BERKELEY – An apple a day keeps the doctor away, but could eating an apple every other day be better?
A new study by researchers at the University of California, Berkeley, raises such a possibility. It shows that healthy mice given only 5 percent fewer calories than mice allowed to eat freely experienced a significant reduction in cell proliferation in several tissues, considered an indicator for cancer risk. The key was that the mice eating 5 percent fewer calories were fed intermittently, or three days a week.
What is encouraging about the findings is that the reduction in cell proliferation from that intermittent feeding regimen was only slightly less than that of a more severe 33 percent reduction in calories. Until now, scientists have been certain only of a link between a more substantial calorie reduction and a reduction in the rate of cell proliferation.
The results of the study are scheduled to appear in the May 2005 issue of the American Journal of Physiology-Endocrinology and Metabolism, but are now available online.
"Cell proliferation is really the key to the modern epidemic of cancer," said Marc Hellerstein, professor of human nutrition in the Department of Nutritional Sciences and Toxicology at UC Berkeley's College of Natural Resources. Hellerstein is principal investigator of the study.
Cancer is essentially the uncontrolled division of cells, and its development typically requires the presence of multiple mutations. "Normally, a cell will try to fix any damage that has occurred to its DNA," said Hellerstein, "But, if it divides before it has a chance to fix the damage, then that damage becomes memorialized as a mutation in the offspring cells. Slowing down the rate of cell proliferation essentially buys time for the cells to repair genetic damage."
Cell proliferation contributes to carcinogenesis in a number of other ways, as well, collectively termed "cancer promotion."
Studies over the past 70 years have established that substantial calorie reduction - up to 50 percent in some studies - not only can reduce the rate of cell proliferation, it can extend the maximum life span of a variety of organisms, including rats, flies, worms and yeast. The results can be dramatic, with 30 to 70 percent increases in life span reported in the studies.
"Significant caloric restriction is the one and only thing that has been scientifically proven to extend life span," said Hellerstein, who has a joint appointment at UC San Francisco. He noted that while exercise and good nutrition can prevent premature death by disease, they have not been shown to extend a maximum life span.
Cutting calories has also been shown to reduce the development of cancer, enhance insulin sensitivity and lower the risk of heart disease.
Yet, as remarkable as those studies may be, their applicability to a human diet is clearly limited. The researchers refer to an old joke that goes along with the findings on caloric restriction: "It's not that you're living longer, it just feels that way."
No doubt, one would be hard pressed to find people willing to embark on what amounts to a lifetime of food deprivation, so the prospect of a more viable intermittent-feeding pattern is appealing.
"What we found is that it may not be necessary to severely restrict calories to reap some of those health benefits," said Elaine Hsieh, a UC Berkeley Ph.D. student in molecular and biochemical nutrition and lead author of the study. "Cutting just a few calories overall but feeding intermittently may be a more feasible eating pattern for some people to maintain."
The researchers conducted several trials with a control group of mice that ate "ad lib," or freely. They compared the control group with mice that ate 5 percent fewer calories but were fed three times a week with mice that were given 33 percent fewer calories. Trial periods ranged from two weeks to three months.
As expected, the researchers found that mice on the 33 percent reduced calorie diet exhibited significantly decreased proliferation rates for skin, breast and T (lymphocyte) cells. The greatest effect was seen after one month on the regimen, when proliferation of skin cells registered only 61 percent of that for mice fed freely.
The surprising finding came with the results of the more modest 5 percent reduced calorie diet that was fed intermittently. Mice in this group had skin cell division rates that were 81 percent of those for mice fed freely.
In all cases, division rates for breast cells were reduced the most. Mice with the lowest calorie diet had breast cell proliferation results that were only 11 percent of those for the control group mice, and mice fed intermittently had results that were 37 percent of those for the control group.
The researchers said this may be partly related to the reduction in estrogen, which stimulates breast cell division. Tests revealed that the estrus cycle stopped for mice on the lowest calorie diet. The mice fed intermittently, on the other hand, continued to cycle regularly.
Results of the refeeding trials indicated that any weight lost during the calorie restriction period was regained once a normal feeding pattern was resumed.
"Overall, we found that the effects of the diet regimens were rapid and reversible, with cell division rates and weight going back to normal after refeeding," said Hsieh. "Although it's too early to say whether similar results would be seen in humans, this study at least provides some hope that another option to severe calorie reduction exists."
"A five percent reduction in calories would be the equivalent of reducing about 100 calories a day in a human diet," said Hellerstein. In other words, for the mice, intermittent feeding seemed to provide similar gain with a bit less pain than a more restrictive diet.
Hellerstein noted that animals in the wild regularly go through cycles of too much and too little food, though not by choice. Major predators, such as lions, may go days without eating and then binge when they make a successful kill. "It may be normal to have periods where we are not eating," said Hellerstein. "But in domestic life, there generally is continuous access to food."
It goes without saying, however, that there is more to changes in eating patterns, such as fasting, than just the physical effects. Both scientific and anecdotal evidence indicates that eating also can impact one's mental state and emotions.
A recent pilot study of 16 non-obese adults by researchers at the Pennington Biomedical Research Center in Louisiana found that eating only every other day was feasible when the participants successfully followed an alternate-day fasting regimen for three weeks. However, the people also reported feeling hungry and irritable on their fasting days.
The authors of the pilot study said that adding a small meal, fulfilling no more than 20 percent of the day's caloric needs, might just take the edge off and make the feeding pattern more palatable.
Notably, the UC Berkeley study is the first to actually quantify the effects of calorie manipulation on cell division. The researchers did so by using heavy water, which is chemically identical to regular water but is about 10 percent heavier because of an extra neutron.
Hellerstein's laboratory pioneered the use of heavy water as a biological marker for cell proliferation. Because heavy water is incorporated into the DNA of new cells, researchers can compare the mass of DNA from tissues in experimental animals to tissues from control animals. They would know that any differences in DNA mass would be attributed to new cells.
"The significance of this labeling is that it allows researchers to accurately gauge the effects of relatively small changes in diet, such as a five percent reduction in caloric intake," said Hellerstein. "Moreover, humans and animals can safely drink heavy water with no ill effect. Everything we did in our study with mice could be safely replicated with humans."
Christine Chai, a UC Berkeley undergraduate student in nutritional sciences and toxicology, also co-authored this study.
The research was funded by a UC Berkeley College of Natural Resources Agriculture Experimental Station award.
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