Considering Cross-Linking Within a Single Extracellular Matrix Collagen Molecule

Here researchers suggest that cross-links in the extracellular matrix can be formed within single collagen molecules as well as between them, and that this can still degrade important properties of tissue. Cross-links form and are broken constantly in the extracellular matrix, consisting of many types of sugary by-products of metabolism. Some are far more resilient than others, and once formed tend to last for a long time. The structural properties of tissue are determined by the particular arrangement of molecules in the matrix, and when hardy forms of cross-link build up over the course of aging the result is loss of elasticity or strength. This is particularly noticeable in skin, but of much greater consequence in blood vessels, where stiffening causes hypertension and all of the cardiovascular dsyfunction that follows on from that.

In humans near all long-lived cross-links involve glucosepane, making clearance an attractive target for rejuvenation treatments, as only one class of compound must be broken down. Yet all too few groups are working on this. Those funded by the SENS Research Foundation might be the only people at the present time trying to build the basic tools needed to work with glucosepane in a cellular environment. It seems crazy to me that such obvious paths forward towards treating the common causes of age-related disease are widely ignored.

The extracellular matrix (ECM) undergoes progressive age-related stiffening and loss of proteolytic digestibility due to an increase in concentration of advanced glycation end products (AGEs). The most abundant AGE, glucosepane, accumulates in collagen with concentrations over 100 times greater than all other AGEs. Detrimental collagen stiffening properties are believed to play a significant role in several age-related diseases such as osteoporosis and cardiovascular disease.

Currently little is known of the potential location of covalently cross-linked glucosepane formation within collagen molecules; neither are there reports on how the respective cross-link sites affect the physical and biochemical properties of collagen. Using fully atomistic molecular dynamics simulations (MD) we have identified six sites where the formation of a covalent intra-molecular glucosepane cross-link within a single collagen molecule in a fibrillar environment is energetically favourable. Identification of these favourable sites enables us to align collagen cross-linking with experimentally observed changes to the ECM. For example, formation of glucosepane was found to be energetically favourable within close proximity of the Matrix Metalloproteinase-1 (MMP1) binding site, which could potentially disrupt collagen degradation.



Loss of proteolytic digestibility is the real problem here. The final option for regenetative medicine is to say "Fine, we'll just remake the collagen then if we can't fix it"- but as long as there isn't a protein that can do that, people are screwed.

Posted by: Slicer at September 30th, 2015 12:10 PM

(enzyme, I mean)

Posted by: Slicer at September 30th, 2015 12:12 PM

Would an enzyme work outside the cells without ATP to drive it?

Posted by: jim at September 30th, 2015 2:37 PM

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