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Synthetic astaxanthin is significantly inferior to algal-based astaxanthin as an antioxidant and may not be suitable as a human nutraceutical supplement


Abstract and Figures

Synthetic astaxanthin (S-AX) was tested against natural astaxanthin from Haematococcus pluvialis microalgae (N-AX) for antioxidant activity. In vitro studies conducted at Creighton University and Brunswick Laboratories showed N-AX to be over 50 times stronger than S-AX in singlet oxygen quenching and approximately 20 times stronger in free radical elimination. N-AX has been widely used over the last 15 years as a human nutraceutical supplement after extensive safety data and several health benefits were established. S-AX, which is synthesised from petrochemicals, has been used as a feed ingredient, primarily to pigment the flesh of salmonids. S-AX has never been demonstrated to be safe for use as a human nutraceutical supplement and has not been tested for health benefits in humans. Due to safety concerns with the use of synthetic forms of other carotenoids such as canthaxanthin and beta-carotene in humans, the authors recommend against the use of S-AX as a human nutraceutical supplement until extensive, long-term safety parameters have been established and human clinical trials have been conducted showing potential health benefits. Additionally, differences in various other properties between SAX and N-AX such as stereochemistry, esterification and the presence of supporting naturally occurring carotenoids in N-AX are discussed, all of which elicit further questions as to the safety and potential health benefits of S-AX. Ultimately, should S-AX prove safe for direct human consumption, dosage levels roughly 20–30 times greater than N-AX should be used as a result of the extreme difference in antioxidant activity between the two forms.
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Original Research
Nutrafoods (2013)
DOI 10.1007/s13749-013-0051-5
Synthetic astaxanthin is significantly inferior
to algal-based astaxanthin as an antioxidant and may
not be suitable as a human nutraceutical supplement
Bob Capelli, Debasis Bagchi, Gerald R. Cysewski
Received 7 January / Accepted 3 December 2013
© Springer Healthcare – CEC Editore 2013
Synthetic astaxanthin (S-AX) was tested against
natural astaxanthin from Haematococcus pluvialis
microalgae (N-AX) for antioxidant activity. In vitro
studies conducted at Creighton University and
Brunswick Laboratories showed N-AX to be over
50 times stronger than S-AX in singlet oxygen
quenching and approximately 20 times stronger
in free radical elimination. N-AX has been widely
used over the last 15 years as a human nutraceutical
supplement after extensive safety data and several
health benefits were established. S-AX, which is
synthesised from petrochemicals, has been used as
a feed ingredient, primarily to pigment the flesh
of salmonids. S-AX has never been demonstrated
to be safe for use as a human nutraceutical supple-
ment and has not been tested for health benefits
in humans. Due to safety concerns with the use of
synthetic forms of other carotenoids such as can-
thaxanthin and beta-carotene in humans, the au-
thors recommend against the use of S-AX as a hu-
man nutraceutical supplement until extensive,
long-term safety parameters have been established
and human clinical trials have been conducted
showing potential health benefits. Additionally,
differences in various other properties between S-
AX and N-AX such as stereochemistry, esterification
and the presence of supporting naturally occurring
carotenoids in N-AX are discussed, all of which
elicit further questions as to the safety and potential
health benefits of S-AX. Ultimately, should S-AX
prove safe for direct human consumption, dosage
levels roughly 20–30 times greater than N-AX
should be used as a result of the extreme difference
in antioxidant activity between the two forms.
Astaxanthin is a member of the carotenoid family.
Carotenoids are divided into two groups: carotenes
such as beta-carotene and lycopene, and xantho-
phylls such as astaxanthin, lutein and canthaxan-
thin. The main structural difference between the
two groups is that xanthophylls exclusively have
hydroxyl groups at the end of the molecules. Astax-
anthin is unique in that it has more hydroxyl groups
than other xanthophylls, which may account for
Bob Capelli (),Gerald R. Cysewski
Cyanotech Corporation
Kailua-Kona, HI, USA
tel +1-808-3261353
fax +1-808-3294533
Debasis Bagchi
Pharmacological and Pharmaceutical Sciences Department
University of Houston, College of Pharmacy
Houston, TX, USA
Correspondence to:
Bob Capelli
synthetic astaxanthin
natural astaxanthin
acid molecules attached to the ends of the astax-
anthin molecule). In Fig. 1, a diester of astaxanthin
is shown where R and Rare 16:0 (palmitic acid),
18:1 (oleic acid) or 18:2 (linolenic acid). Compara-
tively, S-AX is completely different from N-AX; it
is exclusively “free” astaxanthin (meaning that it
is non-esterified and has no fatty acids attached to
the ends of the molecule).
Secondly, the N-AX and S-AX molecules are shaped
differently. This difference in stereochemistry is evi-
denced by the existence of three distinct enantiomers
as seen in Fig. 2: enantiomer 1 is 3S,3S, enantiomer
2 is 3R,3R and enantiomer 3 is 3R,3S (known as
“meso”). So, while natural and synthetic astaxanthin
share the same molecular formula, 75% of the mol-
ecules are shaped differently. The differences between
N-AX and S-AX are also quite profound:
its superior antioxidant activity and its more diverse
and profound health benefits in humans [1].
Natural astaxanthin (N-AX) occurs in Haematococcus
pluvialis, a ubiquitous unicellular microalgae, which
grows in fresh water throughout the world. Com-
mercially, N-AX is extracted from H. pluvialis mi-
croalgae grown in closed systems or open pond sys-
tems by several different companies. When subjected
to environmental stress, these algae hyperaccumu-
late N-AX as a survival mechanism. N-AX protects
the algae cells extremely efficiently; the algae can
live for over 40 years with no food or water and in
extreme heat or cold due to the protective effects of
N-AX. This natural form of astaxanthin was first
sold as a human nutraceutical supplement in the
late 1990s when it was allowed for sale by the US
Food and Drug Administration (FDA) as a new di-
etary ingredient. An extensive array of human clin-
ical trials from around the world have established
health benefits for N-AX in areas such as eye and
brain health, UV protection and skin health, anti-
inflammatory activity, immune system modulation
and cardiovascular health among others [2–10].
Synthetic astaxanthin (S-AX) is produced by a
highly involved, multistep process from petro-
chemicals by a handful of large chemical compa-
nies. During the steps in this process, the molecule
assumes different forms before finally arriving at
its final stage, when it attains the same chemical
formula as N-AX. S-AX is then sold in the animal
feed market where it is added primarily to fish feeds
with the purpose of pigmenting the flesh of certain
species of commercially farmed fish, predominantly
salmonids such as Atlantic salmon and trout. S-AX
has not undergone safety testing for direct human
use and has not been documented to have any
physiological benefits in humans; it has thus never
been registered with regulatory authorities for direct
human use in any country [1].
The main differences between N-AX and S-AX are
three-fold: Firstly, N-AX is comprised of 95% ester-
ified molecules, both monoesterified and diesteri-
fied (meaning they have either one or two fatty
Nutrafoods (2013)
Figure 1 Diester of astaxanthin
11’ 3’
814 7
Figure 2 Three different enantiomers of astaxanthin
OAstaxanthin 3R, 3’R
OAstaxanthin 3R, 3’S
OAstaxanthin 3S, 3’S
The presence of three additional, naturally oc-
curring carotenoids in N-AX [1]
For these reasons, we suggest that the synthetically
produced form must be considered unique from
other forms and should not be introduced for direct
human use until long-range safety parameters are
established and human clinical trials showing po-
tential benefits have been conducted.
Another commercial source of astaxanthin is Xan-
thophyllomyces dendrorhous. This is a species of yeast
formerly known as Phaffia rhodozyma. While the
yeast in nature produces small amounts of astaxan-
thin, commercial manufacturers use a genetically
mutated form to produce higher amounts of astax-
anthin. The astaxanthin present in this yeast is ex-
tremely different from the astaxanthin found in
the marine food chain.For example, similar to S-
AX, it has a completely different stereochemistry
from N-AX. Another key difference is that it is 100%
non-esterified. This astaxanthin product from mu-
tated yeast is allowed for human consumption in
some countries; however, due to insufficient safety
data, use is only permitted with restrictions. For ex-
ample, it is allowed by the US FDA, but with re-
strictions against long-term use, against the use in
children and, perhaps most significantly, at dosage
levels of only 2 mg/day. Generally, a 2 mg dosage
of N-AX has only been shown to be sufficient in
human clinical research in the area of immunomod-
ulation [9], one of many potential physiological
benefits of astaxanthin. The literature does not con-
tain human clinical research on this yeast form of
astaxanthin. For this reason and due to safety con-
cerns, discussion of this form of astaxanthin re-
mains outside the scope of this paper [1].
Materials and methods
The free radicals superoxide anion and hydroxyl
radical were generated in vitro:
Superoxide anion radical: Xanthine (100 µM) in 5
N-AX contains 100% 3S,3S enantiomer.
S-AX contains a combination of three different
enantiomers: It has 25% 3S,3S (the same shaped
molecules as N-AX), but it contains primarily
molecules shaped differently from N-AX: 50% is
meso-astaxanthin comprised of the 3R,3S enan-
tiomer. Lastly, 25% is pure “R” enantiomer 3R,3R.
Thirdly, S-AX is exclusively synthetic astaxanthin
and contains no supporting carotenoids, while N-
AX is naturally complexed in Haematococcus mi-
croalgae with other carotenoids, as seen in Fig. 3.
When lipids are extracted from the algae, the re-
sulting extract contains primarily N-AX, but it also
contains three other naturally occurring carotenoids.
The resulting “natural carotenoid complex” contains
70% monoesterified astaxanthin
10% diesterified astaxanthin
5% free astaxanthin
6% beta-carotene
5% canthaxanthin
4% lutein
Due to three clear differences between these two
forms of astaxanthin, N-AX and S-AX cannot be
considered the same molecule. While they share
the same chemical formula, there are vast differ-
ences between N-AX and S-AX in:
Nutrafoods (2013)
Figure 3 Carotenoid breakdown of N-AX
Astaxanthin free
xanthin freestaA
xanthin sta
xanthin staA
70 aroteneBeta-c
#9335). N-AX proved to be 14–65 times more po-
tent at eliminating free radicals when compared
directly against these other antioxidants, including
S-AX. N-AX was approximately 20 times more po-
tent at free radical elimination than S-AX. Results
are summarised in Table 1 and Fig. 4.
Antioxidant activity of N-AX (as BioAstin®Hawai-
ian Astaxanthin by Cyanotech Corporation, Kailua-
Kona, HI) and S-AX (as Vivital™ AstaFeed by Divis
Laboratories, Morristown, NJ) was measured in a
suite of tests by Brunswick Laboratories (Southbor-
ough, MA). Results are shown in Table 2. N-AX was
mM Tris-HCl buffer was incubated with 8 mU/ml
of xanthine oxidase to generate superoxide anion.
Hydroxyl radical: The incubation mixture to gen-
erate hydroxyl radical contained, in a total vol-
ume of 2 ml, 5 mM Tris-HCl, 100 µM FeCl3, 100
µM EDTA and 100 µM xanthine. Xanthine oxi-
dase (8 mU/ml) was added to initiate the reaction
and to produce hydroxyl radicals [11].
Chemiluminescence measurements
Chemiluminescence, as an index of reactive oxygen
species production, was measured in a Chronolog
Lumivette luminometer (Chronolog Corp., Philadel-
phia, PA). The assay was conducted in 3 ml glass
minivials. The vials were incubated at 37°C prior to
measurement and the background chemilumines-
cence of each vial was checked before use. Samples
were preincubated at 37°C for 15 min, and 4µM lu-
minol was added to enhance chemiluminescence.
All additions to the vials as well as chemilumines-
cence counting procedures were performed under
dim lighting conditions. Results were examined as
counts per unit of time minus background. Chemi-
luminescence was monitored for 6 min at continu-
ous 30-s intervals [12].
Statistical analyses
Significance between pairs of mean values was de-
termined by Student’s t-test. p<0.05 was considered
significant for analysis.
Replicates for the Creighton University free radical
inhibition research were conducted four to six
times. Replicates for the Brunswick Laboratories
analyses were conducted two to three times.
In vitro work done at Creighton University School
of Pharmacy and Allied Health Professions (Omaha,
NE) matched N-AX (as BioAstin®Hawaiian Astax-
anthin from Cyanotech Corporation) against sev-
eral other well known natural antioxidants such as
vitamin C, vitamin E, beta-carotene, Pycnogenol®
pine bark extract and S-AX (as Sigma catalogue
Nutrafoods (2013)
Table 1 Free radical eliminating potency of various antioxidants
Material Active Free radical Free radical N-AX relative
material inhibition inhibition performance
used (mg) in study (%) per mg active
material (%)
Vitamin C 100 19 0.19 N-AX 65×
Vitamin E 50 43 0.86 N-AX 14×
Beta-carotene 100 23 0.23 N-AX 53×
Pycnogenol 100 69 0.69 N-AX 18×
S-AX 100 59 0.59 N-AX 20×
N-AX 5 61.7 12.34 N/A
Figure 4 Free radical eliminating potency of various antioxidants
Vitamin C
Vitamin E
% Free Radical Inhibition per mg
4681012 14
Regardless of this minor issue with the ORAC test,
the outcome of this research is clear: N-AX is a su-
perior antioxidant to S-AX by more than an order
of magnitude. Results range from approximately
14 times stronger in the overall ORAC summary
score to more than 20 times stronger in free radical
elimination to as high as 55 times stronger in sin-
glet oxygen quenching.
N-AX has proven to be exceptionally more power-
ful than other common antioxidants as well as S-
AX; tested against other commonly used antioxi-
dants, it scored a minimum of 14 to a maximum
of 65 times higher in free radical elimination. Two
separate antioxidant tests were performed directly
comparing N-AX with S-AX, one at a leading uni-
versity and the other at an independent laboratory
specialising in antioxidant testing. The results of
this testing showed that:
N-AX is approximately 55 times stronger than S-
AX in singlet oxygen elimination.
N-AX is approximately 20 times stronger than S-
AX in free radical elimination.
N-AX is approximately 14 times stronger than S-
AX in the suite of antioxidant tests known as
For these reasons, should it be commercialised for
human use, S-AX would have to be used at a rate
14–55 times greater than N-AX to obtain the same
antioxidant protection. Current dosage recommen-
55 times stronger than S-AX in eliminating singlet
oxygen in vitro. Similar to the results at Creighton
University cited above, N-AX was over 20 times
stronger than S-AX in eliminating the superoxide
ion. N-AX was 3.5 times stronger against peroxyl
radicals. N-AX performed significantly worse than
S-AX against peroxynitrite, with only 24% of the
antioxidant power of S-AX. Peroxynitrite is pro-
duced from the diffusion-controlled reaction be-
tween nitric oxide and the superoxide anion. Per-
oxynitrite interacts with lipids, DNA and proteins
via direct oxidative reactions or via indirect, radi-
cal-mediated mechanisms. However, N-AX de-
creases nitric oxide production [7] and has very
powerful activity against the superoxide anion and
hence, would decrease the production of perox-
ynitrite, rendering this particular result less mean-
ingful. In the final survey by Brunswick Laborato-
ries, antioxidant activity against hydroxyl radicals
was measured. Unfortunately, a different procedure
from that used at Creighton University was em-
ployed, and no result was obtained for N-AX, ren-
dering this test incomparable. Brunswick Labora-
tories issues a summary score for this suite of
antioxidant tests called oxygen radical absorbance
capacity (ORAC). Including the hydroxyl test for
which the N-AX score was not determined and the
peroxynitrite test in which S-AX performed better
than N-AX, the summary result found N-AX to be
14 times stronger overall as an antioxidant than S-
AX.The results are summarised in Table 2.
Creighton University tests were carried out under
the supervision of Debasis Bagchi, the developer
of a method of free radical generation and an expert
in antioxidant research. Brunswick Laboratories is
regarded as a leading antioxidant research labora-
tory, and while it is unclear why results for hy-
droxyl radicals were unavailable for N-AX, it is clear
that this lab is a competent source for antioxidant
testing. One possible reason why the N-AX score
in the hydroxyl radical test was not determined is
that N-AX may not be soluble in the solvent used
in this ORAC test.
Nutrafoods (2013)
Test N-AX S-AX N-AX vs. S-AX
Antioxidant power against singlet oxygen 12,055 220 55× stronger
Antioxidant power against super oxide ion 5,377 258 21× stronger
Antioxidant power against peroxyl radicals 574 165 3.5× stronger
Antioxidant power against peroxynitrite 28 115 0.24× of S-AX's
Antioxidant power against hydroxyl radicals Not 538 Not
determined comparable
Total ORACFN antioxidant power 18,034 1,296 14× stronge
Table 2 Antioxidant power against various oxidants of N-AX
vs. S-AX (Brunswick Laboratories antioxidant test
results; all numbers in moles TE per gram; N=2–3)
Also, synergy can play an important role in vitamin
E’s effects. In a study published in the Journal of the
National Cancer Institute, it was found that alpha-
tocopherol, gamma-tocopherol and selenium work
in concert to prevent prostate cancer. In other
words, benefits increased with the complete vitamin
complex versus single synthesised molecules [14].
Carotenoids in their synthetic forms in particular
yield very significant safety concerns. The most re-
searched carotenoid to date is beta-carotene. The
literature is full of studies demonstrating a variety
of health benefits for beta-carotene in areas such
as immunity, prevention of cancer and skin health
[15]. However, the differences in absorption be-
tween the synthetic and natural varieties of beta-
carotene are profound; in one study, natural beta-
carotene was absorbed ten times better than the
synthetic form by rats and chickens [16]. Not only
is absorption a concern, but also efficacy. Similar
to our results with S-AX versus N-AX in antioxidant
potential, synthetic beta-carotene does not have
the same antioxidant abilities as its natural cousin.
Synthetic beta-carotene is primarily the trans form,
while natural beta-carotene contains large amounts
of the cis form. The 9-cis beta-carotene form, which
is found in high amounts in natural beta-carotene,
is a more efficient lipophilic antioxidant than the
synthetic trans form. The stereochemistry of this
carotenoid (similar to the situation with astaxan-
thin) is important in antioxidant potential as well
as absorption and transport [17].
Perhaps the most significant difference found in
the literature between natural and synthetic forms
of beta-carotene was demonstrated in the famous
“Finnish Smokers Study” in the 1990s. After scores
of epidemiological studies, in vitro and preclinical
animal trials demonstrated that natural beta-
carotene has cancer-preventative properties [15]. A
study of men from Finland who smoked on average
three packs of cigarettes per day found an unex-
pected outcome: when supplemented with syn-
thetic beta-carotene, there was a slight increase in
cancer among the treatment group versus the
dations for humans for N-AX range from 2 to 16
mg/day based on extensive human clinical trials
showing a wide range of health benefits. Based on
this dosage range for N-AX, should S-AX be allowed
for human use, the resulting recommended range
would be a minimum of 28 mg/day to a maximum
of 880 mg/day when considering the differences in
antioxidant activity. With an average difference of
antioxidant measurements in the range of 20×–30×,
and an average human dosage of 8 mg/day, the av-
erage dose for S-AX would be in the proximity of
160–240 mg/day. Before release to human con-
sumers, long-range safety trials should be conducted
at this dosage level to ensure that, unlike synthetic
beta-carotene and synthetic canthaxanthin, there
are no concerns with S-AX in areas such as carcino-
genesis or retinal crystal formation (see below).
Other nutraceutical supplements that are available
in both synthetic and natural forms show safety
concerns with their synthetic form. This includes
molecules closely related to astaxanthin such as
the carotenoids beta-carotene and canthaxanthin
as well as other nutraceuticals such as vitamin E.
While the exact cause of the differences between
natural and synthesised forms of nutraceuticals is
not known, one logical theory is that synthesised
compounds may not be the most physiologically
valuable part of the natural nutrient complex. For
example, synthesised vitamin E is exclusively DL-
alpha tocopherol, while natural vitamin E is a com-
plex of several mixed tocopherols and tocotrienols.
Nutrients may be synergistic, meaning that they
may work best when taken in concert with other
compounds in their natural forms.
Research has shown that synthetic vitamin E may
be inferior to the natural form in its physiological
properties. Synthetic E, which is exclusively DL-
alpha tocopherol, has a limited ability to yield
health benefits. Members of the natural vitamin E
complex have essential independent functions. For
example, the alpha-tocotrienol component of the
natural E complex prevents neurodegeneration. To-
cotrienols are not found in synthetic vitamin E [13].
Nutrafoods (2013)
2011 found that complete disappearance of the
golden crystals took approximately 20 years [22].
The differences in regards to safety between natural
and synthetic forms of nutraceutical supplements
raise concern for the introduction of new synthetic
versions of supplements. Particularly worrisome are
the safety concerns with synthetic carotenoids. Syn-
thetic beta-carotene’s increase of cancer rates in
smokers and synthetic canthaxanthin causing un-
natural retinal crystallisation are clear evidence that
extensive, long-range safety testing of S-AX and
other synthetic carotenoids are necessary before re-
lease to human consumers. Additionally, serious
questions of efficacy exist with synthetic com-
pounds such as synthetic vitamin E, synthetic beta-
carotene and synthetic canthaxanthin when com-
pared to their natural forms. The lack of efficacy
and safety in synthetic supplements are most likely
due to the profound differences between syntheti-
cally produced nutraceutical compounds and their
naturally occurring counterparts. For example, in
the case of astaxanthin, far-ranging, extensive dif-
ferences in the shape of the molecule; the esterifi-
cation of the molecule; and the presence of other
naturally occurring carotenoids in their natural
form in N-AX lead us to the conclusion that S-AX
and N-AX, although both called “astaxanthin”,
must be considered completely different substances.
For these reasons, the authors recommend against
the use of S-AX in human nutraceutical supple-
ments until extensive, long-range safety parameters
are established and human clinical trials showing
health benefits are conducted. In the event that S-
AX attains these two milestones, due to the exten-
sive differences between the two molecules, it
should be distinctly labelled as “synthetic astaxan-
thin” on consumer product labels, and dosage levels
should be approximately 20–30 times those of N-
AX in order to obtain similar antioxidant activity.
This research was made possible by grants from Cyanotech Cor-
poration, Kailua-Kona, Hawaii, USA.
placebo group [18]. This study was very troubling
to many consumers who were taking beta-carotene
as a cancer preventative supplement. Further re-
search comparing synthetic beta-carotene with nat-
ural beta-carotene extracted from Dunaliella salina
microalgae found that synthetic beta-carotene may
be involved in the formation of cancer. This same
study concluded that natural beta-carotene could
be valuable in tumour prevention and supplemen-
tary treatment [19]. The possibility that synthetic
beta-carotene may cause cancer while natural beta-
carotene may prevent cancer is the most grave con-
cern of all when considering the introduction of S-
AX, a related carotenoid, as a supplement for
human use.
Synthetic canthaxanthin taken as a supplement
has also yielded grave concerns. This is particularly
relevant to our discussion in this paper since can-
thaxanthin is in the same carotenoid family as
beta-carotene and astaxanthin, but is even more
closely related to astaxanthin than beta-carotene
is. Canthaxanthin, like astaxanthin, falls into the
xanthophyll subgroup since it has hydroxyl groups
attached to its molecules. Natural canthaxanthin
is not currently available commercially since
sources for the natural form are limited. Canthax-
anthin is, however, available in its synthetic form,
and is used as an addition to animal feeds similar
to S-AX. It is important to note that governments
around the world consider synthetic canthaxanthin
a safety concern, and limit or prohibit its use in
animal feeds [20,21]. The safety concern centres
on crystallisation in the retina due to supplemen-
tation with synthetic canthaxanthin. In the late
1980s, synthetic canthaxanthin was marketed as
an internal tanning pill for people who wished to
appear sun-tanned without going out in the sun.
The product was abruptly taken off the market
when golden crystals were found in consumers’
retinas. The crystallisation disappeared over time
after discontinuing consumption of synthetic can-
thaxanthin. But it is disconcerting to note how
long reversal took: follow-up research published in
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Conflict of interest
Bob Capelli and Gerald R. Cysewski are employees and stock-
holders of Cyanotech Corporation, the company that sponsored
this research. Debasis Bagchi is a professor at the University of
Houston College of Pharmacy and was formerly a professor at
Creighton University where he oversaw research described
herein. He is independent and has no conflict of interest.
Human and Animal Rights
This article does not contain any studies with human or animal
subjects performed by any of the authors.
An extensive compilation of published research on astaxanthin
is available from the authors. Please contact us at info@cyan-
1. Capelli B, Cysewski G (2012) The world’s best kept health
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Nutrafoods (2013)
... Astaxanthin can also be synthesized chemically, with synthetic astaxanthin chemically synthesized from petrochemicals in a highly involved, multistep process, where the molecules assume different forms before attaining the same chemical formula as natural astaxanthin [11]. However, despite sharing the same chemical formula, synthetic and natural astaxanthin differ substantially in three aspects: esterification, stereochemistry, and the presence of other naturally occurring carotenoids in natural astaxanthin. ...
... One of the most powerful known antioxidant properties is possessed by natural astaxanthin, which is regarded as a super antioxidant. Natural astaxanthin is 55× more potent than synthetic astaxanthin in trapping free radicals in our system [10,11]. Astaxanthin does, however, exist in H. pluvialis in three distinct forms that can be categorized as free (5%), monoesters (70%), and diesters (25%). ...
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Previous reviews have already explored the safety and bioavailability of astaxanthin, as well as its beneficial effects on human body. The great commercial potential in a variety of industries, such as the pharmaceutical and health supplement industries, has led to a skyrocketing demand for natural astaxanthin. In this study, we have successfully optimized the astaxanthin yield up to 12.8 mg/g DCW in a probiotic yeast and purity to 97%. We also verified that it is the desired free-form 3S, 3’S configurational stereoisomer by NMR and FITR that can significantly increase the bioavailability of astaxanthin. In addition, we have proven that our extracted astaxanthin crystals have higher antioxidant capabilities compared with natural esterified astaxanthin from H. pluvialis. We also screened for potential adverse effects of the pure astaxanthin crystals extracted from the engineered probiotic yeast by dosing SD rats with 6, 12, and 24 mg/kg/day of astaxanthin crystals via oral gavages for a 13-week period and have found no significant biological differences between the control and treatment groups in rats of both genders, further confirming the safety of astaxanthin crystals. This study demonstrates that developing metabolically engineered microorganisms provides a safe and feasible approach for the bio-based production of many beneficial compounds, including astaxanthin.
... Previous research assayed that microalgal astaxanthin could be better than synthetic astaxanthin in astaxanthin accumulation, safety, and potential nutritive quality of Chinese mitten crab (Eriocheir sinensis) (Yang et al. 2017;Su et al. 2020). Besides, synthetic astaxanthin is markedly inferior to algal natural astaxanthin as an antioxidant (Capelli et al. 2013). Thus, natural astaxanthin from algae and aquatic animals has shown better benefits than synthetic astaxanthin. ...
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Astaxanthin is the main natural C40 carotenoid used worldwide in the aquaculture industry. It normally occurs in red yeast Phaffia rhodozyma and green alga Haematococcus pluvialis and a variety of aquatic sea creatures, such as trout, salmon, and shrimp. Numerous biological functions reported its antioxidant and anti-inflammatory activities since astaxanthin possesses the highest oxygen radical absorbance capacity (ORAC) and is considered to be over 500 more times effective than vitamin E and other carotenoids such as lutein and lycopene. Thus, synthetic and natural sources of astaxanthin have a commanding influence on industry trends, causing a wave in the world nutraceutical market of the encapsulated product. In vitro and in vivo studies have associated astaxanthin’s unique molecular features with various health benefits, including immunomodulatory, photoprotective, and antioxidant properties, providing its chemotherapeutic potential for improving stress tolerance, disease resistance, growth performance, survival, and improved egg quality in farmed fish and crustaceans without exhibiting any cytotoxic effects. Moreover, the most evident effect is the pigmentation merit, where astaxanthin is supplemented in formulated diets to ameliorate the variegation of aquatic species and eventually product quality. Hence, carotenoid astaxanthin could be used as a curative supplement for farmed fish, since it is regarded as an ecologically friendly functional feed additive in the aquaculture industry. In this review, the currently available scientific literature regarding the most significant benefits of astaxanthin is discussed, with a particular focus on potential mechanisms of action responsible for its biological activities.
... Allergic reactions to the consumption of H. pluvialis proteins cannot be excluded, but their likelihood has been considered low in tested astaxanthinrich novel food ingredients by the European Food Safety Authority (EFSA) [39]. It can also be produced synthetically, but its natural form has gained interest with respect to consumer demands [40,41]. A major source for the biotechnological production of astaxanthin is the green alga Haematococcus pluvialis [11,42]. ...
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Astaxanthin derived from natural sources occurs in the form of various esters and stereomers, which complicates its quantitative and qualitative analysis. To simplify and standardize astaxanthin measurement with high precision, an enzymolysis-based astaxanthin quantification method was developed to hydrolyze astaxanthin esters and determine free astaxanthin in all its diastereomeric forms. Astaxanthin standards and differently processed Haematococcus pluvialis biomass were investigated. Linear correlation of standards of all- E- astaxanthin was observed in a measurement range between extract concentrations of 1.0 μg/mL and 11.2 μg/mL with a coefficient of variation below 5%. The diastereomers 9 Z- , and 13 Z-astaxanthin , and two di- Z -forms were detected. In contrast to the measurement of standards, the observed measurement range was extended to 30 μg/mL in extracts from H . pluvialis . The nature of the sample had to be taken into account for measurement, as cell, respectively, sample composition altered the optimal concentration for astaxanthin determination. The measurement precision of all- E- astaxanthin quantification in dried H . pluvialis biomass (1.2–1.8 mg dried biomass per sample) was calculated with a coefficient of variation of maximum 1.1%, whereas it was below 10% regarding the diastereomers. Complete enzymolysis was performed with 1.0 to 2.0 units of cholesterol esterase in the presence of various solvents with up to 2.0 mg biomass (dry weight). The method was compared with other astaxanthin determination approaches in which astaxanthin is converted to acetone in a further step before measurement. The developed method resulted in a higher total astaxanthin recovery but lower selectivity of the diastereomers. The reliability of photometric astaxanthin estimations was assessed by comparing them with the developed chromatographic method. At later stages in the cell cycle of H . pluvialis , all methods yielded similar results (down to 0.1% deviation), but photometry lost precision at earlier stages (up to 31.5% deviation). To optimize sample storage, the shelf life of astaxanthin-containing samples was investigated. Temperatures below -20°C, excluding oxygen, and storing intact H . pluvialis cells instead of dried or disrupted biomass reduced astaxanthin degradation.
... As a result, astaxanthin is able to modulate biological functions related to lipid peroxidation, resulting in beneficial effects in terms of prevention and co-treatment of chronic degenerative diseases, such as cardiovascular and neurodegenerative diseases, macular degeneration, and cancer [7][8][9][10][11][12][13][14]. Recent studies suggest that natural astaxanthin (NAst) exhibits higher antioxidant and protective activities than other common carotenoids, including its synthetic form [2,9,[15][16][17][18][19][20][21]. Microalgae, its primary bio-synthesizers [20], enhance the reddish-pink colours of the animals that feed on them, such as shrimps, crawfish, crabs, lobsters, trout, and salmonids [22]. It is noteworthy that natural astaxanthin has been approved by the United States Food and Drug Administration (USFDA) as a pigment for use in the aquaculture industry [18,22] and is considered a natural food dye by the European Commission [23][24][25][26]. ...
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Astaxanthin is a red orange xanthophyll carotenoid produced mainly by microalgae but which can also be chemically synthesized. As demonstrated by several studies, this lipophilic molecule is endowed with potent antioxidant properties and is able to modulate biological functions. Unlike synthetic astaxanthin, natural astaxanthin (NAst) is considered safe for human nutrition, and its production is considered eco-friendly. The antioxidant activity of astaxanthin depends on its bioavailability, which, in turn, is related to its hydrophobicity. In this study, we analyzed the water-solubility of NAst and assessed its protective effect against oxidative stress by means of different approaches using a neuroblastoma cell model. Moreover, due to its highly lipophilic nature, astaxanthin is particularly protective against lipid peroxidation; therefore, the role of NAst in counteracting ferroptosis was investigated. This recently discovered process of programmed cell death is indeed characterized by iron-dependent lipid peroxidation and seems to be linked to the onset and development of oxidative-stress-related diseases. The promising results of this study, together with the “green sources” from which astaxanthin could derive, suggest a potential role for NAst in the prevention and co-treatment of chronic degenerative diseases by means of a sustainable approach.
ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review astaxanthin which has plausible mechanisms for slowing ALS progression including antioxidant, anti-inflammatory, and anti-apoptotic effects. While there are no ALS-specific pre-clinical studies, one verified “ALS reversal” occurred in a person using a combination of alternative therapies which included astaxanthin. There have been no trials of astaxanthin in people living with ALS. Natural astaxanthin appears to be safe and inexpensive. Based on the above information, we support further pre-clinical and/or clinical trials of astaxanthin in disease models and PALS, respectively, to further elucidate efficacy.
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The rapid increase in global population and shrinkage of agricultural land necessitates the use of cost-effective renewable sources as alternative to excessive resource-demanding agricultural crops. Microalgae seem to be a potential substitute as it rapidly produces large biomass that can serve as a good source of various functional ingredients that are not produced/synthesized inside the human body and high-value nonessential bioactive compounds. Microalgae-derived bioactive metabolites possess various bioactivities including antioxidant, anti-inflammatory, antimicrobial, anti-carcinogenic, anti-hypertensive, anti-lipidemic, and anti-diabetic activities, thereof rapidly elevating their demand as interesting option in pharmaceuticals, nutraceuticals and functional foods industries for developing new products. However, their utilization in these sectors has been limited. This demands more research to explore the functionality of microalgae derived functional ingredients. Therefore, in this review, we intended to furnish up-to-date knowledge on prospects of bioactive metabolites from microalgae, their bioactivities related to health, the process of microalgae cultivation and harvesting, extraction and purification of bioactive metabolites, role as dietary supplements or functional food, their commercial applications in nutritional and pharmaceutical industries and the challenges in this area of research. Graphical abstract
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Pigments are intensely coloured compounds used in many industries to colour other materials. The demand for naturally synthesised pigments is increasing and their production can be incorporated into circular bioeconomy approaches. Natural pigments are produced by bacteria, cyanobacteria, microalgae, macroalgae, plants and animals. There is a huge unexplored biodiversity of prokaryotic cyanobacteria which are microscopic phototrophic microorganisms that have the ability to capture solar energy and CO2 and use it to synthesise a diverse range of sugars, lipids, amino acids and biochemicals including pigments. This makes them attractive for the sustainable production of a wide range of high-value products including industrial chemicals, pharmaceuticals, nutraceuticals and animal-feed supplements. The advantages of cyanobacteria production platforms include comparatively high growth rates, their ability to use freshwater, seawater or brackish water and the ability to cultivate them on non-arable land. The pigments derived from cyanobacteria and microalgae include chlorophylls, carotenoids and phycobiliproteins that have useful properties for advanced technical and commercial products. Development and optimisation of strain-specific pigment-based cultivation strategies support the development of economically feasible pigment biorefinery scenarios with enhanced pigment yields, quality and price. Thus, this chapter discusses the origin, properties, strain selection, production techniques and market opportunities of cyanobacterial pigments.Graphical AbstractKeywordsAstaxanthinChlorophyllFucoxanthinLuteinPhycocyanin Spirulina
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Phospholipid hydroperoxides (PLOOH) accumulate abnormally in the erythrocytes of dementia patients, and dietary xanthophylls (polar carotenoids such as astaxanthin) are hypothesised to prevent the accumulation. In the present study, we conducted a randomised, double-blind, placebo-controlled human trial to assess the efficacy of 12-week astaxanthin supplementation (6 or 12 mg/d) on both astaxanthin and PLOOH levels in the erythrocytes of thirty middle-aged and senior subjects. After 12 weeks of treatment, erythrocyte astaxanthin concentrations were higher in both the 6 and 12 mg astaxanthin groups than in the placebo group. In contrast, erythrocyte PLOOH concentrations were lower in the astaxanthin groups than in the placebo group. In the plasma, somewhat lower PLOOH levels were found after astaxanthin treatment. These results suggest that astaxanthin supplementation results in improved erythrocyte antioxidant status and decreased PLOOH levels, which may contribute to the prevention of dementia.
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Astaxanthin modulates immune response, inhibits cancer cell growth, reduces bacterial load and gastric inflammation, and protects against UVA-induced oxidative stress in in vitro and rodent models. Similar clinical studies in humans are unavailable. Our objective is to study the action of dietary astaxanthin in modulating immune response, oxidative status and inflammation in young healthy adult female human subjects. Participants (averaged 21.5 yr) received 0, 2, or 8 mg astaxanthin (n = 14/diet) daily for 8 wk in a randomized double-blind, placebo-controlled study. Immune response was assessed on wk 0, 4 and 8, and tuberculin test performed on wk 8. Plasma astaxanthin increased (P < 0.01) dose-dependently after 4 or 8 wk of supplementation. Astaxanthin decreased a DNA damage biomarker after 4 wk but did not affect lipid peroxidation. Plasma C-reactive protein concentration was lower (P < 0.05) on wk 8 in subjects given 2 mg astaxanthin. Dietary astaxanthin stimulated mitogen-induced lymphoproliferation, increased natural killer cell cytotoxic activity, and increased total T and B cell subpopulations, but did not influence populations of Thelper, Tcytotoxic or natural killer cells. A higher percentage of leukocytes expressed the LFA-1 marker in subjects given 2 mg astaxanthin on wk 8. Subjects fed 2 mg astaxanthin had a higher tuberculin response than unsupplemented subjects. There was no difference in TNF and IL-2 concentrations, but plasma IFN-gamma and IL-6 increased on wk 8 in subjects given 8 mg astaxanthin. Therefore, dietary astaxanthin decreases a DNA damage biomarker and acute phase protein, and enhances immune response in young healthy females.
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Astaxanthin (Ax), a carotenoid ubiquitously distributed in microorganisms, fish, and crustaceans, has been known to be a potent antioxidant and hence exhibit various physiological effects. We attempted in these studies to evaluate clinical toxicity and efficacy of long-term administration of a new Ax product, by measuring biochemical and hematological blood parameters and by analyzing brain function (using CogHealth and P300 measures). Ax-rich Haematococcus pluvialis extracts equivalent to 4, 8, 20 mg of Ax dialcohol were administered to 73, 38, and 16 healthy adult volunteers, respectively, once daily for 4 weeks to evaluate safety. Ten subjects with age-related forgetfulness received an extract equivalent to 12 mg in a daily dosing regimen for 12 weeks to evaluate efficacy. As a result, no abnormality was observed and efficacy for age-related decline in cognitive and psychomotor functions was suggested.
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The unicellular halotolerant alga Dunaliella bardawil was previously shown to contain high concentrations of beta-carotene composed of about equal amounts of the all-trans and 9-cis isomers. One-d-old chicks and 7-wk-old male rats were fed diets supplemented with synthetic all-trans-beta-carotene or dry D. bardawil at equivalent levels of beta-carotene. The chicks were fed diets containing up to 0.025% beta-carotene for 2 mo, and the rats up to 0.1% beta-carotene for 2 wk. Liver analyses at the end of these periods indicated that both species showed at least a tenfold higher accumulation of the algal beta-carotene isomer mixture than of the synthetic all-trans-beta-carotene. The ratio of 9-cis-beta-carotene to the all-trans isomer in the livers of the algae-fed rats and chicks was similar to or higher, respectively, than that present in the algae. Retinol plus retinyl ester accumulated to a similar extent in the rats and chicks fed diets supplemented with synthetic all-trans or the natural isomer mixture of beta-carotene. The preferable accumulation of the natural isomer mixture of beta-carotene suggests that attention should be paid to the different sources of beta-carotene when testing their efficacy in effects other than providing retinol, such as in their possible role in the prevention of some types of cancer.
Background. Epidemiologic evidence indicates that diets high in carotenoid-rich fruits and vegetables, as well as high serum levels of vitamin E (alpha-tocopherol) and beta carotene, are associated with a reduced risk of lung cancer. Methods. We performed a randomized, double-blind, placebo-controlled primary-prevention trial to determine whether daily supplementation with alpha-tocopherol, beta carotene, or both would reduce the incidence of lung cancer and other cancers. A total of 29,133 male smokers 50 to 69 years of age from southwestern Finland were randomly assigned to one of four regimens: alpha-tocopherol (50 mg per day) alone, beta carotene (20 mg per day) alone, both alpha-tocopherol and beta carotene, or placebo. Follow-up continued for five to eight years. Results. Among the 876 new cases of lung cancer diagnosed during the trial, no reduction in incidence was observed among the men who received alpha-tocopherol (change in incidence as compared with those who did not, -2 percent; 95 percent confidence interval, -14 to 12 percent). Unexpectedly, we observed a higher incidence of lung cancer among the men who received beta carotene than among those who did not (change in incidence, 18 percent; 95 percent confidence interval, 3 to 36 percent). We found no evidence of an interaction between alpha-tocopherol and beta carotene with respect to the incidence of lung cancer. Fewer cases of prostate cancer were diagnosed among those who received alpha-tocopherol than among those who did not. Beta carotene had little or no effect on the incidence of cancer other than lung cancer. Alpha- tocopherol had no apparent effect on total mortality, although more deaths from hemorrhagic stroke were observed among the men who received this supplement than among those who did not. Total mortality was 8 percent higher (95 percent confidence interval, 1 to 16 percent) among the participants who received beta carotene than among those who did not, primarily because there were more deaths from lung cancer and ischemic heart disease. Conclusions. We found no reduction in the incidence of lung cancer among male smokers after five to eight years of dietary supplementation with alpha-tocopherol or beta carotene. In fact, this trial raises the possibility that these supplements may actually have harmful as well as beneficial effects.
The cosmetic effects on human skin by 4mg per day astaxanthin supplementation were demonstrated in a single blind placebo controlled study using forty-nine US healthy middle-aged women. There were significant improvements in fine lines/wrinkles and elasticity by dermatologist's assessment and in the moisture content by instrumental assessment at week 6 compares to base-line initial values.
To describe the long-term outcome of canthaxanthin retinopathy. We identified 13 patients with small golden particles near the macular region among a group of 35 patients with known consumption of canthaxanthin somewhen between 1983 and 1988. One long-term follow-up examination was possible in 5 of 13 cases after 16-24 years. The examinations included determination of visual acuity, the Amsler grid, slit lamp examination, perimetry, electro-oculography, electroretinography, optical coherence tomography and fluorescein angiography. Complete disappearance of the golden particles took approximately 20 years. The patients in our study were asymptomatic and no functional defect related to canthaxanthin could be detected. Ingestion of canthaxanthin causes no long-term adverse effects.
Astaxanthin has been reported to improve dyslipidemia and metabolic syndrome in animals, but such effects in humans are not well known. Placebo-controlled astaxanthin administration at doses of 0, 6, 12, 18 mg/day for 12 weeks was randomly allocated to 61 non-obese subjects with fasting serum triglyceride of 120-200mg/dl and without diabetes and hypertension, aged 25-60 years. In before and after tests, body mass index (BMI) and LDL-cholesterol were unaffected at all doses, however, triglyceride decreased, while HDL-cholesterol increased significantly. Multiple comparison tests showed that 12 and 18 mg/day doses significantly reduced triglyceride, and 6 and 12 mg doses significantly increased HDL-cholesterol. Serum adiponectin was increased by astaxanthin (12 and 18 mg/day), and changes of adiponectin correlated positively with HDL-cholesterol changes independent of age and BMI. This first-ever randomized, placebo-controlled human study suggests that astaxanthin consumption ameliorates triglyceride and HDL-cholesterol in correlation with increased adiponectin in humans.
The feasibility of polymorphonuclear leucocytes as a potential source of free radicals during reperfusion of ischaemic myocardium was evaluated. Isolated rat heart was perfused in the presence of f-Met-Leu-Phe-activated and normal polymorphonuclear leucocytes for 30 min. To judge the degree of cellular injury which might result from activated polymorphonuclear leucocytes during perfusion, isolated hearts were also perfused with superoxide anions, hydroxyl radicals, and hypochlorous acid-generating systems in the absence or presence of their corresponding scavengers, superoxide dismutase plus catalase, dimethylthiourea, and allopurinol, respectively. Activated polymorphonuclear leucocytes stimulated the release of lactate dehydrogenase, a biological marker of cellular injury, and malondialdehyde, a presumptive marker for lipid peroxidation; increased tissue injury, as evidenced by morphologic examinations using light and electron microscopy; decreased dry/wet ratios of heart, signifying oedema formation; and reduced myocardial adenosine triphosphate and creatine phosphate content as well as coronary flow, indicating decreased myocardial performance. These biological, physiological, and morphologic parameters were reversed significantly, but not completely, by treating the heart with scavengers, superoxide dismutase plus catalase or allopurinol, but were reversed completely by simultaneous treatment with superoxide dismutase, catalase, and allopurinol. Comparable results were obtained when the hearts were treated with each of these free radical-generating systems and their corresponding scavengers. Generation of free radicals was confirmed either by cytochrome c reduction or by examining the chemiluminescence response using a luminometer. These results indicate that activated polymorphonuclear leucocytes can cause myocardial cellular injury equivalent to the damage caused by free radicals and oxidants which are present in an ischaemic-reperfused heart, suggesting that polymorphonuclear leucocytes may be a potential source of free radicals in the reperfused heart.