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 cells—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 genetically 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 genetically engineered mice, tumor growth and metastasis accelerate. David Cheresh, a cancer researcher at the Scripps Institute in La Jolla, California, has demonstrated that both insulin and insulin-like growth factor will 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 cell becomes cancerous, and then they work to keep the cells alive and multiplying. At a 2003 meeting in London to discuss the latest work on IGF, researchers speculated that the development of cancerous cells and even benign tumors is a natural side effect of aging. What’s not natural is the progression of these cells and tumors to lethal malignancies. Such a transformation requires the chronically 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 cells, much of which is unavoidable, but how diets change the environment around cells and tissues to promote the survival, growth, and then metastasis of the cancer cells 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 cells that pushes cells to proliferate further and grow more easily and skip the programmed cell- death events.”
IGF and insulin can be viewed as providing fuel to the incipient fire of cancerous cells and the freedom to grow without limit. The critical factor is not that diet changes the
All 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 will likely live 30 to 50 percent longer than had we let it eat to satiation, and any age-related diseases—cancer in particular—will 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 all 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 naturally prefer to eat. They are normally 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 will live as long as or longer than lean mice of a similar genetic inheritance but without the mutation that causes obesity. They will do this even though they still 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 calorically restricted ob/ob mice lived just as long as calorically 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 semi-starvation, not because they are necessarily leaner or lighter.
So what does eating less do physiologically that leanness does not? With each new study, researchers have honed their hypothesis of why semi-starvation 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 cells and tissues. Eat less food and the cells burn less fuel, and so generate fewer free radicals. Oxidative stress proceeds at a slower pace, and we live longer, just as a car will 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 genetically transformed to overproduce their own antioxidants, they will 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 all these long-lived organisms seem to share definitively are reduced insulin resistance, and abnormally 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 all the toxic sequelae that follow. 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 compelling 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 all 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
