Understanding Pathways of Calorie Restriction: A Way To Prevent Cancer?

For decades, researchers have been intrigued by calorie restriction, a tried and true way of extending lifespans in creatures ranging from yeast and roundworms to flies and mice. Aside from increasing the lifespan of organisms up to 80% in some studies, calorie restriction (with proper nutrition) also leads to lower insulin, glucose, and blood pressure levels, as well as increased white blood cell count. Particularly enticing is the possibility for caloric restriction(definition) to prevent, delay, and shrink a variety of tumors, a finding that seems to complement those of recent studies linking obesity and cancer. In animal studies, researchers reduce food intake by 10%–60%, but because such extreme dieting would be unrealistic in humans, many researchers are now examining the biological pathways affected by caloric restriction with the aim of developing preventive agents for cancer as well as other diseases associated with aging. Together with the growing field of calorie restriction mimetics—finding natural or synthetic compounds that mimic the effects of caloric restriction—they are finding these pathways to be numerous and complex. “The field of [caloric restriction] seems to grow every day with new discoveries of genes, pathways, and proteins that are affected in different ways,” Julie Mattison, Ph.D., a caloric restriction researcher at the National Institute on Aging (NIA), wrote in an e-mail. In gaining information about the systems changed by caloric restriction, she said, researchers can identify targets for mimetics. The link between cancer and caloric restriction was first suggested in the early 1900s when scientists showed that reducing calorie intake slowed the growth of transplanted tumors in mice. Since then, studies have demonstrated that caloric restriction inhibits spontaneous as well as radiation-induced tumors in mammary, prostate, and other animal models of cancer. On a cellular level, less food intake prompts an organism to undergo a transformation. By diverting energy from reproduction and growth, the organism can focus on survival, boosting its defense system and triggering pathways that inhibit tumors. Caloric restriction also decreases cell proliferation and increases apoptosis, a combination that may slow the formation of cells inclined to turn cancerous and the proliferation of preexisting cancer cells. Other effects include more growth of mitochondria, increased levels of the tumor suppressor p53, less DNA damage, and more active antioxidant enzymes. Researchers are divided on which of these influences is most responsible for caloric restriction's longevity and anticancer effects. Some are focusing on insulin-like growth factor (IGF)-1, which stimulates the cell cycle and influences the production of growth hormone, insulin, leptin, and other molecules involved with growth. Levels of IGF-1 decrease with calorie restriction, whereas its receptor, IGF-1R, is overexpressed in many tumors. Studies in vitro have shown that IGF-1 prompted growth in more than a dozen cancer lines. Others suggest that higher levels of IGF-1, in ratio to related molecules, correlate with increased risk of breast and prostate cancers. “If you have high insulin and high IGF-1, you're going to drive a signal through receptors that activates a growth and survival pathway. That's exactly what cancer cells capitalize on,” said Stephen Hursting, Ph.D., of the University of Texas at Austin. Hursting, who studies the effects of exercise and caloric restriction on cancer, has shown that exercise represses tumors to a lesser degree and not by decreasing IGF-1. At the NIA, Rafael de Cabo, Ph.D., and others have focused on the NF-E2–related factor 2 (Nrf2) pathway, which activates antioxidant enzymes when triggered by caloric restriction. This pathway has been studied for years, particularly in relation to a broccoli sprout compound, sulforaphane, that inhibits tumors. In a study published in the Proceedings of the National Academy of Sciences in February, de Cabo and colleagues demonstrated in a chemically induced carcinogenesis model that the Nrf2 pathway is involved with caloric restriction's anticancer effects. They showed that the lack of Nrf2 increases tumor incidence in this model, even in calorie-restricted animals. A lack of Nrf2 did not affect caloric restriction's benefits on longevity and insulin signaling. Other researchers are looking to mitochondria—where damaging free radicals are produced—to explain why caloric restriction prolongs life and health. Richard Weindruch, Ph.D., at the University of Wisconsin and colleagues have shown that tissues from calorie-restricted rodents contain fewer free radicals in their mitochondria than the tissues of mice in a control group. Weindruch, who has cofounded a company called LifeGen Technologies to look for naturally occurring compounds that mimic the effects of caloric restriction, is also interested in PGC-1α, a compound involved in oxidative stress that may be a master regulator of mitochondria. Another team of researchers, led by Harvard pathologist David Sinclair, Ph.D., is focusing on enzymes that stimulate mitochondrial growth as caloric restriction's key mechanism. Sinclair led the well-publicized study showing that resveratrol, a chemical in red wine, had anticancer effects and helped obese mice live longer. Since then, he and colleagues have identified the gene Sirtuin 1 (SIRT1) as a target of resveratrol and shown that a family of seven related enzymes, dubbed sirtuins, is linked to the longevity effects triggered by calorie restriction, possibly by stimulating mitochondrial growth. The continual loss of mitochondria as one grows older “is one of the reasons we think SIRT1 could be beneficial against aging,” Sinclair said. In February, Sirtris Pharmaceuticals in Cambridge, Mass., announced results demonstrating that SIRT1 activation suppressed tumor formation and growth in an animal model of colon cancer. Details of the study should be releas