From cell senescence to age-related diseases: differential mechanisms of action of senescence-associated secretory phenotypes - Age-associated diseases;Cell senescence;Differential expression;Senescence-associated secretory phenotypes (SASP);
Communication between cells is quintessential for biological function and cellular homeostasis. Membrane-bound extracellular vesicles known as exosomes play pivotal roles in mediating intercellular communication in tumor microenvironments. These vesicles and exosomes carry and transfer biomolecules such as proteins, lipids and nucleic acids. Here we focus on exosomes secreted from senescent cells. Cellular senescence can alter the microenvironment and influence neighbouring cells via the senescence-associated secretory phenotype (SASP), which consists of factors such as cytokines, chemokines, matrix proteases and growth factors. This review focuses on exosomes as emerging SASP components that can confer pro-tumorigenic effects in pre-malignant recipient cells. This is in addition to their role in carrying SASP factors. Transfer of such exosomal components may potentially lead to cell proliferation, inflammation and chromosomal instability, and consequently cancer initiation. Senescent cells are ...
Hematologic malignancies are typically associated with leukemogenic fusion proteins, which are required to maintain the oncogenic state. Previous studies have shown that certain oncogenes that promote solid tumors, such as RAS and BRAF, can induce senescence in primary cells, which is thought to provide a barrier to tumorigenesis. In these cases, the activated oncogene elicits a DNA damage response (DDR), which is essential for the senescence program. Here we show that 3 leukemogenic fusion proteins, BCR-ABL, CBFB-MYH11, and RUNX1-ETO, can induce senescence in primary fibroblasts and hematopoietic progenitors. Unexpectedly, we find that senescence induction by BCR-ABL and CBFB-MYH11 occurs through a DDR-independent pathway, whereas RUNX1-ETO induces senescence in a DDR-dependent manner. All 3 fusion proteins activate the p38 MAPK pathway, which is required for senescence induction. Our results reveal diverse pathways for oncogene-induced senescence and further suggest that leukemias harbor genetic or
Can regular aerobic exercise diminish the damaging effects of aging on the vascular system by improving the health of vascular endothelial cells? In this insightful podcast, Associate Editor Nancy Kanagy interviews lead author Matthew Rossman (University of Colorado Boulder) and content expert Raymond Migrino (Phoenix VA Health Care System) about the work by Rossman et al focusing on age-related changes in endothelial cell senescence and associated changes in endothelial cell function that occurs with normal, healthy aging. Habitual exercise has been shown to reduce age-related phenotypic changes such as increased arterial stiffness and reduced endothelial cell function. Did Rossman and colleagues find that regular aerobic exercise in older adults ameliorated increases in endothelial cell senescence? Listen and learn more.. Matthew J. Rossman, Rachelle E. Kaplon, Sierra D. Hill, Molly N. McNamara, Jessica R. Santos-Parker, Gary L. Pierce, Douglas R. Seals, Anthony J. Donato Endothelial cell ...
TY - JOUR. T1 - Oxidative stress-induced senescence markedly increases disc cell bioenergetics. AU - Patil, Prashanti. AU - Falabella, Micol. AU - Saeed, Amal. AU - Lee, Dayeong. AU - Kaufman, Brett. AU - Shiva, Sruti. AU - Croix, Claudette St. AU - Van Houten, Ben. AU - Niedernhofer, Laura J.. AU - Robbins, Paul D.. AU - Lee, Joon. AU - Gwendolyn, Sowa. AU - Vo, Nam V.. PY - 2019/6. Y1 - 2019/6. N2 - Cellular senescence is a phenotype characterized by irreversible growth arrest, chronic elevated secretion of proinflammatory cytokines and matrix proteases, a phenomenon known as senescence-associated secretory phenotype (SASP). Biomarkers of cellular senescence have been shown to increase with age and degeneration of human disc tissue. Senescent disc cells in culture recapitulate features associated with age-related disc degeneration, including increased secretion of proinflammatory cytokines, matrix proteases, and fragmentation of matrix proteins. However, little is known of the metabolic ...
Senescent cells are cells that no longer divide. These cells acquire a large and flat cellular appearance, decrease contacts with other cells, and increase adhesion to the extracellular matrix. In normal replicative senescence, the cell simply enters senescence after a certain number of replications. However, stress-induced senescence causes cells to initiate senescence prematurely due to a variety of stresses. In fact, some hypothesize that the senescence program originally evolved as an antiviral mechanism. This burgeoning field may also yield other important clues about the cellular biology of aging. Molecularly, the cellular senescence program activates p53 and pRb signaling, leading to withdrawal from the cell cycle. Stress pathways that may cause cellular senescence include DNA damage, oxidative stress, interferon-related responses, and signaling via either insulin growth factors (IGF) or mitogen activated protein kinases (MAPK). Due to cellular senescence activation in early stage cancers ...
Pathological angiogenesis is the hallmark of diseases such as cancer and retinopathies. Although tissue hypoxia and inflammation are recognized as central drivers of vessel growth, relatively little is known about the process that bridges the two. In a mouse model of ischemic retinopathy, we found that hypoxic regions of the retina showed only modest rates of apoptosis despite severely compromised metabolic supply. Using transcriptomic analysis and inducible loss-of-function genetics, we demonstrated that ischemic retinal cells instead engage the endoplasmic reticulum stress inositol-requiring enzyme 1α (IRE1α) pathway that, through its endoribonuclease activity, induces a state of senescence in which cells adopt a senescence-associated secretory phenotype (SASP). We also detected SASP-associated cytokines (plasminogen activator inhibitor 1, interleukin-6, interleukin-8, and vascular endothelial growth factor) in the vitreous humor of patients suffering from proliferative diabetic retinopathy. ...
Supplementary MaterialsData?S1 Foam cell-derived 4-hydroxynonenal induces endothelial cell senescence inside a TXNIP-dependent manner. was triggered by 4-hydroalkenals, such as 4-HNE. Pharmacological interventions supported the involvement of the 4-HNE-PPAR axis in the induction of TXNIP and VEC senescence. The association of TXNIP with VEC senescence was further supported by immunofluorescent staining of human being carotid plaques in which the manifestation of both TXNIP and p21 was augmented in endothelial cells. Collectively, order AZD6738 these findings suggest that foam cell-released 4-HNE activates PPAR in VEC, leading to improved TXNIP manifestation and consequently to senescence. by incubating nLDL under sterile conditions with 10?M copper chloride (24?hrs, at 37C), in the absence of antioxidant safety. The oxidative reaction was halted by addition of 1 1?mg/ml EDTA and after extensive dialysis against PBS, pH 7.4, 4C, oxLDL was stored at 4C, under sterile conditions. The copper-OxLDL ...
1. Bastonini E, Kovacs D, Picardo M. Skin pigmentation and pigmentary disorders: Focus on epidermal/dermal cross-talk. Ann Dermatol. 2016;28:279-89 2. Kim M, Han JH, Kim JH, Park TJ, Kang HY. Secreted frizzled-related protein 2 (sFRP2) functions as a melanogenic stimulator; The role of sFRP2 in UV-induced hyperpigmentary disorders. J Invest Dermatol. 2016;136:236-44 3. Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: The dark side of tumor suppression. Annu Rev Pathol. 2010;5:99-118 4. Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL. Cellular senescence and the senescent secretory phenotype: Therapeutic opportunities. J Clin Invest. 2013;123:966-72 5. Kim YH, Choi YW, Lee JH, Soh EY, Kim JH, Park TJ. Senescent tumor cells lead the collective invasion in thyroid cancer. Nat Commun. 2017;8:15208 6. Mine S, Fortunel NO, Pageon H, Asselineau D. Aging alters functionally human dermal papillary fibroblasts but not reticular fibroblasts: A new view ...
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The results of this study demonstrated that statins inhibit oxidative stress-induced endothelial senescence and that, subsequently, upregulation of SIRT1 plays a critical role in prevention of senescence through Akt pathway.. The mechanisms by which statins stimulate the expression and activation of eNOS appear to involve the geranylgeranyl pathway, because mevalonate, GGPP, and FPP reversed the inhibitory effect of statins on senescence. It is well known that inhibition of geranylgeranylation leads to inactivation of Rho kinase. However, pharmacological inhibitors of Rho kinase did not affect endothelial senescence, which indicated that the inhibitory effect of statins on senescence was not mediated by inhibition of Rho kinase. Moreover, treatment with statins increased the phosphorylation of Akt at Ser473. Treatment with Akt siRNA or LY294002, which inhibited phosphorylation of Akt at Ser473, abrogated the eNOS activation and antisenescent property of atorvastatin. These results demonstrate ...
Cellular senescence is a complex phenotype observed in diverse tissues at distinct developmental stages. In adults, senescence likely acts to irreversibly prevent proliferation of damaged cells. Senescent cells appear during chronological aging, aberrant oncogene expression, and exposure to DNA damaging agents. Expression of the tumor suppressor p16INK4a increases with age in numerous mouse and human tissues and, thus, considered a reliable marker. Exposure to ionizing radiation (IR) leads to delayed increase in p16INK4a expression in mice tissues and cancer-treated patients Senescent cells accumulate in tissues and secrete a range of cytokines, chemokines, and proteases known as the senescence-associated secretory phenotype (SASP). Why senescent cells accumulate in vivo remains unclear. One theory suggests senescence accumulates with a decline in immune functions with age. While senescent cells support wound healing, accumulation of senescent cells also appears to contribute to tumor growth and ...
Chronic obstructive pulmonary disease (COPD) is a highly prevalent and devastating condition for which no curative treatment is available. Exaggerated lung cell senescence may be a major pathogenic factor. Here, we investigated the potential role for mTOR signaling in lung cell senescence and alterations in COPD using lung tissue and derived cultured cells from patients with COPD and from age- and sex-matched control smokers. Cell senescence in COPD was linked to mTOR activation, and mTOR inhibition by low-dose rapamycin prevented cell senescence and inhibited the proinflammatory senescence-associated secretory phenotype. To explore whether mTOR activation was a causal pathogenic factor, we developed transgenic mice exhibiting mTOR overactivity in lung vascular cells or alveolar epithelial cells. In this model, mTOR activation was sufficient to induce lung cell senescence and to mimic COPD lung alterations, with the rapid development of lung emphysema, pulmonary hypertension, and inflammation. ...
Cellular senescence is a fundamental cell fate playing significant and complex roles during tumorigenesis and natural aging process. However, the molecular determinants distinguishing senescence from other temporary and permanent cell-cycle arrest states such as quiescence and post-mitotic state and the specified mechanisms underlying cell-fate decisions towards senescence versus cell death in response to cellular stress stimuli remain less understood. In our studies, we aimed to employ multi-omics approaches to deepen our understanding of cellular senescence, in particular, regarding the specific molecular determinants distinguishing cellular senescence from other non-dividing cell fates. Notably, one of the most prominent features of cellular senescence differing from other non-dividing cell fates is the increased expression of senescence-associated beta-galactosidase. Because 5-Dodecanoylaminofluorescein Di-β-D-Galactopyranoside (C12FDG) is known as the substrate catalyzed by ...
Full Text - Vascular calcification is commonly seen in elderly people, though it can also appear in middle-aged subjects affected by premature vascular aging. The aim of this work is to test the involvement of microvesicles (MVs) produced by senescent endothelial cells (EC) and from plasma of elderly people in vascular calcification. The present work shows that MVs produced by senescent cultured ECs, plus those found in the plasma of elderly subjects, promote calcification in vascular smooth muscle cells. Only MVs from senescent ECs, and from elderly subjects plasma, induced calcification. This ability correlated with these types of MVs carriage of: a) increased quantities of annexins (which might act as nucleation sites for calcification), b) increased quantities of bone-morphogenic protein, and c) larger Ca contents. The MVs of senescent, cultured ECs, and those present in the plasma of elderly subjects, promote vascular calcification. The present results provide mechanistic insights into the
Even under conditions where the immune system cannot kill the cancer, the two cytokines interferon (IFN) and tumor necrosis factor (TNF), may drive cancers into senescence. Thus, senescence induction causes a state, where ‚the cancer sleeps well controlled in his host. This was first shown in an islet cancer of the pancreas (1, 4).. The same two cytokines, IFN and TNF, can drive a large number of mouse and human cancer cells into senescence. Clinically, this has two major consequences: Immune-induced senescence (figure 1) is obviously a physiological mechanism that contributes to the natural cancer control in humans (1). On the other side, recent data from cancer immune therapy suggest that the therapy is primarily efficient under conditions where the immune therapy causes permanent growth arrest of the metastases (8, 9).. Two mediators that are long known in cancer and infection immunology turn into the focus: interferon (IFN) and tumor necrosis factor (TNF). Many clinicians and researchers ...
In this work, we found that a MT1‐MMP‐dependent signaling between a defective ECM and the cell nucleus activates a senescence response that could explain some of the phenotypes caused by the loss of Mmp14 in mouse. This senescence process involves p16INK4a and p21CIP1/WAF1 and is also characterized by a series of archetypal senescent features, such as the presence of marked nuclear envelope abnormalities, the occurrence of a reduced proliferative potential, the induction of a chronic DNA damage response, and the triggering of a senescence‐associated secretory phenotype which involves the production of several inflammatory factors. We also show that this senescence program can be partially reversed by interventions on retinoid receptor signaling pathways, as demonstrated by the fact that treatment with ATRA increases life span and restores some of the phenotypic alterations observed in Mmp14‐deficient mice.. Interestingly, most molecular and cellular features observed in Mmp14−/− mice ...
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Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease tightly correlated with aging. The pathological features of IPF include epithelial cell senescence and abundant foci of highly activated pulmonary fibroblasts. However, the underlying mechanism between epithelial cell senescence and pulmonary fibroblast activation remain to be elucidated. In our study, we demonstrated that Nanog, as a pluripotency gene, played an essential role in the activation of pulmonary fibroblasts. In the progression of IPF, senescent epithelial cells could contribute to the activation of pulmonary fibroblasts via increasing the expression of senescence-associated secretory phenotype (SASP). In addition, we found activated pulmonary fibroblasts exhibited aberrant activation of Wnt/β-catenin signalling and elevated expression of Nanog. Further study revealed that the activation of Wnt/β-catenin signalling was responsible for senescent epithelial cell-induced Nanog phenotype in pulmonary
Loss of MDM2 can trigger senescence in WD/DDLS(A) The indicated cells were transduced with two different MDM2 knockdown lentiviral vectors (M376 or M380) or a s
Rationale: Uncontrolled growth of abdominal aortic aneurysms (AAAs) is a life-threatening vascular disease without an effective pharmaceutical treatment. AAA incidence dramatically increases with advancing age in men. However, the molecular mechanisms by which aging predisposes individuals to AAAs remain unknown. Objective: In this study, we investigated the role of Sirtuin 1 (SIRT1), a class Ⅲ histone deacetylase, in AAA formation and the underlying mechanisms linking vascular senescence and inflammation. Methods and Results: The expression and activity of SIRT1 were significantly decreased in human AAA samples. SIRT1 in vascular smooth muscle cells (VSMCs) was remarkably downregulated in the suprarenal aortas of aged mice, in which AAAs induced by Ang II infusion were significantly elevated. Moreover, VSMC-specific knockout of SIRT1 accelerated Ang II-induced formation and rupture of AAAs and AAA-related pathological changes, whereas VSMC-specific overexpression of SIRT1 suppressed Ang ...
Cellular senescence is the phenomenon by which normal ploid cells cease to divide. In culture, fibroblasts can reach a maximum of 50 cell divisions before becoming senescent. This phenomenon is known as "replicative senescence", or the Hayflick limit. Replicative senescence is the result of telomere shortening that ultimately triggers a DNA damage response. Cells can also be induced to senesce via DNA damage in response to elevated reactive oxygen species (ROS), activation of oncogenes and cell-cell fusion, independent of telomere length. As such, cellular senescence represents a change in "cell state" rather than a cell becoming "aged" as the name misleadingly suggests. Nonetheless, the number of senescent cells in tissues rises substantially during normal aging. Although senescent cells can no longer replicate, they remain metabolically active and commonly adopt an immunogenic phenotype consisting of a pro-inflammatory secretome, the up-regulation of immune ligands, a pro-survival response, ...
Cellular senescence is an irreversible state of terminal growth arrest that requires functional p53. Acting to block tumor formation, induction of senescence has also been demonstrated to contribute to tumor clearance via the immune system following p53 reactivation.1, 2 The Hdm2-antagonist, Nutlin-3a, has been shown to reactivate p53 and induce a quiescent state in various cancer cell lines,3, 4 similar to the G1 arrest observed upon RNAi targeting of Hdm2 in MCF7 breast cancer.5 In the present study we show that HdmX, a negative regulator of p53, impacts the senescence pathway. Specifically, overexpression of HdmX blocks Ras mediated senescence in primary human fibroblasts. The interaction of HdmX with p53 and the re-localization of HdmX to the nucleus through Hdm2 association appear to be required for this activity. Furthermore, inhibiting HdmX in prostate adenocarcinoma cells expressing wild-type p53, mutant Ras and high levels of HdmX induced cellular senescence as measured by an increase in
Our studies reveal that the fundamental architecture of the genome undergoes profound alterations during replicative cellular senescence. One consequence is an overall closing of chromatin in euchromatic gene-rich regions, as evidenced by decreased FAIRE enrichment and associated dampening of gene activity, although some specific genes oppose this trend and become expressed at higher levels in senescent cells. Another, somewhat paradoxical trend, is an overall relative opening of chromatin in mostly heterochromatic gene-poor regions, as evidenced by increased FAIRE enrichment. The latter is associated with increased transcription of transposable elements, culminating in active transposition, as evidenced by an increase in copy number of L1 elements.. Telomere dysfunction drives a state of persistent DNA damage, which chronically activates the ATM and p53 pathways, leading to the cell cycle arrest that is the hallmark of senescence. Many forms of oncogene-induced senescence have also been ...
In culturing normal diploid cells, senescence may either happen naturally, in the form of replicative senescence, or it may be a consequence of external challenges such as oxidative stress. Here we present a comparative analysis aimed at reconstruction of molecular cascades specific for replicative (RS) and stressinduced senescence (SIPS) in human fibroblasts. An involvement of caspase-3/keratin-18 pathway and serine/threonine kinase Aurora A/ MDM2 pathway was shared between RS and SIPS. Moreover, stromelysin/MMP3 and N-acetylglucosaminyltransferase enzyme MGAT1, which initiates the synthesis of hybrid and complex Nglycans, were identified as key orchestrating components in RS and SIPS, respectively. In RS only, Aurora-B driven cell cycle signaling was deregulated in concert with the suppression of anabolic branches of the fatty acids and estrogen metabolism. In SIPS, Aurora-B signaling is deprioritized, and the synthetic branches of cholesterol metabolism are upregulated, rather than downregulated.
The characteristic limited reproductive life-span of normal human fibroblasts in culture is due to a steadily decreasing fraction of cells able to proliferate in the standard rich growth media. We have observed that restricting the growth factor supply to old cells for variable lengths of time in culture increases the fraction of cells that can enter S-phase; although these cells do not go on to divide. Thus, it seems that there is a transient phase between the proliferating state and the irreversibly post-mitotic, senescent state. Perhaps a quiescent-G0 state, which can be maintained in the presence of growth factors, is a stage on the pathway to mortalization and senescence. ...
Produced by senescent cells, the senescence-associated secretory phenotype (SASP) is a potential driver of age-related dysfunction. We tested whether circulating concentrations of SASP proteins reflect age and medical risk in humans. We first screened senescent endothelial cells, fibroblasts, preadipocytes, epithelial cells, and myoblasts to identify candidates for human profiling. We then tested associations between circulating SASP proteins and clinical data from individuals throughout the life span and older adults undergoing surgery for prevalent but distinct age-related diseases. A community-based sample of people aged 20-90 years (retrospective cross-sectional) was studied to test associations between circulating SASP factors and chronological age. A subset of this cohort aged 60-90 years and separate cohorts of older adults undergoing surgery for severe aortic stenosis (prospective longitudinal) or ovarian cancer (prospective case-control) were studied to assess relationships between ...
Over half a century ago, Hayflick and Moorhead demonstrated that primary human cells in culture have a limited capacity for replication [1]. After undergoing a finite number of divisions, these cells entered into a permanent cell cycle arrest, subsequently termed replicative or cellular senescence. They hypothesized that cellular senescence was a model‐in‐miniature of processes leading to organismal aging. They also noted that cancer cells divided indefinitely in culture, suggesting a role for replicative senescence in preventing cancer.. The intracellular signals that drive senescence remained obscure until the discovery of telomere erosion and telomerase. Telomeres are repetitive DNA sequences that comprise the ends of many linear chromosomes and protect them from degradation and recombination. Telomeres erode with each cell division due to the biochemical nature of DNA replication: the use of RNA‐based priming of the lagging strand and unidirectionality of DNA polymerases. Thus, ...
Premature or drug-induced senescence is a main cellular response to chemotherapy in stable tumors. results of Wip1 may become credited to its capability to dephosphorylate p53 at Ser15 and to lessen DNA harm response. Nevertheless, we also uncover a regulatory path whereby reductions of g53 Ser15 phosphorylation can be connected with improved phosphorylation at Ser46, improved g53 proteins amounts, and induction of Noxa appearance. On the entire, our data indicate that down-regulation of Wip1 appearance during premature senescence takes on a pivotal part in controlling many g53-reliant elements of the senescent phenotype. and and and and and and data not really demonstrated), an impact most likely attributable to a selection against Wip1-articulating senescent cells. Remarkably, under the circumstances utilized for regular distribution of the cells, in the lack of senescence induction, cells maintain a fairly steady level of FLAG-Wip1 appearance. 3 FIGURE. Cell routine distribution in senescent ...
Endothelial cell senescence is closely related to the occurrence of cardiovascular diseases and microRNAs (miRNAs/miRs) are considered as therapeutic targets for cardiovascular disease. The current study aimed to investigate the role of miR‑20b in the senescence process of endothelial cells and its underlying mechanism. Cell viability, proportion of senescent cells and the cell cycle were respectively determined by Cell Counting Kit‑8, SA‑β‑galactosidase and flow cytometry. The relative expressions of mRNA and protein were detected by reverse transcription‑quantitative polymerase chain reaction and western blotting, respectively. The possible target genes and binding sites of miR‑20b were predicted using Targetscan and further verified by dual luciferase reporter assay. The present study found that H2O2 inhibited cell viability, caused cell cycle arrest in G1 phase, decreased miR‑20b level and induced cell senescence. Moreover, high expression of miR‑20b promoted cell viability ...
TY - JOUR. T1 - PAI-1 contributes to homocysteine-induced cellular senescence. AU - Sun, Tianjiao. AU - Ghosh, Asish K.. AU - Eren, Mesut. AU - Miyata, Toshio. AU - Vaughan, Douglas E.. PY - 2019/12. Y1 - 2019/12. N2 - Cellular Senescence is associated with organismal aging and related pathologies. Previously, we reported that plasminogen activator inhibitor-1 (PAI-1) is an essential mediator of senescence and a potential therapeutic target for preventing aging-related pathologies. In this study, we investigate the efficacies of PAI-1 inhibitors in both in vitro and in vivo models of homocysteine (Hcy)-induced cardiovascular aging. Elevated Hcy, a known risk factor of cardiovascular diseases, induces endothelial senescence as evidenced by increased senescence-associated β-Gal positivity (SA-β-Gal), flattened cellular morphology, and cylindrical appearance of cellular nuclei. Importantly, inhibition of PAI-1 by small molecule inhibitors reduces the number of SA-β-Gal positive cells, normalizes ...
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The tumor suppressor p16INK4a is a potent mediator of cell cycle arrest in transient expression studies, is induced in senescing cells, and can impose morphological features of senescence. Nonetheless, it is unclear whether p16INK4a can block cell proliferation irreversibly. We explored this issue u …
The exact mechanisms that connect the mind to the cell are unknown. Although it is well accepted that cell senescence can include stress-induced processes, psychological stress has not yet been considered as part of the stress pathway. The current findings suggest that stress-induced premature senescence in people might be influenced by chronic or perceived life stress. Psychological stress could affect cell aging through at least three nonmutually exclusive pathways: immune cell function or distribution, oxidative stress, or telomerase activity. We considered whether stress might have decreased naïve T cells and increased memory T cells [which have shorter telomere length (22)], but the data did not support this (Table 2, which is published as supporting information on the PNAS web site). Second, stress could potentially lead to oxidative stress by means of chronic activation of the autonomic and neuroendocrine stress responses. Although this hypothesis has never been tested in vivo, the ...
The p16INK4a cyclin-dependent kinase inhibitor is implicated in replicative senescence, the state of permanent growth arrest provoked by cumulative cell divisions or as a response to constitutive Ras-Raf-MEK signalling in somatic cells. Some contribution to senescence presumably underlies the importance of p16INK4a as a tumour suppressor but the mechanisms regulating its expression in these different contexts remain unknown. Here we demonstrate a role for the Ets1 and Ets2 transcription factors based on their ability to activate the p16INK4a promoter through an ETS-binding site and their patterns of expression during the lifespan of human diploid fibroblasts. The induction of p16INK4a by Ets2, which is abundant in young human diploid fibroblasts, is potentiated by signalling through the Ras-Raf-MEK kinase cascade and inhibited by a direct interaction with the helix-loop-helix protein Id1 (ref. 11). In senescent cells, where the Ets2 levels and MEK signalling decline, the marked increase in ...
Our study provides a method to rapidly screen putative S6K substrates by direct in vivo labelling. Quantitative phospho‐proteomic studies have recently led to the deep and high‐quality coverage of phosphopeptides whose abundance varies with perturbations in mTOR signalling (Moritz et al, 2010; Hsu et al, 2011; Yu et al, 2011; Robitaille et al, 2013). Strikingly, the phosphorylation of approximately 4% of human gene products is under control of the mTOR pathway. The phosphopeptides include direct mTOR substrates but also proteins whose phosphorylation is controlled by kinases and phosphatases downstream of mTOR. This information, in combination with in silico searches for Ser/Thr sites surrounded by basic residues, provides a powerful tool to interrogate the mTOR phospho‐proteome and reveals a subset of S6K direct substrates using an analogue‐specific mutant kinase. In this initial study, out of ten putative candidates, three proteins are reliably phosphorylated by AS‐S6K1: Cux1 is a ...
Background Previous work has demonstrated YPEL3 to be a growth-suppressive protein that acts through a pathway of cellular senescence. We set out to determine whether human colon tumors demonstrated downregulation of YPEL3. Methods We collected colon tumor samples with matched normal control samples and analyzed them forYPEL3 gene expression by reverse transcriptase-polymerase chain reaction and CpG hypermethylation of the YPEL3 promoter by base-specific polymerase chain reaction analysis. Colon cancer cell lines (Caco-2 and HCT116−/− p53) were used to assess YPEL3 gene expression after treatment with 5-azadeoxycytidine or trichostatin A. Results Reverse transcriptase-polymerase chain reaction analysis demonstrated a decrease in YPEL3expression in tumor samples when compared to their patient-matched normal tissue. We determined that DNA methylation of the YPEL3 promoter CpG island does not play a role in YPEL3 regulation in human colon tumors or colon cancer cells lines, consistent with the
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Due to its role in aging and antitumor defense, cellular senescence has recently attracted increasing interest. However, [the] detection of senescent cells remains difficult due to the lack of specific biomarkers. ndeed, most determinants of cellular senescence, such as the upregulation of p53, p16Ink4a, p21WAF/CIP1 or SASP-associated cytokines, are not exclusively observed in senescence, but can also occur in other types of stress responses. In addition, alterations like SAHF or DNA-SCARS formation are frequently observed, but not necessarily a mandatory feature or exclusive to senescent cells. The current gold standard for the detection of senescence is the so-called senescence-associated β-galactosidase (SA-β-Gal) activity. Although SA-β-Gal has been first suggested as a distinct enzyme, its activity is derived from lysosomal β-Gal encoded by the GLB1 gene. β-Gal is an accepted marker of senescence, but its reliability and specificity have been questioned, as a positive β-Gal reaction ...
p53 protein levels increase in HDFs, such as IMR90 and MRC5, during replicative senescence (8-11). Moreover, p53 sequence-specific DNA-binding activity and transcriptional activity also increase during replicative senescence (9, 12). These studies (8-12) have suggested a role for p53 in the onset and maintenance of cellular senescence. Consistent with this idea, the p53-mediated induction of p21 and Gadd45 genes in normal human cells is known (13, 16, 17) to play a role in cell growth arrest. However, the number of p53 target genes whose expression is induced during cellular senescence in HDFs remains rather limited. Therefore, our observations that p53 activates the transcription of IFI16, a candidate cellular senescence gene, in response to certain DNA damage signals in normal human fibroblasts are important.. The IFI16 protein is an IFN-inducible protein and treatment of a variety of cells with IFNs (α, β, or γ) has been shown to result in up-regulation of the IFI16 mRNA and protein (21). ...
Cellular senescence is a state of permanent cell cycle arrest in which a cell is unable to further divide in response to normal growth stimuli. Telomere shortening, believed to be a mechanism of cellular senescence, is a result of numerous rounds of cell division and can be accelerated by heightened levels of oxidative stress. An accumulation of senescent T lymphocytes in blood and tissues has been suggested to contribute to the general immunosuppression seen in the elderly. Obese individuals and athletes taking part in regular high intensity exercise are subjected to heightened states of oxidative stress which appears to result in immunosuppression and increased susceptibility to infection. It was hypothesised that there would be an accumulation of senescent T lymphocytes with ageing, with obesity and during six months training for an Iron man competition ...
How long can human beings live? Is there an outside limit? Do we know enough about aging to break through possible biological barriers? Is the current approach to curing "age associated diseases" like Alzheimers flawed? Experts are sharply divided.. In 1962 eminent biologist Leonard Hayflick discovered that normal human fetal cells replicate a limited number of times. This phenomenon promptly acquired the moniker the "Hayflick Limit." Later, biologists Calvin Harley and Carol Greider provided the molecular explanation for the Hayflick limit with their discovery that telomeres, the DNA biological material in every cell of our bodies, diminish each time cells divide.. In contrast, cancer cells, which are immortal, produce an enzyme called telomerase that maintains the length of telomeres and enables cancer cells to replicate without limit. The strategy of extending the life of normal cells by injecting telomerase has proven thorny, as reported by Dr. Elizabeth Blackburn, co-discoverer of ...
To determine whether 1,25-dihydroxyvitamin D (1,25(OH)2 D) can exert an anti-osteoporosis role through anti-aging mechanisms, we analyzed the bone phenotype of mice with 1,25(OH)2 D deficiency due to deletion of the enzyme, 25-hydroxyvitamin D 1α-hydroxylase, while on a rescue diet. 1,25(OH)2 D deficiency accelerated age-related bone loss by activating the p16/p19 senescence signaling pathway, inhibiting osteoblastic bone formation, and stimulating osteoclastic bone resorption, osteocyte senescence, and senescence-associated secretory phenotype (SASP). Supplementation of exogenous 1,25(OH)2 D3 corrected the osteoporotic phenotype caused by 1,25(OH)2 D deficiency or natural aging by inhibiting the p16/p19 pathway. The proliferation, osteogenic differentiation, and ectopic bone formation of bone marrow mesenchymal stem cells derived from mice with genetically induced deficiency of the vitamin D receptor (VDR) were significantly reduced by mechanisms including increased oxidative stress, DNA ...
Cellular senescence is a physiological phenomenon that has both beneficial and detrimental consequences. Senescence limits tumorigenesis and tissue damage throughout the lifetime. However, at the late stages of life, senescent cells increasingly accumulate in tissues and might also contribute to the development of various age-related pathologies. Recent studies have revealed the molecular pathways that preserve the viability of senescent cells and the ones regulating their immune surveillance. These studies provide essential initial insights for the development of novel therapeutic strategies for targeting senescent cells. At the same time they stress the need to understand the limitations of the existing strategies, their efficacy and safety, and the possible deleterious consequences of senescent cell elimination. Here we discuss the existing strategies for targeting senescent cells and upcoming challenges in translating these strategies into safe and efficient therapies. Successful translation ...
Cellular senescence is a normal consequence of aging, resulting from lifelong accumulation of DNA damage that triggers an end to cell replication. Although senescent cells no longer divide, they persist in their tissue of origin and develop characteristics that can hasten and exacerbate age-related disease. This series addresses the contribution of cellular senescence to cardiovascular, neurodegenerative, and arthritic disorders as well as the senescent phenotypes in various tissues and cell types. In addition to their cell-intrinsic effects, senescent cells develop the ability to negatively influence healthy neighboring cells and immune cells by secreting senescence-associated set of cytokines and mediators known as the SASP. These reviews also highlight ongoing efforts to accurately identify, target, and eliminate senescent cells or otherwise combat their deleterious effects in disease. One day, this work may provide the basis for therapies targeting aging cells in multiple organs.. ...
Tumor development is a multi-step process driven by the collective action of gain-of-function mutations in oncogenes and loss-of-function alterations in tumor suppressor genes. The particular spectrum of mutations in a given cancer is rarely the result of random chance but instead derives from the intimate connections between proliferative networks and those suppressing growth and transformation. Specifically, hyper-active oncogenes directly engage tumor suppressor programs, such that cells harboring oncogenic lesions frequently must acquire secondary mutations that disable these anti-proliferative responses before progressing to overt transformation. This tight coupling represents a critical checkpoint protecting against tumor formation. Whether different cell types exhibit variability in the extent and/or timing of this oncogene-induced tumor suppression is largely unknown. The ability of oncogenic Ras to induce the tumor suppressive p1 9 Arf-p5.3 pathway and cause irreversible cell cycle ...
Several previous studies have pointed to the functional significance of H4K20me3 in senescent and progeroid cells [33, 34]. Here we have confirmed that H4K20me3 is also upregulated in senescent cells in vivo, specifically OIS melanocytes. Compared with proliferating cells, H4K20me3 is relatively enriched in both RS and OIS cells in at least three features of the genome. First, based on immunofluorescence and ChIP-seq analysis, H4K20me3 is enriched in heterochromatic SAHF. Here, H4K20me3 co-localizes with another heterochromatic modification, H3K9me3. H3K9me3 is indirectly responsible for recruitment of SUV420H2 and H4K20me3 to chromatin [49, 55], and in SAHF, H4K20me3 specifically overlapped with H3K9me3, not late-replicating DNA. Thus, H3K9me3 is likely responsible for recruitment of H4K20me3 to SAHF. Previously, we showed that telomeres are largely excluded from SAHF in RS cells [70]. In line with this initially surprising observation and enrichment of H4K20me3 in SAHF, we show here that ...
BMI1 plays critical roles in maintaining the self-renewal of hematopoietic, neural, intestinal stem cells, and cancer stem cells (CSCs) for a variety of cancer types. BMI1 promotes cell proliferative life span and epithelial to mesenchymal transition (EMT). Upregulation of BMI1 occurs in multiple cancer types and is associated with poor prognosis. Mechanistically, BMI1 is a subunit of the Polycomb repressive complex 1 (PRC1), and binds the catalytic RING2/RING1b subunit to form a functional E3 ubiquitin ligase. Through mono-ubiquitination of histone H2A at lysine 119 (H2A-K119Ub), BMI1 represses multiple gene loci; among these, the INK4A/ARF locus has been most thoroughly investigated. The locus encodes the p16INK4A and p14/p19ARF tumor suppressors that function in the pRb and p53 pathways, respectively. Its repression contributes to BMI1-derived tumorigenesis. BMI1 also possesses other oncogenic functions, specifically its regulative role in DNA damage response (DDR). In this process, BMI1
The amount of cellular proteins is a crucial parameter that is known to vary between cells as a function of the replicative passages, and can be important during physiological aging. The process of protein degradation is known to be performed by a series of enzymatic reactions, ranging from an initial step of protein ubiquitination to their final fragmentation by the proteasome. In this paper we propose a stochastic dynamical model of nuclear proteins concentration resulting from a balance between a constant production of proteins and their degradation by a cooperative enzymatic reaction. The predictions of this model are compared with experimental data obtained by fluorescence measurements of the amount of nuclear proteins in murine tail fibroblast (MTF) undergoing cellular senescence. Our model provides a three-parameter stationary distribution that is in good agreement with the experimental data even during the transition to the senescent state, where the nuclear protein concentration changes
The above studies suggest that senescent cells may accumulate with age and at sites of pathology in the brain. However, the significance of senescent cells in both the induction and exacerbation of neurodegenerative disorders is unknown. To date, it has been extremely difficult to discern the overall significance and mechanistic contribution of senescent cells to neuropathology because of a lack of tools to identify, isolate, and/or eliminate these cells. Current methods rely on a combination of markers, including those described in Figure 1. As these markers are not truly unique to senescent cells, it is imperative to establish that these changes occur in the context of senescence and not just as a result of inflammation, for example. A true demonstration that senescent cells causally drive neuropathology can be achieved either by prevention of senescence entry through genetic inactivation of p16INK4A or by direct elimination of senescent cells using genetically engineered mice. To date, these ...