Age-related macular degeneration and antioxidant vitamins:

recent findings
Elizabeth J. Johnson
Jean Mayer US Department of Agriculture Human
Nutrition Research Center on Aging, Tufts University,
Boston, Massachusetts, USA
Correspondence to Elizabeth J. Johnson, PhD, Jean
Mayer US Department of Agriculture Human Nutrition
Research Center on Aging, Tufts University, 711
Washington St, Boston, MA 02111, USA
Tel: +1 617 556 3204; fax: +1 617 556 3344;
e-mail: elizabeth.johnson@tufts.edu
Current Opinion in Clinical Nutrition and
Metabolic Care 2010, 13:28–33
Purpose of review
The purpose of the present review is to evaluate the most recent evidence for a role of
antioxidant nutrients in the prevention or delay in progression of age-related macular
degeneration (AMD), a major cause of visual impairment and blindness in the aging
population.
Recent findings
Recent human studies (>2008) report a decreased AMD risk with increased intakes of
lutein/zeaxanthin, B vitamins, zinc and docosahexaenoic acid but an increased risk with
increased intakes of b-carotene and vitamin E. These latter findings are inconsistent with
previous reports (<2008).
Summary
Findings on the association of certain antioxidants and docosahexaenoic acid support a
role for nutrition in a decreased risk of AMD. The inconsistent findings of an increased
risk with increased intake of b-carotene and vitamin E warrants continued investigation
into these relationships.

Keywords
age-related macular degeneration, antioxidants, nutrition, omega-3 fatty acids

Curr Opin Clin Nutr Metab Care 13:28–33

ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
1363-1950

function of blood vessels in the eye. Additionally, lutein

Introduction
Age-related macular degeneration (AMD) is a major
cause of visual impairment and blindness in the aging
population [1]. The prevalence of AMD increases
dramatically with age. Nearly 30% over the age of 75 years
have early signs of AMD and 7% have late stage disease,
whereas the respective prevalence among people ranging
from 43 to 54 years are 8 and 0.1% [2–4]. Because there
are currently no effective treatment strategies for most
patients with AMD, attention has focused on efforts to
stop the progression of the disease or to prevent the
damage leading to this condition [5].
Modifiable risk factors for AMD include light exposure
and smoking [5,6]. Of particular interest is the possibility
that nutritional counseling or intervention might reduce
the incidence or delay the progression of this disease.
The components in the diet that may be important are
vitamins C and E, B vitamins (B6, B12, folic acid), the
carotenoids (lutein, zeaxanthin, b-carotene), zinc and
omega-3 long chain polyunsaturated fatty acids, for
example docosahexaenoic acid (DHA) and eicosapentae-
noic acid (EPA). Given that the retina suffers oxidative
damage, the antioxidant nutrients are thought to be
protective through their role as antioxidants. The B
vitamins may lower homocysteine levels and improve
1363-1950 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
and zeaxanthin may provide protection as filters against
light damage, that is, absorbers of blue light. EPA is
a precursor to DHA and DHA may affect membrane
composition of the retina, which could alter membrane
structure and function.
The focus of the present review is to evaluate the most
recent evidence from human studies (2008) for evi-
dence of a role for these nutrients in AMD prevention.
Cause of age-related macular degeneration
AMD is a disease affecting the central area of the retina
[7] resulting in loss of central vision. Dry AMD occurs
when the light-sensitive cells in the macula slowly break
down, gradually blurring central vision in the affected
eye. In the early stages of the disease, lipid material
accumulates in deposits underneath the retinal pigment
epithelium (RPE) [8]. This is believed to arise after
failure of the RPE to perform its digestive function
adequately. At this early phase, there are no symptoms
and no vision loss. The lipid deposits are known as
drusen, and are seen as pale yellow spots on the retina.
The presence of a few small, hard drusen is common with
advancing age. The presence of larger and more numer-
ous drusen in the macula is a common early sign of AMD.
DOI:10.1097/MCO.0b013e32833308ff

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Hyperpigmentation and hypopigmentation of the RPE
may also occur in AMD. In the later stages of the disease,
the RPE may atrophy completely and there is a break-
down of light-sensitive cells and supporting tissue in the
central retinal area (geographic AMD). This breakdown
can cause a blurred spot in the center of vision. Over time,
the blurred spot may get bigger and darker, resulting in
increased loss of central vision.
Wet (neovascular or exudative) AMD occurs when abnor-
mal blood vessels behind the retina start to grow under
the RPE and sometimes under the subretinal space.
These new blood vessels tend to be fragile and may leak
blood and fluid. The blood and fluid raise the macula
from its normal place at the back of the eye. Damage to
the macula occurs rapidly and loss of central vision can
occur quickly.
The dry form is more common than the wet form, with
about 85–90% of AMD patients diagnosed with dry
AMD. The wet form of the disease usually leads to more
serious vision loss. In about 10% of cases, dry AMD
progresses to the more advanced and damaging form of
the eye disease.
An estimated 1.75 million individuals in the USA have
advanced AMD (geographic atrophy and neovascular
AMD), which accounts for the most cases of severe vision
loss [1]. Another 7.3 million people have early AMD [1],
which increases the risk of developing advanced AMD. A
major National Eye Institute study, The Age-Related
Eye Disease Study (AREDS) was a randomized, con-
trolled clinical trial that produced strong evidence that a
daily dose of b-carotene (15 mg), vitamins C (500 mg) and
E (400 IU), zinc (80 mg) and copper (2 mg) may help
prevent or slow progression of dry macular degeneration.
The AREDS study shows that taking high-dose formulas
of this nutritional supplement can reduce risk of early
stage AMD progression by 25% and a 19% reduction in
severe vision loss in individuals determined to be at high-
risk of developing the advanced forms of this disease [9].
Since this trial, the use of these nutrient supplements has
become the standard of practice in the USA.
Currently, AREDS 2 is being conducted [10]. This is a
multicenter randomized trial designed to assess the
effects of oral supplementation of high doses of lutein
and zeaxanthin and/or omega-3 fatty acids (DHA and
EPA) for the treatment of AMD. All participants are
being offered additional treatment with the study for-
mulation used in AREDS. This trial includes further
randomization to evaluate the possibility of deleting
b-carotene. This trial will also evaluate the effectiveness
of decreasing the original, pharmacologic dose of zinc
(80 mg) of the AREDS formulation to a level (25 mg) that
is closer to dietary intakes [11].
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AMD and antioxidant vitamins: recent findings Johnson 29
Recent human studies on nutritional factors
and age-related macular degeneration
Chemical and light induced oxidative damage to the
photoreceptors is thought to be important in the dysfunc-
tion of the RPE. The retina is particularly susceptible to
oxidative stress because of its high consumption of oxy-
gen, its high proportion of polyunsaturated fatty acids,
and its exposure to visible light. Nutrients that have a role
in antioxidation and membrane integrity have been
implicated in this regard. Antioxidants of interest include
lutein, zeaxanthin, b-carotene, vitamins C and E, B
vitamins and zinc. EPA is a precursor to DHA that
may play a role in membrane integrity.
Lutein and zeaxanthin
Of the 20–30 carotenoids found in human blood and
tissues [12] only lutein and zeaxanthin are found in the
retina [13,14]. Lutein and zeaxanthin are concentrated in
the macula or central region of the retina and are referred
to as macular pigment. In addition to their role as anti-
oxidants, lutein and zeaxanthin are believed to limit
retinal oxidative damage by absorbing incoming blue
light and/or quenching reactive oxygen species [15].
In a population-based cohort study, it was reported that
higher dietary intake of lutein and zeaxanthin may pro-
vide protection against AMD [16]. It was found that
those with dietary lutein and zeaxanthin intake in the top
tertile (942 mg/day), compared with the remaining
population, were 65% less likely to develop neovascular
AMD, and those above the median (743 mg) also were
34% less likely to develop indistinct soft or reticular
drusen.
However, in a prospective follow-up study of more than
70 000 women and more than 41 000 men without AMD,
during the 18-year follow-up, lutein/zeaxanthin intake
was not associated with risk of self-reported AMD,
although there was a statistically nonsignificant and non-
linear inverse association between lutein/zeaxanthin
intake and neovascular AMD risk [17]. The authors
concluded that lutein and zeaxanthin each may have a
different impact on AMD and that separate evaluation of
their values either from diet or plasma is warranted to
provide further insight on their individual roles in relation
to the development of AMD.
The role of lutein and zeaxanthin supplementation on
AMD progression is being tested in the current AREDS
extension trial (AREDS 2) [10].
b-Carotene
b-Carotene was included in the AREDS 1 intervention,
along with vitamins E and C, zinc and copper [9]. There
 30 Ageing: biology and nutrition
are no recent trials that have specifically evaluated
b-carotene supplementation on AMD risk.
In a population-based cohort study, it was reported that
the highest compared with the lowest tertile of total
b-carotene intake predicted incident neovascular AMD,
with a 2.68-fold increased risk of AMD [16]. b-Carotene
intake from diet alone predicted neovascular AMD, with
a 2.4-fold increased risk in the highest tertile compared
with the lowest tertile. After dividing the cohort into
those with above-median and below-median intakes
(median intake ¼ 6836 mg), with reference to those with
intakes between these, no significant associations were
found between higher or lower intake groups and inci-
dent AMD. The authors state that the findings of
an association between a higher intake of b-carotene
and an increased risk of AMD are inconsistent with past
reports of a protective effect on AMD progression or
development. The role of low and high b-carotene
supplementation on AMD progression is being tested
in the current AREDS extension trial (AREDS 2)
[10]
B Vitamins
Cross-sectional [18–20] and case-control studies [21–25]
indicate a direct relationship between blood levels of
homocysteine and risk of AMD. High plasma concen-
trations of homocysteine induce vascular endothelial
dysfunction [26] that has been suggested to be involved
in the cause of AMD [27]. Treatment with folic acid,
vitamin B6 and vitamin B12 has been shown to reduce
homocysteine levels [28] and to reverse endothelial dys-
function [29,30].
Christen et al. [27] conducted a randomized, double-
blind, placebo-controlled trial in women with heart dis-
ease of at least three risk factors for the disease. Of these,
96% did not have AMD at the start of the study. The
women were randomly assigned to receive either placebo
or a combination of folic acid (2.5 mg/day), vitamin
B6 (50 mg/day) and vitamin B12 (1 mg/day). Over the
course of 7.3 years of intervention and follow-up, there
were 55 cases of AMD in the combination treatment
group and 82 in the placebo group. For visually signifi-
cant AMD, there were 26 cases in the treatment group
and 44 in the placebo group. The combined B vitamin
supplement was associated with a 34% lower risk of any
AMD and a 41% lower risk of visually significant AMD.
The authors noted that beyond lowering homocysteine
levels, other possible modes of action include antioxi-
dant effect and improved function of blood vessels in
the eye.
Vitamin C
Vitamin C is an important water-soluble antioxidant and
also promotes the regeneration of vitamin E [31].
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In a population-based cohort study, it was reported that
total vitamin C intake was not related to AMD [16].
After dividing the cohort into those with above-median
and below-median intakes (median intake ¼ 206 mg),
with reference to those with intakes between these, no
significant associations were found between the higher or
lower intake groups and incident AMD. Vitamin C has
been evaluated in combination with other antioxidants
(see below ‘Antioxidant Combinations’).
Vitamin E
Vitamin E is a lipid soluble oxidant scavenger that
protects biomembranes. Vitamin E was included in the
AREDS 1 intervention [9]. There are no recent trials that
have specifically evaluated vitamin E supplementation
on AMD risk.
In a population-based cohort study, it was reported that
the highest compared with the lowest tertile of total
vitamin E intake predicted incident late AMD, with a
2.83-fold increased risk of AMD [16]. Compared with
the lowest tertile, the median tertile had a 2.55-fold
increase in the risk for late AMD. The authors state that
the findings of an association between higher intake of
vitamin E and increased risk of AMD are inconsistent
with other reports of a protective effect on AMD pro-
gression or development. After dividing the cohort into
those with above-median and below-median intakes
(median intake ¼ 8.2 mg), with reference to those with
intakes between these, no significant associations were
found between the higher or lower intake groups and
incident AMD.
Zinc
Zinc is important in maintaining the health of the retina,
given that zinc is an essential constituent of many
enzymes [32] and, therefore, important for optimal
metabolism of the eye. Zinc ions are present in the
enzyme superoxide dismutase, which plays an important
role in scavenging superoxide radicals.
The AREDS clinical trial reported that zinc, copper and
the antioxidants vitamin E, vitamin C and b-carotene,
reduced the risk of AMD progression by 25%. Such a
reduction was not observed with the antioxidant vitamins
alone [9]. In a population-based cohort study, it was
reported that higher dietary zinc intake may provide
protection against long-term incident AMD [16]. It
was found that those with dietary zinc intake in the
top tertile (15.8 mg/day), compared with the remaining
population, were 46% less likely to develop early AMD or
44% less likely to develop any AMD. After dividing the
cohort into those with above-median and below-median
intakes (median intake ¼ 12 mg), with reference to those
with intakes between these, no significant associations
were found between higher or lower intake groups and

incident AMD. The role of low and high zinc supple-
mentation on AMD progression is being tested in the
current AREDS extension trial (AREDS 2) [10].
Omega-3 fatty acids
In addition to these antioxidants, the omega-3 fatty acids,
DHA and EPA are thought to be important in AMD
prevention. [33,34]. EPA, the substrate for DHA, is the
parent fatty acid for a family of eicosanoids that affect
arachidonic acid-derived eicosanoids implicated in abnor-
mal retinal neovascularization, vascular permeability and
inflammation [35]. DHA is a key fatty acid found in the
retina and is usually present in large amounts in this
tissue [36,37]. Tissue DHA status affects retinal cell
signaling mechanisms involved in phototransduction
[37]. It has been suggested that atherosclerosis of the
blood vessels that supply the retina contributes to the risk
of AMD, similar to the mechanism underlying coronary
heart disease [38]. Therefore, dietary fat components
related to coronary heart disease may also be related to
AMD [39,40]. Long-chain omega-3 fatty acids may have a
special role in the function of the retina in addition to
their antithrombotic and hypolipidemic effects on the
cardiovascular system. Biophysical and biochemical prop-
erties of DHA may affect photoreceptor membrane func-
tion by altering permeability, fluidity, thickness, lipid
phase properties and the activation of membrane-bound
proteins [37].
A recent cross-sectional populations-based study has
found that an increased consumption of the DHA and
EPA reduced the risk of neovascular AMD [41]. Partici-
pants underwent fundus photography and were inter-
viewed for dietary intake using a food frequency ques-
tionnaire. Eating oily fish at least once per week
compared with less than once per week was associated
with a halving of the odds of neovascular AMD. Com-
pared with the lowest quartile, there was a significant
trend for decreased odds with increasing quartiles of
either DHA or EPA.
Furthermore, in a recent meta-analysis, the evidence on
dietary omega-3 fatty acid and fish intake in the primary
prevention of AMD was systematically reviewed [42].
Three prospective cohort, three case-control, and three
cross-sectional studies were evaluated and measures of
associations were pooled quantitatively. A high dietary
intake of omega-3 fatty acids was associated with a 38%
reduction in the risk of late AMD. Fish intake at least
twice a week was associated with a reduced risk of both
early and late AMD. The authors concluded that con-
sumption of fish rich in omega-3 fatty acids may be
associated with lower risks of AMD, but that there was
insufficient evidence from the literature to support their
routine consumption for AMD prevention. The role of
EPA and DHA supplementation on AMD progression is
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
AMD and antioxidant vitamins: recent findings Johnson 31
being tested in the current AREDS extension trial
(AREDS 2) [10].
Antioxidant combinations
There are many mechanisms by which a nutrient may
provide protection against AMD. Combinations of these
various nutrients may act additively or synergistically in
this protection. The AREDS 1 trial suggests this to be the
case, given that the significant reduction in AMD risk
was observed for antioxidant vitamins plus zinc, rather
than either alone.
In a case-control study in older Japanese adults, individ-
uals with no AMD, early or late AMD were evaluated for
serum antioxidants (a-tocopherol, g-tocopherol, retinol,
b-cryptoxanthin, a-carotene, b-carotene, lycopene,
lutein and zeaxanthin) [43]. Tertiles of each serum
antioxidant were obtained and the prevalence of early
or late AMD was compared. Only a-tocopherol and
b-cryptoxanthin were related to late AMD as single
antioxidants. However, a-carotene and b-carotene and
total carotenoids were protectively associated with
late AMD. No relationship was found between serum
antioxidants and early AMD. The authors concluded
that these findings supported the hypothesis that a
combination of serum antioxidants obtained from a
diet is protective for late AMD, but not for early
AMD.
Parisi et al. [44] evaluated the influence of short-term
carotenoids and antioxidant supplementation on retinal
function in nonadvanced AMD. In this randomized con-
trol trial, patients were supplemented with vitamin C
(180 mg), vitamin E (30 mg), zinc (22.5 mg), copper
(1 mg), lutein (10 mg), zeaxanthin (1 mg) and astaxanthin
(4 mg) daily for 1 year. A control group was given no
supplementation for the same period. At 6 and 12 months,
the supplemented group had highly significant increases
in the function of the central retina (zero to five degrees),
whereas no improvements were observed in the periph-
eral retina (five to 20 degrees). The authors concluded
that in nonadvanced AMD, a selective dysfunction in the
central retina can be improved by supplementation with
carotenoids and other antioxidants.
Conclusion
The hypothesis that certain nutrients may provide
protection against AMD risk is biologically plausible.
The most recent evidence to date supports a role of
lutein, zeaxanthin, B vitamins, DHA and EPA. Vitamin
C has been found to be related to decreased risk when
used in combination with other nutrients. The recent
findings of an increased risk with increased intake of
b-carotene and vitamin E is not consistent with past
findings.
 32 Ageing: biology and nutrition
Results of AREDS 2 will aid in the determination of the
role of antioxidant vitamin, minerals and omega-3 fatty
acids supplementation in the delayed progression
of AMD.
Acknowledgement
The present study was supported in part by Agricultural Research
Service, agreement 58-1950-7-707. Any opinions, findings, conclu-
sions or recommendations expressed in this publication are those of the
author and do not necessarily reflect the view of the US Department
of Agriculture.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
 of special interest
 of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 109–110).
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44 Parisi V, Tedeschi M, Gallinaro G, et al. Carotenoids and antioxidants in age-
 related maculopathy Italian study: multifocal electroretinogram modifications
after 1 year. Ophthalmology 2008; 115:324–333; e2.
This randomized controlled study in nonadvanced AMD found that a selective
dysfunction in the central retina can be improved with a combination of supple-
mentation with carotenoids and antioxidants.