One of the issues inherent in research of a late stage age-related condition is that a lot of different things are going wrong with the body at the same time. The comparatively few categories of age-related damage have spilled over into hundreds of different types of malfunctions and the further disarray resulting from those malfunctions. By way of an analogy, consider rust in a machine: rust is a simple process, but the way in which the machine eventually breaks down can be a very complicated sequence of failing components and chained consequences. So it is with aging.
I noticed a review paper today that explores the role advanced glycation endproducts (AGEs) and their cell receptor (RAGE) might play in Alzheimer's disease. The way to walk into this discussion is with a web of known correlations and research results in mind:
- The buildup of AGEs is one of the fundamental causes of aging per the Strategies for Engineered Negligible Senescence (SENS) way of looking at things
- The disarray to biochemical processes due to AGEs is at least partly caused by constant triggering of RAGE
- AGEs build up faster in diabetes, and we know that risk of diabetes is strongly associated with risk of Alzheimer's - both are end-stage metabolic conditions
- A great many other plausible hypotheses for the cause of Alzheimer's exist that don't involve AGEs
- But inflammation appears to worsen Alzheimer's, some research has shown some short-term improvements to Alzheimer's patients by blocking inflammation, and the AGE/RAGE interaction boosts inflammation.
In any case, here's the paper:
Alzheimer's disease (AD) is the most common dementing disorder of late life. Although there might be various different triggering events in the early stages of the disease, they seem to converge on a few characteristic final pathways in the late stages, characterized by inflammation and neurodegeneration. In this review, we revisit the hypothesis that advanced glycation endproducts (AGEs) and their receptor RAGE may play an important role in disease pathogenesis.
Accumulation of AGEs in cells and tissues is a normal feature of aging, but is accelerated in AD. In AD, AGEs can be detected in pathological deposits such as amyloid plaques and neurofibrillary tangles. AGEs explain many of the neuropathological and biochemical features of AD such as extensive protein crosslinking, glial induction of oxidative stress and neuronal cell death. Oxidative stress and AGEs initiate a positive feedback loop, where normal age-related changes develop into a pathophysiological cascade.
RAGE and its decoy receptor soluble RAGE, may contribute to or protect against AD pathogenesis by influencing transport of beta-amyloid into the brain or by manipulating inflammatory mechanisms.
This is characteristic of the present stage of research into end-state conditions of aging. Researchers are piling up correlations and mechanisms, which lead in turn to plausible hypotheses, but nailing down the final answer as to how it all fits together to produce a specific final catastophe has yet to happen. It's a very challenging, complex task. The labor of this final assembly, and then the even greater labor of figuring out what to do next, is the work sidestepped by engineering approaches to longevity science, such as SENS. We know that an accumulation of AGEs is a difference between young and old tissues, therefore we should work to safely get rid of it. While all extra information helps, we don't need to know exactly how this build up of AGEs causes issues to be reasonably certain we're going to create a net benefit in health by removing it.
Srikanth, V., Maczurek, A., Phan, T., Steele, M., Westcott, B., Juskiw, D., & Münch, G. (2009). Advanced glycation endproducts and their receptor RAGE in Alzheimer's disease Neurobiology of Aging DOI: 10.1016/j.neurobiolaging.2009.04.016