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Advanced Glycation End-Products

The non-enzymatic addition of reducing sugar-molecules such as glucose to proteins, lipids or nucleic acids which changes their biochemical function. Advanced glycation end-products (AGEs) commonly accumulate in collagen-rich tissues where they tend to create inter-fibrillar cross-links resulting in increased tissue stiffness, which has a major impact on musculoskeletal tissue-biomechanics

Cyto- and tissue-mechanical effect of AGEs. Red lines represents molecular cross-links.

Formation of AGEs is a very complex and heterogenous process and it can happen for many different reasons, but my suspicion is that in pathological contexts AGEs are mainly created intentionally by immune-cells and gastrointestinal bacteria as means to affect properties related to the cellular stress-response and also cellular adhesion and migration. It probably has a similar role to B-amyloids.

Recognition and signalling-pathway of AGE, leading to inflammation and activation of immune-cells.

Cells mainly recognise AGEs by a membrane-receptor called receptor for AGEs (R-AGE). In general, host cells react to exposure of AGEs with inflammation, and it seems to be treated as a danger signal. After they form, AGEs and associated proteins become resistant to remodelling and proteolytic degradation, and since they preferably accumulate in long-lived tissues, their effects on tissue-biomechanics can be long-lasting and complicated (bot not impossible) to reverse. When appropriate and possible, elimination of AGEs is carried out by the immune-system through inflammatory mechanisms, but since AGEs are irreversibly bound to host cells or tissues, a certain amount of collateral damage is unavoidable.

Supporting Evidence

  • Endogenous AGEs can form both dependent and independent of hyperglycaemia.1)https://www.sciencedirect.com/science/article/pii/S016372581730044X?via%3Dihub
  • The most abundant AGE is synthesised mainly by host macrophages.2)https://www.nature.com/articles/s41598-017-11773-1
  • Protein-bound AGEs seems to be indicative of endogenous AGE-formation.3)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413015/
  • Macrophages are also involved in removal of AGEs.4)https://www.nature.com/articles/s41598-018-24325-y5)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752849/
  • RAGE-activation has been shown to have a pro-oxidative and pro-apoptotic function in various cell-types.6)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752849/
  • AGEs are formed and secreted by bacteria, and RAGE might be a sensor for infection.7)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593110/8)https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017974
  • RAGE can be activated by bacterial LPS.9)https://www.jimmunol.org/content/jimmunol/186/5/3248.full.pdf?with-ds=yes
  • RAGE can be exploited by pathogens.10)https://www.sciencedirect.com/science/article/pii/S1286457915001112?via%3Dihub
  • Inhibition of RAGE increases survival in animal models of sepsis.11)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011309/
  • RAGE can have both pro- and anti-infectious effects depending on the pathogen.12)https://ccforum.biomedcentral.com/articles/10.1186/cc9990
  • AGEs can be fermented and used as food by bacteria.13)https://www.ncbi.nlm.nih.gov/pubmed/2618607514)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413015/
  • Accumulation of AGEs impairs leukocyte adhesion and migration.15)https://www.ncbi.nlm.nih.gov/pubmed/24635174/16)https://www.ncbi.nlm.nih.gov/pubmed/18980529
  • AGEs can facilitate bacterial adhesion to epithelial cells.17)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4444075/
  • AGEs can have an inhibitory effect towards infection and transmission of HIV-1.18)https://www.ncbi.nlm.nih.gov/pubmed/21478402
  • Local rate of protein-turnover is a major determinant of tissue-accumulation of AGEs.19)https://www.jbc.org/content/275/50/39027
  • AGEs can only be degraded if the protein that they are linked to is also degraded.20)http://rheumatology.oxfordjournals.org/content/52/4/599.long
  • Exercise might have potential to reduce tissue-AGEs by increasing protein-turnover.21)https://onlinelibrary.wiley.com/doi/full/10.1002/jor.22824
  • Accumulation of AGEs may also inhibit tissue-plasticity and repair-capabilities.22)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485690/

Association with Disease

  • Elevated levels of AGEs found in serum and muscle-tissue in patients with MPS.23)https://www.ncbi.nlm.nih.gov/pubmed/1236463724)https://www.ncbi.nlm.nih.gov/pubmed/16393769
  • AGEs are found in serum, synovial fluid and articular cartilage from patients with OA.25)https://www.ncbi.nlm.nih.gov/pubmed/12590883
  • Accumulation of AGEs found in TP.26)https://journals.sagepub.com/doi/abs/10.1177/2473011417S000432
  • AGEs found in synovial tissue from RA-patients.27)https://ard.bmj.com/content/annrheumdis/61/6/492.full.pdf
  • AGEs found in DDD and DH, and AGEs might have a role in DH-regression.28)https://onlinelibrary.wiley.com/doi/full/10.1002/jor.2250829)https://www.jstage.jst.go.jp/article/kurumemedj1954/49/1-2/49_1-2_7/_article
  • AGEs found in AT, and are associated with plaque instability.30)https://www.ncbi.nlm.nih.gov/pubmed/24126878

References   [ + ]

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