Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation.
Olga Moiseeva,Xavier Deschênes-Simard,Emmanuelle St‐Germain,Sebastian Igelmann,Geneviève Huot,Alexandra E. Cadar,Véronique Bourdeau,Michael Pollak,Gerardo Ferbeyre +8 more
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It is shown that the antidiabetic drug metformin inhibits the expression of genes coding for multiple inflammatory cytokines seen during cellular senescence, providing a novel mechanism for the antiaging and antineoplastic effects of this drug reported in animal models and in diabetic patients taking this drug.Abstract:
We show that the antidiabetic drug metformin inhibits the expression of genes coding for multiple inflammatory cytokines seen during cellular senescence. Conditioned medium (CM) from senescent cells stimulates the growth of prostate cancer cells but treatment of senescent cells with metformin inhibited this effect. Bioinformatic analysis of genes downregulated by metformin suggests that the drug blocks the activity of the transcription factor NF-κB. In agreement, metformin prevented the translocation of NF-κB to the nucleus and inhibited the phosphorylation of IκB and IKKα/β, events required for activation of the NF-κB pathway. These effects were not dependent on AMPK activation or on the context of cellular senescence, as metformin inhibited the NF-κB pathway stimulated by lipopolysaccharide (LPS) in ampk null fibroblasts and in macrophages. Taken together, our results provide a novel mechanism for the antiaging and antineoplastic effects of metformin reported in animal models and in diabetic patients taking this drug.read more
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Metformin: From Mechanisms of Action to Therapies
Marc Foretz,Bruno Guigas,Luc Bertrand,Michael Pollak,Benoit Viollet,Benoit Viollet,Benoit Viollet +6 more
TL;DR: Convincing data place energy metabolism at the center of metformin's mechanism of action in diabetes and may also be of importance in cardiovascular diseases and cancer.
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Senescent cells: an emerging target for diseases of ageing.
Bennett G. Childs,Martina Gluscevic,Darren J. Baker,Remi-Martin Laberge,Dan Marquess,Jamie Dananberg,Jan M. van Deursen +6 more
TL;DR: Therapeutic strategies that safely interfere with the detrimental effects of cellular senescence, such as the selective elimination of senescent cells (SNCs) or the disruption of the SNC secretome, are gaining significant attention, with several programmes now nearing human clinical studies.
Journal ArticleDOI
Metformin as a Tool to Target Aging.
TL;DR: Metformin, which has demonstrated protective effects against several age-related diseases in humans, will be tested in the TAME (Targeting Aging with Metformin) trial, as the initial step in the development of increasingly effective next-generation drugs.
Journal ArticleDOI
Cellular Senescence: A Translational Perspective.
TL;DR: This work used a hypothesis-driven approach to discover pro-survival Senescent Cell Anti-apoptotic Pathways (SCAPs) and, based on these SCAPs, the first senolytic agents, drugs that cause senescent cells to become susceptible to their own pro-APoptotic microenvironment.
Journal ArticleDOI
Cellular senescence in ageing: from mechanisms to therapeutic opportunities
TL;DR: The mechanisms and modulators of cellularsenescence establishment and induction of a senescence-associated secretory phenotype are discussed, and the potential of senolytic and senomorphic therapies in ageing and associated diseases is provided.
References
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Oncogenic ras Provokes Premature Cell Senescence Associated with Accumulation of p53 and p16INK4a
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The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression
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Clearance of p16 Ink4a -positive senescent cells delays ageing-associated disorders
Darren J. Baker,Tobias Wijshake,Tamar Tchkonia,Nathan K. LeBrasseur,Bennett G. Childs,Bart van de Sluis,James L. Kirkland,Jan M. van Deursen +7 more
TL;DR: Data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.
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TAK1 is a ubiquitin-dependent kinase of MKK and IKK
TL;DR: The purification and identification of TRIKA2, which is composed of TAK1, TAB1 and TAB2, a protein kinase complex previously implicated in IKK activation through an unknown mechanism, indicate that ubiquitination has an important regulatory role in stress response pathways, including those of IKK and JNK.
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IKK-1 and IKK-2: Cytokine-Activated IκB Kinases Essential for NF-κB Activation
Frank Mercurio,Hengyi Zhu,Brion W. Murray,Andrej Shevchenko,Brydon L. Bennett,Jian Wu Li,David B. Young,Miguel Barbosa,Matthias Mann,Anthony M. Manning,Anjana Rao +10 more
TL;DR: In this article, a large multiprotein complex, the IkappaB kinase (IKK) signalsome, was purified from HeLa cells and found to contain a cytokine-inducible IKK kinase activity that phosphorylates IappaB-alpha and IKK-beta.