Target Prioritization of Tissue Crosslinking

Photo by Erin Ashford
Photo by Erin Ashford

The Babraham Institute

Principal Investigator: Jonathan Clark
Research TeamMelanie Stammers

As discussed in the project summary for “Glucosepane Crosslinks and Undoing Age-Related Tissue Damage”, adventitious crosslinking of collagen (and elastin) contributes to the slow stiffening of our arteries and other tissues with age. Some of these crosslinks are the kind of chemistry that can happen spontaneously (like AGE crosslinking), but others are the unintended consequences of metabolic processes that modify collagen — either as “collateral damage,” or to help us get through short-term problems at the cost of contributing to the long-term burden of crosslinking damage that eventually compromises function. Amidst all of this, it’s not obvious that the sheer number of crosslinks of a given kind is a good measure of how high a priority it is for rejuvenation biotechnology: some crosslinks may have a disproportionate effect on tissue elasticity depending on where they occur in the protein strand, how tightly they bind, and how much they interfere with the body’s ability break down and renew the tissue.

Recognizing the importance of prioritizing our targets, SRF is funding a systematic study of this question in the tissues of “normally”-aging, nondiabetic mice at the Babraham Institute in Cambridge. The mice have been administered labeled building blocks for protein, which are then incorporated into extracellular matrix proteins, whose turnover can then be studied. The study has required the development and validation of new experimental methods and assays, which were published in a Royal Society of Chemistry journal in 2018.

Research Highlights:

An early and surprising finding is that crosslinks that one might think permanent in tissue are continuously being broken apart and re-forming under the stress and strain of normal activity: it is the balance between these reversible crosslinks and the truly irreversible ones that gives rise to many of the changing mechanical properties of aging collagen. They have also confirmed the expectation that the crosslink profile in each tissue is distinct from others (which is only partially explained by the tissue-specific mixture of elastin and collagen), and that both the mixture of proteins and the pattern of protein-specific crosslinks changes with age. Importantly, some of the crosslinks that have been reported by others to accumulate in aging tissues were not detected. They are also complementing chemical analysis of the tissues with functional tests of the effect of these crosslinks on tissue mechanical function. Drilling down into these issues will be critical to identifying the next targets as glucosepane crosslink-breakers enter into animal testing.

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