Cellular Senescence: Defining a Path Forward

Cell, Journal Year: 2019, Volume and Issue: 179(4), P. 813 - 827

Published: Oct. 1, 2019

Language: Английский

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Senolytics improve physical function and increase lifespan in old age

Nature Medicine, Journal Year: 2018, Volume and Issue: 24(8), P. 1246 - 1256

Published: July 6, 2018

Language: Английский

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Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: March 29, 2021

Cellular senescence is a stable cell cycle arrest that can be triggered in normal cells response to various intrinsic and extrinsic stimuli, as well developmental signals. Senescence considered highly dynamic, multi-step process, during which the properties of senescent continuously evolve diversify context dependent manner. It associated with multiple cellular molecular changes distinct phenotypic alterations, including proliferation unresponsive mitogenic stimuli. Senescent remain viable, have alterations metabolic activity undergo dramatic gene expression develop complex senescence-associated secretory phenotype. compromise tissue repair regeneration, thereby contributing toward aging. Removal attenuate age-related dysfunction extend health span. also act potent anti-tumor mechanism, by preventing potentially cancerous cells. program acts double-edged sword, both beneficial detrimental effects on organism, an example evolutionary antagonistic pleiotropy. Activation p53/p21 WAF1/CIP1 p16 INK4A /pRB tumor suppressor pathways play central role regulating senescence. Several other recently been implicated mediating Herein we review mechanisms underlie growth particular focus why stop dividing, stability arrest, hypersecretory phenotype how different are all integrated.

Language: Английский

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Targeting cellular senescence prevents age-related bone loss in mice

Nature Medicine, Journal Year: 2017, Volume and Issue: 23(9), P. 1072 - 1079

Published: Aug. 21, 2017

Language: Английский

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Cellular Senescence: A Translational Perspective

EBioMedicine, Journal Year: 2017, Volume and Issue: 21, P. 21 - 28

Published: April 11, 2017

Cellular senescence entails essentially irreversible replicative arrest, apoptosis resistance, and frequently acquisition of a pro-inflammatory, tissue-destructive senescence-associated secretory phenotype (SASP). Senescent cells accumulate in various tissues with aging at sites pathogenesis many chronic diseases conditions. The SASP can contribute to senescence-related inflammation, metabolic dysregulation, stem cell dysfunction, phenotypes, diseases, geriatric syndromes, loss resilience. Delaying senescent accumulation or reducing burden is associated delay, prevention, alleviation multiple We used hypothesis-driven approach discover pro-survival Cell Anti-apoptotic Pathways (SCAPs) and, based on these SCAPs, the first senolytic agents, drugs that cause become susceptible their own pro-apoptotic microenvironment. Several which appear alleviate phenotypes pre-clinical models, are beginning process being translated into clinical interventions could be transformative.

Language: Английский

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Cellular senescence drives age-dependent hepatic steatosis

Nature Communications, Journal Year: 2017, Volume and Issue: 8(1)

Published: June 13, 2017

Abstract The incidence of non-alcoholic fatty liver disease (NAFLD) increases with age. Cellular senescence refers to a state irreversible cell-cycle arrest combined the secretion proinflammatory cytokines and mitochondrial dysfunction. Senescent cells contribute age-related tissue degeneration. Here we show that accumulation senescent promotes hepatic fat steatosis. We report close correlation between markers hepatocyte senescence. elimination by suicide gene-meditated ablation p16 Ink4a -expressing in INK-ATTAC mice or treatment combination senolytic drugs dasatinib quercetin (D+Q) reduces overall Conversely, inducing vitro vivo . Mechanistically, mitochondria lose ability metabolize acids efficiently. Our study demonstrates cellular drives steatosis may be novel therapeutic strategy reduce

Language: Английский

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Inflammaging and ‘Garb-aging’

Trends in Endocrinology and Metabolism, Journal Year: 2016, Volume and Issue: 28(3), P. 199 - 212

Published: Oct. 24, 2016

Language: Английский

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Fisetin is a senotherapeutic that extends health and lifespan

EBioMedicine, Journal Year: 2018, Volume and Issue: 36, P. 18 - 28

Published: Sept. 29, 2018

Senescence is a tumor suppressor mechanism activated in stressed cells to prevent replication of damaged DNA. Senescent have been demonstrated play causal role driving aging and age-related diseases using genetic pharmacologic approaches. We previously that the combination dasatinib flavonoid quercetin potent senolytic improving numerous conditions including frailty, osteoporosis cardiovascular disease. The goal this study was identify flavonoids with more activity.

Language: Английский

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Mechanisms and functions of cellular senescence

Journal of Clinical Investigation, Journal Year: 2018, Volume and Issue: 128(4), P. 1238 - 1246

Published: April 1, 2018

Cellular senescence is a highly stable cell cycle arrest that elicited in response to different stresses. By imposing growth arrest, limits the replication of old or damaged cells. Besides exiting cycle, senescent cells undergo many other phenotypic alterations such as metabolic reprogramming, chromatin rearrangement, autophagy modulation. In addition, produce and secrete complex combination factors, collectively referred senescence-associated secretory phenotype, mediate most their non–cell-autonomous effects. Because influence outcome variety physiological pathological processes, including cancer age-related diseases, pro-senescent anti-senescent therapies are actively being explored. this Review, we discuss mechanisms regulating aspects phenotype functional implications. This knowledge essential improve identification characterization vivo will help develop rational strategies modulate program for therapeutic benefit.

Language: Английский

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Mitochondria are required for pro‐ageing features of the senescent phenotype

The EMBO Journal, Journal Year: 2016, Volume and Issue: 35(7), P. 724 - 742

Published: Feb. 4, 2016

Cell senescence is an important tumour suppressor mechanism and driver of ageing. Both functions are dependent on the development senescent phenotype, which involves overproduction pro-inflammatory pro-oxidant signals. However, exact mechanisms regulating these phenotypes remain poorly understood. Here, we show critical role mitochondria in cellular senescence. In multiple models senescence, absence reduced a spectrum effectors while preserving ATP production via enhanced glycolysis. Global transcriptomic analysis by RNA sequencing revealed that vast number senescent-associated changes mitochondria, particularly phenotype. Mechanistically, ATM, Akt mTORC1 phosphorylation cascade integrates signals from DNA damage response (DDR) towards PGC-1β-dependent mitochondrial biogenesis, contributing to aROS-mediated activation DDR cell cycle arrest. Finally, demonstrate reduction content vivo, either inhibition or PGC-1β deletion, prevents ageing mouse liver. Our results suggest candidate target for interventions reduce deleterious impact tissues.

Language: Английский

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