Astaxanthin - a superb natural antioxidant

ASTAXANTHIN, a member of the carotenoid family, is a dark-red pigment which is the main carotenoid found in the marine world of algae and aquatic animals. ASTAXANTHIN is present in many types of seafood, including salmon, trout, red sea bream, shrimp and lobster, as well as in birds such as flamingo and quail. This pigment is commercially produced from the microalga Haematococcus pluvialis, the richest known natural source for ASTAXANTHIN.

Carotenoids are lipid-soluble pigments and antioxidants, which participate as accessory pigments in the light-absorption process of photosynthetic organisms. To date, over 600 natural carotenoids have been identified. They are responsible for the orange and red colors in plants and algae, and for the wide range of blue, purple and reddish colors in aquatic animals. Only phytoplankton, algae, plants and certain bacteria and fungi synthesize carotenoids. Animals, including humans, must consume carotenoids as part of their diet and rely on this external supply.

Recent scientific findings indicate that ASTAXANTHIN is a powerful antioxidant and can serve as a potent free-radical scavenger. Moreover, ASTAXANTHIN has been found to provide many essential biological functions, including protection against lipid-membrane peroxidation of essential polyunsaturated fatty acids and proteins, DNA damage and UV light effects; it also plays an important role in immunological defense.
Oxygen is necessary for the metabolic production of energy in our bodies. Mitochondria, through the electron-transport chain, use oxygen to oxidize certain molecules and generate energy in the form of ATP. During this process, oxygen is reduced to water, producing several oxygen-derived free radicals or reactive oxygen species (ROS) which play an important role in various diseases. Normally, oxygen free radicals are neutralized by natural antioxidants such as vitamin E, or enzymes such as superoxide dismutase (SOD). However, ROS become a problem when either a decrease in their removal or their overproduction occurs, resulting in oxidative stress. This stress, and the resultant damage, have been implicated in many diseases, and a wealth of preventative drugs and treatments are currently being studied.
ASTAXANTHIN’s powerful antioxidant activity has been demonstrated in numerous studies showing the detrimental effects of free-radical-induced oxidative stress (2-4) and ASTAXANTHIN’s potential to target many important health conditions.
There is increasing testimonial evidence that ASTAXANTHIN may be effective in enhancing general well-being, improving the quality of life and enhancing the immune system. Recent studies have shown enhanced immune response and decreased DNA damage in human subjects following ASTAXANTHIN administration (5). ASTAXANTHIN is capable of crossing the blood-brain barrier in mammals (6), a unique and important property in the realm of antioxidants. This characteristic allows ASTAXANTHIN to extend its superior antioxidant activity to the central nervous system, which, being rich in unsaturated fatty acids is highly susceptible to oxidative damage by ROS (7).
The efficacy of ASTAXANTHIN in limiting the damage produced by ROS-induced oxidative stress and improving health parameters in the tissues and the body was demonstrated in a series of in-vitro experiments, in pre-clinical studies and in human models. The following is a list of diseases and conditions for which ASTAXANTHIN has been shown to have beneficial effects, as described in numerous medical articles, patents and excellent reviews (8,9) over the last 10 years:

· Age-Related Macular Degeneration: the leading cause of blindness in the aging population
· Alzheimer's and Parkinson's Diseases: two of the most important neurodegenerative diseases
· Cholesterol Disease: ameliorates the effects of LDL, the "bad" cholesterol
· Inflammatory, chronic viral and autoimmune diseases
· Dyspepsia
· Semen fertility improvement
· Muscle function
· Sunburn from UV light
· Normalization of cardiac rhythm
· Anti-hypertension agent
· Stress management
· Benign Prostatic Hyperplasia (BPH)
· Stroke: repairs damage caused by lack of oxygen.

A demand for natural ASTAXANTHIN is now emerging in the fast-growing, multi-billion dollar nutraceutical market; in particular, increasing evidence suggests that ASTAXANTHIN was shown to be a much more powerful antioxidant than vitamins C and E, or than other carotenoids such as beta-carotene, lycopene, lutein and zeaxanthin, among others.
The enhanced activity of ASTAXANTHIN may stem from its molecular structure. ASTAXANTHIN belongs to the xanthophyll group of carotenoids, or the oxygenated carotenoids (see other members of the group in Fig. 1). The hydroxyl and keto functional groups (see Fig. 1) present in the ending ionone ring of ASTAXANTHIN may be responsible for its uniquely powerful antioxidant activity and for its ability to span the membrane bilayers as a direct result of its more polar configuration relative to other carotenoids (3,10-14). Carotenoids with polar end groups like ASTAXANTHIN span the lipid membrane bilayer with their end groups located near the hydrophobic-hydrophilic interface, where free-radical attack first occurs.

Haematococcus pluvialis is believed to accumulate the highest levels of ASTAXANTHIN in nature. Commercially grown Haematococcus pluvialis can accumulate more than 40 g of ASTAXANTHIN per kilo of dry biomass
(see Table 1).

TABLE 1 - NATURAL SOURCES OF ASTAXANTHIN

Today, essentially all commercial ASTAXANTHIN for aquaculture is produced synthetically from petrochemical sources, with an annual turnover of over $200 million, and a selling price of ~$2000 per kilo of pure ASTAXANTHIN.
Other developing applications for synthetic ASTAXANTHIN include poultry and egg production.

In recent years, there has been a growing trend toward using natural ingredients in all forms of food nutrients, resulting from increasing concerns for consumer safety and regulatory issues over the introduction of synthetic chemicals into the human food chain. This is also true for the nutraceutical and cosmeceutical markets.
Good examples of commercially important naturally derived carotenoids are beta-carotene, lycopene, lutein and zeaxanthin, commercial carotenoids with antioxidant properties which have become popular ingredients in many vitamin and mineral supplements. Beta-carotene and lycopene can be produced both synthetically (from petrochemicals) and naturally. A decade ago, natural beta-carotene accounted for a tiny percentage of the total world market. Since then, that market has increased several-fold and today, natural beta-carotene accounts for 15 to 20% of world demand (15). Virtually all nutraceutical producers use natural rather than synthetic carotenoids, and pay premium prices as much as five times that of the synthetic product.

The demand for natural ASTAXANTHIN is now emerging in the multi-billion dollar nutraceutical market, and increasingly, medical researchers believe that ASTAXANTHIN may have significant pharmaceutical applications. While only a negligible part of today's market, the demand for such applications is expected to grow significantly in the near term as a result of numerous medical studies performed during the last 5 years in the area of ASTAXANTHIN applications.
More and more research supports the conviction that a daily dose of ~5 mg of ASTAXANTHIN is of tremendous importance for health management, by protecting cells and body tissues from the oxidative stress caused by free radicals, among others.

ASTAXANTHIN producers have conducted several studies in recent years to demonstrate the safety of natural ASTAXANTHIN derived from Haematococcus (16-18). A randomized, double-blind, placebo-controlled, 8-week trial designed to determine the safety of ASTAXANTHIN in 35 healthy adults was published recently (19). Results revealed that healthy adults can safely consume 6 mg of ASTAXANTHIN per day from Haematococcus pluvialis algal extract.
Based on recent findings, we believe that a daily dose of ASTAXANTHIN will have an important influence in preventing a broad array of age related diseases. Moreover, small daily doses of ASTAXANTHIN may prevent or delay the onset of some diseases, thus saving society significant sums of money.

NATURAL vs. SYNTHETIC ASTAXANTHIN

The chemical difference between natural and synthetic ASTAXANTHIN lies in the stereochemical orientation of the molecules in space (those different molecules are called “enantiomers”).
ASTAXANTHIN exists in three main enantiomeric forms, termed 3S-3’S, 3R-3’S, and 3R-3’R, depending on the spatial orientation of the hydroxyl (OH) groups in chiral carbon number 3 (see Fig.1). Quite simply stated, chirality and stereo differentiation are crucial factors in biological activity because in nature, at a molecular level, asymmetry dominates biological processes, such as enzymatic and most immunological reactions. Chirality is not a prerequisite for bioactivity but in bioactive molecules where one or more chiral centers are present, great differences are usually observed in the activities of the different enantiomers. This is a general phenomenon that applies to many bioactive substances, such as drugs, flavors, fragrances and food additives.

A recent study showed that farmed salmon, like most of the salmon sold in supermarkets, can be easily distinguished from wild salmon in its ASTAXANTHIN isomers, because farmed salmon are fed synthetic ASTAXANTHIN (20). The pigment in wild salmon is found overwhelmingly in the 3S-3’S enantiomeric form, the same form as that found in Haematococcus. Synthetic ASTAXANTHIN from petrochemical sources contains a mixture of all the enantiomers of ASTAXANTHIN, as a direct result of its chemical synthesis, primarily (~50%) the 3R-3’S enantiomer (the meso form). Indeed, in an elegant human study, Østerlie and co-workers (74-76) found that humans selectively absorb the different isomers and their relative concentrations were found to differ in various organs. It is important to note that nearly all studies showing ASTAXANTHIN's health-beneficial effects in humans were performed on the stereoisomer found in Haematococcus, 3S-3’S. Although the other stereoisomers may not be harmful, no significant biological effect has been established.

Moreover, natural ASTAXANTHIN exists in algae and fish as mono- and di-esters of fatty acids, while synthetic ASTAXANTHIN is produced and sold for salmon farming as free hydroxy ASTAXANTHIN. In nutraceutical applications as well, scientists have proven that one of the main advantages of natural ASTAXANTHIN esters is that the esterified form is inherently more stable than the free form, providing for a significantly longer shelf life without being oxidized. Several recent studies clearly showed the positive effect of ASTAXANTHIN esters mixed with fat formulations on the oral bioavailability of ASTAXANTHIN in humans (21,22).

THE PRODUCTION OF NATURAL ASTAXANTHIN BY HAEMATOCOCCUS PLUVIALIS

The microalga Haematococcus pluvialis synthesizes and accumulates ASTAXANTHIN to relatively high levels. The commercial production process is based on two distinct cultivation stages. The first is called the "Green Stage," which starts indoors with a single-cell colony of the microalga, and continues outdoors in solar-powered photobioreactors. The aim of this stage is to produce plenty of viable, unstressed "green" algal cells by normal cell-division process (see Fig. 2). The "Green Stage" provides optimal growth conditions in order to achieve maximal biomass production rate. The second cultivation stage is the "Red Stage" (see Fig. 2), in which the algal cells synthesize and accumulate the pigment ASTAXANTHIN. This stage starts by subjecting the cells to severe stress conditions, mainly high radiation intensity and changes in growth media. As a result, the Haematococcus cells start to form cysts by producing thick cell walls, and to synthesize and accumulate ASTAXANTHIN in its esterified form. Cultivating the algal culture in closed systems allows an environmentally controlled process with less biological and chemical contamination. Following the "Red" process, the level of ASTAXANTHIN in the "red cells" may reach up to ~4% of their dry weight. The ASTAXANTHIN content of the "red cells" is correlated to the severity of the stress conditions, mainly to the light flux through the culture. In due time, the "red" culture is pumped to the down-processing area, where the cells are cracked (to render the pigment bioavailable), dried, and vacuum-packed. Haematococcus oleoresin is produced in an additional step, using the CO2 Supercritical Fluid Extraction process. Increasingly, both consumers and regulatory agencies are requiring extracts that contain no residual solvents. U.S. Nutra of Eustis, FL, has the technology to extract Haematococcus with CO2 and without any co-solvents.

Very few companies commercially produce ASTAXANTHIN from Haematococcus pluvialis. The Hawaiian companies Cyanotech Corporation and Mera Pharmaceuticals cultivate the algae using an open pond system for the "Red Stage." The Japanese company Fuji Chemicals operates an indoor facility in Sweden and its "dome-shaped" bioreactors in Hawaii.

Algatech uses tubular solar-powered photobioreactors for both the "Green" and "Red" stages in closed, strictly controlled systems (see Figs. 3 and 4). Algatech produces its ASTAXANTHIN from the microalga Haematococcus pluvialis according to its patented biocontrolled growing process (1). The plant is located in the southern part of Israel, in the Negev Desert, near the resort city of Eilat, thus exploiting the area's high solar radiation year-round.

The major parameters used to assess high-quality commercial Haematococcus biomass and oleoresins are high ASTAXANTHIN content in the product, low levels of biological and chemical contamination, and excellent stability of the ASTAXANTHIN in the product. Producing ASTAXANTHIN in a closed system throughout the entire process ("Green" and "Red") in an area with high solar-radiation intensity year-round, as in the case of Algatech, yields high-quality ASTAXANTHIN products (see Fig. 5). This algal biomass contains ~4% of its dry weight as ASTAXANTHIN. The production of the algal biomass in flake form (as with Algatechnologies’ dry biomass), offers additional clear advantages when an extraction process is required for the production of high-quality oleoresin with ~ 10% ASTAXANTHIN concentration.

See next page for:

• Medical and Nutraceutical Applications of Astaxanthin
• Conclusions and Product Future
• Articles and Scientific References

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