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Advanced glycation end products (AGE) potentiates cell death in p53 negative cells via upregulaion of NF-kappa B and impairment of autophagy.


Maximus Peto’s Commentary

These authors mention the higher AGEs in diabetic patients, so I’m not sure whether they’re talking about things like glucosepane, or something more like MG or CML. But they report in this model that AGEs appear to increase autophagy, but impair clearance of autophagosomes. This upregulates NFkB, and leads to initiation of apoptosis. I wonder whether (1) if there is an age-related increase in the AGEs that these authors tested, and (2) if so, whether this AGE-triggered induction of apoptosis may be causing age-related cell loss, contributing to changes in lysosomal function, or both.


Advanced glycation end products (AGE) potentiates cell death in p53 negative cells via upregulaion of NF-kappa B and impairment of autophagy.
J Cell Physiol. 2017 Dec;232(12):3598-3610.
Verma N, Manna SK
DOI: 10.1002/jcp.25828
PubMed publication date (edat): 1/28/2017

Abstract

Accumulation of advanced glycation end products (AGE) in diabetic patients and ageing people due to excess availability of simple 3- or 4-carbon sugars, is well-known. AGE has multiple deleterious effects including age-related disorders, apoptosis, inflammation, and obesity. We have found that AGE increases autophagy but the sustained amount of autophagosomes is observed till 3 days without maturation. It is important to understand the underlying mechanism of AGE-mediated signaling responsible for impairment of autophagy and its correlation to the induction of several adverse effects. We have identified cross talk between autophagy and apoptosis upon AGE stimulation, specifically in p53 negative cells. AGE impairs autophagosomes’ clearance in p53 negative cells as observed with an autophagosome maturation blocker-bafilomycinA1 treated cells. This autophagy impairment is well supported by upregulation and overexpression of NF-κB in these p53 negative cells. Autophagy impairment acts as a switch to initiate apoptosis via regulation of NF-κB and its dependent genes. Increase in the expression of NF-κB-dependent NEDD4, an E3 ubiquitin ligase, which targets Beclin1 for cleavage is also evident. Beclin1 interacts with Bcl-2, an anti-apoptotic protein thereby engaging it to facilitate apoptosis upon AGE stimulation. For the first time, we are providing data that NF-κB targeted cell signaling is involved in AGE-mediated autophagy impairment in p53 negative/null cells. The p53 acts antagonistically to prevent this impairment. This study will help to control the AGE-mediated detrimental effects associated with ageing and lysosomal storage disorders.

PMID: 28128446
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Maximus Peto

Max Peto is a longevity researcher and founder of Long Life Labs. A biochemist by training, he studies the biochemistry of aging and longevity and has worked with research organizations such as SENS Research Foundation, Methuselah Foundation, BioAge Labs, Life Extension Foundation, and Ichor Therapeutics. His work at Long Life Labs is focused on empowering people to understand and manage the most critical factors for better health and longer life.

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