In the mid-1970s, Rockefeller University biochemist Anthony Cerami and Frank Bunn independently recognized that AGEs and glycation play a major role in diabetes.*56 Both Cerami and Bunn were initially motivated by the observation that diabetics have high levels of an unusual form of hemoglobin—the oxygen-carrying protein of red blood cells—known as hemoglobin A1c, a glycated hemoglobin. The higher the blood sugar, the more hemoglobin molecules undergo glycation, and so the more hemoglobin A1c can be found in the circulation. Cerami’s laboratory then developed an assay to measure hemoglobin A1c, speculating correctly that it might be an accurate reflection of the diabetic state. Diabetics have two to three times as much hemoglobin A1c in their blood as nondiabetics, a ratio that apparently holds true for nearly all glycated proteins in the body. (The best determination of whether diabetics are successfully controlling their blood sugar comes from measuring hemoglobin A1c, because it reflects the average blood sugar over a month or more.)

Since 1980, AGEs have been linked directly to both diabetic complications and aging itself (hence the acronym). AGEs accumulate in the lens, cornea, and retina of the eye, where they appear to cause the browning and opacity of the lens characteristic of senile cataracts. AGEs accumulate in the membranes of the kidney, in nerve endings, and in the lining of arteries, all tissues typically damaged in diabetic complications. Because AGE accumulation appears to be a naturally occurring process, although it is exacerbated and accelerated by high blood sugar, we have evolved sophisticated defense mechanisms to recognize, capture, and dispose of AGEs. But AGEs still manage to accumulate in tissues with the passing years, and especially so in diabetics, in whom AGE accumulation correlates with the severity of complications.

One protein that seems particularly susceptible to glycation and cross-linking is collagen, which is a fundamental component of bones, cartilage, tendons, and skin. The collagen version of an AGE accumulates in the skin with age and, again, does so excessively in diabetics. This is why the skin of young diabetics will appear prematurely old, and why, as the Case Western University pathologist Robert Kohn first suggested, diabetes can be thought of as a form of accelerated aging, a notion that is slowly gaining acceptance. It’s the accumulation and cross-linking of this collagen version of AGEs that causes the loss of elasticity in the skin with age, as well as in joints, arteries, and the heart and lungs.