Good Calories, Bad Calories

sapiens are not very different.”

Consider, for instance, the mutations that control longevity in nematodes, which are the particular type of microscopic worms favored by modern researchers. These mutations, as Cynthia Kenyon and her colleagues from the University of California, San Francisco, reported in Nature in 1993, are in a gene that was known to regulate the passage of young worms into a state known as dauer that is similar to hibernation in mammals. The worms will enter this dauer state, explains Kenyon, only if they have insufficient food to survive. “The way these worms work,” she explains, “is that the worm hatches from the egg, and if there’s not a lot of food around, it goes through various larval stages and ends up in this dauer state…. It doesn’t eat or do anything else. Then, if you give it food, it will exit the state and reproduce and have a normal lifespan.” The particular genetic mutation that Kenyon discovered resulted in worms that lived twice as long as normal worms, and this was, at the time, the longest lifespan extension ever reported in an organism. Kenyon then demonstrated that this increased longevity was not simply a consequence of some kind of developmental arrest—as though the mutation had somehow trapped a young worm in a dauerlike limbo—but was actually the result of the mutation’s triggering a lifespan-extension mechanism in adult worms. In other words, this mutation was keyed into a genetic program that actually regulates longevity, and does it in a way that would be evolutionarily advantageous.

In 1997, the Harvard geneticist Gary Ruvkun reported that the gene in question was the single worm-equivalent of a trio of insulin-related genes in humans. In retrospect, this wasn’t surprising, noted Ruvkun, because here was a gene in worms that regulated a process—dauer—that depended on the presence or absence of food in the environment, and insulin and IGF are the genes in more sophisticated organisms that respond specifically to food availability. As it turns out, particularly long-lived fruit-fly mutants have also been found to have defects in this same insulin-like gene pathway, which serves to regulate in the fly a condition very similar to dauer and hibernation.

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 colleagues from the Institut National de la Sante et de la Recherche Medicale in Paris reported that they had created mice with only a single copy of the gene for the IGF receptor, which meant that the cells 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 colleagues at the Joslin Diabetes Center published the results of their research on mice that they had genetically engineered to lack the insulin receptor only on their fat cells. 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 cells 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 cell division and growth, while the insulin regulates metabolism by apportioning or partitioning the food we consume into those calories that will be used immediately for fuel and those that will 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 still 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 well. This research supports the hypothesis that elevations of insulin and IGF will increase the risk of disease and shorten life, and so any diet or lifestyle that elevates insulin and makes IGF more available to the cells 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, all fat, or perhaps all calories is responsible. Few researchers are willing 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 still 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 tells 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 all 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 collaborators when they discussed the lean, long-lived transgenic mice they had created by knocking out the insulin receptors on the fat cells 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 million 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 well.” 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 cells in humans, we might be able to prevent obesity, as well as Type 2