In flexible, elastic tissues such as skin and blood vessel walls, large molecules of the extracellular matrix must be able to move relative to one another. When undesirable cross-links form between these molecules, tissue loses its elasticity and flexibility. Much of this undesirable cross-linking is the result of interactions with sugars, particularly via a class of compounds known as advanced glycation end-products, AGEs. In addition to the cross-linking, AGEs also provoke inflammation via interaction with the receptor for AGEs, RAGE. This is a well known harmful feature of the high-sugar, dysfunctional diabetic metabolism.
In the late 1990s and early 2000s, alagebrium was developed as a drug candidate on the basis of being able to break forms of AGE-induced cross-links found in arterial tissues, and thus reduce age-related arterial stiffening in preclinical studies in mice. In addition to breaking some forms of cross-link, alagebrium was also found to scavenge methylglyoxal, a particularly obnoxious precursor to AGEs and bad actor in diabetic metabolism. Sadly, the cross-links broken by alagebrium are prevalent in mice, but not in humans. Even more sadly, the failure of alagebrium to improve arterial stiffening in human clinical trials sabotaged any likelihood of further clinical trials in diabetic patients - so we have no idea whether alagebrium may or may not have improved the human diabetic metabolism to a sufficient degree to be useful.
The challenge with AGEs is that there are a lot of them, their chemistry is notably different from one to another, the catalog is incomplete, it is unclear whether the present consensus on which AGEs are important and which are not is correct, and this continues to be a relatively poorly studied part of the field. One of the consequences is a tendency for wheels to be reinvented. One might look at today's paper in which researchers use a novel mix of supplements in mice to try to reduce the aortic stiffening induced by methylglyoxal. That alagebrium improved aortic elasticity in mice, and failed to do so in humans, strongly suggests that the effort here is a dead end (or at least says little about the actual merits of the product undergoing testing), and no amount of skating over that point in the paper's discussion is going to change that reality.
In this study, we investigated the impact of glycation stress on aortic stiffness in young and old mice, induced by advanced glycation end-product (AGE) precursor methylglyoxal (MGO) and its non-crosslinking AGE MGO-derived hydroimidazolone (MGH)-1, explored the potential molecular mechanisms involved, and evaluated the therapeutic potential of the glycation-lowering compound Gly-Low. We used a series of complementary in vivo, ex vivo, and in vitro experimental approaches to determine the causal role of MGO-induced glycation stress in aortic stiffening and the putative underlying mechanisms mediating this response, including excessive oxidative stress and cellular senescence. Additionally, we explored the therapeutic potential of Gly-Low, a cocktail consisting of the natural compounds nicotinamide, pyridoxine, thiamine, piperine, and alpha-lipoic acid, in mitigating aortic stiffening, oxidative stress, and cellular senescence mediated by MGO-induced glycation stress.
While MGO has previously been implicated in endothelial dysfunction, our results demonstrate that chronic MGO exposure significantly increases aortic stiffness in young mice. This effect was particularly pronounced in our pharmacological model of glycation stress, where young adult mice exhibited a marked increase in aortic stiffness after just two months of MGO exposure. Lastly, we also demonstrate the direct influence of glycation stress in mediating age-related aortic stiffening, which underscores the critical role of AGEs in promoting aortic stiffening with aging. Notably, our results also reveal the direct impact of MGO on aortic stiffening, supporting the notion that MGO-induced glycation stress can independently drive this pathology.
View the full article at FightAging
