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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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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Dynamic modelling of pathways to cellular senescence reveals strategies for targeted interventions.
Piero Dalle Pezze,Glyn Nelson,Elsje G. Otten,Viktor I. Korolchuk,Thomas B. L. Kirkwood,Thomas von Zglinicki,Daryl P. Shanley +6 more
TL;DR: This work reports a detailed analysis of senescence signalling via DNA damage, insulin-TOR, FoxO3a transcription factors, oxidative stress response, mitochondrial regulation and mitophagy, and shows in silico and in vitro that inhibition of reactive oxygen species can prevent loss of mitochondrial membrane potential, whilst inhibition of mTOR shows a partial rescue of mitochondrial mass changes during establishment of Senescence.
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Are there roles for brain cell senescence in aging and neurodegenerative disorders
TL;DR: There is a high level of similarity between some of the pathological changes that occur in the brain in Alzheimer's and Parkinson’s diseases and those phenotypes observed in cellular senescence, leading to a proposal that neurons and glia can exhibit hallmarks ofsenescence previously documented in peripheral tissues.
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Hallmarks of progeroid syndromes: lessons from mice and reprogrammed cells
TL;DR: A series of molecular and cellular hallmarks that characterize progeroid syndromes and parallel physiological ageing are defined and the therapeutic strategies developed to date are discussed.
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An early-senescence state in aged mesenchymal stromal cells contributes to hematopoietic stem and progenitor cell clonogenic impairment through the activation of a pro-inflammatory program.
Daniela Gnani,Stefania Crippa,Lucrezia della Volpe,Valeria Rossella,Anastasia Conti,Emanuele Lettera,Silvia Rivis,Marco Ometti,Gianfranco Fraschini,Maria Ester Bernardo,Raffaella Di Micco +10 more
TL;DR: The results reveal that BM‐derived MSC from aged healthy donors display features of senescence and that, during aging, MSC‐associated secretomes contribute to activate an inflammatory transcriptional program in HSPC that may ultimately impair their functionality.
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Integrating cellular senescence with the concept of damage accumulation in aging: Relevance for clearance of senescent cells.
TL;DR: This work critically examines current evidence for a role of cellular senescence in aging and age‐related diseases and proposes a model on the role of aging‐related damage accumulation and the rate of aging observed upon senescent cell clearance.
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