Autophagy during ageing – from Dr Jekyll to Mr Hyde

Wilhelm, Thomas; Richly, Holger

doi:10.1111/febs.14453

Cited by 22 publications

(15 citation statements)

References 87 publications

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“…As a potential mechanism, interference with cell fates controlled by mTOR in response to stress and metabolic cues has been discussed 48 . Autophagy, regulated chiefly by mTORC1, is accorded a central role in the preservation of juvenile cell adaptability 48,49 since it exercises a double function as a survival mechanism in cellular stress conditions: during starvation, when mTORC1 is physiologically inhibited, autophagy regenerates basal metabolic precursors by "self-cannibalism" of cellular structures 24 . On the other hand, cellular debris such as misfolded proteins and dysfunctional organelles that can induce senescence and apoptosis is cleared by autophagy 50 .…”

Section: Discussionmentioning

confidence: 99%

mTORC1 and mTORC2 Differentially Regulate Cell Fate Programs to Coordinate Osteoblastic Differentiation in Mesenchymal Stromal Cells

Schaub

Gürgen

Maus

et al. 2019

Sci Rep

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Vascular regeneration depends on intact function of progenitors of vascular smooth muscle cells such as pericytes and their circulating counterparts, mesenchymal stromal cells (MSC). Deregulated MSC differentiation and maladaptive cell fate programs associated with age and metabolic diseases may exacerbate arteriosclerosis due to excessive transformation to osteoblast-like calcifying cells. Targeting mTOR, a central controller of differentiation and cell fates, could offer novel therapeutic perspectives. In a cell culture model for osteoblastic differentiation of pluripotent human MSC we found distinct roles for mTORC1 and mTORC2 in the regulation of differentiation towards calcifying osteoblasts via cell fate programs in a temporally-controlled sequence. Activation of mTORC1 with induction of cellular senescence and apoptosis were hallmarks of transition to a calcifying phenotype. Inhibition of mTORC1 with Rapamycin elicited reciprocal activation of mTORC2, enhanced autophagy and recruited anti-apoptotic signals, conferring protection from calcification. Pharmacologic and genetic negative interference with mTORC2 function or autophagy both abolished regenerative programs but induced cellular senescence, apoptosis, and calcification. Overexpression of the mTORC2 constituent rictor revealed that enhanced mTORC2 signaling without altered mTORC1 function was sufficient to inhibit calcification. Studies in mice reproduced the in vitro effects of mTOR modulation with Rapamycin on cell fates in vascular cells in vivo. Amplification of mTORC2 signaling promotes protective cell fates including autophagy to counteract osteoblast differentiation and calcification of MSC, representing a novel mTORC2 function. Regenerative approaches aimed at modulating mTOR network activation patterns hold promise for delaying age-related vascular diseases and treatment of accelerated arteriosclerosis in chronic metabolic conditions.

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Section: Discussionmentioning

confidence: 99%

mTORC1 and mTORC2 Differentially Regulate Cell Fate Programs to Coordinate Osteoblastic Differentiation in Mesenchymal Stromal Cells

Schaub

Gürgen

Maus

et al. 2019

Sci Rep

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“…Clearance of misfolded proteins, damaged organelles and global turnover of the components of the cell takes place through autophagy [250]. Autophagy can be of three different types including microautophagy, chaperone mediated autophagy and macroautophagy [250]. Microautophagy is the normal process of engulfment of unwanted material of the cytosol in the lysosomal vesicle [251].…”

Section: Restoring Protein Homeostasis As a Novel Multifactorial Amentioning

confidence: 99%

“…Increase in AMP/ATP ratio during starvation activates AMPK and inhibits protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) pathway, activating the initiation of the autophagosome formation. ROS (dihydronicotinamide-adenine dinucleotide phosphate/NADPH oxidase-induced) accumulation, PI3K/Akt/mTOR inhibition, AMPK, Beclin1, transcription factor EB (TFEB) and sirtuin 1 (SIRT1)/fork head box like protein (FOXO) activation are known pathways for inducing autophagy [250,255,256,257,258].…”

Section: Restoring Protein Homeostasis As a Novel Multifactorial Amentioning

confidence: 99%

Dietary Polyphenols: A Multifactorial Strategy to Target Alzheimer’s Disease

Dhakal

Kushairi

Phan

et al. 2019

IJMS

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Ageing is an inevitable fundamental process for people and is their greatest risk factor for neurodegenerative disease. The ageing processes bring changes in cells that can drive the organisms to experience loss of nutrient sensing, disrupted cellular functions, increased oxidative stress, loss of cellular homeostasis, genomic instability, accumulation of misfolded protein, impaired cellular defenses and telomere shortening. Perturbation of these vital cellular processes in neuronal cells can lead to life threatening neurological disorders like Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease, Lewy body dementia, etc. Alzheimer’s Disease is the most frequent cause of deaths in the elderly population. Various therapeutic molecules have been designed to overcome the social, economic and health care burden caused by Alzheimer’s Disease. Almost all the chemical compounds in clinical practice have been found to treat symptoms only limiting them to palliative care. The reason behind such imperfect drugs may result from the inefficiencies of the current drugs to target the cause of the disease. Here, we review the potential role of antioxidant polyphenolic compounds that could possibly be the most effective preventative strategy against Alzheimer’s Disease.

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“…Macroautophagy, hereafter referred to as autophagy, is a dynamic cellular process in which the cytoplasmic membrane structure encapsulates damaged organelles and misfolded proteins; the membrane structure then fuses with lysosomes to form autophagosomes, where the contents are degraded to maintain physiological cellular homeostasis and improve cellular functions, including survival . Previous studies have confirmed a decrease in autophagy in human OA cartilage , and the activation of autophagy increases the levels of Collagen II and Aggrecan while decreasing the expression of a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS‐5) and matrix metalloproteinase‐13 (MMP‐13) in chondrocytes, which are key factors contributing to anabolism and catabolism, respectively, in cartilage .…”

Section: Introductionmentioning

confidence: 99%

Knockdown of SGK1 alleviates the IL‐1β‐induced chondrocyte anabolic and catabolic imbalance by activating FoxO1‐mediated autophagy in human chondrocytes

et al. 2019

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Osteoarthritis (OA) is a common joint disease characterized by the progressive degeneration of articular cartilage with no effective treatment methods available. Cartilage degeneration is closely related to an anabolic and catabolic imbalance in chondrocytes, and accumulating evidence has revealed that autophagy is a crucial protective mechanism that maintains the balance of anabolic and catabolic activities. Therefore, studies aiming to identify additional genes that regulate autophagy as a promising therapeutic strategy for OA are needed. In this study, we analyzed the http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE113825 datasets from Gene Expression Omnibus and validated that serum‐ and glucocorticoid‐regulated kinase 1 (SGK1) was upregulated in OA cartilage. Based on the results from loss‐of‐function studies, SGK1 silencing promoted the deposition of glycosaminoglycans in interleukin 1 beta (IL‐1β)‐treated chondrocytes, and significantly alleviated IL‐1β‐induced downregulation of Collagen II and Aggrecan, as well as the upregulation of a disintegrin and metalloproteinase with thrombospondin motifs 5 and matrix metalloproteinase‐13. Furthermore, SGK1 knockdown reversed the IL‐1β‐induced chondrocyte anabolic and catabolic imbalance by activating autophagy. Moreover, SGK1 directly bound to forkhead box protein O1 (FoxO1) and increased its phosphorylation, which in turn resulted in its translocation from the nucleus. The decreased FoxO1 levels led to a decrease in LC3‐I/LC3‐II conversion and Beclin‐1 levels, subsequently inhibiting autophagosome formation and increasing P62 levels, thus indicating a downregulation of autophagy. Taken together, we identified a critical role of SGK1 in the IL‐1β‐induced chondrocyte anabolic and catabolic imbalance, which may represent a potential novel therapeutic target for OA.

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Autophagy during ageing – from Dr Jekyll to Mr Hyde

Cited by 22 publications

References 87 publications

mTORC1 and mTORC2 Differentially Regulate Cell Fate Programs to Coordinate Osteoblastic Differentiation in Mesenchymal Stromal Cells

mTORC1 and mTORC2 Differentially Regulate Cell Fate Programs to Coordinate Osteoblastic Differentiation in Mesenchymal Stromal Cells

Dietary Polyphenols: A Multifactorial Strategy to Target Alzheimer’s Disease

Knockdown of SGK1 alleviates the IL‐1β‐induced chondrocyte anabolic and catabolic imbalance by activating FoxO1‐mediated autophagy in human chondrocytes

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