NUTRITIONAL THERAPIES in Preventing Macular Degeneration

REVIEW
COVER FOCUS
The Role of
NUTRITIONAL
THERAPIES
Four prominent experts
discuss the science,
the challenges and
the promise of using
nutritional intervention
against AMD.
in Preventing Macular
Degeneration
ALTHOUGH THE UNDERLYING PHYSIOLOGICAL MECHANISMS OF AMD are not completely understood, available
evidence suggests there may be considerable scope for preventing and treating this syndrome with rationally designed
nutraceuticals. AREDS 1 has established that supplemental zinc, and the combination of vitamin E, vitamin C and beta
carotene, have some modest utility, most notably in later-stage disease. But there is good reason to suspect—as is being
assessed in AREDS 2—that long-chain omega-3s and xanthophyll carotenoids may be at least as useful in this regard,
and quite likely beneficial for primary prevention. Additionally, evidence of varying degrees of cogency suggests that a
wide range of additional agents—including phase-2 inducers, melatonin, N-acetylcysteine, spirulina, coenzyme Q10
and soy isoflavones—may merit consideration for AMD prevention and control.
This article focuses on better understanding the potential role of nutrition in AMD prevention and management.
In the first section, Pedro F. Lopez, MD, reviews the underlying science behind the development and progression of
AMD. This is followed by an interview with several prominent nutrition experts intended to guide us through the maze
of scientific evidence that validates the use of nutritional regimens for controlling AMD. The interview centers on those
supplements currently evidenced to slow progression and effect possible prevention of macular degeneration, and
on measuring and monitoring the presumed effects of supplementation on the eye, enabling integration of a medical
model of nutritional therapy into clinical practice.
The Underlying Science Behind the
Development and Progression of AMD
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Pedro F. Lopez, MD
TO UNDERSTAND WHY NUTRACEUticals may be beneficial for the prevention
and control of AMD, we need to understand the pathophysiology behind AMD.
Drusen Formation
Typically, AMD has a preclinical,
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asymptomatic phase, in which extracellular waste material accumulates in the
space between the basement membrane
(Bruch’s membrane) and the pigmented
epithelial layer (comprised of retinal pigmented epithelial cells) that overlies it.
The result is a formation of yellow-white
spots we all know as drusen.
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Loss of RPE Tight Junctions
RPE cells are remarkably versatile
in their contribution to healthful retinal function, and it is generally believed
that dysfunction or death of these cells is
crucial to AMD pathogenesis. The retinal pigmented epithelium serves as the
blood-retinal barrier and regulates the
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transport of oxygen, substrates and
waste products between the choroidal vasculature and the retina. So,
loss of RPE tight junctions—which
evidently compromises this barrier
function—is a hallmark of AMD.
Decreased Phagocytosis of
Photoreceptor Outer Segments
RPE cells also generate growth
factors that aid the survival of retinal photoreceptors and other cellular constituents of the inner retina,
while suppressing pathological choroidal neovascularization.
The most curious function of
RPE cells is to phagocytize photoreceptor outer segments (POS).
While doing this, they isomerize
all-trans retinyl esters derived from
POS back to 11-cis-retinal, which is
then returned to the photoreceptors
for use in rhodopsin synthesis. This
is a crucial function, as photoreceptors are incapable of performing
this isomerization themselves. The
phagocytic function of RPE cells
entails continual lysosomal activity.
When this activity is sub-optimally efficient, as it appears to be
in AMD, lipofuscin deposits accumulate in these cells. Lipofuscin
has photosensitizing activity, and
components of lipofuscin—notably
A2-E, a retinoid metabolite—can
impair lysosomal function, in part
by blocking the proton pump that
acidifies lysosomes. (This raises the
specter of a vicious cycle in which
lipofuscin accumulation encourages
further accumulation of lipofuscin.)
Drusen that characterizes AMD is
derived largely from inadequately
degraded POS components as well
as lysosomal proteins—suggesting
that stressed RPE cells are disgorging half-digested lysosomal contents into the sub-epithelial space.
Hence, drusen formation begets
further drusen formation, the pro-
AMD & NUTRITION
Pedro Francisco Lopez, MD, is a professor and founding chair of the
department of ophthalmology for the Herbert Wertheim College of
Medicine at Florida International University and the director for retina
and vitreous diseases at the Center for Excellence in Eye Care in Miami.
An author of an extensive list of articles and book chapters on macula,
vitreous and retinal diseases, Dr. Lopez serves as a scientific referee
for various ophthalmology journals. He is both board-certified and an
examiner for the American Board of Ophthalmology. He is an active
member of the American Academy of Ophthalmology, Association for Research in
Vision and Ophthalmology, Society of Heed Fellows, Vitreous and Retina Societies
and the American Medical Association. Dr. Lopez has held teaching and administrative
positions at Harvard University, Johns Hopkins University, University of Miami, Emory
University, University of Southern California and Harvard Medical School.
Sheldon Saul Hendler, MD, PhD, FACP, FACN, FAIC, is one of the world’s
most respected authorities in biochemistry, clinical nutrition and the
role that vitamins, minerals and other nutrients play in health,
wellness, disease and aging. He is the principal author and editor of
the PDR for Nutritional Supplements, considered “the standard
reference in the field” (The New York Times). Additionally he has
written a number of books and articles on functional foods and
dietary supplements, including the award-winning The Doctors’
Vitamin and Mineral Encyclopedia and The Complete Guide to Anti-Aging Nutrients,
the book that popularized the term anti-aging. Dr. Hendler has published papers in
leading journals, including The New England Journal of Medicine, Nature and The
Proceedings of the National Academy of Sciences. He is also co-editor-in-chief of the
Journal of Medicinal Food, and is a frequent contributor to The New York Times’
Science News section.
Dr. Hendler is a voluntary clinical professor of medicine at the University of
California, San Diego, and is a practicing internist. He serves on the Scientific
Advisory Board of the Dietary Supplement Education Alliance and is a fellow of the
American College of Nutrition, the American College of Physicians and the American
Institute of Chemists.
Richard A. Bone, BSc, PhD, FARVO, is a distinguished experimental
biophysicist and professor in the department of physics at Florida
International University. With other researchers, he identified the
biologic mechanisms responsible for the protective role of lutein,
zeaxanthin and meso-zeaxanthin in the eye and devised a way to
measure the protective pigments in the macula of the eye.
Mark F. McCarty is a nutritionist and researcher who has published more than
200 articles on a wide range of biomedical topics in the peer-reviewed
medical literature. He has been awarded seven U.S. patents for a
variety of applied nutritional measures and played a key role in the
development and clinical testing of organic supplemental
selenium (high-selenium yeast, L-selenomethionine) as well as
chromium picolinate.
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gression of which culminates in
an atrophic macula.
Oxidative Stress
Although the pathogenesis
of AMD remains murky, there
is a growing consensus that
oxidative stress plays a key role
in driving this syndrome.1-3
Chemical markers of oxidative stress have consistently
been found to be elevated in
the maculas of patients with
AMD.4 In cell culture studies,
exposure of RPE cells to oxidative stress has been shown
to impair the function and survival of these cells—inducing a
loss of tight junctions, impairing production of pigmented
epithelium-derived factor
(PEDF, which is a growth factor that provides trophic support for photoreceptors while
inhibiting choroidal neovascularization) and of complement
factor H (impaired function
of which has been linked to increased
AMD risk5,6), and promoting apoptosis.
All of these effects are consistent with
the pathology of AMD.7-10
Moreover, oxidative stress can also
induce apoptosis in photoreceptors, an
effect which seems likely to contribute
to the photoreceptor loss characteristic
of dry AMD.11 Of course, the most wellcharacterized risk factor for AMD is
cigarette smoking, which is well known
to promote oxidative stress in tissues.12-15
Exposure to oxidative stress in the
macula is high for a number of reasons.
The rate of oxygen uptake by the retina
is higher than in any other of the body’s
tissues. High mitochondrial respiration
implies high potential for mitochondrial superoxide generation. RPE cells
are phagocytic, and like other phagocytes, possess NAPDH oxidase that
generates superoxide during phagocytosis.16-18 Most obviously, the macula
is exposed to blue light that generates
singlet oxygen and other reactive oxygen species when it interacts with photosensitizing chemicals. The lipofuscin
that accumulates in stressed RPE cells
is rich in such photosensitizers, some of
which, such as A2-E, are derived from
all-trans-retinal.19-21
A further line of evidence implicating oxidative stress in AMD is the fact
that transgenic mice lacking superoxide
dismutase activity have been shown to
develop a syndrome very analogous to
AMD as they age. Drusen, thickened
Bruch’s membrane and choroidal neovascularization are all observed, and the
junctions linking retinal pigment endothelium are disrupted—features characteristic of human AMD.22 Increased
light exposure accelerates accumulation
of drusen in these mice, presumably
because light promotes retinal oxidative
stress.
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AMD & NUTRITION
In summary, degeneration of the RPE cells is considered the most important
hallmark of AMD. This is
clinically characterized by
pigment mottling, accumulation of intercellular lysosomal lipofuscin and extracellular drusen, loss of tight
junctions, and apoptotic cell
death. Chronic oxidative
stress and inflammation are
strongly linked to RPE senescence and the pathogenesis of
AMD. Subjects with a family history of AMD, smokers,
and people who are obese
or sedentary are at increased
risk for this syndrome. People
who are genetically prone to
increased activation of the
alternative complement pathway—such as those carrying
certain alleles of the gene
for complement factor H—
are at greatly increased risk,
perhaps reflecting a role for
complement in drusen formation.23,24
Contributing factors for AMD include
light-induced toxic effects, especially
from blue light and ultraviolet light and
the exogenous chromophores—amiodarone, chloroquine, phenothiazines, lithium and herbs such as St. John’s wort.
These exogenous chromophores can
increase susceptibility to light-induced
toxic effects.
However, subjects who have a favorable risk profile may also develop
AMD. Clearly, the most important risk
factor for AMD is simply getting older.
(Domestically, the vast numbers of
baby boomers are approaching the age
most affected by AMD.) However, the
advancement in understanding nutrients and the possible role they play
in protecting the macula in the past
two decades gives hope to the millions
of individuals worldwide afflicted with
this irreversible, disabling condition.
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AMD & NUTRITION
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Implementing, Measuring, and
Monitoring Nutritional Intervention
An interview with Sheldon Saul
Hendler, MD, PhD, Mark F. McCarty
and Richard A. Bone, PhD
Dr. Lopez: Personally, I derive a
great deal of professional satisfaction
from drawing on the array of medicinal and surgical treatments to help
patients with advancing wet AMD.
However, it is frustrating to me, as I
am sure it is for my fellow retinologists and every general ophthalmologist, not to have clinical solutions
for either preventing or halting the
progression of AMD. It appears that
part of the solution to this dilemma
may reside in the field of nutrition.
Review of Ophthalmology offers a
perfect venue for an on-going dialogue between researchers in the
field of nutrition and the practicing
ophthalmologist. Hence, I asked the
following panel of nutrition experts
to begin this dialogue by summarizing the science behind a nutraceuticals approach to managing AMD.
Future issues will offer further dialogue on this important, burgeoning
field.
Let’s start with what you consider
to be the strongest evidence of an
association between diet and AMD.
Dr. Hendler: The best-established
association between diet and AMD risk
is the finding that those who consume
diets high in EPA/DHA or in oily fish
(the richest food source of these fatty
acids) are at decreased risk for both geographic atrophy (dry) and neovascular
(wet) AMD.25-29 In the AREDS cohort,
after adjustment for appropriate covariants, those in the upper quintile of EPA/
DHA intake (averaging 0.11 percent of
total dietary energy) had an odds ratio
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of 0.65 and 0.68 for progression to geographic atrophy or neovascular AMD,
respectively, over 12 years of followup.28 Note that, in an individual consuming 2,400 kcals daily, this intake of
long-chain omega-3 amounts to about
300 mg daily, suggesting that the protective impact of these fatty acids is
quite powerful and achievable with
modest intakes. In the cross-sectional
EUREYE study, those who consumed
oily fish at least once per week, as contrasted to those who ate oily fish less
frequently, were at only half the risk for
neovascular AMD.29 In a recent study
involving a murine model for AMD
(Ccl2-/-, Cx3cr1-/-),30 a diet enriched
in EPA/DHA was associated with a
slower progression of retinal lesions
and even a degree of lesion reversion.
Additionally, markers of retinal inflammation were substantially reduced in
the omega-3-fed mice.31
Although no completed clinical studies
formed better than placebo with respect
to fundus alterations, with the treated
group achieving a statistically significant
reduction in the drusen-covered area.
Although the authors of this study
attributed the improvements in the treated group to an allegedly favorable impact
of the supplement on retinal mitochondrial function (they refer to the supplement as “mitotropic”), the doses of coenzyme Q10 and acetyl-L-carnitine were
so low relative to dose ranges generally
thought to be clinically relevant, that it
is reasonable to conclude that the chief
benefits of the supplementation were
conferred by the omega-3 component
(well within the dose range associated
with marked protection in epidemiological studies). If this analysis is correct, it
bodes well for the ultimate results of the
ongoing AREDS 2 study, and moreover
suggests that good omega-3 nutrition is
likely to have a favorable impact on early
AMD.
The chemical composition of the macular pigment is a
mixture of lutein and zeaxanthin and meso-zeaxanthin,
which is found in very few food sources and is present in
the macula as a conversion product of lutein.
have yet evaluated the impact of omega3 supplementation alone in AMD, an
intriguing double-blind study examined
a regimen providing daily intakes of 100
mg acetyl-L-carnitine, 530 mg of longchain omega-3s, and 10 mg of coenzyme
Q10 in patients with early AMD over 12
months.32 In the three measures of visual
function employed—visual field mean
defect, visual acuity, and foveal sensitivity—changes in the treated group were
significantly better than those in the placebo group, and on average reflected net
improvement. Active treatment also perO F
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Dr. Bone: In the early ‘80s, I teamed
with Dr. John Landrum at Florida
International University to identify the
chemical composition of the macular pigment. It turned out to be a mixture of the
oxygenated carotenoids (xanthophylls)
lutein and zeaxanthin, and in a later
study we found out that the zeaxanthin
was present as two stereoisomers. One
was the common stereoisomer found
in many plants and referred to as zeaxanthin; the other was meso-zeaxanthin,
which is found in very few food sources
and is present in the macula as a conver-
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AMD & NUTRITION
sion product of lutein.
The zeaxanthin-rich berry, Lycium
barbarum or “Gou Qi Zi,” has been a
constituent of traditional Chinese herbal
medicine for the treatment of visual disorders. However, probably the first real
evidence for a protective effect of lutein
and zeaxanthin against AMD appeared
in the early ’90s in publications of the Eye
Disease Case-Control Study Group. The
group reported significant associations
between either high dietary intakes or
high blood serum levels of these carotenoids and a reduced risk of advanced
neovascular AMD.
More recently, the Age-Related Eye
Disease Study reported that subjects with
a high dietary intake of lutein and zeaxanthin had a significantly lower risk of
developing both the wet and dry forms
of AMD. The current AREDS 2 will
specifically examine the efficacy of lutein
with regard to AMD. Anecdotally, there
have been a number of reports recently
of regression of drusen accompanied by
improvement in visual function in AMD
patients taking a supplement containing
all three macular carotenoids, but mostly
meso-zeaxanthin.
Dr. Lopez: How do nutrients specifically alter the pathophysiologic
processes underlying macular degeneration?
Dr. Hendler: The brain is rich in
long-chain omega-3 fatty acids—most
notably docosahexaenoic acid—and the
retina has the highest omega-3 content
in the body. DHA can constitute up to 50
percent of the fatty acids in rod photoreceptor outer segments.59 This evidently
bespeaks a vital structural or functional
role for DHA in retinal neurons, and
indeed, the DHA-rich phospholipids in
outer segment membranes appear to
be crucial for efficient function of the
rhodopsin that resides in those membranes.66 Moreover, in vitro, rat photoreceptor neurons undergo apoptosis if
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deprived of DHA.67,68 With respect to
DHA’s biosynthetic precursor, eicosapentaenoic acid (EPA), while it is a lessprominent structural component of the
retina, it has important anti-inflammatory
potential owing to its ability to competitively inhibit production of arachidonatederived pro-inflammatory prostanoids,
and to give rise to other mediators
(resolvins, lipoxins), which play a role
in the resolution of inflammation.69-72
Furthermore, EPA has anti-angiogenic
potential reflecting decreased endothelial expression of Flk-1, a key receptor
for vascular endothelial growth factor;73
DHA likewise can suppress endothelial
VEGF signaling.74 Long-chain omega3s are highly susceptible to oxidative
damage; one of the key roles of retinal
xanthophyll carotenoids, present in high
concentrations in photoreceptor outer
segments, may be to preserve the native
structure of DHA in these photoreceptors.60
In foods and in supplements, lutein
and zeaxanthin are found mainly in their
ester forms, which undergo intestinal
hydrolysis to their free forms before
being absorbed and ultimately incorporated into the macula. Xanthophyll
uptake by RPE cells—which constitute
the blood-retinal barrier, and hence regulate the availability of xanthophylls to
photoreceptors—is mediated by scavenger receptor class B type I, which has
relatively low affinity for beta-carotene.33
The characteristically high concentration of xanthophylls in the macula may
also reflect the presence of a xanthophyllbinding protein (XBP). This protein protects xanthophylls from degradation by
reactive oxygen species, and, in particular, the XBP-xanthophyll complex may
have better antioxidant activity than the
free xanthophyll.34-36 A retinal protein
that specifically binds lutein has also been
recently characterized.37
Dr. Bone: We understand the processes by which the carotenoids can exert
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their protective influences against AMD.
Firstly, they are potent antioxidants and
secondly, they screen vulnerable tissues
from actinic blue light that can promote
photo-oxidation. The accumulation of
oxidation products as drusen in the retina
is an indicator of early age-related maculopathy. Thus a group of experts recently
concluded in a Vision Research article
that xanthophyll levels in the eye “potentially serve as a biomarker not only for
predicting the risk for eye disease but also
for visual function.” Another group, writing in the Journal of Food Science, concluded: “It seems clear that MP [macular
pigment] does influence visual performance through, at least, a few optical
mechanisms. The most robust effects
appear to be related to its actions as an
optical filter.”
I would like to add, with important
emphasis, the macula is not the only eye
tissue where lutein and zeaxanthin are
sequestered. They have also been detected in the human lens, and their occurrence in this tissue may be related to the
observation in large epidemiological studies of a lower incidence of cataract among
both men and women having a relatively
high dietary intake of these carotenoids.
Mr. McCarty: Lutein and zeaxanthin
are natural fat-soluble yellowish pigments
found in some plants, most notably green
leafy vegetables (spinach, collard greens,
etc.), algae and photosynthetic bacteria.
Humans are unable to synthesize these
substances and must obtain them from
their diets; hence, they are essential nutrients. In the organisms that make them,
they serve as accessory light-gathering
pigments and provide protection from
the harmful impact of ultraviolet radiation and the reactive oxygen species that
it gives rise to. The light energy that they
collect is used to drive photosynthesis;
in this respect their function is similar to
that of chlorophyll. In humans, these pigments are found in extraordinarily high
concentrations in the macula. They are
also found in the crystalline lens.
Their physiological location, as well
as their ability to absorb blue light and
quench dangerous singlet oxygen, suggest that they function to protect the
macula and the lens from light-induced
oxidative stress.38-39 Indeed, it is now
strongly suspected that carotenoids play
an important role in providing protection
against not only AMD, but possibly cataracts as well—a conclusion that is concordant with reports that macular pigment
density tends to be lower in patients with
AMD.40-44 Macular pigment also functions to reduce the impact of light scatter
and chromatic aberration on visual performance.45,46
Photoreceptors are exceptionally susceptible to oxidative damage, as their
membranes are extremely rich in the
long-chain omega-3 polyunsaturate docosahexaenoic acid. DHA can constitute
up to half of the fatty acids in photoreceptor outer segments.47 This presumably explains why POS membranes are
also unusually rich in xanthophyll carotenoids capable of quenching the singlet
oxygen that otherwise might peroxidize
DHA.11,48 These xanthophylls also are
found in photoreceptor axons, where
their presumed key function is to absorb
blue light before it can penetrate to
deeper levels of the macula and generate
oxidants. The fact that the xanthophyll
content of the macula is subnormal in
patients with AMD might in some measure be a consequence of the disease, but
it is also reasonable to suspect that this
deficit contributes to disease progression
by lessening the macula’s antioxidant protection.42-44
Dr. Hendler: It should be noted that,
unlike beta-carotene, the xanthophyll
carotenoids lack pro-vitamin A activity. In
other words, they cannot give rise to the
11-cis-retinal required for rhodopsin synthesis. Dietary carotene or pre-formed
retinol is required for this purpose. In
light of epidemiological evidence that
dietary pre-formed retinol has the potential to compromise bone density, modest
intakes of dietary beta-carotene, from
foods or supplements, may be the most
prudent way to meet the retina’s requirement for retinol.49 However, there is no
evidence that beta-carotene contributes
notably to antioxidant protection of the
retina. I predict that this observation will
likely be confirmed in the AREDS 2
Trials.
Dr. Lopez: You have all concentrated on xanthophylls (lutein, zeaxanthin and meso-zeaxanthin) and
long-chain fatty acids, namely omega-3 or DHA. Do other nutrients,
perhaps not well-publicized, show
potential for slowing AMD ?
Dr. Hendler: Another intriguing natural xanthophyll is astaxanthin, produced
by certain types of algae; this is what
makes flamingoes pink!50,51 Astaxanthin
has more versatile antioxidant activity
than any of the other xanthophylls, but
it is not a significant component of most
human diets, and its impact on macular
pigment or retinal function remains to
assessed.
A very wide range of dietary phytochemicals can act directly as oxidant scavengers. But far more potent antioxidant
protection can be achieved with phytochemicals, which also can stimulate a
so-called “phase-2” response.52,53 Phase2-inducing phytochemicals are prominent components of common foods such
as green tea, allium vegetables (garlic,
onions) and cruciferous vegetables (broccoli, cabbage, cauliflower, kale, etc.) They
are also found in many commonly used
herbal preparations, including some that
have traditionally been used for ocular
protection (e.g., extracts of bilberry, grape
seed and green tea).
The phase 2-inducing components
of some of these foods or herbs have
shown protective antioxidant activity in
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tion of green tea polyphenols to albino
rats prevents light-induced damage to
photoreceptors.54-57 (In light of the heavy
consumption of green tea in East Asia,
it is striking that so far no published epidemiological studies have attempted to
correlate habitual green tea intake with
AMD risk or prognosis.) However, the
dose-dependency of the clinical phase2-inducing effect achieved by ingestion
of these foods or herbs requires further
clarification, and the concentration of the
active inductive components is likely to
vary as a function of cultivar and method
of preparation.
Mr. McCarty: Alpha-lipoic acid,
an endogenously synthesized cofactor
for several alpha-keto decarboxylase
enzymes, has excellent antioxidant activity in many rodent studies.58 Although its
direct oxidant scavenging activity is versatile, it also has been shown to be a phase2 inducer.59-61 Lipoic acid may have good
potential for use in AMD, as in rodent
studies it has shown central neuroprotective effects, suggesting it has good access
to the brain parenchyma (and likely the
retina as well).62,63 Moreover, in an oral
dose of 600 mg one to three times daily,
lipoic acid has been shown to be therapeutically useful in diabetic neuropathy;
hence, clinical doses within this range
may have potential for protecting the
retina.64
Whether the lower physiological levels
achievable through supplementation can
likewise provide protection to the retina
in vivo, is not yet clear, but the utility of
oral lipoic acid in the management of diabetic neuropathy suggests that this may
be a reasonable possibility. To date, there
do not appear to be any published clinical
studies in which the impact of lipoic acid
on AMD progression has been assessed.
Dr. Hendler: The small tryptophanderived hormone melatonin is synthesized primarily within the pineal gland,
though it is produced in more minor
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quantities by other tissues, including the retina. The nocturnal burst of
melatonin secretion, regulated in part
by retinal light exposure, plays a role in
promoting appropriate circadian physiological rhythms.65 However, acting via
membrane as well as nuclear receptors,
melatonin also exerts potent antioxidant
effects on many tissues, via up-regulated expression of several key antioxidant
enzymes (superoxide dismutase, glutathione peroxidase, glutathione reductase,
catalase) as well as of gamma-glutamylcysteine synthetase.66
In a recent study patients at various
stages of AMD were treated with 3-mg
melatonin nightly for six to 24 months.67
Fifty-five patients received melatonin for
at least six months. The authors noted
that visual acuity remained stable in the
large majority of patients; they also noted
that “change in the fundus picture is also
promising … Only eight eyes showed
an increase in retinal blood and six eyes
showed an increase in retinal exudates.
The majority had a reduction compared
to pathologic changes before treatment
in these patients, although atrophy was
slightly increased.” The authors conclude
that, relative to the clinical course that
could be expected based on literature
reports, the response of their patients
was favorable, and that melatonin merits
more formal study in the prevention and
management of AMD.
A more recent study has attempted
to assess nocturnal melatonin production in AMD patients by measuring the
levels of the chief melatonin metabolite
6-sulfatoxymelatonin in morning urine
(expressed as its ratio to creatinine).68
This ratio was found to be about 40 percent lower in AMD patients than in ageand gender-matched controls. Whether
this striking disparity is a cause or an
effect of AMD (bearing in mind that
light reception regulates pineal melatonin
release) is open to question, although the
authors note that, among their patients
with AMD, sulfatoxymelatonin levels
were no lower in those with poor visual
acuity than in those with better acuity. In
any case, even if the pathologic process
in AMD does somehow decrease pineal
melatonin production, it could be argued
that, owing to melatonin’s key physiological/antioxidant roles, this decline should
be compensated by supplementation.
Moreover, pineal melatonin production
declines during healthy aging,69 and it is
conceivable that this phenomenon contributes to the higher risk for AMD in the
elderly.
Mr. McCarty: Whereas gammaglutamylcysteine synthetase is the ratelimiting enzyme for glutathione synthesis,
intracellular cysteine is the rate-limiting
substrate for this process. The antioxidant effects of N-acetylcysteine (NAC)
supplementation have been traced to
its ability to boost intracellular levels of
free cysteine, and thereby boost cellular glutathione production.70-72 These
considerations suggest that concurrent supplementation with NAC might
amplify the ability of phase-2 inducers
or of melatonin to increase glutathione
in RPE cells or retinal photoreceptors.
In divided doses providing 600 to 1,800
mg daily, NAC is typically well-tolerated
and has shown clinical potential as an
antioxidant.71,72 Although there do not
appear to be any published clinical studies that have evaluated NAC in AMD,
the exposure of RPE cells to NAC in
vitro has been reported to protect them
from apoptosis when they are subjected
to hypoxia or toxic carotenoid-derived
aldehydes.73,74 Moreover, NAC was
found to have a favorable impact on the
efficiency of lysosomal function in RPE
cells pre-loaded with oxidized photoreceptor outer segments, such that accumulation of lipofuscin was decreased.75
In rats subjected to intraocular hypertension, systemic administration of NAC
prevented the induced increase in retinal
oxidative stress.76 These considerations
suggest that NAC may have important
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potential for lessening the contribution
of oxidative stress to the pathogenesis of
AMD. It is reasonable to expect that this
potential will be best actualized if induction of gamma-glutamylcysteine synthetase is achieved concurrently.
Dr. Hendler: Coenzyme Q10 functions as an obligate mediator of electron
transport in mitochondrial respiration.
In the mitochondrial inner membrane,
it can function as either an antioxidant or
a pro-oxidant, depending on the circumstances. A recent study concludes that
coenzyme Q10 content of the human
retina and choroid declines by about 40
percent during the aging process; the
authors suggest that this may compromise the bioenergetics and antioxidant
protection of the aging retina, possibly contributing to the risk for AMD.77
Moreover, plasma levels of coenzyme
Q10 were found to be lower in patients
with wet AMD than in age-matched controls.78 Several studies demonstrate that
pre-administration of coenzyme Q10 to
rats protects the retina from excitotoxicity
induced by transient ischemia or NMDA
administration and also can protect retinal ganglion cells from hydrogen peroxide in vitro.77,79,80 These considerations
suggest that coenzyme Q supplementation may provide worthwhile antioxidant
protection for the retina, and merits evaluation for control of AMD.
Unfortunately, the only published
clinical study to assess a regimen containing coenzyme Q10 in patients with
AMD provided such a low dose (10 mg
daily) that it seems most unlikely that
the favorable results achieved in this
study reflected the impact of this agent.32
Effective oral coenzyme Q10 therapy is
now more feasible than previously, owing
to the development of micellized forms
of ubiquinol, which have increased oral
bioavailability.81-83
Mr. McCarty: There is some reason
to suspect that NADPH [nicotinamide
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adenine dinucleotide phosphate] oxidase
may be a key source of oxidant stress
in RPE cells. RPE cells act as phagocytes, engulfing outer segments of retinal rod photoreceptors. Like other
phagocytes, RPE possess NADPH
activity that increases during phagocytosis.16,17 More recent work establishes that
RPE expresses p22phox, a key membrane component of NADPH oxidase
complexes.18 Intriguingly, viral delivery
of small interfering RNA for p22phox
to the subretinal space prevents choroidal neovascularization in a mouse model
of AMD (involving laser disruption of
Bruch’s membrane).84 The authors conclude that “NADPH oxidase-mediated
ROS production in RPE cells may play
an important role in the genesis of neovascular AMD, and this pathway may
represent a new target for therapeutic
intervention in AMD.”
Additionally, NAPDH oxidase activity is expressed by retinal neurons. This
activity increases when growth factor support is withdrawn (as might be
expected if death or dysfunction of retinal pigment epithelium impairs its trophic function), and there is suggestive
evidence that NADPH oxidase activation
may drive the apoptotic death of cone
cells in retinitis pigmentosa.85,86
These findings are of particular interest in light of the recent discoveries that
intracellular free bilirubin functions as an
inhibitor of NAPDH oxidase87-89 (thereby
rationalizing the antioxidant activity of
heme oxygenase), and that phycocyanobilin (PhyCB), a bilirubin homolog
that functions as a chromophore in spirulina and other microalgae, can mimic this
activity.90
Since orally administered spirulina or
phycocyanin—the spirulina protein that
contains PhyCB as a chromophore—
exerts neuroprotective effects in rodent
studies, there is reason to suspect that
spirulina or PhyCB-enriched spirulina
extracts may have the potential to confer
antioxidant protection to the retina.91,92 So
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Dr. Bone: At about the time Dr.
Landrum and I discovered meso-zeaxanthin, interest in the macular pigment was
growing because of emerging evidence
of its potentially beneficial influence on
eye health. Dr. Landrum and I obtained
NIH funding to compare macular pigment levels in autopsy eyes from donors
with and without AMD, and we found,
on average, lower levels in the diseased
eyes. We also conducted the first suppleDr. Lopez: Fascinating. But, get- mentation study with lutein and were
ting back to current possible effec- able to demonstrate up to 40-percent
tive therapeutic regimens, can mac- increases in macular pigment density in
ular protective pigment density be our subjects over a 120-day supplementation period. The 30-mg daily lutein
increased by dietary supplements?
dose in this case was suspended in a few
milliliters of vegDr. Hendler:
etable oil, which is
In 1 9 9 4 , D r . Although little mesoprobably the reaJohanna Seddon zeaxanthin is found in
son for its dramatic
and co-workers at
effect.
Harvard published natural diets,
As might be
a case-control supplementation studies
expected, serum
study that linked
levels of lutein and
a high intake of show that orally
zeaxanthin have
xanthophyll-rich administered mesobeen found genfood, particularly
zeaxanthin is well
erally to be posidark green leafy
tively correlated
vegetables such as absorbed and can
spinach, with notaimprove macular pigment with high levels of
macular pigment,
bly reduced risk
94
density.
so our study with
for AMD. This
finding accorded
the autopsy eyes is
well with the recent discovery that xan- consistent with the large epidemiological
thophylls constitute the macular pig- studies.
ment, and triggered tremendous interest in the potential of supplemental
Dr. Hendler: I might add that,
or dietary xanthophylls to protect the although little meso-zeaxanthin is found
retina.
in natural diets (it is found in seafood,
A number of studies have demon- but not in vegetables) or in plasma, supstrated that the amount of the macular plementation studies show that orally
pigment can be increased by dietary administered meso-zeaxanthin is wellsupplementation with lutein or zea- absorbed and can improve macular pigxanthin or by ingestion of xanthophyll- ment density.97,100
rich foods.95-99 Lutein and zeaxanthin,
as well as their esters, are efficiently
Dr. Bone: Correct. Dr. Landrum
absorbed—more avidly so than beta- and I have conducted many such supplecarotene—and ultimately wind up in mentation studies, with lutein, zeaxanthe macula; their trans isomers are thin as well as meso-zeaxanthin, and the
most available.
results have been similar. Furthermore,
far, however, no studies have examined
the impact of spirulina or phycocyanin on
retinal function or pathology. It would be
of particular interest to determine whether individuals with Gilbert’s syndrome,93
an innocuous genetic variant associated
with chronically elevated plasma levels of
free bilirubin and reduced risk for cardiovascular disease, are at decreased risk for
AMD.
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AMD & NUTRITION
as a biophysicist, I have also been very
interested in developing techniques for
non-invasively measuring macular pigment optical density in the retina so that
the effects of supplementation can be
readily measured. These techniques are
being designed for cost-effective usage
in the clinical setting.
In our studies we have always found a
very strong association between macular
pigment optical density and the subject’s diet. Those whose diet includes
frequent consumption of green, leafy
vegetables tend to have average to high
MPOD, whereas the vegetable avoiders
tend to be on the low side.
Dr. Lopez: Is evaluation of macular pigment levels important prior to
and during dietary supplementation
with carotenoids?
Dr. Hendler: In a number of subsequent studies, oral administration of
xanthophylls for three months or longer,
either in supplements or natural foods,
was shown to increase macular pigment
density.95-99 However, the response of
macular pigment to xanthophyll intake
was quite variable from person to person. In particular, a lesser response was
noted in overweight subjects. Baseline
body fat also tends to correlate negatively with macular pigment density, and
perhaps an adverse effect of obesity on
macular xanthophyll uptake is at least
partially responsible for the increase in
AMD risk associated with obesity noted
in some epidemiological studies.101
Dr. Bone: We have found that the
average MPOD for the population is
about 0.4 absorbance units (AU), but it
can range from essentially zero to more
than 1.0 AU. Subjects in the below
average category would be those for
whom dietary supplementation with the
macular carotenoids would be advisable. Since subject response to supplementation is quite variable, monitoring
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the subject’s MPOD at, say, six-month
intervals would allow clinicians to reach
decisions concerning the continued use
of the supplement at the same dose or
possibly at an increased or, for that matter, decreased dose.
Dr. Lopez: What are the methods of measuring MPOD and what
are their advantages and disadvantages?
Dr. Bone: The methods of measuring MPOD fall into two categories, the
so-called psychophysical methods and
the objective physical methods.
Many investigators consider the psychophysical method of heterochromatic
flicker photometry (HFP) to be the gold
standard against which other methods
are evaluated. In this method, the subject views a small visual stimulus that
alternates between two colors, blue that
is absorbed by the macular pigment
and green, which is not absorbed. The
subject operates a control to adjust the
brightness of the blue until the perception of flicker is minimized. The second part of the test, which eliminates
the effects of light absorption in the
lens, requires the subject to minimize
flicker while directing his or her gaze
at a peripheral fixation mark so that the
stimulus is seen “out of the corner of the
eye.” Some subjects find this latter task
to be difficult, so I have recently been
directing my efforts towards the development of a user-friendly HFP system.
To date, this new system, which will
hopefully be available on the market in
the near future, has been described by
the subjects who have used it as much
easier than traditional HFP. The uncertainties associated with their measurements bear this out.
I also have had experience with
one of the physical methods, fundus
reflectometry using a retinal camera.
The advantage of this method is that
it provides a profile of MPOD across
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the retina. The disadvantage is that the
clarity of the optic media decreases with
age, resulting in low contrast images
and a concomitant underestimate of
the MPOD that gets worse with age.
In addition, depending on the type of
retinal camera, pupil dilation may be
necessary.
The problem of decreasing lens clarity with age also appears to pose a problem in the method of resonance Raman
spectroscopy. In this method, carotenoid molecules in the retina are stimulated by light of one wavelength and
emit light at a slightly different wavelength which is detected and quantified. Rather than providing the MPOD,
this method provides “Raman counts,”
which are related to the amount of
carotenoid present.
The final physical method is based
on lipofuscin hyperfluorescence. Lipofuscin is a fluorescent material that
accumulates in the RPE anterior to the
macular pigment layer. It can be stimulated by a range of wavelengths and
fluoresces at longer wavelengths in the
yellow part of the spectrum. This fluorescence is measured when the stimulating light is firstly a wavelength that is
strongly absorbed by the macular pigment (blue) and secondly by one that is
not absorbed (green). The differential
lipofuscin fluorescence due to these two
wavelengths provides a means of calculating the MPOD. The advantage of this
method is that it can provide a profile
of MPOD across the retina; the disadvantage is that it requires specialized
and expensive instrumentation such as a
scanning laser ophthalmoscope.
Dr. Lopez: Finally, considering
the protective role of carotenoids,
omega-3 and antioxidants, what
guidelines should ophthalmologists
follow in recommending consumption amounts to their patients?
Dr. Hendler: The foregoing discus-
sion strongly suggests that supplementation with xanthophyll carotenoids,
long-chain omega-3 fatty acids, and
various adjunctive antioxidants may
have important potential for preventing
and controlling AMD. The on-going
AREDS 2 study, as well as other studies in progress or in planning, should
provide more definitive information in
this regard.
Nonetheless, the pathogenesis of
AMD remains poorly understood, and it
seems likely that a point of diminishing
returns will be reached as antioxidant
measures are piled atop each other.
Hence, it may be worthwhile to identify
additional targets that can be addressed
in AMD management—strategies with
potential for complementing the efficacy of antioxidants and omega-3s. A
further examination of the epidemiology
of AMD may provide some useful clues
in this regard.
I might add that it is possible but
very difficult to modify one’s diet with
increased real foods in order to enhance
MPOD significantly. Realistically, the
supplement market is far more likely to
offer concentrated forms of pure ingredients that will successfully provide adequate protection. This is true for everyone, including allegedly low-risk groups,
though in particular high-risk persons
with AMD or with a family history of
AMD.
Dr. Lopez: As we have found in
the epidemiologic studies, certain
non-modifiable risk factors are
associated with AMD. The primary
risk factor is, of course, age. The
Eye Disease Prevalence Research
Group as well as the AREDS Study
found a lower incidence of AMD in
blacks, while the Beaver Dam Eye
Study and the Blue Mountains Eye
Study demonstrated women to be
more likely to develop early and
late AMD. Sadly, we cannot prevent aging, nor choose our race or
Summary of Key Points:
• Oxidative stress plays a key role in AMD.
• It is difficult to increase protection against oxidative stress and other factors
linked to AMD by simply modifying one’s diet of real foods.
• Realistically, the supplement market is far more likely to offer concentrated
forms of pure ingredients that will successfully provide adequate protection.
• Supplements with xanthophyll carotenoids, long-chain omega-3 fatty acids
and various adjunctive antioxidants may have important potential for preventing and controlling AMD.
• New techniques for measuring macular pigment optical density will enable
clinicians to validate the use of nutraceuticals and make more rational decisions regarding optimal dosage.
gender, but we can modify behavior. Please summarize the modifiable risk factor, other than diet or
supplement intake.
Dr. Hendler: The strongest modifiable risk factor is cigarette smoking.
The epidemiologic studies have not
proven that stopping smoking prevents
the development of AMD, but the epidemiologic data give yet another reason to advise patients not to smoke.
Blood pressure, dyslipidemia and obesity are other modifiable risk factors,
that though not confirmed to be directly causal, should be addressed with
patients. Also, there may be an association between cataract surgery and an
increase in frequency of development
and progression of AMD. This latter
risk factor may be due to the spurious association of both early AMD and
cataract in elderly patients, so I would
not alarm patients with this concern,
especially when the benefits of cataract
surgery outweigh this risk. Surgeons
might consider the use of ultra-violet
light protection either with the choice
of implant at the time of surgery or the
use of blue-blocker sunglasses following surgery.
Dr. Lopez: And, finally, with
regard to supplement intake, what
would you recommend?
R
eview
of
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Dr. Hendler: With regard to practical advice for one’s patients, I would
encourage AMD patients to take a general multi-vitamin as well as a product
that contains lutein, zeaxanthin, mesozeaxanthin, and omega-3 (in particular
DHA). Soon, through Dr. Bone’s work,
we will be able to cost-effectively measure, with accuracy and repeatability,
the effects of diet modification on the
health of the eye. The physician will
have the scientific justification for recommending supplements, then measure the effects on the macular pigment
or the effects on the lens, and then subsequently alter those recommendations
based on serial clinical findings/measurements. Recommendations for nonAMD patients may then be defensible
and prudent. RO
Dr. Hendler, Dr. Bone and Mr.
McCarty are paid members of the
Scientific Advisory team at Guardion
Health Sciences, a newly formed nutraceutical company based in California.
The comments in this paper should not
be construed as endorsement of any of
GHS’s current or future products. Dr.
Lopez has no management or financial interest in any related products or
services.
All citations referred to in this
article are available upon request.
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