AmyloSENS
Destroying junk between cells.
Extracellular junk is aggregates of stuff that do not have any function and should ideally have been cleared out of the body, but have proven resistant to destruction. Extracellular junk is different from extracellular cross-linking - it refers only to substances that do not have any function, not even a biophysical one.
Most of this junk is termed "amyloid" of one variety or another. You may have heard of one form of amyloid - Abeta, the stifling, web-like material that forms plaques in the brains of patients with Alzheimer's disease, and also (more slowly) in everyone else's.
There are also a variety of similar aggregates that form in other tissues during aging and age-related diseases, of which the best-known is islet amyloid in Type II diabetes. A range of other amyloids feature in diseases called amyloidoses, which are found most commonly in people with unusual genetic disorders, but also begin to cause organ dysfunction in the very old. In fact, among supercentenarians (those who survive to 110 or older) the condition senile systemic amyloidosis is one of the biggest killers.
The solution
We don't yet know for sure that amyloid is what makes Alzheimer's sufferers lose cognitive function: it may be that it's the stifling influence of the plaques themselves, but some researchers think that the plaques actually protect us from the toxicity of the constituent protein molecules, while still others still believe that those same molecules are themselves a protective mechanism against some other form of brain dysfunction that is lost when they aggregate into plaques. In our current state of ignorance, the solutions to the amyloid problem that are advocated by some researchers – either reducing the formation of their constituent molecules, or breaking the plaques apart with the resulting release of those constituents into the nervous system – could actually turn out to be a long-term therapeutic disaster.
A strategy for reversing the accumulation of such material is being pursued by several scientific teams, including researchers with Elan Pharmaceuticals: vaccination to stimulate the cells of the immune system to clear out the material. As with atherosclerosis, the cells may eventually encounter problems in fully digesting this material – but, if so, its degradation can still be engineered by the approach described in the section on intracellular junk.
The clinical trials of Elan's first vaccine had to be stopped prematurely because of side effects, but several promising alternative vaccines are being tested. Elan's most recent candidate, bapineuzumab, has been the subject of recent excitement after the company launched a full-scale ("Phase III") clinical trial at an unusually early point, leading to speculation that the as-yet-undisclosed preliminary results of its earlier trials may be exceptionally promising.
You might think that there is another important example of extracellular junk that contributes to aging and age-related disease, namely the fatty deposits in the core of mature atherosclerotic plaques. Atherosclerosis is the "hardening" or "clogging" of the arteries that leads to the risk of heart attack and stroke. For a long time, it was thought that the problem was very much like the clogging of pipes, with fatty materials in the blood being deposited on the walls of the arteries like so much grease causing the occlusion of the drain pipe in a sink, which certainly sounds like a problem of extracellular junk. What we now know is that atherosclerosis is not the result of layers of fatty material outside of the blood vessels, but of junk that accumulates inside cells as a result of the body's unsuccessful attempts to clear out the infiltrating fat.
Atherosclerosis begins when the blood vessels are damaged by chemically altered cholesterol from the blood. Fortunately, the body has a way to remove the offending material, by sending immune cells called macrophages into the damaged artery wall to eat up the initial lipid deposit. If this system could be maintained, lipid deposits would never reach a level where it would cause us problems; unfortunately, the system eventually breaks down. This is because some of the fatty materials that macrophages remove from the blood vessels are impossible for them to digest, and eventually they become so stuffed with undigested fatty gunk that they die. It is the build-up of the remains of these lipid-engorged cells within the artery wall that makes up the fatty streaks of atherosclerosis, and that eventually leads to a deadly rupture of the vessel, triggering a heart attack or stroke.
Thus, atherosclerosis is not really a problem of junk accumulating outside of cells, but of junk accumulating inside the macrophage. The build-up of both an acellular lipid core, and of the cellular atherosclerotic plaque, would be completely fixed if we could make the intracellular degradation machinery more powerful, so that macrophages were able to continue clearing out lipid deposits instead of being engaged in an ultimately futile suicide mission. A foreseeable way of doing this is described in the section on intracellular junk.
Our Work
Resources
Talks on this topic at IABG 10: Nitsch