In my post about the CR mice with and without a high AGE diet, I mentioned the researchers noticed a change in two receptor levels (RAGE and AGER1). The control group (non CR’ed mice) and the CR group with a high AGE diet showed more than a triple fold increase in the RAGE receptor while the CR mice with a low AGE diet had only a slight increase in RAGE levels.
RAGE is a receptor for AGEs. Increased levels of two variants of the RAGE receptor are related to the development of neurological diseases including Alzheimer’s and stroke. The first is a cell-membrane bound (full-length), and the second is a soluble form. The full-length RAGE interactions can lead to cellular stress and inflammation, which happens with greater frequency with increased RAGE expression. The soluble RAGE (sRAGE) form can reduce the damage of the full-length RAGE interactions by binding with substances before they bind with the full-length RAGEs.
I wanted to learn more about RAGE expression, and when I found an article detailing RAGE interactions and their relation to disease, I just couldn’t resist. The following paper is a review of how RAGE expression is related to neurological diseases and explores how soluble RAGEs could be used a therapy strategy. I’m going to hit the highlights in bullet format to make for easy reading.
* The AGE receptor, RAGE, was first isolated in 1992. It is now known to not only play a major role in the progression of many neurological diseases including Alzheimer’s, stroke, multiple sclerosis, neurological complications of diabetes, but also in other diseases such as atherosclerosis, coronary arty disease, cancers, and rheumatoid arthritis.
* Besides binding to AGEs, the full-length RAGE can also bind to other molecules which are involved in disease formation and progression. The soluble RAGE can prevent these disease mechanisms by binding to these molecules before the full-length RAGE does.
* There are many different forms of RAGE with different propensities for disease progression or inhibition.
* RAGE levels were significantly increased in the brains of Alzheimer’s vs. a non-demented control, and RAGEs are also able to transport amyloid-beta peptides (the plaques associated with Alzheimer’s) across the blood brain barrier with increased expression of RAGE leading to more of these amyloid plaques entering the cranial region.
* The RAGE-A? peptide interaction is the most studied, but a correlation was also discovered between the most common AGE (N?-(carboxymethyl)-lysine) and level of cognitive impairment. Different RAGE binding molecules are associated with different diseases, but there are overlaps and often several of these molecules will be elevated in a diseased state.
* Studies have shown that sRAGE (a type of soluble RAGE) is able to inhibit the transport of A? peptide across the blood-brain barrier.
* The RAGE-HMGB1 interaction is associated with stoke victims, and damage could possibly be reduced if the subject was treated with sRAGE or an antagonist of HMGB1 thereby reducing the inflammatory damage.
* In chronic diabetics, damage to kidneys, retina, perphery nerves, and blood vessels occur due to RAGE mediated mechanisms. In an interesting study, diabetic induced mice altered to lack the RAGE receptor did not show the same degree of brain atrophy as the diabetic induced wild mice.
* In the past 2-3 years, circulating sRAGE has been shown to act as a protective agent against many different diseases and possibly even promote longevity. Centenarians have shown higher levels of sRAGE than their younger counterparts.
* Two different studies have found lower levels of circulating sRAGE in Alzheimer’s patients vs. disease free controls.
* Blocking RAGE activation in adults may lead to a therapeutic strategy with no significant side effects.
So, this is yet another way AGEs can induce a disease state within the body. Increased dietary AGEs lead to high RAGE expression. High RAGE expression leads to a variety of diseases and aging complications as these RAGEs interact negatively with different molecules in the body. I find it interesting that sRAGE could be used as a disease or anti-aging therapy. I notice that the more I learn about AGEs, the more complex their interaction with the body becomes. So far, the best strategy seems to be minimizing exposure as much as possible while still being reasonable. However, I am sure the definition of reasonable will be up for debate depending on who you talk to.