Yale University

 

Elasticity is essential to the function of many tissues, including the walls of our major arteries and the lens of the eye. The stiffening of these tissues with age leads to impairment of their function, resulting (amongst other conditions) in increasing hypertension and risk of renal failure with age. The increase in systolic blood pressure driven by loss of large artery elasticity is one of the major reasons for the increased risk of stroke and the development of dementia in older people. 
 
The stiffening of our tissues with aging is caused in substantial part by the accumulation of chemical crosslinks between proteins of the extracellular matrix (ECM), the network of proteins between cells that gives our tissues their structure. In youthful tissues, ECM proteins are structured in a regular lattice, but subsequent crosslinks that accumulate during aging are located randomly, which causes the loss of elasticity. The creation of these crosslinks involves many chemical pathways and forms many differently-shaped structures, which are collectively called advanced glycation endproducts (AGE). Of these, it has been established that one specific AGE structure, called glucosepane, is the most abundant in aged human tissue. 
 
A method or compound that would unlink glucosepane crosslinks from aging tissues would therefore be of great therapeutic value in the prevention and reversal of age-related tissue degeneration; yet it is not being energetically pursued in any academic institution or biotech lab, which elevates its priority for SRF research in critical-path analysis. We have therefore established and funded a GlycoSENS collaboration between researchers at Cambridge and Yale Universities, whose aim is to discover and test such a glucosepane “AGE-breaker” therapeutic.
 
Making glucosepane. David Spiegel’s lab at Yale has made a number of AGEs as pure molecules, which have proven an invaluable resource for the Cambridge lab (see below). They have found that methylglyoxal hydroimidazolone isomer 3 (MG-H3), a type of AGE that forms on arginine residues (through a process quite similar to glucosepane formation), has quite unexpected  biological effects, and may actually have a positive role to play in protection against oxidative stress. The model for how MG-H3 formation and removal is regulated by oxidative stimuli is summarized in the Figure below, and is discussed in more detail in a manuscript recently accepted for publication in Journal of the American Chemical Society.  These findings emphasize how important it is to have ‘authentic’ AGE chemicals to test for their effect in living cells and animals. 
 
David and Christian are working on the synthesis of glucosepane. The goal is not just to make the molecule, but to make it so that it can be linked onto proteins without destroying the proteins’ structure, thus reproducing the situation in the body. This is very difficult chemistry, involving the discovery of a series of new chemical reactions: Christian and David are currently only a couple of steps away from completing this, and hope to have authentic glucosepane to test by this summer.
 
Parallel research efforts in the Spiegel lab are focused on identifying chemical reagents capable of detecting glucosepane along with a class of molecules called dicarbonyls, which are the metabolic precursors responsible for glucosepane formation.  Such chemical agents have the potential to serve as useful tools for measuring glucosepane in cells and tissue, but also to provide insight into novel therapeutic strategies for preventing and/or reversing its formation.