RAGE
A little biochemistry today. You have probably heard of AGEs - advanced glycation endproducts - and their contribution to age-related degeneration. But what is RAGE?
RAGE, the receptor for advanced glycation endproducts ... its name comes from its ability to bind advanced glycation endproducts (AGE), a heterogeneous group of non-enzymatically altered proteins. Besides AGEs, RAGE is also able to bind other ligands and is thus often referred to as a pattern-recognition receptor.The interaction between RAGE and its ligands is thought to result in pro-inflammatory gene activation. Due to an enhanced level of RAGE ligands in diabetes or other chronic disorders, this receptor is hypothesised to have a causative effect in a range of inflammatory diseases such as diabetic complications, Alzheimer's disease and even some tumors.
RAGE, then, is a part of the biological mechanisms by which an accumulation of AGEs harms you. I'm sure you know just how bad chronic inflammation is over time:
Chronic inflammation spurred by an immune system run amok appears to play a role in medical evils from arthritis to Alzheimer's, diabetes to heart disease.
If you go digging through recent publications, you'll find a fair amount of work ongoing on relating RAGE to various age-related disease states and metabolic processes. For example:
Advanced glycation end products (AGEs) have been proposed as the pathological mechanisms underlying diabetic chronic complications. They may also play a role in the pathogenesis of diabetic osteopenia, although their mechanisms of action remain unclear. We investigated the [protein and gene expression] of two receptors for AGEs, RAGE and galectin-3, as well as their regulation by AGEs, and the apoptotic effect on osteoblast-like cells ... AGEs up-regulated the expression of RAGE and galectin-3 in both cells lines. ... Finally, we demonstrated that a 24 h exposure to AGEs induced apoptosis in both cell lines. Thus, AGEs-receptors may play important roles in the bone alterations described in aging and diabetic patients.
So, more AGEs, more RAGE, more change - decrease in bone strength in this case, as the cells that produce bone are culled. That extra apoptosis may or may not be damage, but it's certainly change that grows with aging and pathology - we can't go far wrong by assuming all change is damage and working to fix or prevent it.
One thing to bear in mind is the processes associated with AGE acculumation are feedback loops; above a certain threshhold matters start to go awry much more rapidly. Repair technologies work very well in circumstances such as these - just keep the level of AGEs below the runaway point, and accumulation will be slow.
AGEs have been implicated in renal disease associated with ageing, diabetes and other age-related disorders. Reactive oxygen species (ROS) promote formation of AGEs, which cause AGE-receptor-mediated ROS generation with activation of signalling pathways leading to tissue injury and further AGE accumulation.
Learning more about your own biochemistry is a strong incentive to help bring forward the day when all these damaging processes of metabolism can be halted and reversed.
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