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© 2010 Taylor & Francis Group, LLC
 Carotenoids
and Retinal
Disease

Edited by
John T. Landrum • John M. Nolan

Boca Raton London New York

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Taylor & Francis Group, an informa business

© 2010 Taylor & Francis Group, LLC

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Cover microphotograph of the macula, courtesy of Dr. Max Snodderly.

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 Dedication

This volume is dedicated to Dr. Alan Howard,

Wilkins Fellow of Downing College, Cambridge
University, and Honorary Professor at University
of Ulster. His career at Cambridge University
spans more than 60 years. He has held positions
in the Department of Investigative Medicine
and Pathology as well as the Dunn Nutritional
Laboratory, before founding his own laboratory at
Papworth Hospital, Cambridge, until it closed in
1999. He has published over 250 original articles
in medical literature and authored and/or edited
8 major books on coronary heart disease and
obesity. He was cofounder of the International
Journal of Obesity and was involved in the foun-
dation of the International Congress on Obesity and the European Atherosclerosis
Society. Dr. Howard’s inspiration and sponsorship were critically important to the
establishment of the Macular Carotenoids Conferences that led the participants
to collaborate on the contributions found in this work. The Macular Carotenoids
Conference held in July 2011 was the first in this ongoing series of conferences to be
held at Downing College, Cambridge University. This conference was conceived by
Dr. Howard and principally sponsored by the Howard Foundation, a charitable trust
that supports biomedical research at the University of Cambridge. Founded by Dr.
Howard in 1982, the Howard Foundation provides support and encouragement for
research into nutritional sciences, particularly emphasizing efforts to understand the
nutritional factors that influence the genesis and etiology of cardiovascular disease,
obesity, and antioxidants including carotenoids and their functional role in the reduc-
tion of risk for AMD. The Howard Foundation also maintains a strong supportive
relationship with Downing College at Cambridge University. In 1970, Dr. Howard
invented the internationally acclaimed Cambridge Diet, a scientifically designed,
very low calorie diet, as an effort to address ­obesity and consequent cardiovas-
cular heart disease. In 1984, he established a highly successful business venture,

v
© 2010 Taylor & Francis Group, LLC
vi Dedication 

Cambridge Nutrition Ltd, to internationally market the Cambridge Diet (currently

“Cambridge Weight Plan®”), which has continuously supported the work of the
Howard Foundation. In 2005, Cambridge Nutrition Ltd was acquired by investors
providing resources that the Howard Foundation ­committed to construction of the
Howard Theatre (2009), which is now the home site of the Macular Carotenoids
Conferences, the Conference on the Science and Economics of Climate Change, and
the upcoming “Blue Skies” meeting on prostate cancer, among a long list of other
scholarly and artistic events. The Howard Foundation has also funded the recently
renovated car park and new Howard Gate, complementing two other buildings at
Downing College: the Howard Building (1987) and Howard Lodge (1994).
Dr. Howard’s career is unique in that he has successfully bridged the divide
between academic scholarship and research and entrepreneurship, making the ben-
efits of his scientific accomplishments available to the public. Trained as a nutrition-
ist in Cambridge at the Medical Research Council’s Dunn Nutritional Laboratory in
the 1950s, his lifelong research interests have been in the field of nutrition, especially
in nutritional relationships associated with coronary heart disease and the treatment
of obesity. He has served the research community devoting his expertise to the orga-
nization of international and national meetings, an accomplishment for which he
has earned widespread renown. Between 1960 and 1995, he was a founding member
and first secretary of the European Atherosclerosis Discussion Group; organized the
First International Symposium on Atherosclerosis in Athens; a founding member
and secretary of the Association for the Study of Obesity (United Kingdom); a joint
organizer of the First International Congress on Obesity in London; founded and
edited the International Journal of Obesity; organized satellite meetings on very
low calorie diets in Ischia, Cambridge, and Kyoto; founded and organized the First
International Symposium on Clinical Nutrition in London; and acted as secretary
and then chairman of the Food Education Society (United Kingdom).
Following a remarkably productive research career in the Departments of
Pathology and Medicine, University of Cambridge, Dr. Howard established a pri-
vate laboratory at nearby Papworth Hospital where he continued to conduct research
in cardiovascular heart disease, especially antioxidants. A major project completed
by Dr. Howard at the Papworth Hospital was a comparison of the dietary habits of
people from Toulouse, France, where the incidence of cardiovascular heart disease
was reported to be notably low, particularly when compared to that observed for
people from Belfast in Northern Ireland, where cardiovascular heart disease is very
high. He collaborated in this work with Cambridge biochemist Dr. David Thurnham
(later Howard Professor at the University of Ulster) to apply modern analytical meth-
ods to the analysis of vitamin E and carotenoids among the populations of Toulouse
and Belfast. Both cities, although similarly highly industrialized, have populations
whose food preferences differ significantly. Toulouse is renowned for its Le Cordon
Bleu, a high animal fat cuisine, consumed with large amounts of fresh fruit and veg-
etables, and locally produced red wine. This contrasts with the average diet among
residents of Belfast, which also includes high levels of animal fats, but is character-
ized by a limited and low intake of fruit and vegetables, and the principal alcoholic
beverage is beer. The chief finding of their collaboration was that the average con-
centration of the carotenoid lutein in plasma of Toulouse residents was twice as high

© 2010 Taylor & Francis Group, LLC

Dedication vii

as that of Belfast residents (Howard et al. 1996). Dr. Howard concluded that the
so-called “French Paradox” was due to the high consumption of fruit and vegetables
­(especially spinach with its high content of lutein) and red wine, which contains
potent antioxidant polyphenols.
Pursuing this research interest, Dr. Howard attended the 1995 Gordon Conference
on Carotenoids at Ventura in California, where he met Drs. Richard Bone and
John Landrum and became aware of their work on the macular carotenoids, lutein,
­zeaxanthin, and meso-zeaxanthin, and macular degeneration. Dr. Howard initiated
a collaboration to explore the potential benefits of meso-zeaxanthin for the putative
­prevention and treatment of AMD with Professors Bone and Landrum following a
visit to Florida International University in Miami. This collaboration culminated
in the successful commercialization of supplements containing meso-zeaxanthin
­produced from marigold petals by Industrial Orgánica SA of Monterrey, Mexico. Dr.
Howard has since expanded his support of clinical research through development of
collaboration with Professor Stephen Beatty, an ophthalmologist, and Professor John
Nolan, a nutrition scientist, and the Macular Pigment Research Group at Waterford
Institute of Technology in Waterford, Ireland. Dr. Howard’s efforts and support of
research continue to further the understanding of the functional nature of carot-
enoids in the human eye, especially that of meso-zeaxanthin in protecting the ret-
ina from AMD. In July 2013, Dr. Howard hosted the Second Macular Carotenoids
Conference, which convened at the Howard Theatre in Downing College, bringing
together the international macular carotenoids community.
At the 2009 commemoration of the 800th anniversary of the founding of
Cambridge University celebrated at Buckingham Palace, Dr. Howard was recognized
by the Chancellor of Cambridge University, the Duke of Edinburgh, for his dedica-
tion and tenacity and honored by the award of the Chancellor’s 800th Anniversary
Medal for Outstanding Philanthropy.

REFERENCE
Howard, AN; Williams, NR; Palmer, CR; Cambou, JP; Evans, AE; Foote, JW; Marques-Vidal,
P; McCrum, EE; Rudavets, JB; Nigdikar, SV; Radjput-Williams, J; Thurnham, DL. Do
hydroxy-carotenoids prevent coronorary heart disease? A comparison between Belfast
and Toulouse. Int J Vitam Res. 1996; 66(2); 113–18.

© 2010 Taylor & Francis Group, LLC

Contents
Foreword....................................................................................................................xi
Acknowledgments..................................................................................................... xv
Editors.....................................................................................................................xvii
Contributors.............................................................................................................xxi

Chapter 1 Macular Pigment: From Discovery to Function....................................1

John T. Landrum, Richard A. Bone, Martha Neuringer, and Yisi Cao

Chapter 2 Risk Factors for Age-Related Macular Degeneration and

Their Relationship with the Macular Carotenoids.............................. 23
Tos T. J. M. Berendschot

Chapter 3 Epidemiology and Aetiopathogenesis of Age-Related Macular

Degeneration....................................................................................... 41
Sobha Sivaprasad and Phil Hykin

Chapter 4 Relationships of Lutein and Zeaxanthin to Age-Related

Macular Degeneration: Epidemiological Evidence............................. 63
Julie A. Mares

Chapter 5 Clinical Trials Investigating the Macular Carotenoids....................... 75

Sarah Sabour-Pickett, John M. Nolan, and Stephen Beatty

Chapter 6 The Promise of Molecular Genetics for Investigating the

Influence of Macular Xanthophyllys on Advanced Age-Related
Macular Degeneration......................................................................... 93
John Paul SanGiovanni and Martha Neuringer

Chapter 7 A Review of Recent Data on the Bioavailability of Lutein and

Zeaxanthin........................................................................................ 129
Mareike Beck and Wolfgang Schalch

Chapter 8 Multiple Influences of Xanthophylls within the Visual System........ 147

Billy R. Hammond, Jr. and James G. Elliott

ix
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x Contents

Chapter 9 Transport and Retinal Capture of the Macular Carotenoids............. 171

Binxing Li and Paul S. Bernstein

Chapter 10 Measurement and Interpretation of Macular Carotenoids in

Human Serum................................................................................... 187
David I. Thurnham, Katherine A. Meagher, Eithne Connolly,
and John M. Nolan

Chapter 11 Xanthophyll–Membrane Interactions: Implications for

Age-Related Macular Degeneration.................................................. 203
Witold K. Subczynski, Anna Wisniewska-Becker, and Justyna
Widomska

Chapter 12 Light Distribution on the Retina: Implications for Age-Related

Macular Degeneration....................................................................... 223
Richard A. Bone, Jorge C. Gibert, and Anirbaan Mukherjee

© 2010 Taylor & Francis Group, LLC

Foreword
This volume had its origins among the organizers and contributors at the first
Macular Carotenoids Conference held at Downing College, Cambridge University,
in July 2011. That conference provided an open forum for many eminent interna-
tional investigators in this field. Contributions from this international conference
have been updated and “fleshed out.” As a result, Carotenoids and Retinal Disease
presents an up-to-date, thorough, and accessible volume devoted to the chemistry,
pathobiology, visual science, and medical and public health import of the macular
carotenoids.
What purposes are served by a reference on carotenoids and retinal disease?
Pioneering studies beginning in the 1980s showed macular pigment is entirely com-
posed of lutein, zeaxanthin, and the isomer meso-zeaxanthin. The broader health
significance of these “retinal carotenoids” became evident from seminal observa-
tions of a reproducible, inverse relationship between macular pigment density and
advance of age-related macular degeneration (AMD), the most common cause of
acquired blindness for much of the world. Moreover, macular pigment is essential to
maintain visual performance including dark adaptation, contrast, and recovery from
photostress, obvious advantages during human evolution. Unlike provitamin A carot-
enoids (α-carotene, β-carotene, α-cryptoxanthin, and β-cryptoxanthin), the macular
pigments possess distinctive vitamin A–independent visual functions. Lutein and
zeaxanthin are transported across the retinal pigment epithelium to accumulate in
neuroretina cells including photoreceptor outer segments. In the neuroretina, they
assume a cooperative functionality with colocalized omega-3 long-chain polyunsat-
urated fatty acids. Photoreceptors, the body’s most rapidly replenishing cell type, are
exposed to harsh conditions of oxidative and actinic stress. This book advances our
understanding about how macular carotenoids prevent otherwise inevitable damage
and vision loss. This centrality for eye health, as well as the deleterious effects of a
deficiency state, supports the standing of macular carotenoids as vitamins. To date,
this health link is unique among carotenoids.
Initial epidemiological and case cohort studies of macular carotenoid intakes and
protection from retinal disease prevalence/severity have led to dietary ­supplementation
trials. Additionally, dietary modification is increasingly promoted and ­supplementation
is becoming common in several countries. These dietary supplements may have sig-
nificant public health benefits.
This book spans the breadth of numerous disciplines from the lab bench to
­population-based investigation. Black-and-white and color figures and p­ hotographs
enliven the text and enforce concepts of retina topography, visual processing, genetic
and cell signal pathways, disease etiopathogenesis, and epidemiology. Chapter 1
traces eighteenth-century observations of a yellowish region (the macula lutea)
through increasingly refined retinal characterization in the nineteenth and t­ wentieth
­centuries to the functional attribution of the macular carotenoids d­ uring recent
decades. This chapter also introduces essentials of comparative macular anatomy.

xi
© 2010 Taylor & Francis Group, LLC
xii Foreword

Chapter 5 elegantly presents the importance of macular pigment from the p­ erspective
of vision science. The complex visual interactions of regional (macular) distribu-
tion of lutein and zeaxanthin, photoreceptor density, and light exposure in AMD are
­discussed in Chapter 12.
Understanding the highly selective ocular accumulation of lutein and ­zeaxanthin—
from among the dozens of dietary carotenoids—requires insights derived from
chemistry (Chapters 1, 7, 8, 11, and 12), visual science (Chapters 1, 8, and 9), and
bioavailability studies (Chapter 7). Their transport and metabolism are intertwined
with lipid biology and they appear to be trapped in selective sites by the recently
discovered lutein- and xanthophyll-binding proteins (Chapter 9). Chapter 11 explains
the high membrane solubility of these dipolar, terminally dihydroxylated molecules,
and the distinctive perpendicular orientation in retinal membrane bilayers that maxi-
mizes light quenching and free radical scavenging activities. Technical advances in
xanthophyll processing and insights derived from xanthophyll-free animal models
are reviewed in Chapter 7. Chapter 10 explains contemporary separation and iso-
lation methods for lutein, zeaxanthin, and meso-zeaxanthin by high-performance
liquid chromatography.
Key sections of this volume provide a comprehensive treatment of the nutritional,
lifestyle, and genetic risks for AMD. Chapters 2 and 3 trace AMD risk factors,
­epidemiology, pathogenesis, and classifications. Chapter 4 recounts recent longitu-
dinal studies and clinical trials that revealed the relationship between dietary lutein
and zeaxanthin in advanced AMD. Treatment of at-risk and affected individuals
is potentially crucial to avoid visual loss (Chapters 4 and 5). Whether xanthophyll
supplementation decreases risk of vision loss in AMD remains uncertain. However,
clinical trials show supplements can improve visual performance and macular pig-
ment optical density. Results from a large multicenter controlled, randomized trial,
the Age-Related Eye Disease Study 2, may answer more fully unresolved questions.
Major AMD risk factors are poor nutrition, smoking, lifestyle, and genetics.
Hypothesis-driven gene studies and genome-wide association studies are advanc-
ing this field rapidly. Chapter 6 recounts the current status of genetics of macu-
lar pigment and AMD and numerous chapters reference genetic information. Gene
­polymorphisms and deleterious gene mutations have been discovered in many steps
in macular xanthophyll absorption, transport, retinal uptake, accumulation, and asso-
ciation with processes implicated in AMD pathogenesis. Chapter 6 also describes
genetic and bioinformatics strategies essential to this research. Data emerging from
large-scale genotyping projects undoubtedly will enhance approaches to macular
carotenoids in retinal disease.
New advances in the relevant science and health context assuredly will become
more prominent in coming years. Intriguing evidence suggests lutein and zeaxanthin
play a wider role in suppressing severity of other common neovascular retinopathies,
namely, diabetic retinopathy and retinopathy of prematurity. The macular pigments
may have a role, currently anecdotal, as adjunct therapies in several heritable retinal
diseases. Finally, the neuroretina is an extension of the brain and investigations show
lutein and zeaxanthin also accumulate in certain brain regions. Preliminary studies
show cognitive improvements after xanthophyll supplementation, plausibly through
some similar mechanisms.

© 2010 Taylor & Francis Group, LLC

Foreword xiii

In summary, this book is a valuable reference for all those who are investigators
or treat people at risk of vision loss. Investigators will recognize areas in which
research and application are most needed. Clinicians from several disciplines will
be instructed and stimulated to further interdisciplinary collaborations on prevention
and treatment of retinal disease.

Lewis P. Rubin
Texas Tech University Health Sciences Center at El Paso

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© 2010 Taylor & Francis Group, LLC