|It works for mice and fruit flies, but can ultra-low-calorie diets extend the life of humans?
Eric Tucker for Newsweek
Jan. 19 issue - If the world is divided into people who live to eat and those who eat to live, perhaps there ought to be
a third category for Brian Delaney. At 5 feet 11 inches and 139 pounds, Delaney, 40, is really, really thin. Thin, and
hungry. He limits his calories to 1,800 a day, in part by eating just two meals, except when he has a dinner date, in
which case that's the only meal he eats. After 10 years on this regimen—actually, he started out at 1,400 calories a
day, less than half of what the average American male consumes—he still experiences "the same pit in my stomach"
every afternoon, but now finds it "easier to deal with." Especially when he thinks of all the diseases he's avoiding. If
Brian Delaney is right, he may well have the last laugh on the rest of humanity ... sometime in the 22d century.
Delaney, a philosophy professor who lives most of the year in Sweden, is a pioneer in the tiny, controversial calorie-
restriction movement, which aims to prolong human life by cutting back on food to the point of bare subsistence.
The movement makes claims that go far beyond the commonplace observation that it's unhealthful to be fat.
Instead, a handful of zealots assert that extreme deprivation creates biochemical changes that slow the aging
process. In principle, this should increase not just individual life expectancy, but the human life span, the theoretical
maximum that the species can achieve. This is a claim that not even the most committed opponents of obesity would
make, and mainstream medicine is divided on whether Delaney and his thousand-odd followers are merely harmless
kooks, or dangerous kooks. Most doctors would be shocked that Delaney's quest for better health required him to
cut back on exercise. From the calorie-restriction point of view, food per se is a culprit, even if you subsequently
burn it off on the treadmill. Delaney used to run 20 miles a week, but now he's down to 10; he doesn't have the
calories to spare.
Yet Delaney, who is president of the California-based Calorie Restriction Society, might be onto something. The
case for calorie restriction (CR) rests on sound scientific evidence that has been accumulating since the 1930s,
when Cornell University nutritionist Clive McCay discovered that food-deprived rats lived longer and looked younger
than those who ate normally. The effect has been seen in animals from fruit flies to roundworms to mice: reduce
food intake by roughly a third, while maintaining adequate nutrition, and life span goes up by about 30 percent.
Human beings can live to around 120, so if the same holds true for them, they could in theory make it past 150. The
maximum effect is obtained only if you start restricting calories in infancy, a practice that, because it stunts growth
and delays puberty, is unlikely to take hold among people. Still, life-span increases of 10 percent to 20 percent have
been observed in mice who began restricted diets as adults. Delaney is philosophical about the question of dying,
conceding that he could get run over by a truck next week, perhaps while fantasizing about a chocolate-chip cookie.
But he thinks the prospect of another decade or two of life is worth some sacrifice.
What accounts for the strange phenomenon that semistarvation appears to prolong life? One theory is
that calorie restriction slows metabolism, the burning of glucose for energy. This effect—which presumably serves
the evolutionary purpose of conserving calories during periods of famine—is well known to dieters; as they eat less,
their metabolic rate drops, and it becomes progressively harder to burn off fat. It's clear that metabolism slows in
people on CR regimens; in one study, core body temperature dropped by one full degree. Metabolism, an essential
life process, is also a destructive one; it unavoidably produces free radicals, unstable molecules that can damage
the structures of living cells by the process known as oxidation. Antioxidant vitamins and supplements ranging from
vitamin C to green-tea extracts have been the rage for decades, although there is little evidence that taking them by
mouth has any effect on longevity; calorie-restriction diets take the more direct approach of reducing oxygenating
compounds at their source—a plausible, if equally unproven, mechanism for extending life.
But some scientists who have studied CR believe it has other, subtler effects as well. "Protective mechanisms [within
cells] begin to work better," says biologist George Roth, an authority on calorie restriction at the National Institute on
Aging. Monkeys on CR diets don't show the same changes in hormone levels as they age as those who eat normally
(although the experiments haven't gone on long enough to tell if the monkeys actually live longer). Blood-sugar
levels are lower, suggesting a decreased risk of diabetes. Even more impressive, CR diets appear to affect the
pattern of gene expression in mice. As animals age, certain genes seem to "turn off" while others become more
active. Gerontologist Richard Weindruch and geneticist Tomas Prolla, both of the University of Wisconsin at
Madison, found that CR diets suppress this process in mouse cells. "Seventy percent of the major changes in gene
expression were totally or partially prevented by calorie restriction," Weindruch says.
Still, no one has proved that CR can extend life in humans, and the practical problems in running a controlled
experiment are daunting. The first human tests are about to begin at three sites, but they will last only a year, and
confine themselves to studying the potential risks of calorie restriction and measuring indirect indicators of
morbidity, such as cholesterol, blood-sugar levels and free-radical damage. Evan Hadley, associate director of the
National Institute on Aging, which is sponsoring the experiments, says they won't be looking for direct effects on
longevity. "That," he says, "would be a very long trial."
And there are plenty of skeptics warning of possible side effects ranging from loss of bone density to loss of libido.
Dr. Michael Alderman, an epidemiologist at Albert Einstein College of Medicine, says the most recent data from a
major long-term human study showed that "the most powerful determinant of longevity is exercise. And if you're
burning more fuel, you need more food." Thomas Wadden, director of the Weight and Eating Disorders Program at
the University of Pennsylvania, says the classic study on calorie restriction, involving 20 healthy young men who cut
their food intake in half for six months, found many negative effects, including "marked signs of depression and
irritability." The subjects "were despondent, had very low energy and had lost the initiative to do things. They began
to hoard food, and when allowed to eat again, they indulged in binge eating." They did lose weight—almost a
quarter of their body weight—but, Wadden says, "it's hard to argue for [calorie restriction] in the absence of
Meanwhile, scientists are looking at ways to get some of the presumed benefits of CR without actually
forcing people to skip lunch for the rest of their lives. One approach is to tinker with eating patterns in
a way that might be easier for most people to sustain, such as intermittent fasting. Neuroscientist Mark
Mattson at the National Institute on Aging has run experiments on mice who were fed nothing on
alternate days, and double rations the rest of the time. They didn't lose weight, but they showed
changes in blood pressure and heart rate that suggested a lower risk of cardiovascular disease. The
"mild stress" of fasting seemed to have inoculated them against more severe forms of stress that
ordinarily cause adverse reactions in mice, Mattson speculates. He hopes to begin testing the
proposition in humans soon.
Even better, presumably, would be a pill that people could take to mimic some of the biochemical effects of calorie
restriction. Roth has shown that this is possible in rats, using a compound known as 2DG that appears to interfere
with glucose metabolism, "tricking the cells into thinking they're calorie restricted, so less energy is metabolized."
Unfortunately, it sometimes slows metabolism to the point of cardiac arrest, which is an undesirable side effect in a
drug intended to prolong life, but other drugs might be safer. And, following news from a Harvard Medical School
team that a compound found in grape skins—and, therefore, red wine—can extend the life of yeast cells by more
than 60 percent, companies are racing to bring this substance, known as resveratrol, to market.
Any of these are sure to reach a broader segment of the metabolizing public than calorie restriction. Few people are
likely to take the sanguine view of Warren Taylor, the 58-year-old secretary of the Calorie Restriction Society, who
insists that with a proper choice of low-calorie, high-fiber foods, "you can never be hungry" on a CR diet. "Most of us
report greater internal harmony, peacefulness, tranquillity, emotional levelness," he says blissfully. Yes, he's cold all
the time, but he just wears more clothing—two pairs of pants and three shirts when he spoke to NEWSWEEK last
week from Gardena, Calif.—which, he adds, has the benefit of hiding how skinny he is. And yes, he has diminished
libido—"if you consider that a negative. Many people have elevated libidos, which get them into trouble, if you know
what I mean." And, of course, he expects to stay healthy a lot longer, just like all those mice.
Meanwhile, the gene-function tests on CR mice left gerontologist Weindruch "so excited and impressed that I went
on a calorie-restricted diet myself," he told NEWSWEEK. He lasted 10 days.
© 2006 Newsweek, Inc.
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