process<span style="letter-spacing: .05pt;"> </span>occurs<span style="letter-spacing: .05pt;"> </span>during<span style="letter-spacing: .05pt;"> </span>tissue<span style="letter-spacing: .05pt;"> </span>repair<span style="letter-spacing: .05pt;"> </span>within<span style="letter-spacing: .05pt;"> </span>the<span style="letter-spacing: .05pt;"> </span>pancreas<span style="letter-spacing: .05pt;">
</span>by<span style="letter-spacing: .05pt;"> </span>senesce<span style="letter-spacing: .05pt;">n</span>t pancreatic stellate<span style="letter-spacing: 2.2pt;"> </span>cells. <span style="letter-spacing: 1.4pt;"> </span>In<span style="letter-spacing: 2.2pt;"> </span>this<span style="letter-spacing: 2.2pt;"> </span>instance,<span style="letter-spacing: 2.2pt;">
</span>it<span style="letter-spacing: 2.2pt;"> </span>was<span style="letter-spacing: 2.2pt;"> </span>suggested<span style="letter-spacing: 2.2pt;"> </span>that<span style="letter-spacing: 2.2pt;"> </span>lymphocytes<span style="letter-spacing: 2.2pt;"> </span>at<span style="letter-spacing: 2.2pt;"> </span>the<span style="letter-spacing: 2.2pt;"> </span>sites<span style="letter-spacing: 2.2pt;"> </span>of
wounds might play a duel-specific role in pancreatic fibrogenesis by triggering
both the initiation of wound healing by activating stellate cells and its
completion by clearance of senescent stellate cells.<o:p></o:p></span></div>
</div>
<span lang="EN-US" style="font-family: Calibri; font-size: 11.0pt; line-height: 115%; mso-ansi-language: EN-US; mso-ascii-theme-font: minor-latin; mso-bidi-font-family: "Times New Roman"; mso-bidi-language: AR-SA; mso-bidi-theme-font: minor-bidi; mso-fareast-font-family: Calibri; mso-fareast-language: EN-US; mso-fareast-theme-font: minor-latin; mso-hansi-theme-font: minor-latin;"><br clear="all" style="mso-break-type: section-break; page-break-before: always;" />
</span>
<br />
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<span lang="EN-US" style="font-family: Garamond; font-size: 12.0pt; line-height: 200%; mso-bidi-font-family: Garamond; mso-fareast-font-family: Garamond;">Cell
senescence also limits tissue damage at sites of cutaneous wound healing, where
secretion<span style="letter-spacing: 2.35pt;"> </span>of<span style="letter-spacing: 2.35pt;"> </span>CCN1<span style="letter-spacing: 2.35pt;"> </span>induces<span style="letter-spacing: 2.35pt;"> </span>fibroblast<span style="letter-spacing: 2.35pt;"> </span>senescence<span style="letter-spacing: 2.35pt;"> </span>associated<span style="letter-spacing: 2.35pt;"> </span>with<span style="letter-spacing: 2.35pt;"> </span>an<span style="letter-spacing: 2.35pt;"> </span>elevation<span style="letter-spacing: 2.35pt;"> </span>in<span style="letter-spacing: 2.35pt;"> </span>the DNA damage
response and the activation of p53 and RAC1-NOX1 complex. <span style="letter-spacing: .6pt;"> </span>The
expression of anti-fibrotic genes by CCN1-induced senescent cells prevented
excess fibrosis, whereas mice that express a senesce<span style="letter-spacing: .05pt;">n</span>ce-defective Ccn1 mutant resulted in elevated<span style="letter-spacing: .2pt;"> </span>fibrosis.
CCN1<span style="letter-spacing: .2pt;"> </span>also<span style="letter-spacing: .2pt;"> </span>appears<span style="letter-spacing: .2pt;"> </span>to<span style="letter-spacing: .2pt;"> </span>play<span style="letter-spacing: .2pt;"> </span>a<span style="letter-spacing: .2pt;"> </span>role<span style="letter-spacing: .2pt;"> </span>in<span style="letter-spacing: .2pt;"> </span>the<span style="letter-spacing: .2pt;"> </span>regression<span style="letter-spacing: .2pt;"> </span>of<span style="letter-spacing: .2pt;"> </span>liver<span style="letter-spacing: .2pt;"> </span>fibrosis through induction of cell
senescence in HSCs. <span style="letter-spacing: 2.65pt;"> </span>Therefore, cell senescence is a
mechanism<span style="letter-spacing: 1.25pt;"> </span>that<span style="letter-spacing: 1.25pt;"> </span>limits<span style="letter-spacing: 1.25pt;">
</span>tissue<span style="letter-spacing: 1.25pt;"> </span>damage<span style="letter-spacing: 1.25pt;"> </span>in<span style="letter-spacing: 1.25pt;"> </span>multiple<span style="letter-spacing: 1.25pt;"> </span>tissues<span style="letter-spacing: 1.25pt;">
</span>and<span style="letter-spacing: 1.25pt;"> </span>serves<span style="letter-spacing: 1.25pt;"> </span>not<span style="letter-spacing: 1.25pt;"> </span>only<span style="letter-spacing: 1.25pt;"> </span>to<span style="letter-spacing: 1.25pt;"> </span>restrain
the damage, but also to initiate the repair and return the tissue to the
pre-damaged state.<o:p></o:p></span></div>
<div class="MsoNormal" style="line-height: 200%; margin-bottom: .0001pt; margin-bottom: 0cm; margin-left: 6.0pt; margin-right: 2.95pt; margin-top: 3.95pt; text-align: justify;">
<b style="background-color: #fefdfa; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: 13px; line-height: 18.2000007629395px;"><span style="font-family: Arial, Helvetica, sans-serif;"><span style="line-height: 26px;">Link: </span><a href="http://link.springer.com/article/10.1007%2Fs00018-014-1691-3" style="color: #cd5128;" target="_blank"><span style="line-height: 32px;">Dominick G. A. Burton, Valery Krizhanovsky. </span><span style="line-height: 25.8700008392334px;">Physiological and pathological consequences of cellular senescence. CMLS (2014)</span></a> </span></b></div>
<div class="MsoNormal" style="line-height: 200%; margin-bottom: .0001pt; margin-bottom: 0cm; margin-left: 6.0pt; margin-right: 2.95pt; margin-top: 3.95pt; text-align: justify;">
<span lang="EN-US" style="font-family: Garamond; font-size: 12.0pt; line-height: 200%; mso-bidi-font-family: Garamond; mso-fareast-font-family: Garamond;"><br /></span></div>
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</script>Anonymoushttp://www.blogger.com/profile/05125651385504239005noreply@blogger.com0tag:blogger.com,1999:blog-8310696584811817494.post-81856575232503448392014-11-02T15:06:00.000+00:002014-11-02T15:06:36.423+00:00Physiological impact of cell senescence in vivo: Tumour suppression
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<span lang="EN-US" style="font-family: Garamond; font-size: 12.0pt; line-height: 199%; mso-bidi-font-family: Garamond; mso-fareast-font-family: Garamond;">While<span style="letter-spacing: 1.6pt;"> </span>the<span style="letter-spacing: 1.6pt;"> </span>history<span style="letter-spacing: 1.6pt;"> </span>of<span style="letter-spacing: 1.6pt;"> </span>research<span style="letter-spacing: 1.6pt;"> </span>on<span style="letter-spacing: 1.6pt;"> </span>cell<span style="letter-spacing: 1.6pt;"> </span>senescence<span style="letter-spacing: 1.6pt;"> </span>counts<span style="letter-spacing: 1.6pt;"> </span>for<span style="letter-spacing: 1.6pt;"> </span>more<span style="letter-spacing: 1.6pt;"> </span>than<span style="letter-spacing: 1.6pt;"> </span>half<span style="letter-spacing: 1.6pt;"> </span>a<span style="letter-spacing: 1.6pt;"> </span>century, only in the last 10 years the
functional relevance of cell senesce<span style="letter-spacing: .05pt;">n</span>ce
<i>in<span style="letter-spacing: .5pt;"> </span>vivo
</i>was established. The irreversible cell cycle arrest in OIS cells makes it
an ideal mechanism to prevent tumour<span style="letter-spacing: .05pt;"> </span>formation<span style="letter-spacing: .05pt;"> </span>following<span style="letter-spacing: .05pt;">
</span>oncogene<span style="letter-spacing: .05pt;"> </span>activation,<span style="letter-spacing: .05pt;"> </span>and<span style="letter-spacing: .05pt;"> </span>in<span style="letter-spacing: .05pt;"> </span>the<span style="letter-spacing: .05pt;"> </span>first<span style="letter-spacing: .05pt;"> </span>functional<span style="letter-spacing: .05pt;"> </span><i>in<span style="letter-spacing: .55pt;"> </span>vivo </i>studies, cell senescence was established as a tumour
suppressor mechanism. <span style="letter-spacing: .3pt;"> </span>OIS has<span style="letter-spacing: .75pt;"> </span>been<span style="letter-spacing: .75pt;"> </span>shown<span style="letter-spacing: .75pt;"> </span>to<span style="letter-spacing: .75pt;"> </span>be<span style="letter-spacing: .75pt;"> </span>important<span style="letter-spacing: .75pt;">
</span>for<span style="letter-spacing: .75pt;"> </span>preventing<span style="letter-spacing: .75pt;"> </span>lymphoma<span style="letter-spacing: .75pt;">
</span>development<span style="letter-spacing: .7pt;"> </span>and<span style="letter-spacing: .75pt;"> </span>contribute to<span style="letter-spacing: .85pt;"> </span>response<span style="letter-spacing: .85pt;"> </span>to<span style="letter-spacing: .85pt;"> </span>therapy.
Using<span style="letter-spacing: .85pt;"> </span>transgenic<span style="letter-spacing: .85pt;"> </span>mice<span style="letter-spacing: .85pt;"> </span>models<span style="letter-spacing: .85pt;"> </span>to<span style="letter-spacing: .85pt;"> </span>bypass<span style="letter-spacing: .85pt;"> </span>the<span style="letter-spacing: .85pt;"> </span>senescence
response to oncogenic N-Ras resulted in the development of invasive T-cell
lymphomas, whereas control mice only develop non-lymphoid neoplasia at a much
later time point. <span style="letter-spacing: .2pt;"> </span>Another<span style="letter-spacing: 2.05pt;"> </span>mouse<span style="letter-spacing: 2.05pt;">
</span>model<span style="letter-spacing: 2.05pt;"> </span>using<span style="letter-spacing: 2.05pt;"> </span>inducible<span style="letter-spacing: 2.05pt;"> </span>K-ras<span style="letter-spacing: 2.05pt;"> </span>was<span style="letter-spacing: 2.05pt;"> </span>used<span style="letter-spacing: 2.05pt;"> </span>to<span style="letter-spacing: 2.05pt;"> </span>make<span style="letter-spacing: 2.05pt;"> </span>pre-malignant
lesions that can develop into malignant tumours in lung and pancreas. <span style="letter-spacing: 1.9pt;"> </span>In
these models, biomarkers of
cell senescence were
predominantly identified in
the pre- malignant<span style="letter-spacing: 1.25pt;"> </span>lesions<span style="letter-spacing: 1.25pt;">
</span>but<span style="letter-spacing: 1.25pt;"> </span>were<span style="letter-spacing: 1.25pt;"> </span>lost<span style="letter-spacing: 1.25pt;"> </span>once<span style="letter-spacing: 1.25pt;"> </span>tumours<span style="letter-spacing: 1.25pt;">
</span>developed. <span style="letter-spacing: 2.45pt;"> </span>To<span style="letter-spacing: 1.25pt;"> </span>investigate<span style="letter-spacing: 1.25pt;"> </span>OIS<span style="letter-spacing: 1.25pt;"> </span><i>in<span style="letter-spacing: 1.75pt;"> </span>vivo</i>,<span style="letter-spacing: 1.25pt;"> </span>a number of studies have focused on human
nevi (moles), which are benign tumours of melanocytes that frequently harbor
oncogenic mutations of BRAF. <span style="letter-spacing: .65pt;"> </span>The congenital nevi stained<span style="letter-spacing: 1.4pt;"> </span>positive<span style="letter-spacing: 1.4pt;">
</span>for<span style="letter-spacing: 1.4pt;"> </span>markers<span style="letter-spacing: 1.4pt;"> </span>of<span style="letter-spacing: 1.4pt;"> </span>OIS,<span style="letter-spacing: 1.4pt;"> </span>but<span style="letter-spacing: 1.45pt;"> </span>not<span style="letter-spacing: 1.4pt;"> </span>DNA<span style="letter-spacing: 1.4pt;"> </span>damage<span style="letter-spacing: 1.4pt;"> </span>in<span style="letter-spacing: 1.4pt;"> </span>this<span style="letter-spacing: 1.4pt;"> </span>instance. <span style="letter-spacing: 2.85pt;"> </span>Braf</span><span lang="EN-US" style="font-family: Garamond; font-size: 7.0pt; letter-spacing: .05pt; line-height: 199%; mso-bidi-font-family: Garamond; mso-fareast-font-family: Garamond; mso-text-raise: 5.0pt; position: relative; top: -5.0pt;">E</span><span lang="EN-US" style="font-family: Garamond; font-size: 7.0pt; line-height: 199%; mso-bidi-font-family: Garamond; mso-fareast-font-family: Garamond; mso-text-raise: 5.0pt; position: relative; top: -5.0pt;">600<span style="letter-spacing: .05pt;">V</span></span><span lang="EN-US" style="font-family: Garamond; font-size: 12.0pt; line-height: 199%; mso-bidi-font-family: Garamond; mso-fareast-font-family: Garamond;">, which is present in the nevi, induced
p16(INK4a) expression in growth-arrested melanocytes both <i>in<span style="letter-spacing: .5pt;"> </span>vitro </i>and <i>in<span style="letter-spacing: .5pt;"> </span>situ</i>. <span style="letter-spacing: 1.95pt;"> </span>In contrast, another study in
premalignant melanocytic<span style="letter-spacing: .1pt;"> </span>lesions<span style="letter-spacing: .1pt;"> </span>did<span style="letter-spacing: .1pt;"> </span>show<span style="letter-spacing: .1pt;"> </span>the<span style="letter-spacing: .1pt;"> </span>presence<span style="letter-spacing: .1pt;"> </span>of DNA<span style="letter-spacing: .1pt;"> </span>damage<span style="letter-spacing: .1pt;"> </span>foci,<span style="letter-spacing: .1pt;"> </span>primarily<span style="letter-spacing: .1pt;"> </span>located<span style="letter-spacing: .1pt;"> </span>at
telomeric<span style="letter-spacing: 1.35pt;"> </span>regions<span style="letter-spacing: 1.35pt;"> </span>as<span style="letter-spacing: 1.35pt;"> </span>well<span style="letter-spacing: 1.35pt;"> </span>as<span style="letter-spacing: 1.35pt;"> </span>the<span style="letter-spacing: 1.35pt;"> </span>p16(INK4a)<span style="letter-spacing: 1.35pt;"> </span>expression. <span style="letter-spacing: 2.75pt;"> </span>In<span style="letter-spacing: 1.35pt;"> </span>addition<span style="letter-spacing: 1.35pt;">
</span>to<span style="letter-spacing: 1.35pt;"> </span>activating </span><span style="font-family: Garamond; font-size: 12pt; line-height: 200%;">mutations
in oncogenes, cell senescence can be induced as a result of loss of tumor
suppressor Pten in the prostate</span><span style="font-family: Garamond; font-size: 12pt; line-height: 200%;">.
Therefore, these combined studies clearly demonstrate that cell senesce</span><span style="font-family: Garamond; font-size: 12pt; letter-spacing: 0.05pt; line-height: 200%;">n</span><span style="font-family: Garamond; font-size: 12pt; line-height: 200%;">ce acts as a</span><span style="font-family: Garamond; font-size: 12pt; letter-spacing: 0.05pt; line-height: 200%;"> </span><span style="font-family: Garamond; font-size: 12pt; line-height: 200%;">potent tumor suppressor mechanism that prevents the development
of multiple malignancies.</span></div>
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<span style="font-family: Garamond; font-size: 12pt; line-height: 200%;"><br /></span></div>
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<b><span style="font-family: Arial, Helvetica, sans-serif;"><span style="line-height: 200%;">Link: </span><a href="http://link.springer.com/article/10.1007%2Fs00018-014-1691-3" target="_blank"><span style="line-height: 32px;">Dominick G. A. Burton, Valery Krizhanovsky. </span><span style="line-height: 199%;">Physiological and pathological consequences of cellular senescence. CMLS (2014)</span></a> </span></b></div>
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<span lang="EN-US" style="font-family: Garamond; font-size: 12.0pt; line-height: 199%; mso-bidi-font-family: Garamond; mso-fareast-font-family: Garamond;">When
cells become senescent <i>in<span style="letter-spacing: .5pt;"> </span>vitro </i>they<span style="letter-spacing: .05pt;"> </span>often become resistant to apoptotic stimuli in comparison<span style="letter-spacing: .85pt;"> </span>to<span style="letter-spacing: .85pt;"> </span>proliferating<span style="letter-spacing: .85pt;"> </span>cells.
<span style="letter-spacing: 1.65pt;"> </span>It<span style="letter-spacing: .85pt;"> </span>can<span style="letter-spacing: .85pt;"> </span>be<span style="letter-spacing: .85pt;"> </span>speculated<span style="letter-spacing: .85pt;"> </span>that<span style="letter-spacing: .85pt;"> </span>if<span style="letter-spacing: .85pt;"> </span>immune<span style="letter-spacing: .85pt;"> </span>cells<span style="letter-spacing: .85pt;"> </span>are necessary for eliminating senescent
cells, the pro-survival phenotype of senescent cells may function to favor such
elimination. In conjunction with regulating immune ligands and the secretory
phenotype, persistent activation of the DDR, particularly double strand breaks
(DSBs), may also promote a pro-survival response to facilitate DNA repair. However, if senescent cells are not removed by the immune system, this
pro-survival phenotype inadvertently promotes their persistence in tissues. <span style="letter-spacing: 2.05pt;"> </span>Alternatively,
the pro- survival phenotype of senescent cells may be an adaptive response
mediated by stresses within the microenvironment to facilitate protection from
further stress.<o:p></o:p></span></div>
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<br /></div>
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<span lang="EN-US" style="font-family: Garamond; font-size: 12.0pt; line-height: 200%; mso-bidi-font-family: Garamond; mso-fareast-font-family: Garamond;">The
question still arises as to why senescent cells may favor removal by the immune
system rather than undergoing programmed cell death. <span style="letter-spacing: .5pt;"> </span>One plausible explanation
could be<span style="letter-spacing: 2.05pt;"> </span>related<span style="letter-spacing: 2.05pt;"> </span>to<span style="letter-spacing: 2.05pt;"> </span>the<span style="letter-spacing: 2.05pt;"> </span>potential<span style="letter-spacing: 2.05pt;"> </span>function<span style="letter-spacing: 2.05pt;"> </span>of<span style="letter-spacing: 2.05pt;"> </span>senescent<span style="letter-spacing: 2.05pt;"> </span>cells<span style="letter-spacing: 2.05pt;"> </span>during<span style="letter-spacing: 2.05pt;"> </span>cellular<span style="letter-spacing: 2.05pt;">
</span>repair<span style="letter-spacing: 2.05pt;"> </span>following tissue
damage. <span style="letter-spacing: .55pt;"> </span>During wound healing, senescent cells
most likely play a positive role by (1) secreting chemo-attractants that
recruit and activate immune cells to the site of injury,<span style="letter-spacing: .05pt;"> (2) </span>secrete<span style="letter-spacing: .05pt;">
</span>growth factors to stimulate cellular proliferation required for cellular
replacement and protein synthesis and (3) the secretion of proteases to debride
damaged tissue. <span style="letter-spacing: 2.8pt;"> </span>In<span style="letter-spacing: 1.4pt;"> </span>addition,<span style="letter-spacing: 1.4pt;"> </span>senescent<span style="letter-spacing: 1.4pt;">
</span>cells<span style="letter-spacing: 1.4pt;"> </span>may<span style="letter-spacing: 1.4pt;"> </span>help<span style="letter-spacing: 1.4pt;"> </span>to<span style="letter-spacing: 1.4pt;"> </span>preserve<span style="letter-spacing: 1.4pt;">
</span>tissue<span style="letter-spacing: 1.4pt;"> </span>integrity<span style="letter-spacing: 1.4pt;"> </span>during<span style="letter-spacing: 1.4pt;"> </span>wound
healing, that may otherwise be lost if cells underwent apoptosis, until such
time that non- resident cells from other sources, such as stem cells are
present to repopulate the tissue with functional cells. <span style="letter-spacing: .2pt;"> </span>In an orchestrated
response, senescent cells would be subsequently eliminated by the immune system
when no longer required.<o:p></o:p></span></div>
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<b><span lang="EN-US" style="font-family: Garamond; font-size: 12.0pt; mso-bidi-font-family: Garamond; mso-fareast-font-family: Garamond;">Link: <a href="http://link.springer.com/article/10.1007%2Fs00018-014-1691-3" target="_blank">Physiological and Pathological Consequences of Cellular Senescence</a></span></b><span lang="EN-US" style="font-family: Garamond; font-size: 12.0pt; mso-bidi-font-family: Garamond; mso-fareast-font-family: Garamond;"><o:p></o:p></span></div>
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</script>Anonymoushttp://www.blogger.com/profile/05125651385504239005noreply@blogger.com0tag:blogger.com,1999:blog-8310696584811817494.post-11326544153210916052014-08-09T15:25:00.000+01:002014-08-09T15:25:34.224+01:00 Promiscuous Gene Expression in Senescent Cells<div style="text-align: justify;">
The main molecular pathways of senescence, persistent DDR and Rb lead to sustained chromatin remodeling within senescent cells. This stochastic remodeling of chromatin in senescent cells most likely facilitates promiscuous gene expression associated with cell senescence. Promiscuous gene expression refers to changes in gene expression not normally associated with non- senescent counterparts of the same cell type. Promiscuous gene expression is often observed in microarray data and other analysis of gene expression of senescent verses their non- senescent counterparts and appears to also be cell-type specific. It is hypothesised that chromatin rearrangement would allow access to DNA normally tightly packed and restrict other areas of chromatin that are normally open. It has also been suggested that DNA damage may modulate gene expression by altering the binding capacity of transcription factors. In addition, changes in DNA methylation associated with cell senescence may also contribute to promiscuous gene expression. Therefore, genes that may normally be expressed can be suppressed and genes normally suppressed become expressed.</div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
<b>Cellular Dysfunction</b></div>
<div style="text-align: justify;">
<b><br /></b></div>
<div style="text-align: justify;">
A negative consequence of promiscuous gene expression in senescent cells is impairment in cellular function, the inability of cells to carry out their designated normal processes. As a result, the accumulation of these dysfunctional cells most likely leads to tissue dysfunction which compromises tissue structure and function, promoting disease. For example, a study using Klotho-deficient mice, which exhibit an accelerated ageing-like phenotype, investigated whether preventing cell senescence improves health-span in these mice. Plasminogen activator inhibitor-1 (PAI-1) is elevated in Klotho- deficient mice and is a known regulator of cell senescence. Klotho-deficient mice deficient in PAI-1 was reported to delay the induction of cell senescence, extending median lifespan and preserving organ structure and function. Another example of senescent cells that can no longer undertake their normal function might include senescent pancreatic beta cells that have impaired insulin release during diabetes and senescent vascular endothelial cells that display decreased activity of nitric oxide synthase (NOS). NOS is important for the production of nitric oxide (NO) required for maintaining vascular homeostasis and a decrease in NO production is associated with increased risk of cardiovascular disease. Therefore, a better understanding of the differences in the phenotype of senescent cells of different cell-types in relation to their in vivo function, is required to better understand mechanisms of disease development.</div>
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<br /></div>
<div style="text-align: justify;">
<br /></div>
<div style="text-align: justify;">
Links:</div>
<br /><a href="http://www.pnas.org/content/111/19/7090.long" target="_blank">PAI-1–regulated extracellular proteolysis governs senescence and survival in Klotho mice</a><div>
<br /></div>
<div>
<a href="http://physiological%20and%20pathological%20consequences%20of%20cellular%20senescence/" target="_blank">Physiological and pathological consequences of cellular senescence</a><!--EndFragment--><script src="http://www.google-analytics.com/urchin.js" type="text/javascript">
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Anonymoushttp://www.blogger.com/profile/05125651385504239005noreply@blogger.com0tag:blogger.com,1999:blog-8310696584811817494.post-84545732667557784112014-08-09T14:46:00.003+01:002014-08-09T14:46:21.582+01:00Cellular Senescence in Placental Development.<div style="text-align: justify;">
In addition to providing a protective role in tumour suppression and tissue damage, senescent cells may also function in embryonic development. It was suggested that cell- cell fusion induced senescence might play a physiological function in the placenta, thereby aiding embryonic development. ERVWE1, a fusion protein involved in the formation of the syncytiotrophoblast of the placenta causes cell fusion and induction of cell senescence in both cancer cells and normal fibroblasts. Fusion induced senescence (FIS) in vitro and in vivo is accompanied by activation of a DDR, p53 and p16(INK4a) dependent pathways. ERVWE1 mediated physiological cell fusion during embryonic development forms the syncytiotrophoblast that serves as the maternal/fetal interface at the placenta. The question of why the senescence program may be useful in normal placental function remains to be answered. However, it can be suggested that the resistance of senescent cells to apoptosis is necessary to maintain the viability of the syncytiotrophoblast. In addition, secretion of proteases, that are normally associated with senescent cells, may function to maintain feto-placental homeostasis. Placental proteases are required for the metabolism of vasoactive and immunomodulating peptides, thereby controlling the exchange of peptide hormones across the placenta and metabolic breakdown of maternal nutrients. Cytokine production is another feature of senescent cells that may play important roles within the placenta. IL-8, one of the main cytokines secreted by senescent cells, is necessary for normal placental function . Cytokine secretion may help regulate placental growth during pregnancy in addition to protecting the foetus from pathological organisms and facilitating interaction with immune cells. Further research is necessary in order to understand the functional significance of the senescence program in the placenta.</div>
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<a href="http://genesdev.cshlp.org/content/27/21/2356.long" target="_blank">Cell fusion induced by ERVWE1 or measles virus causes cellular senescence</a><div>
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<a href="http://link.springer.com/article/10.1007%2Fs00018-014-1691-3" target="_blank">Physiological and pathological consequences of cellular senescence</a><!--EndFragment--><script src="http://www.google-analytics.com/urchin.js" type="text/javascript">
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Anonymoushttp://www.blogger.com/profile/05125651385504239005noreply@blogger.com0tag:blogger.com,1999:blog-8310696584811817494.post-58424431447659363892014-08-09T14:22:00.000+01:002015-02-19T09:34:11.285+00:00Therapeutic Elimination of Senescent cells<div style="text-align: justify;">
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The persistence and accumulation of senescent cells has been shown to potentially play a role in the pathophysiology of ageing and age-related disease. Therefore, the elimination of senescent cells from tissues has the potential to increase health-span and possibly even lifespan. For example, it was recently demonstrated that the elimination of p16- expressing cells in a transgenic mouse model delays age-associated disorders. As such, there are a number of therapeutic avenues of research that have the potential to eliminate senescent cells or prevent their accumulation. Firstly, telomerase activators could be used to extend telomere length, thereby extending the replicative capacity of cells and preventing RS. Secondly, cellular reprogramming refers to the potential of reverting senescent cells back to their normal functioning state. Alternatively, if quiescent cells inflicted with DNA damage convert to senescence when stimulated to proliferate, then eliminating such damage may prevent this conversion. Thirdly, if senescent cells indeed accumulate due to failure of removal by an ageing immune system, then enhancing the immune response to senescent cells may improve their elimination. Finally, identification of pharmacological compounds that can specifically induce programmed cell death in senescent cells will provide an effective means for targeting senescent cells regardless the reason of their presence. However, the potential use of future pharmacological compounds should be taken with caution, since senescent cells also play a beneficial role during wound healing. Prematurely eliminating senescent cells during tissue damage may impair the wound response. In fact, it can be speculated that a tradeoff may exist between senescent cell removal and wound healing, whereby enhanced senescent cell removal (and possibly slower ageing) results in a slower healing process (and increase risk of infectious disease). Future research will show if pharmacological elimination of senescent cells is a good avenue for treatment of age-related disorders and health-span extension.</div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiaiarAqhY9Ac4vy_DunvPFRJMgsSfySZSwrqi6-RroA1xLdSEkA3yg-ESNZTHp_kQLiBZn1yImpMFk0204pk08pYjYgo3k42SJkyaK4pBKK83-SX2rbLIQP7yeH0J0l8MKlkS9yhhusJN5/s1600/_therapy_eliminating_senescence.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiaiarAqhY9Ac4vy_DunvPFRJMgsSfySZSwrqi6-RroA1xLdSEkA3yg-ESNZTHp_kQLiBZn1yImpMFk0204pk08pYjYgo3k42SJkyaK4pBKK83-SX2rbLIQP7yeH0J0l8MKlkS9yhhusJN5/s1600/_therapy_eliminating_senescence.png" height="380" width="400" /></a></div>
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Link: <a href="http://link.springer.com/article/10.1007%2Fs00018-014-1691-3" target="_blank">Physiological and pathological consequences of cellular senescence</a><script src="http://www.google-analytics.com/urchin.js" type="text/javascript">
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</script>Anonymoushttp://www.blogger.com/profile/05125651385504239005noreply@blogger.com0tag:blogger.com,1999:blog-8310696584811817494.post-42416096281053489582014-08-07T20:20:00.001+01:002014-08-07T20:20:23.423+01:00Quiescent to Senescent Conversion<div style="text-align: justify;">
The presence of DNA damage and subsequent up-regulation of p16(INK4a) in quiescent cells in vivo may induce a pre-senescent state that converts to a full senescent state when cells are stimulated to proliferate. This suggests that DNA replication is required to induce a persistent DDR associated with cell senescence. For example, damage to skeletal muscle in normal young mice causes the activation of quiescent satellite cells (adult stem cells), which proliferate and undergo myogenic differentiation required for muscle repair. However, a recent study has shown that in geriatric mice (28-32 months of age), satellite cell activation is impaired and satellite cells instead convert from a pre-senescent state (quiescent cells with high p16(INK4a) expression) to a full senescent state (including a DDR) when stimulated to proliferate in response to injury. As such, the induction of senescent satellite cells with age can impair satellite muscle regeneration. This study suggests that senescent cells may accumulate in late life due to a conversion from quiescence to senescence (termed geroconversion) in response to a requirement for cells to replicate over time to regenerate tissue. In this model, more and more quiescent cells are likely to accumulate DNA damage over the life-time of an organism and are therefore more likely to become senescent when induced to proliferate later in life. Therefore, if quiescent cells inflicted with DNA damage convert to senescence when stimulated to proliferate, then eliminating such damage may prevent this conversion.</div>
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<a href="http://www.nature.com/nature/journal/v506/n7488/full/nature13013.html">Geriatric muscle stem cells switch reversible quiescence into senescence</a><script src="http://www.google-analytics.com/urchin.js" type="text/javascript">
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<a href="http://link.springer.com/article/10.1007%2Fs00018-014-1691-3">Physiological and pathological consequences of cellular senescence</a></div>
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