Target Prioritization of Adventitious Tissue Crosslinking (Babraham Institute)

Target Prioritization of Adventitious Tissue Crosslinking

Principal Investigator: Jonathan Clark

As discussed in the project summary for “Glucosepane Crosslinks and Routes to Cleavage”, our arteries slowly stiffen with age, in substantial part because of adventitious crosslinking of the structural proteins collagen and elastin. Some of these crosslinks are the result of purely stochastic chemical reactions, including those with blood sugar and other fuels in the circulation. Other crosslinks arise from enzymatic processes that modify collagen — either as “collateral damage,” or for purposes that help with short-term survival but whose cumulative burden over time eventually compromises function.
 
Developing rejuvenation biotechnologies to break these crosslinks is key to restoring youthful arterial function. It is vital, therefore, that we understand which crosslinks are the highest priorities for new crosslink-breakers. Much of what we think we know about the relative importance of different sources of crosslinking relies on work carried out some 40-50 years ago, using old methods that are known to create significant artifacts. Additionally, evaluations undertaken at SRF’s Cambridge center have shown existing commercial antibodies against specific crosslinks to be highly nonspecific or impractical.
 
These and related issues make it critical to get more reliable data on the sources and relative impact of different kinds of crosslinks in aging tissues. SENS Research Foundation is funding groundbreaking work to deliver this data, at the Babraham Institute in Cambridge. Dr. Jonathan Clark and coworkers will be administering heavy isotopes of oxygen and the amino acid lysine (both important building blocks of proteins) to mice. By labeling newly-synthesized collagen and elastin strands with these heavy building blocks, mass spectrometry will allow him to track the laying-down, crosslinking, and breakdown of these key structural proteins during the aging process, without prejudice to the particular proteins or crosslinks involved. They expect to benefit greatly from newly-available samples of pure glucosepane supplied by Dr. David Spiegel, thanks to his SRF-funded research at Yale.