One of the Ways in Which AGEs Contribute to Aging

Advanced glycation end-products, AGEs, are a wide variety of inconvenient biochemical waste products produced by the operation of your metabolism (and, to a much lesser degree, eaten as a part of your diet). AGEs gum up important biomolecular machinery and disable essential macromolecules by glueing them together. Some AGEs can be broken down by your cells, but accumulate faster than they can be removed. Others cannot be broken down at all, and the slow accumulation renders vital functions in your cells ever more hampered and faulty.

So far, there's nothing radical that can be done about this process - no working, sort-the-problem-out AGE-breaker therapies for humans. The best advice is to try and avoid metabolic disease - exercise, keep fit, eat a calorie restriction diet and don't pack on the fat, in other words - because that condition and the diabetes that follows ramps up the rate of AGE accumulation.

Here's a closer look at some of the details.

Cross-link breakers as a new therapeutic approach to cardiovascular disease:

Fibrillar proteins, such as collagens type I and III, and elastin are components of the extracellular matrix. They form an intricate widespread network that provides a basis for maintaining the physical structure of the heart and vessels and also play an important role in determining cardiovascular function.

Physiologically, collagen and elastin fibres are enzymatically cross-linked to form [the] matrix. In addition to these enzymatically formed cross-links, collagen fibres may be linked non-enzymatically, most notably by formation of AGEs (advanced glycation end-products). AGEs are formed by a reaction between reducing sugars and body proteins; they are formed increasingly in diabetes mellitus and hypertension and they accumulate with aging.

There are several mechanisms whereby AGEs may affect cardiovascular structure and function. These include increased myocardial and vascular stiffness and (upon reaction with their receptors) inflammatory reactions, release of growth factors and cytokines, and increased oxidative stress. Therefore breaking AGEs appears as a promising tool in the therapy of cardiovascular injury related to diabetes, hypertension and aging.

Nothing radical to be done at present: that's a pretty grim picture, considering the widespread suffering caused by AGE buildup. Work is presently underway on AGE-breaker and AGE inhibitor drugs, but it's a small, slow-moving field in comparison to regenerative medicine or other well-funded initiatives.

Comments

Off topic:

Hi Reason,

I notice that you've written a few times about Folding@home here, and that there's a LM F@H team.

I was wondering if you knew about Rosetta@Home (http://boinc.bakerlab.org/rosetta/)?

From what I know of both projects, Rosetta@home seems a bit more exciting and worth contributing to, in part because they currently have less CPU cycles than Folding so any contribution makes a bigger marginal difference, but also because the science is really great; predicting the shape (and thus functionality) of proteins based on their amino acid sequences (saving lots of time and efforts to do x-ray crystallography or NMRI -- both of which can be limited) is, afaik, a holy grail of biotech.

Could be tremendously useful in designing cures and speeding up our understanding of proteins. The folding process itself is also useful, but it doesn't seem quite as useful as computational prediction of the final state of proteins.

I could be misunderstanding the science of both projects, though. I'm not yet all that knowledgeable on proteins yet, but I'm working on it.

Either way, I'd love your opinion on this, and if you find Rosetta@home as interesting as I do (Dr. David Baker, the head of the project, posts in a journal on the R@H forums), I hope you'll consider adding it as a recommended project on the LM website.

Cheers,

Posted by: Michael G.R. at October 28th, 2007 1:21 PM
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