Many types of metabolic waste and byproduct molecules are generated by the normal operation of cellular metabolism. You can't run an engine without exhaust or a factory without waste generation. The majority of these unwanted outputs are swept away to be broken down and recycled by a panoply of varied housekeeping mechanisms, but unfortunately this is not not the case for all of them. Some hardy forms of waste linger, accumulating throughout life, and this problem becomes worse in later years as all of the systems in our biology lose their effectiveness due to damage. The damage of aging in living beings is an accelerating downward spiral because it also degrades the very mechanisms that are in place to repair it on an ongoing basis.
Cross-links in the complex structures of the extracellular matrix are a consequence of some classes of metabolic waste, such as advanced glycation end-products (AGEs). The properties of any given tissue are determined by the nanoscale structure and arrangement of proteins in the extracellular matrix, but cross-links degrade that structure by chaining these proteins together. A growing level of cross-linking can reduce elasticity in softer tissues such as skin or blood vessel walls, for example, and that loss of elasticity has serious consequences for health. Similar loss of structural properties can occur for tissues where strength or ability to bear load are the important factors. There are a lot of different types of AGE, many of which are short-lived because a healthy biochemistry is quite capable of removing them. Some are long-lived and resilient, however, such as glucosepane that accounts for the overwhelming majority of AGEs in old human skin.
Despite breaking down AGEs being an obvious potential target for therapies, and this research meshing well with the strengths of the pharmaceutical industry, it is actually the case that very little work takes place on ways to safely remove persistent AGEs from tissues. It can be argued that this is in part due to a high profile failure in AGE-breaker drug development not so many years ago, but also because there are few tools and laboratories capable of working with glucosepane in any meaningful way. It is an odd oversight, one of those scientific blank spots that perpetuates itself because every group than might choose to work on this area looks at the absence of basic tools and then moves on to something easier and more likely to return a profit. The SENS Research Foundation is at present funding a research program to fix this situation by building the tools needed to work with glucosepane.
Here I'll point out an open access review on the topic of cross-links in the collagen structure of the extracellular matrix, with a focus on tendons in particular:
The role of collagen crosslinks in ageing and diabetes - the good, the bad, and the ugly
The non-enzymatic reaction of proteins with glucose (glycation) is a topic of rapidly growing importance in human health and medicine. There is increasing evidence that this reaction plays a central role in ageing and disease of connective tissues. Of particular interest are changes in type-I collagens, long-lived proteins that form the mechanical backbone of connective tissues in nearly every human organ. Despite considerable correlative evidence relating extracellular matrix (ECM) glycation to disease, little is known of how ECM modification by glucose impacts matrix mechanics and damage, cell-matrix interactions, and matrix turnover during aging. More daunting is to understand how these factors interact to cumulatively affect local repair of matrix damage, progression of tissue disease, or systemic health and longevity.Various approaches have been taken to prevent formation of AGEs (for an excellent review see "Characteristics, formation, and pathophysiology of glucosepane: a major protein cross-link"). For instance, a reduced alimentary glucose uptake has been shown to be beneficial, as have approaches seeking to breakdown or block intermediate molecular interactions. Further efforts have shown potential benefit in "protecting" amino acid residues by agents that competitively bind aldehydes. Complementing these preventative approaches, some therapeutic approaches have sought to break existing AGE crosslinks.
Contrary to the mentioned preventative approaches, crosslink breaking can reverse AGE crosslinking and its deleterious effects on tissue mechanics and matrix remodeling. Since AGE crosslinks in tendon are only secondary complications of diabetes, most anti-AGE work has been done in other tissues (such as skin and arteries). However, their potential effectiveness was first demonstrated using rat tail tendon. In any case, as far as we are aware there is no study testing the ability of crosslink breaking therapies to ameliorate the predisposition of tendon to mechanical damage, or promote "healthy" tissue remodeling at a repair site.
View the full article at FightAging
