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Despite the national propensity for fad diets and miracle
health cures, despite the ubiquitous talk of "eating healthy"--a concept so mercurial that every decade brings a new definition--only
a single dietary regime has ever been conclusively demonstrated to extend the life span and improve the health of laboratory animals, let alone humans.
It is known in the scientific lingo as "caloric restriction" or "calorie restriction" and less technically as "eating considerably
less than you might normally prefer"--perhaps 30 to even 50 percent less. In other words, an average-size human on a calorie-restricted
diet might consume 1,500 calories a day, compared with the 2,100 calories of the typical American. It's four or five small
meals a day, predominantly vegetables and fruits, and a life in which you are perpetually cold, painfully thin and constantly
hungry. Calorie restriction, quite simply, is a Draconian diet and a lifelong one at that. "It requires a psychological profile
only one person in 1,000 has," says Richard Miller, associate director for research at the University of Michigan Geriatrics Center.
Nevertheless, the study of calorie-restricted diets has lately
become a hot-ticket item among longevity and nutrition researchers, who have taken to extolling its virtues with remarkably
unrestrained enthusiasm. Their reasons are clear--the list of the beneficial effects of calorie restriction in laboratory
animals reads like the packaging on a miracle cure. Calorie restriction will, for instance, increase both average and maximum
life spans, and the fewer calories consumed, the greater the increase; it will reduce the occurrence of virtually all age-related
diseases, including heart disease, diabetes and cancer. It will prevent kidney disease and cataracts as well as the development
of Parkinson's and Alzheimer's diseases. It will lower blood cholesterol and forestall the age-related deterioration of the
immune system. In mice, calorie restriction from an early age raises the maximum life span from 39 months to 56 months and at the same time preserves what
passes for intellectual function: a three-year-old calorie-restricted mouse, for example, can negotiate a maze with the quickness
and ease of a normally fed mouse of six months, which is the mouse version of salad days.
This harsh regime has been shown to work its life-extending
magic on almost every species that's ever been tested--from paramecium and worms to spiders, insects, rodents and (although
the data are still preliminary) primates. The two caveats are that the later in life the animals start on caloric restriction,
the less the benefit, and that the diets must include plentiful amounts of vitamins and minerals. The animals must be undernourished
without being malnourished, as calorie-restriction researchers say.
All
of this, though, leaves researchers struggling to answer three key questions: What exactly does calorie restriction do physiologically
to extend longevity and fight off disease? Will it have the same effect in humans? And, if so, is there a way to get the benefits
without the actual diet? "The purpose of studying calorie restriction," Miller says, "is not to develop yet another diet that
people won't follow." Rather researchers would ideally like to concoct a pill or potion that will mimic the effects of calorie
restriction and produce the benefits while allowing us to eat to our heart's content.
In the 65 years since Clive M. McKay of Cornell University
first noticed that the regimen doubled the life span of his lab rats, and in the decade or so since calorie restriction moved
from the fringes of longevity research to the mainstream, much of the laboratory work has been aimed at discerning the fundamental
biology underlying the beneficial effects. What researchers generally agree on is that the response to calorie restriction
in organisms seems to be an evolutionary adaptation to periods of scarcity. As food becomes hard to find, organisms evolve
ways to "up-regulate" those defense mechanisms that increase life span and down-regulate reproductive mechanisms. That would
keep the organisms alive long enough to find food, and at that point they could go back to reproducing and to a normal aging
process, which is exactly what happens in the laboratory.
The question of how this might work is still open. The leading
hypothesis is that calorie restriction reduces the amount of oxidative damage to the body. Oxidative damage is the foremost
theory as to what causes the deterioration that comes with age. The concept is known in the business as the "oxygen paradox":
we require oxygen to turn the food we eat into cellular fuel, but the side effects of this oxygen metabolism are detrimental
to our health. The process takes place in cellular factories called mitochondria, where electrons are stripped from energy-rich substances--in
particular, glucose--while converting them to the kind of fuel that cells can use.
The electrons are then captured by oxygen atoms, which join
with hydrogen to form water. But the process is inefficient, and the electrons often go astray, resulting in the formation
of highly reactive molecules known as free radicals. Roy L. Walford, a gerontologist at the University of California at Los Angeles
and a pioneer of calorie-restriction research, refers to free radicals as "great white sharks in the biochemical sea--short-lived
but voracious agents [that] oxidize and damage tissues."
The oxidation that occurs in the human body is identical to
the way in which rust is formed in metals, so it is not unreasonable to say that we will all eventually rust to death if given
the opportunity. The free radicals damage the tissues but also seem to damage the genetic material, the DNA, that codes for
the proteins required for the body's physiological functions. The primary candidate for most of this damage is the mitochondria
themselves, which are not spared by the free radicals they produce. And once damaged, they produce even more free radicals.
Calorie restriction, by this theory, reduces the amount of
fuel available for cells and the amount of oxygen needed by the mitochondria to convert the existing fuel into energy, and
it makes the existing metabolic process more efficient. Not only do the mitochondria generate fewer damaging free radicals,
but the lack of food also seems to up-regulate the production of enzymes that neutralize the free radicals.
In one of the more fascinating experiments in the field, Richard Weindruch and Tomas A. Prolla of the University of WisconsinMadison recently compared the
expression of genes in young mice, normally fed aging mice and calorie-restricted aging mice. Weindruch,
who has been studying calorie restriction since he was a U.C.L.A. graduate student in the mid-1970s with Walford, believes that the process lowers oxidative stress and damage
to the mitochondria while having its effect predominantly in "critical target tissues" such as the brain and nerve cells and
heart and skeletal muscle. "All these tissues depend heavily on mitochondrial energy metabolism to generate cellular energy,
and all these tissues have fairly limited repair capabilities," he says.
Weindruch and Prolla examined tissues from the calf muscles of mice and found that
normally fed aging mice were putting most of their genetic effort into repairing genes and proteins damaged by stress, of
which a good part is oxidative damage. The active genes of calorie-restricted mice, on the other hand, were much less involved
in genetic repair and much more involved in biosynthesis--building new proteins and other cellular components--just like the
mice in the prime of their lives.
Most researchers buy the oxidative-damage theory of calorie
restriction, but they disagree on two controversial aspects. One is whether calorie restriction actually lowers metabolism
to achieve its goal, in which case the relevance to humans might be lessened--do we have to go into something akin to hibernation
to get the benefits of calorie restriction? The second question is whether lowering metabolism is the primary route that allows
calorie restriction to achieve its effect on longevity.
The fact that calorie-restricted rodents have body temperatures
that are considerably lower than normal implies that the benefits of calorie restriction come about because the less food
eaten, the lower the metabolism and, hence, the lower the oxidative damage. "It's known that rodents can decrease their body
temperature, their metabolic rate, and that [that] is how they survive famine periods," says Rajindar S. Sohal, a biologist at Southern Methodist University.
"But mice and rats are not humans. We don't have that mechanism."
Other researchers, however, disagree with this interpretation of the evidence, and the argument often comes down to a dispute
about how best to measure metabolism in normally fed versus calorie-restricted animals. "It's a distinct oversimplification
to say that the calorie-restriction phenomena are merely due to a decline in metabolic rate," Miller comments. "And many of
the changes that occur in calorie-restricted rodents are hard to explain by the idea that fuel and oxygen consumption go down."
A Shot of Hormones
That there is more going on is suggested by the work of James F. Nelson, a physiologist at the University of Texas Health Science Center
at San Antonio. Nelson and his colleagues have shown that calorie restriction subtly raises the levels of hormones called
glucocorticoids. These hormones do "probably a zillion different things" in an organism, Nelson says, of which researchers
have nailed down only a few. Their primary function is to mobilize glucose from the liver to provide fuel to the muscles during
periods of stress or during a şight-or-fight response. "They also mobilize glucose to help you get through a fasting stage,
to keep blood sugar high enough so you can keep going to your next meal," he says. These hormones, too, serve to fight inşammation,
hinting that they play a direct role in the survival of the organism. And glucocorticoids are only one of a host of hormones
in laboratory animals that seem to be affected by calorie restriction.
The Human Question
Nelson and his colleagues are currently testing lab animals
to find out if the hormonal changes in calorie-restricted animals are a side effect of calorie restriction or a mechanism
that directly leads to longevity. In one experiment, for instance, Nelson's laboratory is spiking the drinking water of lab
mice with glucocorticoids to determine if the mice live longer. "The next thing would be to see if any of these effects are
translatable to humans," he asserts.
The human question is the big one. The existing data on humans
are very thin. Most human populations that are forced to survive on low-calorie diets are also malnourished and are as likely
as not to die prematurely from vitamin and mineral deficiencies. The only known exception is on the Japanese island of Okinawa,
Walford notes: "The Okinawans have about 70 percent of the calorie intake of the rest of Japan. They eat mainly fish and vegetables.
They have as much as 40 times the incidence of people over 100. They have less diabetes, tumors and so forth than the rest
of Japan."
On
the other hand, he adds, there could be numerous other factors that contribute to the Okinawans' longevity. Doing a controlled
trial of calorie-restricted humans is impractical for what David B. Allison, an obesity researcher at St. Luke's-Roosevelt
Hospital Center in New York City, calls "the obvious reasons": researchers would have to convince hundreds or thousands of
humans to spend the better part of their lifetime living on an extreme diet, without being able to promise them benefits.
And the trial would, by definition, take the better part of a century to complete.
Instead the National Institute on Aging (NIA), in collaboration
with Weindruch and his colleagues, is testing the calorie-restriction proposition on rhesus and squirrel monkeys, assuming
that if it works for any primates, it's a good bet it would work for humans. They now have some 200 monkeys in the trial,
half on a calorie-restricted diet and half eating normally. Even these monkeys are likely to live 30 or 40 years, so the study
is a long-term endeavor. But the calorie-restricted monkeys are already showing signs of unnaturally robust health.
With so little information on whether calorie restriction
will benefit humans, researchers have barely touched on how to mimic its effect without going on a diet that could take the
fun out of living, and certainly out of eating, for almost anyone willing to try it. One possibility, Allison says, is to
give all people, not just the excessively overweight, antiobesity drugs. This would suppress appetite, but a healthy unsatisfied
appetite may be a necessary factor in convincing an organism that famine has arrived and thus stimulate the beneficial effects.
"That this might lengthen life is real speculation, and it goes far beyond any data," Allison observes. "We've never demonstrated
in humans that antiobesity drugs even make the obese live longer, let alone the average-weight person."
At the NIA, George S. Roth, Donald K. Ingram and Mark P. Mattson
are trying another tack--fooling cells into thinking they've been fed when they haven't. They're using a compound called 2-deoxy-D-glucose,
which is virtually identical to glucose but lacks two oxygen atoms. Once inside the body, it goes where glucose would normally
go, but it can't be metabolized by the cells. The compound is synthetic, relatively inexpensive and has been used in research
laboratories for years. It's also mildly toxic in high enough doses, however, which makes it a debatable intervention for
humans even if it works. The researchers gave moderate doses to rats for six months--not long enough to establish whether
the compound increased longevity but long enough to see if it might. With the 2-deoxy-D-glucose added to their diet, the rats
continued to eat the same amount of calories, and yet they lost weight and their body temperature dropped, as it would have
had they been dieting. Their insulin levels also dropped, another hallmark of calorie restriction. This convinced the NIA
researchers that 2-deoxy-D-glucose was worth testing for the lifetime of the rats, a study that's ongoing. If the rats do
indeed live longer, the NIA researchers will at least have proved that the mimetic phenomenon, as they call this calorie-restriction
mimicry, has promise. "Then we'll look for other kinds of compounds that exert the same effects without any toxicity," Roth
says. That would mark a big step toward the ultimate goal of letting people have their cake and live longer, too.
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