FOR
BETTER
OR WORSE?
ANTIOXIDANTS
& ZINC FOR
MACULAR
DEGENERATION
A disturbing study in the journal Ophthalmology, a publication of the American Academy of Ophthalmology, is likely to turn attempts to prevent and treat macular degeneration with dietary supplements upside down. The report is likely to cause dismay and confusion among patients with the disease who have been faithfully taking mineral or antioxidant formulas to delay visual decline. [Ophthalmology Sept 4, 2014]
The study comes to two opposing conclusions: antioxidant and zinc supplements for macular degeneration are/aren’t beneficial depending upon your genetic makeup. The study’s authors say their research is likely to have “far-reaching health implications.”
Based upon the data in this study, millions of senior Americans are taking antioxidant vitamin or mineral supplements for their eye health that will either hasten or slow the progression of their eye disease. Without genetic screening, there is no way for patients to know which supplements to take to slow the progression of their eye disease.
There are no FDA-approved drugs for the common form of macular degeneration so dietary supplements represent the only hope to avert progressive loss of vision to legal blindness.
Concerns over AREDS formula
Most alarming was the revelation that the AREDS formulation of antioxidants and minerals (Age-Related Eye Disease formula) that is suggested for patients with advanced-stage macular degeneration failed to produce a favorable response in 3 of the 4 genetic groups tested.
Over a 7-year period DNA samples were obtained from 989 patients with macular degeneration and they were broken into four genetically different groups. Subjects were given (a) an inactive placebo tablet; (b) antioxidants beta carotene 15 mg, vitamin C 500 mg, vitamin E 400 units; (3) zinc 80 mg and copper 2 mg; (4) The AREDS formula, a combination of group B and C (minerals + antioxidants).
The chart below summarizes the data from the study.
Effect Of Genetic Grouping Upon Macular Degeneration Patients Taking Antioxidant & Mineral Dietary Supplements
Source: Ophthalmology Sept 4, 2014
|
|
|
Increased (+) or
Decreased (-) Relative Risk Compared To Placebo
|
Experienced Progression Of Their Eye Disease over 7 years
|
|
Genetic Group
|
ZINC
|
Anti-oxidants
|
AREDS Formula
|
Inactive Placebo
|
Zinc
|
AREDS Formula
|
|
1
|
+3.07
(+307%)
|
+1.33
(+133%)
|
+2.73
(+273%)
|
17%
|
43.2%
Not better than placebo
|
40.2%
Not better than placebo
|
|
2
|
0.51
(-49%)
|
0.72*
(-28%)
|
0.57
(-43%)
|
43.3%
|
25.2%
|
27.3%
|
|
3
|
No effect
|
0.380
(-62%)
|
0.80*
(-20%)
|
22.6%
|
Not better than placebo
|
9.17%
|
|
4
|
0.93*
(-7%)
|
0.85
(-15%)
|
0.88*
(-12%)
|
48.4%
|
Not better than placebo
|
Not better than placebo
|
|
* Not considered statistically significant
|
Product liability?
Whether this study forces eye care practitioners to order expensive genetic tests prior to prescribing dietary supplements is unknown at this point. Moreover, will manufacturers, facing possible product liability problems, change product labels to suggest genetic testing prior to use of their products? Dietary supplement makers can make no claim, implied or direct, that their products treat or prevent any disease. They can only say their products support healthy vision.
Universal genetic testing?
It has been known since 2008 that the genetic makeup of macular degeneration patients determines who is most or least likely to benefit from dietary supplementation. Because nutritional therapy was somewhat beneficial for all genetic groups tested up to that point in time, genetic screening was not proposed then. [Ophthalmology June 2008] But the fact the popularly used AREDS formula may not be beneficial and in some instances hasten the progression of this disease puts eye doctors up for criticism that these products are being used generate more expensive treatments.
Once macular degeneration has progressed to its advanced stage where fluid is leaking from the back of the affected eye and/or new outcroppings of blood vessels invade the visual center of the eye (the macula) to deliver oxygen to O2-starved tissues, then eye physicians directly inject medicine into the eyes that causes abnormal blood vessels to recede. This treatment needs to be repeated monthly and costs $1000-2000 each time. Anything that halts the progression of this frightening eye disease would not only avert or delay treatment that costs over $2 billion a year but would avoid painful needle injections into the eye.
The remedy to the problem of dietary supplement selection, universal genetic testing for all patients with macular degeneration, would be onerously expensive in an era when the mandate is to deliver healthcare more economically. Medicare is underfunded by trillions of dollars to meet the health needs of a growing population of senior Americans. And what if all that genetic testing does is tell patients there is nothing that can be done? Genetic testing may be a useless exercise.
With over 100 million Americans now over the age of 50 and 7 million reported to be at substantial risk for macular degeneration, any intervention that may slow, prevent or reverse this dreaded age-related eye disease would be welcome. More than twice as many American adults are concerned with maintaining their eye health as they are for cancer or bone loss (osteoporosis).
It is no surprise to learn that sales of vision dietary supplements in the U.S. reached $419 million in 2012 according to estimated provided by Nutrition Business Journal. Among the 59% of adults who take dietary supplements overall, 7% use a supplement for eye health. [Nutraceuticals World May 1, 2013]
According to Jeffrey Anshel OD, president of the Ocular Nutrition Society, sales of the two leading brands of dietary supplements for macular degeneration reached $80 million in 2012. [Primary Care Optometry News June 4, 2013]
Underlying causes of this lapse in therapeutics and prevention
There are at least eight reasons why modern eye care finds itself in this current therapeutic predicament:
- Overreliance upon large long-term studies that may have no bearing on tailoring therapies for individuals. Most studies would not be instructive to a particular patient, such as a diabetic who over-consumes alcohol, eats sugary foods, is 60-pounds overweight and has alcohol-induced nutrient deficiencies (vitamin B1, magnesium, vitamin A and zinc). The study that validated the original AREDS formula did not even factor for alcohol use or drug-induced nutrient depletion (which is almost never factored).
Large studies are instructive for public health issues like food fortification for the masses, but not for the patient in the exam room. Zinc may or may not be helpful for macular degeneration but it certainly is for the patients that are zinc deficient. The harsh reality is that all AREDS, zinc and antioxidant studies only slowed the progression of macular degeneration. All groups taking the supplements still experienced progression of their disease. It is difficult to convince patients to take pills that in their minds don’t work.
- Foot dragging; failure to put basic research into practice. As the researchers who performed the genetic study pointed out, it would take years to conduct another study to validate their work. Ways to fast-track the science and conduct ongoing studies that report findings on a case by case basis with adverse effects being reported directly to the FDA in real time must be found. A cure that is 20 years away will be too late for the millions of baby boomers entering retirement. It has taken almost 14 years of studies to come to the realization that the dietary supplements in current use for macular degeneration may be deleterious for some individuals.
When a dietary supplement company whose product was shown to be promising petitioned the FDA to proceed with a human study, the FDA balked. The dietary supplement had already been in use for a decade without significant side effects and is safer than aspirin. An estimated 15,000 patients fail medical therapy and progress to legal blindness each year. To file am investigational new drug application and conduct a large long-term study would take at least 3-years and cost over $1 million, while 45,000 more patients slipped into legal blindness. [Petition To FDA]
- Inability to see the bigger picture. The bigger prize is to find what causes aging and slow its progression. And certainly survival should be one of the gold standards to measure any intervention. Analysis of the AREDS study reveals supplemental zinc did significantly reduce mortality by 21%. [Archives Ophthalmology Oct 2001] Authors of published studies often act like they are oblivious to the systemic effects of the drugs and other therapies they are analyzing, as if these medicines only target the eyes. Agents that slow aging in the eyes would likely slow the rate of aging overall. The transparent eye, being an ideal organ for internal examination and imaging, can serve as a meter for the rate of aging in the body. Developed countries are adding years to the end of life of their citizens without improving the quality of their lives. The idea is to prolong the number of years of independent living by 7-years which would avert the impending financial collapse of Medicare. [The Scientist March 1, 2006]
- Disingenuousness: manipulation of data. In the practice of medicine today patients are being gamed as nutrient recommendations are being fashioned to assure there is enough disease to treat. Over 13 years have passed since the first use of dietary supplements fashioned under the auspices and sponsorship of the National Eye Institute. [Archives Ophthalmology Oct 2001; National Eye Institute; com]
It is difficult to fathom that during all this time that no one in ophthalmology recognized the vision among some patients with macular degeneration was deteriorating faster towards the more advanced stages of the disease that requires medical treatment by needle injection due to the type of dietary supplement they were taking.
- This author has already grown suspicious of published recommendations issued by the National Eye Institute. Studies conducted outside the US involving macular degeneration suggest fish oil supplements are beneficial but a sole study sponsored by the National Eye Institute stands in sole opposition to other reports. [JAMA Internal Medicine May 2014; Knowledge of Health Dec 111, 2013]
Over a decade ago a researcher at the University of Michigan reported that omega-3 fish oils instilled into lab dishes of retinal cells activates enzymes (lipase) that clean up and inhibit accumulation cellular debris called lipofuscin that is the earliest sign of age-related retinal disease. [Transactions American Ophthalmology Society 2002] That report was evidence that fish oil is not only an anti-aging agent in the eyes but likely in the entire body.
- Biases against dietary supplements; drugs don’t work for the same reasons. For example, in the AREDS analysis investigators continued to air the mistaken idea that supplemental beta carotene increases the risk for lung cancer and mortality by 18% among smokers. [Archives Ophthalmology Oct 2001] However, re-analysis of that study [New England Journal Medicine April 14, 1994] shows that the difference in hard numbers was only 0.497% (less than one-half of one percent). Furthermore, we now understand that high-dose beta carotene converts to vitamin A which competes with vitamin D for storage in the liver. [Cancer Causes Control Sept 2012] Vitamin D is a known risk reducer for lung cancer and advanced stage macular degeneration. [Anticancer Research Nov 2013; Investigative Ophthalmology Visual Science July 2014] So any alleged increased risk for lung cancer can be attributed to an imbalance between beta carotene-produced vitamin A and vitamin D. The lesson here is for modern medicine to report on all the existing published science not just the negative reports and to learn the lesson of nutritional balance (examples: vitamins A and D, zinc and copper, sodium and potassium).
- Failure to apply epigenetic medicine. Geneticists point to a gene known as ARMS2 (“age-related maculopathy susceptibility 2”) that is associated with risk for macular degeneration.
Mutations in the ARMS2 gene impair internal antioxidant defenses, namely an endogenous enzymatic antioxidant known as SOD2 (superoxide dismutase 2) that utilizes manganese as a mineral precursor. [Human Molecular Genetics July 2014] Its cousin is SOD1 that depends upon copper and zinc.
The provision of mega-dose zinc and copper in the AREDS formula could induce an imbalance between SOD1 and SOD2 which has been shown to induce macular degeneration in mice. [Proceedings National Academy Science July 25, 2006]
Indeed, a study of microscopically small aquatic animals known as rotifers showed that a calorie-restricted diet prolonged the lifespan of these short-lived animals (typical 6-14 days) by virtue of a food deprivation diet elevating the activity of SOD1 and SOD2. The red wine molecule resveratrol increased activity of SOD2 over SOD1. [PLoS One Feb 2013]
Resveratrol likely works to reduce copper-dependent SOD1 by virtue of its ability to chelate (attach to) copper. [Biochemical Pharmacology May 1997]
Certain ratios of zinc, copper and resveratrol can promote or inhibit growth of new destructive abnormal blood vessels that occur in the advanced form of macular degeneration. [Journal Biomedical Science 2012]
However, the AREDS study used low-dose (25 mg) and high-dose (80 mg zinc) with no observed difference in progression of macular degeneration.
Low-dose resveratrol has been shown to normalize the disproportional increase in SOD in cancer cells and may pose an answer to problem of SOD imbalance. [Molecules Cells March 2013] Modern medicine must begin to utilize science like this.
In recent times there have been a number of published studies showing that supplemental antioxidants do not reduce health risks or lower death rates.
What is misunderstood is that the best state of health is achieved when the body is under mild biological stress, that is, when tissues are in a pro-oxidant rather than antioxidant state. Excessive biological stress damages tissues but mild biological stress activates internal antioxidant defenses in the form of enzymatic antioxidants (glutathione, catalase and superoxide dismutase -SOD). Mild biological stress protects light receptor cells at the back of the eyes from damage and cell death. [EMBO Journal May 6, 2009; Experimental Eye Research Feb 2014]
Mild doses of molecules such as resveratrol that molecularly mimic a form of biological stress (food deprivation aka calorie restriction) activate the Nrf2 gene and restore SOD activity and therefore may serve to rescue retinal cells when their survival is threatened. [Neurochemical Research Dec 2011] High-dose antioxidants such as those in the AREDS formula may inhibit Nrf2 activity that would normally protect retinal cells.
- Conflicts of interest: can modern medicine put itself out of business? Can modern medicine be trusted when prevention takes money out of the pockets of doctors and drug companies? The only true ethic for the practice of medicine is to prevent disease from occurring in the first place. Doctor and treatment-centered medicine needs to be replaced by patient-centered self-care.
Genes are not static
While mistaken one conclusion that could be drawn from this recent study showing that dietary supplements may not slow the progression of macular degeneration is that patients are doomed by their genetic makeup.
However, the genetic makeup of humans is not static and fixed (gene mutations) but is also dynamic and modifiable (epigenetics). There may be inborn mutations on the DNA ladder from birth but these genetic predispositions don’t result in vision loss till the last couple of decades of life. There are environmental, dietary and aging factors that determine why macular degeneration strikes some but not others.
For example, the inherited form of juvenile macular degeneration is called Stargardt’s disease and results in vision decline early in life. [Journal American Optometric Association Feb 1988] Only about 2% of chronic age-related disease is genetic, the rest is modifiable via epigenetics.
Dietary factors (refined sugars, metals such as iron and copper) may drive the disease along with environmental factors such as unfiltered solar radiation. [Progress In Retinal Eye Research Jan 2011; Frontiers Aging Neuroscience June 2013]
Oddly, there is no “macular degeneration diet,” though one has been proposed. Dietary supplements are supposed to work in the face of the worst diets and health habits (smoking, over-consumption of alcohol). That seems an impossible mountain to climb. A broader approach may need to be taken that includes anti-aging diets.
Researchers at Tufts University in Boston suggest foods and dietary supplements that control blood sugar levels and inhibit a gene called hypoxia-inducing factor (HIF-1), a gene that responds to decreased oxygen levels in the eyes and other tissues, as the appropriate gene target for macular degeneration, diabetes, cardiovascular disease and aging itself. [Progress In Retinal Eye Research Jan 2011]
One particular dietary supplement has already undergone microRNA genetic testing and was found to inhibit HIF-1 six times better than a red wine molecule (resveratrol) and better than drugs designed for the same purpose. [PLoS One Dec 23, 2010] This same nutraceutical has been reported to rescue patients with macular degeneration from permanent loss of vision. [Nutrients June 4, 2013]
Indeed, genetically altered laboratory mice bred so they don’t produce an important protein (complement factor) involved in the immune response exhibit early features of macular degeneration even when fed a low-sugar diet whereas normal mice that produce this protein are protected from development of macular degeneration when fed a low-sugar diet. [Investigative Ophthalmology Vision Science Jan 2014] So there are gene-nutrient interactions.
Age is the predominant factor in macular degeneration and certain anti-aging molecules that control minerals and switch the active protein-making function of genes (called epigenetics) have already been demonstrated to slow and even reverse some of these changes, even if only in a small number of case presentations. [Nutrients June 4, 2013]
Unfortunately, eye doctors appear to be dragging their feet over entering a new era of disease prevention and reversal with the use of molecules such as resveratrol, vitamin D and fish oil, none which are widely employed in popular dietary supplements designed for the eyes today.
Facing the future
Millions of Americans are living longer and marching toward a dreaded day when they discover they have macular degeneration. Because this age-related visual disorder usually begins in one eye the vision in the healthy eye often delays self-detection of the problem. For senior Americans who don’t obtain frequent eye and vision checkups, closing one eye at a time and focusing on reading material reveal the problem at an earlier stage. Wavy lines of type of blind spots are the common symptoms.
According to the Bright Focus Foundation as many as 11 million senior Americans have some form of macular degeneration and the risk for the advanced form of the disease rising with advancing age from ~2% at age 50-59 to 30% for those over the age of 75. Direct treatment costs for this eye disease is estimated at $255 billion annually. For 90% of diagnosed patients who have the slow-progressive form of the disease these is no proven treatment, though researchers are feverishly working on this problem. The vast majority of the cases of legal blindness (90%) caused by macular degeneration occur among the 10% of patients with the fast-progressive form of the disease, called wet macular degeneration due to leaky blood vessels at the back of the eyes. [Bright Focus Foundation]
Where does this scientific discussion leave desperate macular degeneration patients?
- Start with a low-glycemic /low carbohydrate (no bread, no rice, no pasta, no refined sugar) diet. [Progress In Retinal Eye Research Jan 2011] Cut back on red meat consumption also. [Biomed Research International 2014]
- From all appearances, modern medicine appears to be employing archaic dietary supplement formulations for macular degeneration. Wouldn’t you know that the National Eye Institute (NEI) would formulate a dietary supplement for the eyes that drums up more business for eye doctors. Even if accidental, the NEI needs to conduct a major reformulation of dietary supplements for macular degeneration. Dietary supplements such as vitamin D3, DHA-rich omega-3 fish oil, lutein/zeaxanthin supplements and low-dose resveratrol should be considered. [Retina Sept 2014; Knowledge of Health Dec 11, 2013; Optometry Nov 2011; Nutrients June 2013]
- Avoidance of tobacco, aspirin, supplemental copper or iron and limitations on alcohol consumption are also on the list of preventive measures. [Optometry Vision Science Aug 2014; Expert Opinion Drug Therapy June 2014; Nutrients June 2013]
- Supplemental vitamin C to control blood capillaries is suggested for forms of retinal disease that involve leakage of fluid at the back of the eyes. Notice that none of the ingredients in the AREDS formula made it on this list except vitamin C.
- There is evidence that melatonin, the sleep hormone that is activated in the pineal gland at the base of the brain when we close our eyes, is “an underappreciated player in retinal health.” [Experimental Eye Research Oct 2012] There is a correlation between the level of melatonin and development of macular degeneration with advancing age. [Advances Gerontology 2012] This may underscore the importance of sleep in ocular health. The eye repairs itself during sleep.Melatonin activates the Nrf2 gene switch that turns on internal antioxidant defenses in the retina. [Bulletin Experimental Biology Medicine Aug 2014] Researchers in Europe report 3 milligrams of melatonin at bedtime helps to stabilize vision among patients with macular degeneration. [Annals New York Academy Sciences Dec 2005] Time release melatonin works best to produce prolonged sleep.
- Don’t count out zinc entirely. For those macular degeneration patients with frank zinc deficiency, it may be important. Zinc is necessary for a key protein in the immune system called complement that is needed to ward off macular degeneration. [Journal Biological Chemistry June 2013] A zinc deficiency leads to accumulation of cellular debris called lipofuscin in the retina. [PLoS One 2011] The patients who responded favorably to zinc may have been the zinc-deficient ones. Zinc deficiency is widespread. [Knowledge of Health March 18, 2013] Blood tests to detect zinc deficiency are notoriously inaccurate. [The Merck Manual]
Another tip: don’t ask your eye doctor about all this. He/she will quickly respond that all that is recommended here is unproven. Yes, maybe, but it is not disproven. Readers can wait another decade for the National Eye Institute to come up with the answers or use the best available science presented in this report in an attempt to save their remaining vision. What has now been disproven is the AREDS formula which should be withdrawn from the marketplace. — ©2014 Bill Sardi, Knowledge of Health.com, ResveratrolNews.com
