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

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.

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