Measurement of autophagic flux in humans: an optimized method for blood samples

Bensalem, Julien; Hattersley, Kathryn J.; Hein, Leanne K.; Teong, Xiao Tong; Carosi, Julian M.; Hassiotis, Sofia; Grose, Randall H.; Fourrier, Célia; Heilbronn, Leonie K.; Sargeant, Timothy J.

doi:10.1080/15548627.2020.1846302

Cited by 24 publications

(36 citation statements)

References 75 publications

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Section: Discussionmentioning

confidence: 99%

“…Several methods have recently been developed to serve as reliable autophagy biomarkers in humans 209 . Analysis of autophagy flux in isolated peripheral blood mononuclear cells is used to measure autophagy activity in human blood samples 210 , 211 . Positron emission tomography can be used with hypoxia tracers to correlate hypoxia and autophagy in tumours and also to gauge the level of specific autophagy substrates in tissues by the use of positron emission tomography ligands that bind to autophagy substrates 184 , 209 .…”

Section: Discussionmentioning

confidence: 99%

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Machinery, regulation and pathophysiological implications of autophagosome maturation

Zhao

Codogno

Zhang

2021

Nat Rev Mol Cell Biol

248

170

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Cells in multicellular organisms constantly experience diverse stresses, including protein misfolding, organelle damage, scarcity of nutrients/energy and invasion by pathogens. One mechanism exploited by cells to combat stresses is the lysosome-mediated degradation of intracellular components via autophagy. Autophagy involves the formation of an isolation membrane (or phagophore), which further expands and closes to form the double-membrane autophagosome 1-3 . The mechanism of autophagosome formation was excellently reviewed recently 3 . Various cellular materials can be sequestered in autophagosomes, including unselected cytosolic material or selected cargos such as protein aggregates, damaged organelles and pathogens. Following autophagosome closure via membrane abscission, cargos are delivered to the vacuole (yeasts and plants) or to lysosomes (animal cells) (for an overview of the autophagy process see [4][5][6][7][8] ; Box 1). After degradation of the autophagic cargo, the digested content in the autolysosomes is released and lysosomes are re-formed to sustain the autophagic flux (Box 2). A series of proteins encoded by ATG (autophagy-related) genes and EPG (ectopic PGL granules) genes -identified mainly from genetic screens in Saccharomyces cerevisiae and Caenorhabditis elegans, respectively -act at different membrane remodelling steps for autophagosome formation and maturation 3,4,9,10 .In yeast, autophagosomes are formed in the vicinity of and directly fuse with the much larger vacuole, whereas in multicellular organisms, newly formed autophagosomes fuse with different endolysosomal vesicles such as early/late endosomes and lysosomes to form non-degradative, single-membrane structures called 'amphisomes' , which gradually acquire

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Machinery, regulation and pathophysiological implications of autophagosome maturation

Zhao

Codogno

Zhang

2021

Nat Rev Mol Cell Biol

248

170

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“…Our knowledge about how this pathway operates in healthy human ageing and age‐related disease is very limited and this is holding translation back [ 187 , 188 ]. Although little is currently known, research has now demonstrated that measurement of the activity of the autophagy–lysosome pathway is possible in humans [ 189 ].…”

Section: Discussionmentioning

confidence: 99%

The mTOR–lysosome axis at the centre of ageing

et al. 2021

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Age‐related diseases represent some of the largest unmet clinical needs of our time. While treatment of specific disease‐related signs has had some success (for example, the effect of statin drugs on slowing progression of atherosclerosis), slowing biological ageing itself represents a target that could significantly increase health span and reduce the prevalence of multiple age‐related diseases. Mechanistic target of rapamycin complex 1 (mTORC1) is known to control fundamental processes in ageing: inhibiting this signalling complex slows biological ageing, reduces age‐related disease pathology and increases lifespan in model organisms. How mTORC1 inhibition achieves this is still subject to ongoing research. However, one mechanism by which mTORC1 inhibition is thought to slow ageing is by activating the autophagy–lysosome pathway. In this review, we examine the special bidirectional relationship between mTORC1 and the lysosome. In cells, mTORC1 is located on lysosomes. From this advantageous position, it directly controls the autophagy–lysosome pathway. However, the lysosome also controls mTORC1 activity in numerous ways, creating a special two‐way relationship. We then explore specific examples of how inhibition of mTORC1 and activation of the autophagy–lysosome pathway slow the molecular hallmarks of ageing. This body of literature demonstrates that the autophagy–lysosome pathway represents an excellent target for treatments that seek to slow biological ageing and increase health span in humans.

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“…This underlines the importance of measuring autophagic flux rather than using a static measurement of autophagy-related markers, such as LC3-II, or other autophagy-related proteins, as a measure of autophagy. A newly adapted method that can directly measure autophagic flux in humans ( Bensalem et al, 2021 ) now provides the opportunity to properly assess these previously reported effects.…”

Section: Autophagy and Neurological/psychiatric Diseasementioning

confidence: 99%

Gut Microbiome Regulation of Autophagic Flux and Neurodegenerative Disease Risks

et al. 2021

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The gut microbiome-brain axis exerts considerable influence on the development and regulation of the central nervous system. Numerous pathways have been identified by which the gut microbiome communicates with the brain, falling largely into the two broad categories of neuronal innervation and immune-mediated mechanisms. We describe an additional route by which intestinal microbiology could mediate modifiable risk for neuropathology and neurodegeneration in particular. Autophagy, a ubiquitous cellular process involved in the prevention of cell damage and maintenance of effective cellular function, acts to clear and recycle cellular debris. In doing so, autophagy prevents the accumulation of toxic proteins and the development of neuroinflammation, both common features of dementia. Levels of autophagy are influenced by a range of extrinsic exposures, including nutrient deprivation, infection, and hypoxia. These relationships between exposures and rates of autophagy are likely to be mediated, as least in part, by the gut microbiome. For example, the suppression of histone acetylation by microbiome-derived short-chain fatty acids appears to be a major contributor to upregulation of autophagic function. We discuss the potential contribution of the microbiome-autophagy axis to neurological health and examine the potential of exploiting this link to predict and prevent neurodegenerative diseases.

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Measurement of autophagic flux in humans: an optimized method for blood samples

Cited by 24 publications

References 75 publications

Machinery, regulation and pathophysiological implications of autophagosome maturation

Machinery, regulation and pathophysiological implications of autophagosome maturation

The mTOR–lysosome axis at the centre of ageing

Gut Microbiome Regulation of Autophagic Flux and Neurodegenerative Disease Risks

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