| How Many Xanthophylls Do We Need?
Determining a daily intake
of lutein and zeaxanthin is problematic because food composition
tables often do not analyze or report lutein and zeaxanthin
separately, and comparisons of published data are often
inconsistent. Despite the recommendation by many health
agencies to eat at least five servings of fruits and vegetables
per day, consumption varies widely.
Several major epidemiological studies have linked dietary
carotenoid consumption with reduced risks of macular degeneration
and cataract. The dietary gap between low-and high-risk individuals
was equivalent to about 6 mg/day of lutein and zeaxanthin.22,25,29-32,39 The data suggest that a difference of 4-5 mg/day in consumption
of xanthophylls could influence the risks of contracting eye
disease and may be a basis for a maintenance or preventive
dosage.
For low-risk individuals, perhaps 3-6 mg/day of zeaxanthin
may be extrapolated as a preventive dosage for degenerative
eye diseases, though a dose as low as 0.5 mg/day over an entire
lifetime may be sufficient. A number of other clinical trials
are using 20-30 mg/day of zeaxanthin.
Differences Between Zeaxanthin and Lutein
Zeaxanthin and its
chemical cousin, lutein, differ in several important ways.
Lutein’s three-dimensional structure
is asymmetrical and bent, a perfect fit for its role in harvesting
and transferring light energy in the photoreaction center
of the chloroplast of a plant cell. As noted previously, this
means that the human diet contains 5-20 times more lutein
than zeaxanthin. In human blood serum, lutein is 3-10 times
more predominant than zeaxanthin.1,2,5,6,38 Zeaxanthin is
a straight, symmetrical molecule that can perfectly transverse
a biological membrane and influence and protect membrane-bound
cellular functions more effectively than lutein, regardless
of its orientation.42 This may account for the ocular preference
of zeaxanthin over lutein. This selective preference has also
been seen recently in human cadaver brain.43 This membrane
spanning and greater antioxidant properties may also explain
why the retina makes the unusual isomer meso-zeaxanthin (which
is structurally closer) from the more abundant lutein. Most
likely this is because the eye attempts to supplement the
lower intake of preferred dietary zeaxanthin by converting
lutein to meso-zeaxanthin, which is better than lutein but
not as good as dietary zeaxanthin. This selective deposition
and concentration of dietary antioxidants in the macula’s
center has also been demonstrated with vitamin E and selenium.7
A misconception among consumers is that they get enough
dietary zeaxanthin from their lutein products. A second misconception,
even among eye specialists, is that lutein is converted to
zeaxanthin in the eye. In fact, lutein comes from marigold
flowers and contains only a tiny amount of zeaxanthin compared
to the 2:1 ratio seen in the section of the macula that seems
to be protected. A second fact is that lutein is converted
into a compromise structure, meso-zeaxanthin, in the eye.
Zeaxanthin’s Protective
Effects Against Eye Disease
The
epidemiological evidence for a protective effect of zeaxanthin
in eye health seems reasonably clear but not entirely consistent.3,4,7,9 The
surveys from both dietary and blood serum relations of zeaxanthin
and eye disease progression of incidence show the normal inconsistencies.
Most of the surveys, however, show a clear relationship to
both macular degeneration and cataract for dietary intake
of fruits and vegetables containing significant quantities
of zeaxanthin and lutein. The blood serum relationship data
have been less consistent but may have been clarified by the
Medical Research Council in England last year.41 Gale and
colleagues completed analysis on fasting blood serum levels
and analyzed lutein and zeaxanthin separately. They stated,
for the first time, that the greatest increased risks of both
wet and dry macular degeneration were correlated with low
blood serum levels of zeaxanthin, not lutein.
With trials in Japanese quail and primates, the evidence
from animal trials has recently become much stronger. In the
early 1980s, researchers depleted primate diets of carotenoids
and demonstrated retinal pathologies consistent with symptoms
of macular degeneration. The studies were extended in the
mid-1990s when Dr. C.K. Dorey and colleagues at Harvard Medical
School and the Schepens Eye Institute established the Japanese
quail as a model for studying degenerative eye disease and
xanthophylls.16,44-46 Using
aging and light-insult models, Dr. Dorey was the first to
show directly that the photo-protective effects of zeaxanthin
were related to the retinal levels of zeaxanthin that she
controlled by feeding. This retinal protection extended to
both rods and cones, and prevented the massive losses seen
in late-stage dry macular degeneration. The team also went
on to show that zeaxanthin:
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- Protects the eye via reduced cell death
- Prevents age-related changes
- Showed a four times greater “retinal capture
efficiency” compared to lutein
- Demonstrated for the first time that dietary manipulation
could increase lens levels as much as fivefold, setting
up a model for further work in cataract prevention.
Further results with primates have shown that zeaxanthin
is more photo-protective (blue laser light insult) than lutein
or meso-zeaxanthin.
Increasing the Macular
Pigment’s Thickness
It is well
established that higher intakes of zeaxanthin and lutein maintain
the structure of the macula. The question doctors then asked
is whether consumption of these plant extracts can increase
the density or thickness of the macula. Human studies have
produced fascinating findings indicating that it may be possible
to reverse some of the age-related deterioration of the macula.
Doctors can now measure “macular pigment optical density” indirectly
and noninvasively by at least six different techniques, though
some of these techniques have been subject to criticism. The
human trials that measured macular pigment optical density
in response to lutein and zeaxanthin intake are summarized
in the next column:
- Both food and supplements con- taining zeaxanthin
and lutein are capable of raising retinal levels of the xanthophylls
in most, but not all, volunteers. The reason for nonresponsive
volunteers has not yet been delineated.4,47-51
- The retinal response is very slow relative to the
blood serum response (months versus days), but appears to
remain stable for months upon cessation of supplementation.
This suggests that an intervention dosage may need to be significantly
higher than a preventive or maintenance dosage and must
be maintained to provide the maximum benefit.44-49
- Peak serum levels and ability to increase macular
pigment opti- cal density appear to be related, suggesting
that high dietary intake may raise retinal levels faster and
more effectively.5,47-51
- Factors other than peak blood serum levels appear
to affect the ability to increase macular pig- ment optical
density. These include many of the risk factors for macular
degeneration but may also include genetics, obesity, and other
serum or retinal transport/binding proteins for the xanthophylls.4,51
- To date, only one small trial has directly compared
the ability of lutein and zeaxanthin to influ- ence macular
pigment optical density in humans where bioavailability was
directly controlled.48 In this trial, blood serum responses
were equal, but more individuals had a retinal response to
zeaxanthin.
The association between macular pigment optical density
and risk factors for macular degeneration and cataracts is
compelling. Reduced macular pigment optical density in the
target population has been related to smoking, obesity/high
BMI, age, lens density and opacity, gender, light iris, and
poor zeaxanthin intake.1,2,4,7,9,47-51
Zeaxanthin and Other Eye Diseases
A half dozen smaller intervention
trials using xanthophylls in degenerative eye disease have
been completed. Several small trials have shown xanthophylls’ positive
impact on visual activity and drusen progression in early
maculopathy,52,53 on retinitis pigmentosa, and on visual activity
and glare sensitivity in early age-related cataracts.54 (Drusen
are nodules beneath the retina in a layer called Bruch’s
membrane, which lies beneath the retina and the adjacent retina
pigment epithelium layer). Dr. Stuart Richer and colleagues
conducted a year-long trial of 90 males with dry macular degeneration,
which showed improvements in glare recovery, contrast sensitivity,
and near/distant visual activity. 55
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The results to date are promising, but larger and longer
clinical trials will be necessary to clarify the benefits
for patients and eye-care professionals before zeaxanthin
supplements will receive an unqualified recommendation. The
FDA will need to see statistically relevant data, and the
medical community will need to see these functional improvements
along with reduced progression of symptoms like area of atrophy,
drusen and lipofuscin progression, and reduced risk of neo-vascularization
or its progression.
Major trials on intervention in all stages of macular degeneration
are in various stages of planning and execution. The largest
of these may be the AREDSII trial, with more than 5,000 patients
in late-stage macular degeneration. The National Eye Institute
and National Institutes of Health are scheduled to begin this
trial using lutein and zeaxanthin later this year. Zeaxanthin
and lutein were not commercially available for the first trial.
Finally, since zeaxanthin supplements were introduced, many
patients who were hypersensitive to light (i.e., photophobic)
are reporting dramatic decreases in this unpleasant phenomenon
within months of initiating 20 mg/day doses of zeaxanthin.
These observations are now being assessed objectively at two
colleges of optometry.
Dual Mechanisms of Action
There are currently two leading
theories of how xanthophylls (lutein and zeaxanthin) may protect
the eye: the first involves the xanthophylls’ antioxidant
mechanisms, while the second considers the xanthophylls’ UV-blue
light filtering properties. These mechanisms are not mutually
exclusive, nor is either the only possible mechanism.1,3,4,7
Both lutein and zeaxanthin are capable of quenching free-radical
reactions that create reactive oxygen species. These reactive
oxygen species then react with cell membranes and macromolecules
to create pathogenesis leading to many human degenerative
conditions. In the eye tissues, these oxidative processes
can be further enhanced by the presence of light (which accelerates
photo-oxidation), extremely high metabolic rates (in the retina),
and the highly polyunsaturated lipids found in the retina
and other neural tissues. Both singlet oxygen and peroxyl
radicals are likely generated in eye tissues and quenched
by the xanthophylls.
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Light-driven photo-oxidation likely generates excited triplet-state
species that also cause severe oxidative damage. As noted
earlier, zeaxanthin is a better antioxidant and is more directly
embedded in a manner to protect biological cell membranes
than is lutein. Xanthophylls are particularly effective at
lower oxygen tensions (concentrations) like the interior of
a cell membrane or the center of lens tissue. The tocopherols
are more effective at higher oxygen tensions. Thus it is highly
likely the two lipophilic antioxidants are synergistic and
complement ascorbates and the metal-containing enzyme-based
antioxidant enzymes that are active in ocular tissues for
protection against oxidative damage.
The very earliest steps in eye cells showing oxidative stress
are the generation of lipoperoxides.56 In 2000, these very
early oxidation markers were shown to directly induce the
pathways of angiogenesis or neovasularization.57,58 This means
that the earliest step of oxidation may be capable of increasing
the risk of progressing to wet macular degeneration.
The second biologically plausible mechanism is UV and blue-light
filtering or absorption. The xanthophylls are excellent light
filters and absorb that part of the UV and blue-light spectrum
thought to be most damaging to the eye. In the lens, the xanthophylls
absorb the UV light thought to be the principal initiator
of oxidative stress that results in cross-linking of the component
crystalline that in turn reduces the clearness of the lens.
The xanthophylls would also reduce the amount of blue light
reaching the retina. The absorption of blue light in the lens
and from reflection in the retina would reduce light scatter
and chromatic aberrations. This would suggest a more direct
role in reducing visual effects like glare and starburst effects
seen in early stages of these diseases.7
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This blue-light filtering may directly reduce the photo-oxidation
in the susceptible axons and likely reduces photo-oxidative
damage directly in the photoreceptors and posterior retinal
pigmented epithelium cells that support and maintain the photoreceptors.
In the critically important retinal pigmented epithelium
cells insulted with blue light, zeaxanthin has been shown
to prevent oxidative damage, apoptosis, DNA damage, and cell
death. In these cell culture experiments, zeaxanthin shows
synergy with the other cellular protectants vitamins C and
E, glutathione, and melanin.60
Theories of Aging Explain Degenerative Eye Disease
Readers
of this magazine are aware of most theories of aging, and
almost all are implicated in degenerative, age-related changes
in the human eye. The eye has several special considerations.
It must deal with light-accelerated degeneration, and the
back of the eye has one of the highest oxygen levels, metabolic
rates, and cellular turnover rates, as well as susceptible
components (polyunsaturated lipids).7 The back of the eye
seems to be a microcosm for atherosclerosis susceptibility,
and appears to be at the interface of the blood-brain barrier
(i.e., neural retina). The lens is subject to constant ultraviolet
insult, a low metabolic rate, and operating in a low oxygen
context.
These two disparate and opposing functions are within an
inch of each other inside the eye. Readers should also know
that caloric restriction, the almost universal environmental
anti-aging influence, has also been shown to slow degeneration
or aging of the eye.
In addition to its role in the photo-oxidative mechanism
of degenerative eye disease, it is likely that zeaxanthin
also participates through other protective biological mechanisms.
Because age-related eye degeneration is probably multi-etiological,
it is likely zeaxanthin helps provide protection at multiple
levels.1,4,7,35 |