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senescence-associated secretory phenotype

Alex Wong, Sixun Chen, Lay Kien Yang, Yoganathan Kanagasundaram, Karen Crasta
Aberrant lipid accumulation is a hallmark of cancer known to contribute to its aggressiveness and malignancy. Emerging studies have demonstrated context-dependent changes in lipid metabolism during chemotherapy. However, there is little known regarding the mechanisms linking lipid metabolism to chemotherapy-induced cell fates. Here, we describe lipid accumulation in cells following antimitotic drug treatment. Cells arrested in mitosis, as well as cells that escaped mitotic arrest and underwent mitotic slippage, showed elevated cytoplasmic lipid droplets...
2018: Cell Death Discovery
Penelope D Ruiz, Matthew J Gamble
The histone variant macroH2A1 localizes to two functionally distinct chromatin subtypes marked by either H3K27me3 or H2B acetylations, where it is thought to directly regulate transcription. The recent finding, that macroH2A1 regulates mitochondrial respiration by globally dampening PARP activity, requires the field to re-evaluate which functions of macroH2A1 are due to global effects on cellular metabolism and which are direct effects determined by macroH2A1 chromatin localization. Here, we demonstrate macroH2A1 incorporation into H2B-acetylated chromatin requires a feature in its histone-fold domain, distinguishing this process from incorporation into H3K27me3-containing chromatin in which multiple features of macroH2A1 are sufficient for targeting...
December 3, 2018: Nature Communications
Pavan Parikh, Rodney D Britt, Logan J Manlove, Sarah A Wicher, Anne Roesler, Jovanka Ravix, Jacob Teske, Michael A Thompson, Gary C Sieck, James L Kirkland, Nathan LeBrasseur, Daniel J Tschumperlin, Christina M Pabelick, Y S Prakash
Supplemental O2 (hyperoxia; 30-90% O2) is a necessary intervention for premature infants, but contributes to development of neonatal and pediatric asthma, necessitating better understanding of contributory mechanisms in hyperoxia-induced changes to airway structure and function. In adults, environmental stressors promote formation of senescent cells that secrete factors (senescence-associated secretory phenotype; SASP), which can be inflammatory and have paracrine effects that enhance chronic lung diseases...
December 3, 2018: American Journal of Respiratory Cell and Molecular Biology
Andrew R Mendelsohn, James Larrick
Neuroinflammation is thought to play a key role in progression of neurodegenerative disease such as Alzheimer's disease. Given the apparent nexus of inflammatory disease with the secretory associated senescence phenotype (SASP) of cellular senescence, two reports found that tau-mediated neurodegeneration involves induction of senescence in astrocytes, microglia and possibly even neurons. Elimination of senescent cells by pharmacological induced genetic ablation or by senolytic drugs blocks progression of mutant human tau-mediated neurodegeneration in mice...
November 29, 2018: Rejuvenation Research
Marco Malavolta, Elisa Pierpaoli, Robertina Giacconi, Andrea Basso, Maurizio Cardelli, Francesco Piacenza, Mauro Provinciali
Tocotrienols (T3) have been shown to represent a very important part of the vitamin E family since they have opened new opportunities to prevent or treat a multitude of age-related chronic diseases. The beneficial effects of T3 include the amelioration of lipid profile, the promotion of Nrf2 mediated cytoprotective activity and the suppression of inflammation. All these effects may be the consequence of the ability of T3 to target multiple pathways. We here propose that these effects may be the result of a single target of T3, namely senescent cells...
2018: Biological Procedures Online
Ji-Nuo Wang, Xin-Xin Cao, Ai-Lin Zhao, Hao Cai, Xuan Wang, Jian Li
Background: Accumulating evidence have indicated that regulatory T cells (Tregs) play an essential role in T cell-mediated immune response and development of multiple myeloma (MM). CD4+ FoxP3+ T cells are composed of three phenotypically and functionally distinct subpopulations: CD45RA+ FoxP3lo resting Tregs (rTregs), CD45RA- FoxP3hi activated Tregs (aTregs) and CD45RA- FoxP3lo non-suppressive T cells (non-Tregs). We aimed to clarify the frequency and function of these three subpopulations in newly diagnosed multiple myeloma and monoclonal gammopathy of undetermined significance (MGUS) patients...
2018: Cancer Cell International
Lei Zhang, Jing Zhao, Aditi Gurkar, Laura J Niedernhofer, Paul D Robbins
Nuclear factor κB (NF-κB) is a family of transcription factors important for regulating innate and adaptive immunity, cellular proliferation, apoptosis and senescence. The NF-κB family is comprised of five subunits, RelA/p65, RelB, C-Rel, p50 (p105/NF-κB1), and p52 (p100/NF-κB2). NF-κB activity goes up with age in multiple tissues. The two subunits RelA/p65 and p50 have been implicated in senescence and aging with genetic deletion of p65 and p50 reducing or increasing senescence respectively. Pharmacologic inhibition of NF-κB also extends health span and reduces senescence in mouse models of accelerated aging...
2019: Methods in Molecular Biology
Matthew J Yousefzadeh, Kendra I Melos, Luise Angelini, Christin E Burd, Paul D Robbins, Laura J Niedernhofer
Senescent cells accumulate in multiple tissues as virtually all vertebrate organisms age. Senescence is a highly conserved response to many forms of cellular stress intended to block the propagation of damaged cells. Senescent cells have been demonstrated to play a causal role in aging via their senescence-associated secretory phenotype and by impeding tissue regeneration. Depletion of senescent cells either through genetic or pharmacologic methods has been demonstrated to extend murine lifespan and delay the onset of age-related diseases...
2019: Methods in Molecular Biology
Andrew J Innes, Jesús Gil
Oncogene-induced senescence (OIS) is a cellular response that limits the replication of cells expressing oncogenes. As a result, OIS is a potent tumor suppressor mechanism limiting cancer progression. Here we describe IMR90 ER:RAS, a widely used model to study OIS in cell culture. This model takes advantage of IMR90 human primary fibroblast infected with a 4-hydroxy-tamoxifen (4-OHT) inducible ER:RAS construct. RAS activation upon 4-OHT treatment results in a coordinated induction of senescence, recapitulating different aspects of the phenotype such as the growth arrest and the establishment of a senescence-associated secretory phenotype (SASP)...
2019: Methods in Molecular Biology
Irene Fernández-Duran, Núria Tarrats, Priya Hari, Juan Carlos Acosta
Inflammasomes are multimeric protein complexes that process IL-1β by cleaving the translated full-length protein into its active IL-1β mature fragment. In oncogene-induced senescence, inflammasomes play a crucial role by regulating IL1R signaling and consequently modulating proliferation and the senescence-associated secretory phenotype (SASP). Inflammasome activation requires two steps: (a) priming of the inflammasome by activation of IL1B expression, followed by (b) cleavage and release of mature IL-1β...
2019: Methods in Molecular Biology
Nicolas Malaquin, Véronique Tu, Francis Rodier
Cellular senescence is linked to many normal biological processes, including tumor suppression, development, and wound healing, but it is also associated with age-related pathologies such as cancer progression. Numerous functions of senescent cells depend on their ability to secrete bioactive molecules, a characteristic termed the senescence-associated secretory phenotype (SASP). Although the SASP is generally described as proinflammatory, its true microenvironmental impact and composition may vary according to cell types (i...
2019: Methods in Molecular Biology
Bennett G Childs, Tyler J Bussian, Darren J Baker
Senescence-associated β-galactosidase (hereafter SA-β-gal) staining has now been employed for more than 20 years to identify the presence of senescent cells (Dimri et al., Proc Natl Acad Sci U S A 92:9363-9367, 1995). These cells, characterized by a permanent cell-cycle arrest (Hayflick and Moorhead, Exp Cell Res 25:585-621, 1961) and the production of a distinct secretory phenotype of cytokines, chemokines, and proteases (Coppe et al., PLoS Biol 6:2853-2868, 2008), have received much attention in recent years for their impacts on diverse biological processes...
2019: Methods in Molecular Biology
Gabor A Fulop, Tamas Kiss, Stefano Tarantini, Priya Balasubramanian, Andriy Yabluchanskiy, Eszter Farkas, Ferenc Bari, Zoltan Ungvari, Anna Csiszar
Aging-induced pro-inflammatory phenotypic alterations of the cerebral vasculature critically contribute to the pathogenesis of vascular cognitive impairment. Cellular senescence is a fundamental aging process that promotes inflammation; however, its role in cerebrovascular aging remains unexplored. The present study was undertaken to test the hypothesis that advanced aging promotes cellular senescence in the cerebral vasculature. We found that in cerebral arteries of 24-month-old mice, expression of molecular markers of senescence (p16INK4a , p21) is upregulated as compared to that in young controls...
November 23, 2018: GeroScience
Yi-Chun Tsai, Po-Lin Kuo, Mei-Chuan Kuo, Wei-Wen Hung, Ling-Yu Wu, Wei-An Chang, Ping-Hsun Wu, Su-Chu Lee, Hung-Chun Chen, Ya-Ling Hsu
Diabetic nephropathy (DN) is the major cause of end stage renal disease. Proximal tubular epithelial cell (PTEC) injury occurs early in diabetic kidney, and it is correlated with consequent renal failure. Cellular senescence participates in the pathophysiology of DN, but its role remains unclear. We conducted a cross-disciplinary study, including human, in vivo, and in vitro studies, to explore the novel molecular mechanisms of PTEC senescence in DN. We found that HG induced cell senescence in PTECs, supported by enhanced β-galactosidase staining, p53 and p27 expression, and reduced cyclin E levels...
November 22, 2018: Journal of Clinical Medicine
Ravi Kumar, Anamika Sharma, Amita Kumari, Ashu Gulati, Yogendra Padwad, Rohit Sharma
The phytochemical epigallocatechin gallate (EGCG) has been reported to alleviate age-associated immune disorders and organ dysfunction. However, information regarding the mechanistic role of EGCG in the suppression of cellular senescence is limited. The present study thus assessed the effects and underlying mechanisms of EGCG in the inhibition of senescence as well as its potential to selectively eliminate senescent cells (senolytics) using 3T3-L1 preadipocytes. Premature senescence was established in cells by repeated exposure of H2 O2 at a sub-lethal concentration (150 μM)...
November 19, 2018: Biogerontology
Mari Yamagami, Motoyuki Otsuka, Takahiro Kishikawa, Kazuma Sekiba, Takahiro Seimiya, Eri Tanaka, Tatsunori Suzuki, Rei Ishibashi, Motoko Ohno, Kazuhiko Koike
During cellular aging, many changes in cellular functions occur. A hallmark of aged cells is secretion of inflammatory mediators, which collectively is referred to as the senescence-associated secretory phenotype (SASP). However, the mechanisms underlying such changes are unclear. Canonically, the expression of interferon (IFN)-stimulated genes (ISGs) is induced by IFNs through the formation of the tripartite transcriptional factor ISGF3, which is composed of IRF9 and the phosphorylated forms of STAT1 and STAT2...
2018: NPJ Aging and Mechanisms of Disease
Boyi Zhang, Eric W-F Lam, Yu Sun
Cellular senescence is a typical tumor-suppressive mechanism that restricts the proliferation of premalignant cells. However, mounting evidence suggests that senescent cells, which also persist in vivo, can promote the incidence of aging-related disorders principally via the senescence-associated secretory phenotype (SASP), among which cancer is particularly devastating. Despite the beneficial effects of the SASP on certain physiological events such as wound healing and tissue repair, more studies have demonstrated that senescent cells can substantially contribute to pathological conditions and accelerate disease exacerbation, particularly cancer resistance, relapse and metastasis...
November 19, 2018: Aging Cell
Raffaella Lazzarini, Michele Nicolai, Vittorio Pirani, Cesare Mariotti, Roberto Di Primio
Regenerative medicine approaches based on mesenchymal stem cells (MSCs) are being investigated to treat several aging-associated diseases, including age-related macular degeneration (AMD). Loss of retinal pigment epithelium (RPE) cells occurs early in AMD, and their transplant has the potential to slow disease progression.The human RPE contains a subpopulation of cells - adult RPE stem cells (RPESCs) - that are capable of self-renewal and of differentiating into RPE cells in vitro . However, age-related MSC changes involve loss of function and acquisition of a senescence-associated secretory phenotype (SASP), which can contribute to the maintenance of a chronic state of low-grade inflammation in tissues and organs...
November 16, 2018: Aging
Milan R Stojiljkovic, Quratul Ain, Tzvetanka Bondeva, Regine Heller, Christian Schmeer, Otto W Witte
Microglia, the key innate immune cells in the brain, have been reported to drive brain aging and neurodegenerative disorders; however, few studies have analyzed microglial senescence and the impact of aging on the properties of microglia. In the present study, we characterized senescence- and aging-associated phenotypes of murine brain microglia using well-accepted markers, including telomere length, telomerase activity, expression of p16INK4a , p21, p53, senescence-associated β-galactosidase, and a senescence-associated secretory phenotype...
October 12, 2018: Neurobiology of Aging
Masumi Iketani, Kanako Sekimoto, Tsutomu Igarashi, Mayumi Takahashi, Masaki Komatsu, Iwao Sakane, Hiroshi Takahashi, Hideo Kawaguchi, Ritsuko Ohtani-Kaneko, Ikuroh Ohsawa
The main cause of arteriosclerosis is atherosclerosis in the aorta. Atherosclerosis is recognized as a chronic inflammatory condition that begins with the dysfunction or activation of arterial endothelium. Low-density lipoprotein (LDL) and especially its oxidized form play a key role in endothelial dysfunction and atherogenesis. Recent studies showed that senescent cells are involved in the development and progression of atherosclerosis, and eliminating senescent cells suppresses the senescence-associated secretory phenotype...
November 14, 2018: Scientific Reports
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