When light enters the human eye it passes through the cornea, pupil, and lens to focus on an area of light-sensitive tissue called the retina. Near the center of the retina of the eye is a light yellow spot called the macula. It’s here where lutein and zeaxanthin concentrate to form macular pigment to filter out excess blue and ultraviolet light — acting much like a pair of sunglasses would — and protecting the macula’s high concentration of rods and cones responsible for central vision from their possible degradation. Here is a short story about how lutein and zeaxanthin gained the limelight for eye health:
Blazing the trail dressed in yellow
In the Fall of 1996, a couple of oddly dressed men caused quite the stir when they dropped in on the first day of the American Association of Ophthalmology annual meeting taking place in Chicago. The pair showed up wearing bright yellow blazers that made them appear more like members of musical group than attendees of a scientific conference.
These were representatives of Kemin Foods, Rod Ausich, Ph.D., who was then the director of research and development and has since passed, and Chuck Brice, who was then the vice president of sales for the company. As they set up their booth in the conference center, they caught the gaze of onlookers who asked about their yellow blazers. The two explained that the yellow was characteristic of a new nutritional product they had to offer them and their patients. Lutein, a non-provitamin A carotenoid, was the product they were selling and theirs was the only commercially available form sourced from marigold flowers at the time. Before then, the product had only been sold to farmers as a yellow colorant for use in chicken feed to improve the appearance of egg yolks.
The pair came to the scientific meeting armed with only a sales pitch and the backing of a single observational study. They talked about lutein giving some hope for those suffering from one of the worst of eye diseases: age-related macular degeneration (AMD), which today robs some 2 million U.S. victims their central vision and is the leading cause of blindness in people over age 50. The terrifically horrible disease, Brice and Ausich would say, had no cure and the clinicians could do little else but tell their patients to keep coming back for check-ups to see how far it had progressed. Yet lutein was unique because studies show it collects in the macula of the eye and may lend protection that could save their sight. The only scientific support available at the time for Ausich’s and Brice’s claims was a 1994 epidemiology study. The study, which was published by nutritional epidemiologist Johanna Seddon in JAMA, had found a linear relationship between greater intake of lutein-rich leafy greens and the lower risk of AMD. The participants who consumed the most lutein (up to 6 milligrams per day) had a 43 percent lower risk for AMD.
The visit to Chicago was the first face-to-face meeting that the pair had ever had with ophthalmologists and it didn’t go well to say the least. On that day, you could say, the two raised more eyebrows than they did eye product sales. When the salesmen couldn’t produce support from any clinical trials, the clinicians riddled them with criticisms and slammed them for their baseless claims. “It was a pretty gruesome experience,” Brice told me in a recent interview. “Every one of those doctors thought we were nuts.”
So began the story of how lutein and its sister xanthophyll zeaxanthin would eventually catch the attention of the world for eye health. Much later, National Eye Institute (NEI) scientists would evaluate the effects of lutein and zeaxanthin in a five year, multi-center randomized trial. The much anticipated findings of the Age-related Eye Disease Study 2 (AREDS2) were just published on Sunday, May 5, in JAMA to coincide with NEI’s presentation of the results at the Association for Research in Vision and Ophthalmology (ARVO) meeting in Seattle.
Lobbying for lutein in AREDS
Brice started with Kemin in 1991 as VP of sales of Oro Glo™, a product for agricultural feed; yet, he was keen on expanding the product line of the company by producing lutein as a colorant for human foods. When Ausich came on board in 1994, he offered another idea: getting into the marketplace by selling lutein as a dietary supplement. At the time the Dietary Supplement Health and Education Act (DSHEA) of 1994 had just passed and Ausich, having previously worked for a biotechnology company, had a lot of experience working with other carotenoids, namely beta-carotene, which had become a popular supplement. In addition, Seddon’s study findings on lutein had just come out lending excitement to the air.
Ausich got to work on the technical aspects of the new lutein product. He figured out a way to refine the process for extracting lutein and became the first to create a pure, standardized form of lutein later called FloraGLO™. In the meantime, Brice was responsible for making initial contacts and getting the product ready for market. The observational study from Seddon would be key to substantiating the product as a nutritional for eye health in the marketplace.
The new endeavor proved to be quite the challenge for Brice, who had not had any experience prior in the nutritional product marketplace. However, his undeterred passion as a salesman would lead him to several tradeshows and he created a network of contacts that would put him in front of industry trade groups such as the Council for Responsible Nutrition (CRN). It was the CRN, a group he eventually headed in later years, that facilitated a meeting between Brice and Ausich and NEI’s then-and-first director Carl Kupfer, M.D., who has since passed. Brice and Ausich were there to lobby for inclusion of lutein in the first AREDS trial that was designed to evaluate the effect of a combination of supplements for reducing risk of progression to advanced AMD.
Brice admits in hindsight that it was a crazy idea and not unlike that first ophthalmologists meeting with the yellow blazers, the event didn’t go as well as expected. For one, making changes to the protocol seemed unthinkable to Dr. Kupfer, and Kemin’s new commercially available form of lutein had only just become available. But another reason could have mainly been the bafflement apparent in response to the audacious goal of industrial representatives attempting to modify the design of a government-backed study based on little evidence for its own purposes. Suffice to say, the pursuit of including lutein for AREDS1 failed miserably.
The first AREDS trial would go on to evaluate a supplement containing 500 mg vitamin C, 400 IU of vitamin E, 15 mg of beta-carotene (equivalent to 25,000 IU of vitamin A), 80 mg of zinc as zinc oxide (a really high dose), and 2 mg of copper as cupric oxide on reducing risk of progression of AMD. The trial included 4,000 participants ranging from 50 to 85 years of age. Most of them had some form of intermediate AMD. The results, published in 2001, were that the combination reduced the risk of AMD progression by 25 percent. The findings were considered a tremendous success and offered hope for millions of AMD patients. In addition, a follow-up re-analysis of AREDS1 participants found a persistent beneficial effect of 27 percent reduced risk of progression of AMD after 10 years.
Emily Chew, M.D., who is now NEI’s current deputy director of epidemiology and clinical application, would go on to become the lead researcher of the phase-3 AREDS2 trial that would evaluate lutein, zeaxanthin, and long-chain omega-3 fatty acids for reducing risk of progression to advanced AMD. When I asked Dr. Chew about what led her to consider lutein and zeaxanthin for the trial, she said she had remembered the early years when Ausich and Brice came around to ophthalmology conferences including ARVO.
“Rod Ausich was a major force in encouraging me to do this study,” Dr. Chew told me. She also said that there was growing interest in lutein and zeaxanthin after more animal and observational data were coming available showing an inverse relationship between lutein intake and AMD. “We wanted to improve upon the AREDS formulation.”
The increasing popularity of lutein and zeaxanthin products in the marketplace may also have played a role in stemming the tide of skepticism among ophthalmology researchers, according to Brice. By the time the AREDS2 trial was being considered, FloraGlo lutein and zeaxanthin had been adopted as an ingredient in several companies’ product lines including the popular brand Centrum; and, thanks to strategic partnerships Brice had created overseas, it had been launched in several countries including Japan and Switzerland.
AREDS2 trial findings
The highly complicated, multi-centered AREDS2 trial was conducted in 82 clinical sites in the U.S. from 2006 to 2012. The participants — 4,203 in all, aged 50 to 85 — were randomly assigned to different variations of the AREDS formula. The trial was designed to evaluate the effects of 10 mg of lutein and 2 mg of zeaxanthin (the equivalent to what’s found in half a cup of kale) and/or long-chain omega-3 polyunsaturated fatty acids, 650 mg eicosapentanoic acid (EPA) and 350 mg docosahexonoic acid (DHA), on risk of progression to advanced AMD. DHA is the main fatty acid that makes up retinal tissue (as well as other neural tissues).
The study also had a secondary aim to evaluate whether there was a difference in outcome with the use of low- or high-dose zinc and with the use of lutein and zeaxanthin in place of beta carotene for reducing risk of progression to advanced AMD. Zinc in high doses had led to gastrointestinal complaints in the earlier study. The doses of beta-carotene were of major concern because of research that suggested it led to increased risk of lung cancer in smokers during the study. Approximately 50 percent of AMD sufferers are smokers or former smokers. Additionally, beta-carotene is known to compete with lutein and zeaxanthin for uptake into neural tissues including retinal cells.
Unfortunately, the study reported “no overall effect” in further reducing risk of progression to advanced AMD (the primary outcome required an additional 25 percent decrease) when lutein, zeaxanthin and long-chain omega-3s were added to the AREDS formulation. However, according to Dr. Chew, a subanalysis did find that lutein and zeaxanthin alone reduced risk of progression to advanced AMD by 10 percent and as much as 20 percent on top of AREDS formula reductions. There was also a 26 percent reduction in the risk of progression to advanced AMD in the participants with the lowest dietary intake of lutein and zeaxanthin at baseline.
Most importantly, the non-provitamin A carotenoids proved to be a safer option in comparison to beta-carotene, which the AREDS2 study confirmed increased the incidence of lung cancer in former smokers. These were findings that led Dr. Chew to recommend that lutein and zeaxanthin replace beta-carotene in supplements used by clinicians with patients with high risk for AMD or intermediate AMD. She also said the earlier re-analysis confirmed that maintaining intake of high-dose zinc and the other supplements (with the exception of beta-carotene) included in AREDS1 was beneficial overall for patients. The high-dose zinc, according to Dr. Chew, led to reduced risk of mortality in the re-analysis.
Although Dr. Chew noted that long-chain omega-3s did not show any additional benefit in the study, she and her colleague John Paul Sangiovanni, Ph.D., a staff scientist at NEI, reminded in a press briefing at ARVO that the majority of the subjects were “well nourished” individuals. Their food frequency questionnaires revealed that they likely already had a high intake of long-chain omega-3s (650 mg per day). Sangiovanni added that among those with the lowest intake of long-chain omega-3s, there was likely a benefit in the participants that may have led to reduced risk of progression of advanced AMD.
Mainly, the study outcome confirms that diet can play a role in long-term eye health. Dr. Chew encouraged “eating a healthy diet,” regardless if one has AMD or not. Specifically, she suggested a diet that included a variety of colorful fruits and vegetables that would provide a large array of vitamins, minerals, as well as carotenoids and other phytochemicals.
Brice said the findings of the AREDS2 trial are welcome news. He said he feels proud to have played at least a minor part in making the study happen. He noticeably perks up at the chance of talking to bothersome bloggers who have lots of questions about his early adventures. And he assured me that he doesn’t mind sharing the memories he has about he and his friend Ausich traveling around the world in the ’90s introducing lutein to all who were willing to listen.
Although now retired, Brice says, he still keeps up with all the news and scientific literature surrounding lutein and zeaxanthin. He maintains his passion for encouraging ophthalmologists to recommend the compounds to AMD sufferers, who he believes could really benefit from additional intake through supplements or otherwise. The AREDS2 trial only substantiates what he’s believed was truth after a long while. In celebration of the AREDS2 findings, perhaps he could also be persuaded to don his old yellow blazer.