Pathophysiology 13 (2006) 151162

Review

Oxidative stress in cataracts

Joe A. Vinson
Department of Chemistry, University of Scranton, Linden and Monroe Streets, Scranton, PA 18510, USA

Abstract

Oxidative stress is the result of an imbalance of antioxidants and pro-oxidants. Since toxic free radicals are the result of normal metabolism,
their destruction is imperative. Cataracts are the leading cause of blindness worldwide. Opacity of the lens is a direct result of oxidative
stress. Cataracts occur primarily due to age, but also are common in diabetes where superoxide in the mitochondria is elevated as a result
of hyperglycemia. This review will investigate the risk factors of cataract including diet (vitamins, fat and alcohol) as well as UV light and
diabetes. The pathophysiology of lens opacification will be discussed and related to the biochemistry, especially during the aging process and
in diabetes. Animal and human supplemental antioxidant studies will be reviewed and the mechanisms discussed for cataract prevention and
treatment. New genetic engineering approaches to overexpress antioxidant enzymes have given intriguing results and show promise. Lastly,
a new approach to target mitochondrial superoxide with antioxidant molecules will be outlined.
2006 Elsevier Ireland Ltd. All rights reserved.

Keywords: Aging; Aminoguanidine; Antioxidants; Ascorbate; Cataracts; Diabetes; N-Acetylcarnosine; Oxidative stress; Superoxide; Tea

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
2. Risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
3. Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
3.1. Color. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
3.2. Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
3.3. Lens barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
4. Animal and human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
4.1. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
4.2. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
5. Targeting mitochondrial oxidative damage in diabetes [78] (Fig. 7) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160

1. Introduction From this theoretical basis came the concept of oxidative

stress to describe what is occurring when secondary oxi-
With the exception of anaerobic microorganisms, all liv- dations induced by oxygen and its derivatives are not effec-
ing things require molecular oxygen as an electron acceptor tively neutralized. This can lead to abnormal metabolism,
for efficient production of energy required for life. Since loss of physiological function, disease and then finally death
oxygen is a strong oxidant, it is not possible to avoid sec- [1,2].
ondary oxidations that are involved in ordinary metabolism. Oxidative stress corresponds to an imbalance between the
rate of oxidant production and the rate of their degradation
Tel.: +1 570 941 7551; fax: +1 570 941 7510. [2]. This term is 15 years old and is very prominent in the
E-mail address: vinson@scranton.edu. medical literature (PubMed lists over 38,000 citations from

0928-4680/$ see front matter 2006 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.pathophys.2006.05.006
152 J.A. Vinson / Pathophysiology 13 (2006) 151162
Fig. 1. Illustrations of the types of cataracts and lens anatomy.
1970 to January 2006). The complete four-electron reduc-
tion of oxygen occurs within the mitochondria and the end
product is water. A partial reduction produces superoxide
and various reactive oxidative intermediates (free radicals
and reactive oxygen species or ROS including hydroxyl radi-
cals, singlet oxygen radicals and hydrogen peroxide). Besides
these endogenous oxidants, other sources are food, air pollu-
tants, tobacco smoke, exercise, ionizing radiation, IR and, of
course, the sun. Although the organism adapts by preventing
undesirable reactions with its endogenous and partly redun-
dant antioxidant defense (glutathione superoxide dismutase,
catalase, glutathione peroxidase, glutathione reductase) and
repairing damaged molecules and tissues, the few molecules
and undesirable reactions that are not prevented or repaired
will accumulate over time and be deleterious in the long term.
All of these conditions will lead to the formation of excessive
oxidants and oxidative stress.
Oxidative stress is countered by antioxidants which are
defined as substances that, at low concentrations relative
to the substrate, inhibit the damage to the structural and
functional molecules of the body, namely proteins, lipids,
carbohydrates and DNA.
Antioxidants function by several possible mechanisms:
1. Scavenging of free radicals involved in chain reactions;
tocopherol acting in the lipid phase.
2. Regeneration of other antioxidants; ascorbate reduces
tocopheryloxy radical to tocopherol by donating an H
atom.
3. Reacting with initiating radicals or oxidants (catalase with
hydrogen peroxide).
4. Chelating or sequestering transition metal catalysts which
are pro-oxidants; albumin or polyphenols with cupric ion.
5. Inhibiting or activating an enzyme; tocopherol and
polyphenols inhibit tyrosine kinase and ascorbate acti-
vates nitric oxide synthase.
There are three types of cataracts, each defined by their
location on the lens as shown in Fig. 1, where a picture of the
lens anatomy is also found.
NuclearThis type of cataract is located at the center of
the lens and is usually the result of advancing age.
CorticalThis type of cataract resembles the spokes of
a wheel which extend from the outside of the lens to the
center and is usually associated with patients who suffer from
diabetes.
SubcapsularThis type of cataract develops at the back
of the lens under the capsule and is usually associated with
people working with microwave radiation, and patients who
take steroids or who suffer from diabetes.
Cataract, the opacification of the eye lens, is the lead-
ing cause of blindness worldwide, accounting for 42% of all
blindness [3]. Currently, more than 17 million are blind due to
cataract and 28,000 new cases around the world are reported
each day [4]. In the USA, over 1.3 million cataract opera-
tions are performed annually at a cost of US$ 3.5 billion.
Forty-three percent of all visits to opthalmologists are due to
cataracts, a figure that represents 12% of Medicare costs [3].
About 25% of people over 65 years and 50% over 80 years
have serious loss of eyesight due to cataracts. The population
over 55 years is more susceptible to lens opacification and this
group is expected to increase four-fold worldwide. An esti-
mated 20.5 million (17%) of Americans older than 40 years
have cataract in either eye and this number will increase to
over 30 million by 2020 [5]. One-half of the blindness cases
are in the developing countries of Africa and Asia. As the
 J.A. Vinson / Pathophysiology 13 (2006) 151162
lifespan of these countries increases, delaying the average
age of onset of cataract by 6 months would reduce the num-
ber of blind people by about one million [6]. Cataract is thus
a major disease and a major economic burden.
Although cataract surgery is recognized as being one of the
safest operations, there is a significant rate of complications.
Worldwide, 510 million new cases of visually disabling
cataracts occur with surgery producing 100200,000 irre-
versibly blind eyes. In the US, 300 to 400,000 new visually
disabling cataracts occur each year with surgical complica-
tions resulting in 7000 irreversibly blind eyes. Also, 3050%
of cataract patients develop opacification within 2 years of
surgery and need laser treatments [7]. Most morbidity asso-
ciated with senile cataracts occurs after the operation. In a
New England case study over a period of 1 year. Comparing
167 patients aged 50 years or more who underwent cataract
surgery and 824 patients with 6 other surgical procedures,
it was found that cataract surgery produced over two times
more mortality. This difference was not due to diabetes which
points out the risks of cataract surgery [8].
This critical review will focus on the risk factors, patho-
physiology and antioxidant interventions in animals and
humans to slow down and prevent cataracts linked to oxida-
tive stress.
2. Risk factors
One of the easier and cheaper methods of investigating
a health problem is epidemiology. Although this does not
establish cause unequivocally, it does give insight for possible
mechanistic and intervention studies involving risk factors.
The trick is exclude confounding variables in the analysis.
This is also a well-studied field with 2653 cataract papers
going back to 1958. One interesting result is that birth weight
at 1 year of age is a predictor of later cataract development in
England. This association persists after correction for other
risk factors such as age, sex, smoking, social class, adult
height and diabetes [9]. The authors speculate that alterations
in lens growth or differentiation, at key stages, may ultimately
lead to abnormal structural or functional changes that predis-
pose these individuals to later cataract development. Whether
this finding relates to oxidative stress during early childhood
is unknown and needs to be tested in other populations. The
most obvious risk factor is age. The young lens has substantial
reserves of antioxidants to prevent lens damage and prote-
olytic enzymes, proteases, that selectively remove damaged
proteins. Compromises of function of the lens with aging are
associated and may be causally related to depleted antiox-
idant reserves, diminished antioxidant enzyme capabilities
and decreased proteases.
A well-documented but minor risk factor is sunlight expo-
sure, particularly its UV-B component with 22 studies show-
ing an association with cortical cataracts [10]. An analysis
of data from Australia, China, Tibet and the US that con-
trolled for age, sex, race, income and medical practices, found
153
that probability of cataract surgery increases by 3% for each
degree south in latitude in the USA [11]. A recent population-
based casecontrol study of 445 men and male pilots showed
that for cases versus controls, there was an odds ratio of 3.0
for pilots and risk was cumulative radiation dose-dependent
[12]. By the year 2050, assuming a 520% ozone depletion,
there will be 167830,000 more cases of cortical cataract
which causes an increase in cataract operations resulting in
added costs of US$ 563 million to US$ 2.8 billion [13]. UV
light is an obvious oxidative stress and our eyes are more
susceptible to UV damage as we age. The levels of UV filters
in our lens decrease linearly with age, at a rate of 12% per
decade [14]. These filters become modified and then act as
photosensitizers. Therefore, when we examine the effect of
UV light in epidemiology studies, it might be only after mid-
dle age that the light can promote oxidation and ultimately
cataracts.
An 18th century French politician once said, Tell me
what you eat, and I will tell you what you are which has
been changed over the years to you are what you eat. A
recent epidemiological study investigated diet among Nurses
Health Study participants without cataracts were examined
for 911 years [15]. They found that women who had the
highest quartile category of healthy eating scores (Dietary
Guidelines for Americans) had a significantly decreased
risk of nuclear cataracts, odds ratio of 0.47 (Fig. 2). Inter-
estingly, the association was stronger among non-users of
Vitamin C supplements. This discrepancy corresponds with
the problems of supplementation with isolated compounds,
which usually results in either neutral or negative effects with
respect to chronic diseases. High intake of fruits (odds ratio,
0.58) and whole grains (odds ratio, 0.64) were also bene-
ficial in this epidemiological study. Over 35,000 women in
the Nurses Health Study were free of cataracts in 1993 and
observed for 10 years. Women with high intakes of fruits
and vegetables had a modest 1015% reduction in cataracts,
p < 0.05 for the trend [16].
What are the components of a healthy diet that are respon-
sible for the beneficial effect of a healthy diet? In general,
spinach has been the food that has been most often associated
with a reduced risk of nuclear opacities as reviewed by Mares-
Fig. 2. Relation between the prevalence of nuclear lens opacities and the
healthy eating index quartiles (ranging from low to high) in 479 female
nurses [15].
154 J.A. Vinson / Pathophysiology 13 (2006) 151162
Fig. 3. Chemical structure of lutein and zeaxanthin.
Perlman et al. [17]. Spinach is characterized by a high con-
centration of lutein and zeaxanthin, two carotenoids (Fig. 3)
only obtained from ingestion, and the only carotenoids found
in the human lens. These compounds prevented UV-B dam-
age as shown in an in vitro study with pretreated human
lens epithelial cells where carotenoids were more protec-
tive with respect to lipid peroxidation and stress signaling
than tocopherol at micromolar concentrations [18]. An epi-
demiological study in the Netherlands has given some more
insight about lutein/zeaxanthin. In a cross-sectional design,
367 subjects (aged 1775 years) were studied and serum was
analyzed for vitamins and carotenoids and correlated with
lens optical density. After corrections for age, there were no
associations between optical density and any serum nutrient.
However, there was a significant association between optical
density of the lens and the amount of macular pigment opti-
cal density. The authors conclude that since macular pigment
is composed of lutein and zeaxanthin, they may retard aging
of the lens [19]. Chronic high dose intake of lutein but not
tocopherol has improved visual acuity in small numbers of
subjects with age-related cataracts [20]. These results have
given rise to the addition of lutein to numerous supplements
(some including vitamins and minerals) marketed for healthy
vision.
The non-carotenoid antioxidant Vitamins C and E are gen-
erally regarded to be the most likely inhibitors of oxidative
stress and thus should decrease the risk of cataracts. Studies
examining associations between self-reported nutrient intake
and nuclear cataract have yielded inconsistent findings as
a result of imprecise assessment of intake and in the large
variability in utilization and absorption of the vitamins [21].
Plasma levels of a vitamin at the time of opacity measurement
represent the most common epidemiological methodology.
The results for Vitamin E are mixed in this regard. Plasma
tocopherol was inversely associated with nuclear opacities
in the Baltimore Longitudinal Study on aging [22] and in
the lens opacities casecontrol study [23], but was not asso-
ciated with nuclear cataracts in the IndiaUS casecontrol
study [24] or the Kupio Atherosclerosis Prevention Study
[25]. A 2005 long-term nutrient intake and a 5-year nuclear
lens opacity study in the Boston area found an inverse cor-
relation which was significant between duration of Vitamin
E supplements and change in nuclear opacity [26]. In the
ItalianAmerican Clinical Trial, surprisingly plasma E was
positively associated with cortical cataract and indeed any
cataract [27].
What is the epidemiological evidence for Vitamin C? On
the negative side is the result shown in Fig. 2 indicating a
slight worsening of cataract odds with Vitamin C supplement
use. In addition, Vitale found no association between either
plasma Vitamin C or Vitamin C intake and cortical opacifi-
cation, even when stratified according to age [28]. The lens
opacities casecontrol study also found no association with
Vitamin C intake and cortical cataracts [29]. On the positive
side is the Nurses Health Study which showed that Vitamin C
intake in women of >362 mg/day was associated with a 57%
decreased in risk of developing a cortical cataract compared
to <140 mg/day. Also use of Vitamin C supplements for >10
years decreased the risk 60% compared to no Vitamin C sup-
plement use in a Mediterranean population [30]. The benefit
accrued from long-term supplementation is consistent with
mechanistic interpretations because cataract-related damage
to very long-lived lens proteins occurs after extended peri-
ods of time. In Europe there is a wider variety of fruit and
vegetables and therefore nutrient intake compared to the US
population. A casecontrol study in Valencia, Spain, consum-
ing the typical Mediterranean diet, found that blood levels of
ascorbate >49 M were associated with a 64% reduction in
cataract risk [31]. The average US blood ascorbate is 36 M
compared to Valencia at 55 M with a corresponding aver-
age intake of 157 mg C/day. This study indicates that even in
populations with high blood levels of C, increasing the con-
centration of Vitamin C by supplementation lowers the risk
of cataracts.
The relationship between alcohol consumption and
cataracts is also contradictory. An older but intriguing study
looked at subjects in Edinburgh, Scotland. They found a
J-shaped risk curve (Fig. 4) with significant reduction of
cataracts occurring with light infrequent (once or twice a
month) and light frequent (three or four drinks a week)
intake [32]. The lowest risk was 34% that of abstinence. This
curve is hauntingly similar to that for alcohol consumption
and all-cause mortality as reported in this journal [33]. The
most recent study reported on results of the Nurses Health
Study [34] and found that consumption of alcoholic bever-
Fig. 4. Risk of cataracts and alcohol consumption [32].
 J.A. Vinson / Pathophysiology 13 (2006) 151162
Fig. 5. Chemical structure of aminoguanidine.
ages, particularly hard liquor and wine was positively asso-
ciated to nuclear opacity and wine drinking (increased risk
of 17% for very two glasses of wine per week). On the con-
trary, wine drinking was inversely related to cortical opacity
(Fig. 5).
Regarding fat intake, there were significant positive asso-
ciations for age-related nuclear opacity in Boston area women
studied for 15 years and linoleic and linolenic acid intake,
two 18-carbon polyunsaturated fats [35]. This result could
imply a greater oxidative stress from this type of fat. There
were no associations with any type of fat for either cortical or
posterior subcapsular opacity. On the positive side, women
with the highest quintile of omega-3-fatty acid or fish had
a 12% lower risk of cataract extraction relative to those in
the lowest quintile [36]. This would seem to counteract the
oxidative stress hypothesis since there are even more polyun-
saturated (five to six double bonds) in the omega-3-fatty
acids than the two fats mentioned above (two to three dou-
ble bonds). Indeed, a supplement study with an omega-3-fatty
acid did show an improvement in visual acuity in 10 of 15 sub-
jects with cataracts [37]. It is possible that these compounds
are working in non-antioxidant ways to improve vision as
they profoundly affect membrane structure by biophysical
means.
Available epidemiological evidence indicates hyper-
glycemia as a risk factor for cataract. There are 2678 PubMed
citations for glucose and oxidative stress. For example, 1000
subjects were examined in a casecontrol study and there
were significantly higher levels of plasma glucose in the
cataract group [38]. An Italian study looked at clinical param-
eters and lens opacity in type 1 insulin-dependent diabetes
[39]. In the younger group (<20 years), the only variable
that correlated with opacity was long-term glucose control as
measured by HbA1c. In the older group, opacity correlated
with age. These data indicate that early opacities are influ-
enced by metabolic control in younger diabetics while the
well-known effect of aging on lens transparency becomes
prevalent in older diabetics. Data from the Nurses Health
Study found that cortical opacity incidence was 2.5 times
higher in the women with the highest tertile of carbohydrate
intake [40]. This association was not affected by adjusting for
glycemic load which measures both the quantity and quality
of the carbohydrate, i.e. its effect of plasma glucose after con-
sumption. This indicates that refined carbohydrates alone are
not the primary culprits for causing cataracts. A combined
Physicians Health and Nurses Health Study also found no
155
effect of dietary glycemic load on risk of cataract extraction
[41]. Carbohydrate nutrition was not associated with the odds
of nuclear opacities.
The most obvious oxidative stress risk factor related to
cataracts is the use of tobacco and this is always factored
in when calculating other risk factors. Two recent stud-
ies highlight this risk. A Swedish study examined 35,000
women from 1997 to 2002 [42]. There was a significant
doseresponse association between intensity of smoking and
risk of cataract extraction among current and past smokers.
After cessation of smoking, the risk decreased with time.
However, a longer period of non-smoking was needed with
an initial higher smoking intensity to reduce the risk. An Aus-
tralian study showed that among identifiable cataract risk
factors (which also include female sex, arthritis, calcium
channel blocker use and diabetes), cigarette smoking is most
readily modifiable and preventable [43].
3. Pathophysiology
The human lens consists of three metabolically different
zones of the lens: the epithelium, the cortex and lens nucleus
or core [44]. Epithelial cells are found just under the most
collagenous capsule that surrounds the lens. These are the
most metabolically active cells. Some of these cells divide,
migrate to the lens equator, turn the corner 180 (apex to
apex) as they elongate up to 1000 times to form lens fiber
cells. In these cells, the major gene products of the lens, the
crystallins are produced. The outer layer of the fiber cells
which are laid down at about one cell layer per day, like tree
rings, make up the cortex. These cells also undergo changes
as they denucleate, age and become compressed as new cells
form externally. Buried under the cortical cells are the old-
est cells of the lens, called nuclear or core cells. Therefore,
a gradient exists in the lens, with the most recent proteins
in the epithelium and the oldest proteins, coming during
embryonic states in the nuclear cells. Posterior subcapsular
opacities are primarily due to aberrations in the outermost
layers of the lens. Cortical opacities occur in the inner and
outer cortical tissue. Nuclear opacities are found in the oldest
and central zone which is metabolically quiet. The hypoth-
esis is that opacifications in these three zones have different
etiologies and thus most epidemiological studies treat them
separately.
An excellent review of the oxidative stress hypothesis is
found in a recent review by Truscott [45] which will be sum-
marized and incorporated with other literature. This author
has published 47 papers on the biochemistry of cataracts
during the last 28 years. Age is the most commonly found
risk factor for cataracts. Age-related nuclear cataract (ARN)
is associated with a loss of glutathione in the center of the
lens and extensive modification of the nuclear proteins. They
include coloration, oxidation, insolubilization and cross-
linking. Also, the permeability barrier at the nucleus/cortex
interface will be discussed.
156 J.A. Vinson / Pathophysiology 13 (2006) 151162
3.1. Color
The most widely used classification system is that of Pirie
which categorizes lens into four groups based on degree of
nuclear color [46]. This is the striking physical feature of
extracted human ARN lenses in that they come in a variety
of colors; yellow, brown and even black. The color is mainly
in the nucleus and is found only in primate lenses, making
animal models somewhat suspect. The pigmentation is almost
exclusively protein-bound.
3.2. Oxidation
With respect to the whole lens, the loss of glutathione from
the nuclear region is probably the crucial feature that precedes
ARN cataract formation [47]. Glutathione is the essential
and primary lenticular antioxidant [48]. The loss is appar-
ently due to the oxidation of glutathione (GSH) to GSSG
since its levels rise significantly once the cataract develops.
The loss of GSH occurs in nearly all experimental cataracts
[45]. It is interesting to note that large decreases in GSH
occur in the nuclear region while cortical GSH remains nor-
mal [49]. This result strongly suggests that the postulated
role of extra-lenticular oxidants such as hydrogen peroxide
in cortical cataract development is not important. There also
appears to be a threshold of GSH concentration to maintain
its antioxidant effectiveness. In an in vitro experiment, Halli-
well and Gutteridge showed that hydroxyl radical formation
was inhibited when GSH was above 1 mM [50].
Over 90% of protein sulfhydryl (protein-SH) groups are
lost in the most advanced cataracts and almost one-half of
all the methione residues in the nuclear protein become oxi-
dized to methionine sulfoxide in the most advanced cataracts.
Protein-SH loss correlates well with the Pirie cataract clas-
sification [45]. It is proposed that the insolubilization of the
lens crystallins is the end result of denaturation and aggrega-
tion that has taken place over time. Urea and a reducing agent
dithiothreitol are used to solubilize these insoluble proteins,
some of which are present in early ARN cataracts. Some
protein remains insoluble with these chemicals in advanced
cataracts and this is the majority of the yellow color residing
in the lens. The insoluble protein is enriched in cross-linked
compounds and represents one-half of all the nuclear protein
in the most advanced cataracts [45]. Cross-linking results
from oxidation of sulfur groups and from reactive carbonyls
combining with the amino groups of proteins.
The importance of oxygen levels in cataract is postulated
by Eaton with the statement is the lens canned? [51]. This
refers to the fact that low oxygen in the lens may be neces-
sary to maintain optical clarity in the same way that oxygen is
sealed out from canned food and ascorbate is used to remove
residual oxygen in order to keep food fresh. Hyperbaric oxy-
gen causes cataract in animal models and it is characterized by
a loss of GSH and protein-SH as well as protein insolubiliza-
tion mimicking ARN cataract [52]. Oxygen is indeed present
at the center of the lens and there is a steep gradient from the
outer to the interior parts of the lens. Mitochondria appear to
be responsible for 90% of the oxygen consumption in the lens,
but there are areas of the lens outside the mitochondria where
oxygen consumption also took place [53]. Photo-oxidation,
the mechanism hypothesized for UV-induced cataract was
not found to be an important mechanism for increasing lens
oxygen and thus singlet oxygen, a highly reactive oxidant.
Since oxygen forms superoxide in mitochondria, the oxygen
results give credence to Brownlees proposal that normalizing
mitochondrial superoxide production blocks three pathways
of hyperglycemic damage; glucose-induced activation of pro-
tein kinase; increased formation of glucose-derived advanced
glycation endproducts; and increased glucose flux through
the aldose reductase pathway [54]. Agents that can reduce
superoxide concentration in the mitochondria may prove pre-
ventive for human cataracts.
Redox-active metal ions, copper and iron are the most rel-
evant to ARN cataract. Their possible interaction with hydro-
gen peroxide to produce hydroxyl radical by the Fenton reac-
tion has been extensively studied using in vitro systems. The
first direct evidence implicating the hydroxyl radical in ARN
cataract occurred in 1998 [55]. Significant hydroxylation of
five separate amino acid residues in human cataractous pro-
teins were found and increased with the severity of cataract.
UV light exposure did not produce the same pattern of oxida-
tion, thus Fenton chemistry was the mechanism. Following
this discovery, redox-available copper and iron were found
in human cataract lens [56] and redox-active iron was found
to be elevated in more advanced human ARN cataract [57].
3.3. Lens barrier
With respect to physical changes, the development of an
internal barrier to the diffusion of small molecules may be
important in the development of ARN cataract [45]. This
barrier impedes the flow of antioxidant molecules into the
nucleus and thus disposes the center of the lens to oxida-
tion. Also unstable pro-oxidant molecules may have a longer
residency in the lens. In the case of the primate lens UV
filters, their spontaneous decomposition produces reactive
molecules that bind to proteins, especially if GSH is low [58]
as in middle age [59]. Modifications of the proteins could
also be accelerated by onset of the barrier. This leads to the
nuclear-generated hypothesis of ARN cataract in which small
reactive molecules produced in the nucleus are responsible,
rather than UV light or elevated hydrogen peroxide in the
aqueous humor which should theoretically affect the cortical
rather than the nuclear zone first [45].
4. Animal and human studies
4.1. Animal studies
Over 5000 animal cataract papers have been published, yet
there are significant differences between animal lenses and
 J.A. Vinson / Pathophysiology 13 (2006) 151162
human lenses which include: lens UV filters are non-existent
in animals; less age-related oxidation of proteins in humans;
human lens protein is much lower than most animals; mouse
and rat lens crystallin is much higher in the gamma isomer;
central lens protein levels increase with age in animals but
not in humans; only humans, fruit bats and guinea pigs can
be made scorbutic; human lens ascorbate is millimolar while
in rats it is micromolar; and glutathione related enzymes are
negligible in the animal lens [45]. In spite of these difficulties,
several examples of animal supplementation studies will be
examined which deal with different mechanisms of protec-
tion.
For diabetic cataracts, delay is more probable than com-
plete protection in an animal model. There are three mecha-
nisms of pathology for this cataract, namely the aldose reduc-
tase pathway which increases sorbitol buildup in the lens,
protein glycation which covalently binds sugars to proteins
resulting in cross-linking and loss of structure and function of
the proteins, and lipid peroxidation which produces oxidative
stress. All pathways are linked to each other and the whole
process is thought to be initiated in the mitochondria where
glucose produces excess superoxide.
Aminoguanidine (Fig. 5) is a hydrazine compound that
reacts with compounds at different stages of glycation to pre-
vent the formation of both early and late glycation products
(AGE). AGE is increased in the aged lens and in the dia-
betic lens. AGE is linked to oxidative stress in that some of
the intermediate AGE products are highly reactive dicarbonyl
compounds such as glyoxal which generated reactive oxygen
species. The lenses of smokers have significantly more AGE
in their lens than do non-smokers [60]. The crystallins are
covalently cross-linked by AGE products. Aminoguanidine
slowed the progression of lens opacification in moderately
diabetic rats [61]. There were two groups of diabetic rats
grouped as moderately diabetic (<350 mg/dl) and severely
diabetic (>350 mg/dl). The rate of opacities was the same
in the two groups and the level of advanced glycated end-
products (AGE) was twice as high in the severely diabetic
group. Aminoguanidine inhibited AGE in the moderately
diabetic group more effectively than in the severely diabetic
group. It appears that inhibition of glycation is not sufficient
alone to counter severe diabetes. Aminoguanidine has now
progressed to human clinical trials. Aminoguanidine does
not have an antioxidant role in diabetic cataracts and does
not affect glucose [62]. Probucol, a lipophilic antioxidant,
was almost effective as aminoguanidine in inhibiting diabetic
cataracts by restoring the GSH deficiency in the diabetic ani-
mals [62]. These results indicate that a therapy which has
both anti-glycating and antioxidant activity would be more
effective than either one alone for preventing cataracts.
Aspirin is another anti-glycating compound that inhibited
diabetic animal cataracts and also was an antioxidant (GSH
restoration) probably by means of its metabolites salicylic
acid (a monophenol) and genistic acid (diphenol) which are
both phenolic antioxidants [63]. There is also epidemiolog-
ical evidence for aspirin reducing the risk of cataracts from
157
the Barbados Eye Studies. This study examined cortical and
posterior subcapsular cataracts and found a doseresponse
relationship between glycosylated hemoglobin (glycation of
the hemoglobin molecule which is related to long-term glu-
cose control) and opacity with aspirin use cutting the risk by
80% [64].
One unlikely therapy for diabetic cataracts is chocolate. A
Japanese group investigated the effect of an 8% polyphenol-
containing fraction derived from cacao liquor containing no
added sugar [65]. Streptozotocin-diabetic rats were given a
diet with and without 0.5% of the extract. There was also a
normal control group. There were almost no cataracts in the
cacao group and almost all animals in the diabetic control
group had cataracts. No effect of the extract was found after
10 weeks of treatment on glycemia, glycated protein or lipid
peroxidation in the diabetic group. However, the suscepti-
bility of the plasma to an oxidative stress (peroxy radicals
generated by thermal decomposition of an azo compound)
was increased in the diabetic control group but normalized in
the diabetic group given the cacao extract. Oxidative stress
in the lens as measured by hydroxynonenal immunostain-
ing was found in the diabetic control group but not in the
normal or diabetic cacao lens. Thus, oxidative stress in the
lens was completely inhibited with the cacao treatment and
the plasma oxidative defense was also normalized. Another
study with a higher dose, 13% in the diet, found that glu-
cose was decreased in diabetic rats. Total cholesterol was
decreased and HDL increased. Thus, both glucose and the
lipid profile were improved in this animal study [66].
Our animal study involved the use of standard green or
black tea as prepared for human consumption [67]. We had
a control group of animals given normal chow and water.
The diabetic groups were rendered diabetic with streptozo-
tocin and divided into groups, diabetic control, diabetic green
tea and diabetic black tea. All animals were given rat chow
and artificial sweetener in the drinking water or tea (made
up as a 1.25% solution as for human consumption). Both tea
treatments significantly decreased the severity of cataracts
and hyperglycemia in the plasma and lens. Both teas sig-
nificantly decreased plasma protein glycation, red blood cell
sorbitol and plasma lipid peroxidation and these same param-
eters were significantly decreased in the lens. However, the
teas did not directly affect these mechanisms as there was
no significant difference between the teas and control dia-
betic group when the results were normalized for glucose.
This study for the first time experimentally linked the three
pathological diabetic complication mechanisms to glucose
as evidenced by the significant correlations found between
plasma and lens glucose, plasma and lens glucose and cataract
scores and, lastly, plasma and lens glucose and glycation,
sorbitol and lipid peroxidation (Fig. 6). There were also con-
siderable significant correlations between glycation, sorbitol
and lipid peroxidation demonstrating their interrelation. This
animal study indicates that tea should be investigated in a
human supplementation trial with diabetics. In fact in a large
epidemiology study there was a decreased risk of diabetes
158 J.A. Vinson / Pathophysiology 13 (2006) 151162
Fig. 6. Correlations between lens glucose and the three pathological mech-
anisms in a tea-supplemented animal diabetes model.
and tea drinking. The highest intake of tea, greater than or
equal to 4 cups/day, reduced the risk of type 2 diabetes by
28% [68]. Another study showed that people drinking five
cups of tea a day had a 50% reduction of cataract risk [69].
Two new animal studies have opened another avenue
for prevention of cataracts, namely genetic engineering.
One used the lens as a factory to produce and antioxidant
enzyme. Addition of plasma DNA encoding the human SOD1
(Cu/ZnSOD) gene was done in vitro by uptake through the
rat lens epithelium. Lens SOD increased 140% over controls.
The lenses with overexpressed human SOD1 were com-
pletely protected from ex vivo oxidative stress with 100 M
hydrogen peroxide. No opacity was found after 24 h of incu-
bation and the lens were identical to untreated controls [70].
Another intriguing study used catalase overexpression tar-
geted to mitochondria in mice. Normally, catalase is localized
in the peroxisome but in this study catalase was targeted
to the nucleus and mitochondria of the transgenic mice and
they demonstrated less severe age-related cataracts and less
lipid peroxidation than the controls. However, by the end
of life, there was no difference in cataract severity between
the two groups. This indicates that oxidative stress is not
the only mechanism for age-related cataracts. As an added
benefit catalase overexpression produced a significant 19%
increase in life span [71]. These studies corroborate the oxi-
dation theory of aging as well as cataracts and emphasizes
the importance of superoxide for in vivo oxidative stress.
4.2. Human studies
In a recent review, Mares states unfortunately although a
large body of observational evidence suggests that antiox-
idant supplement use is associated with a lower risk for
cataract, there is insufficient evidence that high-dose antioxi-
dants slow the progression of cataracts beyond that provided
by multivitamins or healthful diets [72]. This negative con-
clusion comes from the four very large clinical supplementa-
tion trials that have failed to show positive results. The choice
of the lipophilic antioxidants E and beta carotene in these
trials is unfortunate since they cannot directly affect the orig-
inal source of the oxidation, namely the superoxide radical
in the mitochondria. In fact, there is no relationship between
Vitamin E in cataractous lenses and plasma or red cell E in
humans [73]. Another finding of this study was that E lev-
els were higher in lens of cataract patients that in control
cadaver lenses, a result unexpected if Vitamin E supplemen-
tation increased lens E to the benefit of the lens. Although
no human studies have yet been reported, supplementation
of beta carotene or zeaxanthin to Japanese quail caused no
increase in lenticular carotene but did increase zeaxanthin
[74]. The aqueous antioxidant Vitamin C however has more
promise for cataract prevention. In humans, plasma and lens
ascorbate were linearly related as was intake of C and lens
ascorbate. Interestingly, there was no saturation of human
lens ascorbate with dietary intake, although plasma is satu-
rated at >250 mg C/day [75].
There is one pro-drug antioxidant that recently has shown
promise, N-acetylcarnosine. This is the acetyl derivative of
the natural dipeptide antioxidant l-carnosine found in meat.
Because of its greater resistance to enzymatic breakdown by
carnosinase and its hydrophobicity compared to carnosine it
is able to cross the cornea of the topically treated eye and
maintain, over a longer period of time, the concentration of
the active principal carnosine in the aqueous humor. Carno-
sine is naturally present in normal lens at 25 M but decreases
to 5 M with cataracts. Carnosine decreases lipid peroxida-
tion and oxidative damage with lens subjected to in vitro
oxidative stress [76]. Acetylcarnosine was used to improve
 J.A. Vinson / Pathophysiology 13 (2006) 151162 159

the eyes of 96% of dogs with age-related cataracts after 6
months of daily topical application of a 1% solution. Two
studies, 6 and 24 months in duration, investigated this com-
pound on human cataracts. All three types of cataracts were
decreased and visual acuity improved 7100% and no wors-
ening of cataracts were seen in the long-term placebo-control
trial of 49 elderly patients with an average age of 65 years.
The treatment also improved visual acuity in subjects without
cataract. There were no ocular or systemic side effects with
this antioxidant medication [77].
5. Targeting mitochondrial oxidative damage in
diabetes [78] (Fig. 7)
Superoxide dismutases (CuZnSOD and MnSOD) are crit-
ical enzymes that protect the lens and epithelial cells in
the lens from oxidative damage [79]. Preventing the pro-
duction of superoxide by the mitochondria or increasing its
rate of decomposition by antioxidants, may block many of
the pathological effects of high glucose. Also -cell mito-
chondria, essential for glucose-stimulated insulin secretion in
the pancreas, are susceptible to oxidative damage during the
hyperglycemia that suppresses this secretion [80]. Within the
mitochondrial phospholipid bilayer, the fat-soluble antiox-
idants Vitamin E and Coenzyme Q both prevent lipid per-
oxidation, while Coenzyme Q also recycles Vitamin E and
is itself regenerated by the respiratory chain. However, it is
inside the mitochondria where the superoxide is formed at all
times but is elevated with hyperglycemia.
Normal metabolism removes electrons from fatty acids,
sugars and amino acids and the electrons then accumulate on
the electron carrier NADH and on the protein-bound FADH2 .
The electrons are then brought down the mitochondrial respi-
ratory chain to drive ATP synthesis by oxidative phosphory-
lation. As electrons move down the potential energy gradient
from NADH/FADH2 to oxygen, the redox energy is con-
served by pumping protons across the inner membrane to
build up a proton electrochemical potential gradient (
H+ ).
This gradient of a membrane potential and a smaller pH gra-
dient is used by the ATP synthase to make ATP which is
then carried to the cytoplasm to carry out work. An elevated

H+ favors superoxide formation and thus decreasing it
should decrease superoxide. Synthetic uncouplers such as
2,4-dinitrophenol make the inner membrane permeable to
protons and lower the
H+ .
The authors have discovered two uncouplers derived
from the lipophophilic Vitamins E and Q and made more
hydrophilic and able to penetrate the membrane of mito-
chondria and all cells by giving them a positive charge (see

Fig. 7. Mitochondrial oxidative damage. The mitochondrial respiratory chain (top) passes electrons from the electron carriers NADH and FADH2 through the
respiratory chain to oxygen. This leads to the pumping of protons across the mitochondrial inner membrane to establish a proton electrochemical potential
gradient (DmH+ ), negative inside: only the membrane potential (Dym) component of DmH+ is shown. The DmH+ is used to drive ATP synthesis by the
FoF1ATP synthase. The exchange of ATP and ADP across the inner membrane is catalysed by the adenine nucleotide transporter (ANT) and the movement
of inorganic phosphate (Pi) is catalysed by the phosphate carrier (PC) (top left). There are also proton leak pathways that dissipate DmH+ without formation
of ATP (top right). The respiratory chain also produces superoxide (O2 ) which can react with and damage iron sulfur proteins such as aconitase thereby
ejecting ferrous iron. Superoxide also reacts with nitric oxide (NO) to form peroxynitrite (ONOO ). In the presence of ferrous iron, hydrogen peroxide forms
the very reactive hydroxyl radical ( OH). Both peroxynitrite and hydroxyl radical can cause extensive oxidative damage (bottom right). The defenses against
oxidative damage (bottom left) include superoxide dismutase (MnSOD) and the hydrogen peroxide it produces is degraded by glutathione peroxidase (GPX)
and peroxiredoxin III (PrxIII). Glutathione (GSH) is regenerated from glutathione disulfide (GSSG) by the action of glutathione reductase (GR) and the NADPH
for this is in part supplied by a transhydrogenase (TH).
160 J.A. Vinson / Pathophysiology 13 (2006) 151162
Fig. 8. Chemical structure of triphenylphosphonium adduct of Coenzyme
Q10.
Fig. 8). These compounds were found in vitro to rapidly and
selectively accumulate in isolated mitochondria and by iso-
lated mitochondria within isolated cells. These compounds
in animal studies have been shown to come to a steady state
of 520 nmol/g of wet tissue or 520 M. In the mitochon-
dria, they are in the millimolar range. Such concentrations
are most probably going to be in the therapeutically effective
range, as antioxidants targeted to mitochondria have pre-
vented oxidative damage at 12.5 M [81]. Their in vivo
efficacy in preventing mitochondrial oxidative damage is cur-
rently being tested in mouse models of oxidative damage.
6. Conclusions
The fact that oxidative stress is responsible for the pathol-
ogy of cataracts is shown by this review and the abundant
literature on the subject. Besides increasing the levels of
endogenous antioxidants, such as vitamins, newer studies are
finding molecules that may well prove to be better preven-
tive or treatment therapies for cataracts. We await this new
research with great interest and anticipation.
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