How autophagy both activates and inhibits cellular senescence

doi:10.1080/15548627.2015.1121361

Journal Article•DOI•

How autophagy both activates and inhibits cellular senescence

Chanhee Kang¹, Stephen J. Elledge¹•Institutions (1)

29 Apr 2016-Autophagy (Taylor & Francis)-Vol. 12, Iss: 5, pp 898-899

TL;DR: This recent study revealed distinctive roles of selective Autophagy and general autophagy in the regulation of senescence, at least in part resolving apparently contradictory reports regarding the relationship between these 2 important homeostatic stress responses.

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Abstract: Autophagy and cellular senescence are stress responses essential for homeostasis. While recent studies indicate a genetic relationship between autophagy and senescence, whether autophagy acts positively or negatively on senescence is still subject to debate. Although autophagy was originally recognized as a nonspecific lysosomal degradation pathway (general autophagy), increasing evidence supports a selective form of autophagy that mediates the degradation of specific targets (selective autophagy). Our recent study revealed distinctive roles of selective autophagy and general autophagy in the regulation of senescence, at least in part resolving apparently contradictory reports regarding the relationship between these 2 important homeostatic stress responses.

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Journal Article•DOI•

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

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Daniel J. Klionsky¹, Amal Kamal Abdel-Aziz², Sara Abdelfatah³, Mahmoud Abdellatif⁴ +2980 more•Institutions (777)

08 Feb 2021-Autophagy

TL;DR: In this article, the authors present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes.

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Abstract: In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

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1,129 citations

Journal Article•DOI•

Resolution of organ fibrosis

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Joon Il Jun, Lester F. Lau

02 Jan 2018-Journal of Clinical Investigation

TL;DR: The present knowledge and gaps in the understanding of how matrix degradation is regulated and how myofibroblast cell fates can be manipulated are discussed, areas that may identify potential therapeutic approaches for fibrosis.

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Abstract: Fibrosis is the excessive accumulation of extracellular matrix that often occurs as a wound healing response to repeated or chronic tissue injury, and may lead to the disruption of organ architecture and loss of function. Although fibrosis was previously thought to be irreversible, recent evidence indicates that certain circumstances permit the resolution of fibrosis when the underlying causes of injury are eradicated. The mechanism of fibrosis resolution encompasses degradation of the fibrotic extracellular matrix as well as elimination of fibrogenic myofibroblasts through their adaptation of various cell fates, including apoptosis, senescence, dedifferentiation, and reprogramming. In this Review, we discuss the present knowledge and gaps in our understanding of how matrix degradation is regulated and how myofibroblast cell fates can be manipulated, areas that may identify potential therapeutic approaches for fibrosis.

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219 citations

Journal Article•DOI•

Molecular mechanisms of UVB-induced senescence of dermal fibroblasts and its relevance for photoaging of the human skin.

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Maria Cavinato¹, Pidder Jansen-Dürr¹•Institutions (1)

University of Innsbruck¹

01 Aug 2017-Experimental Gerontology

TL;DR: In this article, the authors provided updated information about the current model of UVB-induced senescence with special emphasis on the process of protein quality control, which depends on the accumulation of senescent cells, in particular in the dermis.

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157 citations

Journal Article•DOI•

Therapy-Induced Senescence: An "Old" Friend Becomes the Enemy.

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Tareq Saleh¹, Sarah Bloukh², Valerie J. Carpenter³, Enas Alwohoush², Jomana Bakeer², Sarah Darwish¹, Belal Azab², Belal Azab³, David A. Gewirtz³ - Show less +5 more•Institutions (3)

Hashemite University¹, University of Jordan², Virginia Commonwealth University³

29 Mar 2020-Cancers

TL;DR: It is argued that senescence represents a barrier to effective anticancer treatment, and the emerging efforts to identify and exploit agents with senolytic properties as a strategy for elimination of the persistent residual surviving tumor cell population are discussed.

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Abstract: For the past two decades, cellular senescence has been recognized as a central component of the tumor cell response to chemotherapy and radiation. Traditionally, this form of senescence, termed Therapy-Induced Senescence (TIS), was linked to extensive nuclear damage precipitated by classical genotoxic chemotherapy. However, a number of other forms of therapy have also been shown to induce senescence in tumor cells independently of direct genomic damage. This review attempts to provide a comprehensive summary of both conventional and targeted anticancer therapeutics that have been shown to induce senescence in vitro and in vivo. Still, the utility of promoting senescence as a therapeutic endpoint remains under debate. Since senescence represents a durable form of growth arrest, it might be argued that senescence is a desirable outcome of cancer therapy. However, accumulating evidence suggesting that cells have the capacity to escape from TIS would support an alternative conclusion, that senescence provides an avenue whereby tumor cells can evade the potentially lethal action of anticancer drugs, allowing the cells to enter a temporary state of dormancy that eventually facilitates disease recurrence, often in a more aggressive state. Furthermore, TIS is now strongly connected to tumor cell remodeling, potentially to tumor dormancy, acquiring more ominous malignant phenotypes and accounts for several untoward adverse effects of cancer therapy. Here, we argue that senescence represents a barrier to effective anticancer treatment, and discuss the emerging efforts to identify and exploit agents with senolytic properties as a strategy for elimination of the persistent residual surviving tumor cell population, with the goal of mitigating the tumor-promoting influence of the senescent cells and to thereby reduce the likelihood of cancer relapse.

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155 citations

Journal Article•DOI•

Molecular mechanisms of renal aging.

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Roland Schmitt¹, Anette Melk¹•Institutions (1)

Hannover Medical School¹

01 Sep 2017-Kidney International

TL;DR: Recent insight is summarized into cellular and molecular processes that have been shown to contribute to the renal aging phenotype, including the decrease in glomerular filtration rate and the loss of functioning nephrons.

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143 citations

Cites background from "How autophagy both activates and in..."

...The level of autophagic flux, on the other hand, might directly regulate crucial senescence features, such as the SASP.(90) In addition, the consequences of autophagy for senescence induction are highly variable: ablation of Atg5 limited to the S3 segment of the proximal tubule resulted in protection from postischemic senescence, whereas wider Atg5 ablation promoted tubular senescence under conditions of chronologic aging....
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...There is, for example, a complex interrelationship between autophagy, the response to DNA damage, and cellular senescence, which varies depending on mode and duration of autophagy induction, autophagic flux level, and cell type.90–93 Recent studies have indicated that telomeres and telomerase 574 dysfunction might influence the capacity of aged tubular cells to activate stress-induced autophagy.94,95 The level of autophagic flux, on the other hand, might directly regulate crucial senescence features, such as the SASP.90 In addition, the consequences of autophagy for senescence induction are highly variable: ablation of Atg5 limited to the S3 segment of the proximal tubule resulted in protection from postischemic senescence, whereas wider Atg5 ablation promoted tubular senescence under conditions of chronologic aging.89,92 Rapamycin, which has been shown to extend the lifespan in all organisms tested so far, is a strong inducer of autophagy by inhibition of mammalian target of rapamycin complex 1.80 The autophagy-enhancing effect of rapamycin is also detectable in murine and human kidneys.94,96,97 However, longterm functional consequences of rapamycin treatment for the aging phenotype are presently unknown, and it is suspected that beneficial mechanisms might be overshadowed by renal and extrarenal side effects....
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...In cultured cells, the state of sustained senescence is typically accompanied by phenotypic changes, an altered morphology with large and flattened cell bodies, apoptosis resistance, increased expression of senescence-associated b-galactosidase reflecting increased lysosomal b-galactosidase,58,59 accumulation of senescence-associated heterochromatin foci, increases in phosphorylated histone H2AX (g-H2AX), and features of the SASP....
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