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These include antioxidant vitamins, Lutein and Zeaxanthin, Omega 3 fish oils, plus essential minerals.

Nutrof® Total's unique formulation has been shown to help and protect your eye health.

Nutrof® Total is the leading eye nutritional in many countries across Europe including France and Spain.


About Age Related Macular Degeneration (AMD):
Definition:

Due to the significant ageing of the population, prevalence of degenerative diseases such as cancer, heart diseases, or neuro-degenerative diseases is increasing.
This phenomenon also interests ophthalmologists as the prevalence of eye degeneration leads to increasing frequency of diseases such as senile cataract, glaucoma, diabetic retinopathy or age-related macular degeneration (AMD)
Age-related macular degeneration (AMD) is the leading cause of legal blindness in those over the age of 65 years in developed countries. It is characterised mainly by degenerative changes in the macular region of the retina that result in a gradual decrease in central vision.
For instance, age-related macular degeneration affects more than 1.75 million individuals in the United States. Owing to the rapid ageing of the US population, this number will increase to almost 3 million by 20201.
Classification of AMD

According to the French National Agency of Accreditation and Evaluation in Healthcare, three histopathological forms of age-related macular degeneration are described: an early form (or age-related maculopathy), an atrophic form and an exsudative form (both correspond to agerelated macular degeneration).
• The early form (30% of cases) is characterised by the presence of macular drusen and irregular proliferation or atrophy of the retinal pigment epithelium.
• The atrophic or “dry form” (50% of cases) is characterised by damage to the retinal pigment epithelium and thinning of the retinal macula due to drusen confluence; the disease develops slowly over a number of years.
• The exsudative or “wet form” (20% of cases) is characterised by the development of neovascularization under the macula. This form may develop very rapidly causing loss of central vision within a few weeks or months.

Treatment of AMD
Currently, there is no known cure for the early and atrophic forms of AMD. Only preventive measures can be taken such as complementing intake in antioxidant vitamins and minerals.
The other severe form of AMD, the neovascular or “Wet” form, can be treated by laser photocoagulation, photodynamic therapy and more recently, by new drugs that target and inhibit proteins called VEGFs (vascular endothelial growth factors) responsible for the stimulation of new choroidal vessel formation (angiogenesis).
These treatments are expensive and they should be repeated at intervals during the course of the disease.

Risk factors:
The main risk factor for the development of AMD is increasing age.
Although a number of risk factors have been investigated, cigarette smoking is the only risk factor other than age, ethnicity (AMD is more common among whites than blacks) and genetics that has been consistently identified in numerous studies.
Other factors that may play a role in AMD are:
- Exposure to blue light
- Hypertension and other underlying atherosclerotic disease processes
- Fat diets
- Low levels of antioxidants

Physiopathology of AMD: the role of oxidative stress
Little is known about the pathogenesis of AMD.
However there is a general consensus that cumulative oxidative damage is responsi¬ble for ageing and may play an important role.
Oxygen is essential to life. Most of the living species find energy in cell respiration, which normally produces very small quantities of reactive oxygen species (superoxide anion and hydroxile radical, hydrogen peroxide and singlet oxygen) and free radicals.
This physiological production is useful to the organism and is fully controlled by defence systems. Hence, under normal circumstances there is a perfect balance between antioxidant and pro oxidant elements within living organisms.

However, various conditions can induce an accumulation of free radicals and reactive oxygen species (ROS), due to their improper elimination: oxidative stress appears then.
Oxidative stress can, therefore, be defined as an imbalance between the production of free radicals and the body antioxidant defences. This imbalance is a consequence of either over exposure to pro-oxidative factors (blue light, cigarette smoke), lack of antioxidants, ageing, or a combination of these three elements.

The retina is particularly susceptible to oxidative stress because of its high consumption of
oxygen, its high proportion of long chain PolyUnsaturated Fatty Acids, PUFA ) a target of free radicals, and its exposure to visible light. On the other hand, the renewal of the pho-toreceptor discs through phagocytosis produces a high quantity of ROS (hydrogen peroxide) and the retina contains a high concentration of photoreactive substances (rhodopsin and lipofuscin).

Moreover, ageing of the chorio-retina creates a vicious circle: lipofuscin accu-mulates, increasing oxidative stress and thus, accelerating ageing of the choroids and retina The retina contains intra and extracellular antioxidant defence systems against oxidative stress: - Antioxidant Enzymes: Catalase, Superoxide dismutase, glutathione peroxidase and glutathione reduc-tase.

These enzymes need cofactors to work properly. These cofactors are either metal ions (iron, copper, zinc, manganese and selenium) or vitamins (vitamin B2). - Minerals: zinc, copper, selenium, manganese - Vitamins: vitamin C, vitamin E, vita-min A and carotenoids including beta-carotene - Macular pigment: Lutein and Zeaxanthin - PUFA: Omega-3, and especially DHA - Glutathione Most of these compounds cannot be syn-thesized and must be taken in through dietary sources. Elderly patients tend to take inadequate diets that are deficient or totally lacking in fruit and vegetables, which means that they are deficient in antioxidants, minerals and protective carotenoid pigments. Therefore with advancing age, the amount of antioxidant available in tissues reduces. It is thus essential for the elderly to secure the daily intake of such antioxi-dants with a proper diet or / with the intake of dietary supplements.
Beta-carotene Traces Vitamin C + Vitamin E ++ Zinc ++ Copper ++ Selenium ++ Manganese ++ Glutathione ++ Lutein -Zeaxanthin ++++ Omega-3 (DHA, EPA) ++++

Antioxidant vitamins and minerals. Their role in AMD:

Antioxidant vitamins
Biological tissues, particularly those most exposed to oxidative attack such as the retina, contain high concentrations of endogenous antioxidants:

Vitamin C is an antioxidant vitamin that protects the lens and the retina from photo-oxidation. It has a synergic action with vitamin E, the key antioxidant vitamin which protects cell membrane and Vitamin A from oxidation.

Beta-carotene, precursor of vitamin A also presents an antioxidant activity protecting the retina from photo-oxidation.

Vitamin B complex: Includes several B vitamins with different roles. It works as coenzymes to help maintain proper growth and development as well as giving energy. B vitamins work together and also compete in intestines for absorption. Therefore, if you increase the daily intake of one B vitamin you should also increase the others by a proportionate amount.
- B1 (Thiamin): Antioxidant
- B2 (Riboflavin): Essential to ensure proper functioning of antioxidant enzymes such as glutathione reductase
- B3 (Niacine): Reduces level of LDLcho¬lesterol
- B6 (Pyridoxine): Platelet Aggregation Inhibitor
- B9 (Folic acid): Essential for cell division and DNA synthesis
- B12 (Cobalamin): Protects nervous fibres.

Furthermore, several B vitamins (B6, B9, B12) are involved, as cofactors of enzymes, in homocysteine metabolism.

Recent publications showed the possible implication of homocysteine in AMD.
Minerals:
Zinc is a cofactor of various enzymes of the retina such as Superoxyde Dismutase (anti oxidant enzyme) and is highly concentrated at ocular level. It promotes the release of vitamin A to incorporate it in the rhodopsin biocycle.

Copper is also a cofactor of Superoxyde Dismutase.

Selenium is considered as the major antioxidant mineral. Its presence is mandatory to ensure proper functioning of the glutathione peroxidase enzyme. Selenium complements the antioxidant function of vitamin E and Zinc.

Manganese is a component of the Superoxide Dismutase antioxidant system and is concentrated in the retina.

Role in AMD incidence:
In the 90’s, several studies had reported the protective effect associated with high intake of antioxidant vitamins and minerals on AMD development:
- In 19938, a comparison between 421 patients with neovascular age-related macular degeneration and 615 con¬trols reported that high plasma levels of antioxidants (vitamins A, C, E, sele¬nium and carotenoids) are associated with a lower risk to develop neovascular AMD. Additional intake of carotenoid, particularly those present in the retina is associated with a lower risk of developing AMD.

- In the Baltimore Longitudinal Study on Aging (1994) performed on 976 participants, the authors found a protective effect for AMD of high plasma values of Vitamin E, and an antioxidant index composed of Vitamin C, Vitamin E, and beta-carotene was also protec¬tive.

- The Beaver Dam Eye Study10 (1998), in a cohort of 1,709 people who participated in 5-year follow-up eye examination, showed that a high intake in carotenoids and vitamin E is associated with a lower risk of developing large drusen. A high dietary zinc intake would be associated with a lower number of retinal pigment epithelium anomalies.
In 2001, the AREDS study11 (Age-related Eye disease Study Research Group) con¬firmed for the first time the interest of antioxidants and Zinc in advanced AMD patients.

This double-blind, multicentre, randomised, clinical trial (1992-2001) financed by the National Eye Institute, was designed to evaluate the effect of high doses of zinc and selected antioxidant vitamins (C, E and beta-carotene) on the development of advanced AMD in old persons. It included 3640 patients (55-80 years old). The average follow-up of participants was 6.3 years.
Patients were divided into 4 categories determined by the size and extent of drusen and retinal pigment epithelium abnormalities in each eye.
- Category 1: very few drusens or free of age related macular abnormalities
- Category 2: small drusen
- Category 3 : multiple large drusen or geographic atrophy that did not involve the centre of the macula
- Category 4: advanced AMD or reduced visual acuity.

Photographic assessment and visual acuity loss from baseline were the two criteria chosen to evaluate the disease evolution. Serum level measurements, medical histories and mortality rates were used for safety monitoring.
4 different groups were made:
- Group 1: Placebo
- Group 2: Zinc
- Group 3: Vitamins C, E and Beta-carotene
- Group 4: Zinc, Vitamins C, E and Beta-carotene

Patients receiving Zinc had Copper (as Cupric Oxide) in addition to prevent potential anaemia.
Authors said that two carotenoids, lutein and zeaxanthin, were considered for inclusion in the formulation during the planning phase, because they are concentrated in the macula but they were not available for manufacturing in a research formulation at the initiation of the study.
new book JA.indd 7 24/10/08 13:58:36

The results show that Zinc alone, Antioxidants alone and Zinc plus Antioxidants significantly reduced the risk of developing advanced AMD in Category 3 and Category 4 patients. The best supplementation which decreases the risk of AMD evolution was Zinc plus Antioxidants. Reduced risk for advanced AMD: 25 % Reduced risk for moderate vision loss: 19 % There was no statistically significant evidence of a benefit in delaying the progression of Category 1 and
Category 2 eyes to more severe drusen pathology. No statistically significant serious adverse effect was associated with any of the formulations. Conclusions of AREDS: 1. People older than 55 years should have dilated eye examination to determine their risk of developing advanced AMD. 2. Those with extensive intermediate size drusen, at least one large drusen, non central geographic atrophy in one or both eyes, or advanced AMD or vision loss due to AMD in one eye, and without contraindications such as smoking, should consider taking a supplement of antioxidants plus zinc such as that used in this study. In 2004, the AREDS research group assessed the association of ocular disorders and high doses of antioxidants or zinc with mortality12. Results show that participants assigned to receive zinc (alone or completed with antioxidants) had a lower mortality (reduction of 12%) than those not taking zinc. Thanks to all these studies we can concluded that antioxidant vitamins and minerals in retina play a key role in the defence against retinal oxidative stress and AMD evolution. Placebo Groupe 2 Groupe 3 Groupe 4 (n=903) (n=904) (n=945) (n=888) Zinc x 80 mg 80 mg Vitamin C x 500 mg 500 mg Vitamin E x 400 UI 400 UI Beta-carotene x 15 mg 15 mg Copper x 2 mg 2 mg 17% 21% 25% 0% 15% 30% Antioxidants alone Risk reduction (%) Zinc alone Antioxidants + zinc

Macular pigment: Lutein and Zeaxanthin. Their role in AMD
Macular pigment: Lutein and Zeaxanthin. Their role in AMD Two hundred years ago, a yellow colour was first observed in the macular region (macula is called macula lutea; yellow spot for its characteristic yellow colour). We know now that the yellow colour of macula is due to the presence of the pig-ments Lutein and its isomer Zeaxanthin called macular pigment. Lutein and Zeaxanthin are members of the carotenoid family - a group of natural plant pigments that also includes beta-carotene and lycopene. They are the only carotenoid found in high concentration in the macula. In contrast to human blood and tissues, no other major carotenoids including beta-carotene or lycopene are found in this tissue. Lutein is the second most prevalent carotenoid in human serum and is abundantly present in dark, leafy green vegetables, such as spinach and kale. Lutein is believed to function in two important ways: primarily as a filter of high energy blue light (toxic for the eye), and secondly as an antioxidant that quenches and scavenges photo-induced reactive oxygen species. The concentration of Lutein and Zeaxanthin in the macula decreases with age. Not synthesized by the organism, they should be taken through dietary sources. In AMD incidence Several scientific studies have demonstrated a reduction in the occurrence of the most severe forms of AMD in persons with high dietary intakes of fruits and vegetables containing Lutein and Zeaxanthin. Cross section of human macula Macular pigment Role in AMD incidence new book JA.indd 9 24/10/08 13:58:38
10Specifically, people who consume large quantities of fruits and vegetables rich in Lutein and Zeaxanthin (6mg/day) had a43% reduced risk of developing the most severe form of macular degeneration15.Another observational study conducted in200216showed that average levels of Lutein and Zeaxanthin were 32% lower in AMD eyes versus normal elderly control eyes as long as the subjects were not consuming high-doses of Lutein supplements. This study demonstrated that patients who had begun to consume supplements containing high doses of Lutein (4 mg/day) regularly after their initial diagnosis of AMD, had average macular pigments levels that were in the normal range and that were significantly higher than in AMD patients not consuming these supplements. Recently, Delcourt et al in the POLA study found that high plasma lutein andtotal lutein and zeaxanthin concentrations are associated with a reduced risk of age-related maculopathy ( ARM).These results were confirmed in 2004 by the LAST study. In this clinical trial, 90 AMD patients were supplemented daily with 10 mg of lutein,10 mg of lutein plus a mixed antioxidant formula (containing vitamin A, beta-carotene, vitamin C, vitamin E, complex of vitamin B, copper, zinc, manganese, magnesium, selenium and other minerals) or placebo for 12 months. The results showed that patients ingesting the Lutein supplement experienced significant improvement in several objective measurements of visual function (contrast sensitivity or visual acuity) versus placebo. Slightly better results were observed in those subjects consuming the combined supplement. The LAST trial was the first study to show that Lutein supplementation improved visual function in AMD patients. Furthermore, it reinforces the notion that AMD is a nutrition responsive disease. All these findings are consistent with the hypothesis that low levels of Lutein and Zeaxanthin in the human macula may represent a pathogenic risk factor for the development of AMD. It also suggests that supplementation can contribute to maintaining eye health.

Omega-3 and AMD
Also known as Long-Chain Polyunsaturated Fatty Acids (LCPUFAs), omega-3 are considered essential fatty acids, which means that they are essential to human health.

Omega-3 fatty acids cannot be synthesized by the body, and must be obtained from food, especially from fish and sea food.

There are three major types of omega-3 fatty acids that are ingested in food and used by the body: alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA).
Once ingested, the body converts ALA to EPA and DHA, the two types of omega-3 fatty acids more readily used by the body.

Omega-3 are highly concentrated in the brain and appear to be particularly important for cognitive and behavioural function. In fact, infants who do not get enough omega-3 from their mothers during pregnancy are at risk for developing vision and nerve problems.

Extensive research indicates that omega-3 has a protective effect against diabetes and hypertension, reduces inflammation and helps prevent certain chronic diseases such as heart disease and arthritis thanks to their antithrombotic and hypolipidemic properties19.

It is important to maintain an appropriate balance of omega-3 and omega-6, another essential fatty acid. An inappropriate balance of these essential fatty acids contributes to the development of disease while a proper balance helps maintain and even improve health.

A healthy diet should consist of roughly one to four times more omega-6 fatty acids than omega-3 fatty acids. The occidental diet tends to contain 10 to 30 times more omega-6 fatty acids than omega-3 fatty acids20.

Omega-3 and visual function
Omega-3 plays a key role in the structure and function of the sensory retina19.
- DHA is a major structural component of retinal membranes. DHA is the major fatty acid in structural lipids of retinal photoreceptor outer segment disc membranes.
- DHA deficiency is associated with structural and functional abnormalities in the visual system.
• Some people exhibit abnormalities in the metabolism of LCPUFAs leading to a deficiency of DHA in the retina, brain, liver or blood. People with DHA deficiency demonstrate gross visual processing deficits that can be improved with omega-3 supplementation.
- DHA participates in retinal cell signalling mechanisms involved in phototransduction. Phototransduction is the mechanism through which the retina processes light energy and converts it into a nervous signal.
- DHA protects photoreceptors from oxidative stress-induced apoptosis21.
- DHA may reduce lipofuscin accumulation in retinal pigment epithelium and lipid deposits in Bruch’s membrane (these accumulations are frequent in the AMD pathology).
Omega-3 and AMD

It has been hypothesized that atherosclerosis of the blood vessels that supply the retina contributes to the risk of AMD, similar to the mechanism underlying coronary heart disease.
According to this hypothesis, dietary fat components related to coronary heart disease may also be related to AMD.
In order to confirm this hypothesis, several epidemiological studies have evaluated the relationship between intake of total and specific types of fat and risk for advanced AMD.
Results confirm that a higher intake of vegetable and animal fat is associated with a greater risk for advanced AMD.
However the risk for advanced AMD decreases with increasing intake of omega-3.

Three clear examples of this fact are:
- The prospective study conducted by Cho et al22 in 2001 showed a positive association between intake of total fat and incidence of AMD. A fat diet increases the risk for advanced AMD. Nevertheless a fish intake ³ 4/week (fish is a major source of DHA) decreases the relative risk of AMD by 35%.
- The case-control study conducted by San Giovanni et al concluded that higher intake of omega-3 and fish is associated with a decreased risk of neovascular AMD.
- Snodderly, in a poster presented at the ARVO meeting in 200524 concluded that a supplementation with Lutein + omega-3 increases the plasma levels of Lutein and Macular pigment density compared to a Lutein supplementation without omega-3.12 liver or blood.

People with DHA defi-ciency demonstrate gross visual pro-cessing deficits that can be amelio-rated with omega-3 supplementa-tion. - DHA participates in retinal cell signalling mechanisms involved inphototransduction. Phototransduction is the mechanism through which the retina processes light energy and converts it in nervous signal.
- DHA protects photoreceptors from oxidative stress-induced apoptosis.
- DHA may reduce lipofuscin accumulation in retinal pigment epithelium and lipid deposits in

Bruch’s membrane (these accumulations are frequent in the AMD pathology).
Omega-3 and AMD:
It has been hypothesized that atherosclerosis of the blood vessels that supply the retina contributes to the risk of AMD, analogous to the mechanism underlying coronary heart disease. According to this hypothesis, dietary fat components related to coronary heart disease may also be related to AMD. In order to confirm this hypothesis, several epidemiologic studies have evaluated the relationship between intake of total and specific types of fat and risk for advanced AMD. Results confirm that a higher intake of vegetable and animal fat is associated with a greater risk for advanced AMD. However the risk for advanced AMD decreases with increasing intake ofomega-3.Three clear examples of this fact are:

- The prospective study conducted byChoet al in 2001 showed a positive association between intake of total fat and incidence of AMD. A fat diet increases the risk for advanced AMD. Nevertheless a fish intake 4/week (fish is a major source of DHA) decreases he relative risk of AMD by35%.

- The case-control study conducted by San Giovanni et al concluded that higher intake of omega-3 and fish is associated with decreased risk of neovascular AMD

- Snodderly, in a poster presented at the ARVO meeting in 2005 concluded that a supplementation with Lutein + omega-3 increases the plasma levels of Lutein and Macular pigment density compared to a Lutein supplementation without omega-3. All these results support the idea that a supplementation of omega-3 could be proposed in products aimed to control the evolution of AMD

Conclusion:
Although AMD is a leading cause of blindness in the elderly, its pathogenesis is not clearly understood. In recent years, there has been increasing interest in the potential role of antioxidants, macular pigment and more recently omega-3 in the AMD pathogenesis. Several studies suggest that antioxidants, macular pigment and omega-3 may act as modifiable factors capable of modulating processes implicated in AMD pathogenesis and progression.
AREDS study was the first clinical trial that established the key role of oxidative stress in AMD pathogenesis. Furthermore the results showed that people at high risk of developing advanced stages of AMD, lowered their risk by about 25% when treated with a high-dose combination of vitamin C, vitamin E, beta-carotene and zinc. In the same high risk group -- which includes people with intermediate AMD, or advanced AMD in one eye but not the other eye -- the nutrients reduced the risk of vision loss caused by advanced AMD by about 19%.

The AREDS formula is the first demonstrated treatment for people at high risk for developing advanced AMD, Since the AREDS study, several epidemiologic studies have reported an inverse relationship of dietary omega-3 or lutein intake with advanced AMD that are statistically significant. All these studies and clinical trials support the different formulations commercialised, including antioxidants (vitamins and minerals), lutein and omega-3 (DHA). A new large-scale phase III randomized clinical trial sponsored by the National Eye Institute (NEI, USA), AREDS II25 or “The Lutein/Zeaxanthin and Omega-3 Supplement Trial”, has been initiated. The primary objective of AREDS II is to evaluate the effect of dietary Lutein and/or Zeaxanthin and/or omega-3 LCPUFAs (DHA and EPA) on progression to advanced AMD. This objective will be accomplished by col-lecting and assessing the data on approxi-mately 4000 participants aged 55 to 80 years with AMD advanced (stage 3 and stage 4 from AREDS). The other objectives of

AREDS II are to: 1. Study the effects of high supplemen-tal doses of lutein and omega-3 on cataract and moderate vision loss 2. Study the effects of eliminating beta-carotene in the original AREDS formulation on the development and progression of AMD

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