Good Calories, Bad Calories

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.

The process can be compared to the toughening of leather. Both the meat and hide of an old animal are tougher and stiffer than those of a young animal, because of the AGE-related cross-linking that occurs inevitably with age. As Cerami explains, the aorta, the main artery running out of the heart, is an example of this stiffening effect of accumulated and cross-linked AGEs. “If you remove the aorta from someone who died young,” says Cerami, “you can blow it up like a balloon. It just expands. Let the air out, it goes back down. If you do that to the aorta from an old person, it’s like trying to inflate a pipe. It can’t be expanded. If you keep adding more pressure, it will just burst. That is part of the problem with diabetes, and aging in general. You end up with stiff tissue: stiffness of hearts, lungs, lenses, joints…. That’s all caused by sugars reacting with proteins.”

AGEs and the glycation process also appear to play at least one critical role directly in heart disease, by causing the oxidation of LDL particles and so causing the LDL and its accompanying cholesterol to become trapped in the artery wall, which is an early step in the atherosclerotic process. Oxidized LDL also appears to be resistant to removal from the circulation by the normal mechanisms, which would also serve to increase the LDL levels in the blood. As it turns out, LDL is particularly susceptible to oxidation by reactive oxygen species and to glycation.^*57 In this case, both the protein portion and the lipid portion (the cholesterol and the fats) of the lipoprotein are susceptible. These oxidized LDL particles appear to be “markedly elevated” in both diabetics and in nondiabetics with atherosclerosis, and are particularly likely to be found in the atherosclerotic lesions themselves.

That glycation and AGEs are critical factors in diabetic complications and in heart disease has recently been demonstrated by experiments with compounds known as anti-AGE compounds or AGE breakers. These will reverse arterial stiffness, at least in laboratory animals, and, as one recent report put it, ameliorate “the adverse cardiovascular and [kidney-related] changes associated with aging, diabetes and hypertension.” Whether these or similar compounds will work in humans remains to be seen.

When biochemists discuss oxidative stress, glycation, and the formation of advanced glycation end-products, they often compare what’s happening to a fire simmering away in our circulation. The longer the fire burns and the hotter the flame, the more damage is done. Blood sugar is the fuel. “Current evidence points to glucose not only as the body’s main short-term energy source,” as the American Diabetes Association recently put it, “but also as the long-term fuel of diabetes complications.”

But there is no reason to believe that glucose-induced damage is limited only to diabetics, or to those with metabolic syndrome, in whom blood sugar is also chronically elevated. Glycation and oxidation accompany every fundamental process of cellular metabolism. They proceed continuously in all of us. Anything that raises blood sugar—in particular, the consumption of refined and easily digestible carbohydrates—will increase the generation of oxidants and free radicals; it will increase the rate of oxidative stress and glycation, and the formation and accumulation of advanced glycation end-products. This means that anything that raises blood sugar, by the logic of the carbohydrate hypothesis, will lead to more atherosclerosis and heart disease, more vascular disorders, and an accelerated pace of physical degeneration, even in those of us who never become diabetic.

Chapter Twelve

SUGAR

M. Delacroix, a writer as charming as he is prolific, complained once to me at Versailles about the price of sugar, which at that time cost more than five francs a pound. “Ah,” he said in a wistful, tender voice, “if it can ever again be bought for thirty cents, I’ll never more touch water unless it’s sweetened!” His wish was granted….

JEAN ANTHELME BRILLAT-SAVARIN, The Physiology of Taste, 1825

WHEN BIOCHEMISTS TALK ABOUT “SUGAR,” they’re referring to a whole host of very simple carbohydrate molecules, all of which are characterized, among other things, by their sweet taste and ability to dissolve in water. Their chemical names all end in “-ose”—glucose, fructose, and lactose, among others. When physicians talk about blood sugar, they’re typically talking about glucose, although other sugars can be found in the bloodstream at very much lower concentrations. Then there’s the common usage of “sugar,” meaning the sweet, powdered variety that we put in our coffee or tea. This is sucrose, which in turn is constituted of equal parts glucose and fructose. In the discussion to come, when we refer to “sugar” we’ll always be talking about sucrose. When we use the term “blood sugar,” we’ll be talking about glucose.

When nutritionists in the 1960s discussed the pros and cons of sugar and starches, their concern was whether simple carbohydrates were somehow more deleterious than complex carbohydrates of starches. Chemically, simple carbohydrates, as in sugar and highly refined flour, are molecules of one or two sugars bound together, whereas the complex carbohydrates of starches are chains of sugars that can be tens of thousands of sugars long. Complex carbohydrates break down to simple sugars during the process of digestion, but they take a while to do so, and if the carbohydrate is bound up with fiber—i.e., indigestible carbohydrates—the digestion takes even longer. Since the early 1980s, both simple and complex carbohydrates have played a role in determining the glycemic index, which is a measure of how quickly carbohydrates are digested and absorbed into the circulation and so converted into blood sugar. This concept of a glycemic index has had profound consequences on the official and public perception of the risks of starches and sugar in the diet. But it has done so by ignoring the effect of fructose—in sugar and high-fructose corn syrup—on anything other than its ability in the short term to elevate blood sugar and elicit an insulin response.

In the mid-1970s, Gerald Reaven initiated the study of glycemic index to test what he called the “traditionally held tenet” that simple carbohydrates are easier to digest than more complex carbohydrates “and that they therefore produce a greater and faster rise” in blood sugar and insulin after a meal. Reaven’s experiments confirmed this proposition, but he was less interested in blood sugar than in insulin, and so left this research behind. It was taken up a few years later by David Jenkins and his student Thomas Wolever, both of whom were then at Oxford University. Over the course of a year, Wolever and Jenkins tested sixty-two foods and recorded the