A complex secretory program orchestrated by the inflammasome controls paracrine senescence
Juan Carlos Acosta,Ana Banito,Torsten Wuestefeld,Athena Georgilis,Peggy Janich,Jennifer P. Morton,Dimitris Athineos,Tae-Won Kang,Felix Lasitschka,Mindaugas Andrulis,Gloria Pascual,Kelly J. Morris,Sadaf Khan,Hong Jin,Gopuraja Dharmalingam,Ambrosius P. Snijders,Thomas L. Carroll,David Capper,Catrin Pritchard,Gareth J. Inman,Thomas Longerich,Owen J. Sansom,Salvador Aznar Benitah,Lars Zender,Jesús Gil +24 more
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TLDR
It is demonstrated that the SASP can cause paracrine senescence and impact on tumour suppression andSenescence in vivo and TGF-β ligands play a major role by regulating p15INK4b and p21CIP1.Abstract:
Oncogene-induced senescence (OIS) is crucial for tumour suppression. Senescent cells implement a complex pro-inflammatory response termed the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence, activates immune surveillance and paradoxically also has pro-tumorigenic properties. Here, we present evidence that the SASP can also induce paracrine senescence in normal cells both in culture and in human and mouse models of OIS in vivo. Coupling quantitative proteomics with small-molecule screens, we identified multiple SASP components mediating paracrine senescence, including TGF-β family ligands, VEGF, CCL2 and CCL20. Amongst them, TGF-β ligands play a major role by regulating p15(INK4b) and p21(CIP1). Expression of the SASP is controlled by inflammasome-mediated IL-1 signalling. The inflammasome and IL-1 signalling are activated in senescent cells and IL-1α expression can reproduce SASP activation, resulting in senescence. Our results demonstrate that the SASP can cause paracrine senescence and impact on tumour suppression and senescence in vivo.read more
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Dissertation
The role of chondrocyte senescence in the pathogenesis of canine osteoarthritis
TL;DR: It is demonstrated that experimentally induced oxidative stress in chondrocytes in monolayer culture increases levels of cellular senescence and alters the expression of genes relevant to the pathogenesis of canine OA.
Journal ArticleDOI
Down-Regulation of the Proteoglycan Decorin Fills in the Tumor-Promoting Phenotype of Ionizing Radiation-Induced Senescent Human Breast Stromal Fibroblasts.
Eleni Mavrogonatou,Adamantia Papadopoulou,Asimina Fotopoulou,Stathis Tsimelis,Heba Bassiony,Andreas M Yiacoumettis,Petros N. Panagiotou,Harris Pratsinis,Dimitris Kletsas +8 more
TL;DR: In this article, the authors showed that senescent human breast stromal fibroblasts are characterized by the down-regulation of decorin at the mRNA and protein level, as well as by its decreased deposition in the pericellular extracellular matrix in vitro.
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The secretome of senescent preadipocytes influences the phenotype and function of cells of the vascular wall.
TL;DR: Maladaptive changes in response to senescent cell exposure provide early evidence in support of a hypothesis that senescent preadipocytes trigger phenotypic and functional changes in key cellular components of blood vessels that may contribute to vascular disease.
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A geroscience motivated approach to treat Alzheimer's disease: Senolytics move to clinical trials.
Mitzi M. Gonzales,Sudarshan Krishnamurthy,Valentina R. Garbarino,Ali S. Daeihagh,Gregory J. Gillispie,Gagan Deep,Suzanne Craft,Miranda E. Orr,Miranda E. Orr +8 more
TL;DR: A recent review as discussed by the authors describes the path to translating this promising treatment strategy to clinical trials and summarizes the goals of the first senolytic trials for the treatment of Alzheimer's disease (NCT04063124 and NCT04685590).
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The multifaceted role of the SASP in atherosclerosis: from mechanisms to therapeutic opportunities
TL;DR: In this article , a review of the role of the senescence-associated secretory phenotype (SASP) in the development of atherosclerosis is presented, focusing on a variety of novel therapeutic strategies aimed to reduce the burden of aging individuals by targeting senescent cells and inhibiting the regulatory mechanisms of the SASP.
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