All the proteins inside our cells are destroyed and rebuilt quite regularly, as a way to keep them in a generally undamaged state. Sometimes these mechanisms are incomplete – a problem which I address in the section on junk inside cells – but they are generally satisfactory.
Some of the proteins outside our cells, however, are laid down early in our life and then never recycled at all; while some others are only recycled very slowly. The proper functioning of the tissues composed of these structural proteins – the elasticity of the artery wall, or the transparency of the lens of the eye, or the high tensile strength of the ligaments – relies on their maintaining their proper structure. But chemical reactions with other molecules in the extracellular space occasionally result in a chemical bond (a so-called crosslink) between two nearby proteins that were previously free-moving, impairing their ability to slide across or along each other. This effect is especially prominent in the case of the artery wall, which becomes much more rigid as its proteins are crosslinked – leading to high blood pressure.
Luckily, it happens that a lot of the cross-links that accumulate in this way have very unusual chemical structures, not found in proteins or other molecules that the body makes on purpose. This means that it is theoretically possible to identify chemicals that can react with the cross-links and break them, without reacting with anything that we don't want to break. Indeed, several years ago a group of chemists found such a molecule, which has now been tested in many different animals and also in humans and seems to lower blood pressure quite substantially – especially the kind of blood pressure ("systolic") most directly elevated by crosslinking in the vessel walls. These chemists formed a company (named Alteon) to turn their discovery into an FDA-approved drug for systolic hypertension and several other diseases related to the crosslinking of proteins. The drug (named ALT-711, or alagebrium), has been moderately successful in preliminary clinical trials, but its progress through the drug development pipeline has been slowed considerably by financial difficulties with the company.
However, there are plenty of other types of crosslink that alagebrium doesn't break, so we need other chemicals that will complement what alagebrium does. Many such crosslinks will be breakable with simple, small-molecule drugs like alagebrium itself, but it's likely that at least some of them will turn out to be too stable for this approach. It will therefore be necessary to investigate more sophisticated approaches, such as:
SENS Foundation is currently planning out a project to engineer enzymes capable of cleaving the ubiquitous glucosepane crosslinks, which may comprise as much as 98% of all the long-lived crosslinks in aged human tissue. This work is still in the early planning stages, but we hope to be able to begin full-time research before the end of 2009.
Talks on this topic at IABG 10: Lakatta
At SENS3: Moreau
