Chebulic acid: Is it a potential AGE cross linking breaker?



When discussing cross-linking of proteins through glycation and advanced glycation end products (AGE’s), there are two issues:

  • Inhibiting or preventing cross-linking, and
  • Breaking existing AGE’s (reversing existing AGE cross links)

There are a number of natural substances that inhibit or prevent AGE’s:

  • Acetyl-L-Carnitine
  • Aged Garlic
  • Allspice
  • Aminoguanidine
  • Arginine
  • Asiatic Dogwood
  • Astragalus
  • Centrophenoxine
  • Chromium (Chromium Picolinate)
  • Cinnamon
  • Cloves
  • Coumestrol
  • Dimethylaminoethanol (DMAE
  • Diosmin
  • Ethylene-Diamine-Tetra-Acetate (EDTA
  • Glutathione Peroxidase
  • Grape Seeds (extract)
  • Green Tea
  • Inositol
  • Korean Ginseng
  • Lipoic Acid
  • Luteolin
  • Marjoram
  • Methylsulfonylmethane (MSM
  • Myricetin
  • N-Acetyl-Cysteine (NAC)
  • Oligomeric Proanthocyanidins (OPCs)
  • Oregano
  • PABA (Para Aminobenzoic Acid
  • Papain
  • Pyridoxamine
  • Quercetin
  • Rosemary
  • Rutin
  • Taurine
  • Vitamin A
  • Vitamin B1
  • Vitamin B5
  • Vitamin B6
  • Vitamin C
  • Vitamin E
  • Zinc

As can be seen, there are quite a few natural substances that inhibit or prevent AGE’s. However, the real holy grail is in substances that can break or reverse existing AGE’s. 

AGE’s in humans exist in one of three following molecular structures:

  • Glucosepane
  • Alpha-Diketone linkers
  • Lysine-dihydropyridinium-lysine (L2P or K2P)

There are two known potential Cross-link breakers that have been studied and researched:

  • Alagebrium (formerly known as ALT-711) (3-phenacyl-4, 5-dimethylthiazolium chloride)
  • N-phenacyl-4,5-dimethylthiazolium bromide (DMPTB)

Alagebrium was a drug candidate developed by Alteon Corporation. It was the first drug candidate to be clinically tested for the purpose of breaking the crosslinks caused by advanced glycation endproducts (AGEs).

Alagebrium entered into Phase I and II clinical trials but Alteon Coproration ceased their research due to financial issues. The company that bought Alteon, Synvista Therapeutics, Inc, discontinued further research on Alagebrium in January 2009. [1]

N-phenacyl-4,5-dimethylthiazolium bromide (DMPTB) is a thiazolium compound which is known to cleave preformed advanced glycation end products. [2] Treatment of pre-glycated αA-crystallin with DMPTB gave evidence for the degradation of the already formed cross–linked HMW aggregates. [3]

Alagebrium and N-phenacyl-4,5-dimethylthiazolium bromide (DMPTB) are known to only break Alpha-Diketone linkers. They are not known to break the other two AGE’s Alpha-Diketone linkers and Lysine-dihydropyridinium-lysine.

According to current research, no agent has been found that breaks the prevalent glucosepane and K2P crosslink structures. [4]

Chebulic acid is a phenolic compound isolated from the ripe fruits of Terminalia chebula. Terminalia chebula is a tree grown in India and Asia. In Ayruvedic medicine it is called Haritaki in the Hindi language. Terminalia chebula extract is also found in the ayruvedic formula called Triphala which means “Three Fruits”.


An interesting article appeared in the April 2014 edition of the Biology & Pharmaceutical Bulletin regarding chebulic acid on advanced glycation end products. It is entitled Effects of chebulic acid on advanced glycation end products-induced collagen cross-links, written by Lee JY, Oh JG, Kim JS, and Lee KW. [5]

The author’s first state the purpose of their study:

“We report the antiglycating activity of chebulic acid (CA), isolated from Terminalia chebula on breaking the cross-links of proteins induced by AGEs and inhibiting the formation of AGEs.”

The author’s research illustrated very promising potential of chebulic acid as a cross-link breaker, stronger than ALT-711.

“Also, the breaking activity on collagen cross-links induced by glycol-BSA was potent with CA (IC50=1.46 ± 0.05 mM), exhibiting 50-fold stronger breaking activity than with ALT-711, a well-known cross-link breaker (IC50=72.2 ± 2.4 mM).”

The author’s conclusion shows that chebulic acid is not only an inhibitor of AGE cross linking but also a breaker of AGE cross-linking:

“Thus, CA could be a breaker as well as an inhibitor of AGE cross-linking, the activity of which may be explained in large part by its chelating and antioxidant activities, suggesting that CA may constitute a promising antiglycating candidate in intervening AGE-mediated diabetic complications.”

UPDATE:  Michael Rae examines whether Chebulic Acid has potential as an AGE cross link breaker. LINK TO QUORA 



[1] Synvista Therapeutics Announces Termination of Clinical Trials of Alagebrium and SYI-2074 and Provides Business Update

[2] The cross-link breaker, N-phenacylthiazolium bromide prevents

vascular advanced glycation end-product accumulation

[3] Cleavage of in vitro and in vivo formed lens protein cross-links by a novel cross-link breaker

[4] Extracellular Glycation Crosslinks: Prospects for Removal

[5] Effects of chebulic acid on advanced glycation endproducts-induced collagen cross-links

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