Advanced Glycation End Product Crosslinking Part 2

April 22, 2019 11 min read

Natural compounds that have shown to aid in the fight
Part 2 of 3
By Alex Tarnava (parts contributed by Dr. Richard Holland)

Is there anything that can help prevent AGE accumulation?
Although there is nothing known that can break glucosepane once formed, the most common advanced glycation end product crosslink, there are quite a number of natural substances which have shown to either inhibit formation, or break other less common crosslinks. I have personally read dozens- maybe hundreds- of studies on AGEs, compounds designed to break or inhibit them, and those that purport to help mitigate the side effects and damages they cause. Through my extensive readings I have identified a ‘personal AGE protection stack’, a list of ingredients which show the most promise.
Rosmarinic Acid
Rosmarinic acid is a caffeic ester of Salvianic acid found in variety of plants. It has significant antioxidant properties and is perhaps the most important ingredient in the stack. Rosmarinic acid has been shown to have a greater affect at reduction in AGE crosslinks than diabetic nephropathy drug candidate aminoguanidine or Alagebriumi. Aminoguanidine is a clinically tested investigational drug that interacts with 3-deoxyglucosone to reduce the formation of AGEs. Alagebrium is a substituted thiazole drug candidate that was designed to reverse cell membrane stiffening by breaking down AGE crosslinks to reduce hypertension and cardiovascular disease. Rosmarinic acid has also shown promising- albeit very preliminary- results as a GABA transaminase inhibitorii which could have potential benefits for anxiety disorders and epilepsy. Furthermore, Rosmarinic acid has shown anti viral and anti-inflammatory properties in a mouse model of Japanese encephalitis. Of course, this would need to be shown in humans. Mouse models can be helpful but do not always translateiii. Despite these many and varied potential benefits, Rosmarinic acid is widely unknown as a supplement, and brands that purport to carrying it often list it as ‘currently unavailable’. This is likely due to the fact that a dosage of it is incredibly expensive. Most companies opt for cheap, well known ingredients rather than taking a marketing risk on something that is expensive with no traction- even if the expensive yet esoteric ingredient is the best candidate.
Curcumin is a diarylheptanoid from the curcuminoid group of chemicals. It is a bright yellow compound found in turmeric and has a diverse pharmacology. However, its use is limited by poor oral bioavailability meaning that to be efficacious, more than two grams are required daily. This limitation is circumvented with the introduction of CurcuWIN, a highly bioavailable, water soluble curcuminoid. In a “first of its kind” human clinical trial, CurcuWin has been shown to have an increased relative absorption of total curcuminoids by a factor of 46x over standard curcumin. In addition to its antioxidant properties, curcumin has also been shown to prevent the negative affects of AGE formations, specifically by countering AGE formation suppression of the Nrf2 pathway via RAGE (receptor for advanced glycation end products) induced gene expression of leptin and its receptors. Suppression of the Nrf2 pathway leads to increased oxidative stress which curcumin negated in a 2014 study.iv
L-Carnosine, an imidazole containing dipeptide formed by beta-alanine and histidine, is a naturally occurring compound found in red meat. This biologically active and important compound has beneficial antioxidative effectsvvi but more importantly helps prevent AGEs from forming by acting as an antiglycating agent.viiviiiix L-Carnosine has also been shown to reduce cellular senescence in a 96 patient trial in patients with cataracts, demonstrating an 80% success rate in advanced senile cataracts and a 100% success rate in patients with mild to moderate cataracts over the 6 month trial period.x Carnosine is known as a geroprotector (i.e a compound that can address the root causes of aging and consequently prolong life), it can also reduce the telomere shortening rate.xi
Bilberry Extract
Bilberry extract is included both for its own benefit in fighting AGEs, and also to complement L-Carnosine. One trial has shown that the combination of carnosine and blueberry extract in vitro increased stem cell proliferation in by 86%.xiiBilberries are a closely related Northern European berry that have a similar composition to blueberries, and often show much higher levels of vitamins and anthocyanins, anthoncyanins being involved in glucose and lipid metabolismxiii and showing to effectively prevent the formations of AGEs by trapping methylglyoxalxiv. It has also been suggested that bilberry may be able to lower blood glucose levelsxv and that the naturally occurring flavonoids found in Bilberries such as Rutin and Quercetin have been found to inhibit various stages of AGE formation.xvixvii Oxerutin, a hydroxyethyl acetylation of rutoside (Rrutin) has shown to work in conjunction with Taurine, also found in this formula, the pair was found to be significantly more effective in a rodent model of diabetes resulting in reduced accumulation of collagen-linked fluorescence in skinxviii

Taurine is a product with wide public awareness due to its heavy supplementation and use in the energy drink market. A little-known benefit of L-Taurine is its potential ability to abolish fructose driven crosslinking in collagen; Fructose has been shown to be a more potent glycating agent than glucose in-vitro.xixFurthermore it has been postulated that diabetic crosslink formations could be largely attributed to fructose in-vivo. Our current consumer climate is inundated with high fructose corn syrup as a sweetening agent, and L-Taurine presents itself as an important preventative supplement to completely decimate AGE crosslinks caused by fructose consumption.xx
Alpha Lipoic Acid (ALA)
ALA’s potential role in AGEs is complicated; ALA has been shown to protect against 4-hydroxynonenal (HNE) mediated oxidative stress and neurotoxicity, making it a potential adjunct therapy for AlzheimersAlzheimer’s.xxi HNE is a toxic and reactive alpha, beta unsaturated aldehyde formed by lipid peroxidation in cells with implication in neurodegenerative diseases, various cancers, diabetes and chronic inflammationxxii. HNE, as a reactive carbonyl species can lead to the following AGEs: Nε-carboxyethyllysine, arginine pyrimidine, pentosidine, pyrralin, methylglyoxal, glyoxal lysine and Nε-carboxymethyllysine.xxiii ALA can mitigate AGE formations while simultaneously providing other benefits. Lipoic acid has also shown to prevent collagen abnormalities in high fructose diets in rats.xxiv In Germany, ALA is prescribed as a drug to treat diabetic neuropathy.xxv

Benfotiamine is a synthetic derivative of Vitamin B1 and though classified as a drug in many countries around the world it is available as a supplement in the United States and Canada. It has been studied as a possible treatment for diabetic nephropathyxxvi, retinopathyxxvii and neuropathyxxviii. Benfotiamine is an AGE formation inhibitor and has been shown to significantly attenuate the formation of AGEs and collagen crosslinking.xxix

Vitamin C
Vitamin C needs no introduction. Perhaps the most widely studied and supplemented product, ascorbic acid has also shown promise in fighting AGEs by decreasing serum protein glycationxxx xxxiMore than its antioxidant activity it is a required cofactor for collagen synthesis and other critical enzymatic functions.xxxii

Vitamin B6
Vitamin B6 has been heavily studied for its’ potential role in advanced glycation end products and has shown evidence for efficacy in all common forms, such as pyridoxinexxxiiixxxivxxxv, pyridoxalxxxvixxxvii and pyridoxamine.xxxviiixxxix xl In 2009, the FDA ruled pyridoxamine an illegal form of vitamin B6 due to it being the only active ingredient in Biostratum’s diabetic nephropathy drug Pyridorin, following a several year successful lobbying campaign by Biostratum.xlixlii While many would read this and think ‘Big Pharma conspiracy’, the truth is Dietary Supplement manufacturers are often completely negligent in performing their legal responsibilities. The manufacturers of Pyridoxamine had not successfully obtained a ‘No Objection’ New Dietary Ingredient Notification, nor had they obtained a GRAS ruling (Generally Regarded As Safe) on file with the FDA. As such, this form of B6 was ‘no status’, and Biostratum was able to argue that they were the first to file its use- as an investigational new drug. Fortunately, pyridoxine and pyridoxal remain available to the public with pyridoxine showing benefits alongside lipoic acid, previously mentioned in this stack, (ref xvi). Additionally, pyridoxine has also show improvements in diabetic patients with symptomatic peripheral neuropathy when used in conjunction with Vitamin b1, also found together in this stackxliii. Vitamin B6 acts as a coenzyme function in roughly 100 enzyme reactions in glucose, amino acids and lipid metabolism.xliv Cinnamaldehyde has also shown to exhibit anti inflammatory and neuroprotective effects.45

Clove and Cinnamon
The addition of clove and cinnamon are important in that they contain high levels of eugenol in both spices, and cinnamaldehyde in cinnamon. Eugenol, in addition to being a potential anti inflammatory agent via inhibition of prostaglandin synthesisxlvxlvi has also shown to potentially have a dual role in inhibition of AGEsxlvii Cinnamaldehyde has likewise shown to attenuate AGEs by the the suppression of AGE-induced biological responses mediated by inactivating the JAK2-STAT1/STAT3 cascade or activating the NO pathway.xlviii Cinnamaldehyde has also shown to exhibit anti inflammatory and neuroprotective effects.xlix
Resveratrol is one of the most hyped and marketed putative anti-aging supplements to emerge in the last few decades and has been studied for its implications in life span, cancer, metabolism, cardiovascular issues and neurodegenerative issues. Its potential for reducing AGEs is less well reported, however. A recent study found that Resveratrol inhibits AGE induced proliferation and collagen synthesis activity.l Resveratrol also shows positive results in studies pertaining to diabetes such as its effect in type II diabetic

End Note
Remember, while this is our current preferred approach to mitigating the damages AGEs are showing to cause after considerable reading and interest in the subject over several years, none of the above is intended to treat or cure any disease mentioned in the article. Most of the studies have been done in vitro or on animals, with those done in humans needing replicated research. The scientific community does not currently have a consensus approach on dealing with AGEs, so there is little (if anything) your health practitioner can do or recommend. While AGEs may potentially lead to more serious issues, in and of themselves they are not a disease or ailment and are in fact necessary in certain amounts, existing from birth. We stand by our stack and believe it to be the best currently researched protocol. In installment 3 of this series, we will talk about our hypothesis on what may end up being the cherry on top in this stack.

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iii Swarup V, Ghosh J, Ghosh S, Saxena A, Basu A. Antiviral and Anti-Inflammatory Effects of Rosmarinic Acid in an Experimental Murine Model of Japanese Encephalitis . Antimicrobial Agents and Chemotherapy. 2007;51(9):3367-3370. doi:10.1128/AAC.00041-07.
iv Youcai Tang and Anping Chen Curcumin eliminates the effect of advanced glycation end-products (AGEs) on the divergent regulation of gene expression of receptors of AGEs by interrupting leptin signaling Laboratory Investigation (2014) 94, 503–516; doi:10.1038/labinvest.2014.42
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