Antioxidant supplements in age-related macular degeneration: are they actually beneficial?

Abstract

Age-related macular degeneration (ARMD) is one of the prominent causes of central visual loss in the older age group in the urbanized, industrialized world. In recent years, many epidemiological studies and clinical trials have evaluated the role of antioxidants and micronutrients to prevent the progression of ARMD. In this article, we review some of these major studies. In addition, we review the absorption and bioavailability and possible undesirable effects of these nutrients after ingestion. The role of genotypes and inappropriate use of these supplements are also discussed. From all the above evidence, we conclude that it may not be prudent to prescribe these formulations without a proper assessment of the individual’s health and dietary status. The effectiveness of all the components in antioxidant formulations is controversial. Thus, these supplements should not be prescribed just for the purpose of providing patients some kind of therapy, which may give a false sense of mental satisfaction.

Keywords

Age-related macular degeneration (ARMD) is one of the foremost causes of central visual loss in the older age group in the industrial world affecting 10% of people above 65 years and more than 25% of people above 75 years of age.¹ Progressive visual loss in ARMD has been attributed to the late-onset neurodegeneration of the photoreceptor–retinal pigment epithelial complex in the macular area.

In recent years, many epidemiological studies and clinical trials have been conducted to assess the role of antioxidants and micronutrients in delaying the progression of visual loss in patients suffering from ARMD. AREDS (age-related eye disease studies) has been one of the major clinical trials highlighting the effectiveness of antioxidant supplements in ARMD, and thereafter, numerous primary studies and review papers have suggested a positive association between antioxidant supplements and a decrease in progression of ARMD,^2–9 making it a promising strategy for slowing the progression of the disease. A common trend of self-medicating has been noted without taking into consideration the correct ingredients and the proper dosage, which are almost always available over the counter without a prescription.

Review of literature

Literature searches of the PubMed and Cochrane Library databases were last conducted on 3 November 2020, with no date restrictions. The keywords used while searching the PubMed database were: “role of antioxidants in ARMD,” “bioavailability and absorption of” (individual components of antioxidant formulations), “side effects of” (individual components in antioxidant formulations), “composition of” (different antioxidant formulations available in the market). Further details regarding side effects of antioxidant supplements were explored with the keywords “association of” / “role of” (particular micronutrient) “with” (particular disease/side effects described). The National Institutes of Health (NIH) website was also visited to confirm the recommended dose allowances of various micronutrients. All our searches were limited to articles published in English language. Our data are based on both primary studies and review articles focussed on the metabolism of the micronutrients in antioxidant supplements to highlight the factors associated with their absorption and bioavailability.

Besides AREDS, few other major studies evaluated the effectiveness of antioxidants in the prevention of development or progression of ARMD. Cochrane Database of Systematic Reviews^10–12 has studied the role of antioxidant supplements in ARMD extensively, and the results are tabulated in Table 1.

Table 1.

Summary of Cochrane database of systematic reviews on the role of antioxidant supplements in ARMD.

Study	Aim	Methodology	Results
1. Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration⁶	Assess whether antioxidant vitamin and mineral supplements prevent the development of ARMD in healthy people in the general population	5 relevant studies were included (total of 76,756 people)—in Australia, Finland, and the United States. They compared vitamin C, vitamin E, β-carotene, and multivitamin supplements with placebo.	Taking vitamin E/vitamin C/β-carotene supplements made little or no difference to the chances of developing ARMD (high-certainty evidence). Taking multivitamin tablets may slightly increase the chances of developing any ARMD or late ARMD (moderate-certainty evidence).
2. Antioxidant vitamin and mineral supplements to slow down the progression of age-related macular degeneration⁷	Assess the effects of antioxidant vitamin or mineral supplementation on the progression of ARMD in people with ARMD.	19 studies conducted in the United States, Europe, China, and Australia. Compared antioxidant vitamin or mineral supplementation (alone or in combination) with placebo or no intervention, in people with ARMD.	Taking lutein alone (or combined with zeaxanthin) may have little or no effect on progression to late ARMD and vision loss (low-certainty evidence). Taking vitamin E alone may have little or no effect on the progression to late ARMD and vision loss (low-certainty evidence). Taking antioxidant vitamins plus zinc probably slows down the progression to late ARMD and vision loss (moderate-certainty evidence). This may result in a small improvement in quality of life (low-certainty evidence).
3. Omega 3 fatty acids for preventing and slowing the progression of age-related macular degeneration⁸	Whether increased dietary intake of omega-3 fatty acids prevented or slowed the progression of age-related macular degeneration	Randomized controlled trials where increased dietary intake of omega-3 fatty acids was compared with placebo or no intervention. People from the general population were recruited with or without ARMD. Any type and any dose of omega-3 fatty acids, either as fish oil capsules or dietary manipulation (e.g. increased consumption of oily fish).	Omega-3 supplementation for periods up to 5 years did not reduce the rate of progression to advanced ARMD or reduce significant visual loss compared with a placebo. The incidence of adverse effects was similar in the intervention and placebo groups. Omega-3 supplementation in people with ARMD does not reduce the risk of progression to advanced ARMD or the development of moderate to severe visual loss.

ARMD: age-related macular degeneration.

High certainty: very confident that the true effect lies close to that of the estimate of the effect; moderate certainty: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; low certainty: the true effect may be substantially different from the estimate of the effect; very low certainty: The true effect is likely to be substantially different from the estimate of effect.

Before dwelling on the effectiveness of these antioxidants and micronutrients, let us also review the absorption and bioavailability of these nutrients after ingestion.

Absorption and bioavailability of micronutrients and antioxidants

Zinc

Zinc is one of the most important constituents of antioxidant supplements recommended in a dosage of 80 mg of elemental zinc in the form of zinc oxide by AREDS2. Zinc is an essential co-factor for various metabolic activities in the eye and plays an important role in physiological processes such as immunity, reproduction, and neuronal development.^13,14 A high concentration of zinc has been observed in the retina and retinal pigment epithelium (RPE), which helps in modifying photoreceptor plasma membranes, modulating synaptic transmission, and regulates the phototransduction pathway.^13,15

Absorption of exogenous dietary zinc

A carrier-mediated process in the small intestine is involved in zinc metabolism.¹⁶ It is difficult to estimate the proportion of dietary zinc absorption because secretions from the gut also contain zinc. The absorption rate of zinc depends on a variable range of factors such as stress, alcohol consumption, caffeine, drug intake, exercise, diet, and phytate: zinc molar ratio.¹⁷ An increase in dietary zinc consumption increases zinc absorption up to a maximum rate.^17,18 The zinc status of the host determines the rate of zinc absorption. Increased efficacy of absorption has been observed in zinc-deprived individuals and vice versa.¹⁹

A dynamic relationship has been observed between absorbed zinc and intestinal excretion. A compensatory reduction in the amount of zinc excreted via the intestine has been noted when absorption is low and vice versa.²⁰ Therefore, intestinal regulation of endogenous zinc excretion plays an important role in zinc homeostasis. Istfan and colleagues²¹ observed zinc absorption of 92% in young men fed with a low-zinc diet and 81% in those fed with a high-zinc diet.

Bioavailability of exogenous dietary zinc

Bioavailability of zinc is dependent on dietary factors and physiological factors such as mucus layer and intestinal fluid.²² Phytate remains the main nutritional inhibitor of zinc bioavailability and alteration in human zinc absorption pattern is observed beyond molar phytate: zinc ratio of 5.²² Dietary protein (especially from animal sources) increases the bioavailability of zinc by forming complexes with zinc, which facilitates solubility of the cation in the intestinal lumen.²³ Calcium also has a possible negative impact on zinc bioavailability.²² Albumin concentration on the serosal side of the intestinal epithelium is another determinant factor of zinc bioavailability having a high zinc affinity and acts as a binding and transport protein.^22,24

Thus, adding Zinc to the diet of people who are not malnourished may not actually enhance its blood levels and availability to retinal tissue.

Xanthophylls

Lutein and zeaxanthin are two dietary xanthophylls recommended in a dosage of 10 mg and 2 mg, respectively, by AREDS. Lutein and zeaxanthin are short-wavelength light filters that preserve the redox balance in the body.²⁵ Green leafy vegetables and fruits are the main sources of lutein and zeaxanthin. Studies have documented a positive role of these xanthophylls in the prevention of progression of ARMD. The bioavailability of lutein and zeaxanthin, however, is dependent on variable factors, which should be taken into account while prescribing supplements.

Absorption of dietary xanthophylls

It involves four major events: release of the xanthophylls from the food matrix, transfer of the released particles to lipid micelles in the small intestine (facilitated by dietary fat intake and biliary secretions), uptake by the intestinal cells via passive diffusion, and transportation to the lymphatic system.^26,27 Roodenburg and colleagues²⁸ reported that more than 3 g of fat was required to enhance the solubility of lutein diesters and facilitate pancreatic secretions of lipases and esterases. Lutein diesters being hydrophobic requires fat and hydrolysis by pancreatic enzymes to make them soluble.²⁸

Bioavailability of xanthophylls

Olive oil (monounsaturated fatty acid) can improve lutein bioaccessibility and bioavailability by regulating the activity of intestinal lipases in mice with a lutein-deficiency state.²⁹ Highly saturated-fat containing butter and palm oil are better enhancers of xanthophyll bioavailability than oils with high polyunsaturated fatty acid (PUFA) content.³⁰ Egg yolk is a better source of zeaxanthin than oral supplements.³¹ Thus, it is also important to assess the type of fat intake of an individual before prescribing these xanthophylls.

Vitamin A

It is an essential micronutrient for cell growth and differentiation, immunity, and preserving vision.³² Animal-based foods [containing preformed vitamin A in the form of retinyl esters (REs)] and fruits and vegetables (enriched with provitamin A carotenoids) are the natural sources of Vitamin A. Increased amounts of dietary vitamin A intake has been proven to be associated with decreased risk for any stage of ARMD.^33,34 A recommended daily intake of 700 µg/day of REs for men and 600 µg/day of REs for women has been observed to protect from macular degeneration and associated complications.³⁵ Other epidemiological studies, however, could not find any association between dietary intake of vitamin A and reduced risk of ARMD and its progression.^7,36

Digestion and absorption of exogenous preformed vitamin A

During the process of digestion, fat-soluble vitamin A is incorporated with other lipids into mixed micelles, which is presumably necessary for absorption by the enterocyte. Incorporation of the vitamin A particles into the micelle during dietary lipid lipolysis by gut lipases is affected by several factors involving micronutrient molecular structure, pH and bile lipid concentration, and the presence of dietary fat.^37,38 Hydrolysis of the REs is required prior to absorption by the intestinal mucosa, and pancreatic enzymes cholesterol ester hydrolase and pancreatic lipase play an important role in achieving this hydrolysis.^39,40 Dietary fat stimulates pancreatic juice and biliary secretion, which are necessary for lipid digestion and micelle formation providing the necessary lipids to structure the mixed micelles. Higher the percentage of lipid micronutrient incorporated in micelles (known as “bioaccessibility”), higher its absorption efficiency by the intestinal mucosa.⁴¹

Bioavailability of vitamin A

The bioavailability of vitamin A depends on retinol-binding protein (RBP), retinol: RBP ratio, and RBP: transthyretin ratio.⁴² Low retinal concentration can also be associated with systemic inflammation, infections, and macronutrient deficiency due to reduction in plasma carrier proteins, including RBP and prealbumin.^43,44 Interindividual variability of vitamin A in transport, conversion efficacy, or both has been described in literature due to the genetic variations in genes encoding transport proteins for this micronutrient.⁴⁵ A varied bio-efficacy due to “low responder” and “high responder” phenotypes should be taken into account for providing an adequate dietary amount of vitamin A. Thus, dietary modifications and assessment of associated systemic conditions are necessary before the administration of exogenous vitamin A supplementation.

Vitamin C (Ascorbic acid)

Vitamin C is one of the important antioxidants in the body protecting from free radicals and reactive oxygen species.⁴⁶ Fruits (e.g. Kiwi, strawberry) and vegetables are well-known sources of vitamin C.⁴⁷ The beneficial effect of vitamin C in the human eye and the role of high intake of vitamin C in reducing the likelihood of neovascular ARMD had been described in the literature.⁴⁸ On the contrary, studies have shown a higher relative risk of exudative macular degeneration with increased vitamin C intake⁴⁹ and no significant association between vitamin C intake and prevention of ARMD.^6,34 The recommended daily intake of vitamin C is <1000 mg/day.³⁵

Absorption of dietary vitamin C

The majority of intestinal uptake, tissue distribution, and renal reuptake of vitamin C is regulated by sodium-dependent vitamin C transporter (SVCT) family of proteins.⁵⁰ Vitamin C absorption takes place across intestinal epithelium via membrane transporters either as ascorbate or dehydroascorbic acid (DHA). DHA is either converted to ascorbate inside the cell or transported into the bloodstream via glucose transporters. Ascorbate reaches the blood circulation either via passive diffusion or facilitated diffusion or some unknown active transporters.⁵¹

Bioavailability of vitamin C

About 70–90% of vitamin C absorption occurs at dietary intake levels of 30–180 mg/day.⁵² At doses above 1 g/day, more than 50% reduction in absorption has been observed with excretion of unabsorbed vitamin C via the kidney.⁵² Once a plasma concentration of 70–80 µM is achieved, it does not increase further even with increasing dietary intake of vitamin C.^53,54 From the available literature, a daily intake of about 200–400 mg of vitamin C is adequate in healthy individuals.⁵⁵ Polymorphism in SVCTs, smoking, pregnancy, infectious diseases, cancer, cardiovascular disease, stroke, diabetes mellitus, and septicemia affect vitamin C homeostasis and bioavailability.⁵⁰ Thus, there is no proven benefit of increased dietary intake of vitamin C.

Vitamin E

It is an essential micronutrient and antioxidant. Vitamin E deficiency could result in lipofuscin accumulation, leading to retinal damage and loss of photoreceptors.^56–58

A favorable role of vitamin E for preventing the progression of ARMD has been suggested.⁵⁹ AREDS2 recommended dosage of 400 IU vitamin E in ARMD.

Absorption of dietary vitamin E

Vitamin E is incorporated in mixed micelles along with lipid digestion products (similar to vitamin A metabolism), which facilitates intestinal absorption. It is dependent on the amount of fat in the meal, which stimulates micelle formation and biliary secretion.⁶⁰

Bioavailability of vitamin E

A multitude of factors affect vitamin E bioavailability. A significant difference in relative absorption rate of vitamin E stereoisomers and between α- and γ-tocopherol has not been observed in humans.^61–63 Dietary fibers are suspected to hamper chylomicron formation by inhibiting lipases and increasing the viscosity of chyme and limiting the diffusion of micelles containing vitamin E to the intestinal brush border. Dietary fibers, however, did not affect vitamin E bioavailability in humans.^64,65 Lipids, however, are considered a major effector of vitamin E metabolism.⁶⁰ Genetic factors, including mutation and polymorphism of intestinal proteins involved in vitamin E metabolism, can modulate vitamin E bioavailability. Polymorphism in SCARB1 (scavenger receptor class B type 1), the gene encoding SR-B1 was associated with plasma levels of α- and γ-tocopherol.⁶⁶ Besides, health conditions like obstructive jaundice, pancreatitis, and celiac disease affecting enterohepatic circulation affect vitamin E metabolism. Thus, dietary modification and assessment of associated health disorders are important before prescribing vitamin E supplements to enable high bioavailability.

Copper

Copper plays a vital role in the survival of retinal cells.⁶⁷ A reduced RPE and choroid complex copper level by 23% was noted in ARMD subjects compared to controls without ARMD.⁶⁸ Vegetables, milk, and animal proteins are the common natural sources of copper.

Absorption of exogenous copper

Enterohepatic circulation plays a critical role in copper absorption. Copper absorption has an inverse relationship with the rate of absorption and can fall as low as 12% with a very high quantity of copper intake.^69,70 The reduction in the fraction of copper absorbed at higher dietary intakes is compatible with a carrier-mediated transport process carried out by ceruloplasmin, albumin, and other copper binders.

Bioavailability of exogenous copper

Copper bioavailability from different copper salts has been determined by the slope-ratio technique. With copper bioavailability from acetate salts taken as the reference (100%), bioavailability from sulfate, carbonate, and oxide salts were 88.5%, 54.3%, and 0%, respectively.⁷¹ Studies have hypothesized the role of sodium in increasing the bioavailability of copper by upregulating copper uptake by the intestinal mucosa.⁷² Natural vegetable fibers (crude soybean proteins, hemicellulose) have been shown to reduce copper bioavailability.^73,74 Ascorbic acid causes a significant lowering of the bioavailability of copper due to its reduction from cupric to cuprous form.⁷⁵ The presence of other organic acids like citric, lactic, and acetic acid, however, contributes to the solubilization of copper and increased bioavailability of the element.⁷⁶

The antagonistic interaction between zinc and copper has been known for decades. Serum and liver copper value reduces linearly as dietary zinc concentration increases.⁷⁷ A ternary relation has been noted between zinc, copper, and protein intake where copper deficiency is noted with increased dietary intake of zinc with low protein consumption.⁷⁸ Carrier-mediated transportation of copper acts as a rate-limiting factor, and thus, a higher intake of copper is not beneficial.

Omega-3 fatty acids

Alpha linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) are the primary omega-3 fatty acids. For maintaining a healthy life, recommended dosage of omega-3 fatty acids ranges from 200 mg/day to 1 g/day.⁷⁹ Higher doses of omega-3 fatty acids have been thought to trigger oxidative stress, whereas lower doses exert antioxidant activity.⁸⁰ Flaxseed, canola oil, nuts, and oily fish are the main sources of omega-3 fatty acids in the diet.⁸¹

Absorption of exogenous omega-3 fatty acids

The pathway of metabolism is similar to that of fat-soluble vitamin A. Cholesterol supplementation stimulates absorption by triggering micelle formation and its binding to the intestinal brush border.⁸² EPA and DHA are first hydrolyzed into free fatty acids with the help of pancreatic carboxylic acid ester lipase.⁸¹ Factors such as bile secretion, intestinal pH, microorganisms, and fatty acid transport proteins play an integral part in the absorption of these essential fatty acids.⁸³

Bioavailability of omega-3 fatty acids

There are varied theories regarding the bioavailability of these essential fatty acids. Phospholipid-bound acids are believed to be absorbed better than triglyceride form due to better accessibility of beta-oxidation pathways.⁸⁴ Others believe that the fat content of food is the only decisive factor of rate of absorption and bioavailability.⁸⁴ Bioavailability is also influenced by the form in which they exist. A diet rich in ester form of omega-3 fatty acids has lower bioavailability than free fatty acids.⁸⁵

A recommended dosage of omega-3 fatty acids is beneficial for a healthy lifestyle; however, no benefit is obtained from higher doses.

Side effects of antioxidant supplements

Zinc: High dose of Zinc has been reported to be associated with prostate cancer, memory loss, genitourinary infection, and stress incontinence in women. Excessive absorption of zinc has an inhibitory effect on copper and iron absorption.⁸⁶ Zinc toxicity can manifest with nausea, vomiting, loss of appetite, abdominal cramps, gastrointestinal disturbances, and headaches.⁸⁷ Misuse of easily available over-the-counter zinc supplements has been reported to cause iatrogenic microcytic hypochromic anemia and leucopenia, not treated by iron supplements. Cupric salts have been used in such cases to treat zinc-associated anemia.⁸⁸

Xanthophyll: Literature does not mention any short- or long-term toxicity with xanthophyll supplementation.^89,90

Vitamin A: Vitamin A intake in higher doses is reported to be associated with abdominal pain, loss of appetite, diminution of vision, lethargy, headache, hypercalcemia, irritability, myalgia, nausea, vomiting, peripheral neuritis, skin desquamation.⁹¹ Beta carotene supplements increase the risk of lung cancer both in smokers and in nonsmokers irrespective of the tar or nicotine content of the cigarettes smoked.^92–97

Vitamin C: General consensus is that consumption of supplemental vitamin C does not lead to significant adverse health effects. Occasionally, some people might experience diarrhea and gastrointestinal disturbances.^52,98 Formation of calcium oxalate stones due to the enzymatic conversion of ascorbic acid into oxalate in the body has been postulated. Reports on the effect of vitamin C in lithogenesis, however, have yielded contradictory results.^99–104 Individuals with kidney stones should exercise caution before using high doses of vitamin C.

Vitamin E: Vitamin E supplementation (⩾400 IU) is associated with an increased risk of prostate cancer.^105,106 Studies have shown vitamin E could act as a procarcinogenic agent by upregulating bioactivation of carcinogenic enzymes and can promote DNA damage and frequency of cell transformation.¹⁰⁷

Copper: Excessive copper intake results in nausea, vomiting, gastrointestinal disturbances, headache, drowsiness, fatigue, diarrhea, and a metallic taste in the mouth, anemia (associated with copper concentrations more than 6 mg/L).⁸⁸

Omega-3 fatty acids: They are usually not been reported with any severe adverse effects. There is a controversy regarding the association of increased levels of long-chain omega-3 fatty acids in blood with high-grade prostate cancer.¹⁰⁸ This study, however, could not prove fish oil as the cause for prostate cancer, as it is an observational study and not a randomized controlled trial. Contrary to the above-mentioned speculation, Dr. Harris has stated that fish and higher omega-3 fatty acid intake is associated with a lower incidence of prostate cancer and death and a better survival rate among those who already had prostate cancer by delaying the progression of cancer.¹⁰⁹

Studies highlighting the positive and negative effects of antioxidants have been summarized in Table 2.

Table 2.

Studies depicting positive and negative outcomes of individual antioxidants in ARMD.

Compounds	Study design	Doses	Outcomes
1. Lutein, zeaxanthin, and meso-zeaxanthin in sunflower oil suspension¹¹⁰	Double-blind, placebo-controlled, block-randomized human trial (12 months)	10 mg lutein, 10 mg meso-zeaxanthin, and 2 mg zeaxanthin	Positive outcomes: Significantly improved contrast sensitivity of the visual function after 12 months supplementation compared with baseline. Treatment group had significant increase in serum concentrations of the xanthophylls in retina and macular pigment optical density compared with placebo.
2. Anthocyanin supplement¹¹¹	Randomized, parallel study. Postmenopausal, one woman (8 months)	60 mg/day	Negative outcome (compared with baseline): No significant increase in macular pigment optical density
3. Vitamin A, vitamin C, and vitamin E⁸	Case-control study		Positive outcomes: Low dietary intake of vitamin C and vitamin E was associated with neovascular ARMD.Negative outcome: Dietary vitamin A showed no association with neovascular AMD.
4. Vitamin E¹¹²	Randomized controlled trial (4 years)	500 IU daily	Negative outcome: Failed to prevent the development and progression of AMD.
5. Vitamin C and vitamin E⁶	Eye disease case-control study		Negative outcome: No statistically significant overall association was found between serum vitamin status and neovascular AMD
6. Vitamins and carotenoids¹¹³	Prospective observational study		Positive outcome: Higher fruit intake related to reduced risk of neovascular ARMD.Negative outcome: Vitamins and carotenoid supplements did not have any significant association with ARMD.
7. Vitamins A, C, and E³⁶	Prospective population-based study		Positive outcome: Strong inverse relation between ARMD and plasma levels of α-tocopherol (vitamin E).Negative outcome: No significant association between ARMD and plasma retinol (vitamin A) and ascorbic acid (vitamin C) levels.
8. Vitamins A, C, E, or multivitamins⁴⁹	Prospective cohort study		Positive outcome: Vitamin E users had possible but nonsignificant 13% reduced risk of ARMD, while multivitamin users had 10% reduced risk.Negative outcome: No reduction in risk for ARMD in vitamin C users.
9. Vitamin E and zinc⁵⁸	Prospective case control study		Positive outcome: ARMD patients had lower levels of serum vitamin E and zinc than ARMD-free patients emphasizing the role of zinc and vitamin E in ARMD.
10. Omega-3 fatty acids¹¹⁴	Randomized double-blinded placebo-controlled clinical trial		Positive outcome: Significant improvement in visual parameters and decrease in drusen cover are were noted in treated early ARMD patients
11. Omega-3 fatty acids¹¹⁵	Prospective observational study		Positive outcome: Regular consumption of DHA and EPA and fish was associated with significant decreased risk of incident ARMD and may help in primary prevention of ARMD.
12. Zinc and copper⁶²	Cross-sectional study (eye tissue from human donors collected at the time of autopsy)		Positive outcome: Mean RPE and choroid complex zinc and copper were reduced in ARMD patients compared with ARMD-free patients, suggesting that metal homeostasis plays a role in ARMD and retinal health.
13. Zinc¹¹⁶	Randomized, double-blinded, placebo-controlled study (2 years intervention	Zinc sulfate(200 mg daily)	Positive outcome: Significantly increased serum zinc.Negative outcome: No significant improvement of eye conditions for patients with AMD.
14. Zinc⁹	Randomized, placebo-controlled clinical trials (followed up for up to 10 years)	Zinc oxide(80 mg daily)	Positive outcome: Significantly reduced the risk of developing advanced AMD.
15. Zinc¹¹⁷	Prospective, randomized double-masked placebo-controlled study		Positive outcome: Vision loss was significantly less in oral zinc–treated group than the placebo group in patients with macular degeneration.
16. Zinc, carotenoids, and vitamins¹¹⁸	Retrospective longitudinal cohort study		Positive outcome: Zinc supplementation was associated with slow progression of dry form of ARMD (weak association).Negative outcome: Zinc intake was unrelated to late ARMD. Carotenoids intake was unrelated to both early and late ARMD.

ARMD: age-related macular degeneration; DHA: dehydroascorbic acid; EPA: eicosapentaenoic acid; RPE: retinal pigment epithelium.

It is probably time to rethink the role of antioxidant supplementation in ARMD. Increased prescription and over-the-counter supply of antioxidant formulations have led us to evaluate the risk versus benefit ratio of the supplements.

Various questions have been raised from time to time regarding the actual benefit of antioxidants and the stage at which it is more beneficial. AREDS regimen proved to be beneficial only for the group of cases with intermediate ARMD in one eye and advanced ARMD in the other eye. No other groups showed any benefit. AREDS study had a conflict of interest as many investigators had ties to the Bausch + Lomb company (which funded the AREDS study).¹¹⁹ There are issues of deceptive marketing as well—formulations of some of the top-selling ocular antioxidant supplements in the United States are not identical to those tested in AREDS 1 and 2 trials. Ellingson and Ambati reported in ARVO annual meeting in September 2016 that 73.5% of patients who were taking vitamins did not meet the AREDS guidelines and only 29.6% of the vitamin supplements had a preparation similar to the AREDS formulation.¹¹⁹

As an example, Brand X and brand Y are two popular antioxidant supplement brands available in the market at present:

1. Brand X has the following ingredients:

Astaxanthin: 1 mg

Lutein 20%: 5 mg

Zeaxanthin: 1 mg

Vitamin A: 1470 µg

Vitamin C: 50 mg

Vitamin E: 5 mg

Zinc oxide: 40 mg

Cupric oxide: 2 mg

Sodium selenite pentahydrate: 40 µg

PRICE: US$3/pack in India (10 units/pack)

2. Brand Y comprises the following:

Beta carotene: 4800 IU

Elemental Copper: 2 mg

Elemental Manganese: 2 mg

Elemental selenium: 40 µg

Elemental zinc: 10 mg

Lutein: 302 mg

Vitamin C: 40 mg

Vitamin E: 10 IU

PRICE: Rs US$3/pack in India (10 units/pack)

We observed a huge difference in the composition and the dosage of the available supplements, and they also do not seem to adhere to the AREDS 2 formulation given below:

AREDS 2 formulation:

500 mg of vitamin C

400 IU of vitamin E

80 mg of zinc oxide

2 mg of cupric oxide

10 mg of lutein

2 mg of zeaxanthin

Following are some additional points that we would like to highlight regarding antioxidant use:

Role of genotype: Independent association of CFH (complement factor H) and LOC387715 genetic variants with progression to advanced stages of ARMD was first reported in 2007 by Seddon and colleagues.¹²⁰ A seven times increase in the risk of progression was noted among combined homozygous risk genotypes. Awh and colleagues¹²¹ evaluated the impact of CFH and ARMS2 (age-related maculopathy susceptibility 2) on treatment-specific progression to advanced ARMD. Their results depicted that maximum benefit from zinc-only supplementation could be achieved in patients with no CFH risk alleles and one or two ARMS2 risk alleles. Patients with one or two CFH risk alleles and no ARMS 2 risk alleles had a maximum response from supplementation containing only antioxidants. Treatment with zinc supplement was associated with rapid progression to advanced ARMD in this group. Individuals homozygous for both the risk alleles did not have any benefit from either category of AREDS treatment. Thus, the pharmacogenomic selection of nutritional supplements was postulated in moderate ARMD. Chew and colleagues,¹²² however, did not find any significant interaction between supplements and genetics. Another study by Seddon and colleagues¹²³ published in 2016 noted that subjects with nonrisk genotype for CFH had a significantly lower risk of progression to advanced ARMD after treatment, while those with one or two risk alleles of CFH did not benefit from AREDS treatment.

Further genetic studies are required to determine the biological mechanism behind this interaction and its implication to formulate a comprehensive treatment approach for ARMD.

The increased financial burden on patients using inappropriate antioxidant supplements.

Unawareness among active smokers regarding the risk of lung cancer with beta carotene in the supplements.

Side effects of vitamins and antioxidants.

A large number of variables affecting the bioavailability of the individual ingredients as discussed above.

Conclusion

Antioxidant supplements have their pros and cons. Perhaps it is advisable to prescribe antioxidant supplementation only to patients who strictly meet the criteria as stated by the AREDS study after weighing the risk versus benefit ratio for each individual. Dietary modification should also be discussed for better absorption and bioavailability of the individual vitamins and minerals. Several formulations with variable compositions are available in the market and hence health care professionals should be very careful before advising expensive antioxidants routinely to patients. It may not be prudent to prescribe these formulations without a proper assessment of the individuals’ health and dietary status. These supplements should not to be given to patients just for the purpose of providing them with some kind of therapy, as effectiveness of all the components in antioxidant formulations is controversial.

Footnotes

Conflict of interest statement

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Rohan Chawla

References

Smith

Assink

Klein

, et al. Risk factors for age-related macular degeneration: pooled findings from three continents. Ophthalmology 2001; 108: 697–704.

Chew

. Nutrition effects on ocular diseases in the aging eye. Investig Ophthalmol Vis Sci 2013; 54: ORSF42–ORSF47.

Schleicher

Weikel

Garber

, et al. Diminishing risk for age-related macular degeneration with nutrition: a current view. Nutrients 2013; 5: 2405–2456.

Gorusupudi

Nelson

Bernstein

. The Age-Related Eye Disease 2 Study: micronutrients in the treatment of macular degeneration. Adv Nutr 2017; 8: 40–53.

Hogg

Chakravarthy

. AMD and micronutrient antioxidants. Curr Eye Res 2004; 29: 387–401.

Antioxidant status and neovascular age-related macular degeneration. Eye Disease Case-Control Study Group. Arch Ophthalmol 1993; 111: 104–109.

Seddon

Ajani

Sperduto

, et al. Dietary carotenoids, vitamins a, c, and e, and advanced age-related macular degeneration. JAMA 1994; 272: 1413–1420.

Aoki

Inoue

Nguyen

, et al. Dietary n-3 fatty acid, tocopherol, zinc, vitamin D, vitamin C, and carotene are associated with age-related macular degeneration in Japan. Sci Rep 2016; 6: 20723.

Wang

Suter

, et al. Spirulina is an effective dietary source of zeaxanthin to humans. Br J Nutr 2012; 108: 611–619.

10.

Evans

Lawrenson

. Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration. Cochrane Database Syst Rev 2017; 2017: CD000253.

11.

Evans

Lawrenson

. Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration. Cochrane Database Syst Rev 2017; 2017: CD000254.

12.

Lawrenson

Evans

. Omega 3 fatty acids for preventing or slowing the progression of age-related macular degeneration. Cochrane Database Syst Rev 2015; 2015: CD010015.

13.

Grahn

Paterson

Gottschall-Pass

, et al. Zinc and the eye. J Am Coll Nutr 2001; 20: 106–118.

14.

King

. Zinc: an essential but elusive nutrient. Am J Clin Nutr 2011; 94: 679S–684S.

15.

Prasad

. Zinc deficiency in humans: a neglected problem. J Am Coll Nutr 1998; 17: 542–543.

16.

Cousins

. Absorption, transport, and hepatic metabolism of copper and zinc: special reference to metallothionein and ceruloplasmin. Physiol Rev 1985; 65: 238–309.

17.

Steel

Cousins

. Kinetics of zinc absorption by luminally and vascularly perfused rat intestine. Am J Physiol 1985; 248: G46–G53.

18.

FAO/WHO. Expert consultation on human vitamin and mineral requirements, vitamin and mineral requirements in human nutrition: report of joint FAO/WHO expert consolation. 2nd ed. Bangkok, Thailand: FAO/WHO, 2004, p. 341.

19.

Krebs

. Overview of zinc absorption and excretion in the human gastrointestinal tract. J Nutr 2000; 130(5 Suppl.): 1374S–1377S.

20.

Lee

Prasad

Hydrick-Adair

, et al. Homeostasis of zinc in marginal human zinc deficiency: role of absorption and endogenous excretion of zinc. J Lab Clin Med 1993; 122: 549–556.

21.

Istfan

Janghorbani

Young

. Absorption of stable70 Zn in healthy young men in relation to zinc intake. Am J Clin Nutr 1983; 38: 187–194.

22.

Maares

Haase

. A guide to human zinc absorption: general overview and recent advances of in vitro intestinal models. Nutrients 2020; 12: 762.

23.

Lönnerdal

. Dietary factors influencing zinc absorption. J Nutr 2000; 130(5 Suppl.): 1378S–1383S.

24.

Maares

Duman

Keil

, et al. The impact of apical and basolateral albumin on intestinal zinc resorption in the Caco-2/HT-29-MTX co-culture model. Metallomics 2018; 10: 979–991.

25.

Eggersdorfer

Wyss

. Carotenoids in human nutrition and health. Arch Biochem Biophy 2018; 652: 18–26.

26.

Deming

Erdman

Jr.

Mammalian carotenoid absorption and metabolism. Pure Appl Chem 1999; 71: 2213–2223.

27.

Zaripheh

Erdman

Jr.

Factors that influence the bioavailability of xanthophylls. J Nutr 2002; 132: 531S–534S.

28.

Roodenburg

Leenen

van het Hof

, et al. Amount of fat in the diet affects bioavailability of lutein esters but not of alpha-carotene, beta-carotene, and vitamin E in humans. Am J Clin Nutr 2000; 71: 1187–1193.

29.

Nidhi

Mamatha

Baskaran

. Olive oil improves the intestinal absorption and bioavailability of lutein in lutein-deficient mice. Eur J Nutr 2014; 53: 117–126.

30.

Gleize

Tourniaire

Depezay

, et al. Effect of type of TAG fatty acids on lutein and zeaxanthin bioavailability. Br J Nutr 2013; 110: 1–10.

31.

Thurnham

. Macular zeaxanthins and lutein—A review of dietary sources and bioavailability and some relationships with macular pigment optical density and age-related macular disease. Nutr Res Rev 2007; 20: 163–179.

32.

Gerster

. Vitamin A—Functions, dietary requirements and safety in humans. Int J Vitam Nutr Res 1997; 67: 71–90.

33.

Goldberg

Flowerdew

Smith

, et al. Factors associated with age-related macular degeneration. An analysis of data from the first national health and nutrition examination survey. Am J Epidemiol 1988; 128: 700–710.

34.

de Koning-Backus

APM

Buitendijk

GHS

Kiefte-de Jong

, et al. Intake of vegetables, fruit, and fish is beneficial for age-related macular degeneration. Am J Ophthalmol 2019; 198: 70–79.

35.

Scientific Committee on Food. Tolerable upper intake levels for vitamins and minerals. Parma: European Food Safety Authority, 2006.

36.

Delcourt

Cristol

Tessier

, et al. Age-related macular degeneration and antioxidant status in the POLA study. POLA Study Group. Pathologies Oculaires Liées à l’Age. Arch Ophthalmol 1999; 117: 1384–1390.

37.

Borel

. Factors affecting intestinal absorption of highly lipophilic food microconstituents (fat-soluble vitamins, carotenoids and phytosterols). Clin Chem Lab Med 2003; 41: 979–994.

38.

Bengtsson

Larsson Alminger

Svanberg

. In vitro bioaccessibility of beta-carotene from heat-processed orange-fleshed sweet potato. J Agric Food Chem 2009; 57: 9693–9698.

39.

Lombardo

Guy

. Studies on the substrate specificity of a carboxyl ester hydrolase from human pancreatic juice. II. Action on cholesterol esters and lipid-soluble vitamin esters. Biochim Biophys Acta 1980; 611: 147–155.

40.

Lauridsen

Hedemann

Jensen

. Hydrolysis of tocopheryl and retinyl esters by porcine carboxyl ester hydrolase is affected by their carboxylate moiety and bile acids. J Nutr Biochem 2001; 12: 219–224.

41.

Reboul

. Absorption of vitamin A and carotenoids by the enterocyte: focus on transport proteins. Nutrients 2013; 5: 3563–3581.

42.

Degerud

Manger

Strand

, et al. Bioavailability of iron, vitamin A, zinc, and folic acid when added to condiments and seasonings. Ann N Y Acad Sci 2015; 1357: 29–42.

43.

Duncan

Talwar

McMillan

, et al. Quantitative data on the magnitude of the systemic inflammatory response and its effect on micronutrient status based on plasma measurements. Am J Clin Nutr 2012; 95: 64–71.

44.

Arroyave

Calcano

. Decrease in serum levels of retinol and its binding protein (RBP) in infection. Arch Latinoam Nutr 1979; 29: 233–260.

45.

Borel

Grolier

Mekki

, et al. Low and high responders to pharmacological doses of beta-carotene: proportion in the population, mechanisms involved and consequences on beta-carotene metabolism. J Lipid Res 1998; 39: 2250–2260.

46.

Zampatti

Ricci

Cusumano

, et al. Review of nutrient actions on age-related macular degeneration. Nutr Res 2014; 34: 95–105.

47.

Andreatta

El-Sherbiny

. Evidence-based nutritional advice for patients affected by age-related macular degeneration. Ophthalmologica 2014; 231: 185–190.

48.

Age-Related Eye Disease Study Research Group, SanGiovanni

Chew

, et al. The relationship of dietary carotenoid and vitamin A, E, and C intake with age-related macular degeneration in a case-control study: AREDS report no. 22. Arch Ophthalmol 2007; 125: 1225–1232.

49.

Christen

Ajani

Glynn

, et al. Prospective cohort study of antioxidant vitamin supplement use and the risk of age-related maculopathy. Am J Epidemiol 1999; 149: 476–484.

50.

Lykkesfeldt

Tveden-Nyborg

. The pharmacokinetics of vitamin C. Nutrients 2019; 11: 2412.

51.

Lindblad

Tveden-Nyborg

Lykkesfeldt

. Regulation of vitamin C homeostasis during deficiency. Nutrients 2013; 5: 2860–2879.

52.

Jacob

Sotoudeh

. Vitamin C function and status in chronic disease. Nutr Clin Care 2002; 5: 66–74.

53.

Levine

Conry-Cantilena

Wang

, et al. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc Natl Acad Sci USA 1996; 93: 3704–3709.

54.

Levine

Wang

Padayatty

, et al. A new recommended dietary allowance of vitamin C for healthy young women. Proc Natl Acad Sci USA 2001; 98: 9842–9846.

55.

Frei

Birlouez-Aragon

Lykkesfeldt

. Authors’ perspective: what is the optimum intake of vitamin C in humans? Crit Rev Food Sci Nutr 2012; 52: 815–829.

56.

Robison

Kuwabara

Bieri

. The roles of vitamin E and unsaturated fatty acids in the visual process. Retina 1982; 2: 263–281.

57.

Tanito

Yoshida

Kaidzu

, et al. Acceleration of age-related changes in the retina in a-tocopherol transfer protein null mice fed a vitamin E–deficient diet. Investig Ophthalmol Vis Sci 2007; 48: 396–404.

58.

Katz

Eldred

. Failure of vitamin E to protect the retina against damage resulting from bright cyclic light exposure. Invest Ophthalmol Vis Sci 1989; 30: 29–36.

59.

Belda

Romá

Vilela

, et al. Serum vitamin E levels negatively correlate with severity of age-related macular degeneration. Mech Ageing Dev 1999; 107: 159–164.

60.

Reboul

. Vitamin E bioavailability: mechanisms of intestinal absorption in the spotlight. Antioxidants (Basel) 2017; 6: 95.

61.

Traber

Burton

Ingold

, et al. RRR- and SRR-alpha-tocopherols are secreted without discrimination in human chylomicrons, but RRR-alpha-tocopherol is preferentially secreted in very low density lipoproteins. J Lipid Res 1990; 31: 675–685.

62.

Traber

Kayden

. Preferential incorporation of alpha-tocopherol vs gamma-tocopherol in human lipoproteins. Am J Clin Nutr 1989; 49: 517–526.

63.

Reboul

Klein

Bietrix

, et al. Scavenger receptor class B type I (SR-BI) is involved in vitamin E transport across the enterocyte. J Biol Chem 2006; 281: 4739–4745.

64.

Riedl

Linseisen

Hoffmann

, et al. Some dietary fibers reduce the absorption of carotenoids in women. J Nutr 1999; 129: 2170–2176.

65.

Greenwood

Cade

White

, et al. The impact of high non-starch polysaccharide intake on serum micronutrient concentrations in a cohort of women. Public Health Nutr 2004; 7: 543–548.

66.

Witt

Kolleck

Fechner

, et al. Regulation by vitamin E of the scavenger receptor BI in rat liver and HepG2 cells. J Lipid Res 2000; 41: 2009–2016.

67.

Wills

Ramanujam

Kalariya

, et al. Copper and zinc distribution in the human retina: relationship to cadmium accumulation, age, and gender. Exp Eye Res 2008; 87: 80–88.

68.

Erie

Good

Butz

, et al. Reduced zinc and copper in the retinal pigment epithelium and choroid in age-related macular degeneration. Am J Ophthalmol 2009; 147: 276–282.

69.

Turnlund

King

Gong

, et al. A stable isotope study of copper absorption in young men: effect of phytate and a-cellulose. Am J Clin Nutr 1985; 42: 18–23.

70.

Turnlund

Keyes

Anderson

, et al. Copper absorption and retention in young men at three levels of dietary copper by use of the stable isotope 65Cu. Am J Clin Nutr 1989; 49: 870–878.

71.

Ledoux

Henry

Ammerman

, et al. Estimation of the relative bioavailability of inorganic copper sources for chicks using tissue uptake of copper. J Anim Sci 1991; 69: 215–222.

72.

Wapnir

Stiel

. Intestinal absorption of copper: effect of sodium. Proc Soc Exp Biol Med 1987; 185: 277–282.

73.

Davis

Norris

Kratzer

. Interference of soybean proteins with the utilization of trace minerals. J Nutr 1962; 77: 217–223.

74.

Drews

Kies

Fox

. Effect of dietary fiber on copper, zinc, and magnesium utilization by adolescent boys. Am J Clin Nutr 1979; 32: 1893–1897.

75.

Van Campen

Gross

. Influence of ascorbic acid on the absorption of copper by rats. J Nutr 1968; 95: 617–622.

76.

Sable-Amplis

Sicart

Reynier

. Apparent retention of copper, zinc and iron in hamsters influence of a fruit-enriched diet. Nutr Rep Int 1987; 35: 811–818.

77.

Fischer

PWF

Giroux

L’Abbé

. The effect of dietary zinc on intestinal copper absorption. Am J Clin Nutr 1981; 34: 1670–1675.

78.

Sandstead

. Copper bioavailability and requirements. Am J Clin Nutr 1982; 35: 809–814.

79.

Patten

Brocardo

Christie

. Omega-3 supplementation can restore glutathione levels and prevent oxidative damage caused by prenatal ethanol exposure. J Nutr Biochem 2013; 24: 760–769.

80.

Giordano

Visioli

. Long-chain omega 3 fatty acids: molecular bases of potential antioxidant actions. Prostaglandins Leukot Essent Fatty Acids 2014; 90: 1–4.

81.

Shahidi

Ambigaipalan

. Omega-3 polyunsaturated fatty acids and their health benefits. Ann Rev Food Sci Technol 2018; 9: 345–381.

82.

Dupasquier

Dibrov

Kneesh

, et al. Dietary flaxseed inhibits atherosclerosis in the LDL receptor-deficient mouse in part through antiproliferative and anti-inflammatory actions. Am J Physiol Heart Circ Physiol 2007; 293: H2394–H2402.

83.

Punia

Sandhu

Siroha

, et al. Omega 3-metabolism, absorption, bioavailability and health benefits—A review. Pharmanutrition 2019; 10: 100162.

84.

Cholewski

Tomczykowa

Tomczyk

. A comprehensive review of chemistry, sources and bioavailability of omega-3 fatty acids. Nutrients 2018; 10: 1662.

85.

Schuchardt

Schneider

Meyer

, et al. Incorporation of EPA and DHA into plasma phospholipids in response to different omega-3 fatty acid formulations-a comparative bioavailability study of fish oil vs. krill oil. Lipids Health Dis 2011; 10: 145.

86.

Fosmire

. Zinc toxicity. Am J Clin Nutr 1990; 51: 225–227.

87.

Sandstead

. Understanding zinc: recent observations and interpretations. J Lab Clin Med 1994; 124: 322–327.

88.

Hoffman

Phyliky

Fleming

. Zinc-induced copper deficiency. Gastroenterology 1988; 94: 508–512.

89.

Kruger

Murphy

DeFreitas

, et al. An innovative approach to the determination of safety for a dietary ingredient derived from a new source: case study using a crystalline lutein product. Food Chem Toxicol 2002; 40: 1535–1549.

90.

Dagnelie

Zorge

McDonald

. Lutein improves visual function in some patients with retinal degeneration: a pilot study via the Internet. Optometry 2000; 71: 147–164.

91.

Hathcock

Hattan

Jenkins

, et al. Evaluation of vitamin A toxicity. Am J Clin Nutr 1990; 52: 183–202.

92.

Alpha-Tocopherol Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994; 330: 1029–1035.

93.

Albanes

Heinonen

Huttunen

, et al. Effects of alpha-tocopherol and beta-carotene supplements on cancer incidence in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study. Am J Clin Nutr 1995; 62(6 Suppl.): 1427S–1430S.

94.

Albanes

Heinonen

Taylor

, et al. Alpha-Tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance. J Natl Cancer Inst 1996; 88: 1560–1570.

95.

Omenn

Goodman

Thornquist

, et al. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J Natl Cancer Inst 1996; 88: 1550–1559.

96.

Goralczyk

. Beta-carotene and lung cancer in smokers: review of hypotheses and status of research. Nutr Cancer 2009; 61: 767–774.

97.

Middha

Weinstein

Männistö

, et al. β-Carotene supplementation and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: the role of tar and nicotine. Nicotine Tob Res 2019; 21: 1045–1050.

98.

Gershoff

. Vitamin C (ascorbic acid): new roles, new requirements? Nutr Rev 1993; 51: 313–326.

99.

Ferraro

Curhan

Gambaro

, et al. Total, dietary, and supplemental vitamin C intake and risk of incident kidney stones. Am J Kidney Dis 2016; 67: 400–407.

100.

Jiang

Tang

Liu

, et al. Ascorbic acid supplements and kidney stones incidence among men and women: a systematic review and meta-analysis. Urol J 2019; 16: 115–120.

101.

Massey

Liebman

Kynast-Gales

. Ascorbate increases human oxaluria and kidney stone risk. J Nutr 2005; 135: 1673–1677.

102.

Pullar

Carr

Vissers

. Vitamin C supplementation and kidney stone risk. N Z Med J 2013; 126: 133–134.

103.

Knight

Madduma-Liyanage

Mobley

, et al. Ascorbic acid intake and oxalate synthesis. Urolithiasis 2016; 44: 289–297.

104.

Traxer

Pearle

Gattegno

, et al. Vitamine C et risque lithiasique [Vitamin C and stone risk. Review of the literature]. Prog Urol 2003; 13: 1290–1294.

105.

Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS Report No. 8. Arch Ophthalmol 2001; 119: 1417–1436.

106.

Klein

Thompson

Jr Tangen

, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2011; 306: 1549–1556.

107.

Vivarelli

Canistro

Cirillo

, et al. Co-carcinogenic effects of vitamin E in prostate. Sci Rep 2019; 9: 11636.

108.

Brasky

Darke

Song

, et al. Plasma phospholipid fatty acids and prostate cancer risk in the SELECT trial. J Natl Cancer Inst 2013; 105: 1132–1141.

109.

DeFina

Bassett

Finley

, et al. Association between omega-3 fatty acids and serum prostate-specific antigen. Nutr Cancer 2016; 68(1): 58–62.

110.

Nolan

Power

Stringham

, et al. Enrichment of macular pigment enhances contrast sensitivity in subjects free of retinal disease: Central Retinal Enrichment Supplementation Trials–Report 1. Investig Ophthalmol Vis Sci 2016; 57: 3429–3439.

111.

Olmedilla-Alonso

Estévez-Santiago

Silván

, et al. Effect of long-term xanthophyll and anthocyanin supplementation on lutein and zeaxanthin serum concentrations and macular pigment optical density in postmenopausal women. Nutrients 2018; 10: 959.

112.

Taylor

Tikellis

Robman

, et al. Vitamin E supplementation and macular degeneration: randomised controlled trial. Br Med J 2002; 325: 11.

113.

Cho

Seddon

Rosner

, et al. Prospective study of intake of fruits, vegetables, vitamins, and carotenoids and risk of age-related maculopathy. Arch Ophthalmol 2004; 122: 883–892.

114.

Feher

Kovacs

, et al. Improvement of visual functions and fundus alterations in early age-related macular degeneration treated with a combination of acetyl-L-carnitine, n-3 fatty acids, and coenzyme Q10. Ophthalmologica 2005; 219: 154–166.

115.

Christen

Schaumberg

Glynn

, et al. Dietary ω-3 fatty acid and fish intake and incident age-related macular degeneration in women. Arch Ophthalmol 2011; 129: 921–929.

116.

Stur

Tittl

Reitner

, et al. Oral zinc and the second eye in age-related macular degeneration. Investig Ophthalmol Vis Sci 1996; 37: 1225–1235.

117.

Newsome

Swartz

Leone

, et al. Oral zinc in macular degeneration. Arch Ophthalmol 1988; 106: 192–198.

118.

Mares-Perlman

Klein

, et al. Association of zinc and antioxidant nutrients with age-related maculopathy. Arch Ophthalmol 1996; 114: 991–997.

119.

Hall

. Re-thinking antioxidant supplementation for macular degeneration. ClinicalTrials 2017, https://sciencebasedmedicine.org/re-thinking-antioxidant-supplementation-for-macular-degeneration/

120.

Seddon

Francis

George

, et al. Association of CFH Y402H and LOC387715 A69S with progression of age-related macular degeneration. JAMA 2007; 297: 1793–1800.

121.

Awh

Lane

Hawken

, et al. CFH and ARMS2 genetic polymorphisms predict response to antioxidants and zinc in patients with age-related macular degeneration. Ophthalmology 2013; 120: 2317–2323.

122.

Chew

Klein

Clemons

, et al. Genetic testing in persons with age-related macular degeneration and the use of the AREDS supplements: to test or not to test? Ophthalmology 2015; 122: 212–215.

123.

Seddon

Silver

Rosner

. Response to AREDS supplements according to genetic factors: survival analysis approach using the eye as the unit of analysis. Br J Ophthalmol 2016; 100: 1731–1737.