National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
July 14, 2009 • Volume 6 / Number 14

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A Closer Look

Cutting Calories to Prevent Cancer

Weight and height are used in computing body mass index, an indicator of risk for developing obesity-associated diseases. Weight and height are used in computing body mass index, an indicator of risk for developing obesity-associated diseases.

A great deal of effort has been spent trying to understand how the food we eat—diets that are high in red meat, vitamins, minerals, or fiber, for example—affects our cancer risk. A similar question, fueled no doubt by the rising rates of obesity around the world, relates to the calorie content of our diet. What happens if we simply take in fewer calories?

To survive and proliferate, all cells, including cancer cells, need energy. Since the early 1900s, researchers could see how this axiom might be used in treating cancer; their experiments showed that calorie reduction inhibited the growth of transplanted tumors in mice.

Today it is the most widely studied and effective strategy for prolonging survival in mammals, said Dr. Stephen Hursting, formerly a deputy director in NCI’s Division of Cancer Prevention and now the chair of the Department of Nutritional Sciences at the University of Texas.

“It is the most potent broadly acting dietary intervention we know of that actually prevents cancer in experimental models,” he said. A study that appeared July 10 in the journal Science, for example, provided some evidence that a diet 30 percent lower than normal may be delaying diseases and extending the lifespan of rhesus monkeys. It was the first study to test this long-term intervention in primates, but whether it works in humans, and in the real world, is a question that hasn’t yet been answered.

Watching What We Eat

Dietary interventions used in animal experiments are sometimes called dietary energy restriction (DER). Ad libitum is a term that describes eating freely as much as one wishes; DER reduces calories usually in the range of 10 to 40 percent below ad libitum.

Even small differences in energy intake have been shown to have an effect in animal studies, noted Dr. Henry J. Thompson, director of the Cancer Prevention Laboratory at Colorado State University. “In fact, as little as a 10 percent reduction from ad libitum correlates with significant health benefits,” he explained.

How DER may be causing these benefits is still unclear—is it a simple gross reduction of calories consumed, could the same effect be seen if more calories are burned with exercise, or is a combination of the two the optimal approach? Researchers have found some clues, which they are now using as the basis for several clinical studies in humans.

Moving Beyond Mice

By slowing the metabolic rate, DER seems to interfere with the production of reactive oxygen species and also interfere with cell growth factors and signals, impeding angiogenesis and bolstering tissue breakdown. And by diverting stored energy from growth and development to basic cellular survival, DNA replication appears to happen less often, with less energy available to drive the transformation of healthy cells into cancer cells.

Underfeeding mice to test these relationships is simple. The calories that animals eat each day can be limited to levels below what they would normally eat, which is usually in the range of 115 calories per week.

It’s much trickier to test DER in humans. Outside of observational studies, most of the clinical research on dietary restriction and cancer prevention has focused on those who are overweight or obese, a population for whom the health risks of staying at their current weight (including cancer) clearly warrant an intervention.

The largest project funded by NCI in this area is the Transdisciplinary Research on Energetics and Cancer (TREC) initiative, a $54 million, 5-year project that began in 2005 to help molecular biologists, nutritionists, clinicians, behavioral scientists, epidemiologists, and others who work in the diet/exercise/cancer arena translate findings from cells into mice and then into clinical studies more efficiently. Many of the TREC projects are studying factors that contribute to obesity, but some are looking more closely at the link between calories in/calories out and cancer.

At the Fred Hutchinson Cancer Research Center, for example, Drs. Cornelia Ulrich and Anne McTiernan, the principal investigator of the Hutchinson TREC Center, are leading a project with overweight or obese post-menopausal women who are put on a restricted-calorie weight loss diet, a moderate-intensity aerobic exercise regimen, or both. The study’s goal is to explore what happens with biomarkers that in mouse studies have been linked to carcinogenesis and DER.

Women in the general U.S. population who are aged 50 to 70 eat approximately 1,700 to 1,800 calories a day, according to a survey by the CDC in which participants recalled what they had eaten from the most recent day or two; in Drs. McTiernan and Ulrich’s study, women assigned to the diet arms of the experiment are restricted to somewhere between 1,200 and 1,500 calories a day, depending on their weight at the start. The goal is to reduce their weight by 10 percent in the first 6 months. Meanwhile, their blood is checked for markers of DNA damage and repair to lymphocytes. Inflammation markers, including interleukin 6, serum amyloid A, and C-reactive protein, are also checked to see how the interventions affect these factors, which have been linked with increased cancer risk and poorer outcomes for cancer patients.

“We want to know whether health benefits for cancer can be achieved if women exercise regularly, even if they do not lose much weight or, alternatively, if weight loss is essential, which is achieved more easily through caloric restriction,” Dr. Ulrich explained. “We can also figure out whether body fat loss or other changes in body composition are critical to reduce risk factors for cancer, or whether an increase in fitness is equally important.”

A previous study with this group has shown that women who are part of the exercise intervention (45 minutes a day of brisk exercise, like walking, 5 days a week) decreased C-reactive protein, one of their markers for inflammation, by 10 percent over the course of a year, while those in the control arm who performed simple stretches showed an increase of 12 percent in this marker. Measurements from the ongoing TREC trial of exercise and caloric restriction will be collected in the next few months, with the results most likely published early in 2010.

More than Simple Subtraction

Most evidence shows that people resist lifestyle changes, even when it is clear that what they are doing may eventually kill them after making them very, very sick. With overweight and obesity, the issue is especially complicated because of contributing socioeconomic and cultural factors.

Dr. Linda Nebeling, who oversees the TREC initiative and is chief of the Health Promotion Research Branch in NCI’s Division of Cancer Control and Population Sciences, says that an important result from the TREC studies will be helping clinicians understand why it is physiologically harder for some people to lose weight through simple diet and exercise than it is for others.

“We used to think that body fat was inert, basically nothing more than a storage tank. But now we know that it is very different,” she explained. “Body fat has hormonal effects, it influences how your body responds to physiologic demands, and even the kinds of fat in our bodies—whether it’s brown or white fat, located within the muscle or wrapped around your abdomen like a blanket—can make a difference.” Learning about the biomarkers associated with cancer risk and obesity, weight loss, dietary energy restriction, and exercise may one day help clinicians tailor their interaction with patients for more effective cancer prevention strategies, Dr. Nebeling said.