Eye Health: Looking Good

Over the past several years, federal governments have shown increased interest in several natural ingredients believed to support optimal eye health. Largely by way of the Age-Related Eye Disease Study 2 (AREDS2), federal support in the United States is giving eye health greater recognition than in years past.

AREDS2 is an ongoing study to assess the potential benefit of lutein, zeaxanthin, and omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on eye health in 4000 patients over five years. The trial has been funded entirely by the National Eye Institute of the National Institutes of Health, and if positive results come from this long-term, federally funded study by its completion in 2012, market success of these ingredients could skyrocket.

For a population increasingly using computers and other visual stimulation, attention to eye health is all the more appropriate. Now, let’s take a look at some ingredients that could help.

Lutein and Zeaxanthin

Lutein and zeaxanthin are the only active carotenoids found naturally in the eye’s macula. Their antioxidative benefits have been the subject of ongoing eye-health research worldwide. Unfortunately, active levels of these precious carotenoids are easily influenced by some common complications, like smoking¹ and obesity². While the two ingredients may offer uniquely individual benefits, existing science has often lumped lutein and zeaxanthin together due to their mutual presence in the macula and the fact that lutein can convert naturally into meso-zeaxanthin, a form of zeaxanthin.³ The ability of these antioxidants to filter blue light has been the subject of ongoing curiosity.

Recent studies with human subjects have demonstrated that lutein and zeaxanthin may reduce glare, increase toleration of light, and even increase photo-stress recovery time in subjects.^4–5

Several studies have also indicated that consuming these ingredients will increase macular pigment optical density (MPOD), a measure of how well the macula can absorb harmful blue light. Most recently, the National Institutes of Health funded a study on lutein-supplied by Cognis Nutrition and Health (Cincinnati)-which found that MPOD increased linearly with lutein supplementation (most effectively at 10 mg of lutein).⁶ MPOD levels have also been shown to decline with age.^7–8

But what’s the greater implication of MPOD? Industry members hope higher MPOD levels may reduce risk of Age-Related Macular Degeneration (AMD), a condition which, in its early stages alone, affects an estimated 10 million Americans.⁹

“When, or if, the density of the macula decreases with age due to AMD, it affects the eye’s capacity to focus, resulting in irreparable loss of vision that progresses until central vision is completely lost,” says Cecilia McCollum, executive vice president of Blue California Ingredients (Rancho Santa Margarita, CA). “Supplementation with lutein may prevent the onset of AMD or, at least, arrest its progress.”

Some human clinical trials support the theory that high MPOD results in lower AMD risk. In a 2001 study, MPOD was measured in 46 subjects with healthy eyes and nine subjects with advanced neovascular AMD. When nine pairs of healthy eyes were matched with AMD eyes, eight of the nine cases showed higher MPOD levels in healthy eyes, leaving researchers to conclude, “The two most important risk factors for AMD, age and advanced disease in the fellow eye, are associated with reduced [MPOD].”¹⁰

Beyond improvements noted in small isolated trials, there remains a need for long-term studies to be certain of whether lutein and zeaxanthin can reduce the risk of AMD. So far, the gap has been filled with population studies. Below is a brief look at some of those notable studies:

• Eye-Disease Case-Control Study, 1994: For 876 American adults with neovascular AMD, subjects in the top quintile of dietary intake of lutein and zeaxanthin (approximately 5.8 mg/day) had a significantly lower risk compared to subjects in the lowest quintile of intake (approximately 1.2 mg/day).¹¹

• POLA Study, 2006: In a cohort of 899 subjects, those with high zeaxanthin intake experienced a reduced risk of AMD (93% improved) and cataracts (47% improved) compared to those who did not have high zeaxanthin intake.¹²

• Blue Mountains Eye Study, 2008: 2454 subjects submitted to food-frequency questionnaires and were examined at five years, ten years, or both. Participants in the top tertile of lutein/zeaxanthin intake showed 35% reduced risk for neovascular AMD and 34% reduced risk for drusen damage, compared to median-intake subjects.¹³

• NHANES Study, 2010: The National Health and Nutrition Examination Survey assessed dietary lutein and zeaxanthin intake in 8525 patients. Low zeaxanthin and lutein intake was associated with higher incidence of AMD, leaving researchers to conclude that the two ingredients “may be important to age-related macular degeneration risk.”¹⁴

These studies bear particular significance because of their sources of funding: international governments. The ongoing AREDS2 is further evidence of increasing recognition from federal bodies.

“Epidemiology studies have shown strong associations between higher intakes of lutein and zeaxanthin (6 mg total or higher) and reduced risk of both AMD and cataracts,” says James G. Elliott, PhD, director of nutritional science for DSM Nutritional Products Inc. (Parsippany, NJ), which markets FloraGlo brand lutein. “However, epidemiology studies do not prove cause and effect. This is why randomized, placebo-controlled clinical intervention trials need to be run. The currently running AREDS2 trial is designed to test these relationships.”

Dosages of Lutein and Zeaxanthin

In a varied market of dietary supplement formulations, it’s worth asking the question-how much lutein and zeaxanthin should a supplement contain?

“Initially, when people were looking at lutein and its role in eye health, they were measuring the patterns of lutein in diets and what levels of lutein correlated with good eye health,” says Abhijit Bhattacharya, COO of OmniActive Health Technologies (Mumbai, India), which supplies Lutemax 2020, a GRAS-affirmed lutein/zeaxanthin formula. “Today, there is a better understanding that besides lutein, zeaxanthin isomers also play an important role in eye health. We believe higher levels of these isomers along with lutein in dietary supplementation is nutritionally appropriate. Most lutein and zeaxanthin is traditionally made from marigolds, and the native ratio of lutein to zeaxanthin in marigolds is around 5 to 0.2. When you’re making a lutein supplement, there’s only so much zeaxanthin that will come with it.”

But does this mean that lutein is more important than zeaxanthin? “That’s a tough question to answer,” says Elizabeth Johnson, PhD, scientist at the Carotenoids and Health Laboratory at the Jean Mayer USDA Human Nutrition Research Center at Tufts University. “The reason we think they may be different is because if you look in the retina, the distribution is distinct. In the very center of the retina, the majority of the pigment is zeaxanthin. However, much of that zeaxanthin is actually derived from lutein, so there’s really no one clear answer.”

Lutein Bioavailability Study

“Not all lutein ingredients are the same,” says Diane Alexander, PhD, technical services manager for Kemin Health LC (Des Moines, IA), who notes that manufacturing methods are key to bioavailability.

This is the selling point for Kemin’s FloraGlo Lutein, now available with Actilease technology from DSM Nutritional Products. The branded, patented technology from DSM puts FloraGlo in microsized particles protected by a water-soluble shell-a manufacturing method which the companies believe makes all the difference in terms of bioavailability.

In a recent study conducted by the two companies, 48 health subjects were assigned to a single dose of 20 mg of unesterified lutein in an alginate matrix or a starch matrix using Actilease. Lutein with Actilease technology was shown to increase lutein bioavailability to a high of 169.7% compared to a high of 34.5% with the control technology.

DHA

Here’s another constituent of human eyes: the omega-3 fatty acid DHA. Research confirmed its high concentration, specifically in the human retina, over two decades ago¹⁵, and science suggests that its presence is for good reason.

Historically, DHA’s natural presence in breast milk has prompted research on infants and pregnant and nursing women-with much of that research showing a link to eye health. In infants, DHA has repeatedly shown a benefit in what are called visual evoked potential (VEP) tests-tests designed to measure how fast the eye responds to visual stimuli.¹⁶

In one study published in The Journal of Nutrition in 2004, blood levels of DHA increased 83% in 25 infants supplementing with DHA compared to 26 control infants who were only receiving DHA from breast milk. The increase was linked to better VEP scores not just from DHA supplementation, but also from higher breast milk intake.¹⁷

Bringing science up to speed, the 2009 DHA Intake and Measurement of Neural Development (DIAMOND) Study may provide the strongest data on DHA and infant vision yet. Conducted at the University of Kansas and the Retina Foundation at the University of Texas Southwestern, the DIAMOND Study investigated the effects of four different infant formulas-0.00%, 0.32%, 0.64%, or 0.96% DHA-on visual acuity in 244 infants for 12 months. It found that infants receiving 0.00% DHA experienced significantly lower VEP scores compared to all DHA-active formula groups. No significant differences in VEP (or in adverse health effects) were reported in any of the three DHA-active formula groups.¹⁸ The DIAMOND Study is pending future publication in The American Journal of Clinical Nutrition.

As for DHA’s benefit beyond infancy, recent science suggests it could benefit adults, too. This summer, the Journal of Lipid Research published a study in which human donor eyes from subjects with and without AMD were dissected and observed for fatty acid content. Compared to AMD eyes, non-AMD eyes showed significantly higher levels of DHA and better-balanced ratios of omega-6s to omega-3s (more omega-6 and fewer omega-3 was found in AMD eyes on average).¹⁹

Still ongoing, the gamut of research on DHA and eye health appears so strong that it warranted a positive opinion from the European Food Safety Authority (EFSA; Parma, Italy). In October, EFSA determined that a minimum dosage of 250 mg of DHA “contributes to the maintenance of normal vision.” This follows another EFSA opinion, from January 2009, stating that “DHA contributes to visual development of infants.”

Bilberry

This close cousin of the blueberry is regarded for its active content of anthocyanosides. Bilberries are capable of providing a steady flow of these antioxidants not just to the eyes, but throughout the body’s vascular system. The benefit, as animal and human research indicates,²⁰ is normalized blood flow, with anthocyanosides exhibiting the ability to reduce permeability of the capillaries. After all, no one wants a leaky circulatory system or the many ill symptoms that can result from it.

Blood flow is no joke when it comes to eyes. The most pressing concern relating to ocular blood flow is glaucoma, a condition that affects an estimated four million Americans and 70 million people worldwide.²¹

In order to reduce risk of glaucoma, intraocular pressure, or fluid pressure in the eye, needs to be kept down-and science suggests that bilberry can help here. In a 1998 study, 20 patients were assigned to 250 mg of bilberry extract daily for 28 days, and patients reported reduced ocular fatigue (70%), eyesight dimming (73%), and visual sparks (80%).²²

In an unpublished multicenter study in Germany, 88 patients supplemented daily with 510 mg of bilberry extract for one year, and contrast sensitivity was improved in these patients. The bilberry extract used was Mirtoselect, supplied by Indena S.p.A. (Milan, Italy).

Beyond helping the blood, this antioxidant can fight off oxidative damage that is all too familiar to the eye. “Bilberry tends to concentrate in the eye, where there is a lot of oxidative stress going on, especially from reading,” says Giovanni Appendino, chief scientific advisor of Indena. “This is especially a problem with computer work because, when you read, you need to accommodate and contract the ciliary muscles in the eyes. Muscle contraction means consumption of ATP and the need to regenerate it. That means free radicals all around [and the need to eliminate them].”

For computer users, the situation is even worse, says Appendino, noting that computer screens emit blue light capable of inhibiting the activity of physiological antioxidant enzymes present in the eye, such as catalase.

Another area of bilberry eye research has been on night vision, but results have been varied here.

Buyer, beware-if you are shopping for bilberry extract, adulteration of the ingredient is common. Indena says that’s because bilberry is a top-priced botanical. With a Mirtoselect brand bilberry, which is the basis of over 50 bilberry studies, the company says using UV and HPLC tests to verify active content is an ideal route for standardization.

McCollum echoes concern for standardization. “Customers need to be aware that if the price of berries-the starting raw material-is about $3.50/kg, and it takes 90 to 100 kg of berries to produce 1 kg of the 25% extract, paying $140.00/kg should be a sign that the product is not what the supplier claims,” she says.

Pycnogenol

Another ingredient showing potential for retinal health is Pycnogenol, the branded pine bark extract from Horphag Research (Geneva).

Pycnogenol is believed to work by giving antioxidant protection to the retina (and with documented synergistic effects in combination with lutein)²³ and strengthening retinal capillaries and blood circulation.

In a multicenter German study published in International Ophthalmology, 1169 patients were assigned to 20 to 120 mg of Pycnogenol for half a year. Pycnogenol protected the eyes from vision loss and was shown to be effective to stop progression of retinopathy.²⁴ In a similar study conducted in 2009, 46 patients were assigned to 150 mg of Pycnogenol or placebo daily for three months. Patients supplementing with Pycnogenol experienced statistically significant improvements in vision after two months, which was shown to coincide with relief from retinal swelling. Six of eleven patients supplementing with Pycnogenol saw edema scores go from moderate to mild, while all 22 placebo patients remained stuck in moderate scores for retinal edema and retinopathy symptoms.²⁵

The ingredient has been the subject of several published studies citing positive benefits (albeit without eye-health markers) of normalizing blood flow in diabetes patients.²⁶

Mirtoselect and Pycnogenol

Already introduced in Europe and Asia, Mirtogenol is a patent-pending formula of Indena’s Mirtoselect bilberry extract and Pycnogenol. These aren’t the subject of AREDS2, but these branded ingredients warrant equal consideration for their synergistic effect on ocular pressure.

In May, the journal Clinical Ophthalmology published a study in which 79 patients with ocular hypertension were assigned to Mirtogenol, the FDA-approved drug Latanoprost, or a combination of both treatments for 24 weeks. Intraocular pressure was monitored each month, and Mirtogenol was found to be nearly as effective as Latanoprost in reducing pressure (from 38.1 to 29.0 mmHG and 37.7 to 27.2 mmHG, respectively). The combination of Mirtogenol and Latanoprost was found to be more effective than Latanoprost alone. Mirtogenol and Latanoprost were reported as having comparable effects on retinal blood flow.²⁷

References:

1. A Iannaccone et al., “Macular pigment optical density in the elderly: findings in a large biracial Midsouth population sample,” Investigative Ophthalmology & Visual Science, vol. 48, no. 4 (April 2007):  1458–1465

2. E Johnson et al., “Obesity, lutein metabolism, and age-related macular degeneration: a web of connections,” Nutrition Reviews, vol. 63, no. 1 (January 2005): 9–15.

3. R Bone et al., “Distribution of lutein and zeaxanthin stereoisomers in the human retina,” Experimental Eye Research, vol. 64, no. 2 (February 1997): 211–218.

4. J Kvansakul et al.,“Supplementation with the carotenoids lutein or zeaxanthin improves human visual performance,” Ophthalmic and Physiological Optics, vol. 26, no. 4 (July 2006): 362–71.

5. A Yagi et al., “The effect of lutein supplementation on visual fatigue: a psychophysiological analysis,” Applied Ergonomics, vol. 40, no. 6 (November 2009):1047–54.

6. R Bone et al., “Dose-dependent response of serum lutein and macular pigment optical density to supplementation with lutein esters,” Archives of Biochemistry and Biophysics, vol. 504, no. 1 (December 2010): 50–55.

7. MA Sandberg et al., “The relationship of macular pigment optical density to serum lutein in retinitis pigmentosa,” Investigative Ophthalmology and Visual Science, vol. 51, no. 2 (February 2010): 1086–1091.

8. J Nolan et al., “Macular pigment optical density in an ageing Irish population: the Irish longitudinal study on ageing,” Ophthalmic Research, Vol. 44, no 2: 131–139.

9. American Optometric Association. "Lutein and Zeaxanthin Eye-Friendly Nutrients." Accessed October 25, 2010. http://www.aoa.org/documents/LuteinZeax_public.pdf

10. S Beatty et al., “Macular pigment and risk of age-related macular degeneration in subjects from a Northern European population,” Investigative Ophthalmology and Visual Science, vol. 42, no. 2 (February 2001): 439–446.

11. JM Seddon et al., “Dietary carotenoids, vitamins A, C and E, and advanced age-related macular degeneration. Eye disease case-control study group," JAMA, vol. 272, no. 18 (November 1994): 1413–20.

12. C Delcourt et al., “Plasma lutein and zeaxanthin and other carotenoids as modifiable risk factors for age-related maculopathy and cataract: the POLA Study,” Invest Ophthalmology and Visual Science, vol. 47, no. 6 (June 2006): 2329–35.

13. J Tan et al., “Dietary antioxidants and the long-term incidence of age-related macular degeneration: the blue mountains eyes study,” Ophthalmology, vol. 115, no. 2 (February 2008): 334–341.

14. E Johnson et al., “Intake of lutein and Zeaxanthin differ with age, sex and ethnicity,” Journal of the American Dietetic Association, vol. 110, no. 9 (September 2010): 1357–62.

15. SJ Fliesler et al., “Chemistry and metabolism of lipids in the vertebrate retina.” Progress in Lipid Research, vol. 22, no. 2 (1983): 79–131.

16. D Hoffman et al., “Toward optimizing vision and cognition in term infants by dietary docosahexaenoic acid and arachidonic acid supplementation: A review of randomized controlled trials,” Prostaglandins, Leukotrienes and Essential Fatty Acids, vol. 81, no. 2–3 (August 2009): 151–158.

17. Hoffman D, et al. “Maturation of visual acuity is accelerated in breast-fed term infants fed baby food containing DHA-enriched egg yolk,” The Journal of Nutrition, vol.134, no. 9 (September 2004): 2307–13.

18. E Birch et al., “The DIAMOND (DHA Intake And Measurement Of Neural Development) Study: a double-masked, randomized controlled clinical trial of the maturation of infant visual acuity as a function of the dietary level of docosahexaenoic acid.” Pending publication.

19. Liu, et al. “Long-chain and very long-chain polyunsaturated fatty acids in ocular aging and age-related macular degeneration,” Journal of Lipid Research, published online August 5, 2010.

20. S de Pascual-Teresa et al., “Flavanols and Anthocyanins in Cardiovascular Health: A Review of Current Evidence,” International Journal of Molecular Sciences, published online April 13, 2010.

21. Glaucoma Research Foundation. Accessed October 23, 2010. http://www.glaucoma.org/

22. O Kajimoto et al., “Clinical evaluation of the oral administration of vaccinium myrtillus anthocyanosides (VMA) in mental fatigue and asthenopia”. Food Style  , vol. 21, no. 3 (1999): 143–150.  

23. T Nakanishi-Ueda et al., “Inhibitory Effect of Lutein and Pycnogenol on Lipid Peroxidation in Porcine Retinal Homogenate,” Journal of Biochemistry, vol. 38, no. 3 (2006): 204–210.

24.  F Schönlau et al., “Pycnogenol for diabetic retinopathy. A review,” International Ophthalmology, vol. 24, no. 3 (May 2001): 161–171.

25. R Steigerwalt et al., “Pycnogenol Improves Microcirculation, Retinal Edema, and Visual Acuity in Early Diabetic Retinopathy.” Journal of Ocular Pharmacology and Therapeutics, vol. 25, no. 6 (December 2009): 537–540.

26. Pycnogenol. "Diabetes Care." Accessed October 23, 2010. http://www.pycnogenol.com/pdf/Diabetes%20Care.pdf

27. R Steigerwaltz Jr. et al., Mirtogenol Potentiates Latanoprost in Lowering Intraocular Pressure and Improves Ocular Blood Flow in Asymptomatic Patients,” Clinical Ophthalmology, vol. 4 (May 2010): 471–476.