Vision for the Future

References

In Andrew Lloyd Webbers musical adaptation of Sunset Boulevard, the aging actress Norma Desmond proclaims she wont go quietly into the night, as she still holds the power to captivate With One Look. Shes not the only one to realize the striking impact visual connection holds. Frankie Valli cant take his eyes off of you, while Bruce Springsteen knew sad eyes never lie. Beyond the emotional appeal, sight itself is a complex process involving the eye as well as the nerves and brain. As light hits the corneal surface, it is focused and passes through the pupil and the lens. After traveling through the vitreous humora jelly-like compoundit reaches the retina, a light-sensitive layer that covers approximately 65 percent of the interior surface of the eye. Photoreceptor cells, including rods and cones, absorb light at the retina and turn it into nerve impulses that are fed through the optic nerve and into the brain for interpretation. The peripheral retina distinguishes light from dark and permits peripheral vision, while the macula focuses on fine detail and colors.

Vision is a fine-tuned process that relies on all parts working in healthy coordination. However, the photoreceptor membranes are rich in polyunsaturated fatty acids, making them susceptible to oxidative damage from highly reactive free radicals. The retina is an ideal environment for the generation of free radicals since it has both high levels of blood (and thus oxygen) supply and high light exposure. Therefore, environmental factors and simple UV radiation lead to oxidative stress, while nutritional imbalance can exacerbate visual impairment.

Two degenerative conditions of the eye have been linked to nutritional factors: age-related macular degeneration (AMD) and cataract. AMD is among the leading causes of blindness in Western countries, affecting about 20 percent of all people above 65; it is believed to be the leading cause of irreversible blindness in the elderly in Western populations. AMD is characterized by irreversible progressive degeneration of the macula lutea, the site of the highest visual acuity of the retina. Dry AMD, the more common form, occurs when light-sensitive cells in the macula slowly break down, blurring central vision. Its most common early symptom is the presence of drusen, yellow deposits under the retina. Wet AMD occurs when abnormal blood vessels behind the retina start to grow under the macula, raising the macula from its normal position and causing rapid damage.

Cataract remains the leading cause of blindness in the world. Associated with aging, it is even more significant as a cause of low vision, as the cataract clouds the eyes lens. Researchers from the U.S. National Eye Institute (NEI) report cataract is the leading cause of low vision among all Americans, responsible for about 50 percent of all cases, and they estimate 20 million Americans over age 40 have at least one cataract. Cataracts are commonly treated with surgery; in fact, cataract surgery is the most frequently performed medical procedure in the United States, with more than 1.5 million cataract surgeries done annually.

Glaucoma is the second leading cause of blindness globally. The term refers to a group of eye diseases that cause vision loss through damage to the optic nerve. Approximately 2.2 million Americans over age 40 have glaucoma, according to NEI, and it is the leading cause of blindness in Hispanics. The two primary types of glaucoma are open angle glaucoma (also known as primary open angle glaucomaPOAG) and angle closure glaucoma. POAG is the most common form and occurs when the eyes drainage canals become clogged, increasing intraocular pressure (IOP). While vision loss from glaucoma is irreversible, it can be managed with medication or surgery.

One additional cause of blindness is diabetic retinopathy, whereby the disease damages the blood vessels that nourish the retina, causing the vessels to leak or break. It affects more than 4 million Americans. Macular edema (swelling) in diabetic retinopathy can be treated with laser surgery to slow fluid leakage and reduce the fluid levels in the retina.

A report released in April 2007, Economic Impact of Vision Problems from Prevent Blindness America, estimates adult vision problems in the United States have a financial impact of $51.4 billion annually, including the costs to the individual and their caregivers, and on the U.S. economy. The report was assembled by two groups of health economists, one from the Johns Hopkins Bloomberg School of Public Health, and the other from RTI International and the Centers for Disease Control and Prevention.

Estimates from NEI put the number of Americans over the age of 40 suffering blindness or low vision at 3.3 million, a number expected to increase to 5.5 million by 2020.

Currently, there are no cures for conditions such as glaucoma or AMD, making prevention critical. Nutrition plays a vital role, with antioxidants leading the support brigade. In fact, NEI has urged adults who have or are at risk of AMD to consider taking supplements based off the formulation used in the long-term Age-Related Eye Disease Study (AREDS)vitamins C, E, beta-carotene and zinc.¹ In addition, they found data suggesting high dietary intake of the macular xanthophylls lutein and zeaxanthin and omega-3 essential fatty acids (EFAs) are associated with a lower risk of advanced AMD.

In fact, the data was so convincing that the National Institutes of Health (NIH) is supporting a second AREDS trial (AREDS2) to build upon the original results, which found high-dose antioxidant supplementation reduced the risk of progression to advanced AMD by 25 percent, and the risk of moderate vision loss by 19 percent.² AREDS2 will refine the findings of the original study by adding the carotenoids lutein and zeaxanthin and long-chain polyunsaturated fatty acids (LC-PUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), derived from fish oils, to the study formulation.

Further research is also planned to evaluate the effect of a multivitamin (as Centrum) on the development and progression of age-related cataract development, after a subgroup in the AREDS trial taking the multivitamin plus the AREDS formula did show a reduction in lens opacity progression.³ The trial, sponsored by NEI, is scheduled for completion by years end. Interestingly, the AREDS antioxidant formulation alone did not appear to influence cataract formation.⁴

German researchers from Philipps University of Marburg further noted in a review that antioxidants impact on cataract has been minimal in clinical trials, including the AREDS and REACT (Roche European American Cataract Trial) studies.⁵ They concluded, any effect of antioxidants on cataract development is likely to be very small and not of great significance. Antioxidants also do not appear to impact glaucoma progression, as Harvard researchers examined data from the Nurses Health Study and the Health Professionals Follow-up Study and found no strong associations between antioxidant intake and the risk of primary open-angle glaucoma.⁶

However, antioxidant efficacy may be linked to timing, according to a review by Swiss researchers.⁷ They noted while the AREDS trial did not show a benefit for cataract formation, and the REACT trial showed only a small impact on cataract progression, the REACT intervention started earlier in the disease process, suggesting earlier supplementation added to a healthy diet may prevent disease onset.

In addition, a combination of antioxidants may prove beneficial in preventing onset of diabetic retinopathy. Researchers from Wayne State University, Detroit, examined the impact of an antioxidant combination (including alpha-tocopherol, N-acetyl cysteine, ascorbic acid, beta-carotene and selenium) on retinal health in diabetic rats and under in vitro conditions.⁸ They found increased oxidative stress activated the enzyme retinal caspase-3, leading to increased apoptosis of endothelial cells and pericytes; antioxidant treatment helped inhibit microvascular apoptosis.

Individual antioxidant nutrients have also been investigated for their role in eye health. Studies looking at vitamin C, for example, have focused on its role in preventing cataract formation. In vitro studies have found high levels of ascorbate can minimize the effects of radical oxygen species (ROS) on membrane transport activity and levels of endogenous antioxidants, protecting the lens.⁹ Vitamin C also has the ability to protect retinal pigment epithelial (RPE) cells from blue light-induced DNA damage.¹⁰ Furthermore, researchers from Tufts University studied 492 non-diabetic women (age 53 to 73) from the Nurses Health Study Cohort, and found a vitamin C intake of at least 362 mg/d lowered the odds of cataract formation by 43 percent, compared to those with vitamin C intake below 140 mg/d.¹¹ The use of vitamin C supplements for at least 10 years dropped cataract incidence by 40 percent compared to women who never used vitamin C supplements.

Fat-soluble vitamin E has also been studied for its impact on cataract development. Studies in rats have found vitamin E administration helped prevent the development of cataracts induced by selenite,¹² and by UV light,¹³ through both direct antioxidant activity and by increasing levels of endogenous antioxidants such as glutathione. Human research has yielded mixed results. Researchers from Monash University, Australia, provided 1,193 adults with early or no cataract either vitamin E (500 IU/d) or placebo for four years.¹⁴ There was no significant difference seen in incidence or progression of nuclear, cortical or posterior subcapsular cataracts. However, researchers from Tufts University reported more positive results after they examined supplement use among 408 women participating in the Nurses Health Study.¹⁵ There was an inverse association between the five-year change in nuclear density and duration of vitamin E supplement use; an inverse association was also seen with higher intakes of riboflavin and thiamin.

Zinc, another part of the AREDS antioxidant formulation, also appears to play a specific role in fighting AMD. An ancillary study of AREDS, conducted at Atlantas Emory University School of Medicine, found providing 80 mg/d zinc oxide could prevent increased levels of cystine, which are linked to oxidative stress and age-related diseases.¹⁶ Zinc also appears to be more beneficial to those with darker eyes, as a German in vitro study found brown irides had significantly greater zinc concentration after 24 hours of zinc chloride treatment, while blue irides had almost no zinc uptake.¹⁷ However, researchers have also cautioned that higher intakes of zinc alone, without a complex of antioxidants, could actually induce oxidation¹⁸ and possibly increase formation of sub-retinal pigment epithelial deposits in AMD.¹⁹

Colorful Carotenoids

While antioxidants in general appear to have eye health benefits, the big dog in the category is definitely carotenoidsparticularly the xanthophylls lutein and zeaxanthin. It was first suggested in 1945 that the yellow color of the macula lutea in the retina is due to the presence of xanthophylls. This has been termed macular pigment and is entirely of dietary origin; humans are not able to synthesize carotenoids, nor has conversion of other carotenoids such as alpha-carotene or beta-carotene to lutein and zeaxanthin been reported. The retinal carotenoids have two distinct effects: blue light filtering and antioxidant activity. Photoreceptors are very susceptible to short wave length blue light. Lutein and zeaxanthin absorb blue light because of their physical properties and are located in the retina between the incoming light and the photoreceptors, rather like internal sunglasses.

Consumption of lutein and zeaxanthin through the diet, however, is significantly lacking, according to Chrysantis Inc., which recently sponsored a project at Tufts University with Elizabeth J. Johnson, Ph.D. While the study is in process of being written for publication, early results indicate actual consumption of lutein and zeaxanthin are significantly below those estimated by USDA. Very young males are consuming 80 percent less than previously thought; young and middle aged men are consuming 40 percent less, and older men consuming 50 percent less. Women over age 18 are about 20 percent under estimated intake.

The benefits of increasing intake of xanthophylls could be significant. In May 2007, the Dietary Supplement Education Alliance (DSEA) released results of a systematic literature review combined with economic analysis that found daily intake of 6 to 10 mg/d of lutein with zeaxanthin could save $3.6 billion over five years by helping people with age-related macular degeneration (AMD) avoid the transition to dependence.

The market potential is also promising. Market research firm Frost & Sullivan reported the global lutein market earned revenues of $105.1 million in 2006 and estimates this will reach $124.5 million in 2013. In the firms 2006 report, Strategic Analysis of the Global Markets for Lutein in Human Nutrition, it noted: A growing and exhaustive body of scientific evidence supporting luteins eye health benefits is the primary reason driving the growth of this market globally. This augurs well for the global lutein market, given that eye health ranks among the top five health concerns in the United States, as well as in various countries across the European Union (EU).

That basis of scientific evidence for lutein continues to grow. The Lutein Antioxidant Supplementation Trial (LAST), conducted out of the Department of Veterans Affairs, Chicago, included 90 patients with atrophic AMD who received 10 mg of purified lutein (as FloraGLO® Lutein, from Kemin Health), purified lutein plus a broad spectrum antioxidant (as OcuPower, from Vitacost.com), or placebo for 12 months.²⁰ Visual parameters including macular pigment optical density (MPOD), visual acuity and contrast sensitivity were improved in both the lutein and lutein combination groups, suggesting luteins key role in treating AMD. University of Pennsylvania, Philadelphia, researchers reported similarly positive findings after they administered lutein for six months to patients with foveal fixation; supplementation significantly increased serum lutein levels in 91 percent of patients and augmented MPOD in almost two-thirds of subjects, although there was no change in central vision.²¹

Another human study, this one a pilot study conducted in the United Kingdom, examined plasma and macular responses to lutein supplementation.²² The researchers examined the effect of daily supplementation with 20 mg lutein ester (as XANGOLD®, from Cognis Nutrition & Health), supplying 10 mg/d free lutein, on seven early AMD sufferers and six age-matched controls over 20 weeks. Supplementation increased plasma lutein and mean MPOD significantly. The researchers noted the findings suggest AMD is not associated with intestinal malabsorption of macular carotenoids and even a diseased macula can accumulate lutein and/or zeaxanthin; further, they suggest the beneficial effects of lutein supplementation could be extended to subjects with established age-related maculopathy (ARM).

There has been some discussion as to the bioavailability of lutein in dietary supplements. In a study at the University of Illinois at Chicago, 18 healthy subjects received a single dose of an unesterified lutein formulation of 20 g/100 g lutein as crystalline suspension in safflower oil followed by a washout and a supplement of 36.7 g/100 g lutein in esterified form.²³ The esterified form showed greater bioavailability, leading the researchers to suggest the bioavailability of lutein from supplements may depend on industrial formulation and processing. However, in a study of 10 healthy men who received one of four lutein doses in a crossover design, the highest lutein bioavailability was found for lutein-enriched egg, with that of purified lutein, lutein esters and spinach approximately equal.²⁴ In this study, the investigators suggested the use of the different formulations (crystalline lutein versus powder lutein esters) in the University of Illinois study may have lead to the different dissolution and different bioavailability they reported.

In addition to improving levels of macular pigment, lutein may also help reduce inflammation, thereby preventing macular degeneration, according to researchers from Catholic University of Korea, Seoul.²⁵ Using a rat model of transient ischemia and high intraocular pressure, researchers injected lutein (as FloraGLO®) into the intraperitoneal or intravitreous before inducing ischemia. Lutein dose-dependently inhibited ischemia-induced cell death and expression levels of inflammatory markers in retinas.

Studies on zeaxanthin alone have also shown tremendous benefits. Studies using quail retinas have found increased levels of retinal zeaxanthin dose-dependently reduce light-induced photoreceptor apoptosis.²⁶ And like lutein, zeaxanthin may have an impact on apoptosis.²⁷ Researchers from the University of Teramo, Italy, investigated the impact of zeaxanthin on neuroblastoma cells, and found the carotenoid could induce apoptosis in diseased cells without inhibiting activity of lipoxygenase, while preventing apoptosis in healthy cells.

Intervention trials have shown positive results for zeaxanthin. London researchers found zeaxanthin (as OPTISHARP, from DSM Nutritional Products) improved human color vision, visual acuity and vision in low light conditions in healthy adults.²⁸ Participants were given regular supplementation of zeaxanthin, lutein, a combination of the two, or placebo; participants taking lutein and zeaxanthin showed significant improvements in visual acuity and color vision. In another study, DSM researchers found the xanthophylls increased MPOD, but in different areas of the maculalutein appears to be predominantly deposited in the fovea, while zeaxanthin covers a wider retinal area.²⁹

Another study, supported by Kalsec Inc., sought to determine whether supplementation with a novel high-zeaxanthin paprika extract could impact plasma carotenoid levels.³⁰ The open-label, non-randomized, single-pair treatment in six healthy adults involved 10 mg zeaxanthin oral supplement for 28 days. Average zeaxanthin plasma levels compared favorably with results for synthetic zeaxanthin; supplementation significantly increased plasma levels of beta-cryptoxanthin, which was a secondary component of the formulation.

In general, combination xanthophyll consumption does appear to reduce the risk of AMD. For example, an ancillary study from the Womens Health Initiative (WHI)the Carotenoids in Age-Related Eye Disease Study (CAREDS)found women age 75 or younger who consume diets rich in lutein and zeaxanthin have a lower risk of developing AMD.³¹ Follow-up work by the group found MPOD was directly related to dietary intake of lutein and zeaxanthin; however, higher abdominal body fat and diabetes were related to lower MPOD, suggesting physical factors may influence the uptake and distribution of the xanthophylls.³²

The link between adiposity and xanthophyll uptake has drawn recent attention in the scientific community. A research review from Tufts University noted risk factors for AMD include lower xanthophyll status and obesity; the physiological changes that occur with obesity, including increased oxidative stress, increased inflammation and increased destruction of lutein and zeaxanthin, could explain the link between obesity, AMD and xanthophylls.³³

Gender differences may also play a role. Researchers from TNO Nutrition and Food Research, Zeist, Netherlands, investigated the associations between MPOD, serum lutein, serum zeaxanthin and adipose lutein in a cross sectional design in 376 adults.³⁴ Mean MPOD was 13 percent higher in men than in women, while adipose lutein concentrations were higher in women than in men. Further, there was a significant positive association between MPOD and xanthophyll markers in men, but not in women. Similar findings were reported by Irish researchers, who found there was a significant inverse relationship between adiposity and MPOD in men, but not in women; further, higher adiposity in women was associated with lower serum zeaxanthin levels.³⁵

However, given the breadth of research on zeaxanthin and lutein, it is no wonder researchers from Johns Hopkins University, Baltimore,³⁶ stated: Although lutein and zeaxanthin are not essential nutrients, studies are beginning to suggest they fit the criteria for conditionally essential nutrients. Low plasma lutein and zeaxanthin concentrations or dietary intake are associated with low macular pigment density and increased risk of AMD. Dietary deprivation of lutein and zeaxanthin in primates causes pathological changes in the macula. Should controlled clinical trials show lutein and/or zeaxanthin supplementation protects against the development or progression of AMD and other eye diseases, then lutein and zeaxanthin could be considered as conditionally essential nutrients for humans.

While lutein and zeaxanthin have taken center stage in the eye health category, other carotenoids are also waiting in the wingsand research is substantiating their own benefits. Astaxanthin, for example, was shown in an in vitro trial to be as efficacious as lutein and zeaxanthin in protecting against DNA damage in neuroblastoma cells.³⁷ Astaxanthin is also an effective anti-inflammatory, working to reduce inflammation in the eyes by impacting levels of nitric oxide synthase (NOS),³⁸ and downregulating proinflammatory factors in cases of induced uveitis.³⁹

Clinical trials in Japan have ascertained astaxanthin (as AstaREAL®, from Fuji Health Sciences) can improve retinal blood flow,⁴⁰ and modulate parameters of asthenopia, an eye overuse condition marked by fatigue, red eyes, eye strain, pain in or around the eyes, blurred vision, headache and occasional double vision.⁴¹ In a double blind study involving 40 healthy adults with asthenopia, ingestion of 6 mg/d of H. pluvialis astaxanthin (as AstaREAL) improved accommodation times and subjective degree of asthenopia.⁴² Follow-up work found the 6 mg/d dose to be optimal for addressing accommodation power and subjective symptoms related to asthenopia.⁴³ Additional research investigated the effects of astaxanthin on visual function in 40 healthy volunteers.⁴⁴ Researchers provided 0, 2, 4 or 12 mg/d of astaxanthin (as AstaREAL) for 28 consecutive days; at studys end, subjects taking 4 or 12 mg/d had significantly improved uncorrected far visual acuity and shorter positive accommodation time.

Lycopene also may have an impact in the eye health arena. Researchers from the All India Institute of Medical Sciences, New Delhi, examined the impact of lycopene on human lens epithelial cells, and found lycopene could protect against osmotic stress linked to diabetic cataract development.⁴⁵ Further work by the research team involved selenite- or galactose-induced cataract in rats, who received intraperitoneal lycopene or 200 mcg/kg of lycopene in the diet.⁴⁶ Lycopene supplementation protected against both types of experimental cataract via antioxidant mechanisms, particularly restoring endogenous superoxide dismutase (SOD) and catalase activities.

Flavonoid Fields

Fat-soluble carotenoids are joined in their quest to protect the eyes from oxidative stress by a host of water-soluble flavonoid compounds. Researchers from The Scripps Research Institute, La Jolla, Calif., examined the impact of specific flavonoids to protect human RPE cells from oxidative-stress-induced death, finding a host of flavonoids with high efficacy and low toxicity, including luteolin, quercetin and epigallocatechin gallate (EGCG).⁴⁷ The same research team has also found flavonoids may protect retinal ganglion cells, possibly preventing neuronal degeneration linked to glaucoma and diabetic retinopathy.⁴⁸

One of the largest groups of flavonoids is the anthocyanins, which appear to have an array of health benefits, including supporting the eyes. A review from The Horticulture and Food Research Institute of New Zealand Ltd., Auckland, specifically cited anthocyanins antioxidant and anti-inflammatory effects, as well as their ability to preserve capillary integrity and improve vision.⁴⁹ Anthocyanins are found in a wide range of fruits, particularly berries.

Bilberry (Vaccinium myrtillus), for example, has been used as food for centuries with medicinal use dating back to the Middle Ages, according to a monograph in the Alternative Medicine Review.⁵⁰ While more traditionally used for scurvy and inflammatory conditions, current research is focusing on the treatment of ocular disorders. The monograph noted bilberry extract was studied by French researchers on Royal Air Force pilots during World War II, who found bilberry extract improved nighttime visual acuity.

In vitro work has sought to elucidate the mechanism of action of bilberry anthocyanins. A study out of Columbia University, New York, explored nine anthocyanin fractions from bilberry and found all suppressed photooxidation of the autofluorescent pigment A2E, which can accumulate in RPE cells in retinal disorders.⁵¹ In addition, cells treated with anthocyanins had greater resistance to membrane permeabilization linked to A2Es detergent-like perturbation. Similarly, Finnish researchers reported anthocyanins from bilberry, lignonberry (Vaccinium vitis-ideae) and black currant (Ribes nigrum) were effective at protecting against lipid and protein oxidation.⁵² And a study out of Japan found four anthocyanins from black currant could help regenerate rhodopsin in rod photoreceptors.⁵³

Despite the promising findings in vitro, clinical trials have not been as universally positive. Researchers from the Universities of Exeter and Plymouth in England systematically reviewed trials of bilberry anthocyanosides for effects on night vision.⁵⁴ They found mixed results, but noted negative outcomes were associated with more rigorous methodology, lower dose levels and extracts from berries with more varied anthocyanoside content. They concluded further trials into the effects of bilberry anthocyanosides and night vision are warranted.

Specific clinical work done on a standardized extract of bilberry anthocyanosides (as MIRTOSELECT®, from Indena) has shown beneficial activity. Pharmacological studies have shown this bilberry extract, which is standardized to 36-percent anthocyanosides, increases capillary resistance, reduces abnormal vascular permeability and has antioxidant activity. In addition, the extract may promote resynthesis of retinal pigments, benefiting visual acuity. A clinical study showed MIRTOSELECT helped recover reduced visual function caused by overuse of the eyes, improving subjective symptoms such as vision with sparks, dimming of eyesight and ocular fatigue in computer operators, office workers and students compared to subjects treated with a placebo.⁵⁵

A clinical trial at the University of Tsukuba, Tokyo, reported black currant anthocyanosides may have a positive impact on asthenopia and dark adaptation.⁵⁶ The crossover, double blind, placebo-controlled study used 12 healthy adults who received black currant extract at 12.5, 20 or 50 mg levels. Statistical analysis comparing the values before and after intake indicated there was a significant difference at the 50 mg dose in dark adaptation threshold. Significant improvement was also seen in the assessment of subjective asthenopia symptoms.

As noted earlier, the flavonoid EGCG, found in green tea, appears to have antioxidant benefits for the eye. Chinese researchers examined the oxidative modification of the water-soluble crystallins of the human fetal lens and found EGCG could prevent oxidative damage induced by H2O2 and metal ions.⁵⁷ Researchers from Oxford University also found EGCG was able to attenuate oxidative stress-induced degeneration of the retina, attenuating lipid peroxidation caused by an NO donor.⁵⁸

Further studies have investigated green teas role specifically in cataract formation. Researchers at the All India Institute of Medical Sciences examined the ability of green tea extract to prevent lens opacification in enucleated rat lenses treated with selenite, as well as in rat pups given a subcutaneous injection of selenite.⁵⁹ In both cases, green tea extract positively modulated oxidative stress and reduced the incidence of selenite cataract. Chinese researchers reported similar results, noting green tea extract could prevent postcapsular opacity in cultured rabbit lens epithelial cells.⁶⁰

Another powerful source of polyphenols is French maritime pine bark extract. Pharmacological studies on the extract (as Pycnogenol®, from Natural Health Science) have focused on its ability to dose dependently strengthen capillaries and prevent diabetic retinopathy. Pycnogenol is a potent inhibitor of matrix metallo proteinases and possesses significant anti-inflammatory activity, working to counteract edema and bleedings in retinopathy; it also normalizes platelet activity by increasing endothelial NO synthesis, preventing retinal vein occlusion.⁶¹ One specific double blind, placebo-controlled trial in Italy examined patients diagnosed with diabetic-, hypertensive- or atherosclerotic retinopathy.⁶² After two months treatment with Pycnogenol, the intensity of retinal bleedings was significantly reduced. There was also a slight improvement in visual acuity. Further, a German multi-center field study of 1,169 retinopathy patients found Pycnogenol (20 to 160 mg/d) for six months not only stopped further deterioration of visual acuity, but improved eyesight.⁶³

Another botanical extract that works to boost eye health through a range of activities is Ginkgo biloba. It appears to have inherent antioxidant, antiapoptotic and cytoprotective properties, as well as potential anti-cataract abilities;⁶⁴ its ability to improve central and peripheral blood flow and inhibit platelet activating factor may also make it useful in preventing glaucoma.⁶⁵ Animal trials support the hypotheses. Japanese researchers investigated the efficacy of Ginkgo biloba extract (EGb 761) against neurotoxicity of retinal ganglion cells in rats with chronic moderately elevated IOP; pretreatment and early post-treatment with EGb 761 significantly protected against retinal cell loss.⁶⁶ And in a cataract study, EGb 761 protected rat lenses from radiation-induced cataract through antioxidant scavenging and support of endogenous SOD and antioxidant enzymes.⁶⁷

Clinical trials have also shown great potential. A three-month study at Taipei Medical University, Taiwan, involved 25 adults with type 2 diabetes and retinopathy who received Ginkgo biloba extract (as EGb 761).⁶⁸ Supplementation significantly improved blood viscosity and viscoelasticity, facilitating blood perfusion, and improved retinal capillary blood flow. Similarly, a study involving 15 teenagers with type 2 diabetes found treatment with Ginkgo biloba extract (as EGb 761) helped stabilize retinal health and improved performance on color vision tests.⁶⁹ And a double blind study in 99 adults with dry AMD found six months of supplementation with EGb 761 caused pronounced improvement in visual acuity.⁷⁰

Go Fish!

As evidenced by NIHs decision to add EFAs to the new AREDS2 formulation, LC-PUFAs have a role to play in eye health. Researchers from the AREDS Coordinating Center, Rockville, Md., evaluated the association of lipid intake with baseline severity of AMD and concluded high intake of long-chain omega-3s and fish decreased the likelihood of neovascular (NV) AMD.⁷¹ Dietary total omega-3 intake was inversely associated with NV AMD, as was DHA; arachidonic acid was found to be directly associated with NV AMD prevalence.

Similar findings were reported in reviews of two other population studies. Researchers from the University of Sydney reviewed longitudinal associations between dietary fat and incident ARM⁷² and nuclear cataract⁷³ from participants in the Australian Blue Mountains Eye Study (1992-1999). Participants with the highest vs. lowest quintiles of omega-3 polyunsaturated fat intake had a 60-percent lower risk of incident early ARM; Consuming fish at least once a week dropped the risk by 40 percent, while thrice weekly consumption netted a 75-percent reduction. Similarly, participants with the highest omega-3 PUFA intake had a 42 percent reduced risk of nuclear cataract, compared to those in the lowest quintile of intake.

In the other population study, the U.S. Twin Study of AMD, researchers from the Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston, reviewed data on 222 twins with AMD, and 459 twins with no AMD or only early signs.⁷⁴ Current smokers had almost twice (1.9-fold) the risk of AMD, while past smokers had a 1.7-fold increased risk. Increased intake of fish and higher intake of omega-3 EFAs were both inversely associated with AMD. Reduction in risk of AMD with higher intake of omega-3 EFAs was seen primarily among subjects with lower intake of omega-6 linoleic acid.

EFAs appear to have several beneficial effects in the eye. A review from NEI noted LC-PUFAs modulate a number of metabolic processes linked to oxidative stress, inflammation and aging, and that tissue status of LC-PUFAs is dependent onand able to be modified bydietary intake.⁷⁵ They concluded LC-PUFAs may protect against oxidative-, inflammatory- and age-related pathology of the retina. EFAs are critical to the structural and functional integrity of the retina;⁷⁶ they further influence the expression of inflammatory cytokines, suggesting a higher intake of anti-inflammatory omega-3 EFAs and reduced intake of pro-inflammatory omega-6 EFAs could beneficially influence intraocular pressure.⁷⁷

Manufacturers of nutraceutical products have a great opportunity to develop efficacious formulations with scientifically-substantiated ingredients that can keep consumers seeing clearly now and into the future. Its easy to see, with one look, at the market potential eye health products afford visionary marketers.

References

1. Coleman H, Chew E. Nutritional supplementation in age-related macular degeneration. Curr Opin Ophthalmol. 2007 May;18(3):220-3.

2. Sackett CS, Schenning S. The age-related eye disease study: the results of the clinical trial. Insight. 2002 Jan-Mar;27(1):5-7.

3. Milton RC et al. Centrum use and progression of age-related cataract in the Age-Related Eye Disease Study: a propensity score approach. AREDS report No. 21. Ophthalmology. 2006 Aug;113(8):1264-70.

4. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. Arch Ophthalmol. 2001 Oct;119(10):1439-52.

5. Meyer CH, Sekundo W. Nutritional supplementation to prevent cataract formation. Dev Ophthalmol. 2005;38:103-19.

6. Kang JH et al. Antioxidant intake and primary open-angle glaucoma: a prospective study. Am J Epidemiol. 2003 Aug 15;158(4):337-46.

7. Schalch W, Chylack LT. [Antioxidant micronutrients and cataract. Review and comparison of the AREDS and REACT cataract studies.] Ophthalmologe. 2003 Mar;100(3):181-9.

8. Kowluru RA, Koppolu P. Diabetes-induced activation of caspase-3 in retina: effect of antioxidant therapy. Free Radic Res. 2002 Sep;36(9):993-9.

9. Hegde KR, Varma SD. Protective effect of ascorbate against oxidative stress in the mouse lens. Biochim Biophys Acta. 2004 Jan 5;1670(1):12-8.

10. Zhou JW et al. [Study of blue light induced DNA damage of retinal pigment epithelium(RPE) cells and the protection of vitamin C.] Shi Yan Sheng Wu Xue Bao. 2003 Oct;36(5):397-400.

11. Taylor A et al. Long-term intake of vitamins and carotenoids and odds of early age-related cortical and posterior subcapsular lens opacities. Am J Clin Nutr. 2002 Mar;75(3):540-9.

12. Mathew JP, Thomas VC, Thomas I. Selenite cataract and its attenuation by vitamin E in Wistar rats. Indian J Ophthalmol. 2003 Jun;51(2):161-70.

13. Ayala MN, Söderberg PG. Vitamin E can protect against ultraviolet radiation-induced cataract in albino rats. Ophthalmic Res. 2004 Sep-Oct;36(5):264-9.

14. McNeil JJ et al. Vitamin E supplementation and cataract: randomized controlled trial. Ophthalmology. 2004 Jan;111(1):75-84.

15. Jacques PF et al. Long-term nutrient intake and 5-year change in nuclear lens opacities. Arch Ophthalmol. 2005 Apr;123(4):517-26.

16. Moriarty-Craige SE 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. 2007 Feb;143(2):206-211. Epub 2006 Nov 9.

17. Wood JP, Osborne NN. Zinc and energy requirements in induction of oxidative stress to retinal pigmented epithelial cells. Neurochem Res. 2003 Oct;28(10):1525-33.

18. Lengyel I e al. High concentration of zinc in sub-retinal pigment epithelial deposits. Exp Eye Res. 2007 Apr;84(4):772-80. Epub 2007 Jan 9.

19. Kokkinou D et al. The pigmentation of human iris influences the uptake and storing of zinc. Pigment Cell Res. 2004 Oct;17(5):515-8.

20. Richer S el al. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial). Optometry. 2004 Apr;75(4):216-30.

21. Aleman TS et al. Macular pigment and lutein supplementation in ABCA4-associated retinal degenerations. Invest Ophthalmol Vis Sci. 2007 Mar;48(3):1319-29.

22. Koh HH et al. Plasma and macular responses to lutein supplement in subjects with and without age-related maculopathy: a pilot study. Exp Eye Res. 2004;79:21-7.

23. Bowen PE et al. Esterification does not impair lutein bioavailability in humans. J Nutr. 2002;132:3668-73.

24. Chung HY, Rasmussen HM, Johnson EJ. Lutein bioavailability is higher from lutein-enriched eggs than from supplements and spinach in men. J Nutr. 2004;134(8):1887-93.

25. Choi JS et al. Inhibition of nNOS and COX-2 expression by lutein in acute retinal ischemia. Nutrition. 2006 Jun;22(6):668-71. Epub 2006 May 2.

26. Thomson LR et al. Elevated retinal zeaxanthin and prevention of light-induced photoreceptor cell death in quail. Invest Ophthalmol Vis Sci. 2002 Nov;43(11):3538-49.

27. Maccarrone M et al. The photoreceptor protector zeaxanthin induces cell death in neuroblastoma cells. Anticancer Res. 2005 Nov-Dec;25(6B):3871-6.

28. Kvansakul J et al. Supplementation with the carotenoids lutein or zeaxanthin improves human visual performance. Ophthalmic Physiol Opt. 2006 Jul;26(4):362-71.

29. Schalch W et al. Xanthophyll accumulation in the human retina during supplementation with lutein or zeaxanthin - the LUXEA (LUtein Xanthophyll Eye Accumulation) study. Arch Biochem Biophys. 2007 Feb 15;458(2):128-35. Epub 2006 Nov 7.

30. Locey CL et al. The response of serum carotenoid levels to supplementation with a zeaxanthin/beta-cryptoxanthin formulation derived from a novel paprika source. Presented at ARVO Summer Eye Research Conference 2006.

31. CAREDS Research Study Group. Associations between intermediate age-related macular degeneration and lutein and zeaxanthin in the Carotenoids in Age-related Eye Disease Study (CAREDS): ancillary study of the Womens Health Initiative. Arch Ophthalmol. 2006 Aug;124(8):1151-62.

32. Mares JA et al. Predictors of optical density of lutein and zeaxanthin in retinas of older women in the Carotenoids in Age-Related Eye Disease Study, an ancillary study of the Womens Health Initiative. Am J Clin Nutr. 2006 Nov;84(5):1107-22.

33. Johnson EJ. Obesity, lutein metabolism, and age-related macular degeneration: a web of connections. Nutr Rev. 2005 Jan;63(1):9-15.

34. Broekmans WM et al. Macular pigment density in relation to serum and adipose tissue concentrations of lutein and serum concentrations of zeaxanthin. Am J Clin Nutr. 2002 Sep;76(3):595-603.

35. Nolan J et al. Macular pigment and percentage of body fat. Invest Ophthalmol Vis Sci. 2004 Nov;45(11):3940-50.

36. Semba RD, Dagnelie G. Are lutein and zeaxanthin conditionally essential nutrients for eye health? Med Hypotheses. 2003 Oct;61(4):465-72.

37. Santocono M et al. Lutein, zeaxanthin and astaxanthin protect against DNA damage in SK-N-SH human neuroblastoma cells induced by reactive nitrogen species. J Photochem Photobiol B. 2007 May 1; [Epub ahead of print]

38. Ohgami K et al. Effects of astaxanthin on lipopolysaccharide-induced inflammation in vitro and in vivo. Invest Ophthalmol Vis Sci. 2003 Jun;44(6):2694-701.

39. Suzuki Y et al. Suppressive effects of astaxanthin against rat endotoxin-induced uveitis by inhibiting the NF-kappaB signaling pathway. Exp Eye Res. 2006 Feb;82(2):275-81. Epub 2005 Aug 26.

40. Yasunori N et al. The effect of astaxanthin on retinal capillary blood flow in normal volunteers. J Clin Ther Med. 2005 May;21(5):537-42.

41 Nagaki Y et al. Effects of astaxanthin on accommodation, critical flicker fusion, and pattern visual evoked potential in visual display terminal workers. J Trad Med. 2002; 19:170-3.

42. Kenji S et al. Effect of astaxanthin on accommodation and asthenopia - efficacy identification study in healthy volunteers. J Clin Ther Med. 2005 June;21(6).

43. Nitta T et al. Effects of astaxanthin on accommodation and asthenopia dose finding study in healthy volunteers. J Clin Ther Med. 2005 May;21(5).

44. Nakamura A et al. Changes in visual function following peroral astaxanthin. Jpn J Clin Ophthalmol. 2001;58(6):1051-554.

45. Mohanty I et al. Lycopene prevents sugar-induced morphological changes and modulates antioxidant status of human lens epithelial cells. Br J Nutr. 2002 Oct;88(4):347-54.

46. Gupta SK et al. Lycopene attenuates oxidative stress induced experimental cataract development: an in vitro and in vivo study. Nutrition. 2003 Sep;19(9):794-9.

47. Hanneken A et al. Flavonoids protect human retinal pigment epithelial cells from oxidative-stress-induced death. Invest Ophthalmol Vis Sci. 2006 Jul;47(7):3164-77.

48. Maher P, Hanneken A. Flavonoids protect retinal ganglion cells from oxidative stress-induced death. Invest Ophthalmol Vis Sci. 2005 Dec;46(12):4796-803.

49. Ghosh D, Konishi T. Anthocyanins and anthocyanin-rich extracts: role in diabetes and eye function. Asia Pac J Clin Nutr. 2007;16(2):200-8.

50. [no author]. Monograph: Vaccinium myrtillus (Bilberry). Alt Med Rev. 2001;6(5):500-4.

51. Jang YP et al. Anthocyanins protect against A2E photooxidation and membrane permeabilization in retinal pigment epithelial cells. Photochem Photobiol. 2005 May-Jun;81(3):529-36.

52. Viljanen K et al. Inhibition of protein and lipid oxidation in liposomes by berry phenolics. J Agric Food Chem. 2004 Dec 1;52(24):7419-24.

53. Matsumoto H et al. Stimulatory effect of cyanidin 3-glycosides on the regeneration of rhodopsin. J Agric Food Chem. 2003 Jun 4;51(12):3560-3.

54. Canter PH, Ernst E. Anthocyanosides of Vaccinium myrtillus (bilberry) for night vision--a systematic review of placebo-controlled trials. Surv Ophthalmol. 2004 Jan-Feb;49(1):38-50.

55. Kajimoto O. et al. Scient Rep Collect. 1998;19:1.

56. Nakaishi H et al. Effects of black current anthocyanoside intake on dark adaptation and VDT work-induced transient refractive alteration in healthy humans. Altern Med Rev. 2000 Dec;5(6):553-62.

57. Xiang H, Pan S, Li S. Studies on human fetal lens crystallins under oxidative stress and protective effects of tea polyphenols. Yan Ke Xue Bao. 1998 Sep;14(3):170-5.

58. Zhang B, Osborne NN. Oxidative-induced retinal degeneration is attenuated by epigallocatechin gallate. Brain Res. 2006 Dec 8;1124(1):176-87. Epub 2006 Nov 3.

59. Gupta SK et al. Green tea (Camellia sinensis) protects against selenite-induced oxidative stress in experimental cataractogenesis. Ophthalmic Res. 2002 Jul-Aug;34(4):258-63.

60. Huang W et al. Growth inhibition, induction of apoptosis by green tea constituent (-)-epigallocatechin-3-gallate in cultured rabbit lens epithelial cells. Yan Ke Xue Bao. 2000 Sep;16(3):194-8.

61. Grimm T, Schafer A, Hogger P. Antioxidant activity and inhibition of matrix-metalloproteinases by metabolites of maritime pine bark extract (Pycnogenol®). Free Rad Biol Med. 2004;36:811-22.

62. Spadea L, Balestrazzi E. Treatment of vascular retinopathies with Pycnogenol®. Phytother Res. 2001;15:219-23.

63. Schonlau F, Rohdewald P. Pycnogenol for diabetic retinopathy. A review. Int Ophthal. 2001;24(3):161-71.

64. Thiagarajan G et al. Molecular and cellular assessment of ginkgo biloba extract as a possible ophthalmic drug. Exp Eye Res. 2002 Oct;75(4):421-30.

65. Ritch R. Potential role for Ginkgo biloba extract in the treatment of glaucoma. Med Hypotheses. 2000 Feb;54(2):221-35.

66. Hirooka K et al. The Ginkgo biloba extract (EGb 761) provides a neuroprotective effect on retinal ganglion cells in a rat model of chronic glaucoma. Curr Eye Res. 2004 Mar;28(3):153-7.

67. Ertekin MV et al. Effects of oral Ginkgo biloba supplementation on cataract formation and oxidative stress occurring in lenses of rats exposed to total cranium radiotherapy. Jpn J Ophthalmol. 2004 Sep-Oct;48(5):499-502.

68. Huang SY et al. Improved haemorrheological properties by Ginkgo biloba extract (Egb 761) in type 2 diabetes mellitus complicated with retinopathy. Clin Nutr. 2004 Aug;23(4):615-21.

69. Bernardczyk-Meller J et al. [Influence of Egb 761 on the function of the retina in children and adolescent with long lasting diabetes mellitus--preliminary report.] Klin Oczna. 2004;106(4-5):569-71.

70. Fies P, Dienel A. [Ginkgo extract in impaired vision--treatment with special extract EGb 761 of impaired vision due to dry senile macular degeneration.] Wien Med Wochenschr. 2002;152(15-16):423-6.

71. Age-Related Eye Disease Study Research Group. The relationship of dietary lipid intake and age-related macular degeneration in a case-control study: AREDS Report No. 20. Arch Ophthalmol. 2007 May;125(5):671-9.

72. Chua B et al. Dietary fatty acids and the 5-year incidence of age-related maculopathy. Arch Ophthalmol. 2006 Jul;124(7):981-6.

73. Townend BS et al. Dietary macronutrient intake and five-year incident cataract: the blue mountains eye study. Am J Ophthalmol. 2007 Jun;143(6):932-939. Epub 2007 Apr 24.

74. Seddon JM, George S, Rosner B. Cigarette smoking, fish consumption, omega-3 fatty acid intake, and associations with age-related macular degeneration: the US Twin Study of Age-Related Macular Degeneration. Arch Ophthalmol. 2006 Jul;124(7):995-1001.

75. SanGiovanni JP, Chew EY. The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina. Prog Retin Eye Res. 2005 Jan;24(1):87-138.

76. Singh M. Essential fatty acids, DHA and human brain. Indian J Pediatr. 2005 Mar;72(3):239-42.

77. Desmettre T, Rouland JF. [Hypothesis on the role of nutritional factors in ocular hypertension and glaucoma.] J Fr Ophtalmol. 2005 Mar;28(3):312-6.