11th May 2004
THE WALL STREET JOURNAL
If there were a magic elixir that extended life to 150 years,
most people would drink it gladly. But as scientists begin to uncover
the secrets of longevity, they are finding a prescription for long
life that few will want to take: a diet so low in calories that to
most Americans, it would feel close to starvation.
The diet, dubbed "calorie restriction" in the clinical
parlance of science, would be called severe deprivation in any other
lexicon. Calorie restriction was first shown to create exceptionally
long-lived rats in the 1930s. It later had the same effect in guppies,
water fleas,
yeast, spiders and a microscopic water invertebrate called
the rotifer. Last month, Labrador retrievers became the first large
mammals to join the list.
Now, scientists appear on the verge of a finding that calorie
restriction also extends the lifespan of monkeys, who share more than
90% of their genes with humans. At the National Institutes of Health,
where researchers have been studying a colony of 120 rhesus monkeys
for 15 years, evidence for calorie restriction is mounting. The
control animals, fed a healthy lowfat diet, are dying at a normal
rate, while animals fed 30% less appear to be living far longer -- and
avoiding age-linked maladies. One of the underfed monkeys is 38 years
old, the human equivalent of 114 years.
"Calorie restriction has worked in every species in which it has
ever been tested," says Massachusetts Institute of Technology
biologist Leonard Guarente. "I'd be shocked if it doesn't work in
humans."
Catalyzing Change
Calorie
restriction appears to create biochemical changes in the body that
have a more-profound effect on lifespan than simply avoiding diseases
caused by excess fat. No one knows for sure how it works. It might
lower the levels of free radicals, or potentially toxic particles
created by the breakdown of food. Other scientists believe it triggers
a state of emergency called "survival mode" in which the
body eliminates all unnecessary functions to focus only on staying
alive.
If scientists could figure out what the changes are and bottle them as
a drug, "we'd have it made," says Roger McCarter, a
scientist at the University of Texas Health Science Center in San
Antonio.
Encouraged by the animal research, the NIH plans to spend $20 million
to test the effects of calorie restriction on hundreds of Americans.
Some people have seen enough evidence already and have started
self-depriving. Bob Cavanaugh, a 54-year-old landscaper from Morehead,
N.C., has trimmed his intake to two meals a day, totaling 1,500
calories. Breakfast consists of one cup of quick oats, two tablespoons
of toasted wheat germ, one cup of skim milk and blueberries. For
dinner, he eats vegetables, fruit and a small portion of fish.
"I'm hoping to see my great, great grandchildren," he says.
Mr. Cavanaugh's diet may sound extreme, particularly since at 5-feet
9-inches tall and 158 pounds, he isn't overweight. But over the next
several years, if the monkey results hold up, they could represent a
major shift in how we view food and nutrition. The U.S. Department of
Agriculture says the average sedentary woman should eat 1,600 calories
a day and the average man 2,200 -- benchmarks already significantly
overshot by most Americans.
Minimal Intake
But those guidelines are based on ideal weight, and a
calorie-restricted diet has nothing to do with weight. Rather, the NIH
monkey experiments limit food intake to the minimum necessary to
prevent negative effects on health -- or at least 30% less than the
current "healthy" diet. Translated into human terms, that
would be 1,120 calories a day for the average woman, or 1,540 for a
man.
For the average American, eating at that level would create deep
hunger pangs. One meal at McDonald's -- a Big Mac, supersize fries,
and small Coke -- weighs in at 1,450 calories. And if a woman on 30%
calorie restriction had a cappuccino and a large muffin during her
morning commute, she would already have consumed 75% of her allocation
for the day, says Cathy Nonas, director of the Van Itallie Center for
Nutrition and Weight Management at St. Luke's-Roosevelt Hospital in
New York.
In the NIH tests, which will last as long as three years, volunteers
will be asked to cut their current intake by 20% to 30%. Since many of
those chosen will likely be overeaters, theirs will be a modest effort
by comparison with the NIH monkeys. Still, to ensure compliance, the
Pennington Biomedical Research Center in Baton Rouge, La., will
initially require volunteers to eat only food provided by the
scientists -- and two of the three daily meals must be eaten in the
laboratory cafeteria. Scientists will catalog the test subjects'
metabolism and other biochemical markers, such as blood sugar, lipid
levels and body temperature.
The goal of the tests, says Evan Hadley, head of geriatrics at the
National Institute on Aging, is to give scientists insight into how
deprivation changes body chemistry. Residents of developing countries
eat very low calorie diets. Their nutrition is so poor, though, that
any positive effects are masked by medical problems caused by
malnourishment, scientists say. But a study of the Japanese island of
Okinawa -- whose 1.3 million inhabitants have traditionally eaten a
spartan, but nutrition-packed diet of about 1,800 calories a day --
provides some evidence for calorie restriction.
On Okinawa, where the diet consists of soy, vegetables and small
amounts of fish, meat and rice, there are 34 centenarians for every
100,000 people -- more than triple the U.S. rate, says Bradley Willcox,
a gerontologist at Beth Israel Deaconess Medical Center in Boston. The
oldest person in the world, 113-year-old Kamato Hongo, lives on a
nearby island, he adds.
The Okinawa data fall short of a controlled experiment, because
genetics or other factors could be at work. In rats, the effects of
calorie restriction have been shown repeatedly, and they are dramatic.
University of Wisconsin researcher Richard Weindruch says that broadly
speaking, a 30% calorie restriction results in a 30% increase in
maximum lifespan. Translated into human years, that would mean that
the oldest members of the species would make it to about 150 on such a
diet.
Even more striking is that the caloric intake of the rat, not its
weight, matters most. Well-fed rats kept lean by regular exercise are
less likely to die prematurely of disease than well-fed sedentary rats
-- but their maximum lifespan remains the same.
Primates, similar enough to humans that they have been used to study
everything from congenital vision defects to Alzheimer's disease,
remain the gold standard for proof when human experiments aren't
practicable. But monkeys haven't been easy to study, because they live
to be around 25, compared with three years for rodents.
At the NIH facility in Poolesville, Md., in a bucolic area about 40
miles from downtown Washington, scientists are growing increasingly
excited about the results they are seeing. The experiment began in
1987, with monkeys of various ages. They were divided into two groups.
One group was fed a normal low-fat diet, equivalent to the healthy
diet recommended by nutritionists for humans. The other group received
30% less than that, or just barely enough to stave off starvation.
And that's the group that's thriving. Today, 14% of the
calorie-restricted monkeys have died, compared with 22% of the monkeys
on the normal healthy diet, says Mark Lane, a co-investigator on the
study. Those figures exclude monkeys whose deaths were deemed
accidental, such as when a batch of overcooked food caused a fatal
stomach ailment called gastric bloat.
"We're very excited," says Dr. Lane. "We think it's
working."
Healthier Monkeys
Not only do the calorie-restricted monkeys appear to be living longer,
they also seem to be healthier. Only 14% of them have developed an
age-related disease, such as cancer, cardiovascular disease, diabetes
or failing kidneys, compared with 32% in the control group, Dr. Lane
says.
Also, calorie restriction staved off the normal age-related decline in
a multifunctioned hormone called dehydroepiandrosterone sulfate. DHEA,
sold as a dietary supplement, has touched off a craze among Americans
even though many scientists say there is no proof it will forestall
aging.
It's too early to predict what the maximum lifespan will be in either
group. But one of the calorie-restricted monkeys, a rhesus from Indian
stock who goes only by the name given him by his breeders, C58, turned
38 in January.
That makes him one of the oldest rhesuses ever recorded. The
University of Wisconsin, widely believed to have housed the
oldest-ever rhesus, says the oldest monkey for which it had a firm
date of birth lived to be 36. Another animal, still alive but without
a well-documented birthdate, is believed to be about 39 years old.
Neither of those monkeys were on calorie-restricted diets.
C58 looks thin but not gaunt. He weighs 17 pounds, compared with an
average of 24 pounds for elderly control monkeys. Other than a touch
of arthritis and a cataract, he appears in excellent health. Each day,
he eats about 3.7 ounces of monkey chow -- dried pellets compressed
from wheat, corn, soybean, alfalfa, fish and brewer's yeast.
In his younger days, scientists say, C58 was an aggressive "alpha
male," reaching out of his cage to grab passersby. But he's
mellowed in his old age. On a recent day, he sat quietly, munching
contentedly on a handful of chow and gazing out of his cage with mild
curiosity.
A small group of humans are practicing C58-style calorie restriction
in the hopes that it will provide a fountain of youth. These people,
who communicate through an online chat group with 800 participants,
call their philosophy "Calorie Restriction with Optimal
Nutrition." Its practitioners, who dub themselves Cronies, follow
their own personalized diets, which share the common goal of minimal
calories.
For information and resources visit www.calorierestriction.org
Many draw their inspiration from the Biosphere 2 project in the early
1990s. Volunteers attempting to live a self-contained existence in a
glass-enclosed community were forced to reduce their calories sharply
when food became unexpectedly restricted. One of the volunteers on
Biosphere 2 was Dr. Roy Walford, a scientist at the University of
California Los Angeles who is one of the pioneers of calorie
restriction.
Michael Rae, a six-foot-tall 31-year-old from Calgary, Canada, weighs
a gaunt 115 pounds after three years on a strict calorie-restricted
diet. "I'd much rather weigh 50 more pounds, but I want to live
longer and this is the only proven way to do it," says Mr. Rae.
"Every calorie you eat is a second off your life."
Cronies monitor their vital signs carefully. Like the Biospherians,
their blood sugar, weight, blood pressure and cholesterol levels have
dropped. They draw hope from the fact that they have few colds and
flus, and that their bodies seem to be changing in ways similar to
animal models. For example, just as the body temperature of rats and
monkeys drops with calorie restriction, Mr. Rae's has fallen to 97
degrees, below the normal human temperature of 98.6 degrees.
But many Cronies become irritable and snappish. Testosterone drops,
causing some of the
men to lose interest in sex. Several men have developed early
signs of osteoporosis -- a disease of brittle bones commonly found in
elderly women. One Cronie suddenly found himself severely anemic. He
had to start taking iron supplements and eating more red meat.
Families sometimes resent the enormous amount of time it takes to
maintain the Cronie lifestyle. For the most part, prepackaged food is
out -- because it would shoot the daily limit quickly, while providing
inadequate nutrition.
Dean Pomerleau, a 37-year-old technology entrepreneur from Wexford,
Pa., grows sprouts -- bean, alfalfa, broccoli, arugula and a dozen
other kinds -- in his basement. "If you like arugula, you'd
really like arugula sprouts," says Mr. Pomerleau, who is 5-foot-8
and weighs 127 pounds.
Terry, his wife, isn't enthusiastic. She told her husband the
time-consuming preparation of his giant salads was dirtying the
kitchen, he says. The solution: He spent $1,000 to build a
mini-kitchen for himself in the basement, adjacent to the sprout farm.
If scientists could discover what makes calorie restriction work,
people might be able to enjoy the same effect without the hassle, and
without the deprivation. One theory is that the lower body temperature
caused by near-starvation somehow extends life. In case low
temperature is in fact the secret, Mr. Rae avoids putting on a sweater
even when he feels chilly.
There is mounting evidence for another favorite theory -- that lower
food intake results in fewer free radicals, or unstable particles
created as a result of the breakdown of food. These particles can
seriously damage genes and proteins, resulting in potentially fatal
diseases. Advocates of this theory got a major boost when samples of
thigh muscles from the calorie-restricted monkeys at the University of
Wisconsin were shown to have suffered remarkably little free-radical
damage, says Dr. Weindruch.
NIH scientists have also found preliminary evidence for the
"survival mode" theory. The scientists found that human and
rat cells grown in the blood of calorie-restricted monkeys are
enormously resistant to heat and toxins -- suggesting there is
something in the blood that is fighting dangers aggressively.
Several groups of researchers are now racing to find which genes are
"expressed," or turned on, during calorie restriction. In
mice, the "gene-expression profile," or the list of genes
whose functions are turned on and off, is strikingly similar in
calorie-restricted animals to younger animals -- indicating that
calorie restriction may be directly reversing age-related biochemical
changes.
In monkeys, so far, dozens of genes have been found turned on or off
as a result of calorie restriction. But in preliminary data, the
gene-expression profile of the restricted monkeys doesn't appear to
mirror that of younger animals, says Stephen Spindler, a professor of
biochemistry at the University of California at Riverside.
By LAURA JOHANNES
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