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By Christopher Wanjek
It used to be so simple, a battle between good
and evil.
Rogue chemicals called free radicals roam about
the body like brazen street punks, the story went, smashing cellular
walls and roughing up innocent DNA molecules, causing cancers and
the diseases of middle and old age.
Their flagrant disregard for the law would continue
unchecked if it weren't for swashbuckling antioxidants swooping
in on the wings of dietary supplements, disarming the free radicals
of their menacing electrons and converting them into respectable
molecular citizens.
At least that's how the theory went. And the
public bought it - both the story and millions of doses of antioxidant
supplements, which they
believed would reduce disease, boost system performance and maybe
even slow the aging clock.
But as a bewildering cascade of contradictory,
inconclusive and outright negative research reports over the past
several years suggests, the human body isn't governed by a B-movie
script. The antioxidant story isn't as simple as some - largely,
those who make and sell them - would have us believe.
"Free
radicals are as good as they are bad," says Walter
Bortz of Stanford University Medical School. He is a past president
of the American Geriatric Society and author of several popular
books on aging and scientific articles on vitamins.
He says that antioxidants
in high doses may do the body harm; in other cases they
may help. We simply don't know yet which ones do which and when.
"It's a very complicated story," he
says.
You know many antioxidants by name, whether
you take them or not: vitamins C and E, beta carotene and selenium
are just the most common. Their purported health benefits adorn
the packaging for everything from cereals to cosmetics. One can
easily walk through the aisles of any grocery, drug or vitamin store
thinking that antioxidants are scientifically validated wonder pills.
They're not, "although the data don't seem
to make any difference to the sales of supplements," says Richard
Veech, chief of the Laboratory of Membrane Biochemistry at the National
Institute on Alcohol Abuse and Alcoholism, who has reported on the
interplay of free radicals and antioxidants for more than 30 years.
Americans spent $31 billion on vitamin supplements
in 1999, according to the U.S. General Accounting Office.
Nearly $2 billion of that was for vitamins E
and C, beta carotene and selenium, according to Nutrition Business
Journal. Up to 30 percent of the population is taking antioxidant
supplements regularly, according to the American Heart Association.
While the efficacy of antioxidant supplements
remains gospel in the health-marketing community, Bortz says the
accumulating scientific record does not verify it.
For every study
that shows benefits, he says,
there is another study that doesn't.
So with antioxidants and free radicals now seen
as playing dual roles of good guys and bad guys, just what exactly
is the state of antioxidant research? And what health claims can
you believe? The experts - you were about to guess this - have a
variety of opinions.
Armor All for the
Body
It's generally recognized that antioxidants
have the ability to serve as sort of a rust protector for the body,
putting a stop to a process called
oxidation.
Important molecules in the body, such as those
that form the walls of arteries, become oxidized when they lose
an electron. Once oxidized, they become unstable and easily break
apart.
The culprit, without
a doubt, is the free radical, Veech
says. Free radicals are highly reactive molecules, or single atoms
with unpaired electrons, looking for a mate. So they steal an electron
from the first thing they encounter, perhaps a cell wall or a strand
of DNA.
As free-radical damage mounts, cells can no
longer perform properly. Tissues degrade. Disease sets in. An excess
of free radicals has been cited in the development of cardiovascular
disease, Alzheimer's disease, Parkinson's disease and cancer. Aging
itself has been defined as a gradual accumulation of free radical
damage.
Yet not all free radicals are bad.
In fact, free
radicals are necessary for life, according to Britton
Chance, professor emeritus of biophysics, physical chemistry and
radiologic physics at the University of Pennsylvania, a renowned
expert on free-radical production.
The body cannot turn air and food into chemical
energy without a chain reaction of free radicals, for instance.
Free radicals are also a crucial part of the immune system, floating
through the veins and attacking foreign invaders. They help fight
against bacteria.
Without free radicals, says Chance, "we
couldn't have this conversation."
Free radicals are a natural byproduct of breathing;
antioxidants mop some of them up. A balancing act emerges, says
Veech. The body hopes to avoid excessive free-radical production,
but it certainly doesn't want to get rid of all of them.
A diet rich in fruit, vegetables, nuts and some
meats supplies most people with the antioxidants needed to walk
this tightrope, according to a report last year from the Institute
of Medicine.
The IOM could find no convincing evidence that
the bulk of the American population needs additional armaments in
the form of antioxidant supplements to fight free-radical damage.
The very notion that free radicals, produced naturally, are some
type of unwelcome houseguest is silly, according to Veech.
Veech says that free radicals have been incorporated
into the functioning human system over millions of years of evolution.
The idea that they should
be wiped out or minimized is nonsense, he says.
"God," he says, "is no fool."
Low Levels, High
Levels
Studies indicate fairly consistently that having
too few antioxidants is a bad thing. One study, published
in 1983 in the British medical journal The Lancet, found that people
with low blood levels of selenium were twice as likely to develop
cancer compared with people with normal levels.
Another study, published in 1986 in the New
England Journal of Medicine (NEJM), found that patients with a certain
type of lung cancer were four times more likely to be deficient
in beta carotene than a control group.
A 1989 study from the Netherlands associated
low selenium levels with an increased risk of heart attacks. More
convincingly, the Harvard-based Physicians Health Study - which
has recorded the lifestyles of some 50,000 male health professionals
for the past 15 years - found that men who ate a diet rich in vitamin
E (from nuts, seeds and soybeans) were half as likely to develop
heart disease as those with very low levels of dietary vitamin E.
Although these epidemiological studies suggest
an association between antioxidants and good health, this does not
mean that the antioxidants caused the improved health. Nor does
it imply that taking antioxidants in a pill form improves health.
In the studies cited above, it is not clear
what is responsible for the lower levels of the nutrients - a poor
diet, a certain environment, some unknown metabolic factor.
Taking generous doses of antioxidant supplements
showed some promise in studies published in the mid-1990s. Skin
cancer patients given daily selenium supplements were twice as likely
to survive their cancer as those patients not given selenium, the
Journal of the American Medical Association (JAMA) reported in 1996.
This was a multi-center, double-blind, randomized,
placebo-controlled study with more than 1,300 patients - all the
markings of good science. The findings were so dramatic, wrote the
authors, that they stopped the study after six years so that all
patients could benefit from the selenium supplement.
Other studies showed similar positive results:
Vitamin E postponed the onset of debilitating Alzheimer's symptoms
in a small study published in the NEJM in 1997; slowed the progress
of coronary artery disease in a study at the University of Southern
California School of Medicine that was published in JAMA in 1995;
cut the risk of cataracts by half in a 1998 Stony Brook (N.Y.) Medical
Center study published in the journal Ophthalmology; and lowered
the risk of prostate cancer in a 1994 NEJM article.
Vitamin C helped stave off blindness, kidney
failure and the need for amputation among diabetics, according to
a 1998 Duke University Medical Center report.
Extra selenium, a mineral needed only in trace
quantities, reduced the risk of prostate, colorectal and lung cancer,
according to the National Institutes of Health's Clinical Center
(as reported in 1997 and 1998 in journals such as the American Journal
of Epidemiology, Cancer Prevention and Nutrition Review).
Consumers tuned in to these results. Sales of
vitamin E grew from $590 million to $860 million from 1995 to 1999,
according to Nutrition Business Journal. Sales of other antioxidants
climbed by millions of dollars as well.
But the story doesn't end there. Side by side,
over the years, came a wave of neutral and even negative reports
about the benefits of antioxidant supplements. One study, reported
in NEJM in 1994, found that Finnish male smokers were 18 percent
more likely to develop lung cancer after taking a beta carotene
supplement.
In 1997, The Lancet published a study of nearly
2,000 men receiving vitamin E, beta carotene, both or a placebo
after suffering their first heart attack. The two beta carotene
groups were about twice as likely to die from a second heart attack
or heart disease as the placebo group, and the vitamin E-only group
was about 1.5 times as likely to die.
Other studies showed similar negative results:
no evidence that vitamins C and E or beta carotene prevented colorectal
cancer; no evidence that these "big three" prevented arteries
from re-clogging after angioplasty; no evidence that beta carotene
prevented cancer or heart disease in more than 22,000 physicians
over 12 years; no evidence that extra selenium prevented cancer
in 60,000 nurses; and more bad news for smokers taking beta carotene,
this time with a 28 percent higher incidence of lung cancer. These
studies were reported in NEJM from 1994
to 1997.
Criticisms naturally flowed back and forth,
with the pro-supplement camp finding methodological errors in studies
casting doubt on pills, and the anti-supplement folks finding similar
problems in the work that seemed to contradict their findings. .
Strangely, Veech says, all these studies might
be absolutely right, pointing to the complex heart of the matter
- that we don't understand the
intricate relationship between certain types of antioxidants and
certain types of free radicals at different moments over
the course of one's lifetime.
"You can't talk about antioxidants en masse,"
says Veech. "They all have different potentials."
The Antioxidant
Paradox
Barry Halliwell of the National University in
Singapore wrote a short article in The Lancet last year entitled
"The Antioxidant Paradox." Halliwell was lamenting the
fact that although diets rich in antioxidants seem to have a positive
effect on health, popping antioxidant
supplements can be either beneficial or harmful, and
the results are not at all predictable.
If the chemistry is all the same (that is, pairing
up free electrons and converting free radicals to neutral molecules),
why would a given antioxidant have different effects at different
times on different regions of the body? Several entirely different
mechanisms might be taking place, researchers say:
Extra amounts of
antioxidants might be turning into pro-oxidants
(which promote the removal of electrons from atoms), fueling free-radical
production and its damage.
Supplements might do nothing at all because
they can't get to where they are needed.
Or antioxidants might not be the magic beneficial
chemical in the food we eat after all.
Can antioxidants turn on you? Several studies
have shown that people who did not get the daily recommended allowance
of vitamin C had an increase in free-radical damage to their DNA.
But, paradoxically, people who took megadoses of C also had an increase
in DNA damage. The second scenario might happen, Halliwell says,
because vitamin C can worsen cell damage once it has already started.
Within a cell, certain metal compounds are released
as a result of free-radical damage. These metals themselves can
act as a catalyst for further free-radical damage when they are
in a "reduced" state, with a missing oxygen or extra hydrogen
atom. Antioxidants place metals in this reduced state. Thus, in
this environment, antioxidants become pro-oxidants, Halliwell
says.
This was demonstrated in laboratory animals
exposed to the pesticide paraquat, a known carcinogen. Animals that
received vitamin C before exposure were largely protected from cancer.
Animals that received vitamin C after exposure didn't fare so well:
The antioxidant aggravated the damage caused by the herbicide and
led to more cancers.
The American Cancer Society (ACS) advises cancer
patients not to prescribe themselves antioxidants because of this
potential effect, although it has never been demonstrated convincingly
in human studies.
"Think of antioxidants as drugs,"
says Michael Thun, who heads epidemiological research for the ACS
in Atlanta. There are gaps in our understanding, Thun says, and
"antioxidants are not necessarily safe or beneficial."
Compounding this is the fact that free
radicals can kill cancer cells; that's how some cancer treatment
works.
And rapidly multiplying cancer cells can use
antioxidants to their advantage to fuel their growth, Thun says.
So taking antioxidants at the wrong time essentially arms the bad
guy with the weapons to stay alive and multiply.
We should point out that none of this has convinced
some practitioners of alternative medicine not to prescribe antioxidants
for cancer. Many do, and insist mainstream medicine is depriving
patients of valuable cures and treatments.
Another baffling complication is that - despite
the assurances of pill makers who advise simply taking their pills
by mouth and feeling confident that the body will know what to do
with them - no one knows how to get antioxidants to travel where
they are needed, when they are needed.
Most free-radical damage occurs in the mitochondria,
according to the University of Pennsylvania's Chance. The process
of making energy in the mitochondria, called the respiratory chain,
depends on the availability of free radicals. And extra free radicals
are made in the process.
The mitochondria house a tiny, circular strain
of DNA that contains 30 genes. This is separate from the double-helix
DNA in the cell's nucleus. The mitochondrial DNA, called mDNA, is
often the free radical's first point of attack. When mDNA is damaged,
it cannot do its job of creating the proteins (molecular messengers)
needed for daily bodily maintenance.
This is where a magic bullet could come in handy,
Chance says - something that could penetrate the mitochondria and
mop up a rogue free radical set on doing damage, while steering
clear of the intricate respiratory chain. Yet mitochondria are veritable
fortresses with tough outer walls, moat-like inner barriers and
meandering inner walls protecting their precious contents. Proteins
get out, but antioxidants have a tough time getting in.
"This is where the problem is," Harmon
says, "getting into the mitochondria."
No one is sure whether brute force - which is
to say, a megadose of antioxidants - is the way into the mitochondria,
says Bortz, who was a colleague of Linus Pauling, the Nobel laureate
who recommended megadoses of vitamin C to ward off colds, flus and
even cancer. Perhaps the body has more subtle ways of permitting
entry.
Diet Vs. Supplements
And so it is that doctors
are split on whether to recommend antioxidant supplements
to their patients. The camps are broken down into those who believe
there are not enough data to make blanket recommendations; those
who feel that Americans (particularly children) have such a poor
diet that they need a supplement to ensure adequate levels for basic
function; and those who say that anyone can benefit from increased
antioxidants regardless of how healthy the diet is. A smaller camp
sees in the reports about negative effects of antioxidant pills
reason enough not to take any.
For Bortz, who is in his sixties and runs a
marathon once a year, whether or not to take an antioxidant supplement
is "an intellectual issue."
"Anything that will work, I'm for,"
Bortz says. "I just don't want people spending their money
on false hopes... Exercise is the master therapy."
Bortz says "maybe" to vitamin E; "nah"
to vitamin C; and "no way" to beta carotene.
Halliwell argues that a varied diet seems to
be more healthy than simple supplement-taking because the isolated
antioxidant might not be the superhero. Fruit and vegetables are
rich in antioxidants, but these plants contain hundreds of other
chemicals. Any single chemical or combination of chemicals might
pack the therapeutic punch.
Nutrients from food
enable the body to make its own antioxidants.
Veech says that a chemical produced by the body
called glutathione is ultimately responsible for neutralizing free
radicals, and the glutathione concentration in cells dwarfs that
of the free-radical scavengers such as vitamin C and E.
So diet and energy demands determine the amount
of free radical generation and removal, with supplements
playing a minuscule role, if any.
"The production of free radicals, absent
genetic defects, results from normal metabolic processes,"
says Veech. "Likewise, the destruction of free radicals in
a non-harmful manner is also the result of normal metabolic processes.
"People don't want to exercise. They don't
want to eat healthy food. They don't want to stop drinking; they
don't want to stop smoking; they don't want to stop having dangerous
sex. They want to take a pill. Well, good luck."
The Washington Post
August 7, 2001; Page HE01
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