Autophagy as a promoter of longevity: insights from model organisms

Nature Reviews Molecular Cell Biology, Journal Year: 2018, Volume and Issue: 19(9), P. 579 - 593

Published: July 13, 2018

Language: Английский

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Overexpression of Atg5 in mice activates autophagy and extends lifespan

Nature Communications, Journal Year: 2013, Volume and Issue: 4(1)

Published: Aug. 13, 2013

Autophagy has been implicated in the ageing process, but whether autophagy activation extends lifespan mammals is unknown. Here we show that ubiquitous overexpression of Atg5, a protein essential for autophagosome formation, median mice by 17.2%. We demonstrate moderate Atg5 enhances autophagy, and transgenic showed anti-ageing phenotypes, including leanness, increased insulin sensitivity improved motor function. Furthermore, mouse embryonic fibroblasts cultured from are more tolerant to oxidative damage cell death induced stress, this tolerance was reversible treatment with an inhibitor. Our observations suggest leanness extension may be result autophagic activity. Changes have shown modulate lower organisms. Here, Pyo et al.show globally overexpressing live longer leaner than normal mice, providing first evidence mammals.

Language: Английский

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The role of protein clearance mechanisms in organismal ageing and age-related diseases

Nature Communications, Journal Year: 2014, Volume and Issue: 5(1)

Published: Dec. 8, 2014

Language: Английский

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Autophagy failure in Alzheimer's disease—locating the primary defect

Neurobiology of Disease, Journal Year: 2011, Volume and Issue: 43(1), P. 38 - 45

Published: Feb. 4, 2011

Language: Английский

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AMP-activated protein kinase: the current landscape for drug development

Nature Reviews Drug Discovery, Journal Year: 2019, Volume and Issue: 18(7), P. 527 - 551

Published: March 13, 2019

Language: Английский

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Cell death assays for drug discovery

Nature Reviews Drug Discovery, Journal Year: 2011, Volume and Issue: 10(3), P. 221 - 237

Published: March 1, 2011

Language: Английский

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Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques

Nature Neuroscience, Journal Year: 2022, Volume and Issue: 25(6), P. 688 - 701

Published: June 1, 2022

Autophagy is markedly impaired in Alzheimer's disease (AD). Here we reveal unique autophagy dysregulation within neurons five AD mouse models vivo and identify its basis using a neuron-specific transgenic mRFP-eGFP-LC3 probe of pH, multiplex confocal imaging correlative light electron microscopy. Autolysosome acidification declines well before extracellular amyloid deposition, associated with lowered vATPase activity build-up Aβ/APP-βCTF selectively enlarged de-acidified autolysosomes. In more compromised yet still intact neurons, profuse Aβ-positive autophagic vacuoles (AVs) pack into large membrane blebs forming flower-like perikaryal rosettes. This pattern, termed PANTHOS (poisonous anthos (flower)), also present brains. Additional AVs coalesce peri-nuclear networks tubules where fibrillar β-amyloid accumulates intraluminally. Lysosomal permeabilization, cathepsin release lysosomal cell death ensue, accompanied by microglial invasion. Quantitative analyses confirm that individual exhibiting are the principal source senile plaques precursor protein models.

Language: Английский

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LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer’s Disease

Cell, Journal Year: 2019, Volume and Issue: 178(3), P. 536 - 551.e14

Published: June 27, 2019

Language: Английский

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Exosomes and Autophagy: Coordinated Mechanisms for the Maintenance of Cellular Fitness

Frontiers in Immunology, Journal Year: 2014, Volume and Issue: 5

Published: Aug. 20, 2014

Conditions resulting from loss of cellular homeostasis, including oxidative stress, inflammation, protein aggregation, endoplasmic reticulum metabolic and perturbation mitochondrial function, are common to many pathological disorders contribute aging. Cells face these stress situations by engaging quality control mechanisms aimed restore homeostasis preserve cell viability. Among them, the autophagy-lysosomal pathway mediates specific degradation damaged proteins organelles, its proper function is related protection increased life span in model organisms. Besides autophagy, increasing evidence underscores a role for exosomes selective secretion harmful/damaged RNAs thus maintenance fitness. In this perspective article, we discuss emerging as means alleviating intracellular conditions, how harmful or unwanted material exosomes, coordination with pathway, essential RNA homeostasis. Finally, provide an overview about consequences spreading exosome content physiological situations, suggest putative therapeutic strategies exosome-mediated alterations.

Language: Английский

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Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification

Circulation, Journal Year: 2016, Volume and Issue: 133(17), P. 1668 - 1687

Published: March 17, 2016

Background— The clinical use of doxorubicin is limited by cardiotoxicity. Histopathological changes include interstitial myocardial fibrosis and the appearance vacuolated cardiomyocytes. Whereas dysregulation autophagy in myocardium has been implicated a variety cardiovascular diseases, role cardiomyopathy remains poorly defined. Methods Results— Most models cardiotoxicity involve intraperitoneal injection high-dose drug, which elicits lethargy, anorexia, weight loss, peritoneal fibrosis, all confound interpretation autophagy. Given this, we first established model that provokes modest progressive without constitutional symptoms, reminiscent effects seen patients. We report blocks cardiomyocyte autophagic flux vivo cardiomyocytes culture. This block was accompanied robust accumulation undegraded autolysosomes. go on to localize site as defect lysosome acidification. To test functional relevance doxorubicin-triggered autolysosome accumulation, studied animals with diminished activity resulting from haploinsufficiency for Beclin 1 . +/− mice exposed were protected terms structural within myocardium. Conversely, overexpressing manifested an amplified cardiotoxic response. Conclusions— Doxorubicin impairing acidification lysosomal function. Reducing initiation protects against

Language: Английский

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