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.