30 day supply: 60 capsules
MacularProtect Plus Highlights
Powerful nutritional formulation for individuals concerned about preserving macular health.
Contains blend of antioxidants and zinc at levels found to support eye health in the AREDS clinical trial, with the exception of beta-carotene.
Features low levels of beta-carotene for those who should avoid high beta-carotene intake, such as smokers.
Contains 15 mg of FloraGLO® lutein and 1 mg of zeaxanthin, consistent with the latest scientific findings.
Delivers broad spectrum of natural source vitamin E, from alpha to gamma tocopherol.
Made from premium ingredients and manufactured according to the highest quality standards.
Recommended dose: two capsules per day of MacularProtect Plus (one capsule, taken twice daily) and two softgels per day of Omega-3 Upgrade (one softgel, taken twice daily).
An appropriate choice for smokers and non-smokers.
For comprehensive protection for macular and whole body health, consider MacularProtect Complete-S, an all-in-one AREDS-based formula (beta-carotene free) with a built-in multinutrient.
Consider adding Omega-3 Companion, an EPA and DHA-rich fish oil supplement to your daily macular health regimen to get the added benefit of the nutrients being studied in the AREDS 2 clinical trial. EPA and DHA have also been found to help preserve macular health.
Suggested Use: take a total of two capsules daily, with meals (one capsule taken orally, twice daily).
Note: pregnant or lactating women or individuals with medical conditions should consult a physician before using.
Note: MacularProtect Plus contains 80 mg of zinc, a level that was found to support eye health in the AREDS clinical trial. It is important to check with your physician prior to taking this product to ensure that this level of zinc is appropriate for you.
Vitamin A (5,000 IU)
MacularProtect Plus provides 100% of the recommended Daily Value of
vitamin A; half as pre-formed retinyl palmitate and half as beta-carotene,
which is converted to vitamin A only as required by the body.
Vitamin A as Retinyl Palmitate
(50%; 2,500 IU)
A (also known as pre-formed A or retinyl palmitate) is essential
for proper eye health. It protects night vision and is vital for the
health of the eyes cornea. It also works with zinc
to support the proper function of various eye structures. vitamin
A serves an important role in interactions with zinc
and the amino acid taurine within the photoreceptors of the retina.
Vitamin A as Beta-Carotene
(50%; 2,500 IU)
Beta-carotene functions primarily as an antioxidant and is converted
itamin A only as needed by the body. MacularProtect Plus contains
one-tenth the level of beta-carotene
administered to AREDS participants. High doses of beta-carotene
are linked to increased health risks in smokers; therefore, levels of
supplemental beta-carotene similar to the amount utilized in AREDS
may not be advisable for current or recent former smokers. It is important
to note that since AREDS
began in 1991, new science has emerged suggesting that lutein and zeaxanthin
are the carotenoid antioxidants more positively associated with macular
Vitamin C (1,000 mg)
C is a water-soluble antioxidant that is concentrated in ocular
tissues where it inactivates free radicals. Free radicals are the highly
reactive compounds produced through the bodys use of oxygen, and
generated by outside sources such as UV light. As an integral component
of the bodys antioxidant defenses, vitamin
C also aids in the recycling of other antioxidants such as vitamin
E. Evidence indicates that the requirements for both vitamin
C and E
are higher in those who smoke. MacularProtect Plus supplies the form
and level of vitamin
C administered in the AREDS
clinical trial, plus an additional 500 mg.
Vitamin E (400 IU)
Fat soluble vitamin E is the major chain-breaking antioxidant present
in retinal and macular membranes. As a first line of defense against
fatty acid peroxidation, vitamin E helps protect cell membranes against
free radical attack. MacularProtect Plus provides the natural source
rather than synthetic vitamin E, as studies demonstrate that this form
offers superior bioavailability and is better retained in tissues. It
also delivers broad spectrum vitamin E from alpha to gamma tocopherol,
that together play a health-protective role. MacularProtect Plus includes
400 IU of vitamin E, the level used in AREDS .
Zinc (80 mg)
Zinc is an essential mineral that is selectively concentrated in the eye.
It is found in the retina and choroid, ciliary body, iris, optic nerve,
sclera, cornea and lens. Within these ocular structures zinc is believed
to interact with vitamin A and taurine to modify photoreceptor membranes,
to help regulate the light-rhodopsin reaction, to influence nerve transmission
and to serve as an antioxidant. MacularProtect Plus provides 80 mg of
zinc, the form and level administered in AREDS
(15 mg) and Zeaxanthin (1 mg)
are two similarly-structured carotenoids found in green leafy vegetables
like spinach, kale and mustard greens. These carotenoids make up the
macular pigment of the retina, the tissue with the highest concentration
of lutein and zeaxanthin in the body. As part of the macular pigment, lutein and zeaxanthin
filter blue (visible) light that causes photo-oxidative stress. Population
health studies have noted that macular pigment density is positively
associated with age-related macular health. Several intervention studies
also indicate that consumption of these carotenoids from foods or supplements
can favorably modify the density of macular pigment.
The amount of lutein supplied by MacularProtect
Plus is within the range of lutein
intake (approximately 10-20 mg) found in studies to increase macular
pigment density on average by about 18-19%, although the response appears
to vary among individuals. MacularProtect Plus provides FloraGLO®
lutein, a premium source with proven bioavailability. The ratio
to lutein within this formula reflects the levels naturally present
in the diet.
Selenium (70 mcg)
Selenium is an essential mineral required for the proper function of
glutathione peroxidase, an antioxidant enzyme found in the eyes
lens and localized in photoreceptor and retinal pigment epithelial cells.
MacularProtect Plus delivers Selenium as selenomethionine, a bioavailable
source. Selenium is included in MacularProtect Plus at 100% of the recommended
Copper (2 mg)
is a mineral that is necessary for normal development of connective
tissue, nerve sheaths, skin pigment and for the proper utilization of
iron. Since high levels of zinc compete with copper for absorption, copper
is included in MacularProtect Plus to help ensure an adequate level
of this essential mineral in the body. MacularProtect Plus features
2 mg of copper oxide, the form and level administered in the AREDS
AMD Forecasters Call for Wider Vitamin Use
In a newly published analysis
(1), researchers predict that cases of age-related macular
degeneration (AMD) will nearly double in the coming decades, increasing
from 9.1 million in 2010 to 17.8 million in 2050. The study also
found that newer therapies have the potential to reduce AMD-related
visual impairment and blindness by as much as 35%.
According to the authors, the use of antioxidant
vitamins - specifically those used in the Age-Related
Eye Disease Study (AREDS) - is a key preventive strategy in
slowing the progression of AMD from early to late stages. The
authors point out that AREDS
formulas are not widely used among patients with early-stage disease,
and suggest that public prevention efforts should focus on expanding
the use of antioxidant vitamins in people with early AMD, and
making sure those people are getting the correct vitamin doses.
So for those who have been diagnosed with
AMD, a first step is to talk with your eye care professional about
high dose antioxidants, and to be consistent with supplementation
when it is recommended.
Genetic Risk Factors May Be Critical
It's now understood that those with a family
history of AMD have a greater risk of getting the disease. Scientists
have identified a number of genes that seem to make some people
more susceptible to AMD by creating inflammation or increasing
oxidative damage (2). Adopting good
dietary and lifestyle habits early may help prolong health and
save eyesight later in life, especially for susceptible individuals.
Food Combinations Reduce AMD Risk
Foods provide many nutrients that may work
together to help counter AMD from developing. Researchers from
Tufts University developed a scoring system to examine the combined
effect of nutrients, and applied this to the diets of people in
trial. Those whose diets were high in protective nutrients and
low-GI (glycemic index) foods had a much lower risk of getting
early and advanced AMD (3).
A food's GI value is based on how fast its carbohydrates raise
the body's blood sugar levels; low GI foods like whole grains
have less impact on blood sugar fluctuations.
Protective foods included good sources of
trial nutrients: vitamin
E and zinc,
as well as the nutrients being tested in AREDS 2: the omega-3s
from fish oil - DHA
(Another antioxidant included in the original AREDS
clinical trial, beta-carotene,
did not affect AMD risk levels).
Putting it All Together: Preventive Actions
The CAREDS Study
A number of studies have looked at the relationship
between dietary lutein and zeaxanthin intake and the risk for age-related
macular degeneration (AMD). Many - though not all - of the findings from these
population health studies suggest that eating more lutein-rich foods is
The authors of the Carotenoids in Age-Related Eye Disease
Study (CAREDS) now report that a stable intake of these nutrients over time
could reduce the risk of AMD by 43% in healthy women under 75.
CAREDS, an off shoot of the Women's Health Initiative
(WHI), looked at over 1780 women aged 50-79 who had either high or low intake of
lutein plus zeaxanthin when they entered the WHI study. These women were later
asked to participate in CAREDS, and researchers determined which of them had
developed AMD using special photographic techniques.
Regular Lutein Intake Supports Visual Health
Women with higher intakes of lutein plus zeaxanthin (at
least about 3 milligrams or more daily) had a substantial 43% lower risk for
intermediate AMD compared to those eating about ¾ of a milligram or less every
day. This protective effect was seen in women 75 years and younger who had
stable intakes of these nutrients.
Safely Achieving a Lutein-Rich Diet
If a higher and consistent intake of lutein and
zeaxanthin is important, how do we go about achieving it?
A commonly eaten, concentrated source of lutein is green
leafy vegetables such as spinach. Some people are leery of eating fresh spinach
because of the recent contamination of certain fresh spinach brands with the
illness-causing, bad bug E. coli 0157:H7. Information about the brands and
batches that were recalled can be found at the Center for Food Safety and
Applied Nutrition (CFSAN) (http://www.cfsan.fda.gov/list.html).
According to CFSAN, no frozen or canned spinach was
implicated in this most recent outbreak.
Should an E. coli 157:H7- related outbreak occur in the
future, CFSAN indicates that cooking fresh spinach at 160 degrees Fahrenheit for
at least 15 seconds will kill any E. coli O157:H7 present.
Eat a Variety of Lutein-Containing Foods
While terrific, spinach isn't the only source of lutein
and zeaxanthin. These nutrients can also be obtained from eating corn, broccoli,
peas, squash and other green leafy vegetables like kale, collards and mustard
greens. Consuming a wide variety of produce is healthful overall, and the CFSAN
website offers a handy booklet of general safety tips for storing and preparing
fresh produce and juices called Safe Handling.
Eggs yolks are another excellent source. Though they
contain considerably less of these nutrients than spinach, the lutein and
zeaxanthin they do contain is very well absorbed according to several recent
studies. The good bioavailability is likely due to the fats found in egg yolk.
Lutein and zeaxanthin are fat-soluble, so absorption is enhanced when fat is
present. While eggs contain 213 mg of cholesterol - and the recommended intake
of dietary cholesterol is 300 mg. daily - eggs can fit into the daily
cholesterol budget several times weekly if you limit cholesterol from other
sources such as meats, poultry and dairy products.
Lutein Supplements Can Also Play a Role
While the ideal intake of lutein has not been pinned
down, we do know that the typical American intake of 1-2 mg daily from foods
falls short of the 3-7 mg daily that studies suggest may be beneficial.
Supplements of lutein and zeaxanthin can also be of help in closing this dietary
gap and ensuring regular intake.
Moeller SM et al. Age-Related Macular Degeneration
and Lutein and Zeaxanthin in the Carotenoids in Age-Related Eye Disease Study
(CAREDS). Archives of Ophthalmology 124:1151-1162, 2006.
New Study Shows Lutein Improves Eyesight for AMD Patients
Lutein Antioxidant Supplement Trial (LAST) is the first study to report
actual improvement in key visual functions among patients who already have "dry"
age-related macular degeneration (AMD), the most common form of this disease.
Prior to the publication of LAST in April (1),
studies had linked greater consumption of
lutein solely to a lower risk of AMD in healthy people.
This double-blind, year
long study looked at the effects of 10 mg of
lutein alone or combined with other antioxidants, on a number of visual
measures in 90 patients with atrophic AMD. The amount of
lutein supplemented in LAST is equivalent to eating about 3-4 ounces of
spinach each day. While
lutein is concentrated in dark green leafy vegetables such as spinach,
collards and kale, the U.S. intake is estimated to be only 1-2 mg daily.
Compared to those getting
a placebo, the lutein/antioxidant supplemented group experienced a 50% increase
in macular pigment density, indicating an improved ability to filter out
damaging UV light. Patients taking
lutein or the combination showed improvement in quality of vision (measured
by contrast sensitivity) and glare recovery, a test of macular function. They
were also better able to distinguish near object details and shape (near visual
acuity). According to lead author
Dr. Stuart Richer, patients taking
lutein were able to see the equivalent of one line more on standard eye
tests at the end of the year, while those receiving placebo continued to
decline-- a clinically meaningful finding for those trying to preserve their
Vitamin C Fights
Inflammation-Risk Factor for Heart Attack
A second study published
in April is also a "first" of its kind--the first to report that
vitamin C can lower C-reactive protein (CRP). CRP is a biomarker for
inflammation that has garnered increasing attention as a new way to identify
those at risk for heart attack (2). It's now
understood that chronic inflammation can lead to heart attack and stroke by
making cholesterol-laden artery plaque less stable and more likely to rupture
(See newsletter issues for
CRP levels can rise up to
a 100 fold for short periods during illness, because inflammation occurs as part
of the body's normal defense against infection. However a persistent, moderately
elevated level of CRP in the blood reflects chronic inflammation, and has been
linked to increased risk of heart disease, diabetes, Alzheimer's disease, and
even age-related macular degeneration.
In this double-blind
study, researchers at University of California at Berkeley tested 160 healthy
adults who either smoked or were exposed to second hand smoke. Those who had
greatly elevated CRP likely due to existing illness were excluded from the
study. The remaining participants were assigned to receive placebo, 500 mg of
vitamin C, or a mixture of antioxidants (C, E and alpha-lipoic acid). Plasma
levels of CRP in the volunteers were measured before and at the end of the two
Levels of CRP decreased a
significant 24% among those supplementing with
vitamin C compared to placebo takers. CRP levels also declined for those
taking the antioxidant mixture, but not as much as
vitamin C group. The researchers noted that much higher levels of
vitamin E than were utilized in this study have previously been reported to
lower CRP in diabetics and healthy individuals (3).
These same investigators will be conducting a second trial in an attempt to
replicate these findings. According to lead author Dr. Gladys Block, "If our
vitamin C's ability to lower CRP is confirmed,
vitamin C could become an important public health intervention."
The Age-Related Eye
Disease Study (AREDS) is a major study sponsored by the National Eye Institute
and conducted at 11 medical research centers around the country. This
large-scale clinical trial was undertaken because age-related macular
degeneration (AMD) is the leading cause of vision impairment among people 65 and
older, and because the treatments for preventing its advanced forms are very
limited. Started in 1992, the results of this study were reported in
Over 3,600 older
participants were followed for about six years during the trial. Patients were
initially assigned to different categories based on the extent and type of their
disease €“ from early to intermediate, and more advanced stages of AMD. They then
received one of four supplements: a placebo, high-dose
copper and antioxidants (vitamins C, E and
beta-carotene), or a combination of
copper plus the antioxidants.
Both the antioxidants and
the mineral supplements each appeared to offer protection. But the benefits were
greatest for those who received the antioxidant and
zinc combination, and who were in the highest-risk categories (patients with
intermediate and advanced forms). Supplementation with antioxidants and
zinc significantly reduced the risk of progressing to more advanced AMD in
these groups by 25%, and reduced their risk of vision loss by 27%.
The study was not able to
show that supplements could prevent AMD, or restore vision already lost. But
supplements can play a key role in helping people at risk for advanced AMD curb
its advancement and preserve their vision. With the caveats that high dose
beta-carotene should be avoided by smokers and ex-smokers, and that
supplement takers need to be routinely monitored, the study confirmed the
general safety and benefit of these high-potency supplements in maintaining
While the researchers
lutein along with vitamins
E, this carotenoid was not available when the study started. Instead they
beta-carotene, which was being studied at the time in heart disease.
Antioxidants, Zinc & Omega-3s Reduce Genetic Risk of Early AMD
Introduction: Genes, Nutrients and AMD Risk
AMD is clearly a complex disease with multiple environmental and genetic risk factors. In terms of genetics, two of the more prominent AMD susceptibility genes identified to date are Complement Factor H (CFH) and LOC387715 / HTRA1.
There are several different forms (variants) of these genes that significantly raise the risk of AMD. Carrying the CFH Y402H variant increases risk of AMD up to 11 times. For carriers of the variant LOC387715 A69S, the risk is up to 15 times greater.
Together, these variants may contribute to late AMD in more than 80% of cases. Thus finding ways to counter these major gene effects is of public health importance.
The only protective factors for AMD known to date are nutrients. Zinc and antioxidants were shown in the AREDS trial to reduce the risk of progression from intermediate to advanced AMD. Population based studies have also found a reduction in AMD risk progression with higher intakes of lutein/zeaxanthin, or with higher intakes of the omega-3 fatty acids EPA and DHA.
Is the protection afforded by these nutrients sufficient to reduce AMD risk in carriers of well-known risk variants? To address this question, authors of The Rotterdam Study have explored the relationship between a healthy diet, genetic risk and early AMD in a nested, case-control study (1).
Dietary intake was assessed at baseline using a food frequency questionnaire for 2167 participants (> 55 years) at risk of AMD from the population-based Rotterdam Study. Genetic variants were determined using TaqMan assay. Incident early AMD was determined by fundus photography at 3 follow-up visits.
The synergy index was used to evaluate biological interaction between risk factors; Hazard ratios were calculated to estimate risk of early AMD in strata of nutrient intake (stratified by tertiles) and genotypes.
During a median follow-up of 8.6 years, 517 participants developed early AMD. Significant synergy indices supported a biological interaction between:
Homozygotes of CFH Y402H with zinc intake in the highest tertile reduced their hazard ratio of early AMD from 2.25 to 1.27. For intakes of beta carotene, lutein / zeaxanthin, and EPA / DHA, these risk reductions were from 2.54 to 1.47, 2.63 to 1.72, and 1.97 to 1.30, respectively. (See table).
Graphic courtesy of Archives of Ophthalmology
Carriers of LOC387715 A69S with the highest intake of zinc and EPA / DHA reduced their risk from 1.70 to 1.17 and 1.59 to 0.95, respectively (all p trends < .05).
These results suggest that higher dietary intake of zinc, carotenoids and EPA/DHA can attenuate the incidence of early AMD in those carrying important genetic variants. The authors conclude that “clinicians should provide dietary advice to young, susceptible individuals to postpone or prevent the vision-disabling consequences of AMD”.
It’s well established that complement activation and inflammation play an important role in development of AMD. The CFH gene is a key regulator of complement, and the Y420H variant impairs its regulatory function. As for LOC387715, evidence suggests that the A69S variant may jeopardize mitochondrial function and lead to free radical formation and apoptosis.
There are plausible mechanisms that could explain the effect of these nutrients in carriers of both variants. For example, antioxidant nutrients can counter oxidative damage, an activator of the complement cascade, while omega-3s act as anti-inflammatory agents in the retina. Dysfunctional mitochondria may increase complement activation which, evidence suggests, zinc may counter.
Ho L, et al. Reducing the genetic risk of age-related macular degeneration with dietary antioxidants, zinc, and ω-3 fatty acids. The Rotterdam Study. Arch Ophthalmol 129:758-66, 2011.
In the News: Vitamin C & Retinal Cell Function, Metformin & Vitamin B12 Depletion, Meta-analysis: Lutein & AMD
Background: Role of GABA in Retina
GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the central nervous system (CNS). GABA receptors modulate the rapid communication between brain cells by acting as an inhibitory ‘brake’ on excitatory nerve cells.
There are different types of GABA receptors: The ‘a’ type, for example mediates fast inhibition, while the ‘c’ receptor mediates slow and sustained responses. GABAc receptors are expressed in many regions of the brain, with prominent distribution on retinal neurons. These receptors are thought to play important roles in retinal signal processing.
Vitamin C Needed for Retinal Neuron Function
Researchers at Oregon Health and Science University report this month that the function of both retinal GABAa and c receptors is regulated by vitamin C (1).
According to the authors, “the cells need to be bathed in relatively high doses of vitamin C inside and out” for proper receptor function. Conversely, the receptors failed to function in the absence of the vitamin.
Vitamin C appears not only to play an indispensible role in retinal nerve cells, it may also be important for brain function. “Because the retina is part of the CNS, this suggests there’s likely an important role for vitamin C throughout our brains, to a degree we had not realized before”, explained the lead investigator. Vitamin C stores in the brain are known to be the last to be depleted during times of vitamin C deprivation.
The findings may also have implications for other conditions involving malfunctioning nerve cells in the retina and brain, such as glaucoma and epilepsy, the investigators theorize, and it “may be that a vitamin C-rich diet could be neuroprotective for the retina”.
Metformin and Vitamin B12 Depletion
There’s been increasing concern over the risk of vitamin B12 deficiency in type 2 diabetics taking the common diabetes medication metformin (2) (e.g. Glucophage®). According to some studies, 10-30% of people taking this drug show evidence of decreased B12 absorption. Since people over 50 are generally less efficient at absorbing B12, this drug-nutrient interaction could exacerbate levels that are already low. Vitamin B12 depletion is more common in people who’ve been taking metformin the longest, and/or at high doses.
Clinicians suggest that patients who’ve used the medication for several years or who take a high dose, should have their B12 levels tested. Checking blood levels of B12 should always be done with signs of deficiency, especially those related to nerve problems such as numbness, pain or tingling in the hands or feet.
Lutein Reduces Risk of Late Stage AMD
Lutein and zeaxanthin are thought to decrease the incidence of AMD; however, findings have not always been consistent. A team of Chinese researchers from Peking University recently conducted a systematic literature review and meta-analysis to evaluate the relationship between dietary intake of lutein and zeaxanthin and AMD risk (3).
Six longitudinal cohort studies met the strict inclusion criteria, and their results were pooled for analysis. The researchers excluded studies that examined the use of supplemental carotenoids.
Comparing the highest with lowest category of intake showed that higher intakes of these carotenoids were associated with a 26% reduction in the risk of late-stage AMD, and a risk reduction of 32% for neovascular AMD.
Little effect of lutein and zeaxanthin in the early stages of this disease was found.
Research Briefs: Vitamin D, AREDS Antioxidants & Citrus Flavonoids
Introducing EduFacts Research Briefs
While EduFacts will continue to highlight a newly published study or review article on nutrition and ocular health, it will now occasionally present Research Briefs: short summaries of several studies from various journals.
Vitamin D Again Linked to Reduced AMD Risk
Researchers from the University of Wisconsin and elsewhere examined the relationship between serum vitamin D and the prevalence of early AMD among 3000+ postmenopausal women (1). Higher serum vitamin D concentrations (> 38 nmol/L) were found to be significantly associated with a 48% decreased odds of early AMD and a 57% decreased risk of pigmentary abnormalities in women under 75 yrs. For those over 75, the association was of borderline significance.
In terms of vitamin D intake from supplements and foods, those consuming the highest amount (on average about 600 IU) daily, had a 59% lower risk of AMD compared to those obtaining the least (about 300 IU on average). This is the 2nd study to report a relationship between vitamin D and AMD. Because vitamin D has known anti-inflammatory and immune modulating actions, the authors speculate this nutrient may suppress destructive inflammation that occurs at the RPE-choroid interface in early stage disease.
AREDS, Ocular Blood Flow & Endothelial Function
Oxidative stress is a contributor to ocular diseases such as diabetic retinopathy, cataract, AMD, uveitis, and possibly glaucoma. The presence of increased oxygen radicals in vascular tissue is believed to cause endothelial dysfunction, leading to decreased dilation, more inflammatory cell and platelet adhesion, and increased coagulation activity. The retina is especially vulnerable to oxidative stress because of its high oxygen consumption, its high concentration of poly-unsaturated fatty acids, and its direct exposure to light.
Using an experimental protocol, clinicians from the Medical University of Vienna showed that systemic
inflammation diminishes the retinal vascular response to hyperoxia. (The protocol uses an endotoxin to reduce the response of retinal blood flow under conditions of excess oxygen). The reduced response is due to endothelial dysfunction caused by oxidative stress. In a double-blind, placebo-controlled parallel study (2), 21 healthy volunteers were given the AREDS formula or a placebo for two week periods. At the beginning and end of each period, retinal blood flow and retinal blood flow reactivity to hyperoxia was assessed.
The investigators found that the AREDS antioxidants restored retinal vascular reactivity. According to the authors, this was likely due to oxygen radical scavenging by the antioxidants. The results suggest that this model might be a good approach to screening antioxidants for their relative beneficial effects in the retina.
Flavonoids, Inflammation and Blood Pressure
Researchers studied the effects of orange juice (OJ) and its major flavonoid, hesperidin, on blood pressure and blood vessel function in overweight but otherwise healthy men (3). About 1/3 of the men had elevated blood pressure but were taking no anti-hypertensive medications. During 3 month-long periods, the men drank either 17 oz of OJ daily, a control drink with 300 mg hesperidin capsules (the same amount as the OJ contained), or a control drink plus a placebo capsule. At the end of both the OJ and hesperidin test periods, diastolic pressure was significantly lower than after the placebo period. Studies suggest that even a decrease of just 3-4 points in diastolic pressure could result in a 20% reduction in the incidence of coronary heart disease. Hypertension also appears to raise the risk of retinopathy in non-diabetics (4).
The researchers also tested a variety of measures of blood vessel activity, including the ability to dilate. Both OJ and hesperidin showed positive effects compared to placebo. This finding is consistent with recent data linking higher intake of citrus flavonoids with lower markers of inflammation and endothelial dysfunction in participants of the Nurses Health Study (5).
Positive News on the AMD Front: Prevalence Down
Prevalence of AMD May be Declining
In 2004, the Eye Diseases Prevalence Group, using a meta-analysis of regional population-based studies, estimated that late AMD was present in more than 1.75 million people in the US. They also projected that the number with AMD would increase to almost 3 million by 2020, since Americans are living longer.
Those projections didn’t take into account the effects of changes in treating people at high risk for late AMD, such as more frequent recommendations for the use of zinc and antioxidant vitamins following publication of results from the AREDS trial in 2001. The predictions also assumed that AMD risk factor rates would remain unchanged.
More recently, another study forecast that the number of people with early AMD would jump from 9.1 million to 17.8 million, and that late AMD would go from 620 000 to 1.6 million over the next 40 years, owing to the aging of our population.
Now, an updated estimate (1) based on the 2005-2008 National Health and Nutrition Examination Survey (NHANES) tells us that AMD prevalence has actually declined since the last report (1988-1994 NHANES).
Retinal photographs (45° digital images) from both eyes of more than 5,500 people 40 and older from the 2005-2008 NHANES were graded for severity using a standard protocol, with AMD as the main outcome.
Overall, the prevalence of any AMD was 6.5%, which is considerably lower than the 9.4% prevalence reported in the 1988-1994 NHANES. The prevalence of large and soft drusen, RPE de-pigmentation, increased retinal pigment, exudative macular degeneration, geographic atrophy, and early / late AMD are shown in Table 2 below.
This study estimates that about 1 in 15 people over 40 – 7.2 million Americans in all – have AMD. In addition to a greater number of at risk people taking AREDS supplements, the authors speculate that reductions in smoking and cholesterol levels, and/or improvements in diet, exercise and blood pressure may have contributed to the decrease in prevalence.
Currently, however, adults and children are more overweight than ever, and a large portion of Americans fail to meet dietary recommendations. 2011 is also the year that the first wave of baby boomers will turn 65 – at the rate of 7000 per day. So it’s important to delve deeper and try to understand why the drop in AMD prevalence occurred. If we can better understand what’s behind the decline, it might provide insights to help prevent future generations from developing this disease.
Review: Lutein & Zeaxanthin Metabolism
Metabolism is Key to Lutein’s Protective Role
Growing evidence suggests lutein and zeaxanthin play an important role in protection against AMD by filtering out blue light or quenching free radicals. While much remains to be learned, researchers from Waterford Institute and Regional Hospital in Ireland and the University of Utah’s Moran Eye Center have reviewed mechanisms involved in absorption and transport of these carotenoids, their uptake by the retina and how they are stabilized (1). Below are highlights of these findings, along with editorial comment on implications for diet, lifestyle and supplement use.
Absorption of Lutein and Zeaxanthin
Dietary fat is important for the absorption of xanthophyll carotenoids like lutein and zeaxanthin. Fat stimulates bile flow from the gall bladder to emulsify fat-soluble vitamins into lipid micelles – microscopic fat droplets – so they can be absorbed in the small intestine. Inadequate fat intake can result in reduced absorption of carotenoids, even if the diet is carotenoid-rich. Experimental data suggest absorption of lutein is mediated by a non-specific transporter protein (this protein, scavenger receptor class B type I, appears to play a primary role in intestinal absorption, but other proteins or passive diffusion may also be involved). Of note, some competition for absorption is seen when similarly structured carotenoids like beta-carotene and lutein are consumed together.
Comments: Though different carotenoids compete for absorption, some evidence suggests that balanced amounts of various carotenoids consumed together over time don’t interfere with each other in terms of bioavailability (2). Importantly, doses of lutein (10 mg) and zeaxanthin (2 mg) now being used in the AREDS 2 trial, did not reduce serum levels of other important carotenoids in a dosing study (3).
Transport of Lutein and Zeaxanthin
Dietary lutein and zeaxanthin are delivered to the retina via plasma lipoproteins, chiefly LDL and HDL cholesterol. While LDL is the primary carrier for most carotenoids, LDL and HDL carry about equal amounts of lutein and zeaxanthin. Several studies suggest relatively low HDL levels could hinder transport and capture of these carotenoids. Lower HDL levels have been found in overweight and obese individuals, for example, and higher body fat percentage is linked to risk of AMD progression as well as to lower macular pigment density. Lipoproteins also include protein components known as apolipoproteins. Researchers are investigating whether a person’s apolipoprotein profile might influence transport and delivery of these carotenoids to the retina. Of many apolipoproteins types, ApoE has the strongest link with AMD.
Comments: Lower levels of HDL have been found in overweight individuals, consistent with the possibility that a relative lack of HDL may impair transport and/or retinal capture of the carotenoids. Obesity has been identified as a risk factor for AMD. Take home message? Aerobic exercise, which aids weight loss and increases HDL, may prove useful in lowering AMD risk.
Retinal Uptake of the Xanthophyll Carotenoids
The mechanisms governing retinal capture and accumulation of lutein and zeaxanthin to the exclusion of other carotenoids are still poorly understood. However, retinal capture of xanthophyll carotenoids is performed by xanthophyll-binding proteins (XBP). XBPs may also be involved in: a) stabilizing xanthophylls in cell membranes, the cytosol or the cytoskeleton, b) mediating inter-conversion of lutein, zeaxanthin and various metabolites within the retina, and c) facilitating antioxidant activity of macular carotenoids. Importantly, it has been found that XBPs can become saturated, with implications for xanthophyll carotenoid supplementation.
Comments: Macular pigment density often increases dramatically in the first 4 weeks of supplementation, and then levels off. In a number of studies testing 10-12 mg of lutein, macular pigment density reached a plateau after the first month. This may be due to saturation of binding proteins, and suggests higher doses may not further enhance macular pigment over time.
Is CVD a Major Risk Factor for AMD?
That very question was addressed in an editorial (1) appearing in the September issue of the American Journal of Ophthalmology, and the evidence to date suggests that CVD is an important risk factor for AMD. Epidemiologic studies conducted over the past two decades indicate (with the possible exception of diabetes) that all of the traditional cardiovascular risk factors such as smoking, hypertension, elevated cholesterol levels, and higher body mass index (BMI) are associated with AMD risk.
So far, the link between smoking, hypertension and AMD is stronger than that between cholesterol, BMI and AMD, while newer studies suggest that less traditional markers of CVD such as inflammation and endothelial dysfunction are also involved in AMD pathogenesis. Overall, there is good evidence that AMD and CVD share similar risk factors and mechanisms that underlie disease development, according to the editorial.
Are AMD Patients at Greater Risk for CVD?
Conversely, emerging data indicates that the presence of AMD also signals an increased risk of CVD, independent of the effects of age and shared risk factors. “Taken in totality, these newer data suggest that patients with signs of AMD, particularly younger patients, may be at increased risk of CVD”, the editorial concludes.
Newly published findings from The Cardiovascular Health Study (2) provide further support that AMD is associated with underlying systemic vascular disease.
Study Design and Methods
The Cardiovascular Health Study is a population-based prospective cohort study of CVD in adults 65 years of age and older. To examine the associations of AMD with incident coronary heart disease (CHD), AMD was evaluated by fundus photographs in 1,786 white and Afro-American participants free of CHD or 2,228 participants free of stroke, aged 69-97 years.
Incident CHD and stroke were ascertained using standardized methods. Participants underwent a
standardized assessment of cardiovascular risk factors, including examiner-administered questionnaires,
Of the 1786 persons free of CHD, 303 developed incident CHD over 7 years. The 277 participants with early AMD had a higher cumulative incidence of CHD than participants without early AMD (25.8% vs. 18.9%,
P = 0.001).
The presence of early AMD was associated with a 57% increased risk of CHD, after adjusting for age, gender, race, systolic and diastolic blood pressure, hypertension status, fasting glucose, triglyceride, low-density lipoprotein cholesterol, cigarette smoking, pack years of smoking, and C-reactive protein. Late AMD (n= 25) was not associated with incident CHD. Among 2228 persons at risk, 198 developed incident stroke; neither early nor late AMD was associated with incident stroke.
The findings suggest that early AMD raises the risk of CHD, though not stroke. According to the authors, the association may be explained by broad underlying pathogenic mechanisms shared with both conditions. For example, atherosclerosis may represent a pathogenic process in AMD development, based on its effects upon the choroid capillaries and extracellular drusen (lipid) deposits. Inflammatory mechanisms seem to be another plausible biological basis that may involve both coronary and retinal circulation.
Preventive Steps May Lower AMD Costs
Preventing Age-Related Macular Degeneration (AMD) and delaying its progression would best preserve people's quality of life while containing health care system costs. The results from two new analyses suggest that adopting dietary habits or using supplements that slow progression from early to late stages, could ease the future burden of this disease.
Combined Dietary Factors Reduce AMD Risk
Foods provide many nutrients that may interact to modify the risk for AMD. Therefore, instead of looking at isolated nutrients, researchers from Tufts University developed a composite scoring system to examine the combined effect of dietary nutrients on AMD risk.
Study Design and Results
Data was analyzed for 4,003 Age-Related Eye Disease Study (AREDS) participants, involving 7,934 eyes. Levels of AMD-protective nutrients, including vitamins C and E, zinc, lutein, zeaxanthin, omega-3 fatty acids (DHA and EPA), as well as low-GI (Glycemic Index) foods, were assessed using participants' food intake reports. Each dietary factor was assigned a percentile score, and factor scores were added up to find each participant's compound score. Compound scores were related to participants' AMD risk, based on stereoscopic fundus photographs of the macula taken when they joined AREDS.
Participants whose diets included higher levels of these protective nutrients and of low-GI foods were at substantially lower risk for early and advanced AMD. Validation analyses showed the relationships to be robust.
Conclusion and Comments
The results suggest that the compound score summarizing the overall effect of diets rich in the AREDS trial nutrients (vitamin C, vitamin E, and zinc), the AREDS 2 trial nutrients (DHA, EPA, lutein and zeaxanthin), and low-GI foods are independently associated with lower risk for prevalent drusen and advanced AMD. Beta-carotene did not affect risk levels. The findings are in accord with earlier research linking low GI-diets with reduced risk of AMD and cataract, and further research is warranted.
New Therapies May Mitigate Rise in AMD
The Vision Health Cost-Effectiveness Study Group - encompassing investigators from the CDC, the National Center for Chronic Disease and Prevention and other institutions - report that while the prevalence of AMD will increase substantially by 2050, the use of new therapies can mitigate its effects.
The study simulated cases of early AMD, choroidal neovascularization (CNV), geographic atrophy (GA), and AMD-attributable visual impairment and blindness with five possible scenarios:
Cases of early AMD nearly doubled, increasing from 9.1 million in 2010 to 17.8 million in 2050 across all scenarios. In non-vitamin-receiving scenarios, cases of CNV and GA increased from 1.7 million in 2010 to 3.8 million in 2050 (25% lower in vitamin-receiving scenarios). Cases of visual impairment and blindness increased from 620,000 in 2010 to 1.6 million in 2050 when given no treatment and were 2%, 22%, 17%, and 35% lower in scenarios 2, 3, 4, and 5, respectively (see Figure 2E).
Figure 2E Number of Americans with pre-vision-threatening age-related macular degeneration (AMD) and blindness, with 5 alternative treatment scenarios from 2010 to 2050. Scenario 1 indicates no treatment (baseline); scenario 2, focal laser or photodynamic therapy (PDT) for CNV; scenario 3, universal vitamin prophylaxis at early AMD incidence with focal laser or PDT for CNV treatment; scenario 4, no vitamin prophylaxis followed by focal laser treatment for extrafoveal and juxtafoveal CNV and anti-vascular endothelial growth factor (anti-VEGF) treatments for subfoveal CNV for 2 years followed by PDT; scenario 5, universal vitamin prophylaxis followed by focal laser and anti-VEGF treatments for subfoveal CNV for 2 years followed by PDT.
The authors found that use of vitamins and existing therapies could reduce AMD by as much as 35%, translating to 565,000 fewer cases of visual impairment and blindness in 2050.
A 23% reduction in cases of visual impairment and blindness could be achieved using only vitamin prophylaxis in conjunction with focal laser and PDT therapies for patients who develop CNV - which amounts to a reduction of 375,000 cases of visual impairment and blindness five decades from now.
According to the authors, additional efforts to expand the use of AREDS level dietary supplements Is a cost-effective method of delaying AMD progression and cost-effective use of health care resources. However, research indicates it is not widely used among patients with early-stage disease and the correct dosage is seldom used. For example, though 68% of patients with early AMD who visited a retinal specialty practice in Edmonton, Canada, took some form of AREDS-recommended antioxidant supplement, no patients were taking the correct dosage of all 4 recommended vitamins. Public prevention efforts should focus on expanding the use of antioxidant vitamins in people with early AMD, and ensuring that these patients use the correct dosage.
Retina is Vulnerable to Effects of Blue Light
While wavelengths in the UV radiation range are largely absorbed by the cornea and lens, the retina is exposed to visible light, including blue light. Animal and laboratory studies have shown that blue light damages the retinal pigment epithelium and choriocapillaris through generation of reactive oxygen species and may be a factor in the pathogenesis of age related macular degeneration (AMD).
Protection against the harmful effects of blue light is provided by the retinal antioxidant defense system, which includes antioxidant enzymes supported by vitamins C and E, lutein and zeaxanthin, and zinc. Lutein and zeaxanthin are highly concentrated in the macula, where they act as scavengers of reactive oxygen species and filter blue light.
Only a few studies have investigated associations of sunlight exposure with AMD in human populations, and the results have been inconsistent. Up to now, however, studies have paid little attention to possible interactions between antioxidant levels and light exposure, though the adverse effects of sunlight may be attenuated by the protective effects of antioxidants.
Now, the European Eye (EUREYE) Study has examined the association of sunlight exposure and antioxidant levels with AMD. The study was designed to maximize a diversity of sunlight exposure and antioxidant levels by selecting study centers throughout Europe.
Study Design and Methods
Four thousand seven hundred fifty-three participants 65 years or older in the EUREYE Study underwent fundus photography, were interviewed for adult lifetime sunlight exposure, and gave blood for antioxidant analysis. Blue light exposure was estimated by combining meteorological and questionnaire data.
Data on sunlight exposure and antioxidants were available in 101 individuals with neovascular AMD, 2182 with early AMD, and 2117 controls. No link was found between blue light exposure and neovascular or early AMD. However significant associations were found between blue light exposure and wet AMD in participants in the lowest quartile of individual antioxidant levels - vitamin C, zeaxanthin, vitamin E, and dietary zinc - with an odds ratio (OR) of about 1.4, or a 40% higher risk, for 1 standard deviation unit increase in blue light exposure.
Low blood levels of certain antioxidant combinations showed higher ORs of blue light exposure compared with single antioxidants. Higher odds ratios for blue light were observed with low levels of vitamin C, zeaxanthin and vitamin E, especially (odds ratio, 3.7; 95% CI 1.6-8.9), which were also associated with early AMD stages.
These results suggest that higher UV exposure may contribute to AMD in those with sub-optimal levels of select antioxidants. The authors conclude that … " people in the general population should use ocular protection and follow dietary recommendations for the key antioxidant nutrients."
Reference Fletcher AE, et al. Sunlight exposure, antioxidants, and age-related macular degeneration. Archives Ophthalmology 126:1396-1403, 2008.
Oxidative Stress and AMD
Oxidative stress is one of the pathogenic mechanisms in AMD. The retina is thought to be highly susceptible to oxidative stress given its high oxygen consumption, high concentration of polyunsaturated fatty acids and photosensitizers, and exposure to light. Phagocytosis by the retinal pigment epithelium also leads to oxidative stress.
AREDS provided evidence that high dose zinc and antioxidant vitamin supplementation can slow AMD progression in relatively advanced early AMD cases (1). Additionally, the Rotterdam Study reported that above-median dietary intake of all 4 of the nutrients studied in the AREDS trial was associated with a statistically significant 35% reduction in incident AMD risk (2).
The Blue Mountains Eye Study is a population-based cohort study of vision, common eye diseases, and other health outcomes in an urban Australian population. A new analysis from this study confirmed the AREDS result that zinc is protective against AMD, and found that higher intake of lutein and zeaxanthin reduced the risk of long-term incident AMD (3).
Of the 3,654 participants in the study at baseline, 2,454 were re-examined after 5 years, 10 years, or both. The Wisconsin Grading System was used to evaluate stereoscopic retinal photographs. Risk ratios and 95% confidence intervals were calculated after adjusting for age, gender, smoking and other factors. Energy-adjusted intakes of vitamins A, C, and E; alpha-carotene; beta-carotene; beta-cryptoxanthin; lutein and zeaxanthin; lycopene; iron and zinc were assessed via food frequency questionnaires.
Those in the highest decile of total zinc intake (> or = 15.8 mg/day) were found to be significantly less likely to develop early or any AMD compared with the remaining population (RR 0.54; CI 0.30-0.97 and RR 0.56; CI 0.32-0.97 respectively).
Similarly, for dietary lutein and zeaxanthin intake, those in the top tertile (> or = 972 mcg/day) had a 65% reduced risk of incident neovascular AMD (RR 0.35; CI 0.13-0.92). For those with above-median intakes, 34% reduction in risk of incident indistinct soft or reticular drusen was noted (RR 0.66; CI 0.48-0.92).
In contrast, the highest vs. the lowest tertile of total beta-carotene intake from diet predicted incident neovascular AMD in both smokers and non-smokers (RR 2.68; CI 1.03-6.96).
These results suggest a possible threshold effect of total zinc intake on risk of early or any AMD. A protective effect from high intakes of zinc is biologically plausible. Zinc is concentrated in the retina and is a cofactor for many enzymes, including the antioxidant enzymes present in human retinal pigment epithelium. Zinc is also a cofactor for vitamin A metabolism and is essential for the synthesis of retinol binding protein. In AREDS, the protective effect shown with combined zinc and antioxidants seemed driven largely by zinc. The recently reported findings from the Rotterdam Study also seemed to be driven by zinc, and perhaps vitamin E.
These results also suggest a possible threshold protective effect of dietary lutein and zeaxanthin intake on the risk of neovascular AMD or indistinct soft drusen. Lutein and zeaxanthin are the only carotenoids that concentrate in the macula, where they are the main components of macular pigment.
The finding of a link between higher intake of beta-carotene and increased risk of AMD are inconsistent with other reports. In addition to the previously mentioned findings of AREDS and the Rotterdam Study, the Eye Disease Case-Control Study Group also reported a reduced risk for AMD with higher dietary intakes of carotenoids, particularly beta-carotene, lutein and zeaxanthin.
Zinc and the AMD Disease Process
Zinc is concentrated in the choriocapillaries, retinal pigment epithelium (RPE) and retina. Long term supplementation with zinc, either alone or combined with antioxidants, was shown to slow AMD progression in the AREDS trial. Not much is known, however, about the effects elicited by this mineral.
Recent results from an ancillary study to AREDS suggest one way that zinc may help protect against AMD. Zinc appears to improve the transport and use of cysteine - a sulfur containing amino acid and rate limiting factor in the manufacture of glutathione, the major antioxidant within cells.
Glutathione helps inactivate the reactive oxygen species hydrogen peroxide by reducing it to water. In this process, the reduced form of glutathione (GSH) is oxidized to produce GSSG. Like glutathione, cysteine also contains a thiol or sulphhydryl group. Thiol groups can undergo oxidation/reduction (redox) reactions; when cysteine (Cys) is oxidized it forms cystine (CySS). Due to its ability to undergo redox reactions, cysteine has antioxidant properties.
Studies have shown that plasma levels of cysteine and glutathione become more oxidized with age, age-related diseases, and oxidative stress. Plasma levels of the reduced and oxidized forms of these metabolites are thought to be a reliable marker for oxidative stress and antioxidant defenses.
Plasma samples were obtained from AREDS participants at the Emory and Wilmer Eye Centers sites. At both study sites, blood specimens were obtained at two time points, an average of 1.7 and 6.7 years after enrollment. For this study, the four AREDS treatment groups were combined into two groups: zinc supplementation and no zinc. Plasma was analyzed for the reduced and oxidized forms of glutathione and cysteine (GSH / GSSG and cysteine / cystine), and their redox status.
To control for factors that may have an effect on the plasma levels of these metabolites, demographic characteristics were compared. There were no significant differences in these characteristics between subjects receiving zinc or no zinc at either blood draw.
At the first blood draw (20 months), most subjects had already entered the study and were receiving zinc or placebo. No differences were seen in any of the thiols, disulfides or redox states between the two groups.
At the second blood draw (80 months), a significant decrease in plasma levels of oxidized cysteine (cystine, CySS) was found in the group receiving zinc compared to the non-zinc group (Fig. 1 below).
FIGURE 1. Long-term zinc supplementation resulted in lower plasma cystine (CySS) in the AREDS patients. Plasma CySS was measured in AMD patients before and after five years of zinc supplementation. Subjects who had received zinc had significantly lower CySS than their baseline values (P= .05). Additionally, at draw 2, plasma CySS was significantly higher in the no zinc group compared to the zinc group (P = .02).
How might the lower plasma levels of oxidized cysteine (CySS) affect retinal cells? Whether the magnitude of change found in this study affects RPE function remains to be determined. However, earlier studies found that exposing cultured human RPE cells to a more oxidized "cystine environment" makes them more susceptible to apoptosis or programmed death.
Moriarty-Craige BS, et al. Effects of long-term zinc supplementation on plasma thiol metabolites and redox status in patients with age-related macular degeneration. Am J Ophthalmol 143:206-11, 2007.
Lutein/Zeaxanthin and AMD Risk
Lutein and zeaxanthin are the only carotenoids that concentrate in the macula. There is evidence of three mechanisms by which lutein and zeaxanthin may afford protection against AMD: by absorbing blue light, by quenching free radicals and by increasing membrane stability.
Many previously published studies which have examined the relationship between AMD and these carotenoids have reported an inverse association between the disease and intake of lutein plus zeaxanthin. These carotenoids are commonly obtained from leafy green vegetables, corn, egg yolks, broccoli, peas, squash - as well as from supplements.
The authors of the Carotenoids in Age-Related Eye Disease Study (CAREDS) now report that a stable intake of these carotenoids over time could reduce the risk of AMD by about 43% in healthy women under 75.
Design and Methods
CAREDS is an ancillary study of the Women's Health Initiative (WHI), a prospective cohort study. CAREDS was designed, in part, to evaluate the relationship between lutein/zeaxanthin and the prevalence of intermediate AMD. Over 1780 women aged 50-79 who had high or low intake of lutein plus zeaxanthin at WHI enrollment were recruited into CAREDS 4-7 years later, when the presence of AMD was determined by fundus photographs.
To maximize extremes in intake of these carotenoids in the study sample, women with intakes of lutein plus zeaxanthin above the 78th (high) and below the 28th (low) percentiles at baseline in the WHI were recruited. Dietary assessments were performed by means of food frequency questionnaires administered at the study's start and over the previous 15 years. Logistic regression analyses examined the prevalence of AMD, after accounting for potential covariates.
While an association between dietary intake of these carotenoids and AMD was not observed in the overall study population, secondary analyses disclosed a statistically significant protective effect in women younger than 75 with stable intakes of lutein and zeaxanthin.
Higher intakes of lutein/zeaxanthin (2,868 mcg or more daily) compared to lower consumption (792 mcg daily) in women with stable intakes resulted in a substantial 43% lower risk of intermediate AMD (odds ratios [0.57; 95% confidence interval, 0.34-0.95]). The younger women (< 75 years) did not have a history of chronic diseases such as cardiovascular disease and diabetes that are often associated with diet changes and instable intakes of lutein/zeaxanthin rich foods.
Similar protective associations were observed for large drusen. While not statistically significant, associations in this sub-sample were in the protective direction for the more advanced lesions of pigmentary abnormalities, as well as for the exploratory outcome, advanced AMD.
The researchers observed the strongest inverse associations between intermediate AMD and high intake of vegetables in general, as well as of green vegetables. Blood levels of the carotenoids were not associated with risk of AMD.
According to lead author Dr. Suzen Moeller of the University of Wisconsin, the findings are consistent with a broad body of evidence from observational and experimental studies suggesting that these carotenoids may protect against AMD. There was evidence that diet instability may have biased the associations and, together with the possibility of selective mortality bias, may explain our inability to detect the hypothesized association in the full study population, wrote Dr Moeller.
Reference Moeller SM et al. Age-Related Macular Degeneration and Lutein and Zeaxanthin in the Carotenoids in Age-Related Eye Disease Study (CAREDS). Archives of Ophthalmology 124:1151-1162, 2006.
The Rotterdam Study Findings
The Rotterdam Study is an ongoing population-based, prospective cohort study of the factors influencing cardiovascular, neurologic and ophthalmologic diseases. Unlike AREDS, which focused on antioxidant supplementation for people who already had signs of AMD, the current investigation examined whether regular dietary intake of antioxidants could impact the risk of developing AMD in an older Dutch population free of clinical signs of the disease at baseline.
The results, reported in the December 28, 2005 issue of JAMA, strongly suggest that regular intake of antioxidants can markedly lower the risk of developing AMD, in this case by approximately one third (1).
Dietary intake was assessed at baseline for 4,170 people who were at risk of AMD and who completed the follow-up. This at risk population was 55 or older and had no AMD in either eye. Participants had no drusen or pigment irregularities, hard drusen only, or soft drusen without pigment changes.
Incident AMD until final follow-up in 2004 was determined by grading fundus color transparencies. Potential for bias was minimized by grading the photographs in a blinded manner. The main outcome measure was incident AMD, defined as soft distinct drusen with pigment changes, indistinct or reticular drusen, geographic atrophy, or choroidal neo-vascularization.
After a mean follow-up of 8 years (0.3-13.9 years), AMD occurred in 560 participants. After adjusting for known confounders such as atherosclerosis and smoking, dietary intake of vitamin E and zinc were found to be inversely associated with incident AMD. A dose-response relationship between both vitamin E and zinc intake and a reduced risk of AMD was noted.
The researchers also analyzed the combined intake of all 4 antioxidants studied in the AREDS trial: vitamins E and C, zinc and beta-carotene. An intake above the median for all 4 nutrients reduced AMD risk by 35%.
While no relationship between lutein consumption and risk of AMD risk was seen, the difference in intake levels among the lowest and highest quartiles of dietary intake (1.4 vs. 3.6 mg) was small.
These findings may have important public health implications, for they strongly suggest that long-term consumption of antioxidants could prevent or delay the development of early AMD. Recent data, in fact, suggests that oxidative modification of retinal proteins play a critical role in the formation of drusen, implying that antioxidants may have their strongest effect at the initiation of AMD (2).
Risk reduction was observed for dietary intake above the RDA for all 4 antioxidant nutrients compared to each one alone. This indicates that the combination acted synergistically in exerting a protective effect, and underscores the need to maintain a regular, above-RDA intake of all of 4 nutrients over time.
The majority of people in this Dutch cohort appeared to consume a healthy diet. Additionally, the independent relationship between antioxidant supplements and AMD could not be examined in this study since the number of antioxidant supplement users was relatively small, and the necessary data on dose and duration of use was lacking. However supplementation may be helpful in US populations where subgroups fail to consistently consume adequate amounts of antioxidant nutrients.
Findings from this multicenter, NEI and NIH sponsored study were reported in the October 2001 issue of Archives of Ophthalmology. The study followed 3,640 participants, aged 55-80, for an average of 6.3 years. Patients were initially enrolled in four AMD categories based on the size and extent of retinal drusen and level of visual acuity decline (Table 1), and were randomly assigned to one of four treatment arms:
While the investigators acknowledged the importance of lutein and zeaxanthin for macular health, these carotenoids were not available for use in supplements when the study began. Instead, the investigators chose beta-carotene, which was then being studied for heart disease and cancer.
AMD Categories In AREDS
Category 1: few small or no drusen
Category 2: several small drusen or a few medium-sized drusen in one or both eyes, or pigment abnormalities
Category 3: many medium-sized drusen or one or more large drusen in one or both eyes
Category 4: advanced AMD in one eye, or vision loss due to AMD in one eye only
Although the antioxidant and zinc supplements each appeared to offer some protection, the benefits of supplementation were greatest for those patients who received the antioxidant and zinc combination, and who were in the highest-risk category groups.
Supplementation with combined antioxidants and zinc significantly reduced the risk of progression to advanced AMD in these groups by 25%. A significant risk reduction in vision loss was also seen in the higher-risk groups taking both zinc and antioxidants, with an odds reduction of 27% (Table 2).
Very few patients with less severe AMD went on to develop advanced cases. Therefore the study was unable to detect whether the zinc and antioxidant combination might delay or prevent progression in subjects at an earlier stage. However, when the researchers included the less severe category (category 2) with the more advanced categories (3 and 4), the combined supplements showed an odds reduction in the visual acuity outcome that approached statistical significance (Table 2).
Most of the participants experienced few side effects. People in the zinc groups had more frequent urinary-tract related problems than placebo-takers (7.5% vs. 5%), although it's not clear whether zinc played a role in their occurrence. Another caveat is that high dose beta-carotene is contra-indicated for smokers and recent ex-smokers. The ARED Study confirmed the general safety and benefit of these high-potency nutrients in preserving vision among well-nourished, older people with intermediate to more advanced AMD.
Effect of Treatment on Risk of Visual Acuity Loss Score Greater or Equal to 15 Letters from baseline
Participants in AMD Categories 2, 3 & 4 (n=3597)
Participants in AMD Categories 3 and 4 (n=2549)
OR (99% CL)
Antioxidants vs. placebo
zinc vs. placebo
Antioxidant + zinc - Combination vs. Placebo
*Significant at p≤.01
Click here to read the full text of the AREDS clinical trial on the Archives of Opthalmology website.
MacularProtect Plus reflects scientific evidence on nutrition's role in macular health. MacularProtect Plus includes nutrients at levels studied in the AREDS clinical trial and also includes a robust 15 mg of FloraGLO® lutein, 1 mg of zeaxanthin. It features a low level of beta-carotene for those who should avoid high intake, such as smokers.
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Executive Director, Ophthalmic Consultants of Connecticut
Clinical Professor, New England College of Optometry, Fairfield, CT
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