A Look at Some of the Biomechanical Damage Caused by AGEs

Advanced glycation end-products (AGEs) are perhaps the most frustrating of the mechanisms that cause aging. Frustrating because the overwhelming majority of AGEs are of the same basic type in humans - glucosepane - and all it will take to remove this contribution to aging is a designed molecule that can break down this specific compound without harming the rest of our biology. To my eyes finding that basis for therapy is a goal well within reach of a sensible, $20 million, five year program at this time, or pretty much any time over the last decade. Yet no-one is putting more than a pittance into this research, and no more than a handful of researchers pay any attention. This is why development of a glucosepane AGE-breaker therapy is low in the list of plausible near future advances in rejuvenation biotechnology. Not because it's harder than the rest, far from it, but because no-one with a large budget is trying.

AGE buildup is one of the root causes of aging. Advanced glycation end-products accumulate as a consequence of the ordinary operation of metabolism, and wherever they lurk in the body they gum up important molecular machinery, deliver harmful signals to cells that spur inflammation, and generally cause all sorts of damage and dysfunction. Aging is no more than unrepaired damage, and as you can see, a part of that stems from something that should be very easy to fix in the grand scheme of things.

Yet next to no-one is trying. The SENS Foundation is one of the few groups that does put funding into finding ways to clear glucosepane, but that is still a small amount in the grand scheme of things - certainly nowhere close to millions of dollars yet. You can read a summary at the Foundation website that discusses the science and gives an overview of the current research collaboration.

Here is an up-close look at just one of the numerous ways in which the presence of AGEs degrades the functionality and integrity of your tissues. Like the others, it is something that could be reversed by breaking down the AGEs in question - if anyone actually cared to try doing that:

Advanced Glycation End-Products Diminish Tendon Collagen Fiber Sliding

Connective tissue aging and diabetes related comorbidity are associated with compromised tissue function, increased susceptibility to injury, and reduced healing capacity. This has been partly attributed to collagen cross-linking by advanced glycation end-products (AGEs) that accumulate with both age and disease. While such cross-links are believed to alter the physical properties of collagen structures and tissue behavior, existing evidence to support this view is contradictory.

In this study, we utilized a rat tail tendon model to quantify the micro-mechanical repercussion of AGEs at the collagen fiber-level. Individual tendon fascicles were incubated with methylglyoxal (MGO), a naturally occurring metabolite known to form AGEs. After incubation in MGO solution or buffer only, tendons were stretched on the stage of a multiphoton confocal microscope and individual collagen fiber stretch and relative fiber sliding were quantified.

MGO treatment strongly reduced tissue stress relaxation, with concomitantly increased tissue yield stress and ultimate failure stress. Microscopic analysis of collagen fiber kinematics yielded striking results, with MGO treatment drastically reducing fiber-sliding with a compensatory increase in fiber-stretch. We thus conclude that the main mechanical effect of AGEs is a loss of tissue viscoelasticity driven by matrix-level loss of fiber-fiber sliding. This has potentially important implications to tissue damage accumulation, mechanically regulated cell signaling, and matrix remodeling.


I'm guessing no one is working on it because there is no clear associated disease identified, and thus no real prospect for a drug commercialization.
Even if SENS identifies a way to remove glucosepane, does it have a chance of being authorized and used in the US and EU?

Posted by: Hervé Musseau at January 31st, 2013 2:39 AM

@Hervé Musseau: It's my understanding that enough of the etiology of vascular disease depends on the loss of elasticity resulting from AGE cross-links so that any glucosepane breaker could be approved against that indication. Erectile dysfunction is another possible indication. Off-label use against wrinkles and sagging skin would be very popular.

All told, I think there are enormous and perhaps even unprecedented prospects for commercialization. Viagra was a blockbuster drug. Vascular disease is a major killer. Add to that insurance-friendliness the appeal to people's vanity and what do you get?

I'm guessing no one is working on it because heavily regulated drug companies prefer the low-risk strategy of turning out slight but patentable variants within existing drug categories (like the atypical anti-psychotics) rather than striking out after a drug with a novel sort of target (not a receptor ligand).

Posted by: José at February 1st, 2013 3:33 AM

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