Good Calories, Bad Calories (42 page)

The ultimate evidence, at least so far, that insulin and insulin-like growth factor affect longevity and disease comes from a type of transgenic animal experiment known as a knockout. The working assumption of such experiments is that the function of a gene can be elucidated by creating an animal that lacks the gene entirely—the gene has been knocked out—or has only one copy instead of the usual two. In January 2003, Martin Holzenberger and his col eagues from the Institut National de la Santé et de la Recherche Médicale in Paris reported that they had created mice with only a single copy of the gene for the IGF receptor, which meant that the cel s of such mice would be comparatively unresponsive to any IGF that might be available in the circulation. The result was that these mice lived 25 percent longer than their littermates who had both copies of the gene, despite the fact that their weights were effectively identical. That same month, C. Ronald Kahn and his col eagues at the Joslin Diabetes Center published the results of their research on mice that they had genetical y engineered to lack the insulin receptor only on their fat cel s. With their fat tissue immune to the effect of insulin, Kahn’s mice weighed 25 percent less than normal mice. These mice remained lean, even when forced to overeat. They were simply incapable of putting on fat. As Kahn later explained, this wasn’t surprising, since fat cel s require insulin for fat synthesis. If they have no receptor to detect the insulin that’s present, then no fat can accumulate. The transgenic mice lived almost 20 percent longer than normal mice.

These experiments have led to the working hypothesis that insulin and insulin-like growth factor emerged in simple organisms in part to promote the survival of the species when food is hard to come by. These hormone/growth factors regulate metabolism and fat storage and reproduction. The IGF

regulates cel division and growth, while the insulin regulates metabolism by apportioning or partitioning the food we consume into those calories that wil be used immediately for fuel and those that wil be stored for use at a later time. When food is plentiful, activity in the insulin and IGF pathways increases and pushes the animal to grow, mature, and reproduce. When food is scarce, activity in these pathways is reduced, and this shifts the organism into a mode that favors long-term survival over immediate reproduction. As Cynthia Kenyon explains:

When food becomes limiting, an animal lacking this system would either die of starvation, or produce progeny that die of starvation. In contrast, with this food-sensing system in place, as food declines, the animal begins to build up fat and/or glycogen [the molecular storage form of glucose]

reserves, elaborates stress-resistance mechanisms, and delays or suspends reproduction until food is restored. It also activates pathways that extend lifespan, which increases the organism’s chance of being alive and stil youthful enough to reproduce if it takes a long time for conditions to improve.

If we accept the evolutionary argument that genetic mechanisms are conserved from simple organisms to humans, then we have at least to contemplate the implications: if a regulatory system as fundamental as that of insulin and IGF is capable of influencing longevity and susceptibility to disease in flies, worms, and mice, then it is likely to do so in humans as wel . This research supports the hypothesis that elevations of insulin and IGF wil increase the risk of disease and shorten life, and so any diet or lifestyle that elevates insulin and makes IGF more available to the cel s and tissues is likely to be detrimental.

To accept these implications at face value, however, we have to be capable of dismissing the conventional wisdom on diet and chronic disease—that an excess of saturated fat, al fat, or perhaps al calories is responsible. Few researchers are wil ing to take this approach. One who has is Cynthia Kenyon. Once it became clear that the mutations that prolonged longevity in worms were those that reduced the level of activity in the worms’ insulin-IGF

pathway, Kenyon began a series of experiments based on a single question: what would happen if she fed worms glucose, in addition to their preferred diet of bacteria? Kenyon added 2 percent glucose to the bacterial medium in which the worms lived, and the lifespan of the worms was reduced by a quarter. Kenyon is stil working to establish the nature of this adverse effect of glucose. Her hypothesis: just as mutations increase lifespan in worms by decreasing activity in their insulin-IGF pathway, glucose shortens the lifespan of worms by increasing activity in the same pathway. In October 2004, when Kenyon presented the results of these experiments at a conference on the molecular genetics of aging, she concluded her presentation with a simple, albeit radical question: “Could a low-carb (i.e., low-glycemic-index) diet lengthen lifespan in humans?”

Kenyon is unusual in this kind of laboratory research in that she had already interpreted the results of her research as relevant to her own life. As Kenyon tel s it, the day she realized that glucose shortened the lives of her worms, she decided to restrict her own consumption of carbohydrates to a bare minimum. She lost thirty pounds, she says; her blood pressure, triglycerides, and blood-sugar levels al dropped; and her HDL increased. Kenyon recognizes her experience as anecdotal, but it certainly influenced her suspicion that carbohydrates would also cause chronic disease in humans through their effect on insulin and insulin-like growth factor.

A more common approach to this research implicating insulin and IGF in the causation of chronic disease is to avoid any possible dietary implications and focus solely on the connotations for drug or gene therapies. This was the approach used by Dennis Selkoe and Rudolph Tanzi, who concluded their April 2004 report on insulin and Alzheimer’s by suggesting that the results “have attendant therapeutic implications.” The only therapeutic implication they discussed was the possibility of creating “compounds” that increase the activity of insulin-degrading enzyme—the equivalent of reducing insulin levels

—and so inhibiting the accumulation of Alzheimer’s plaques in the brain.

This same approach was used by Ronald Kahn and his col aborators when they discussed the lean, long-lived transgenic mice they had created by knocking out the insulin receptors on the fat cel s of the mice. The publication of the research in Science was accompanied by a press release from the Joslin Diabetes Center, of which Kahn is president, focused almost exclusively on the “dream of 60 mil ion overweight American adults,” which it described as the desire to “throw away those diet books and eat whatever you want without becoming fat, and—as a bonus—not develop diabetes and live longer as wel .” The press release implied that this dream might be accomplished by the insights gleaned from these transgenic mice, and Kahn was quoted discussing therapeutic implications, although once again diet was not one of them. “Perhaps one day if we are able to find a drug to reduce or block insulin action in fat cel s in humans, we might be able to prevent obesity, as wel as Type 2 diabetes and other metabolic diseases,” Kahn wrote.

“And who knows, they might also live longer too.” Diabetologists implicitly take the same tack whenever they discuss the need for their diabetic patients to

“normalize” blood sugar, while recommending that this be accomplished primarily with “intensive insulin therapy” rather than restricting the carbohydrate content of their diets.

Another common approach today is to accept the chronic elevation of insulin, and so IGF, as a likely cause of chronic disease, but then assume that the hyperinsulinemia is caused by insulin resistance, which in turn is induced by a combination of high-fat, energy-dense, high-calorie diets, physical inactivity, and excess weight. By this logic, any research that implicates increased insulin activity in disease only confirms that too much food and too little exercise are the true banes of our existence. This approach is the one employed by those clinicians and public-health authorities who now acknowledge that hyperinsulinemia, insulin resistance, and the associated physiological abnormalities of metabolic syndrome are important risk factors for heart disease, but then blame the syndrome itself on excess weight or, if the patient happens to be lean, on physical inactivity. The guidelines from the National Cholesterol Education Program manage to merge both of the latter two approaches, by first enumerating the causes of metabolic syndrome as overweight, physical inactivity, and an “atherogenic diet”—defined as a diet high in saturated fat and calories—and then suggesting that “pharmacological modification of the associated risk factors” is the most effective treatment.

In this approach, high-calorie, high-fat diets and sedentary lifestyles are seen as the causes of al the diseases of civilization. The causal link in this chain from diet and lifestyle to disease is excess weight. “Weight sits like a spider at the center of an intricate, tangled web of health and disease,” as the Harvard epidemiologist Walter Wil ett has described it in Eat, Drink, and Be Healthy: The Harvard Medical School Guide to Healthy Eating. Or, as Jeremiah Stamler suggested back in 1961, about heart disease in particular, “Excess weight and the common American pattern of gain in weight from young adulthood into middle age are highly prevalent and serious risk factors…. The problem is not the severe, marked, huge, circus-type-of obesity, but rather the 25 or 40 pounds put on gradual y over the years—the moderate, creeping obesity so common among middle-aged American men.”

That excess weight is accompanied by an elevated risk of chronic disease is a given. The questionable assumption is that it is an excess of calories of all types, and the dense calories of dietary fat in particular, combined with a relative lack of physical activity, that causes weight gain. In the prevailing wisdom, a simple caloric imbalance is the culprit: we get fat because we consume more calories than we expend.

The alternative is that excess weight and obesity, like al diseases of civilization, are caused by the singular hormonal effects of a diet rich in refined and easily digestible carbohydrates. The fattening of our adult years, after al , is not just associated with chronic diseases of civilization, it is a disease of civilization, and so it, too, may be a symptom of an underlying disorder. In this hypothesis, it is the quality of the calories consumed that regulates weight, and the quantity—more calories consumed than expended—is a secondary phenomenon. Whatever causes weight gain is at the heart of this tangled web, and that is the question we must now address.

OBESITY AND THE REGULATION OF WEIGHT

How may the medical profession regain its proper role in the treatment of obesity? We can begin by looking at the situation as it exists and not as we would like it to be…If we do not feel obliged to excuse our failures we may be able to investigate them.

ALBERT STUNKARD AND MAVIS MCCLAREN-HUME, in “The results of treatment for Obesity: A Review of the Literature and Report of a Series,” 1959

To cultivate the faculty of observation must then be the first duty of those who would excel in any scientific pursuit, and to none is this study more necessary than to the student of medicine. Without the habit of correct observation, no one can ever excel or be successful in his profession.

Observation does not consist in the mere habitual sight of objects—in a kind of vague looking-on, so to speak—but in the power of comparing the known with the unknown, of contrasting the similar and dissimilar, in justly appreciating the connection between cause and effect, the sequence of events and in estimating at their correct value established facts.

THOMAS HAWKES TANNER, A Manual of Clinical Medicine and Physical Diagnosis, 1869

THE MYTHOLOGY OF OBESITY

A col eague once defined an academic discipline as a group of scholars who had agreed not to ask certain embarrassing questions about key assumptions.

MARK NATHAN COHEN, Health and the Rise of Civilization, 1989

CRITICAL TO THE SUCCESS OF any scientific enterprise is the ability to make accurate and unbiased observations. “To have our first idea of things, we must see those things,” is how Claude Bernard explained this in 1865; “to have an idea about a natural phenomenon, we must, first of al , observe it…. Al human knowledge is limited to working back from observed effects to their cause.” But if the initial observations are incorrect or incomplete, then we wil distort what it is we’re trying to explain. If we make the observations with preconceived notions of what the truth is, if we believe we know the cause before we observe the effect, we wil almost assuredly see what we want to see, which is not the same as seeing things clearly.

The trouble with the science of obesity as it has been practiced for the last sixty years is that it begins with a hypothesis—that “overweight and obesity result from excess calorie consumption and/or inadequate physical activity,” as the Surgeon General’s Office recently phrased it—and then tries and fails to explain the evidence and the observations. The hypothesis nonetheless has come to be perceived as indisputable, a fact of life or perhaps the laws of physics, and its copious contradictions with the actual observations are considered irrelevant to the question of its validity. Fat people are fat because they eat too much or exercise too little, and nothing more ultimately need be said.

The more closely we look at the evidence and at obesity itself, the more problematic the science becomes. Lean people wil often insist that the secret to their success is eating in moderation, but many fat people insist that they eat no more than the lean—surprising as it seems, the evidence backs this up

—and yet are fat nonetheless. As the National Academy of Sciences report Diet and Health phrased it, “Most studies comparing normal and overweight people suggest that those who are overweight eat fewer calories than those of normal weight.” Researchers and public-health officials nonetheless insist that obesity is caused by overeating, without attempting to explain how these two notions can be reconciled. This situation is not improved by the prevailing attitude of many nutritionists, obesity researchers, and public-health authorities that it is evidence of untoward skepticism to raise such issues, or to ask questions that lead others into contemplating the contradictions themselves.