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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Molecular pathways of senescence regulate placental structure and function.
Hilah Gal,Marina Lysenko,Sima Stroganov,Ezra Vadai,Sameh A. Youssef,Sameh A. Youssef,Keren Tzadikevitch-Geffen,Ron Rotkopf,Tal Biron-Shental,Tal Biron-Shental,Alain de Bruin,Alain de Bruin,Michal Neeman,Valery Krizhanovsky +13 more
TL;DR: It is proposed that molecular mediators of senescence regulate placental structure and function, through both cell‐aut autonomous and non‐autonomous mechanisms.
Journal ArticleDOI
Senescent endothelial cells: Potential modulators of immunosenescence and ageing
TL;DR: The possibility that age-related changes in Toll-like receptors (TLRs) and microRNAs can affect the phenotypes of senescent endothelial cells and immune cells via a negative feedback loop aimed at restraining the excessive pro-inflammatory response is described.
Journal ArticleDOI
Generation and Release of Mitochondrial-Derived Vesicles in Health, Aging and Disease.
Anna Picca,Flora Guerra,Riccardo Calvani,Hélio José Coelho-Júnior,Maurizio Bossola,Francesco Landi,Roberto Bernabei,Cecilia Bucci,Emanuele Marzetti +8 more
TL;DR: The dissection of EV trafficking may help unravel new pathophysiological pathways of aging and diseases as well as novel biomarkers to be used in research and clinical settings and the relevance of MQC failure to several disorders, including neurodegenerative conditions and cardiovascular disease.
Journal ArticleDOI
Bclaf1 is an important NF-κB signaling transducer and C/EBPβ regulator in DNA damage-induced senescence.
TL;DR: This work reveals Bcl-2-associated transcription factor 1 (Bclaf1) as a novel player in the therapeutic drug doxorubicin-induced senescence (TIS) in multiple cancer cells and suggests that the responsiveness of B claf1 to NF-κB may determine the effectiveness of therapeutic drugs.
Journal ArticleDOI
Perspective: Targeting the JAK/STAT pathway to fight age-related dysfunction.
TL;DR: Targeting senescent cells could be a promising way to improve healthspan in aged population because inhibition of the JAK pathway suppresses the SASP in senescence-associated secretory phenotype and alleviates age-related tissue dysfunction.
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