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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Mechanisms and functions of cellular senescence
Nicolás Herranz,Jesús Gil +1 more
TL;DR: The mechanisms regulating different aspects of the senescent phenotype and their functional implications are discussed, essential to improve the identification and characterization of senescent cells in vivo and will help to develop rational strategies to modulate the senescence program for therapeutic benefit.
Journal ArticleDOI
A proteomic atlas of senescence-associated secretomes for aging biomarker development.
Nathan Basisty,Abhijit Kale,Ok-Hee Jeon,Chisaka Kuehnemann,Therese Payne,Chirag Rao,Anja Holtz,Samah Shah,Vagisha Sharma,Luigi Ferrucci,Judith Campisi,Judith Campisi,Birgit Schilling +12 more
TL;DR: The analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA).
Journal ArticleDOI
mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype
Nicolás Herranz,Suchira Gallage,Massimiliano Mellone,Torsten Wuestefeld,Sabrina Klotz,Christopher J. Hanley,Selina Raguz,Juan Carlos Acosta,Andrew J. Innes,Ana Banito,Athena Georgilis,Alex Montoya,Katharina Wolter,Gopuraja Dharmalingam,Peter Faull,Thomas L. Carroll,Juan Pedro Martinez-Barbera,Pedro R. Cutillas,Pedro R. Cutillas,Florian Reisinger,Mathias Heikenwalder,Mathias Heikenwalder,Richard A. Miller,Dominic J. Withers,Lars Zender,Gareth J. Thomas,Jesús Gil +26 more
TL;DR: A mechanism by which mTOR controls the SASP is reported by differentially regulating the translation of the MK2 (also known as MAPKAPK2) kinase through 4EBP1.
Journal ArticleDOI
Cellular Senescence: Aging, Cancer, and Injury
Arianna Calcinotto,Jaskaren Kohli,Elena Zagato,Laura Pellegrini,Marco Demaria,Andrea Alimonti +5 more
TL;DR: The known key features of senescence, the cell-aut autonomous, and noncell-autonomous regulators of senescent cells are described, and the functional role of this fundamental process in different contexts is discussed in light of the development of novel therapeutic targets.
Journal ArticleDOI
Mitochondria are required for pro‐ageing features of the senescent phenotype
Clara Correia-Melo,Clara Correia-Melo,Francisco D.M. Marques,Rhys Anderson,Graeme Hewitt,Rachael N. Hewitt,John J. Cole,Bernadette Carroll,Satomi Miwa,Jodie Birch,Alina Merz,Michael D. Rushton,Michelle Charles,Diana Jurk,Stephen W.G. Tait,Rafal Czapiewski,Laura C. Greaves,Glyn Nelson,Mohammad Bohlooly-Y,Sergio Rodriguez-Cuenca,Antonio Vidal-Puig,Derek A. Mann,Gabriele Saretzki,Giovanni Quarato,Douglas R. Green,Peter D. Adams,Thomas von Zglinicki,Viktor I. Korolchuk,João F. Passos +28 more
TL;DR: The results suggest that mitochondria are a candidate target for interventions to reduce the deleterious impact of senescence in ageing tissues.
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