30 day supply: 120 capsules VIEW DRINK MIX
Suggested Use: take a total of four capsules daily, with meals (two capsules taken orally, twice daily).
Note: pregnant or lactating women or individuals with medical conditions should consult a physician before using.
Note: MacularProtect Complete AREDS2 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 (500 IU)
Vitamin A is essential for protecting night vision and is vital for corneal health. It also works with zinc and the amino acid taurine to support function of eye structures such as retinal photoreceptors. The formula contributes a conservative level (as retinyl palmitate) to ensure adequate body stores.
Vitamin C (750 mg)
Vitamin C is a water-soluble antioxidant that is concentrated in ocular tissues where it deactivates free radicals. Free radicals are the highly reactive compounds produced through the body’s use of oxygen and generated by outside sources such as UV light. Oxidative damage to the retina is believed to be a risk factor for macular degeneration. Vitamin C also aids in the recycling of other antioxidants such as vitamin E. Evidence indicates that vitamin C and E requirements are higher in smokers – a group at higher risk for AMD. MacularProtect Complete AREDS2 supplies the form and level of vitamin C used in AREDS, plus an additional 250 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 Complete AREDS2 uses natural source vitamin E rather than synthetic, as research shows that natural source 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. The formula 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, 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 Complete AREDS2 provides the same form and level provided to AREDS participants.
Copper (2 mg)
The mineral copper is necessary for function of a key antioxidant enzyme. It is also needed to produce 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 Complete AREDS2 to help ensure adequate levels of this essential mineral. The formula's copper level represents 100% of the Daily Value and is the form and amount use in the AREDS trial.
Lutein, FloraGLO® (10 mg) and Zeaxanthin (2 mg)
Lutein and zeaxanthin 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, zeaxanthin and lutein filter blue (visible) light that can cause photo-oxidative stress.
Intervention studies indicate supplementation with these carotenoids can favorably modify the pigment density of the macula. AREDS2 reported an 18% reduction in progression to advanced AMD in participants who received the AREDS supplement with lutein/zeaxanthin in place of beta-carotene (compared to those taking the original AREDS supplement with beta-carotene). For participants receiving lutein/zeaxanthin supplements, a 26% reduced risk of progression was seen in those consuming the least lutein/zeaxanthin at the study’s start, compared to those consuming the most. The average daily intake of these two carotenoids among Americans 50 and older is less than 2 mg – far lower than the 12 mg tested in AREDS2. The formula's lutein/zeaxanthin level reflects that used in AREDS2.
Other Essential Nutrients for Eye and Whole Body Health
MacularProtect Complete AREDS2 provides robust levels of key B-vitamins, particularly vitamin B12, which can be difficult to absorb by those over 50, as well as vitamin B6 and folate for artery and colon health. A large clinical trial found this B vitamin trio reduced AMD risk in women with or at risk for heart disease, and higher vitamin B12 and folic acid blood levels have been linked to lower AMD risk in an observational study. These B-vitamins may also support cognitive function.
Plant compounds with antioxidant activity such as the flavonoids contribute to the health benefits of eating five or more fruit and vegetable servings daily. Regular intake of berry flavonoids, for example, is linked to better odds of retaining heart health. MacularProtect Complete AREDS2 contains a unique array of protective flavonoids from diverse sources: bilberry, citrus, grape seed, Ginkgo biloba, turmeric and quercetin, which is found in many fruits and vegetables.
The AREDS2 clinical trial, published in May, 2013, examined whether additional nutrients or formula modifications could further increase the effectiveness of the original AREDS formula. Based on the results of this study, the National Eye Institute is now recommending a macular health formulation with lutein and zeaxanthin, and without beta-carotene. Read more about the AREDS2 clinical trial.
In the News: Magnesium & Heart Disease; Omega-3 & Skin Health; B-vitamins & AMD
Magnesium Reduces Risk of Heart Disease
Magnesium helps maintain muscle and nerve function, keeps heart rhythm steady, supports the immune system, and helps keep bones strong. It also helps regulate blood sugar levels, promotes normal blood pressure, and is involved in energy metabolism.
Researchers have long been interested in the role of magnesium in preventing and managing disorders such as diabetes, hypertension and cardiovascular disease (CVD). A new review of studies from Harvard’s School of Public Health bolsters the support for magnesium’s role in reducing the risk of CVD.
The review (1), which included data for over 313,000 people from 16 studies, found that the risk of CVD fell by 30% (for every 0.2 mmol/L increase in circulating magnesium levels). Dietary intake of magnesium (per 200 mg/day increment) was associated with a 22% lower risk of ischemic heart disease.
The recommended daily intake for magnesium is 320 mg for women and 420 mg for men – amounts that many adult Americans fail to meet according to government surveys. To get more of this important mineral, eat a wide variety of leafy green veggies, beans, nuts, whole grains, and fish.
Can Omega-3 Fats Help Protect the Skin?
A preliminary, but promising study suggests that omega-3 fatty acids may have a role in helping to keep skin healthy.
Exposure to UV radiation in sunlight suppresses the skin’s immune system, specifically cell-mediated immunity. This suppression of immune activity can affect the body’s ability to fight skin cancer and possibly infections.
The omega-3s have been shown to protect against UV-caused immune suppression in mice, but their impact in humans isn’t known. This led Investigators at the University of Manchester in England to clinically test whether a regular dose of fish oil can boost skin immunity to sunlight (2).
B-vitamin Intake Linked to Lower AMD
A clinical trial published in 2009 reported that daily supplementation over time with high dose vitamin B6 and B12, and folic acid could reduce the risk of age-related macular degeneration (AMD) in women.
Results of a new study (3) lend credence to these clinical findings, and suggest that more moderate intakes of folic acid and supplemental B12 may lower AMD risk.
Participants in the Blue Mountains Eye Study were followed for 10 years. Those with elevated blood levels of damaging homocysteine, low levels of folic acid, or vitamin B12 deficiency, were at significantly greater risk of developing early or late stage AMD.
Participants who reported taking B12 supplements were 47% less likely to develop AMD. That’s important because B12 deficiency is fairly common in older people, and supplemental B12 is more bioavailable than dietary sources of this vitamin.
Results of AREDS2
2nd Age-Related Eye Disease Study (AREDS2)
Results of the second AREDS trial (AREDS2) were released in early May (1). The bottom line? Consider taking the original AREDS formula with beta-carotene replaced by lutein and zeaxanthin if you have at least intermediate AMD.
AREDS2 had a complex study design. All participants were randomly assigned to one of four groups: placebo (the control group), lutein (10 mg) plus zeaxanthin (2 mg), omega-3 fatty acids (1000 mg), or both.
Everyone in the trial was also offered the original AREDS formula (vitamins C and E, beta-carotene, zinc and copper). Many opted to take the original supplement, while others agreed to take modified formulas with reduced zinc and/or no beta-carotene.
The main goal of the study was to see whether adding lutein + zeaxanthin or omega-3 fatty acids to an AREDS formula would be more effective in reducing the risk to advanced AMD than taking the AREDS formula alone.
Compared to taking only the AREDS formula, neither the added omega-3 nor lutein/zeaxanthin met the additional 25% decrease in risk that was required to show effectiveness.
However, there were other important sub-group findings – not widely covered by the media – that may well have influenced the main outcome in the lutein + zeaxanthin groups.
Lutein and Zeaxanthin May Be of Benefit
High dose beta-carotene appeared to interfere with the absorption of lutein/zeaxanthin, as evidenced by lower blood levels of lutein/zeaxanthin in those getting the original formula with beta-carotene.
In fact, when beta-carotene was removed from the formula, the researchers did find evidence that lutein + zeaxanthin can slow progression to advanced AMD.
Those taking lutein + zeaxanthin and no beta-carotene had an 18% lower risk compared to people getting beta-carotene (and no lutein + zeaxanthin).
In addition, the lutein/zeaxanthin supplements made a real difference for those with the lowest dietary intake of these carotenoids. A 26% reduction in risk of progression was seen for those with the poorest dietary intake who received lutein and zeaxanthin.
The investigators noted that overall, AREDS2 participants tended to have diets richer in lutein and zeaxanthin than the general population. That’s important because a substantial portion of Americans typically consume less than 1-2 mg of these carotenoids daily.
According to the investigators, it’s possible that a greater benefit would have been seen for lutein/zeaxanthin if the diets of the AREDS2 patients had been more representative of the general population.
What About Zinc and Beta Carotene?
Another goal of the study was to assess the effects of lowering the zinc dose from the original 80 mg to 25 mg, and eliminating beta-carotene. Neither of these changes made a significant difference in the effectiveness of the formula.
The higher dose of zinc, however, showed a favorable trend toward better protection, and there was no difference observed between the two zinc doses in terms of safety. Therefore the research group recommends the higher dose of zinc, while noting that the zinc results were not definitive.
AREDS Benefits Are Long-Lasting
In a recently published follow-up study of the original AREDS trial, researchers found that the effects of taking the AREDS supplement are long- lasting (2).
After the original trial ended, participants were followed for another 5 years. At the end of that period, those who had taken the AREDS formula were 25-30% less likely to develop advanced AMD.
Considering the findings of this follow-up study and of AREDS2, there’s every reason to be confident that the AREDS formula (with lutein and zeaxanthin replacing beta carotene) will provide at least similar protection against the progression of AMD.
AREDS2 also asked whether adding lutein/zeaxanthin or omega-3s to the original AREDS formula would impact the need for cataract surgery (3). No statistically significant overall effect was seen.
However, again, participants with the poorest intake of dietary lutein and zeaxanthin did benefit by getting supplements of these carotenoids. This group was 32% less likely to progress to a level of cataract requiring cataract surgery. A 36% reduction in the development of any severe cataract was seen as well.
Take Home Message?
While AREDS2 was a complicated trial, the overall message is simple: If you have at least intermediate AMD, discuss taking the AREDS formula (containing lutein + zeaxanthin) with your doctor. This is especially important if you have AMD or cataract and don’t include enough lutein and zeaxanthin-rich leafy greens such as kale, collards and spinach in your diet.
Omega-3s: More Research Needed
AREDS2 found that the omega-3s taken with the AREDS formula did not provide further benefit for those with intermediate to advanced AMD. However, that does not rule out a possible benefit for people with early stage AMD or who are at risk for the disease.
One population health study (4) with over 38,000 women who were free of AMD at the study’s start, reports that regular intake of the omega-3s over a 10-year period significantly lowered the risk of developing AMD. While these findings suggest that the omega-3s could be helpful in primary prevention of AMD, more research is needed to understand what role the omega-3s may play in maintaining visual health.
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
Four New Studies Underscore Vital Role of Vitamins
Latest Findings are Encouraging
Four new studies reinforce previous findings
for some essential nutrients, while suggesting potential new benefits
for others. Calcium, vitamin
D and three of the B-vitamins
are featured in a quartet of studies published in the Archives
of Internal Medicine.
The Calcium and Cancer Connection
Some previous population-health studies have
found a link between calcium intake and cancer, but the evidence
has been inconsistent. The calcium-cancer relationship appears
to be affirmed in the large National Institutes of Health AARP
Diet and Health Study which followed nearly 294,000 men and 199,000
women aged 50-71 for seven years (1).
Women consuming up to 1,300 mg of calcium
daily from foods and supplements had a decreased risk of any type
of cancer. A 23% lower risk for digestive types of cancer, particularly
colorectal cancer, was seen for those women in the top 20% of
calcium intake compared to those consuming the least. The highest
consumers among men also had a 16% lower risk of cancer in the
digestive cancer category.
Higher Vitamin D for Fewer Broken Bones
Though calcium may prove important in cancer
prevention, the results of another study suggest that calcium
may play second fiddle to higher levels of vitamin
D when it comes to protecting bones. Harvard researchers
performed a meta-analysis (review) of 12 clinical trials involving
D supplements in over 42,000 adults aged 65 or older
(2). They found that supplemental
D was associated with a 14% decrease in the risk of
non-vertebral fractures and a 9% decrease in the risk of hip fractures.
More importantly, when they looked at 9 of the studies using doses
over 400 IU per day, the supplements were associated with a 20%
and 18% reduction in non-vertebral and hip fractures, respectively.
The researchers noted that while calcium was protective, the mineral
did not have an additional effect in individuals taking high doses
Risk of Colds Influenced by Vitamin D?
D deficiency has resurfaced in recent years, resulting
in diseases such as rickets in children. Vitamin
D research has also exploded, with better blood levels
D now linked to lower incidences of cancer, multiple
sclerosis and heart disease. Another line of inquiry under hot
pursuit is vitamin
D's role in the immune system.
In an analysis of the 3rd National Health
and Nutrition Examination Survey (3),
researchers found that people with low blood levels of this vitamin
were more likely to have an upper respiratory tract infection
(URTI) which can include colds, sinusitis, pharyngitis and flu.
Compared to people with higher vitamin
D blood levels (30 ng/mL or more), those with lower
values (under 10 ng/mL) were 36% more likely to have had a recent
URTI. People with intermediate values (10-29 ng/mL) had 24% higher
odds. Whether getting more vitamin
D will actually help prevent URTIs needs to be confirmed
in controlled trials.
B-Vitamins Lower AMD Risk in Women
Previous studies have suggested an association
between age-related macular degeneration (AMD) and elevated blood
levels of homocysteine - a compound that can be lowered by folic
To determine whether B-vitamins
might help prevent AMD, about 5,400 female health professionals
who already had, or were at high risk for, heart disease were
given very high doses of these 3 B's or a placebo (4).
After more than 7 years of follow-up, the
women assigned to the supplemental B-vitamin group lowered their
risk of developing any AMD by 34%. The risk for visually significant
AMD was reduced by a solid 41%. These findings are exciting, and
the next step is to test whether lower, more reasonable levels
of the B's are just as effective when supplemented over time.
Scientists Examine Lutein's Effect on Glare
New research indicates that the carotenoids
zeaxanthin may help our vision when we
have difficulty seeing due to the glare encountered in very bright light
These two carotenoids have been shown to slow down
the progression of moderate to advanced age-related macular degeneration) in
the AREDS trial. But in this new study,
zeaxanthin appear to improve visual
function even in healthy people with normal vision.
Researchers from the University of Georgia recruited
40 healthy young people (average age of about 24 years), and examined their
reaction to glare. Glare is commonly encountered in bright sunlight, when
staring at a computer monitor, and when facing the bright beams of oncoming
The investigators determined lutein and
zeaxanthin's effects on glare by
studying how the carotenoids affected macular pigment density. The eye's
macula is made up of lutein and
zeaxanthin, which help filter out
certain damaging light waves. When the concentration of these carotenoids in
the macula is higher, the macula is better able to absorb these light waves.
Taking lutein and
zeaxanthin increased the density of
macular pigment significantly after six months of supplementation.
When the study volunteers performed visual tasks
following exposure to glare, lutein and
zeaxanthin supplements significantly
reduced the damaging effects of the exposure for both of the visual
performance tasks that were measured.
Improved Visual Performance under Glare
The researchers concluded, "Four to six months of 12
mg daily lutein plus
zeaxanthin supplementation significantly
increases macular pigment density and improves visual performance in glare
for most subjects."
How can we achieve the level of
zeaxanthin tested in this study? By
consuming good sources of these carotenoids such as leafy green vegetables,
corn, egg yolks, squash, broccoli and peas, and augmenting those foods with
daily supplementation of lutein and
Vitamin D Status Linked to Artery Health
Increased levels of
vitamin D may improve cardiovascular health and reduce the prevalence of
peripheral arterial disease, or "PAD", suggests a new study
(2). People who suffer from PAD often
experience decreased blood flow in their legs. PAD occurs when arteries in
the legs become narrowed or clogged with fatty deposits. According to 2008
statistics from the American Heart Association, PAD affects about 8 million
Americans and is associated with significant disease and death.
In the new study, researchers looked at over 4,800
participants of the National Health and Nutrition Examination Survey
(NHANES). They found that people with higher blood levels of
vitamin D were far less likely to have
Blood samples from the NHANES participants were
divided into 4 groups according to the concentration of
vitamin D in the samples. The
investigators found that the higher the level of
vitamin D, the lower the risk for this
artery disease. In fact, PAD was 64% more common in the group with the
lowest compared with the highest blood levels of the vitamin.
How Might Vitamin D Lower Risk for PAD?
According to the study's lead author,
vitamin D might directly affect blood
vessels. We know that in laboratory animals
vitamin D regulates one of the hormone systems that effects blood
pressure. It may affect this same hormone system in humans too. The authors
also point out that the study does not prove that increased levels of
vitamin D protect against PAD directly.
However, they called for large randomized clinical trials to test whether
vitamin D supplementation offers
protection against PAD.
Turmeric - In India it's the 'Spice of Life'
Many herbs and spices are thought to have healthful
properties in addition to adding zing and flavor to foods. Ginger helps settle
upset stomachs for instance, while rosemary and thyme contain anti-oxidants.
Though less commonly found on American menus, one spice that has garnered
attention in the scientific arena is turmeric.
The source of turmeric is a leafy plant in the ginger
family called Curcuma longa. Ground turmeric is made from the brightly
colored flesh of finger-like rhizomes which extend from the root. The bright
yellow color of turmeric comes mainly from pigments known as curcuminoids.
Curcumin is the principal and most active curcuminoid.
Turmeric is grown and consumed in China and Indonesia,
but the world's primary producer of turmeric is India where it's been used as a
spice and for medicinal purposes for centuries. More recently, evidence that
curcumin may have anti-inflammatory and anti-cancer activities has prompted
scientific interest in its potential to prevent and treat disease.
Curcumin and Colon Health
The incidence rate of most digestive tract cancers,
including colon cancer, is lower in India than in developed countries
(1). Observational studies also suggest that the presence of natural
antioxidants such as curcumin in Indian cooking may contribute to these low
To date, five phase I or preliminary clinical trials have
been completed showing the safety of curcumin in colorectal cancer patients
(2). The success of these trials has led to the development of phase II
trials that are currently underway to test whether high dose curcumin has a role
in helping to treat the disease. Extremely high doses are required because the
bio- availability of curcumin is low (3).
How Might Curcumin Act?
Experimental work has shown that curcumin posses potent
antioxidant and anti-inflammatory activity. It may intervene in cancer
development from a number of different angles. Studies in cultured cancer cells
or in animals suggest that it may help eliminate potential carcinogens, for
example, or block the growth of new blood vessels needed by cancer cells to fuel
their rapid growth. Curcumin may also stimulate colon cancer cell death through
cell signaling pathways.
While there is no conclusive proof that curcumin helps
maintain colon health, it makes sense to include this spice in your diet along
with minimizing intake of red and processed meat and getting adequate calcium
and vitamin D - factors that reduce colon cancer risk (4).
Spice Up Your Diet
Turmeric has a warm and bitter flavor, with a mild
fragrance reminiscent of orange and ginger. While it is best known as one of the
ingredients used to make curry, it also gives mustard its bright yellow color.
You'll find turmeric in many Southeast Asian and Indian foods, including lentil
and meat dishes, mustard blends and chutneys. In addition to traditional
curries, rice and chicken dishes, try some new ways to include turmeric:
In general, choose turmeric rather than prepared curry
blends, which contain less curcumin.
More Vitamin D = Better Public Health
From a nutritionist's point of view, 2007 should be
declared the Year of
Vitamin D. Over the past year alone, there have been three major conferences
on this topic and a multitude of research papers published. Now, a consensus
among experts is emerging: We're not getting enough of this nutrient for optimal
What Does the Research Tell Us?
Many studies have linked higher intakes or blood levels
vitamin D with a lower risk of cancer. The evidence shows a protective
effect against colon cancer, and suggests that
vitamin D may also help reduce cancers of the breast and prostate.
Vitamin D has been found to help prevent falls and preserve bone density in
older people. In addition, researchers are exploring the role of
vitamin D in such diverse conditions as MS and macular degeneration.
One recent and skillfully done study
(1) looked at 18 clinical trials of
vitamin D, each of which reported results for total mortality - an accurate
measurement of poor health effects. "The results were remarkable" wrote
Harvard's Dr. Edward Giovannucci in an accompanying editorial. Those who
vitamin D in these studies had a significant 7% reduction in death from any
cause. Importantly, no "negative surprises" were seen from the doses given,
which ranged from 300-2000 IU
vitamin D daily.
More compelling evidence comes from a recent trial that
supplemented postmenopausal women with 1,100 IU
vitamin D plus calcium or calcium alone for 4 years
(2). Women who received
vitamin D had significantly fewer cancers of all types.
How Much Vitamin D Is Needed?
Experts from Tufts and Harvard put their heads together
to tackle this question. They examined studies which looked at dental health,
risk of falls, fractures and colon cancer, and that also reported blood levels
vitamin D. It was clear that blood levels associated with beneficial health
outcomes began at 75 nmol/L. Calculations showed that at least 1000 IU
vitamin D daily is needed to bring half the population into that healthy
range (3). These findings led to a safety
vitamin D (4), and eventually to
vitamin D experts urging that the RDA be raised (5).
The "D" Dilemma: How Do We Get More?
Getting enough of this important vitamin can be
challenging since very few foods contain significant amounts. The best sources
are fatty fish such as mackerel, salmon, sardines and tuna, as well as fortified
milk, which contains about 100 IU per glass. Diet alone, however, can't provide
the amounts that researchers suggest we need to achieve.
vitamin D is produced when skin is exposed to sunlight, specifically
ultraviolet B radiation (UVB), most people follow advice to apply UVB blocking
sunscreen when outdoors. Making sufficient levels of the "sunshine vitamin" is
even more difficult for Afro-Americans who need longer sun exposure to produce
the same amount of "D"
generated within lighter skin.
In fact the American Academy of Dermatology is concerned
that reports about
vitamin D's health benefits could lead to higher rates of skin cancer.
People should avoid unprotected sun exposure, and take a multivitamin or drink a
few glasses of
vitamin D fortified milk every day, according to the Academy. But there's
one glaring problem with that advice.
Sound Supplementation Can Bridge the Gap
"The amount of
vitamin D in supplements isn't nearly enough," states Creighton University's
Dr. Robert Heaney who has conducted nearly 2 decades of research on vitamin D.
The response of a forward-thinking, responsible
supplement company might be to provide 800-1000 IU in supplements for adults.
Along with a healthy diet and lifestyle that includes fish, whole foods, low-fat
dairy, and regular exercise, supplementation based on good science can help
improve public health.
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.
AREDS 2: Primary Results & Beyond
For those who have read about the primary findings in the abstract of the AREDS2 paper, the trial’s instructive secondary and sub-group findings may have gone unnoticed. Those findings are highlighted here, and help explain the current recommendation of the National Eye Institute:
Synopsis: AREDS2 Study Design & Methods
AREDS2 (1) enrolled 4203 patients with bilateral moderate AMD (large drusen with or without pigment changes) or advanced AMD in one eye.
The primary objective was to determine whether the addition of lutein/zeaxanthin (L+Z) or omega-3 fatty acids (omega-3s ) to the AREDS formula would be more effective in reducing the 5-year risk of advanced AMD or cataract (results of the cataract portion of the trial were published separately) (2).
Another goal was to assess whether eliminating beta-carotene or changing zinc levels in the original AREDS formula would affect risk of progression.
To accomplish these goals, all participants were randomly assigned to receive daily: L+Z (10 mg, 2 mg), omega-3s (1,000 mg), both, or placebo. The placebo group served as controls.
Patients also received either the original AREDS formula or a modified AREDS formula with no beta-carotene and/or lower zinc.
A description of participants’ baseline characteristics can be found in EduFacts Vol. 13, No. 9. Fifty-nine percent (59%) had bilateral large drusen, and 32% had advanced AMD in one eye and mean visual acuity of 20/32 in non-advanced eyes.
About 50% of AREDS2 participants were former smokers, and another 7% were current smokers. Those who smoked and those who had stopped less than a year prior to enrolment were excluded from receiving beta-carotene.
Serum Levels of Lutein & Zeaxanthin:
After 5 years, serum levels of lutein and zeaxanthin in those receiving L+Z and getting a beta carotene-containing AREDS formula were significantly lower than those getting L+Z and no beta-carotene. The three carotenoids compete with each other for absorption, and this finding indicates that high dose beta-carotene interferes with the absorption of lutein and zeaxanthin.
Compared to taking only the AREDS formula (controls), neither L+Z nor omega-3s co-supplemented with an AREDS formula met the 25% additional decrease in risk required to show effectiveness.
Main Effects Analyses:
Comparing participants who received L+Z to those who did not, showed a 9% reduction in risk of progression for the L+Z group.
Secondary Randomization Analyses:
Participants in the secondary randomization who were assigned to formulas with no beta-carotene were compared to those receiving formulas that contained beta-carotene.
Eliminating this carotenoid did not curb the protective effect of the AREDS formula against developing advanced AMD, as the removal of beta-carotene had no significant effect on risk of progression.
Similarly, comparing formulas modified with low dose zinc (25 mg) vs. the original zinc dose (80 mg) showed no statistical difference for risk of progression. However a trend favoring better protection was observed for the higher dose of zinc.
Further Sub-group Analysis:
To investigate relative treatment effects, those taking L+Z and modified AREDS formulas without beta-carotene were compared to those taking no L+Z, plus an AREDS formula with beta-carotene.
An 18% lower risk of advanced AMD was seen for participants taking no beta-carotene plus L+Z. Essentially, this analysis addressed the question ‘what would happen if you replaced beta-carotene with L+Z in the original AREDS formula?
Lung cancers were observed in 2% of participants who took AREDS containing beta-carotene compared to 0.9% who received no beta-carotene, and about 91% of those who developed lung cancer were former smokers. Lutein/zeaxanthin was not associated with lung cancer risk. Thus, lutein and zeaxanthin appears to be a safer choice for former smokers.
No clinically or statistically significant differences in adverse events were seen when comparing the low versus high dose zinc groups.
The preponderance of evidence from AREDS2 suggests that lutein and zeaxanthin offer some protection against AMD advancement. Though subgroup analyses are rigorously interpreted with a measure of caution, many of the secondary and sub group analyses were pre-specified to be evaluated in the study’s design.
The apparent competitive absorption between high dose beta-carotene and lutein/zeaxanthin may have reduced the ability of the study to detect a significant impact of L+Z on progression to advanced AMD compared to controls.
Importantly, L+Z appeared to benefit those with inadequate intake of these carotenoids. While AREDS2 patients were generally well nourished, their intake of lutein and zeaxanthin is not representative of the general US population, where low consumption is common. The authors suggest that a greater reduction in risk may have been seen if the subjects’ diets had more closely resembled that of the overall population.
Though not discussed above, results from the age-related cataract portion of AREDS2 indicate that those consuming insufficient levels of lutein and zeaxanthin also gained some protection.
While L+Z plus an AREDS formula did not help reduce the risk of progression to cataract surgery, there was a 32% reduction in the subsequent need for surgery for those consuming the least dietary lutein and zeaxanthin. A 30% lower risk of developing any cataract – and a 36% reduction in risk of developing any severe cataract – was also noted in this group.
Omega-3 fatty acids demonstrated no benefit above and beyond that conferred by the AREDS formula to those with at least moderate AMD. Whether or not the omega-3s have a role in the primary prevention of AMD awaits further investigation.
Zinc and Ocular Health: From Antiquity to Modern Times
Wide-Ranging Cellular Functions of Zinc
Although zinc was found to be essential to living organisms in 1869, the idea that zinc deficiency can occur in humans wasn’t established until much later. Pioneering work by Annada Prasad, and co-workers in 1961-63, identified zinc deficiency as the cause of dwarfism and hypogonism prevalent in Iranian men at the time. It was later found that phytate, a compound naturally occurring in the high cereal grain-diets of these men, greatly impaired the absorption of zinc, leading to deficiency and retarded growth.
Since then, zinc has gained considerable recognition of its role in human health, and extensive research has elucidated its structural, regulatory and catalytic functions. Zinc plays an important role in stabilizing the structure of proteins and cell membranes; is involved in regulating gene expression and cell signaling; and over 100 different depend on zinc to help catalyze chemical reactions.
Zinc is required for proper growth and development, reproduction, and neurological function. Zinc also acts as an intracellular signal molecule for immune cells, and is involved in many immunological processes. Evidence suggests that even marginal deficiencies of zinc contribute to the decline in immune function associated with aging.
The Role of Zinc in Ocular Health and AMD
Zinc serves important functions in the eye as well. It is needed to mobilize vitamin A from the liver to the eye, and several key enzymes in the chorioretinal complex require zinc. In the retina and retinal pigment epithelium, zinc is believed to interact with taurine and vitamin A, modify photoreceptor plasma membranes, regulate the light-rhodopsin reaction, and modulate the passage of a neural impulse across synapses.
Zinc is thought to play a part in the development of age-related macular degeneration (AMD) for several reasons. First, zinc is highly concentrated in the retinal pigment epithelium, a key area of the retina that is affected by AMD. Secondly, the retinal content of zinc has been shown to decrease with age, as have the activities of some zinc-dependent retinal enzymes.
Ophthalmic Use of Zinc Dates to Ancient Times
While the benefits of supplemental zinc came to the forefront with publication of the AREDS trial in 2001, it appears that a role for this mineral in ocular health is rooted in history.
Italian researchers recently analyzed disc-shaped tablets that were uncovered in a 2000 year-old shipwreck off the coast of Tuscany, and reported their findings in the Proceedings of the National Academy of Sciences. The zinc-containing supplements were found in the Pozzino, a ship that sank in the 2nd century B.C., and were preserved underwater in oxygen-free metal tins called pyxis. According to the researchers, the composition and form of the tablets are consistent with an ophthalmic use of zinc as described in several ancient texts – some dating back as far as 300 B.C.
AREDS 2 and Future Research Directions
In 1988, David Newsome and colleagues reported that zinc-treated patients with drusen or AMD had significantly less vision loss than those receiving a placebo – findings that led to the AREDS trial. AREDS then demonstrated that treatment with zinc alone slowed the progression to advanced stages in patients with intermediate stage AMD, and when combined with antioxidants not only slowed disease progression but also reduced vision loss. The results of AREDS 2, expected later this year, may reveal whether a lower dose of zinc (25 mg) is as effective as that assessed in the first trial (80 mg).
There remains much to learn about zinc’s role in AMD. The exact mechanism(s) by which zinc slows this disease is still unclear, for instance. How does zinc interact with genetic risk factors for AMD such as different variants of complement Factor H? These questions and more await further investigation.
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.
Women's Antioxidant & Folic Acid Study
Results from the vision component of the Women's Antioxidant and Folic Acid Cardiovascular Study, also known as WACS, were presented at the ARVO 2007 Annual Meeting. Researchers from the Brigham and Women's Hospital and the National Eye Institute concluded that the data from this randomized trial indicate that supplementation with folic acid, vitamins B6 and B12 reduced the risk of AMD in women with cardiovascular disease (CVD) (1).
These three B-vitamins, particularly folic acid, have been shown to reduce high levels of the naturally occurring compound, homocysteine. Research has implicated elevated plasma levels of homocysteine in the development of vascular diseases including choroidal neovascularization in exudative AMD.
A total of 8,171 female health professionals, 40 years or older with pre-existing CVD or having at least three risk factors for the disease were enrolled in the trial. The women were randomized to receive vitamin C (500 mg daily), vitamin E (600 IU every other day), beta-carotene (50 mg every other day) or placebo in the WACS secondary prevention trial.
Of this group, 5,422 women were subsequently randomized to also receive a placebo or folic acid (2.5 mg), vitamin B6 (50 mg) and vitamin B12 (1 mg) daily. Of these women, 5,205 did not have a diagnosis of AMD, and were included in this analysis. There were two primary outcome measures: a) confirmed AMD (self reported and supported by medical record evidence of an AMD diagnosis after randomization) and b) confirmed AMD with vision loss - defined as vision to 20/30 or worse which was attributable to this condition.
A total of 137 cases of AMD were documented, including 69 cases of AMD with vision loss, during an average of 7.3 years of treatment and follow-up. Fifty-five cases occurred in the treatment group, while the placebo group had 82 documented cases. Relative risk was 0.66 (95% confidence interval, p = 0.02). For AMD with vision loss, there were 26 cases in the B-vitamin group compared to 43 among placebo takers. Relative risk was 0.60 (95% confidence interval, p = 0.04). In summary, women taking supplemental B vitamins were 34% less likely to develop AMD and 40% less likely to have AMD-related vision loss than women in the control group.
While very high doses of the 3 B vitamins were tested in this group of women with CVD, lower doses may well have been effective. For example, a placebo-controlled, randomized dose response study in people with a history of CVD found that the decrease in homocysteine was proportionate to the folate dose up to - and not beyond - 800 mcg daily (2). This dose achieved an average 23% drop in plasma homocysteine compared to placebo - a drop of about the same magnitude found in trials using up to 5,000 mcg folate daily (3). Additionally, excessive amounts of folic acid have recently been implicated in colorectal tumor growth (4,5).
Antioxidant - CVD Outcomes in WACS
The WACS authors report that vitamins C, E or beta-carotene had no overall effects on CVD events in these high-risk women (6), pointing out that antioxidants are no magic bullets for the secondary prevention of this disease. However, the study did confirm the safety of high potency antioxidants, and women who received both vitamins C and E experienced fewer strokes. The same research group is following up to determine whether the combination of vitamins C and E affect the biomarkers in blood that strongly predict stroke. That work will use blood samples from 300 participants taken at the beginning and end of the WACS study.
Vitamin D: Beyond Bone Health
Most people think of vitamin D simply as a regulator of calcium homeostasis and bone mineralization. Over the past decade, however, it has become clear that the active or hormonal form of this vitamin also plays a significant role in xenobiotic metabolism, in the immune system, and in cellular proliferation and differentiation. As a result, adequate vitamin D status is viewed as important for reducing the risk of many malignancies and autoimmune diseases. Now, a recent study suggests that vitamin D is also involved in protecting macular health.
The objective of the study was to evaluate the association between levels of vitamin D (25-hydroxyvitamin D) in serum and prevalence of both early and advanced age-related macular degeneration (AMD) among participants of the 3rd National Health and Nutrition Examination Survey (NHANES III). NHANES III, which is conducted by the Centers for Disease Control, is a representative sampling of the general population. Of 7,752 people (> 40 years) analyzed from this survey, 11% had AMD as determined by non-mydriatic fundus photographs. Questionnaires assessed dietary and supplemental intake, and blood samples were taken to determine vitamin D serum levels.
Protective Effect Seen for Higher Serum D
When participants were split into five groups based on serum vitamin D levels, those in the highest quintile had a 40% lower risk for early AMD compared to those in the lowest quintile (see table). An inverse association between AMD and greater vitamin D-fortified milk consumption was observed. The researchers also found a significantly reduced prevalence of AMD among consistent vitamin D supplement users who did not consume milk daily.
Anti-Inflammatory Role is Likely Connection
A growing body of epidemiologic evidence suggests that inflammation underlies AMD pathology, and the authors of this study speculate that vitamin D may reduce AMD risk by its anti-inflammatory actions. Studies report that vitamin D decreases proliferation of T helper cells, T cytotoxic cells, and natural killer cells, while enhancing T suppressor cell activity. Vitamin D also decreases the production of pro-inflammatory interleukins such as IL-6 and 8. In addition, a recent study has shown that vitamin D intake reduces C-reactive protein, a marker of systemic inflammation.
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.
Dietary Flavonoids Afford Cellular Protection
It is increasingly clear that new approaches to treating AMD should focus on both preventing the initial insults that lead to disease progression, and rescuing the retinal pigment epithelium (RPE) and photoreceptor cells that have been damaged. Mounting evidence suggests that chronic oxidative stress may damage the retinal-RPE and predispose it to developing age-related macular degeneration (AMD).
Flavonoids are a large class of polyphenolic compounds found in fruits, vegetables, teas and wine that have evolved to protect plants from the oxidative damage caused by chronic UV exposure. Flavonoids are potent antioxidants that can also influence many cellular enzyme functions. They directly neutralize reactive oxygen species (ROS), and they modulate cell-signaling pathways. In particular they can induce expression of phase-2 proteins that enhance the cell's natural defenses against oxidative stress.
Large-scale observational studies have linked greater dietary intake of certain flavonoids with a lower risk of cardiovascular disease and some cancers. In addition, many of the foods associated with a reduced risk of AMD in epidemiologic studies contain high concentrations of flavonoids, and at least one flavonoid has been identified in the mammalian retina. Earlier experiments report that specific flavonoids can protect retinal ganglion cells from oxidative stress.
Taken together, these observations led investigators from the Scripps Research Institute to determine whether specific flavonoids found in common fruits and vegetables can protect human RPE cells from oxidative stress-induced death.
Research Questions and Methods
A series of experiments were conducted utilizing cultured adult human RPE cells to address the following questions: 1) Can specific dietary flavonoids protect RPE cells from oxidative stress induced cell death? 2) Can these flavonoids prevent cell death after the exposure has occurred? 3) Can these flavonoids act through an intracellular route to reduce the accumulation of ROS? 4) Do flavonoids activate Nrf2 in human RPE cells and induce the expression of phase-2 genes? The techniques employed to answer these questions included cytotoxicity assays, microscopy, isolated RNA analysis, delayed response cyto-protection assay, determination of ROS production and Western blot analysis of HO-1 and Nrf2 expression.
All six flavonoid classes were tested, and the most effective were the flavones and flavonols. Specific members of these two classes which protected against oxidative-stress induced death with good efficacy and low toxicity include quercetin, fisetin, luteolin and EGCG.
These same flavonoids and several others induced the expression of phase-2 detoxification enzymes in the cultured RPE cells. Compared with control cells, quercetin was more protective of RPE cells than vitamin C or various vitamin E compounds (see figure below), although both of these vitamins are known to be better absorbed in vivo than quercetin.
These findings raise the possibility that flavonoids may be among the natural compounds that contribute to the ocular benefits associated with foods identified in epidemiologic studies. Spinach, for example, is not only a source of the more familiar lutein and zeaxanthin, but is a rich source of quercetin and luteolin which were two of the most effective flavonoids in this study. Quercetin is also found red wine, and is highly concentrated in foods such as onions, peppers, currants and black tea, which is also a rich source of EGCG.
Reference Hanneken A, et al. Flavonoids protect human retinal pigment epithelial cells from oxidative stress-induced dealth. Inv Ophthalmol Vis Sci. 47:3164-77, 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.
Yes. MacularProtect Complete AREDS2 uses exactly the same formula as MacularProtect Complete-S.
The findings for the Age-Related Disease Study (AREDS) were released
in October, 2001. The AREDS clinical trial has been heralded by doctors
and nutrition experts as the most significant clinical trial on nutrition
and age-related macular degeneration (AMD) ever. Findings of the 6
½ year AREDS clinical trial, demonstrated a statistically significant
reduction in the rate of progression of AMD in 3,640 patients taking
a supplement containing vitamins, antioxidants and zinc.
The AREDS2 clinical trial, released in May, 2013, tested several variations of the original AREDS supplement, in addition to omega-3 fatty acids from fish oil, and lutein and zeaxanthin. Read more about the findings here. Based on the findings from AREDS2, the National Eye Institute now recommends a beta-carotene free formula (with lutein and zeaxanthin), such as MacularProtect Complete AREDS2.
A recent analysis of genetic data from the AREDS clinical trial questions the role of zinc for those with certain genetic risk factors for age-related macular degeneration. However, these findings are not supported by an earlier analysis of AREDS data, which found health benefits from zinc across all genetic profiles examined. SBH has consulted with top experts in the fields of genetics and nutrition - including Elizabeth Johnson, PhD of the USDA Human Nutrition Research Center on Aging, and Professor, Friedman School of Nutrition and Science Policy at Tufts University.
Since there have been only two studies of limited size on this topic, and since the most recent findings have not been corroborated, more research is clearly needed. The National Eye Institute continues to recommend a macular formula that includes 80 mg of zinc for those with intermediate to advanced AMD. SBH will continue to monitor the research on this topic. To view SBH's detailed response to this issue, click here.
MacularProtect AREDS2 is a stand-alone product based on AREDS and AREDS2 - but does not provide a multinutrient component.
MacularProtect-Complete AREDS2 was created in response to doctor concern that patients combining a potent AREDS formula with a separate multivitamin may be exceeding safe levels of certain nutrients, such as zinc. MacularProtect-Complete AREDS2 is carefully formulated to provide complete support for macular and whole body health while ensuring proper nutrient levels. It is also a convenient alternative to having to manage multiple nutritional products. Choose a link below to view a comparison:
"Recent studies have validated the importance of nutraceuticals in the prevention and treatment of various eye conditions. It is important
that patients select a quality product that provides optimal levels of key nutrients that have scientifically been shown to protect our eye
health. MacularProtect Complete delivers the key nutrients found to protect macular health in the National Eye Institute's AREDS research and also includes a
comprehensive multivitamin that provides maximum support for overall body health. This all-in-one product is a convenient solution to the confusion and safety
issues that both clinicians and patients face when trying to combine various products to achieve this level of coverage."
- James Thimons, OD, FAAO
Executive Director, Ophthalmic Consultants of Connecticut
Clinical Professor, New England College of Optometry, Fairfield, CT
"I began taking MacularProtect Complete AREDS2 about a year ago. I had just been diagnosed with macular degeneration and wanted to do whatever I could to at least slow down the process and protect my eyesight. The retinologist recommended this product to me and I have taken it faithfully since then. I feel it has been a big help as my eyesight seems to be about the same as it was a year ago. In the past, my eyesight was getting a little worse every year.
Thank you for making such a wonderful product!"
- B. Lessard,
"I have used Macular Protect Complete regularly for several years as recommended by my ophthalmologist. I had been undergoing frequent prescription changes for several years. I replaced my regular daily vitamin supplement with MacularProtect Complete and my eyeglass prescription has now been stable for a couple of years. "
Saint Joseph, IL
"I began taking MacularProtect Complete more than four years ago at the recommendation of my ophthalmologist. In that period of time, there has been no appreciable change in my vision. That's not bad for an 89-year old!"
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