The AGE-Breaker TRC4186 From Torrent Pharmaceuticals

Back in late 2006, a lifetime ago in Internet Time, I briefly mentioned the efforts of Torrent Pharmaceuticals. They are one of the few groups doing any sort of serious work on AGE-breakers, compounds aimed at breaking down the advanced glycation endproducts (AGEs) that build up with age and cause all sorts of havoc in our biochemistry.

One of the ways in which normal metabolic processes degrade important components in your body (such as kidneys, heart, skin and blood vessels) is through the generation of advanced glycation endproducts (AGEs). Your body needs certain proteins in order to work properly; the creation of AGEs involves taking two or more of these proteins and sticking them together with chemical gunk, preventing them from doing their jobs. This is known as crosslinking; day in and day out, it is taking place in your body. Some AGEs are short-lived but common, growing or declining in population in response to your diet and metabolic peculiarities. Others are very long-lived or impossible for the body to break down; they build up over the years, and eventually there's enough of this gunk to seriously damage you.

Problems caused - or not helped - by AGE buildup include kidney disease, and the many variations of blood pressure and heart conditions caused by a lack of elasticity in the tissues of heart and blood vessels. Diabetics in particular suffer due to more rapid accumulation of AGEs based on their metabolic biochemistry (e.g. high blood sugar, inflammation, free radicals).

AGEs may cause harm by hitting a receptor for AGEs (or RAGE) on cell surfaces. This might be thought of as hammering on a keyboard designed for more subtle inputs; cells constantly receiving input at their RAGE receptor don't behave well - and enough cells behaving badly will cause your organs to degrade, damage themselves, and fail.

In accordance with a SENS-like view of how to move forward to defeat the processes of aging, the best approach to dealing with AGEs is to remove them before they build up to damaging levels. Researchers could search for some form of biochemical, drug, or therapy to safely break down AGEs. Fortunately, we live in an era of rapidly advancing biotechnology in which exactly this sort of this task is becoming ever easier and less costly. Unfortunately, not all that many people are working on it at present.

Torrent Pharmaceuticals researchers recently published an update on their work in developing the AGE-breaker compound TRC4186 for commercial use:

TRC4186 is an AGE-breaker that has been evaluated in vitro and in vivo and shown to reduce AGE burden. The aim of this study was to determine the effect of TRC4186 on diabetic cardiomyopathy and nephropathy in [an] animal model of diabetes with progressive cardiac and renal dysfunction.


TRC4186, an AGE-breaker, clearly preserved cardiac function and reduced the severity of renal dysfunction in [an] animal model with persistent severe hyperglycemia leading to diabetic heart failure and renal failure.

As an aside, most commercial AGE-breaker research focuses on diabetes because regulatory bodies such as the FDA do not recognize aging or "normal" AGE accumulation as diseases, and won't approve any medical application of therapies to that end. Thus researchers are forced into channeling research towards officially approved and defined diseases that happen to include some of the same issues in their pathology. Diabetes is the best option for commercial application of AGE-breakers under these imposed limits because of its biochemistry and the fact that it is widespread in this age of too much food and not enough exercise.

Without meaning to denigrate the hard work of the researchers here, TRC4186 isn't all that exciting based on these results. In fact, this looks very much like a repeat of ALT-711 or alagebrium, an early AGE-breaker compound - predating modern designer drug methodologies enabled by new biotechnology - that performed well in rats but terribly in humans. As it turns out, the difference in rat versus human life span leads to very different types of AGEs being important. The lesson learned there is that animal studies of AGE-breakers are in no way a convincing demonstration of their utility, as is unfortunately sometimes the case in new medical technology.

ResearchBlogging.orgJoshi, D., Gupta, R., Dubey, A., Shiwalkar, A., Pathak, P., Gupta, R., Chauthaiwale, V., & Dutt, C. (2009). TRC4186, a Novel AGE-breaker, Improves Diabetic Cardiomyopathy and Nephropathy in Ob-ZSF1 Model of Type 2 Diabetes Journal of Cardiovascular Pharmacology, 54 (1), 72-81 DOI: 10.1097/FJC.0b013e3181ac3a34


Used to work with the compound. Further update based on public knowledge is that the compound has finished Phase-1 successfully. Looking to start Phase-2 in near future. Not sure if they have collected efficacy data in Phase-1 on AGE breaking ability. That would provide info on whether 4186 is better than 711

Posted by: Abhishek at August 18th, 2009 3:42 AM

"As it turns out, the difference in rat versus human life span leads to very different types of AGEs being important"

Well if we are working on the assumption that glycation is a cause of aging and therefore more of it would lower ones life span, it would be very interesting to understand WHY the rats lifespan is shorter than our own. If AGE's limit the rat lifespan then how does the human body work to counteract those particular AGE's as it must already do? How does a Macaw's body handle AGE's? A Galapagos Tortoise?

Posted by: Michael A. at July 29th, 2011 6:07 PM

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