Reversing AGE in the cardiovascular system

Advanced glycation endproducts — a name that lends itself to a provocative acronym, AGE — are the result of nonenzymatic reactions between sugars and proteins, resulting in molecules that are chemically similar to those that form when meat is seared or cured. True to their acronym, AGE accumulate over the course of aging (much more rapidly in the case of diabetics, whose blood sugar levels tend to spike frequently).

While their role in biological aging has yet to be fully characterized, there’s a growing body of evidence (largely circumstantial) that AGE are associated with the onset of “age- and diabetes-related chronic inflammatory diseases such as atherosclerosis, asthma, arthritis, myocardial infarction, nephropathy, retinopathy or neuropathy” (Wikipedia).

AGE accumulate in part because they’re tough for cells to clear: the molecules contain Schiff base bonds that don’t arise in other sorts of biomolecules, and the catalytic Swiss Army knife encoded by metazoan genomes simply doesn’t include the right kind of blade. Their very recalcitrance in this regard, however, makes them ideal drug targets: If one could design a pharmaceutical means of reversing Schiff bases, one could introduce it into patients without fear of disrupting “intentional” bonds of this sort (i.e., in molecules that are serving some adaptive purpose) — because there essentially aren’t any to begin with.

The first efforts at compounds targeting AGE on the basis of Schiff base chemistry are starting to undergo clinical trials, with promising results. Zieman et al. studied the drug alagebrium (aka ALT-711, from Alteon), focusing on the effect on hypertension of AGE reversal in the cardiovascular system:

OBJECTIVES: Arterial stiffening and endothelial dysfunction are hallmarks of aging, and advanced glycation endproducts (AGE) may contribute to these changes. We tested the hypothesis that AGE crosslink breakers enhance endothelial flow-mediated dilation (FMD) in humans and examined the potential mechanisms for this effect.
METHODS: Thirteen adults … with isolated systolic hypertension … on stable antihypertensive therapy were studied. Subjects received placebo (2 weeks) then oral alagebrium (ALT-711; 210 mg twice a day for 8 weeks). … Arterial stiffness was assessed by carotid augmentation index (AI) and brachial artery distensibility (ArtD) …
RESULTS: Alagebrium reduced carotid AI by 37% (P = 0.007) and augmented pressure (16.4 +/- 10 to 9.6 +/- 9 mmHg; P < 0.001). …
CONCLUSIONS: Alagebrium enhances peripheral artery endothelial function and improves overall impedance matching. Improved endothelial function correlates better with reduced vascular fibrosis and inflammation markers than with vessel distensibility. AGE-crosslink breakers may reduce cardiovascular risk in older adults by reduced central arterial stiffness and vascular remodeling.

In addition to the primary result (a decrease in blood pressure), the authors also observed a decrease in markers of inflammation — consistent with the role AGE are thought to play in inflammatory disease.

As with all such vine-fresh data, caveat emptor: The study is tiny (only 13 patients), so despite the impressive P values, the conclusions will be more convincing when we can see data from the larger follow-up study that is presumably planned or underway.

More importantly, it’s not clear that AGE reversal is actually the mechanism of action: For understandable reasons involving the risk and difficulty of cardiac biopsy, the authors didn’t measure AGE levels either before or after treatment. So while alagebrium is known to reverse AGE in vitro, and the patients did exhibit a significant decrease in blood pressure, it’s not clear that the former caused the latter. Without these measurements (and again, I’m sympathetic with the reasoning behind forgoing them), it’s possible that alagebrium is simply a very good anti-hypertension drug operating by a completely unrelated mechanism.

Sharp readers will no doubt have leaped ahead to the observation that even if we knew that AGE reversal were taking place, we still wouldn’t have established causation, because the AGE reversal could be an epiphenomenon independent of the primary mode of action on hypertension. So how can we satisfy ourselves that this is how alagebrium is working? We can’t, at least not until we have in hand another efficacious compound that is structurally dissimilar to alagebrium but shares the ability to reverse AGE.

This is basically a quibble, but I think it’s important to keep in mind that even a much larger study with the same compound won’t prove the mechanism, and this has implications about how to proceed with future drug development.

Having stated these qualifications, I shall now set them aside, and that I think these preliminary results are nonetheless very promising. A drug was designed against a specific form of age-related damage, demonstrated to attack this damage in vitro, and then shown to be efficacious in a clinical setting. In addition to providing good news for sufferers of hypertension, the study takes an important step toward verifying the model that AGE in fact do play a causative role in the onset of age-related disease.

Most enticing is the idea that AGE reversal (in this case via treatment with alagebrium) appears not to delay the onset of of damage but to actually reverse it — even in elderly patients, even after that damage has contributed to a potentially life-threatening clinical condition. Slowing the accumulation of damage will be an important part of the anti-aging pharmacopoeia of the future — an ounce of prevention being worth a pound of cure — but unless the rate of damage accumulation can be slowed to zero, methods of reversing existing damage will also be required.

For those of us who will have lived a large share of our lives before these methods become available, that’s heartening news indeed.

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11 comments

  1. Ouroboros,

    I know of a few people taking ALT-711. I will ask them if they have seen any changes in their blood pressure.

  2. How are they getting their hands on it? My understanding is that it hasn’t been approved, so there must be something a bit nontraditional about their acquisition of the drug. If you know the answer, email me.

  3. Preclinical research was done on old dogs fed Alagebrium for several weeks. (Asif et al PNAS 14 March 2000) Not only did blood pressure improve, but their aortas were dissected out and their elasticity measured. Elasticity was restored to the large arteries. Alagebrium is NOT just a very good anti-hypertensive drug. It really works, in vivo and in vitro.

  4. This sounds like a good place to emphasize that I in no way advocate taking pharmaceuticals that have not been taken through clinical trials to verify their safety and efficacy — nor do I advocate taking any drug outside the care of a physician.

    In response to my comment above, I’ve received a few emails from people, generally folks who know someone who claims to have obtained quantities of what they believe is alagebrium.

    I’m afraid that my overall impression of these stories is that the people involved could very easily be victims of fraud, and — unless they have access to sophisticated analytical chemistry facilities — would have absolutely no way of knowing whether they are being ripped off. (It’s not like Viagra, where at least there’s a simple assay to determine whether one has gotten one’s hands on the real deal.)

    Furthermore, distributing pharmaceuticals for human use prior to FDA approval is illegal in the US. Say what you will about the approval process; the fact remains that anyone distributing a drug prior to approval (or after approval, if they’re not the owner of the intellectual property) is breaking the law. I suspect that the set of people willing to do that is enriched in charlatans.

    Finally: We simply don’t know enough about this product in humans yet. It does seem to be reasonably safe (from a standpoint of cellular toxicity, and use in experimental animals, as well as the small-scale clinical trials in humans), but the jury is still out.

    My advice to all readers is to await full approval of pharmaceuticals and then use them only under the care and supervision of a physician. Alpha-testing a chemical on your own body just seems like a bad idea. As does getting duped.

  5. I’ve not yet read the full paper, but if the antihypertensive effect of alagebrium continues after cessation of use, that would be further circumstantial evidence that a “repair” of damaged macromolecules had occured.

  6. Good point, niner. One corollary of this is that anti-AGE compounds in general might only have to be taken periodically, rather than chronically, to “re-initialize” cells.

  7. Based on the large amount of data in-vitro and in-vivo in animals, I don’t think this extent of worry about the mechanism of action is really justified. My main questions are: Does it work? Is it safe? And a corollary to whether it works is, do humans produce high levels of the kind of AGEs that alagebrium breaks? There are *many* different chemical forms of AGEs. Alteon reportedly has over 350(!) different drugs for preventing and/or breaking all the different kinds of glucose crosslinks! Which are the best ones?

  8. I know for sure that anti-oxydant like selenium, green teen, black chocolate and others help to live longer – Jeanne Calmant the oldest French lady lived 120 years in eating 1 kg of black chocolate per week because of the flavonoid in

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