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.