In 1935, a nutritionist at Cornell University named Clyde McCay reported that in a series of experiments involving laboratory rats, he found that those eating a low-calorie, high-nutrient diet lived several months longer than their normally fed cage mates, a major improvement in lifespan for these short-lived animals. The implication being: cut calories, live longer.
As the years passed, many molecular biologists have remained skeptical of the finding. Like the line from the movie Jerry Maguire, "Show me the money," molecular biologists have demanded, "Show us the mechanisms." And that is where the conversation came screeching to a halt. With limited data and laboratory tools at their disposal, scientists could not even begin to contemplate how to isolate the cellular mechanisms influenced by caloric restriction.
But that could soon change in the new century. Pointing to the arrival of genomics and higher-powered laboratory technologies, scientists say the field is now poised to systematically explore how a calorie-reduced diet affects many of the most basic processes of life, such as hormone secretion, gene expression, DNA repair, oxidative stress, and apoptosis.
Although there is a mountain of work to be done, researchers say they are optimistic that these studies will play a leading role in helping to link molecular biology, genetics, and nutrition, a meeting of the minds that would greatly benefit cancer research.
When Susan Perkins, Ph.D., steps into the animal room near her laboratory at the National Cancer Institute-Frederick Cancer Research and Development Center, in Frederick, Md., she said it is easy to spot the mice that eat a calorie-restricted diet. "The caloric-restricted mice jump up and down," said Perkins. "They are extremely active because they are hungry."
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Within the "healthy" range, though, the animals tend to live long and exceedingly ravenous lives. Most are slow to develop typical aches and pains of aging. "Caloric restriction is still the only intervention that is known to increase the median lifespan in animals," said Perkins.
That includes mice with tumors. Starting with the seminal work of Moreschi in 1909, scientists have reproducibly reported over the last 90 years that rats and mice with transplanted, spontaneous, or chemically induced tumors live longer when fed a calorie-reduced diet. In fact, rodents with tumors also often live longer on a calorie-reduced diet than their normally fed, cancer-free counterparts.
But, like all of the "miracle" mouse studies that dot the scientific literature, cancer researchers have always walked a fine line between hope and hype when interpreting work on caloric restriction. They say that, intuitively, it makes sense that a low-energy diet might stress energy-guzzling cancer cells, impeding their ability to grow.
Age More Slowly
It also seems reasonable that when cells are forced to conserve energy, the organism will age more slowly. "Caloric restriction makes good evolutionary sense," said Julian Leakey, Ph.D., a scientist with the National Center for Toxicological Research in Jefferson, Ark. "It is a mechanism that allows you to adapt your lifespan and reproductive potential to the environment for the benefit of the species. It gives you the dynamic to reproduce like mad when conditions are good, but survive otherwise."
Does this theory also translate to fact in people? Nobody knows. Because people live decades longer than rodents, which makes studies logistically and financially a tall order, human data are scarce in the literature.
But, for now, scientists seem to have found an experimental middle ground on which to approach this major question. In 1989, the National Institute on Aging established the first of two large colonies of calorie-restricted rhesus monkeys, a close evolutionary cousin to humans. The monkeys, which started the diet at age 10 and are now approaching their mid 20s, will likely live about 40 years.
Richard Weindruch, Ph.D., a scientist at the University of Wisconsin at Madison who oversees one of NIAs calorie-restricted monkey colonies, said the final results of the study are still at least 15 years off. He said these final data will help to pin down the big-ticket health issues, including the effects of a calorie-restricted diet on longevity and age-related diseases, including cancer.
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Show Us the Mechanisms
Already, the first inroads have been made in generating a genomic profile of caloric restriction. A year ago, Weindruch and his colleague Tomas Prolla, Ph.D., a geneticist at the University of Wisconsin, published a profile of genes expressed in cells from normally fed young and old mice compared with those that consumed a calorie-restricted diet. Weindruch said this initial comparison, generated from an Affymetrix array of 6,500 mouse genes, was performed in non-dividing skeletal muscle cells.
"The first data set compared the young and the old animals, then about 2 weeks later, we got the data on caloric restriction," said Weindruch. "It was incredibly exciting because nearly all of the genes that were getting messed up with agingeither going up or down in transcription activitywere almost all being prevented by caloric restriction. It was just picking them off one at a time."
Although this study was only a first step, Weindruch predicts that subsequent genetic profiling studies will generate a wealth of leads into the biology of aging. "Aging is a very complex phenomenon, and caloric restriction induces hundreds, if not thousands, of biological changes," he said. "Though this complexity is unwanted, that should not prevent one from using it as a window to explore the biology of aging."
Many contend that decades of research already have placed several excellent hypotheses on the table. One is that increased production of a stress-reducing hormone glucocorticoid mediates the anti-aging effects of caloric restriction. Other viable theories involve proposed changes in oxidative stress, DNA repair, apoptosis, T-cellmediated immune responses, and other fundamental biologic processes.
Big Picture
Some note that the greatest challenge of all may be simply overcoming the reductionistic mindset that dominates modern biology. "Whats happened over the years in caloric restriction is different people have jumped on different bandwagons," said Leakey. "Everybody is looking at it from their own fields, but the whole concept is more dynamic than that. Sometimes, you need to step back and look at the big picture."
As microarrays and other more powerful technologies pave the way to seeing the big picture, some warn that the field may find itself fending off the same shrug of the shoulders that greeted their predecessors.
"We still struggle with the few who say this isnt relevant to people because we are starving our animals in order to get these effects," said Diane Birt, Ph.D., a scientist at Iowa State University in Ames. "I really think that we have biological effects in ranges of consumption that are deemed to be healthy human consumption."
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In this age of designer drugs, Weindruch added that the fields harvest could also be in therapeutics. "In rodents, where we know that caloric restriction retards aging and a broad spectrum of diseasesincluding cancerwe really need to understand the underlying mechanisms of those effects," he said. "The importance there is it may allow for the development of caloric restriction mimetics, where one could find drugs or other interventions to mimic the critical effects of caloric restriction."
Leakey said the take-home lesson from caloric restriction already may be abundantly clear for people who live in affluent Western nations. That message is: Eat less.
However the story plays out in caloric restriction, most scientists agree that the field will begin to wrap its fingers around the cellular mechanisms that have been so elusive for so long. "Oh, its as exciting as can be," said Weindruch, who has studied caloric restriction since the 1970s. "The field has grown and will continue to grow tremendously."
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