Advanced Glycation End Product Crosslinking

April 15, 2019 8 min read

What they are, what damage do they lead to, and why you can’t avoid them

Part 1 of 3

What are Advanced Glycation End Products or AGEs?

Advanced Glycation End (AGE) product crosslinking is a naturally occurring physiological phenomena. Many pathological states implicated in age related diseases increase the degree and rate of crosslinking and as such present a challenge to maximizing health and lifespan. AGE crosslinks are formed when binding occurs between sugars (e.g glucose) and lipids or proteins in the intracellular and extra cellular matrix. This affects nearly every cell in the body.

While crosslinking is a natural and necessary physiological process, excessive binding results in cell stiffening which results in them becoming more susceptible to damage and premature ageing. AGE crosslinking has been predominantly studied for its involvement in specific disease models (e.g cardiovascular disease mortality[1] and diabetes)[2] however, it has also been proposed by the anti-aging community as one of the main causes of degenerative aging and senescence (Aubrey De Grey and the SENS Research Foundation).[3]

What Damage do Advanced Glycation End Products cause?

Formation of advanced glycation end product crosslinking in collagen has been suggested as a causative factor in vascular stiffening.[4][5] Healthy vascular endothelium,  a membrane that lines the inside of the heart and blood vessels that release substances which controls vascular contractions and relaxation as well as enzymes which control our blood clotting, immune function and other roles, are necessary in prevention of atherosclerosis, acting as a critical protective barrier for leukocyte transmigration into the intima (the inner most layer of the endothelial cells in our veins and arteries, in direct contact with blood flow) and cholesterol accumulation[6].

Leukocytes, which are our white blood cells, are necessary for our immune response or ‘inflammatory response’, however an over reaction leads to damaging excess inflammation.  Accumulation of AGEs leads to these endothelium to stiffen, increasing permeability- basically making bigger holes in our bodies ‘strainer’, and increased transmigration basically means an increase in the white blood cells leading to inflammation making it through our entire body/system. In other words, our body reacts as it should, but part of our system isn’t functioning properly, leading to a potentially massive over reaction and excess inflammation which can lead to the majority of health issues.

Over time this leads to a complete dysregulation of our inflammatory response, and an increase in unnecessary chronic inflammation.  Studies have shown that Advanced glycation end product drives stiffening of the extracellular matrix, increases endothelial permeability and leukocyte transmigration both in vitro and in vivo[7], with leukocyte transmigration attributed to increased adhesion molecule expression in endothelial cells. Increased endothelial permeability has been linked to increased levels of cholesterol and inflammation.10 

In a cause-effect cyclical nature, AGEs can both be caused by and lead to excesses in oxidative stress, and as well both require ROS to be formed and produce them during formation[8][9]. Chronically elevated AGEs have been shown to be potent suppressors of NAD+, a molecule becoming increasingly more popular in antiaging research, in part by reducing Nicotinamide phosphoribosyltransferase leading to SIRT1 depletion.

Decreased SIRT1 levels lead to excess activation of NF-kB p65 and increased transcription of inflammatory genes such as TNF-alpha contributing to insulin resistance.[10] As many of you know, SIRT1 activation has shown to extend lifespan in mice, and resveratrol’s original claim to fame is that it is a SIRT1 activator(as are other substances, such as Molecular Hydrogen which has shown to both activate SIRT1 and protect against damages which would otherwise lead to depletion[11][12][13]).

So, let’s take a tally. Elevated AGEs have been shown to increase oxidative stress, lead to excessive and chronic inflammation, lowers SIRT1 and NAD+ levels, increases cholesterol and increases insulin resistance? The last part which would ironically lead to a faster accumulation of the very thing causing these problems, AGEs? Yeesh. Talk about a full-blown assault on our health.

AGEs have also been suggested as a causative factor of sarcopenia[14], the loss of muscle mass and weakening of muscles in the elderly, which further leads to a decrease in healthspan. Although not currently supported by research- as no study on the subject exists- I have hypothesized that early AGE formation is a factor in an increase in muscle tears in athletes as they approach their late 20s, 30s and into their 40s. Why have you probably not have heard of them? Because after 2 decades of study we have no drug candidates for aiding in them, and no single natural compound has a significant enough effect. We will get to this more in the next paragraph, as well as the next two parts in this three part series.

Why you can’t avoid Advanced Glycation End Product Crosslinking

Despite the growing body of evidence regarding the catastrophic consequences of excessive AGE formation, AGEs have shown to be a poorly understood area of biology with no approved drugs or candidates showing promise with breaking down glucosepane emerging after 21 years of study.[15] To date, no experimental drug or enzyme has been shown to break glucosepane in vitro, prevalent in levels 10 to 10,000x any other AGE.[16] Drug candidates such as aminoguanidine and alagebrium have shown to be less effective than some of the natural compounds we will write about in the next part of this series. 

How do AGEs accumulate?

We accumulate AGEs through our diet, both taking them in through exogenous sources (meaning outside our body) and creating them endogenously (inside our body). No diet is completely safe from AGE accumulation, as they will always occur; although at different rates. In a very simplified explanation to a complex chemical reaction beginning with the amadori rearrangement[17] which is part of and leads to the irreversible Maillard reaction[18], in our bodies sugar or ketones will react with free radicals to bind our proteins or lipids. The higher your intake of calories the more AGEs will form. Likewise, when your redox status (balance between reactive oxidative species and antioxidants) becomes dysregulated and skewed to excess free radicals, a higher rate of reaction will occur.  A perfect breeding ground for AGE formation is excess sugar in your system[19], this is the tragic irony I previously mentioned in AGEs actually leading to increased insulin resistance, and elevated levels of free radicals; which will happen from the creation of oxidative stress, which again AGEs lead to, and excess inflammation. Basically, everything that AGEs cause drives more AGEs to form. It’s inescapable. On top of endogenous formation, unfortunately we can consume exogenous AGEs, and they will wreak the same havoc. From reference xiv, here is a great breakdown of exogenous dietary AGEs

Exogenous Sources of AGEs

In addition to in vivo production, AGEs can also be found in cigarettes and in foods. The curing of tobacco leaves has been proposed as the source for compounds that can readily increase in vivo AGEs. Cerami et al. found that glycotoxins from cigarettes are inhaled into the alveoli, and then they are transported to blood stream or to lung cells where they can interact with other glycation products and contribute with AGEs formation [46].

4.1. Dietary AGEs

Heat has been used for treatment of foods to improve their safety, bioavailability and taste. In addition to these positive effects, overheating of foods can also provoke protein degradation and other deteriorative reactions [47]. Heat treatment in some foods results in promotion of the Maillard reaction, which adds desirable flavor, color and aroma. In the food industry, the Maillard reaction has been used for caramel production, coffee roasting, and bread baking among others. Some products of the Maillard reaction can be added to industrialized products such as sodas and juices [48]. There is growing evidence that the average Western diet is a plentiful source of exogenous AGEs. The AGEs content of a diet depends on the nutrient composition (foods rich in protein and fat have the highest content) and on the way food is processed [49,50]. AGEs formation can be rapidly accelerated by increasing the time and degree of exposure to heat and can be introduced into the body in heat–processed foods [47,49,50]. These findings were demonstrated using an AGE-specific, enzyme–linked immunosorbent assay (ELISA), and it was estimated that ≈10% of ingested immunoreactive AGEs are transported into circulation, two-thirds of which remain in the body, and are incorporated covalently in tissues. Only one third is excreted via the kidneys [51].

Conclusion

AGE accumulation is a big problem, and for now there is no clear-cut solution. Whether your diet is full of sugars and AGEs form endogenously, or rich in cooked fat and proteins and added exogenously, they will build up in your system over time. A full arsenal of defenses is needed to stave off the effects for as long as possible. Hopefully the research will reveal more strategies in the near future. In our next 2 parts we will talk about the known available compounds that have shown promise in combating some AGE formation, or in assisting in protecting against their damages.

 


[1] Semba RD, Ferrucci L, Sun K, et al. Advanced glycation end products and their circulating receptors predict cardiovascular disease mortality in older community-dwelling women. Aging clinical and experimental research. 2009;21(2):182-190.  

[2] Singh VP, Bali A, Singh N, Jaggi AS. Advanced Glycation End Products and Diabetic Complications. The Korean Journal of Physiology & Pharmacology : Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology. 2014;18(1):1-14. doi:10.4196/kjpp.2014.18.1.1.  

[3]https://en.wikipedia.org/wiki/Strategies_for_Engineered_Negligible_Senescence#Extracellular_junk.E2.80.94AmyloSENS  

[4] Sims T. J., Rasmussen L. M., Oxlund H., Bailey A. J. (1996). The role of glycation cross-links in diabetic vascular stiffening. Diabetologia 39 946–951 10.1007/s001250050536

[5] Schleicher E. D., Wagner E., Nerlich A. G. (1997). Increased accumulation of the glycoxidation product N(epsilon)- (carboxymethyl)lysine in human tissues in diabetes and aging. J. Clin. Invest. 99457–468 10.1172/JCI119180

[6] Initiation of atherosclerotic lesions in cholesterol-fed rabbits. II. Selective retention of LDL vs. selective increases in LDL permeability in susceptible sites of arteries. D C Schwenke and T E Carew Arteriosclerosis, Thrombosis, and Vascular Biology. 1989;9:908-918, originally published November 1, 1989 https://doi.org/10.1161/01.ATV.9.6.90

[7] Huynh J, Nishimura N, Rana K, et al. Age-Related Intimal Stiffening Enhances Endothelial Permeability and Leukocyte Transmigration. Science translational medicine. 2011;3(112):112ra122. doi:10.1126/scitranslmed.3002761.

[8] Hyung-Soon Yim, Sa-Ouk Kang, Yung-Chil Hah, P. Boon Chock and Moon B. Yim RADICALS Methylglyoxal: A MODEL STUDY OF PROTEIN-CROSS-LINKED FREE Free Radicals Generated during the Glycation Reaction of Amino Acids by doi: 10.1074/jbc.270.47.28228 J. Biol. Chem. 1995, 270:28228-2

[9] Nowotny K, Jung T, Höhn A, Weber D, Grune T. Advanced Glycation End Products and Oxidative Stress in Type 2 Diabetes Mellitus. Breitenbach M, Eckl P, eds. Biomolecules. 2015;5(1):194-222. doi:10.3390/biom5010194.

[10] Vlassara H, Uribarri J. Advanced Glycation End Products (AGE) and Diabetes: Cause, Effect, or Both? Current diabetes reports. 2014;14(1):453. doi:10.1007/s11892-013-0453-1.

[11] Robert Settineri, Jin Ji, Chunlan Luo, Rita R. Ellithorpe, Gonzalo Ferreira de Mattos, Steven Rosenblatt, James LaValle, Antonio Jinenez, Shigeo Ohta, Garth L. Nicolson. Effects of Hydrogenized Water on Intracellular Biomarkers for Antioxidants, Glucose Uptake, Insulin Signaling and SIRT 1 and Telomerase Activity. American Journal of Food and Nutrition. Vol. 4, No. 6, 2016, pp 161-168

[12] Li S et al, Molecular hydrogen protects against ischemia-reperfusion injury in a mouse fatty liver model via regulating HO-1 and Sirt1 expression Scientific Reportsvolume 8, Article number: 14019 (2018)

[13] Fumihiko Hara, Junko Tatebe, Ippei Watanabe, Junichi Yamazaki, Takanori Ikeda, Toshisuke Morita, Molecular Hydrogen Alleviates Cellular Senescence in Endothelial Cells, Circulation Journal, 2016, Volume 80, Issue 9, Pages 2037-2046, Released August 25, 2016, [Advance publication] Released July 29, 2016, Online ISSN 1347-4820, Print ISSN 1346-9843, http://dx.doi.org/10.1253/circj.CJ-16-0227, https://www.jstage.jst.go.jp/article/circj/80/9/80_CJ-16-0227/_article/-char/en, Abstract:

[14] Luevano-Contreras C, Chapman-Novakofski K. Dietary advanced glycation end products and aging. Nutrients. 2010;2(12):1247-65.

[15] Sara VasanXin ZhangXini ZhangAphrodite KapurniotuJürgen BernhagenSaul TeichbergJohn BasgenDilip WagleDavid ShihIhor TerleckyRichard BucalaAnthony CeramiJohn EganPeter Ulrich An agent cleaving glucose-derived protein crosslinks in vitro and in vivo Nature 382, 275-278(18 July 1996)

[16] Monnier, V. M., Mustata, G. T., Biemel, K. L., Reihl, O., Lederer, M. O., Zhenyu, D.; et al. (2005). "Cross-linking of the extracellular matrix by the maillard reaction in aging and diabetes: An update on "a puzzle nearing resolution"". Annals of the New York Academy of Sciences1043: 533–544. doi:10.1196/annals.1333.061PMID 16037276.

[17] https://en.wikipedia.org/wiki/Amadori_rearrangement

[18] https://en.wikipedia.org/wiki/Maillard_reaction#Physiology

[19] Aragno M, Mastrocola R. Dietary Sugars and Endogenous Formation of Advanced Glycation Endproducts: Emerging Mechanisms of Disease. Nutrients. 2017;9(4):385. Published 2017 Apr 14. doi:10.3390/nu9040385


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