Eat less live longer? Does calorie restriction work?

Mark Cummins wants to live as long as he can. So the 46-year-old Southern California accountant is doing the one thing that's been proven to dramatically increase longevity, at least in small animals: He's drastically cutting back on calories.

Cummins eats just 1,500 to 1,900 calories a day--the amount a slender, sedentary man who is five feet tall would need to keep his weight stable. Cummins is 6'2". What's the potential payoff? Twenty, maybe thirty more years. "I'm not sure if there's an afterlife," says Cummins. "In the meantime, I'll hedge my bets and try to get as much life out of this universe as I am able to."

Is calorie restriction the Fountain of Youth? and How practical would it be in a nation where two out of three adults can't even stay at a normal weight?

If you're a worm or a spider, a guppie or a hamster, or a mouse, a rat, or a dog the evidence is clear: Cut calories by 25 to 30 percent and you'll increase your lifespan by 10, 25, maybe even 40 percent. It helps if you haven't hit puberty when you start, though you'll also get some benefit if you begin in middle age.

The promise of calorie restriction (CR) is so intriguing that the National Institutes of Health is launching $20 million worth of research over seven years to study CR's effect on metabolism in humans. And pharmaceutical and gene therapy companies are scrambling to find out how people can get the benefits of calorie restriction without having to go hungry.

A few brave souls like Mark Cummins can't wait. They're willing to tinker with one of life's great pleasures now on the chance that it might pay off later.

Mark Cummins says that he has been eating from 1,500 to 1,900 calories a day for most of the last 14 years. That's 850 to 1,250 fewer calories than what most men his size should eat (he's 6'2" and weighs 175 pounds).

Cummins is not alone. He serves on the board of directors of the Calorie Restriction Society (www.calorierestriction.org), a small group of (mostly) men who hope to live far longer by eating far less.

Using a computer program, Cummins and his fellow members have each calculated exactly how much food they need to consume every day to get all the protein, vitamins, and minerals to stay healthy, while cutting back on their recommended calorie intake by 25 percent of more. (Most take a multivitamin for insurance.)

"The only way you can do this is by eating lots of fruits and vegetables," says Cummins. "I have it easier than many CR people, who spend one to three hours a day preparing their food. I eat pretty much the same food each day and I buy it ready-made."

One of Cummins's two main meals is a large salad that he assembles from the fixings he buys from local salad bars and tops off with pieces of fish, chicken, or tofu. "For the other one, I buy a 650-calorie vegetarian burrito that contains rice, beans, and vegetables, but no cheese or sour cream." That's pretty much all he eats. Every day.

Cummins and the others in the Calorie Restriction Society will never know whether their diets prolong their lives. Even so, they see some short-term benefits.

"My LDL [bad cholesterol] and my blood pressure are low, and my HDL [good cholesterol] is high," Cummins says. "And I know this is only anecdotal, but I feel full of energy and I think my mind and my memory are sharper than they've ever been."

Isn't he always hungry? "Hunger can be an issue," concedes Cummins. "But I'm not tempted by food all the time like some other CR people are." A survey of calorie restriction followers a few years ago found that all were hungry to some degree. Roy Walford, the University of California at Los Angeles pathologist whose pioneering research launched the CR movement, has acknowledged that it's not a diet for everyone.

"Walford is a kind of patron saint of CR," says George Roth, a senior guest scientist at the National Institute on Aging (NIA) in Baltimore. "He's the guy we credit with sparking today's interest in calorie restriction and in how it might apply to people."

The 79-year-old Walford now suffers from amyotrophic lateral sclerosis (ALS), of Lou Gehrig's disease, and no longer expects to come close to the age of 120 that he once predicted for himself. He blames his disease on a poisonous gas he was exposed to in Biosphere 2--the two-year experiment in the Arizona desert in the early 1990s that was supposed to simulate conditions in a space colony.

When the Biosphere environment couldn't produce enough food to give each of the eight inhabitants who were sealed in the colony 2,500 calories a day, Walford put them all, including himself, on an 1,800-to-2,200-calorie diet.

Six months on the calorie-restricted regimen produced dramatic results: Average cholesterol plummeted from 191 to 123, fasting blood sugar dropped from 92 to 74, blood pressure went from 109/74 to 89/58, and weight fell from 163 to 136 pounds (for the men) and from 134 to 119 pounds for the women)(1).

That's not all the diet did. Contemporary news accounts based on interviews with the participants described them as obsessed with food and meals.

"Hunger was an almost constant companion," said one. At mealtimes they would stare at each others' plates to make sure no one took a morsel more than his or her share. Dessert became a time to fantasize about the sweets they were missing. And the food in the movies they watched held them mesmerized.

OF MICE AND DOGS

Where did Walford get the idea to restrict calories? In the mid-1970s, he and his co-workers at UCLA found that laboratory mice and rats deprived of a full food ration, but not vitamins, minerals, or other essential nutrients, lived longer and aged more slowly than similar animals who weren't calorie deprived.

In the 25 years since then, "moderate calorie restriction has proven beneficial for prolonging life or slowing the progression of disease in essentially every species of animal that's been tested," says Roth.

For example, Labrador retrievers fed 25 percent fewer calories than other Labs throughout their lives lived about 15 percent longer and were in better health, according to research published last year by the Purina Pet Institute in St. Louis(2).

"It's the first study completed in an animal larger than laboratory rodents that proves the significant power that diet restriction wields in extending life," says Richard Weindruch, who studied under Roy Walford at UCLA before setting up a CR research program at the University of Wisconsin in Madison.

Longer life isn't the only benefit researchers have seen in calorie-restricted animals:

* Cancer. "Caloric restriction inhibits the growth of tumors in virtually every study done in rats or mice," says researcher David Kritchevsky of the Wistar Institute in Philadelphia. In one study, mice destined to develop tumors because of a genetic defect got fewer tumors when they were on a CR diet or a one-day-a-week fast--even when the restriction started late in life(3).

"Calorie restriction is the most potent, broadly acting cancer-prevention regimen in experimental cancer models," concludes Stephen Hursting of the National Cancer Institute.

One possible explanation: Calorie restricted animals have lower body temperatures than non-CR animals. And "at lower temperatures, the body may be more efficient at repairing damaged DNA," speculates Donald Ingram, acting chief of the Laboratory of Experimental Gerontology at the Gerontology Research Center of the National Institute on Aging (NIA).

In the Baltimore Longitudinal Study of Aging, a lower body temperature is one of the characteristics of men who live longer.(4)(Some members of the Calorie Restriction Society report typical body temperatures of 97[degree]F.)

* Insulin Sensitivity. Calorie-restricted animals have lower levels of insulin and blood sugar and greater insulin sensitivity, which means that their bodies need less insulin to control the sugar in their blood. And that reduces their risk of diabetes and cardiovascular disease. "Lower insulin levels are also characteristic of the men who are living the in the Baltimore Study of Aging," says George Roth.

* Brain cells. Mice susceptible to Alzheimer's or Parkinson's disease are slower to develop those conditions if they've been put on a CR diet. What's more, "If you restrict the calories of rodents, they'll perform better at learning and memory tasks later in life than rodents eating a normal diet," says Ingram.

But healthier rats and dogs with an extra couple of years to chase the postman aren't exactly proof that people who slash their calories will live longer. Evidence in monkeys would be more impressive.

MONKEYING AROUND

"Rhesus monkeys are the next best thing we have to doing a long-term human study," says Roth. "If you go by the DNA, they're 90 to 95 percent human, and they certainly have brains and patterns of disease more similar to people than rodents have."

In the late 1980s, both the NIA and the University of Wisconsin started studying calorie restriction in large colonies of rhesus monkeys.

* National Institute on Aging (NIA). Researchers are feeding about 60 control monkeys a normal diet that maintains a healthy body weight. "We took pains to make sure that they're not fat of pre-diabetic," says Roth. Sixty similar monkeys are being fed the same food, but with 30 percent fewer calories than are recommended for their age and body weight.

"Both groups are supplemented with vitamins, minerals, and trace elements to make sure they don't get short changed on micronutrients," says Roth. So far, the results are tantalizing. "Two control monkeys are dying for every one calorie-restricted monkey," says Roth. "Even the monkeys who started CR later in life are tending to out-survive the control monkeys, though this isn't statistically significant." (So it's possible that the longer lifespan of the monkeys who started calorie restriction in middle age is due to chance.)

"We're also seeing that they have about half the rates of diseases like cancer, cardiovascular disease, and diabetes," Roth adds.

Both groups of monkeys look and behave the same, according to Roth, with two exceptions: The calorie restricted monkeys tend to be shorter and thinner (especially if they started cutting calories before puberty)...and they get more excited at mealtimes.

* University of Wisconsin. In 1989, researchers started feeding young adult rhesus monkeys 30 percent fewer calories than they were eating before the study began.

"Our restricted monkeys are healthier than the conventionally red controls," says researcher Richard Weindruch. "They're much leaner, have lower levels of circulating glucose and insulin, and have greater insulin sensitivity."

Researchers caution that the monkey studies aren't complete, and that the promising results could change. The 25-year average lifespan of normal rhesus monkeys will be up for both the NIA and University of Wisconsin colonies during the next five years, so we should have some answers by then, notes Ingram.

MONKEY DO, PEOPLE SEE

"Calorie restriction has worked in every species it's been tried in, and it would probably work in people, too," says the National Institute on Aging's George Roth. But is "probably" enough to embark on a difficult and demanding experiment for the test of a person's life? "No," says the NIA's Donald Ingram. "We don't know for certain whether this kind of severe diet will have the same effect in humans. We differ from small animals in our metabolism and in how we develop and reproduce."

He points out that the rhesus monkeys at NIA don't go outside, play with other monkeys, or reproduce. "Who knows what would happen to them in the real world that has bugs, environmental dangers, and other animals?

"Until we know more, it's just too soon for us to say that we'll respond to calorie restriction in the same way with the same benefits."

The first step in finding out: "We're trying to see if CR is feasible for motivated people to do in a controlled scientific experiment," says Eric Ravussin of the Pennington Biomedical Research Center in Baton Rouge, Louisiana, the site for one of the upcoming human studies.

It hasn't been easy. After nine months of recruiting, Ravussin has found only 26 willing participants of the 48 he will need. And he's only looking for overweight people who are willing to cut a quarter of their calories, not normal-weight people who are willing to become underweight.

At Tufts University in Boston, researchers will also take overweight people and cut 30 percent of the calories "that they are currently eating to maintain their unhealthy weight," according to researcher Susan Roberts.

But by starting with overweight people, these first human studies may not be a true test of calorie restriction. Why not use volunteers who are normal weight? "We wanted to avoid any risks from excessive weight loss in skinny people as well as people with possible eating disorders," explains Ravussin.

"CR is going to be a struggle for people to do in our food-rich environment that's so unconducive to eating less," he says. "It may be possible for people to do on their own, but they would have to be very, very motivated."

That describes the members of the Calorie Restriction Society. Yet just 34 people have registered member profiles on the society's Web site.

An informal survey six years ago found that half the members thought their alertness had increased, and two thirds thought they didn't need as much sleep as before. But about half also reported suffering low moods or depression and hall thought that their sex drive had diminished. All reported occasional hunger and sensitivity to cold weather.

"The society attracts a certain kind of person," says member Mark Cummins. "They have very high IQs and they're introverted problem-solvers who can carry out intellectual tasks with a high degree of self-discipline and persistence." He adds that many work out of their homes, which gives them extra time to prepare meals.

THE FAST LANE?

Is it possible to reap the gains of calorie restriction without the pain? Perhaps. "Intermittent fasting may become an effective alternative to cutting back on calories every day," says Donald Ingram. His research group at the National Institute on Aging found that out by trying to make their lives a little easier. "Our lab workers didn't want to go into work every Saturday and Sunday to feed the animals, so they started going in only once and giving the mice two days' worth of food at a time," he recalls.

Eventually, Ingram and his co-workers discovered that an every-other-day feeding produced the same drops in cholesterol and blood pressure, and the same other health benefits as calorie restriction. It also prolonged the animals' lives.

"After some interval of no food, the body apparently switches on some protective defenses that produce the benefits we see from calorie restriction," Ingram explains. The National Institutes of Health is so intrigued by the discovery that it's considering a study of fasting in older people, he adds.

The other potential alternative to calorie restriction: a drug or other chemical that can trigger the same changes.

"It's clear from the research in animals that CR extends the lifespan through several major metabolic pathways in the body," says Pennington's Eric Ravussin. "If that's the case, then we should be able to develop drugs that produce the same effects."

"It's a very competitive field," adds the NIA's George Roth. "A number of companies are trying to develop drugs of substances derived from food that will mimic calorie restriction. Most of the research is proprietary right now, so we'll have to wait a few more years to find out if they've been successful."

The Bottom Line

* Calorie restriction prevents disease and prolongs the lifespan of every species of animal in which it has been tested. (Studies in monkeys aren't finished.)

* Studies in humans are just beginning, so researchers don't yet know the benefits-or risks-of calories restrictions.

* Researchers are looking at whether regular fastings or drugs offers the same benefits as calorie restriction.

(1) Proc. Nat. Acad. Sci. 89: 11533,1992.

(2) J. Amer. Vet. Med. Assoc. 220: 1315, 2002.

(3) Carcinogenesis 23: 817, 2002.

(4) Science 297: 811, 2002.