Good Calories, Bad Calories (41 page)

IGF and its receptors appear to play a critical role in cancer. In mice, functioning IGF receptors are a virtual necessity for cancer growth, a discovery that Renato Baserga of Thomas Jefferson University says he “stumbled” upon in the late 1980s, after nearly forty years spent studying the growth processes of normal and cancerous cel s. Shutting down the IGF receptor in mice wil lead to what Baserga cal s “strong inhibition, if not total suppression of [tumor]

growth” it is particularly lethal to those tumors that have already metastasized from a primary site elsewhere in the body.

In the bloodstream, virtual y al insulin-like growth factors are attached to smal proteins that ferry them around to various tissues where they might be needed. But the IGFs, when attached to these proteins, are too large and unwieldy to pass through the wal s of blood vessels and get to the tissues and cel s where the IGF might be used. At any one time, only a smal percentage of IGF in the circulation is left unbound to stimulate the growth of cel s.

These binding proteins constitute yet another of the mechanisms used by the body to regulate hormonal signals and growth factors. Insulin appears to depress the concentration of IGF-binding proteins, and so high levels of insulin mean more IGF itself is available to effect cel growth—including that of malignant cel s. Anything that increases insulin levels wil therefore increase the availability of IGF to the cel s, and so increase the strength of the IGF

proliferation signals. (Insulin has been shown to affect estrogen this way, too, one way in which elevated levels of insulin may potential y cause breast cancer.)

The role of IGF in cancer appears to be fundamental, albeit stil controversial. As is the case with insulin, IGF has been found in the laboratory to enhance the growth and formation of tumor cel s directly; IGF signals prompt cel s to divide and multiply. (This effect seems to be particularly forceful with breast-cancer cel s when IGF and estrogen are acting in concert.) IGF has an advantage over other growth factors that might play a role in cancer because it can reach tumors either through the bloodstream—after being secreted by the liver—or as a result of production by nearby tissue. There’s even evidence that tumors can stimulate their own further growth and proliferation by secreting their own insulin-like growth factors. In the early 1980s, cancer researchers discovered that tumor cel s also overexpress IGF receptors, just as they overexpress insulin receptors. The surfaces of tumor cel s have two to three times as many IGF receptors as healthy cel s, which makes them al that much more responsive to the IGF in their immediate environment.

This is another way in which cancer cel s gain their al -important survival growth advantage, suggests Derek LeRoith, whose laboratory at the National Institute of Diabetes and Digestive and Kidney Diseases did much of this research. The extra insulin receptors wil cause cancerous cel s to receive more than their share of insulin from the environment, which wil convey to the cel more blood sugar for fueling growth and proliferation; the extra IGF receptors wil assure that these cel s are supplied with particularly forceful commands to proliferate. Another critical role of IGF in the development of cancer may be its ability to inhibit or override the cel suicide program that serves as the ultimate fail-safe mechanism to prevent damaged cel s from proliferating.

In the past decade, LeRoith and others have demonstrated that the various molecules involved in the communication of the IGF signal from the bloodstream to the nucleus of cel s—the insulin-like growth factors themselves, their receptors, and their binding proteins—work together with insulin to regulate both the growth and metastasis (the spread of tumors to secondary sites) of colon and breast cancer. LeRoith has done a series of experiments with mice genetical y engineered so that their livers do not secrete IGF. As a result, these mice have only a quarter as much IGF in their circulation as normal mice. When colon or mammary tumors are transplanted into these mice, both tumor growth and metastasis are significantly slower than when identical tumors are implanted in normal mice with normal IGF levels. When insulin-like growth factor is injected back into these genetical y engineered mice, tumor growth and metastasis accelerate. David Cheresh, a cancer researcher at the Scripps Institute in La Jol a, California, has demonstrated that both insulin and insulin-like growth factor wil prompt otherwise benign tumors to metastasize and migrate through the bloodstream to secondary sites.

The working hypothesis of cancer researchers who study IGF is not that these molecules initiate cancer, a process that occurs through the accumulation of genetic errors, but, rather, that they accelerate the process by which a cel becomes cancerous, and then they work to keep the cel s alive and multiplying. At a 2003 meeting in London to discuss the latest work on IGF, researchers speculated that the development of cancerous cel s and even benign tumors is a natural side effect of aging. What’s not natural is the progression of these cel s and tumors to lethal malignancies. Such a transformation requires the chronical y high levels of insulin and IGF induced by modern diets. This hypothesis is supported by epidemiological studies linking hyperinsulinemia and elevated levels of IGF to an increased risk of breast, prostate, colorectal, and endometrial cancer.

This hypothesis, if not refuted, would constitute a significant shift in our understanding of the development of malignant cancer. It would mean that the decisive factor in malignant cancer is not the accumulation of genetic damage in cel s, much of which is unavoidable, but how diets change the environment around cel s and tissues to promote the survival, growth, and then metastasis of the cancer cel s that do appear. “People were thinking a bit too much that diet could be a risk factor for cancer almost exclusively based on the idea that it contained carcinogenic substances,” explains Rudolf Kaaks, director of the Hormones and Cancer Group at the International Agency for Cancer Research. “Now the idea is that there is a change in the endocrine and growth-factor environment of cel s that pushes cel s to proliferate further and grow more easily and skip the programmed cel -death events.

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IGF and insulin can be viewed as providing fuel to the incipient fire of cancerous cel s and the freedom to grow without limit. The critical factor is not that diet changes the nature of cel s—the mutations that lead to cancer—but that it changes the nurturing of those cel s; it changes the environment into one in which cancerous and precancerous cel s can flourish. Simply by creating “an environment that favored, even slightly, survival (rather than programmed cel death),” says the McGil University oncologist Michael Pol ak, insulin and IGF would increase the number of cel s that accumulate some genetic damage, and that would increase the number of their progeny that were likely to incur more damage, and so on, until cancer is eventual y achieved. “When applied simultaneously to large numbers of at-risk cel s over many years,” notes Pol ak, “even a smal influence in this direction would serve to accelerate carcinogenesis.”

Al of this leads us back to the spectacular benefits of semi-starvation on the health and longevity of laboratory animals. If we take a young rat and restrict its eating to less than two-thirds the calories of its preferred diet, and if we keep this up for its entire life, our rat wil likely live 30 to 50 percent longer than had we let it eat to satiation, and any age-related diseases—cancer in particular—wil be delayed in their onset and slowed in their progression. This has been shown to hold true for mice and other rodents, and for yeast, protozoans, fruit flies, and worms (and maybe even monkeys).

Two possibilities for how these diets work are that the animals live longer because they are less encumbered by body fat, or because they’re leaner al around and so weigh less. Neither of these can explain the evidence, however. Consider a strain of mice known as ob/ob mice. These have a mutation in a single gene that results in such extreme obesity that a mouse ends up looking like a loaf of bread with fur, eyes, whiskers, and a mouth. Nonetheless, these mice can be kept at a normal weight by restricting their food consumption to half of what they would natural y prefer to eat. They are normal y short-lived, which supports the idea that the greater the body fat the shorter the lifespan, but on a lifelong very low-calorie diet they wil live as long as or longer than lean mice of a similar genetic inheritance but without the mutation that causes obesity. They wil do this even though they stil have more than twice the body fat of the lean mice. Indeed, when these experiments were done in the early 1980s by David Harrison of the Jackson Laboratory in Bar Harbor, Maine, these calorical y restricted ob/ob mice lived just as long as calorical y restricted lean mice, even though the former were nearly four times as fat as the latter. “Longevities,” Harrison concluded, “were related to food consumption rather than to the degree of adiposity.” This has inevitably been the case, whenever these experiments are done. The calorie-restricted animals live longer because of some metabolic or hormonal consequence of semistarvation, not because they are necessarily leaner or lighter.

So what does eating less do physiological y that leanness does not? With each new study, researchers have honed their hypothesis of why semistarvation leads to these anti-aging and disease-delaying processes, and what this says about human aging and disease. This has led to some remarkable revelations about insulin and insulin-like growth factor, and what is likely to happen when these two hormone/growth factors are perturbed by modern diets.

One hypothesis proposes that calorie restriction reduces the creation of toxic reactive oxygen species—free radicals—which are considered to be crucial factors in the aging of cel s and tissues. Eat less food and the cel s burn less fuel, and so generate fewer free radicals. Oxidative stress proceeds at a slower pace, and we live longer, just as a car wil last longer in a dry climate that doesn’t promote rust. Certainly, calorie restriction suppresses free-radical production. And if fruit flies are either fed antioxidants or genetical y transformed to overproduce their own antioxidants, they wil live up to 50

percent longer. But similar experimental interventions seem to do nothing for rodents. The genetic evidence suggests that something more profound is happening, although this reduction in oxidative stress likely plays some role.

The characteristics that al these long-lived organisms seem to share definitively are reduced insulin resistance, and abnormal y low levels of blood sugar, insulin, and insulin-like growth factor. As a result, the current thinking is that a lifelong reduction in blood sugar, insulin, and IGF bestows a longer and healthier life. The reduction in blood sugar also leads to reduced oxidative stress and to a decrease in glycation, the haphazard binding of sugars to proteins, and glycation end-products and al the toxic sequelae that fol ow. The decrease in insulin and IGF also apparently bestows on the organism an enhanced ability to protect against oxidative stress and to ward off other pathogens.

The most compel ing evidence now supporting this hypothesis has emerged since the early 1990s from genetic studies of yeast, worms, and fruit flies, and it has recently been confirmed in mice. In al four cases, the mutations that bestow extreme longevity on these organisms are mutations in the genes that control both insulin and IGF signaling.

Geneticists and developmental biologists refer to yeast, worms, fruit flies, and mice as model organisms because they’re easy to study in the laboratory and what we learn from them about genetics wil almost assuredly apply to humans as wel . This is considered the fundamental principle underlying modern genetic research: once evolution comes upon a genetic mechanism that works, it reuses it again and again. Those genes that regulate the development and the existence of any single living organism wil likely be used in some similar fashion in all of them. “When reduced to essentials,” as the cancer researcher J. Michael Bishop suggested in his 1989 Nobel Prize lecture, “the fruit fly and Homo 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 col eagues 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 wil 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 wil 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 actual y 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 actual y 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 specifical y 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.