Antioxidants
not heaven-sent
“It may come as a
surprise that the
current scientific
consensus is
that there is no
health benefit to
taking antioxidant
supplements.”
32 Harvard Science Review • spring 2010
32-34.indd 32
By Stefan Andrei Anghel
W alk into any pharmacy or health
food store and you are sure to
find antioxidant supplements, probably
in a wide selection of brands and sizes.
For a long time, antioxidants have been
viewed as a method to prevent certain
diseases and possibly even retard aging.
Any randomly chosen person on the
street would most likely tell you that
antioxidants are “healthy”, or “good
for you”, though they would probably
not be able to tell you how. It may come
as a surprise that the current scientific
consensus is that there is no health ben-
efit to taking antioxidant supplements
(1). Even more unexpected news came
this year when an article announced
that antioxidants may actually prevent
the health-promoting effects of physi-
cal exercise (2). If the model proposed
by the authors of the study is correct,
then it may turn out that we have been
systematically “poisoning” ourselves,
increasing our disease risk and short-
ening our lifespan through antioxidant
supplements.
So what exactly are antioxidants?
The concept of antioxidants relates to
what are collectively termed reactive
oxygen species (ROS). Reactive oxygen
species (or “free radicals” as they are
still sometimes called, although incor-
rectly from a chemical perspective)
are a natural by-product of human
metabolism. Because oxygen abounds
in each of our cells, it can sometimes
pick up electrons from the enzymes
that are naturally present to break down
nutrients from our food, giving rise to
the various types of ROS. These spe-
cies are called “reactive” because of
the ease with which they react with
and damage crucial cellular molecules
including DNA, proteins and fats (Fig-
ure 1). This is where antioxidants come
in: they can neutralize ROS. They are
able to achieve this by interacting with
ROS and becoming oxidized them-
selves, generating a harmless oxygen
compound (like O2 or water) in the
process. The oxidized antioxidant can
then be recycled (by reduction) or sim-
ply disposed of(3). Many chemicals can
act as antioxidants, but among the ones
most widely consumed by humans are
vitamin C (L-ascorbic acid) and vitamin
E (alpha-tocopherol) (4).
However, it is important to under-
stand that we are not test tubes. While
it is true that ROS will attack DNA and
proteins, living cells are able to “fight
back” against all sorts of stress through
special “repair and neutralize” tools.
In the case of ROS, there are multiple
protection systems: special enzymes
like superoxide dismutase and catalase
exist for the sole purpose of ROS neu-
tralization, and a small peptide known
as glutathione can efficiently scavenge
ROS throughout the cell (5). Despite
the existence of these systems, a para-
digm has been in place for some years
throughout the scientific community
that some ROS escape and are able to
cause damage to cells, ultimately being
responsible for various pathologies and
possibly the process of aging (5-6).
Lately, however, evidence has surfaced
that ROS are not simply unfortunate
by-products of our aerobic metabolism.
ROS are now regarded as important sig-
naling molecules inside the cell, crucial
for the communication between differ-
ent cell compartments (7-8). Even more
2/17/2010 3:01:39 AM
 cal exercise increases insulin sensitivity,
but one hypothesis (which is tested by
Ristow et al.) is mitohormesis. Mitohor-
mesis postulates that the burst of ROS
induced by the increased metabolism
during physical exercise (15), alerts
the body to make specific proteins
that eventually bring about the final
health effects (what these proteins are
or how they accomplish the task is still
Figure 1. Reactive Oxygen Species pro- not known). What the authors of the
duced in Mitocondria can act both on
study did was simple: two statistically
the mitochondria themselves and on other cell
compartments, causing oxidative damage. indistinguishable groups of individuals
were asked to exert themselves physi-
strangely, studies in model organisms cally; one group received high doses of
have shown that ROS can be media- antioxidants (vitamins C and E) while
tors of some health-promoting effects the other did not. Their findings fit very
(9-10). The most recent of such studies well with the mitohormesis model: the
suggests that ROS may be crucial for group that received no antioxidants had
the proper functioning of the immune higher-levels of ROS-repair enzymes
system (11). This finding underscores and higher insulin sensitivity, while the
the importance of seeking a better group that received the supplements
understanding of antioxidants, con- showed none of these “health-promot-
sidering vitamin C is often consumed ing” effects. The antioxidants essentially
in large quantities as a remedy for the canceled out all the beneficial effects of
common cold, despite no evidence of exercise. The authors proceeded to put
any efficiency (12). together a model of the process that
Another study, conducted by Ristow fits their experimental data (Figure 2).
et al., sought to analyze the effects of As any new (16) scientific paradigm,
antioxidants in relation to the health- mitohormesis has the problem of any
promoting effects of physical exercise. emerging model: it lacks substantial evi-
This study is particularly significant dence, but mostly because little research
because it was carried out in humans, has been done on the subject, not
rather than in model organisms. It because the research was not fruitful.
is known that However, some
physical exercise “Mitohormesis postulates that supporting evi-
has many posi- the burst of ROS, induced by dence has re-
tive effects with cently surfaced.
respect to gen-
the increased metabolism A mitohorme-
eral health (13) during physical exercise, alerts sis-like process
and is especially the body to make specific seems to be the
efficient at im- proteins that eventually bring cause of isch-
proving glucose about the final health effects” emic precondi-
metabolism and tioning, a reac-
fighting and pre- tion that makes
venting type 2 diabetes( 14). These lat- heart cells more tolerant to ischemia-
ter effects are mediated by an increase reperfusion (a type of damage to the
in insulin sensitivity: the more sensitive heart caused by irregular blood flow)
one’s body is to insulin, the less of the (17). Shortly before this article went
hormone it takes to lower blood sugar to print, Loh et al. (18) provided direct
levels and the less susceptible one is to causal evidence that a transient increase
type 2 diabetes. in ROS increases insulin sensitivity in
It is not well understood how physi- mice. In addition, one study in the mod-
spring 2010 • Harvard Science Review 33
32-34.indd 33
el organism Caenorhabditis elegans (a
credit: http://www.nia.nih.gov/NR/rdonlyres/1460469B-C224-4259-9004-A6FAABB5F71D/10861/03_mitochondria_lg.jpg
worm) concluded that mitohormesis
may be the underlying mechanism by
which caloric restriction extends life-
time in this organism (10). Extension
of life through caloric restriction is a
phenomenon seen in organisms from
budding yeast to mammals (19-23), so
if the mitohormesis explanation for
calorie restriction is indeed true and
universal, it may mean that mitohor-
mesis-inducing drugs could someday
extend lifespan. Whether mitohorme-
sis turns out to be an accurate model
remains to be seen as more research is
carried out on the subject.
Studies like Ristow et al. are impor-
tant because antioxidants are widely
consumed as nutritional supplements.
Perhaps surprising for some, a recent
meta-analysis of a large number of an-
tioxidant studies performed on humans
(totaling an incredible 550,000 subjects)
established that such supplements have
no health-promoting effects(1). Then
why do people take antioxidants? Such
an analysis is beyond the scope of this
article, but the cause is most likely simi-
lar to that for the consumption of other
supplements such as homeopathic
remedies: some questionable science
started the trend, and then companies
willing to make a profit perpetuated and
amplified the legend. The fact that the
scientific giant Linus Pauling recom-
mended consumption of vitamin C in
doses two orders of magnitude above
conventional ones (24) probably did
not help the general public focus on
the scientific evidence underlying such
advice. Also, the so-called free radical
theory of aging, which postulates that
accumulation of ROS-induced damage
brings about aging (5-6) surely con-
tributed to the spread of antioxidant
supplements. Regardless of the reason
for their popularity, such supplements
have become extremely widespread,
despite the lack of any data supporting
their efficiency.
Now, it is becoming apparent that an-
tioxidants might actually be detrimental
to one’s health. It is important to note,
2/17/2010 3:01:39 AM
 drugs known to increase oxida-
tive stress in model organisms,
effectively trying to simulate
physical exercise. These stud-
ies would need to be designed
to induce short bursts of ROS
and not a constant increase, and
to the best of my knowledge
such a design has never been
employed. Extreme care is nec-
essary though: tampering with
cellular signaling molecules is a
very tricky business, and such
Figure 2. The model of Ristow et al. that explains approaches might turn out to
the effects observed effects (higher levels of
ROS clearance enzymes and higher insulin sensitivity).
be counterproductive, similar to
In the model the authors also extrapolate that exercise- antioxidant supplements. Also,
induced mitohormesis lowers general disease risk, an as some ROS-inducing drugs like
of yet untested hypothesis. According to this same model,
antioxidants block the pathway at the very beginning, paraquat are toxic to humans
precluding the necessary burst of ROS. (27) while others, like the an-
timalarial-drug artemisin (28)
however, that these studies were con- clearly are not. Extensive research in
ducted using antioxidant supplements, model organisms is therefore needed
not antioxidant-rich foods like fruits before human trials of such drugs
and vegetables. A high intake of such are deployed, but the mitohormesis
foods has actually been associated with hypothesis might ultimately provide a
a decreased risk of type 2 diabetes (25), pharmaceutical strategy for harness-
probably due to ing some of the
the presence of “the group that received no health benefits
numerous other antioxidants had higher-levels of exercise.
biologically ac- One last
of ROS-repair enzymes and
tive molecules. thought to take
One final pre- higher insulin sensitivity” away from such
caution must be studies relates to
noted: some antioxidants also have nutritional supplements in general.
confirmed and perfectly legitimate roles Currently antioxidant supplements can
in humans. Vitamin C, for example, is be sold with virtually no restrictions in
a vital coenzyme in the synthesis of a most countries, even considering the
form of collagen, a protein contained consensus in the scientific community
in human skin (26). Not consuming that they don’t actually do anything(1).
adequate quantities of vitamin C will After all, homeopathic remedies are
lead to the disease known as scurvy. still around and quite popular in some
If the mitohormesis hypothesis is communities, despite the fact that
anywhere near accurate, then it may be there is nothing in them but water
that for some compounds like vitamin (29). However, studies such as the one
C the golden rule will turn out to be performed by Ristow et al. show that
what can be described as the Goldilocks some supplements might actually have
rule: “Not too little, not too much, just deleterious effects on one’s health,
right.” although not immediately observable.
So what is the next step? There are Just think about how many supple-
numerous ways of testing the mitohor- ments out there say “extract of […]” on
mesis hypothesis. An interesting study the packaging (in the United States, for
which might reveal key pieces of the example, anything that contains an herb
puzzle would be to test the effects of can be sold as a nutritional supplement)
34 Harvard Science Review • spring 2010
32-34.indd 34
(30). Probably most of those don’t have
any health effects and only a very small
fraction contain any active ingredients
in sufficient quantities to show any
improvement. But some, as appears
to be the case with antioxidant supple-
ments, might have adverse effects that
are so complex that they are hard to
identify in safety trials. Therefore, next
time you are in a pharmacy or health
food store reaching for a supplement,
it might be a good idea to ask yourself
“What scientific evidence shows this
will actually help me?”
—S. Andrei Anghel ‘12 is a Molecular and
Cell Biology concentrator in Quincy House
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