Autophagy in Age-Related Human Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Autophagy".

Deadline for manuscript submissions: closed (31 December 2018) | Viewed by 47810

Special Issue Editor

Department of Molecular Biology, Interfaculty Institute of Cell Biology, Eberhard Karls University Tuebingen, Tuebingen, Germany
Interests: autophagy; longevity; tumor metabolism; WIPI genes
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Increasingly, the process of autophagy (“self-eating”) is attracting tremendous research efforts. Exciting new data are shedding light on the molecular details of the process of autophagy and its pertubation in human diseases. Moreover, it is becoming evident that autophagy activity and capacity decrease during the aging process, giving rise to the onset of a great variety of age-related diseases. Strikingly, autophagy is also essential to the development of certain diseases (e.g. tumor progression). Hence, the modulation of autophagy is regarded as a new therapeutic opportunity for the future treatment of many pathological conditions. Further, targeting autophagy during the aging process may in fact prove to effectively prevent the onset of age-related human diseases. However, specific autophagy modulators have not yet been developed and tested.

This special issue aims to summarize the current knowledge on the role of autophagy in the process of aging and in age-related human diseases such as neurodegeneration and cancer.

We look forward to your contributions.

Prof. Dr. Tassula Proikas-Cezanne
Guest Editor

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Keywords

  • autophagy
  • aging
  • longevity
  • cancer
  • neurodegeneration

Published Papers (7 papers)

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Research

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17 pages, 6406 KiB  
Article
The Precision Control of Autophagic Flux and Vesicle Dynamics—A Micropattern Approach
by André Du Toit, Sholto De Wet, Jan-Hendrik S. Hofmeyr, Kristian K. Müller-Nedebock and Ben Loos
Cells 2018, 7(8), 94; https://0-doi-org.brum.beds.ac.uk/10.3390/cells7080094 - 03 Aug 2018
Cited by 13 | Viewed by 4829
Abstract
Autophagy failure is implicated in age-related human disease. A decrease in the rate of protein degradation through the entire autophagy pathway, i.e., autophagic flux, has been associated with the onset of cellular proteotoxity and cell death. Although the precision control of autophagy as [...] Read more.
Autophagy failure is implicated in age-related human disease. A decrease in the rate of protein degradation through the entire autophagy pathway, i.e., autophagic flux, has been associated with the onset of cellular proteotoxity and cell death. Although the precision control of autophagy as a pharmacological intervention has received major attention, mammalian model systems that enable a dissection of the relationship between autophagic flux and pathway intermediate pool sizes remain largely underexplored. Here, we make use of a micropattern-based fluorescence life cell imaging approach, allowing a high degree of experimental control and cellular geometry constraints. By assessing two autophagy modulators in a system that achieves a similarly raised autophagic flux, we measure their impact on the pathway intermediate pool size, autophagosome velocity, and motion. Our results reveal a differential effect of autophagic flux enhancement on pathway intermediate pool sizes, velocities, and directionality of autophagosome motion, suggesting distinct control over autophagy function. These findings may be of importance for better understanding the fine-tuning autophagic activity and protein degradation proficiency in different cell and tissue types of age-associated pathologies. Full article
(This article belongs to the Special Issue Autophagy in Age-Related Human Diseases)
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8 pages, 1126 KiB  
Article
Novel Modulators of Proteostasis: RNAi Screen of Chromosome I in a Heat Stress Paradigm in C. elegans
by Andreas Kern, Natalie Spang, Heike Huesmann and Christian Behl
Cells 2018, 7(6), 49; https://0-doi-org.brum.beds.ac.uk/10.3390/cells7060049 - 26 May 2018
Cited by 6 | Viewed by 4396
Abstract
Proteostasis is of vital importance for cellular function and it is challenged upon exposure to acute or chronic insults during neurodegeneration and aging. The proteostasis network is relevant for the maintenance of proteome integrity and mainly comprises molecular chaperones and two degradation pathways, [...] Read more.
Proteostasis is of vital importance for cellular function and it is challenged upon exposure to acute or chronic insults during neurodegeneration and aging. The proteostasis network is relevant for the maintenance of proteome integrity and mainly comprises molecular chaperones and two degradation pathways, namely, autophagy and the ubiquitin proteasome system. This network is characterized by an impressive functional interrelation and complexity, and occasionally novel factors are discovered that modulate proteostasis. Here, we present an RNAi screen in C. elegans, which aimed to identify modulators of proteostasis in a heat stress paradigm. The screen comprised genes that are located on chromosome I of the nematode and has identified 185 genetic modifiers, whose knockdown has enhanced the misfolding of a reporter protein upon temperature increase. Subsequently, we evaluated the effect of a distinct number of the identified candidates in an additional C. elegans model strain, which expresses the aggregation-prone PolyQ35::YFP protein. Moreover, we annotated the human orthologs of the identified proteins and analyzed their enrichment in functional clusters and, as appropriate, their association with human neuropathologies. The achieved data collection includes several factors that have already been functionally associated with the proteostasis network, which highlights the potential of this heat stress-based proteostasis screen in order to detect novel modulators of proteome integrity. Full article
(This article belongs to the Special Issue Autophagy in Age-Related Human Diseases)
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Review

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22 pages, 791 KiB  
Review
Modulation of Autophagy for Controlling Immunity
by Young Jin Jang, Jae Hwan Kim and Sanguine Byun
Cells 2019, 8(2), 138; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8020138 - 09 Feb 2019
Cited by 51 | Viewed by 6395
Abstract
Autophagy is an essential process that maintains physiological homeostasis by promoting the transfer of cytoplasmic constituents to autophagolysosomes for degradation. In immune cells, the autophagy pathway plays an additional role in facilitating proper immunological functions. Specifically, the autophagy pathway can participate in controlling [...] Read more.
Autophagy is an essential process that maintains physiological homeostasis by promoting the transfer of cytoplasmic constituents to autophagolysosomes for degradation. In immune cells, the autophagy pathway plays an additional role in facilitating proper immunological functions. Specifically, the autophagy pathway can participate in controlling key steps in innate and adaptive immunity. Accordingly, alterations in autophagy have been linked to inflammatory diseases and defective immune responses against pathogens. In this review, we discuss the various roles of autophagy signaling in coordinating immune responses and how these activities are connected to pathological conditions. We highlight the therapeutic potential of autophagy modulators that can impact immune responses and the mechanisms of action responsible. Full article
(This article belongs to the Special Issue Autophagy in Age-Related Human Diseases)
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41 pages, 1641 KiB  
Review
Therapeutic Modulation of Autophagy in Leukaemia and Lymphoma
by Mojgan Djavaheri-Mergny, Sylvie Giuriato, Mario P. Tschan and Magali Humbert
Cells 2019, 8(2), 103; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8020103 - 30 Jan 2019
Cited by 37 | Viewed by 7270
Abstract
Haematopoiesis is a tightly orchestrated process where a pool of hematopoietic stem and progenitor cells (HSPCs) with high self-renewal potential can give rise to both lymphoid and myeloid lineages. The HSPCs pool is reduced with ageing resulting in few HSPC clones maintaining haematopoiesis [...] Read more.
Haematopoiesis is a tightly orchestrated process where a pool of hematopoietic stem and progenitor cells (HSPCs) with high self-renewal potential can give rise to both lymphoid and myeloid lineages. The HSPCs pool is reduced with ageing resulting in few HSPC clones maintaining haematopoiesis thereby reducing blood cell diversity, a phenomenon called clonal haematopoiesis. Clonal expansion of HSPCs carrying specific genetic mutations leads to increased risk for haematological malignancies. Therefore, it comes as no surprise that hematopoietic tumours develop in higher frequency in elderly people. Unfortunately, elderly patients with leukaemia or lymphoma still have an unsatisfactory prognosis compared to younger ones highlighting the need to develop more efficient therapies for this group of patients. Growing evidence indicates that macroautophagy (hereafter referred to as autophagy) is essential for health and longevity. This review is focusing on the role of autophagy in normal haematopoiesis as well as in leukaemia and lymphoma development. Attenuated autophagy may support early hematopoietic neoplasia whereas activation of autophagy in later stages of tumour development and in response to a variety of therapies rather triggers a pro-tumoral response. Novel insights into the role of autophagy in haematopoiesis will be discussed in light of designing new autophagy modulating therapies in hematopoietic cancers. Full article
(This article belongs to the Special Issue Autophagy in Age-Related Human Diseases)
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21 pages, 1619 KiB  
Review
Chronic Infections: A Possible Scenario for Autophagy and Senescence Cross-Talk
by Milton O. Aguilera, Laura R. Delgui, Patricia S. Romano and María I. Colombo
Cells 2018, 7(10), 162; https://0-doi-org.brum.beds.ac.uk/10.3390/cells7100162 - 10 Oct 2018
Cited by 12 | Viewed by 4798
Abstract
Multiple tissues and systems in the organism undergo modifications during aging due to an accumulation of damaged proteins, lipids, and genetic material. To counteract this process, the cells are equipped with specific mechanisms, such as autophagy and senescence. Particularly, the immune system undergoes [...] Read more.
Multiple tissues and systems in the organism undergo modifications during aging due to an accumulation of damaged proteins, lipids, and genetic material. To counteract this process, the cells are equipped with specific mechanisms, such as autophagy and senescence. Particularly, the immune system undergoes a process called immunosenescence, giving rise to a chronic inflammatory status of the organism, with a decreased ability to counteract antigens. The obvious result of this process is a reduced defence capacity. Currently, there is evidence that some pathogens are able to accelerate the immunosenescence process for their own benefit. Although to date numerous reports show the autophagy–senescence relationship, or the connection between pathogens with autophagy or senescence, the link between the three actors remains unexplored. In this review, we have summarized current knowledge about important issues related to aging, senescence, and autophagy. Full article
(This article belongs to the Special Issue Autophagy in Age-Related Human Diseases)
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18 pages, 601 KiB  
Review
Autophagy in Metabolic Age-Related Human Diseases
by Manon Moulis and Cecile Vindis
Cells 2018, 7(10), 149; https://0-doi-org.brum.beds.ac.uk/10.3390/cells7100149 - 24 Sep 2018
Cited by 34 | Viewed by 7450
Abstract
Autophagy is a highly conserved homeostatic cellular mechanism that mediates the degradation of damaged organelles, protein aggregates, and invading pathogens through a lysosome-dependent pathway. Over the last few years, specific functions of autophagy have been discovered in many tissues and organs; however, abnormal [...] Read more.
Autophagy is a highly conserved homeostatic cellular mechanism that mediates the degradation of damaged organelles, protein aggregates, and invading pathogens through a lysosome-dependent pathway. Over the last few years, specific functions of autophagy have been discovered in many tissues and organs; however, abnormal upregulation or downregulation of autophagy has been depicted as an attribute of a variety of pathologic conditions. In this review, we will describe the current knowledge on the role of autophagy, from its regulation to its physiological influence, in metabolic age-related disorders. Finally, we propose to discuss the therapeutic potential of pharmacological and nutritional modulators of autophagy to treat metabolic diseases. Full article
(This article belongs to the Special Issue Autophagy in Age-Related Human Diseases)
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24 pages, 1234 KiB  
Review
Autophagy in Age-Associated Neurodegeneration
by Athanasios Metaxakis, Christina Ploumi and Nektarios Tavernarakis
Cells 2018, 7(5), 37; https://0-doi-org.brum.beds.ac.uk/10.3390/cells7050037 - 05 May 2018
Cited by 92 | Viewed by 11094
Abstract
The elimination of abnormal and dysfunctional cellular constituents is an essential prerequisite for nerve cells to maintain their homeostasis and proper function. This is mainly achieved through autophagy, a process that eliminates abnormal and dysfunctional cellular components, including misfolded proteins and damaged organelles. [...] Read more.
The elimination of abnormal and dysfunctional cellular constituents is an essential prerequisite for nerve cells to maintain their homeostasis and proper function. This is mainly achieved through autophagy, a process that eliminates abnormal and dysfunctional cellular components, including misfolded proteins and damaged organelles. Several studies suggest that age-related decline of autophagy impedes neuronal homeostasis and, subsequently, leads to the progression of neurodegenerative disorders due to the accumulation of toxic protein aggregates in neurons. Here, we discuss the involvement of autophagy perturbation in neurodegeneration and present evidence indicating that upregulation of autophagy holds potential for the development of therapeutic interventions towards confronting neurodegenerative diseases in humans. Full article
(This article belongs to the Special Issue Autophagy in Age-Related Human Diseases)
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