Nutrition, Cataract and AMD: an Interview with Allen Taylor, PhD, World-Renowned Vision Researcher

Introduction:
Cataract is the major cause of treatable blindness worldwide, while age-related macular degeneration (AMD) is the leading cause of non-treatable blindness among the elderly. The costs associated with both conditions are enormous and will continue to rise. Over the next few decades, the number of those affected by cataracts and AMD here in the US is expected to increase

Results from the National Eye Institute's Age-related Eye diseases study have already shown that antioxidants can delay vision loss in moderate to advanced AMD for at risk individuals. It's been estimated that delaying cataract by only 10 years would reduce the number of extractions by 50%. Modifying dietary patterns and increasing intakes of specific nutrients may very well be factors that can impact the onset or progression of these age-related eye disorders.

For insight into the current state of nutrition, cataract, and AMD research, we turn to Allen Taylor, PhD, a distinguished scientist and recipient of multiple awards for research excellence. Dr. Taylor's work on the influence of nutrition and aging on vision has led to significant advances in our understanding of eye diseases and has opened up new avenues of research. Allen Taylor (AT) is interviewed by nutritionist Penelope Edwards, MPH, CNS (PE).

View biographies of the interview participants

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Penelope Edwards - Dr. Taylor: you and your collaborators, including epidemiologist Dr. Chung-Jung Chiu, have led the field in investigating the effects of carbohydrate intake on AMD and cataract. Several studies indicate that high glycemic index diets (dGI) raise the risk for early AMD, or that low dGI patterns might be protective for nuclear cataracts.

The glycemic index-a weighted measure of how quickly carbohydrates raise blood glucose levels-speaks to carbohydrate quality. Please tell us more about your research in this area, and can you elaborate on how carbohydrates may be harmful to eye tissues?

Allen Taylor - We were the first to demonstrate that people who consume diets which are richer in more readily available sugar from carbohydrates have higher risk for all grades of AMD and prevalent types of cataract. We think that the carbohydrate damages proteins which are directly needed for the visual function of the lens and retina. The carbohydrate also causes indirect damage by compromising the function of pathways which usually serve to identify and remove the damaged proteins. This leaves the cells with accumulations of dysfunctional and cytotoxic proteins. Thus, the carbohydrates cause "double trouble".

PE - The data also suggest that carbohydrate quantity rather quality is important for cortical cataracts. Does that imply that nuclear and cortical cataracts form in different ways?

AT - We are not sure why there are different relationships with cortical cataract, or cataract in general, from the relationships that are observed for AMD and dGI. It might be that there is far lower blood supply and slower migration of sugars into the cortical or nuclear areas of the lens as compared with the retina. We are currently investigating this.

PE - Do you think it would it be appropriate to begin labeling foods with dGI information to help consumers plan a healthy diet?

AT - In my opinion, yes. I base my opinion on practical considerations that include: 1) eating a lot of simple carbohydrate is unnecessary and leads to many adverse health effects, including obesity, metabolic syndrome and all of their complications, as well as vision problems, 2) diminishing sugar intake is not difficult, 3) having excess sugars does damage the protein workhorses of the cells of the body, and 4) consumption of simple sugars has increased dramatically during the last 30 or so years.

PE - You've also investigated the relationship between cataract and dietary fats which can affect the composition and function of cellular membranes in the lens. What have you found?

AT - Higher intake of alpha-linolenic acid was associated with slightly higher risk for, and more rapid progress of early nuclear cataracts. Because nuclear cataracts are often right in the visual axis they disturb vision more than some cortical cataracts and it is important to diminish risk for such cataract. In comparison, higher intake of long-chain omega-3 fatty acid (eicosapentaenoic acid and docosahexaenoic acid) and consumption of fish may modestly reduce the risk of cataract. Higher intake of omega-3 fatty acids is associated with several health benefits.

PE - Realizing that people eat groups of foods rather than single nutrients, you've analyzed the effects of eating according to the food guide pyramid and by looking at food groupings. Tell us what your findings indicate about eating

AT - Generally we found that people who consume lower glycemic index diets and who consume larger proportions of fruits and vegetables as well as dark-meat fish containing meals enjoy better eye health, as measured by lower risk for AMD and cataract.

PE - You designed and directed the Nutrition and Vision Project (NVP)-a long time collaboration between your group, the Brigham and Women's Hospital, and the Nurses' Health Study at Harvard. Please tell us a little about the NVP and some of the project's key findings.

AT - The NVP was an outgrowth of the larger Nurses' Health Study (NHS). Because the NHS was already obtaining state of the art nutritional information and we were generously given access to the cohort in the Boston area by Drs. Frank Speizer and Walter Willett, we asked those nurses who live locally if they would undergo a thorough eye examination at approximately 5 year intervals. We also were able to collaborate with ophthalmologists like Dr. Lahav at Tufts Medical Center and Dr. Chylack at Harvard, who generously provided the eye examinations. Using a "reading" center at Wisconsin and photo-grading at Harvard, we obtained numerically graded images of the retinas and lenses at both visits. Thus, we obtained photographs of different aspects of the lenses and retinas of each nurse and we were also able to monitor the change over 5 or so years by comparing images from the "baseline" and the 5-year follow up. By collaborating we saved millions of dollars in set up costs and we were able to complete analysis at a fraction of the cost. Because we were also given access to a wealth of additional data about the participants, we were able to associate our new findings with prior information, thus, to get added value to the work, and to provide a more mature perspective to prior NVP investigations, such as relations between risk for cataract extraction and fat intake or post-menopausal hormone use.

Since we now invest over $57 billion in eye care in the US, if we can save a small proportion of the population from loss of sight this would enhance their life quality immeasurably and the small cost of these studies is an excellent investment of public dollars. Our studies regarding carbohydrate indicate that we can diminish risk significantly. In fact, we predict that we can save about 200,000 people from advanced AMD in only 5 years just by limiting simple carbohydrate intake. Thus, we are already repaying the small investment.

PE - One finding from the NVP is the observed link between vitamin C supplement use for a decade or more and a decreased risk of cortical or nuclear cataract in women. Will you fill us in on how long term antioxidant intake dovetails with the process of catarogenesis?

AT - Many tissues of the body replace their constituents often. For example, every few days you get new cells in your intestine. Every 10 days you get new receptors for light in your retina. In comparison, lens proteins last for decades and are damaged by the light, oxygen, and sugars to which they are exposed. The accumulation of such damage is causally related to onset and progress of cataract. Stated a different way, if we are to protect the lens, the protection should begin early and last a long time. Thus, we rationalize our observations that prolonged intake of adequate levels of antioxidants, such as vitamin C, confers protection to lens proteins as compared to lens proteins in persons who are poorly nourished.

PE - A large-scale prospective study of women health professionals followed for 10 years just reported in January that higher intakes of lutein, lutein and vitamin E are associated with a reduced risk of cataract. A month prior to that, the same research group found that giving women 600 IU natural-source vitamin E every other day for nearly 10 years provides no benefit for age-related cataract or subtypes. Your thoughts?

AT - Measuring and quantifying cataract is a highly specialized field. My guess is that in the former case photograding of the opacities was not possible, and this may have compromised their ability to execute the study properly. But certainly there are different opinions. There are several studies that failed to find associations between vitamin E intake and cataract, although we did find such a relationship. One might hypothesize that the lens is primarily an aqueous environment and thus rationalize stronger roles for vitamin C, which is also aqueous soluble. vitamin E is lipid soluble. But, the confusion is unsatisfactory. Given the huge rewards and returns on maintaining sight among the elderly, the returns are certainly worth the investment and more intervention studies should be done.

PE - You've said that daily dietary intake of about 250 mg vitamin C, 90 mg vitamin E, and 3 mg/day lutein – begun early in life – should provide sufficient reserves to provide lens and macular health benefits. These levels are considerably higher than the current recommended daily intakes for C and E, and higher than the average amount of lutein we consume. How "early in life" should a higher level of intake begin in your estimation?

AT - I think that healthy eating should begin at birth and be inculcated early and reinforced regularly. Our health would be certainly be improved if by young adulthood we were already consuming diets which are rich in fruits and vegetables and not high in fats or simple carbohydrates.

PE - For older individuals participating in the cataract portion of AREDS, high dose C, E and beta-carotene had no apparent benefit. Yet a subsequent AREDS analysis found a reduced risk of nuclear cataract-and any cataract -– in those who elected to take a simple multi-nutrient supplement throughout the trial. Can you comment on these findings?

AT - I have several responses to this question. First, it is important to remember that a large proportion of the AREDS subjects were already taking a multivitamin. Additional analyses of the AREDS cohort implied some benefit to consuming multivitamins with respect to risk for cataract. The benefit of taking the high dose supplement with respect to nuclear cataract is consistent with several other studies. It should be pointed out, however, that only high dose supplements were used. It is also possible that the benefit could be gained using lower levels. Clearly, more study is required.

PE - Can you tell us more about why cataract and AMD form or occur?

AT - The lens and retina both have the job of "processing" light. The lens receives it and transmits it to the retina where it is received and converted to chemical and electrical impulses. Just as a newspaper in the back of a car window gets brown from the light of the day and the oxidation that the light energy causes to the paper, so do our retinas and lenses get oxidized. The oxidation of the proteins and sugars in these cells cause the proteins to clump and precipitate. Such precipitation in the lens results in opacification of the normally clear milieu.

In the retina the oxidation has many repercussions, including accumulation of deposits, called drusen, which push cells away from their blood supply, thus, resulting in their dysfunction and loss. Such loss results in AMD-associated blindness. Moreover, cells usually have protein quality control machinery that can identify and destroy damaged proteins before they become cytotoxic. This "machinery" is also damaged by oxidative or glycoxidative stress. Thus, in the aged tissue, the cells are subject to multiple insults and an inability to recover from those insults. For example, one system for identifying damaged proteins involves the "ubiquitin pathway". Discovery of this ubiquitous protein digesting pathway was awarded the Nobel Prize in 2004 because it has so many uses. Among them is the tagging of the damaged protein prior to its degradation. We find that the function of the ubiquitin pathway is itself compromised upon aging, hence the multiple jeopardy of aged tissues. We hypothesize that similar compromises occur in many tissues upon aging.

PE - Dr. Taylor, in your opinion what are the biggest challenge(s) to reducing the prevalence of cataract and AMD in our aging population?

AT - I think that identifying the optimal ways to protect the eye and when protection needs to be started, is crucial. Also, it is important to instill in children and youths the value of good sight and good health in general. As it is said, "you do not even think about it when you have sight, but when it is gone it is invaluable". When we compare the expenditures on health care or less rewarding investments vs. the costs of research, given the repeating returns of the research it is clearly well worth the investment. But, the time required for that research may exceed political memories of a few months or a few years. Thus, the public must demand that this research be given high priority.

Given that we will all eventually have compromised vision, it is essential to understand how the lens and retina are originally assembled and maintained and to harness such capabilities to prolong their function over time and in the face of stress.

Suggested further reading:

1. Chiu C-J, Taylor A. (Review) Nutritional antioxidants and age-related cataract and maculopathy. Experimental Eye Research 84: 229-245, 2007
   
2. Chiu C-J et al. Long-term dietary carbohydrate intake, glycemic index and odds for early nuclear and cortical lens opacities. Am J Clin Nutr 81:1411-6, 2005.
   
3. Nutritional and Environmental Influences on the Eye (A. Taylor, ed.). CRC Press, Boca Raton, FL 1999.
   
4. Lu M et al. Dietary linolenic acid intake is positively associated with five-year change in eye lens nuclear density. J Am Coll Nutr 26: 133-40, 2007.
   
5. Chiu C-J et al. Dietary carbohydrate and glycemic index in relation to Age-Related Macular Degeneration - The Age-Related Eye Disease Study. Am J Clin Nutr 86:180-88, 2007.
   
6. Chiu C-J et al. Dietary glycemic index is related to progression of age-related macular degeneration: A prospective study from the Age-Related Eye Diseases Study. Am J Clin Nutr 86:1210-8, 2007.
   
7. Chiu C-J et al. Diet, supplement and risk of age-related macular degeneration in the Age-Related Eye Disease Study. Manuscript submitted.
   

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• Allen Taylor, PhD is Director of the Laboratory for Nutrition and Vision Research and Senior Scientist at the Jean Mayer USDA Human Nutrition Research Center on Aging. Dr. Taylor is also a professor at the Friedman School of Nutrition Science and Policy at Tufts University, and at the Biochemistry Department and Department of Ophthalmology of Tufts University Medical School. He is the 2007 recipient of the Osborne and Mendel Award for outstanding basic research in nutrition, and the 2007 Denham Harmon Award for Excellence in Aging Research.
  
  
• Penelope Edwards, MPH, CNS is a UCLA-trained nutrition scientist and consultant. She is immediate past president of the Certification Board of Nutrition Specialists, the certifying arm of the American College of Nutrition.

 

Interview with John D. Sheppard, MD and Steven C. Pflugfelder, MD:
New Developments in Dry Eye Treatment and Diagnosis

Dry eye is often said to be the most common condition seen in ophthalmology practice. While it affects people of all ages, this is a condition that increases with age. That means clinicians will be seeing even more patients with dry eye as a large portion of our population ages. What advances have been made in understanding the etiology, diagnosis and treatment of this condition, including the role of nutritional intervention? For insight into the latest developments, we turn to John D. Sheppard, MD (JDS) and Steven C. Pflugfelder, MD (SCP), interviewed by Penelope Edwards, MPH, CNS (PE).

View biographies of the interview participants

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Penelope Edwards - Regardless of the pre-disposing factors, inflammation is now widely considered a cause of dry eye rather than simply a symptom. Some have even theorized that KCS – whether Sjögren's or non-Sjögren's – is really an autoimmune state in which lacrimal gland epithelial cells are detected as antigens by the immune system and attacked by activated T-cells. Can each of you elaborate on this notion of KCS as an "autoimmune state"?

Steven C. Pflugfelder, MD - It is now recognized that we all have a small population of T lymphocytes that are capable of reacting to stress induced antigens on mucosal epithelial cells, including the ocular surface that is the most exposed mucosal surface in the body. Normally these autoreactive T cells are suppressed by immunoregulatory mechanisms (cytokines and various types of regulatory T cells). When the system is overwhelmed by an excess of antigens or when there is disruption of immunoregulation, autoimmunity develops.

John D. Sheppard, MD - Topical anti-inflammatory therapy with cyclosporine has been shown clinically, and by conjunctival biopsy, to down-regulate T cell expression while decreasing tear cytokines and increasing goblet cell density. Interestingly, these marked changes in ocular surface cytology were identical for Sjögren's and non-Sjögren's patients. This important information indicates that the mechanism for ocular surface dryness is independent of systemic autoimmune disease, and that inflammation is a hallmark of aging as well as age-related hormonal decline and autoimmunity.

PE - Dr. Pflugfelder, you took part in a panel of national and international specialists that attempted to reach consensus on treatment recommendations for dry eye. Apparently more than half the respondents felt that the current classification of aqueous deficient vs. evaporative dry eye fails to reflect inflammatory mechanisms and the significant overlap between these disorders. Why did the group propose the new term for dry eye: dysfunctional tear syndrome or DTS?

SCP - The panel members agreed that dry eye is not as much a disease of decreased tear volume as abnormal tear composition. Based on this concept, dry eye was renamed Dysfunctional Tear Syndrome (DTS). Many dry eye patients have severe irritation symptoms or ocular surface disease with adequate or even excessive tear volume. These patients are found to have inflammatory signs and respond to anti-inflammatory therapies.

PE - Was consensus reached on what factors drive decisions in choosing treatment strategies?

SCP - It was felt that Level 1 dry eye disease is episodic, whereas Level 2 and greater severity disease is chronic. Once the disease occurs on a chronic basis, the consensus was that there is an inflammatory component and effective therapy requires one or more anti-inflammatory therapies.

PE - There is growing interest in supplementation with certain fatty acids that modulate the inflammatory response. Results from several controlled clinical trials suggest that one fatty acid, gamma-linolenic or GLA - may be efficacious for patients undergoing PRK, for those with Sjögren's, or those with general inflammatory dry eye. Dr. Sheppard, can you tell us what, if any, clinical experience you've had with GLA -containing supplements in your practice?

JDS - We recommend GLA supplements to all of our dry eye and blepharitis patients, many of whom also take beneficial natural omega-3 supplements. Some patients do not tolerate fish oil well and so take flaxseed oil instead, though fish oil is generally significantly more bio-available. The GLA supplement is the best tolerated of all, and produces a noticeable improvement in many patients with dry eye or blepharitis accompanied by evaporative dry eye.

PE - In your opinion, Dr. Pflugfelder, when would nutritional support with "anti-inflammatory" fatty acids such as GLA be appropriate as intervention or adjuvant treatment for patients within any of the 3 of the clinical categories the panel proposed-KCS with lid margin disease, without lid margin disease, and altered tear distribution or clearance?

SCP - There is evidence of inflammation in DTS with and without lid margin disease. Our group has found that hyperosmolarity is a potent inflammatory stress on cells. Tear hyperosmolarity is a common denominator in all types of DTS. Therefore, anti-inflammatory essential fatty acids, such as GLA are indicated. GLA is an omega 6 fatty acid that has unique anti-inflammatory properties. GLA is converted to DGLA when released from cell membranes by phospholipase A and DGLA competes with arachadonic acid for cyclo-oxygenase and lipo-oxygenase. DGLA is converted by COX to PGE1 and thromboxane A2, agents that have anti-inflammatory properties and inhibit platelet aggregation. It may work directly on T cells which have been found to play a key role in the pathogenesis of keratoconjunctivitis sicca. The mechanism of action of cyclosporine is inhibition of T cell activation.

PE - There seem to be some misconceptions about GLA . Some, for example, think that GLA -rich oils such as black currant seed should be avoided because they only add to our over-consumption of omega-6 fats relative to omega-3s. Can you identify some of these misconceptions or concerns and put them into perspective?

JDS - It's important to remember that GLA is an anti-inflammatory fatty acid, unlike other omega-6 fatty acids such as arachidonic acid found in red meats and egg yolks for example. The beneficial effects of the omega-3 fatty acids found in fatty fish, canola oil, pecans, walnuts, or flax seed oils, can complement GLA 's anti-inflammatory actions. We recommend GLA along with a source of omega-3 fatty acids for our ocular surface disease patient population. One product, for instance, combines EPA and DHA from fish oil with black currant seed oil – a source of both GLA and the omega-3 alpha-linolenic acid.

PE - Post-menopausal women represent a large at risk group for KCS (or DTS). As I understand it, the decline of protective androgens after menopause can leave the lacrimal glands vulnerable to inflammation. Are meimobian glands involved as well? Dr. Sheppard, can you explain more about dry eye etiology in this group and bring us up to date on any research directions toward treatment strategies?

JDS - Chronic dry eye, KCS or dysfunctional tear syndrome all describe a spectrum of conditions involving deterioration of youthful ocular surface physiology. Serum androgen levels provide critical supportive protection to the ocular surface as well as other mucus membranes and a wide variety of other tissues. Androgen production declines with time, more rapidly and from a lower baseline in women. This is why there are more females with dry eye compared to men of the same age.

Some patients with meibomian secretory imbalances may develop symptomatic dry eye at a younger age than other unaffected patients with identical aqueous tear production. This is due in large part to tear film instability and resultant evaporative tear loss. Upon close inspection at the slit lamp, most individuals have some degree of meibomian inspissations - thickening of oil secretions and, perhaps also plugging of the glands.

Newer investigational approaches to evaporative dry eye include secretagogue therapy, topical androgens, mucin analogues and topical doxycycline. It has been postulated that some essential fatty acids might beneficially affect the composition of meibomian gland secretions, but this needs to be more formally evaluated.

PE - Drs. Sheppard and Pflugfelder, what do you see as the biggest challenge(s) ahead in reducing the prevalence of dry eye? Is it more clearly delineated detection and treatment guidelines by NEI or AAO? Greater awareness of the disorder by primary care physicians so that patients presenting with symptoms will be referred to an eye care professional? More research?

JDS - The short answer here is early detection. We can modify the adverse effects of DTS, but we are unlikely to reduce the prevalence or find a cure in the near future. Eye care professionals should recognize that all severe dry eye was once mild, and that prevention of symptomatic and ocular surface deterioration is one of our primary roles as care givers. We really need to look at dry eye as a chronic condition of aging, very much akin to hypertension, hypercholesterolemia or glaucoma. Thus early intervention is paramount, and we should seek out dry eye signs and symptoms. Even though the patient is relatively unaware and doesn't complain, the astute clinician will pursue the diagnosis in patients with early signs, or demographically predisposed to DTS. Thus, unless specifically asked about wind intolerance, hatred for overhead fans, difficult reading at night or foreign body sensation, many early DTS patients remain unidentified for years. These patients instead seek out topical OTC remedies, which almost universally include vasoconstrictors and preservatives, further worsening their condition.

SCP - Perhaps early intervention or prophylaxis in at risk groups, such as peri- and post-menopausal women, elderly, post-LASIK and those with systemic autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosis should be investigated. Certainly the role of diet needs further investigation. The role of hormones on cause or therapy has not been established.

PE - Dr. Sheppard, you emphasis the importance of early detection. Among your patient population, are there certain patients likely to develop dry eye who you particularly watch out for?

JDS - The classic dry eye patient is frequently the central health care decision maker for her family, the peri-menopausal woman. She finds health care providers for her children, her spouse, her own aging parents, and her spouse's parents. She may have early disease, but often ignores her own medical concerns because she's too busy caring for others. Due to the heterogeneity of dry eye, the classic symptom of foreign body sensation is often masked by less obvious complaints including itching, computer difficulties, contact lens intolerance, make-up sensitivity or perceived fatigue. As with any disease process, earlier intervention produces superior long term results.

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• John D. Sheppard, MD is President of Virginia Eye Consultants, specializing in diagnosis and treatment of infectious, inflammatory and surgical diseases of the eye. He is Professor of ophthalmology, microbiology, and molecular cell biology at Eastern Virginia Medical School (EVMS), where he serves as Ophthalmology Program Director. He also serves as Clinical Director of the Thomas R. Lee Center for Ocular Pharmacology , and with the EVMS Development Committee. A recipient of the American Academy of Ophthalmology Honor Award, Dr. Sheppard serves on the Academy editorial board for EyeNet Magazine, and as Uveitis Editor for eMedicine online. A Mentor Examiner for the American Board of Ophthalmology, Dr. Sheppard has authored over 100 peer-review abstracts, journal articles, and chapters, and served as principal investigator in over 60 clinical research trials. He is the founder of ProVision-Network.com and EyeRx research, and holds 2 competitively funded NIH research grants.
  
  
• Steven C. Pflugfelder, MD is a professor and Director of the Ocular Surface Center at Baylor College of Medicine's Cullen Eye Institute, where he was awarded the James and Margaret Elkins Chair in 2001. Dr. Pflugfelder co-edited the textbook "Dry Eye and Ocular Surface Disorders", and is on the editorial boards of the journals Cornea, American Journal of Ophthalmology, Eye & Contact Lens and The Ocular Surface. He received the American Academy of Ophthalmology (AAO) Senior Achievement Award in 2000, and has served as chairman of the AAO Preferred Practice Pattern Committee on Corneal and Ocular Surface diseases. His research interests include the role of inflammation in dry eye and he has numerous peer-reviewed articles, book chapters and monographs.
  
  
• Penelope Edwards, MPH, CNS is a UCLA-trained nutrition scientist and consultant. She is immediate past president of the Certification Board of Nutrition Specialists, the certifying arm of the American College of Nutrition.

Paul Bernstein, MD, PhD on the Role of Lutein & zeaxanthin in Macular Health

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Paul Bernstein, MD, PhD is an Associate Professor of Ophthalmology and Visual Sciences in the Retina Division at the Moran Eye Center, University of Utah School of Medicine. Extensively published, Dr. Bernstein has conducted research on the topic of macular lutein and zeaxanthin concentrations, and the relationship of these carotenoids to AMD. His findings have contributed significantly to our current understanding of the role lutein plays in eye health. Dr. Bernstein was interviewed in December, 2005 by Penny Edwards, MPH, CNS, ScienceBased Health's Science and Education Advisor.

• How are levels of lutein and zeaxanthin measured in the eye's macula?
• Do levels of the carotenoids decrease with age?
• Will the National Eye Institute be studying the effects of lutein and zeaxanthin on macular health?
• Who may want to take lutein supplements?
• Is supplemental lutein more or less important than zeaxanthin?

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Penny Edwards, MPH, CNS - Dr. Bernstein, you pioneered the use of Raman spectroscopy to measure the levels of lutein, zeaxanthin and their metabolites in the macula. Can you give a short explanation of how this technology works?

Paul Bernstein, MD, PhD - While a number of important epidemiological studies have found that high dietary intakes of foods rich in lutein and zeaxanthin are associated with decreased risk of AMD, the critical information on how much of these protective nutrients actually make it to the macula is more challenging to obtain. We and other research groups have endeavored to develop methods to measure macular carotenoid pigments non-invasively in living human subjects.

At the Moran Eye Center we have found that resonance Raman spectroscopy is a particularly useful method that is sensitive and specific for the macular carotenoids. In this technique, we flash a low power blue laser spot on the macula of the human eye for less than a second, and we collect the light that is scattered back. A small amount of this returning light is shifted to longer wavelengths owing to molecular vibrations of the lutein and zeaxanthin in the macula. It turns out that the concentration of the macular carotenoids is so high and their Raman vibrations are so strong that we can readily detect their signature Raman spectrum even in a complex biological system such as the eye. We can then calculate the levels of lutein and zeaxanthin from the strength of the collected Raman shifted light.

PE - What have you found out about lutein and macular health using the Raman method?

PB - Using this technique, we have measured hundreds of subjects with and without AMD. We have learned that macular carotenoid levels decline with age, reaching an especially low level after age 60, just when the risk of AMD rises dramatically. We have also found that macular pigment levels are significantly lower in AMD patients who were not taking lutein supplements, relative to age-matched controls. Interestingly, AMD patients who had been taking high dose lutein supplements for at least three months after their diagnosis of AMD had levels that were nearly the same as the normal controls. These results are consistent with the hypothesis that AMD is in part a disorder related to low macular levels of lutein and zeaxanthin, and that supplementation can alter these levels in a potentially beneficial manner.

PE - Some research suggests that 6-7 mg of lutein/zeaxanthin represents a reasonable level for supporting macular health, while the average dietary intake is only 1-2 mg daily. Should people who are not consuming enough consider supplementation of these carotenoids?

PB - Yes, I think that greater intake of lutein and/or zeaxanthin is probably beneficial for macular health. Six milligrams is a reasonable intake based on our Raman results and on various epidemiological studies. Increasing dietary intake of lutein and zeaxanthin is clearly a healthy approach, but most Americans would have a hard time consuming that many fruits and vegetables daily, so supplements will certainly play an important role, too. Ultimately, when noninvasive measurement of carotenoids is more widely available, individuals who have unusually low levels could be identified and targeted for aggressive nutritional intervention. For now, however, supplemental lutein doses considerably higher than 6-10 mg probably do not provide further enhancement because specific binding proteins in the macula become saturated.

PE - Well, let's talk about these specific binding proteins. You and your colleagues discovered that the uptake of lutein and zeaxanthin into the retina from the circulation is carried out via xanthophyll binding proteins called XBP. Explain a little about lutein, zeaxanthin and meso-zeaxanthin - how they get into the macula, where they're located in the retina and macula, and the importance of finding these xanthophyll binding proteins.

PB - All lutein and zeaxanthin in the human body must come from dietary sources, usually fruits and vegetables or from supplements. The macula of the human eye contains by far the highest concentrations of carotenoids anywhere in the human body. In the macula, there are approximately equal amounts of three xanthophyll carotenoids: lutein, zeaxanthin and meso-zeaxanthin. lutein's dietary source is primarily dark green leafy vegetables. zeaxanthin is less common in the human diet - coming from certain orange and yellow fruits and vegetables. Meso-zeaxanthin is not found in the normal human diet, and is thought to originate from lutein. The high concentrations and specific uptake of the macular carotenoids is mediated by specific binding proteins that draw them into the tissue and stabilize them. My laboratory has recently identified the first xanthophyll binding protein (XBP) in any vertebrate system. This XBP binds zeaxanthin and meso-zeaxanthin and seems to enhance their antioxidant functions.

PE - Earlier this year you published a paper describing an XBP that appears to be specific for zeaxanthin. Since most food sources like spinach contain far more lutein than zeaxanthin, is the body able to convert sufficient amounts of lutein to zeaxanthin or meso-zeaxanthin?

PB - The human macula seems to want unusually high levels of zeaxanthin, yet we get very little in the normal human diet. lutein is much more common in our diet, and it appears that some of our dietary lutein is converted to meso-zeaxanthin in the macula, although the enzymes responsible for this conversion have not yet been identified.

PE - Just what is our state of knowledge about the relative importance of these two carotenoids? Do we need to be supplementing higher levels of zeaxanthin as well as lutein?

PB - The jury is still out on this question. There is much more experience with lutein supplements, and there is some evidence that lutein can be a precursor for macular meso-zeaxanthin, but it is also true that there is an exceptionally large amount of zeaxanthin in the macula. Eventually, there will have to be head to head studies of these two compounds to determine if one is better than the other.

PE - Some papers have hinted at gender differences in handling lutein. In one study, lutein supplements raised plasma levels of this carotenoid equally well in both sexes, yet some women did not increase their macular pigment density as well as the men. It's been suggested that some lutein may get diverted away from the eye and stored in fat tissue instead-more so in women than in men. What's your read?

PB - I am not convinced there is a major difference between women and men in this regard. At least in our Utah Raman studies, we do not see a major difference between women and men.

PE - The antioxidant treatment arm of the age-related eye disease study (AREDS) included beta-carotene, not lutein. The findings showed that zinc and the antioxidant combination given in this trial was best at slowing AMD progression and vision loss. Do you think that beta-carotene plays a role in protecting retinal tissues, and if so, how?

PB - In the AREDS study, it is impossible to sort out the effect of beta-carotene independently from the effects of vitamin E and vitamin C. Very little beta-carotene is actually present in the retina, so if it is having any effect, it probably is due to its vitamin A precursor role. Since high doses of beta-carotene are associated with increased risk of lung cancer in smokers, many people would like to use lower doses and add lutein and/or zeaxanthin to the AREDS formula.

PE - The National Eye Institute (NEI) is planning a large-scale trial examining the effects of lutein in AMD patients. Will they be utilizing the Raman technology to measure carotenoid levels in the macula? Will you be involved in this study?

PB - As of December 2005, the NEI is evaluating applications for up to 60 sites for the AREDS II study, which is expected to begin in 2006. A combination of 10 mg of lutein and 2 mg of zeaxanthin will be tested against a placebo. There will also be an omega-3 fatty acid arm of the study. If we are selected as a site, we would be interested in monitoring patient response to supplementation with our ocular resonance Raman instruments.

PE - What do you see as the most important gaps in our knowledge when it comes to the role of lutein and zeaxanthin in the macula?

PB - Although there is good epidemiologic and anecdotal evidence, we still don't have good prospective results that lutein and zeaxanthin can decrease risk of developing AMD; hopefully AREDS II will give us some answers. From a basic science standpoint, there are still many gaps in our knowledge of the uptake, metabolism, and function of lutein and zeaxanthin that my laboratory hopes to solve.

PE - If you won some sort of research grant lottery and had unlimited funding, what study would you conduct?

PB - On the clinical side, I would like to see a large scale multiyear placebo-controlled head to head study of lutein and zeaxanthin supplementation in high risk patients for AMD using multiple methods to assess macular response. On the basic science side, I would like to bring the state of knowledge of carotenoid metabolism in humans to a level comparable to the intricate knowledge we have of their roles in photosynthesis and photoprotection in plants.

PE - Thank You, Dr. Bernstein, for shedding light on our current state of knowledge about these important carotenoids, and your insights about future research directions.