Although the induction of senescence in cancer cells is a potent mechanism of tumor suppression, senescent cells remain metabolically active and may secrete a broad spectrum of factors that promote tumorigenicity in neighboring malignant cells. Here we show that androgen deprivation therapy (ADT), a widely used treatment for advanced prostate cancer, induces a senescence-associated secretory phenotype in prostate cancer epithelial cells, indicated by increases in senescence-associated beta-galactosidase activity, heterochromatin protein 1 beta foci, and expression of cathepsin B and insulin-like growth factor binding protein 3. Interestingly, ADT also induced high levels of vimentin expression in prostate cancer cell lines in vitro and in human prostate tumors in vivo. The induction of the senescence-associated secretory phenotype by androgen depletion was mediated, at least in part, by down-regulation of S-phase kinase-associated protein 2, whereas the neuroendocrine differentiation of prostate ...

TY - JOUR. T1 - Restoration of senescent human diploid fibroblasts by modulation of the extracellular matrix. AU - Choi, Hae Ri. AU - Cho, Kyung A.. AU - Kang, Hyun Tae. AU - Lee, Jung Bin. AU - Kaeberlein, Matt. AU - Suh, Yousin. AU - Chung, In Kwon. AU - Park, Sang Chul. PY - 2011/2. Y1 - 2011/2. N2 - Human diploid fibroblasts have the capacity to complete a finite number of cell divisions before entering a state of replicative senescence characterized by growth arrest, changes in morphology, and altered gene expression. Herein, we report that interaction with extracellular matrix (ECM) from young cells is sufficient to restore aged, senescent cells to an apparently youthful state. The identity of the restored cells as having been derived from senescent cells has been confirmed by a variety of methods, including time lapse live cell imaging and DNA finger print analysis. In addition to cell morphology, phenotypic restoration was assessed by resumption of proliferative potential, growth factor ...

Premature senescence of human diploid fibroblasts (HDFs) can be induced by exposures to a variety of oxidative stress and DNA damaging agents. In this study we developed a robust model of UVB-induced premature senescence of skin HDFs. After a series of 10 subcytotoxic (non-proapoptotic) exposures to UVB at 250 mJ/cm2, the so-called biomarkers of senescence were markedly expressed: growth arrest, senescence-associated β-galactosidase activity, senescence-associated gene overexpression, deletion in mitochondrial DNA. A set of 44 stress- and senescence-associated genes were found to be differentially expressed in this model, among which clusterin/apolipoprotein J (apo J) and transforming growth factor-β1 (TGF-β1). Transfection of apo J cDNA provided protection against premature senescence-inducing doses of UVB and other stressful agents. Neutralizing antibodies against TGF-β1 or its receptor II (TβRII) sharply attenuated the senescence-associated features, suggesting a role for TGF-β1 in ...

TY - JOUR. T1 - Suppression of Nucleotide Metabolism Underlies the Establishment and Maintenance of Oncogene-Induced Senescence. AU - Aird, Katherine M.. AU - Zhang, Gao. AU - Li, Hua. AU - Tu, Zhigang. AU - Bitler, Benjamin G.. AU - Garipov, Azat. AU - Wu, Hong. AU - Wei, Zhi. AU - Wagner, Stephan N.. AU - Herlyn, Meenhard. AU - Zhang, Rugang. PY - 2013/4/25. Y1 - 2013/4/25. N2 - Oncogene-induced senescence is characterized by a stable cell growth arrest, thus providing a tumor suppression mechanism. However, the underlying mechanisms for this phenomenon remain unknown. Here, we show that a decrease in deoxyribonucleotide triphosphate (dNTP) levels underlies oncogene-induced stable senescence-associated cell growth arrest. The decrease in dNTP levels is caused by oncogene-induced repression of ribonucleotide reductase subunit M2 (RRM2), a rate-limiting protein in dNTP synthesis. This precedes the senescence-associated cell-cycle exit and coincides with the DNA damage response. Consistently, ...

Curcuminoids are well known for their capabilities to combat risk factors that are associated with ageing and cellular senescence. Recent reports have demonstrated that curcuminoids can extend the lifespan of model organisms. However, the underlying mechanisms by which these polyphenic compounds exert these beneficial effects remain unknown. In this study, t-BHP-induced premature senescence model in human fibroblasts was chosen to explore the protective effects of a curcuminoid, bisdemethoxycurcumin (BDMC), on cellular senescence. The results demonstrated that BDMC attenuated oxidative stress-induced senescence-like features which include the induction of an enlarged cellular appearance, higher frequency of senescence-associated beta-galactosidase staining activity, appearance of senescence-associated heterochromatic foci in nuclei, decrease in proliferation capability, and alteration inrelated molecules such as p16 and retinoblastoma protein. Notably, we found that BDMC treatment activated ...

Adult skin stem cells are recognized as potential therapeutics to rejuvenate aged skin. We previously demonstrated that human dermal stem/progenitor cells (hDSPCs) with multipotent capacity could be enriched from human dermal fibroblasts using collagen type IV. However, the effects of hDSPCs on cellular senescence remain to be elucidated. In the present study, we investigated whether conditioned medium (CM) collected from hDSPC cultures (hDSPC-CM) exhibits beneficial effects on senescent fibroblasts. We found that hDSPC-CM promoted proliferation and decreased the expression level of senescence-associated β-galactosidase in senescent fibroblasts. In addition, p53 phosphorylation and p21 expression were significantly reduced in senescent fibroblasts treated with hDSPC-CM. hDSPC-CM restored the expression levels of collagen type I, collagen type III, and tissue inhibitor of metalloproteinase, and antagonized the increase of matrix metalloproteinase 1 expression. Finally, we demonstrated that hDSPC-CM

The Wnt signaling pathway has key roles in development and generally promotes proliferation of stem cells and inhibits apoptosis. These effects are essentially opposite to the changes that occur in senescent stem cells. Thus, Ye et al. examined whether reduced Wnt signaling might have a role inhibitory in senescence. They monitored the formation of specialized domains of heterochromatin known as senescence-associated heterochromatin foci or SAHF, which are thought to repress transcription of genes that promote proliferation. In human WI38 fibroblasts, expression of Wnt2 mRNA was decreased as cells approached senescence. Formation of SAHF was inhibited when pharmacological inhibitors were used to decrease activity of glycogen synthase kinase 3β (a kinase activated downstream of Wnt). Furthermore, small hybrid RNAs were used to decrease expression of Wnt2 in young fibroblasts, and this promoted formation of SAHF, the authors marker of senescence. Accordingly, exposure of cells to a Wnt ligand ...

Cellular senescence (deterioration) is a critical factor of biological aging that occurs in almost all peripheral tissues but little is known about its role in age-related neurodegenerative disorders, such as Parkinsons disease (PD). Senescence occurs in dividing cell types and halts cell proliferation (growth) in an irreversible manner. This process is caused by stress and puts cells at risk for tumor formation. Once established, these cells express a senescence-associated secretory phenotype (SASP), the pro-inflammatory secretion of cytokines and other factors that contribute to the age-related loss of peripheral tissue function. We aim to interrogate induction of senescence and SASP in response to alpha-synuclein (protein clumps) within the most prevalent dividing cell type in the brain, the astrocyte (cells that provide support and clean waste in the brain), and how this in turn affects dopaminergic cell health in relation to PD.. Hypothesis ...

OBJECTIVE: Human diploid fibroblasts undergo a limited number of cellular divisions in culture and progressively reach a state of irreversible growth arrest, a process termed cellular aging. The beneficial effects of vitamin E in aging have been established, but studies to determine the mechanisms of these effects are ongoing. This study determined the molecular mechanism of γ-tocotrienol, a vitamin E homolog, in the prevention of cellular aging in human diploid fibroblasts using the expression of senescence-associated genes. METHODS: Primary cultures of young, pre-senescent, and senescent fibroblast cells were incubated with γ-tocotrienol for 24 h. The expression levels of ELN, COL1A1, MMP1, CCND1, RB1, and IL6 genes were determined using the quantitative real-time polymerase chain reaction. Cell cycle profiles were determined using a FACSCalibur Flow Cytometer. RESULTS: The cell cycle was arrested in the G0/G1 phase, and the percentage of cells in S phase decreased with senescence. CCND1, ...

Sigma-Aldrich offers abstracts and full-text articles by [Suzana Makpol, Azalina Zainuddin, Kien Hui Chua, Yasmin Anum Mohd Yusof, Wan Zurinah Wan Ngah].

Link to Pubmed [PMID] - 27503890. Proc. Natl. Acad. Sci. U.S.A. 2016 Aug;113(34):E5024-33. Oncogene-induced senescence (OIS) is a critical tumor-suppressing mechanism that restrains cancer progression at premalignant stages, in part by causing telomere dysfunction. Currently it is unknown whether this proliferative arrest presents a stable and therefore irreversible barrier to cancer progression. Here we demonstrate that cells frequently escape OIS induced by oncogenic H-Ras and B-Raf, after a prolonged period in the senescence arrested state. Cells that had escaped senescence displayed high oncogene expression levels, retained functional DNA damage responses, and acquired chromatin changes that promoted c-Myc-dependent expression of the human telomerase reverse transcriptase gene (hTERT). Telomerase was able to resolve existing telomeric DNA damage response foci and suppressed formation of new ones that were generated as a consequence of DNA replication stress and oncogenic signals. Inhibition ...

Glycans play essential roles in biological functions such as differentiation and cancer. Recently, glycans have been considered as biomarkers for physiological aging. However, details regarding the specific glycans involved are limited. Here, we investigated cellular senescence- and human aging-dependent glycan changes in human diploid fibroblasts derived from differently aged skin donors using a lectin microarray. We found that α2-6sialylated glycans in particular differed between elderly- and fetus-derived cells at early passage. However, both cell types exhibited sequentially decreasing α2-3sialylated O-glycan structures during the cellular senescence process and showed similar overall glycan profiles. We observed a senescence-associated decrease in sialylation and increase in galactose exposure. Therefore, glycan profiling using lectin microarrays might be useful for the characterization of biomarkers of aging.

Senescent fibroblasts are known to promote tumor growth. However, the exact mechanism remains largely unknown. An important clue comes from recent studies linking autophagy with the onset of senescence. Thus, autophagy and senescence may be part of the same physiological process, known as the autophagy-senescence transition (AST). To test this hypothesis, human fibroblasts immortalized with telomerase (hTERT-BJ1) were stably transfected with autophagy genes (BNIP3, CTSB or ATG16L1). Their overexpression was sufficient to induce a constitutive autophagic phenotype, with features of mitophagy, mitochondrial dysfunction and a shift toward aerobic glycolysis, resulting in L-lactate and ketone body production. Autophagic fibroblasts also showed features of senescence, with increased p21(WAF1/CIP1), a CDK inhibitor, cellular hypertrophy and increased β-galactosidase activity. Thus, we genetically validated the existence of the autophagy-senescence transition. Importantly, autophagic-senescent ...

The ends of linear chromosomes in eukaryotic cells are protected by telomeres. The telomeric DNA interacts with many proteins including the telomerase enzyme complex that extends telomere ends and compensates for the end replication problem. Human stem and cancer cells express telomerase to facilitate immortality. Without telomerase however, telomeres shorten with each round of DNA replication; this gradual erosion eventually leads to cell senescence, an irreversible cell cycle arrest, and serves to control cellular life span.

Cancer-associated fibroblasts (CAF) remain a poorly characterized, heterogeneous cell population. Here we characterized two previously described tumor-promoting CAF sub-types, smooth muscle actin (SMA)-positive myofibroblasts and senescent fibroblasts, identifying a novel link between the two. Analysis of CAF cultured ex vivo, showed that senescent CAF are predominantly SMA-positive; this was confirmed by immunochemistry in head & neck (HNSCC) and esophageal (EAC) cancers. In vitro, we found that fibroblasts induced to senesce develop molecular, ultrastructural and contractile features typical of myofibroblasts and this is dependent on canonical TGF-β signaling. Similar to TGF-β1-generated myofibroblasts, these cells secrete soluble factors that promote tumor cell motility. However, RNA-sequencing revealed significant transcriptomic differences between the two SMA-positive CAF groups, particularly in genes associated with extracellular matrix (ECM) deposition and organization, which

Senescence is an irreversible growth arrest phenotype adopted by cells that has a key role in protecting organisms from cancer. There is now considerable interest in therapeutic strategies that reactivate this process to control the growth of cancer cells. Protein kinase C iota (PKCι) is a member of the atypical protein kinase C family and an important downstream mediator in the phosphoinositide pathway. PKCι expression was found to be upregulated in a subset of breast cancers and breast cancer cell lines. Introduction of mutant, oncogenic PIK3CA, but not wild-type PIK3CA, into breast mammary epithelial cells increased both the expression and activation of PKCι. In breast cancer cell lines overexpressing PKCι, depletion of PKCι increased the number of senescent cells, as assessed by senescence-associated β-galactosidase, morphology and bromodeoxyuridine incorporation. This phenomenon was not restricted to breast cancer cells, as it was also seen in glioblastoma cells. Senescence induction ...

Circulating Glioma Cells Exhibit Stem Cell-Like Properties Genetic probes showed that mouse glioblastoma (GBM)-derived circulating tumor cells (CTC) exhibited Sox2/ETn transcriptional activation and expressed glioma CSC markers, consistent with robust expression of stemness-associated genes including SOX2, OCT4, and NANOG in human GBM patient-derived samples containing CTC. Wnt activation induced stemness and chemoresistance in CTC. [Cancer Res] Abstract Tumor Cell-Secreted PLD Increases Tumor Stemness by Senescence-Mediated Communication with Microenvironment Phospholipase D2 (PLD2) was overexpressed in colon tumors and was secreted by cancer cells, inducing senescence in neighboring fibroblasts. Senescence induced by its product, phosphatidic acid, led to a senescence-associated secretory phenotype able to increase the stem properties of cancer cells. [Oncogene] Abstract CD24 Regulates Cancer Stem Cell (CSC)-Like Traits and a Panel of CSC-Related Molecules Serves as a Non-Invasive Urinary ...

TY - JOUR. T1 - A genome-wide loss-of-function screen identifies SLC26A2 as a novel mediator of TRAIL resistance. AU - Dimberg, Lina Y.. AU - Towers, Christina G.. AU - Behbakht, Kian. AU - Hotz, Taylor J.. AU - Kim, Jihye. AU - Fosmire, Susan. AU - Porter, Christopher C.. AU - Tan, Aik-Choon. AU - Thorburn, Andrew. AU - Ford, Heide L.. PY - 2017/4/1. Y1 - 2017/4/1. N2 - TRAIL is a potent death-inducing ligand that mediates apoptosis through the extrinsic pathway and serves as an important endogenous tumor suppressor mechanism. Because tumor cells are often killed by TRAIL and normal cells are not, drugs that activate the TRAIL pathway have been thought to have potential clinical value. However, to date, most TRAIL-related clinical trials have largely failed due to the tumor cells having intrinsic or acquired resistance to TRAIL-induced apoptosis. Previous studies to identify resistance mechanisms have focused on targeted analysis of the canonical apoptosis pathway and other known regulators of ...

Formation of aortic aneurysms as a consequence of augmented transforming growth factor β (TGF-β) signaling and vascular smooth muscle cell (VSMC) dysfunction is a potentially lethal complication of Marfan syndrome (MFS). Here, we examined VSMC senescence in patients with MFS and explored the potential mechanisms that link VSMC senescence and TGF-β. Tissue was harvested from the ascending aorta of control donors and MFS patients, and VSMCs were isolated. Senescence-associated β-galactosidase (SA-β-gal) activity and expression of senescence-related proteins (p53, p21) were significantly higher in aneurysmal tissue from MFS patients than in healthy aortic tissue from control donors. Compared to control-VSMCs, MFS-VSMCs were larger with higher levels of both SA-β-gal activity and mitochondrial reactive oxygen species (ROS). In addition, TGF-β1 levels were much higher in MFS- than control-VSMCs. TGF-β1 induced VSMC senescence through excessive ROS generation. This effect was suppressed by Mito-tempo,

Aging is the biggest risk factor for cancer, but the mechanisms linking these two processes remain unclear. Using GTEx and TCGA data, we compared genes differentially expressed with age and genes differentially expressed in cancer among nine human tissues. In most tissues, aging and cancer gene expression pattern changed in the opposite direction. The exception was thyroid and uterus, where we found transcriptomic changes in the same direction in aging and in their corresponding cancers. The overlapping sets between genes differentially expressed with age and genes differentially expressed in cancer across tissues were enriched for several processes, mainly cell cycle and the immune system. Moreover, cellular senescence signatures, derived from a meta‐analysis, changed in the same direction as aging in human tissues and in the opposite direction of cancer signatures. Therefore, transcriptomic changes in aging and in cellular senescence might relate to a decrease in cell proliferation, while cancer

locus, play critical roles in inducing and maintaining permanent cell cycle arrest during cellular senescence. Although the elimination of p16INK4a-expressing cells extends the life span of the mouse, it is unclear whether tissue function is restored by the elimination of senescent cells in aged animals and whether and how p19ARF contributes to tissue aging. The aging-associated decline in lung function is characterized by an increase in compliance as well as pathogenic susceptibility to pulmonary diseases. We herein demonstrated that pulmonary function in 12-month-old mice was reversibly restored by the elimination of p19ARF-expressing cells. The ablation of p19ARF-expressing cells using a toxin receptor-mediated cell knockout system ameliorated aging-associated lung hypofunction. Furthermore, the aging-associated gene expression profile was reversed after the elimination of p19ARF. Our results indicate that the aging-associated decline in lung function was, at least partly, attributed to ...

TY - JOUR. T1 - The senescence marker protein (SMP-2) of the rat liver. T2 - purification, immunochemical characterization and age-dependent regulation. AU - Chatterjee, Bandana. AU - Mancini, Michael A.. AU - Roy, Arun K.. N1 - Funding Information: The work was supportedb y NIH grant AG-03527. A.K.R. is the recipient of a MERIT Award from NIDDK. We thank MasarratA li, Richard Lorch and C.V.R. Murty for their contributiontso this work.. PY - 1990/5/16. Y1 - 1990/5/16. N2 - In vitro translation of total rat hepatic mRNAs has identified a 31 kilodalton senescence marker protein (SMP-2) which is present in higher amounts in prepubertal and senescent males than in the post-pubertal adult male (more than 10-fold). SMP-2 is an androgen-repressible protein. The negative regulation of the SMP-2 gene activity by androgen accounts for its increased expression during the androgen insensitive states of the prepubertal and senescent livers, and its constitutive expresion in the female liver. A combination of ...

Cardiomyocytes cease to divide shortly after birth and an irreversible cell cycle arrest is evident accompanied by the downregulation of cyclin-dependent kinase activities. To get a better understanding of the cardiac cell cycle and its regulation, the effect of functional recovery of the mitosis-promoting factor (MPF) consisting of cyclin B1 and the cyclin-dependent kinase Cdc2 was assessed in primary cultures of postmitotic ventricular adult rat cardiomyocytes ( ARC). Gene transfer into ARC was achieved using the adenovirus-enhanced transferrinfection system that was characterized by the absence of cytotoxic events. Simultaneous ectopic expression of wild-type versions of cyclin B1 and Cdc2 was sufficient to induce MPF activity. Reestablished MPF resulted in a mitotic phenotype, marked by an abnormal condensation of the nuclei, histone H3 phosphorylation and variable degree of decay of the contractile apparatus. Although a complete cell division was not observed, the results provided ...

TY - JOUR. T1 - Epithelial innate immunity mediates tubular cell senescence after kidney injury. AU - Jin, Heng. AU - Zhang, Yan. AU - Ding, Qiong. AU - Wang, Shan Shan. AU - Rastogi, Prerna. AU - Dai, Dao Fu. AU - Lu, Dongmei. AU - Purvis, Madison. AU - Cao, Chao. AU - Wang, Angela. AU - Liu, Dingxiao. AU - Ren, Chongyu. AU - Elhadi, Sarah. AU - Hu, Ming Chang. AU - Chai, Yanfen. AU - Zepeda-Orozco, Diana. AU - Campisi, Judith. AU - Attanasio, Massimo. PY - 2019/1/24. Y1 - 2019/1/24. N2 - Acute kidney injury (AKI) is a common clinical condition of growing incidence. Patients who suffer severe AKI have a higher risk of developing interstitial fibrosis, chronic kidney disease, and end-stage renal disease later in life. Cellular senescence is a persistent cell cycle arrest and altered gene expression pattern evoked by multiple stressors. The number of senescent cells increases with age and even in small numbers these cells can induce chronic inflammation and fibrosis; indeed, in multiple organs ...

Project Description. Tumours are commonly described as wounds that do not heal. Tumours and chronic wounds comprise dysregulated epithelial cells, senescent fibroblasts, and share similar gene expression profiles. Fibroblast senescence is the major hallmark of chronic wounds, as proliferation defects prevent wound contraction and alters secretion that in turn directs epithelial cell behaviour. Cancer-associated fibroblasts (CAFs) play a similar role in tumour formation. Senescent CAFs promote the growth and metastasis of cancer cells.. Over time, fibroblasts naturally tend towards senescence, which results in a decrease in healing rates and predisposition towards cancer as we age. We recently discovered that low-intensity ultrasound can promote healing in mice with pathological healing defects caused by diabetes or old age, by reversing and protecting fibroblasts from senescence. This PhD will investigate the effect of ultrasound on CAF senescence, leading to the development of new cancer ...

FtSH4 showed a high expression level in the rosette leaves, and its transcript levels were stable during different growth stages (Zhang et al., 2014). These results, combined with the premature senescence phenotype of the ftsh4-4 mutant, indicate that FtSH4 may be an upstream regulator of senescence. Although FtSH4 plays important roles in regulating premature senescence by altering the levels of ROS (Gibala et al., 2009; Kicia et al., 2010; Smakowska et al., 2014, 2016), the detailed mechanism behind this process is not clear. ROS are important multifaceted signaling molecules that can regulate a number of cellular pathways and, thus, play critical roles in plant development (Foyer and Noctor, 2013). ROS and autophagy are associated with cell death, and more recent evidence indicates that both ROS and autophagy play important roles in signaling and cellular adaptation to stress (Wang et al., 2011). Mitochondria are known to play key roles in triggering cell death via altering cellular redox to ...

posted from: https://www.fightaging.org/archives/2017/01/cellular-senescence-as-a-contributing-cause-of-osteoarthritis/. A fair few good scientific papers on the role of cellular senescence in the progression of osteoarthritis have emerged in the last year. Given that UNITY Biotechnology aims to initially trial senolytic therapies to clear senescent cells as a treatment for inflammatory joint diseases, a list in which osteoarthritis features prominently, and that the UNITY principals now have quite a lot of funding to work with, I expect that well be hearing a lot more on this topic over the course of the next few years. There is nothing quite like the existence of a funded company in a field to spur a great deal more investment in related research from all sources. The rate at which reviews of the relevant science are published tends to increase as well, with the paper linked below as an example of the type.. Senescent cells accumulate in tissues with age, and that accumulation is thought to ...

Our Cellular Senescence Flow Cytometry Assay provides an efficient method to measure Senescence Associated (SA) ß-galactosidase activity. A fluorogenic substrate is added directly to senescent cells in a 35 mm dish. Results can be measured by either flow cytometry or epifluorescence microscope.

09.30 - 09.45h Welcome/ Introduction: Clemens A. Schmitt Session I: 09.45 - 11.00h Chair: Fabrizio dAdda di Fagagna 09.45 - 10.15h Leonard Hayflick: A Brief History of the Discovery of the Relationship between Cell Senescence and Cancer 10.15 - 10.45h Jerry Shay: How Human Cells Bypass Telomere-associated Replicative Senescence In Cancer Development 10.45 - 11.00h Lars-Gunnar Larsson: Cdk2 inhibition delays Myc driven leukemia in vivo through restoration of cellular senescence (Abstract Talk) 11.00 - 11.30h Coffee break Session II: 11.30 - 12.45h Chair: Scott Lowe 11.30 - 12.00h Gerardo Ferbeyre: Regulation of E2F gene expression and senescence by the tumor suppressor PML 12.00 - 12.30h Masashi Narita: Gene expression in cellular senescence - from chromatin to proteins 12.30 - 12.45h Kristina Kirschner: Global analysis of tumour suppressor protein p53 shows plasticity in phenotype regulation (Abstract Talk) 12.45 - 14.15h Lunch/ Postersession Session III: 14.15 - 16.00h Chair: Daniel Peeper ...

Fibrosis involves activation of fibroblasts, increased production of collagen and fibronectin and transdifferentiation into contractile myofibroblasts. The process resembles aspects of wound-healing but remains unresolved and can be life-threatening when manifest in the kidneys, lungs and liver, in particular. The causes are largely unknown, but recent suggestions that repetitive micro-injury results in the eventual failure of epithelial cell repair due to replicative senescence are gaining favour. This is consistent with the onset of fibrotic diseases in middle age. Because epithelial injury often involves blood loss, inflammatory responses associated with the fibrotic response have been considered as therapeutic targets. However, this has proved largely unsuccessful and focus is now switching to earlier events in the process. These include EMT (epithelial-mesenchymal transition) and fibroblast activation in the absence of inflammation. TGFβ1 (transforming growth factor-β1) induces both EMT ...

Fibrosis involves activation of fibroblasts, increased production of collagen and fibronectin and transdifferentiation into contractile myofibroblasts. The process resembles aspects of wound-healing but remains unresolved and can be life-threatening when manifest in the kidneys, lungs and liver, in particular. The causes are largely unknown, but recent suggestions that repetitive micro-injury results in the eventual failure of epithelial cell repair due to replicative senescence are gaining favour. This is consistent with the onset of fibrotic diseases in middle age. Because epithelial injury often involves blood loss, inflammatory responses associated with the fibrotic response have been considered as therapeutic targets. However, this has proved largely unsuccessful and focus is now switching to earlier events in the process. These include EMT (epithelial-mesenchymal transition) and fibroblast activation in the absence of inflammation. TGFβ1 (transforming growth factor-β1) induces both EMT ...

Accelerated senescence of cancer stem cells (CSCs) represents an adaptive response allowing withstand cell death. TP53, the pivotal tumor suppressor plays an important role in this process by inducing a prolonged dual state with senescence and self-renewal as potential outcomes. Molecularly, this is achieved by activating both OCT4A (POU5F1) and p21CIP1. OCT4A suppresses the excessive activity of p21 preventing the immediate precipitation of apoptosis or terminal senescence. It persists as long as sufficient cellular energy remains; generated through autophagy, itself sequestrating p16INK4A in the cytoplasm. As such, autophagic capacity is the bottleneck of these TP53-dependent senescence reversal processes, as well terminal senescence will follow if DNA damage is not ultimately repaired. In TP53 mutants the CSC-like state is boosted by stressed cells overcoming the tetraploidy barrier. These cells acquire additional DNA repair capacity through mitotic slippage and entrance to a sequence of ploidy

TY - JOUR. T1 - ZNF313 is a novel cell cycle activator with an E3 ligase activity inhibiting cellular senescence by destabilizing p21WAF1. AU - Han, J.. AU - Kim, Y. L.. AU - Lee, K. W.. AU - Her, N. G.. AU - Ha, T. K.. AU - Yoon, S.. AU - Jeong, S. I.. AU - Lee, J. H.. AU - Kang, M. J.. AU - Lee, M. G.. AU - Ryu, B. K.. AU - Baik, J. H.. AU - Chi, S. G.. PY - 2013/8. Y1 - 2013/8. N2 - ZNF313 encoding a zinc-binding protein is located at chromosome 20q13.13, which exhibits a frequent genomic amplification in multiple human cancers. However, the biological function of ZNF313 remains largely undefined. Here we report that ZNF313 is an ubiquitin E3 ligase that has a critical role in the regulation of cell cycle progression, differentiation and senescence. In this study, ZNF313 is initially identified as a XIAP-associated factor 1 (XAF1)-interacting protein, which upregulates the stability and proapoptotic effect of XAF1. Intriguingly, we found that ZNF313 activates cell cycle progression and ...

In aging societies, the discrepancy between the total lifespan and the healthy lifespan is becoming a major problem. Chronological aging is associated with a higher prevalence of age-related diseases, including heart failure, diabetes, and atherosclerotic disorders with or without various comorbidities, resulting in impairment of the quality of life by limitation of normal activities. Thus, aging is associated with several undesirable processes. The mechanisms of aging and age-associated disorders are complex, and thus cannot be comprehended by a simple approach. However, recent studies have indicated a pivotal role of cellular senescence in the progression of age-related disorders. p53 signaling is thought to have a central role in cellular senescence. Somatic cells have a finite lifespan and eventually enter a state of irreversible growth arrest termed replicative senescence. Telomeres are repetitive nucleotide sequences located at the terminals of mammalian chromosomes that undergo ...

d-galactose (d-gal)-induced cardiac alterations and Doxorubicin (Dox)-induced cardiomyocyte senescence are commonly used models to study cardiac aging. Accumulating evidence has suggested that microRNAs (miRNAs, miRs) are critically involved in the regulation of cellular and organismal aging and age-related diseases. However, little has been revealed about the roles of miRNAs in cardiac alterations induced by d-gal and Dox. In this study, we used miRNA arrays to investigate the dysregulated miRNAs in heart samples from 15month-old versus 2month-old male C57BL/6 mice and further validated them in d-gal-induced pseudo-aging mouse model and Dox-induced cardiomyocyte senescence in vitro model ...

Many cancers overexpress ATF4, a stress-induced transcription factor that promotes cell survival under hypoxic conditions and other stresses of the tumor microenvironment, but the potential contributions of ATF4 to oncogenesis itself have been little explored. Here, we report that ATF4 promotes oncogene-induced neoplastic transformation by suppressing the expression of cellular senescence-associated genes. Strikingly, primary embryo fibroblasts from ATF4-deficient mice were resistant to transformation by coexpression of H-rasV12 and SV40 large T antigen. In wild-type cells these oncogenes induced expression of the murine Atf4 gene along with the cyclin-dependent kinase inhibitor Cdkn2a, which encodes the cell senescence-associated proteins p16INK4 and p19ARF. Elevated levels of ATF4 were sufficient to suppress expression of these proteins and drive oncogenic transformation. Conversely, genetic ablation of ATF4 led to constitutive expression of p16INK4a and p19ARF, triggering cellular senescence. ...

Immune aging may underlie various aging-related disorders, including diminished resistance to infection, chronic inflammatory disorders, and autoimmunity. PD-1+ and CD153+ CD44high CD4+ T cells with features of cellular senescence, termed senescence-associated T (SA-T) cells, increasingly accumulate with age and may play a role in the immune aging phenotype. In this article, we demonstrate that, compared with young mice, the aged mouse environment is highly permissive for spontaneous proliferation of transferred naive CD4+ T cells, and it drives their transition to PD-1+ and CD153+ CD44high CD4+ T cells after extensive cell divisions. CD4+ T cells with essentially the same features as SA-T cells in aged mice are also generated from naive CD4+ T cells after extensive cell divisions under severe T-lymphopenic conditions by gamma irradiation or in developmental T cell defect, often in association with spontaneous germinal centers, as seen in aged mice. The increase in SA-T cells is significantly enhanced

Supplementary MaterialsSupplementary data 41598_2017_2380_MOESM1_ESM. a variable ability to undergo senescence in response to serum. However all were able to undergo senescence in response to TGF, although for cells from one patient this required concomitant inhibition of Ras pathway signalling. Primary glioblastoma cells therefore retain a functional senescence program that is inducible by acute activation of the TGF signalling pathway. Introduction Glioblastoma is an aggressive form of brain cancer. A characteristic feature of glioblastoma is usually its heterogeneity. This was originally observed in its histology, giving rise to the term glioblastoma multiforme. More recently genetic studies have created a detailed picture of extensive heterogeneity at the molecular level. Analysis of microarray expression data has led to the subdivision of glioblastoma into four or five different molecular subtypes, designated G-CIMP/proneural, neural, classical and mesenchymal1. These tend to be associated ...

This page contains the abstract: Premature T Cell Senescence in Ovx Mice Is Inhibited By Repletion of Estrogen and Medicarpin: A Possible Mechanism For Alleviating Bone Loss http://www.chiro.org/nutrition/ABSTRACTS/Premature_T_Cell_Senescence.shtml

Judith Campisi has received international recognition for her contributions to understanding why age is the largest single risk factor for developing a panoply of diseases, ranging from neurodegeneration to cancer. Her highly acclaimed research integrates the genetic, environmental and evolutionary forces that result in aging and age-related diseases, and identifies pathways that can be modified to mitigate basic aging processes. See video interview.. Dr. Campisi also makes significant contributions to understanding why aging is the largest single risk factor for developing cancer. She is widely recognized for her work on senescent cells -- older cells that have stopped dividing -- and their influence on aging and cancer. Senescence occurs when cells experience certain types of stress, especially stress that can damage the genome. The senescence response helps prevent cancer by blocking damaged cells from multiplying. But there is a trade off - the lingering senescent cells may also cause harm ...

A Lack of Cellular Senescence, Formation of Microenvironment, and Role of Soluble CD30 in Development of Adult T-Cell Leukemia/Lymphoma Abstract.

TY - JOUR. T1 - 3′ UTR lengthening as a novel mechanism in regulating cellular senescence. AU - Chen, Meng. AU - Lyu, Guoliang. AU - Han, Miao. AU - Nie, Hongbo. AU - Shen, Ting. AU - Chen, Wei. AU - Niu, Yichi. AU - Song, Yifan. AU - Li, Xueping. AU - Li, Huan. AU - Chen, Xinyu. AU - Wang, Ziyue. AU - Xia, Zheng. AU - Li, Wei. AU - Tian, Xiao Li. AU - Ding, Chen. AU - Gu, Jun. AU - Zheng, Yufang. AU - Liu, Xinhua. AU - Hu, Jinfeng. AU - Wei, Gang. AU - Tao, Wei. AU - Ni, Ting. N1 - Funding Information: We thank Dr. Haijian Wang for providing the psiCHECK-2 Vector, Professor Hongyan Wang for luciferase assay instrument support, and Professors Li Jin and Jun Zhu for insightful suggestions regarding bioinformatic analyses. This work was supported by the National Basic Research Program of China (973 program: 2013CB530700 and 2015CB943000), National Natural Science Foundation of China (31771336, 31471192, 31521003, and 31471205), and the 111 Project of China (B13016). We thank Genergy Biotech ...

30 June 2017 Researchers at the Institute of Molecular Biology (IMB) and at the Faculty of Biology at Johannes Gutenberg University Mainz (JGU) have further uncovered the secrets of telomeres, i.e., the caps that protect the ends of our chromosomes. They discovered that an RNA molecule called TERRA helps to ensure that very short (or broken) telomeres get fixed again. The work, which was recently published in the journal Cell, provides new insights into cellular processes that regulate cell senescence and survival in ageing and cancer. Telomeres protect the ends of our chromosomes, much like the plastic cap at the end of a shoelace that prevents the lace from unravelling. Over a cells lifetime, telomeres get gradually shorter with each cell division and therefore the protective cap becomes less and less effective. If they get too short, it is a signal for the cell that its genetic material is compromised and the cell stops dividing. Telomere shortening and reduced cell division are considered a ...

FOXO3, also known as FOXO3a (and previously as FKHRL1), is a Forkhead protein of the O subclass. FOXOs have overlapping expression profiles and activities, but FOXO3a is known to be particularly important in cell cycle control and apoptosis, the immune system, fertility, and longevity [1][2][3]. It has a widespread distribution in the body, although expression levels are not equal throughout tissues. It contains a characteristic Forkhead box DNA binding domain, and is able to up- and downregulate expression of a variety of genes via binding of its consensus Forkhead Recognition Element, or similar sequences (including Insulin Response Elements). DNA recognition is performed by helix 3 of the DBD, although other parts of the DBD also contact the DNA to increase binding stability. FOXO3 is a human orthologue of C. eleganss daf-16, a gene required for the long-lived phenotype of daf-2-null nematodes. FOXO3s involvement in longevity, aging and senescence may be linked to its roles in oxidative ...

This product is a simple detection kit by plate assay for senescence-associated β-galactosidase (SA-β-gal) activity which is used as a marker for senescent cells. By simply adding SPiDER-βGal, a reagent for detection of β-galactosidase, to 96 well plates, this kit allows you to quantify SA-β-gal activity and makes it possible to evaluate multiple specimens. When normalization is done by the results obtained by counting cells, quantifying nucleic acids (the relevant product), or quantifying proteins, the measured values obtained using this kit become available for evaluating SA-β-gal activity according to cell number.. ...

Leonard Hayflick studied the processes by which cells age during the twentieth and twenty-first centuries in the United States. In 1961 at the Wistar Institute in the US, Hayflick researched a phenomenon later called the Hayflick Limit, or the claim that normal human cells can only divide forty to sixty times before they cannot divide any further. Researchers later found that the cause of the Hayflick Limit is the shortening of telomeres, or portions of DNA at the ends of chromosomes that slowly degrade as cells replicate.. Format: Articles Subject: People ...

Leonard Hayflick studied the processes by which cells age during the twentieth and twenty-first centuries in the United States. In 1961 at the Wistar Institute in the US, Hayflick researched a phenomenon later called the Hayflick Limit, or the claim that normal human cells can only divide forty to sixty times before they cannot divide any further. Researchers later found that the cause of the Hayflick Limit is the shortening of telomeres, or portions of DNA at the ends of chromosomes that slowly degrade as cells replicate.. Format: Articles Subject: People ...

Supplementary MaterialsSupplemental Shape?S1 Cells transduced using the indicated constructs were collected and set at day time 7 after infection (A), at day time 6 after infection (B), or at day time 10 after infection (C). lysine 9. Significantly, ectopic coexpression of TS and RR or addition of deoxyribonucleosides suppressed DNA harm considerably, senescence-associated phenotypes, and proliferation arrest in two types of NHF-expressing HRASG12V. Reciprocally, brief hairpin RNA-mediated suppression of RR and TS triggered DNA harm and senescence in NHFs, although less efficiently than HRASG12V. However, overexpression of TS and RR in quiescent NHFs did not overcome proliferation arrest, suggesting that unlike quiescence, OIS requires depletion of dNTP pools and activated DNA replication. Our data identify a previously unknown role of deoxyribonucleotides in regulation of OIS. Oncogene-induced senescence (OIS) represents an important fail-safe mechanism that suppresses proliferation of ...

Hi everybody. Today, it was published a paper in which its described the research that led to the identification and testing of a peptide that reduces the amount of senescent cells in the skin, and that peptide is being used in the first product in the whole world (as far as I know) that is already in the market and reduces the amount of senescent cells in humans (in this case, in the skin). The paper can be found in I dont think its an ordinary thing that a product that reduces the amount of senescent cells is being sold in the market. After many years watching Aubrey de Greys talks, and reading news about promising researches about senescent cells, and about the formation of many companies to research how to reduce the amount of senescent cells, finally there is something that reached the public. This paper is very important as it allows that the rejuvenation field analyzes it and be prepared to seize this opportunity to show to the world, in practice, that the theoretical base of the rejuvenation

And here we come to the next misleading argument that is posited to rationalize or justify the use of aborted babies in the production of vaccines. If youll notice in the list of vaccine ingredients above, the vaccines that are currently in use today are all derived from two fetal cell strains: WI-38 and MRC-5. Our vaccines come from only two aborted babies. Again, Megan over at Whole Living puts it best with her This Wasnt Just a One-Night Stand analogy, You might have also heard that only two babies were used and it was a really long time ago, which justifies the continued use of shooting up live babies with dead babies. Sometimes a little perspective goes a long way…. It may seem like common sense to some to realize that to arrive at WI number 38, numbers 1-37 logically preceded. You would be correct in this logical assumption. Hayflick also references WI-44 in his report, so you can be sure, very many more than one aborted baby has gone into the development of the WI-38 cell line ...