Testing PTB as an AGE-Breaker in Bone

Advanced glycation endproducts, AGES, are a class of undesirable sugary metabolic waste that accumulate in tissues over time. They gum together important protein structures and cause cells to react to their presence in ways that are damaging and raise levels of chronic inflammation. There are many different types of AGE, but most are not all that relevant to the aging process in healthy people, being short-lived and well controlled by our biochemistry. More hardy types of AGE that cannot be effectively cleared are a fundamental difference between old and young tissues, and a contribution to degenerative aging. Of these glucosepane is the most important in human tissues.

Much of the limited work of past decades that aimed to produce AGE-breaker drugs capable of clearing out AGEs went nowhere, as drug candidates established in animal studies performed very poorly in people. It turned out that the types of AGE important in mice and rats are quite different from those that are important in humans. So researchers now realize that they have to work with human tissues to draw any reasonable conclusions, such as in this study. Note that the drug candidate PTB has been known as a potential AGE-breaker on the basis of animal studies for some years now, but it remains unclear as to its utility as a treatment for people:

Nonenzymatic glycation (NEG) describes a series of post-translational modifications in the collagenous matrices of human tissues. These modifications, known as advanced glycation end-products (AGEs), result in an altered collagen crosslink profile which impacts the mechanical behavior of their constituent tissues. Bone, which has an organic phase consisting primarily of type I collagen, is significantly affected by NEG. Through constant remodeling by chemical resorption, deposition and mineralization, healthy bone naturally eliminates these impurities. Because bone remodeling slows with age, AGEs accumulate at a greater rate. An inverse correlation between AGE content and material-level properties, particularly in the post-yield region of deformation, has been observed and verified.

Interested in reversing the negative effects of NEG, here we evaluate the ability of n-phenacylthiazolium bromide (PTB) to cleave AGE crosslinks in human cancellous bone. Cancellous bone cylinders were obtained from nine male donors, ages nineteen to eighty, and subjected to one of six PTB treatments. Following treatment, each specimen was mechanically tested under physiological conditions to failure and AGEs were quantified by fluorescence. Treatment with PTB showed a significant decrease in AGE content versus control NEG groups as well as a significant rebound in the post-yield material level properties. The data suggest that treatment with PTB could be an effective means to reduce AGE content and decrease bone fragility caused by NEG in human bone.

Link: http://dx.doi.org/10.1371/journal.pone.0103199


Given that PTB has been know about for a long time, why hasn't it undergone more testing in vivo? Why is their no reference to it on the SENS website or on Dr William Bains' website?

Posted by: Jim at August 6th, 2014 7:20 AM

AGE-breaker work is pretty sparse and has been all along, which was no doubt helped along by the noted failure of the earliest funded biotech startup based on delivering an AGE-breaker, Alteon. It just isn't a field that gets much traction in general.

Posted by: Reason at August 6th, 2014 2:32 PM

Hi Jim,

PTB is the parent compound of Alagebrium/ALT-711, with less catalytic activity. Alagebrium went all the way to clinical trials and then promptly failed. It's quite clear that these compounds don't work to reduce in any clinically-meaningful way in humans, for reasons that are debated, but that may be chalked down to an interspecies difference in the species of AGE crosslink: ie, the class of AGE that Alagebrium putatively breaks is common in rodents, but rare in humans (in whom the most quantitatively important AGE crosslink in collagen appears to be glucosepane). See Ending Aging for more on the history of this compound.

This is why SENS Research Foundation is now sponsoring research aimed at the eventual development of glucosepane crosslink breakers.

Posted by: Michael at August 6th, 2014 4:40 PM

Well good luck to Dr Bains and all those involved.

About the only thing I can do is talk to friends about it, but I get about as frosty a reception as a traveling bible salesman. Everyone's life could always be better, so they'll spend their pennies on themselves until someone on the evening news says otherwise (that life extension research is possible and should be heavily funded). There is also the free rider problem. Hopefully some demo breakthrough technology will come along soon which I batter people about the head with.

Posted by: Jim at August 6th, 2014 8:47 PM

Breaking a cross link in bone tissue is still nothing to sneeze at. Is there an effective way to classify or measure crosslinks in living tissue?

Posted by: Michael at August 7th, 2014 12:19 AM

@Michael: If you look at the paper here the researchers are using a fairly indirect method of measurement. As I understand it one if the issues is that good tools don't exist for working for these compounds. So if you look at the glucospane research funded by the SENS Research Foundation, they are building the fundamental toolkit needed to even work effectively and evaluate potential treatments in tissue.

Posted by: Reason at August 7th, 2014 3:41 PM

Given that Alagebrium made it so far through trials, it probably passed through safety profile checks and other hurdles. This may make it easier to start another study with a focus on bone - or perhaps a followup study can look at the participants of the failed trial and see if there's a bone fracture difference.

Posted by: Dennis Towne at August 8th, 2014 1:16 PM

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