Cross-Links Stiffen the Extracellular Matrix With Age

One of the root causes of degenerative aging is the accumulation of sugary metabolic wastes known as advanced glycation end-products that are in some cases very hard to for our evolved biochemistry to break down. Some types can form cross-links, gluing together important proteins such as those making up the supporting extracellular matrix scaffold. The properties of elastic tissues such as skin and blood vessel walls derive from the particular structure of the extracellular matrix, and cross-links degrade that structure, preventing it from functioning correctly. Their presence contributes to blood vessel stiffening with age and all the problems that result from that, for example, but there are plenty of other affected tissues.

The SENS approach to this contributing cause of aging is to build the necessary tools to work with the most common cross-link compound in human tissues, glucosepane. It is hoped that other research groups will pick up the work once they no longer have to start by building the very fundamental tools for the job. As things stand few research institutions are willing to start from scratch when there are so many other lines of research presently available that do not need a complete tool infrastructure built before anything can be accomplished.

Advanced age is associated with increases in muscle passive stiffness, but the contributors to the changes remain unclear. Our purpose was to determine the relative contributions of muscle fibers and extracellular matrix (ECM) to muscle passive stiffness in both adult and old animals. Passive mechanical properties were determined for isolated individual muscle fibers and bundles of muscle fibers that included their associated ECM, obtained from tibialis anterior muscles of adult (8-12 mo old) and old (28-30 mo old) mice. Maximum tangent moduli of individual muscle fibers from adult and old muscles were not different at any sarcomere length tested. In contrast, the moduli of bundles of fibers from old mice was more than twofold greater than that of fiber bundles from adult muscles at sarcomere lengths of more than 2.5 μm.

Because ECM mechanical behavior is determined by the composition and arrangement of its molecular constituents, we also examined the effect of aging on ECM collagen characteristics. With aging, muscle ECM hydroxyproline content increased twofold and advanced glycation end-product protein adducts increased threefold, whereas collagen fibril orientation and total ECM area were not different between muscles from adult and old mice. Taken together, these findings indicate that the ECM of tibialis anterior muscles from old mice has a higher modulus than the ECM of adult muscles, likely driven by an accumulation of densely packed extensively crosslinked collagen.

While looking at this research it is worth bearing in mind that short lived rodents have a different cross-link biochemistry in comparison to we long-lived humans. Early attempts to develop cross-link-breaking drugs floundered on this issue: promising results in rats didn't translate to human medicine at all. The overall picture of how this degeneration proceeds and why it happens is very similar, so there is much that can be learned, but the types of cross-link are different in ways that matter greatly for the development of treatments.