". . .phytochemicals stress our bodies in a way that leaves us stronger."
". . . evidence has mounted to suggest that antioxidant vitamin supplements, long assumed to improve health, are ineffectual."
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| Illustration by John Hendrix |
by Moises-Velasquez Manoff via Nautilus.
You probably try to exercise
regularly and eat right. Perhaps you steer toward “superfoods,” fruits, nuts,
and vegetables advertised as “antioxidant,” which combat the nasty effects of
oxidation in our bodies. Maybe you take vitamins to protect against “free
radicals,” destructive molecules that arise normally as our cells burn fuel for
energy, but which may damage DNA and contribute to cancer, dementia, and the
gradual meltdown we call aging.
Warding off the diseases of aging
is certainly a worthwhile pursuit. But evidence has mounted to suggest that
antioxidant vitamin supplements, long assumed to improve health, are
ineffectual. Fruits and vegetables are indeed healthful but not necessarily because
they shield you from oxidative stress. In fact, they may improve health for
quite the opposite reason: They stress you.
That stress comes courtesy of
trace amounts of naturally occurring pesticides and anti-grazing compounds. You
already know these substances as the hot flavors in spices, the mouth-puckering
tannins in wines, or the stink of Brussels sprouts. They are the
antibacterials, antifungals, and grazing deterrents of the plant world. In the
right amount, these slightly noxious substances, which help plants survive, may
leave you stronger.
Eating food from plants that have
struggled to survive toughens us up as well.
Parallel studies, meanwhile, have
undercut decades-old assumptions about the dangers of free radicals. Rather
than killing us, these volatile molecules, in the right amount, may improve our
health. Our quest to neutralize them with antioxidant supplements may be doing
more harm than good.
The idea that pro-oxidant
molecules are always destructive is “oversimplified to the point of probably
being wrong,” says Toren Finkel, chief of the center for molecular medicine at
the National Heart, Lung, and Blood Institute in Bethesda, Maryland. “Oxidants
may be a primordial messenger of stress in our cells, and a little bit of
stress, it turns out, may be good for us.”
Although far from settled, a wave
of compelling science offers a remarkably holistic picture of health as a
byproduct of interactions among people, plants, and the environment. Plants’
own struggle for survival— against pathogens and grazers, heat and drought—is
conveyed to us, benefitting our health. This new understanding begins, in part,
on a treadmill.
In the mid-20th century, as modern medicine seemed
poised to vanquish the infectious diseases of yore, some scientists turned to
the degenerative diseases associated with aging. Attention fell on a class of
molecules called “reactive oxygen species,” or ROS. These volatile substances
could damage DNA. Degenerative diseases, such as cancer and cardiovascular
disease, often showed evidence of “oxidative stress,” suggesting that ROS
spurred disease.
Oddly, our mitochondria, the
energy factories of our cells, emitted ROS naturally. So degenerative disease
seemed to stem in part from our own metabolic function: Your mitochondria
“burned” fuel, emitted this toxic exhaust, and inadvertently set the limits on
your existence. That was the working hypothesis, at any rate.
Experiments on rats and worms
showed that reactive oxygen species, such as hydrogen peroxide, tear atoms from
other molecules, destroying them in the process. That can be problematic when
those molecules are DNA, our cellular instruction manual. We produce native
antioxidants, such as the molecule glutathione, to counteract this pro-oxidant
threat. They react with ROS, neutralizing the pro-oxidants before they can
damage important cellular machinery.
When scientists blocked rodents’
ability to manufacture these protective molecules, lifespan declined.
Observational studies, meanwhile, suggested that people who regularly ate
vitamin-laden fruits and vegetables were healthier. So were people with higher
levels of vitamins E and C in their blood.
Vitamins were strongly
antioxidant in test tubes. So the ROS theory of aging and disease rose to
prominence. You could slow aging, it followed, by neutralizing free radicals
with antioxidant pills. A supplement industry now worth $23 billion yearly in
the U.S. took root.
But if those ROS were so harmful,
some scientists asked—and the basic design of our (eukaryote) cells was over 1
billion years old—why hadn’t evolution solved the ROS problem? At the same
time, scientists began finding that exercise and calorie restriction increased
lifespan in animals. Both elevated ROS. According to the ROS model of aging,
animals that exercised and fasted should have died younger. But they lived
longer.
For Michael Ristow, a researcher
of energy and metabolism at the Swiss Federal Institute of Technology in
Zurich, the inconsistencies became impossible to overlook. In worms, he found
that neutralizing those allegedly toxic ROS reduced lifespan, so he designed a
similar experiment in humans.
He had 39 male volunteers
exercise regularly over several weeks; half took vitamin supplements before
working out. The results, published in 2009, continue to reverberate throughout
the field of exercise physiology, and beyond. Volunteers who took large doses
of vitamins C and E before training failed to benefit from the workout. Their
muscles didn’t become stronger; insulin sensitivity, a measure of metabolic
health, didn’t improve; and increases in native antioxidants, such as
glutathione, didn’t occur.
Exercise accelerates the burning
of fuel by your cells. If you peer into muscles after a jog, you’ll see a
relative excess of those supposedly dangerous ROS—exhaust spewed from our
cellular furnaces, the mitochondria. If you examine the same muscle some time
after a run, however, you’ll find those ROS gone. In their place you’ll see an
abundance of native antioxidants. That’s because, post-exercise, the muscle
cells respond to the oxidative stress by boosting production of native
antioxidants. Those antioxidants, amped up to protect against the oxidant
threat of yesterday’s exercise, now also protect against other ambient oxidant
dangers.
Contrary to the ROS dogma, Ristow
realized, the signal of stress conveyed by the ROS during exercise was
essential to this call-and-response between mitochondria and the cells that
housed them. To improve health, he figured, perhaps we shouldn’t neutralize ROS
so much as increase them in a way that mimicked what happened in exercise. That
would boost native antioxidants, improve insulin sensitivity, and increase
overall resilience.
Ristow called this idea
“mitohormesis.” The term “hormesis” came from toxicology (“mito” was for
mitochondrion). It describes the observation that some exposures generally
considered toxic can, in minute amounts, paradoxically improve health. For
instance, minuscule quantities of X-ray radiation, a known carcinogen,
increases the lifespan of various insects.
Hormesis may be most easily
grasped when considering exercise. Lift too much weight or run too long, and
you’ll likely tear muscle and damage tendons. But lift the right amount and run
a few times a week, and your bones and muscles strengthen. The intermittent
torque and strain increases bone mineralization and density. Stronger bones may
better tolerate future shocks that might otherwise cause fractures.
In his experiment, Ristow saw
that vitamin supplements interrupted this sequence of stress followed by
fortification, probably because they neutralized the ROS signal before it could
be “heard” elsewhere in the cell. By interfering in the adaptive response,
vitamins prevented the strengthening that would have otherwise followed the
stress of physical exertion. Antioxidant supplementation paradoxically left you
weaker.
Vitamins are necessary for
health. And supplements can help those who are deficient in vitamins.
Insufficient vitamin C, for instance, causes scurvy, which results from
defective collagen, a protein in connective tissue.
Among other functions,
vitamin C aids collagen synthesis. But the primary role of vitamins
in our body, according to Ristow and others, may not be antioxidant. And the
antioxidant content of fruits and veggies does not, he thinks, explain their
benefits to our health. So what does?
Mark Mattson, Chief of the Laboratory of Neurosciences
at the National Institute on Aging, has studied how plant chemicals, or
phytochemicals, affect our cells (in test tubes) for years. The assumption in
the field has long been that, like vitamins, phytochemicals are directly
antioxidant. But Mattson and others think they work indirectly. Much like
exercise, he’s found, phytochemicals stress our bodies in a way that leaves us
stronger.
Plants, Mattson explains, live a
stationary life. They cannot respond to pathogens, parasites, and grazers as we
might—by moving. To manage the many threats posed by mobile life, as well as
heat, drought, and other environmental stresses, they’ve evolved a remarkable
number of defensive chemicals.
Health doesn’t result solely from
the instructions your genome contains, but your relationship with the world.
We’re familiar with many
components of their arsenal. The nicotine that we so prize in tobacco slows
grazing insects. Beans contain lectins, which defend against insects. Garlic’s
umami-like flavor comes from allicin, a powerful antifungal. These
“antifeedants” have evolved in part to dissuade would-be grazers, like us.
Mattson and his colleagues say
these plant “biopesticides” work on us like hormetic stressors. Our bodies recognize
them as slightly toxic, and we respond with an ancient detoxification process
aimed at breaking them down and flushing them out.
Consider fresh broccoli sprouts.
Like other cruciferous vegetables, they contain an antifeedant called
sulforaphane. Because sulforaphane is a mild oxidant, we should, according to
old ideas about the dangers of oxidants, avoid its consumption. Yet studies
have shown that eating vegetables with sulforaphane reduces oxidative stress.
When sulforaphane enters your
blood stream, it triggers release in your cells of a protein called Nrf2. This
protein, called by some the “master regulator” of aging, then activates over
200 genes. They include genes that produce antioxidants, enzymes to metabolize
toxins, proteins to flush out heavy metals, and factors that enhance tumor
suppression, among other important health-promoting functions.
In theory, after encountering
this humble antifeedant in your dinner, your body ends up better prepared for
encounters with toxins, pro-oxidants from both outside and within your body,
immune insults, and other challenges that might otherwise cause harm. By
“massaging” your genome just so, sulforaphane may increase your resistance to
disease.
In a study on Type 2 diabetics,
broccoli-sprout powder lowered triglyceride levels. High triglycerides, a
lipid, are associated with an increased risk of heart disease and stroke.
Lowering abnormally elevated triglycerides may lessen the risk of these
disorders. In another intervention, consuming broccoli sprout powder reduced
oxidative stress in volunteers’ upper airways, likely by increasing production
of native antioxidants. In theory, that might ameliorate asthmatics’ symptoms.
Elevated free radicals and
oxidative stress are routinely observed in diseases like cancer and dementia.
And in these instances, they probably contribute to degeneration. But they may
not be the root cause of disease. According to Mattson, the primary dysfunction
may have occurred earlier with, say, a creeping inability to produce native antioxidants
when needed, and a lack of cellular conditioning generally.
Mattson calls this the “couch
potato” problem. Absent regular hormetic stresses, including exercise and
stimulation by plant antifeedants, “cells become complacent,” he says. “Their
intrinsic defenses are down-regulated.” Metabolism works less efficiently.
Insulin resistance sets in. We become less able to manage pro-oxidant threats.
Nothing works as well as it could. And this mounting dysfunction increases the
risk for a degenerative disease.
Implicit in the research is a new
indictment of the Western diet. Not only do highly refined foods present
tremendous caloric excess, they lack these salutary signals from the plant
world—“signals that challenge,” Mattson says. Those signals might otherwise
condition our cells in a way that prevents disease.
Another variant of the hormetic
idea holds that our ability to receive signals from plants isn’t reactive and
defensive but, in fact, proactive. We’re not protecting ourselves from
biopesticides so much as sensing plants’ stress levels in our food.
Harvard scientist David Sinclair
and his colleague Konrad Howitz call this xenohormesis: benefitting from the
stress of others. Many phytonutrients trigger the same few cellular responses
linked to longevity in eukaryotic organisms, from yeasts to humans. Years of
research on Nrf2 in rodents suggest that activating this protein increases
expression of hundreds of health-promoting genes, including those involved in
detoxification, antioxidant production, control of inflammation, and tumor
suppression.
In the dance between animals and
plants, there’s true mutualism. “We’re in this together, the plants and us.”
Sinclair studies another class of
native proteins, called sirtuins, associated with health. They’re triggered by
exercise and also, Sinclair contends, a molecule called resveratrol, found in
grape skins and other plants. “It’s too coincidental that time and time again
these molecules come out of nature that have the surprising multifactorial
benefit of tweaking the body just the right way,” Sinclair says.
They’re not all antifeedants, he
argues. Plants churn these substances out when stressed, prompting further
adaptations to the particular threat, be it drought, infestation by grazing
insects, or excessive ultraviolet radiation from the sun.
For grazers, these stress
compounds in plants may convey important information about environmental
conditions. So grazers’ ability to “perceive” these signals, Sinclair argues,
likely proved advantageous over evolutionary time. It allowed them to prepare
for adversity. A grape vine stressed by fungi churns out resveratrol to fight
off the infection. You drink wine made from those grapes, “sense” the harsh
environmental conditions in the elevated tannins and other stress compounds,
gird your own defenses, and, in theory, become more resistant to degenerative
disease.
One implication is that modern
agriculture, which often prevents plant stress with pesticides and ample
watering, produces fruits and vegetables with weak xenohormetic signals. “I buy
stressed plants,” Sinclair says. “Organic is a good start. I choose plants with
lots of color because they are producing these molecules.” Some argue that
xenohormesis may explain, at least in part, why the Mediterranean diet is
apparently so healthful. It contains plants such as olives, olive oil, and
various nuts that come from hot, dry, stressful environments. Eating food from
plants that have struggled to survive toughens us up as well.
Philip Hooper, an endocrinologist
at the University of Colorado Anschutz Medical Campus, points out that
plant-animal relationships are often symbiotic, and communication goes both
ways. One example of direct plant-to-animal, biochemical manipulation comes
from the coffee bush. Flowering plants compete with one another for the
attention of pollinators, such as bees. Coffee bushes seem to gain advantage in
this “marketplace” by using caffeine. The drug excites pollinators’ neurons,
etching the memory of the plant’s location more deeply in their brains. Some
think that biochemical tweaking increases the probability that the pollinator,
which faces a panoply of flower choices, will return to that particular coffee
bush.
In the dance between animals and
plants, says Hooper, “I think there’s true mutualism. We’re in this together,
the plants and us.”
While xenohormesis is a compelling idea, it remains
unproven. Barry Halliwell, a biochemist at the National University of
Singapore, and an expert on antioxidants, has seen the dietary fads, from vitamins
to fiber, come and go. He says the hormetic and xenohormetic ideas are
plausible, but not certain. Various studies suggest that people who consume a
lot of fruits and vegetables have healthier lifestyles generally. Those people
probably go easy on the junk food, which alone may improve health.
Even within the hormetic idea,
Halliwell sees the attempts to bore down on the individual chemicals as
problematic. “That’s worked very well in pharmacology, but it hasn’t worked at
all well in nutrition,” he says. He doesn’t think any single phytonutrient will
explain the apparent health-promoting benefits of fruits and veggies. “Variety
seems to be good,” he says. That critique speaks to a larger problem: It’s
often unclear how lab research on simple organisms or cell cultures will
translate, if at all, into recommendations or therapies for genetically
complex, free-living humans.
What works in genetically uniform
organisms, or cells, living in highly controlled environments, does not
necessarily work in people. Human studies on resveratrol in particular have
yielded contradictory results. Proper dosage may be one problem, and interaction
between the isolates used and particular gene variants in test subjects
another. Interventions usually test one molecule, but fresh fruits and
vegetables present numerous compounds at once. We may benefit most from these
simultaneous exposures.
The science on the intestinal
microbiota promises to further complicate the picture; our native microbes
ferment phytonutrients, perhaps supplying some of the benefit of their
consumption. All of which highlights the truism that Nature is hard to get in a
pill.
These caveats aside, research
into xenohormesis reminds us that we are not at the complete mercy of our
genetic inheritance. Genes matter, but health depends in large part on having
the right genes expressed at the right time—and in the right amount. If our
genome is a piano, and our genes are the keys, health is the song we play on
the piano. The science on hormesis, the stresses that may keep us strong,
provides hints about what kind of song we should play. Keep the body
conditioned with regular exercise. Keep your cells’ stress-response pathways
intermittently engaged with minimally processed, plant-based food.
These recommendations end up
sounding rather grandmotherly—if your grandmother was a spartan, no-nonsense
peasant who lived off the land. But the underlying thrust contradicts
assumptions about the need to protect oneself from hardship. Certain kinds of
difficulty, it turns out, may be required for health. That’s because health
doesn’t result solely from the instructions your genome contains, but from your
relationship with the wider world. Resilience isn’t completely inherent to your
body; it’s cultivated by outside stimuli. And some of those stimuli just happen
to be mildly noxious, slightly stressful chemicals in plants.
Moises Velasquez-Manoff is a
science writer and author of An Epidemic of Absence: A New Way of
Understanding Allergies and Autoimmune Diseases. He lives in California.
