Which Links Must Be Broken?

Dr. Jonathan Clark's SRF-funded group at the Babraham Institute have published two new papers showing that the current model in which aging tissues lose elasticity due to the accumulation of stable crosslinks is not the full story - results which will be crucial to reversing that deterioration.

The collagen strands that provide strength and flexibility to our tissues are crosslinked by chemical bonds that tie the component proteins into a mesh-like structure. Until recently, the consensus in the field has been that a gradual increase in such crosslinks – and particularly those considered ‘irreversible’ due to their high stability – is a principle driver of the age-related loss of elasticity that leads ultimately to mechanical failure of the blood vessels, muscles, and other tissues.

The SENS platform proposes to resolve this class of damage by introducing enzymes or small molecule drugs capable of selectively degrading the offending crosslinks. However, the sheer number of crosslinks of a given kind may not be a good measure of how high a priority it ought to be 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.

Our funded project in the laboratory of Dr. Jonathan Clark at Cambridge’s Babraham Institute is focused on precisely this question of prioritization. Three new papers released by the group this year have established that the simple model in which highly stable crosslinks accumulate over the lifespan is unlikely to be the full story; provided the first evidence that crosslinking within collagen can vary in response to mechanical forces; and identified a potential relationship between specific crosslink precursors and the cancer microenvironment. These results will be crucial to the development of effective therapeutics.

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