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From yeast to monkeys, dietary restriction extends health and lifespan. But can it work in humans?

This article first appeared in the St. Louis Beacon, May 3, 2010 - As the average American has grown fatter, researchers have been investigating the effects of severe calorie restriction on the lifespan and "healthspan" of organisms, ranging from yeast, worms, fruit flies, mice, monkeys to, most recently, humans.

Locally, Washington University is one of three institutions in the "Calerie" study. An acronym for the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy, Calerie is a clinical trial funded by the National Institutes of Health with participants at Washington University, Tufts in Boston and the Pennington Biomedical Research Center in Baton Rouge.

The 30-year gap

According to Dr. Luigi Fontana, a co-investigator on the Calerie study at Washington University, a large gap exists between people's average lifespan and the age at which they cease to be healthy.

"The average lifespan in the United States is about 80. But the average healthy lifespan is around 50," Fontana said. "So there is a 30-year gap where people are sick. They require medications, surgical interventions, and so on. This gap will increase soon because of the epidemic of obesity," he said.

While calorie restriction is not guaranteed to increase human lifespan dramatically, it may lengthen the period of time that people stay healthy, improving quality of life and closing the 30-year gap. In people, calorie restriction has been shown to reduce insulin resistance, inflammation, cholesterol, and blood pressure, among other markers of disease.

The goal of this study is not to investigate weight loss (they do not enroll the very overweight), but to study the way reducing calories by roughly a quarter changes the molecular pathways that cause aging -- and lead to healthier and possibly longer lives. A remarkable aspect of this research is that the aging pathways that calorie restriction shuts down are largely the same across animal species, from mice to monkeys to people.

According to Fontana's article in the April 16 issue of Science, the common pathways shut down are those that sense nutrients like glucose and protein. Calorie restriction of 10 to 50 percent in animals reduces the activity of these pathways and increases lifespan. In addition, animals with genetic mutations that shut down these pathways show similar longevity and similar protection against age-related diseases, such as cancer, cardiovascular disease and cognitive decline.

Fontana says these molecular pathways may have been conserved through evolution because they help organisms of any size and complexity survive periods of starvation. Of course, surviving periods of starvation is hardly a problem in America today. At a time when high-calorie foods with low nutritional value are abundant and heavily advertised and most Americans eat more than they need, who volunteers to restrict their diet?

The participants

"Our participants are mostly interested in health," said Kathleen Obert, a dietitian and nutritionist at Washington University. Some participants have parents with diabetes or heart disease and hope to avoid the same problems, she said. Some want to lead active lives and avoid the weight gain that might limit their mobility, Obert said.

Patricia Ivey had her kids in mind when she signed up. "I am one of the older moms," said Ivey, 46, of Ballwin, whose kids are in the 3rd and 5th grade. "When I heard it was a study about slowing the aging process, I found that interesting for me in my situation. I'm trying to maintain my health as much as possible, so I'm around and active," she said. "And of course one of the nice side effects is weight loss," she added.

At the beginning of the two-year program, participants can range from normal weight to slightly overweight, with body mass indexes between 22 and 28. The investigators calculate the number of calories each participant burns in one day. Each person's baseline is then reduced by 25 percent and this becomes the target number of calories they should be consuming daily. Obert calls it the calorie prescription. Ivey's daily prescription was 1,800 calories. Investigators felt a 25 percent reduction in calories was large enough to show an effect and achievable for the participants.

Ivey has certainly seen the effects, losing 38 pounds over the course of the two years. Other measures of health improved as well, such as blood pressure, she said. She completed the study about four months ago and says she is continuing to try to meet her calorie prescription each day. She no longer formally logs her calories, "but I mentally find myself doing it," she said. "Because I was doing it for two years, I have an idea of how many calories are in what I commonly eat. It's almost automatic for me now," she said.

On a typical day, Ivey said she might have non-fat yogurt with fresh fruit, honey, and almonds for breakfast, a frozen entree with some additional frozen vegetables for her work lunch, and whatever the family eats for dinner, such as chicken or fish with vegetables and a starch. At dinner, she makes sure half her plate consists of vegetables (about 1 cup), and the other half of her plate is divided between the protein (a 4 ounce piece of chicken, for example) and the starch. For snacks, she has a granola bar or fruit or a small piece of chocolate.

"I'm a bit of a chocoholic, so I couldn't give that up," she said. "It was never about deprivation," she added. "They never dictated what I could or could not eat. If I felt like ice cream one day, I had ice cream. I just counted for it. It was more about portion control and staying in that alloted number of calories you were given."

The study gathers new participants on a rolling basis and Brad Beggs, 42, is half way through his two-year stint. At the beginning, they determined that Beggs, nearly six feet tall and 200 pounds, burned about 3,100 calories a day. The 25 percent reduction put his prescription at 2,300 calories. One year later he's lost about 30 pounds and is approaching "weight stability," where participants reach a plateau. To maintain this weight, participants must concentrate on meeting their calorie prescription as closely as possible or they will start gaining the weight back.

"I thought it would be harder than it has been," Beggs said. "If you make it more of a lifestyle change, it's easier." He explained that he's given up high calorie drinks like soda and even milk. "I eat a dramatically larger amount of fruits and vegetables. I'm talking about a pound or more of fruit for breakfast," he said. Like Ivey, he adds yogurt (half a cup of full-fat plain), granola, and nuts to the fruit (both fresh and frozen, depending on the season). Such meals reflect the wisdom passed on from the study investigators -- foods higher in protein, fiber, and even a little fat help you feel full longer.

Weight maintenance and support

During the weight loss period, Obert said, there is a bit more flexibility in calorie consumption. As long as they have a deficit of calories, even if it's slightly more than the calorie prescription, their weight will go down. "But as they get to weight maintenance, even 50 calories more will show up as a weight gain," Obert said. In the second year, she said "we work a lot harder" to fight off that tendency to regain.

Participants have a lot of support throughout the study. The study provides new participants with meals for the first few weeks to help them understand portion control and menu planning. After that the participants plan and fix their own meals. But if they run into difficulty, such as at the one-year mark when weight loss slows down, the study can again provide meals to help get them back on track.

They also meet with behavior therapists to help navigate any mental and social roadblocks. Cherie Massmann, a licensed professional counselor at Washington University, says she helps people stay motivated. People rarely have problems with hunger, she said. Instead, people may find some social situations difficult -- going out with friends or attending a wedding while sticking to their calorie prescription.

While some participants will continue the diet after the two years is over, she said, many may miss the accountability of the study. "Those who haven't built a good support system outside the study may face more challenges with it," she said.

The accountability is intense, especially early on. "The first month, they come twice a week," said Massmann. One session is with a dietitian to learn portion control, and the second session is with the dietitian and the behavior therapist to talk about the study and get support. Then, until the six month-mark, they come every week alternating between individual and group sessions. There are also periodic clinical tests, including overnight stays in the hospital. Toward the end, participants come in two times a month. "But we found that that's not nearly enough contact," said Massmann. "Most people needed more. They wanted to come in for a mid-month weigh-in. They wanted to talk to us on the phone. And those who asked for a little bit more support did a little bit better," she said.

"I couldn't have done it without their support," said Beggs, who is pleased with the results so far. Twice over the course of the first year he has bought new, smaller, clothes.

A word of caution

While trying to improve personal health is an admirable goal, Fontana does not recommend severe calorie restriction (about 25 to 30 percent) for normal-weight people unless they are monitored by an expert. "They can run into malnutrition," he said.

Even among their closely monitored participants, Obert said, they occasionally see problems such as a decrease in red blood cell count or a decrease in bone density. If bone density is too low, for example, they slow the person's weight loss and increase calcium and vitamin D, she explained. "These situations have all corrected themselves," Obert said of any problems found in the participants. "But just doing it on your own, without some kind of medical supervision is not the wisest idea," she said.

But for people who are overweight or obese, Fontana calls calorie restriction necessary. Of course, calorie restriction for the overweight is just weight loss. Getting down to a normal weight will certainly improve markers of health, but it is not sufficient to shut down the aging pathways seen in calorie restriction in normal weight people.

With one year left, Beggs remains enthusiastic about the study and even has plans to target a calorie prescription slightly lower than his 2,300 to ensure that he doesn't start to edge back up. And after his two years are up, will he continue to try to meet his calorie prescription? "I have to," he said with a laugh. "I gave away all my other clothes."

Julia Evangelou Strait is a freelance science writer based in St. Louis. 

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