Astaxanthin

Astaxanthin is a reddish pigment that belongs to the structural class known as the 'carotenoids' alongside some others dietary carotenoids such as β-carotene, fucoxanthin, and lutein. It was first the shells of lobster (Astacus gammaus) in 1942 and was later to be widespread among other aquatic organisms including microalgae, fish, and crustacea.^[1][2][3] Astaxanthin is mostly aquatic in nature (except for some instances where it is the red pigmentation of the feathers of flamingos and quail,^[4][5] where it is thought to be stored due to these birds consuming fish), and the two major souces of it are either salmon (dietary) and the microalgae haematococcus pluvialis (supplemental).^[3]

Astaxanthin is a red pigmented carotenoid structure that appears to mostly be aquatic in its origin (similar to fucoxanthin) and is most well known to be a component of wild salmon, conferring the red coloration of these salmon

Dietary sources of Astaxanthin include:

• Red-pink seafood and crustaceans^[5][6]
• Sea Urchin gonads, at 1mcg/g wet weight^[7]
• Algae and Microalgae^[4]

Astaxanthin can also be synthesized from the bacteria Haematococcus pluviali in the (3S, 3S') isomer,^[8] although dietary supplements tend to be a mixture of various isomers.^[9] Astaxanthin can now be produced on an industrial scale.^[10] Astaxanthin can be derived from other sources (marine in nature, such as shrimp or krill) although the isomer in the final nutraceutical will depend on what the creature ingested during its life; due to this variability, Haematococcus pluvialis astaxanthin is most commonly used.^[6][10]

Synthetic astaxanthin also exists. The first synthetic version contained 3 isomers, the standard (3S, 3S') isomer alongside (3R,3′R) and (3R,3′S) in a 1:1:2 ratio and was known as Disodium Disuccinate Astaxanthin; this formulation was used in some studies and is notable. It is no longer available,^[6] but the same company that produced DDA (Cardax Pharmaceuticals) now has a new compound which is claimed to be more water-soluble and bioavailable relative to natural astaxanthin and DDA, this compound is known as CDX-085, and was used in one study thus far.^[11]

As different sources have differing levels of the active isomer, one form may have different biological effects (in regards to potency) than others.

Astaxanthin is known as a xanthophyll carotenoid.^[6] As carotenoids (parent classification) can be divided into either xanthophylls or carotenes (like vitamin A precursors) Astaxanthin falls into the former category.^[12] Of the carotenoids, it is the only common dietary carotenoid to have ketone groups on its ends.

Astaxanthin has two chiral centers and can exist as three isomers in nature as (3S, 3S'), (3R,3′R) and (3R,3′S). The first, 3S,3S', is the most common in nature.^[13]

Additionally, the three isomers can exist in four configuations. An All-E configuration (straight chained) and three Z-isomers (bent chain). The All-E isomer is most prominent in nature, but the Z-isomers have greater oral bioavailability.^[14] This may help explain how farm-fed fish provide more dietary astaxanthin than wild.

It exerts itself as an anti-oxidant due to multiple oxygenated groups, two per ring.^[8] Along with the xanthophyll canthaxanthin, astaxanthin has carbonyl groups at the end of its structure (polyethylene backbone) which make it a more potent anti-oxidant than β-carotene.^[12][15][16] It appears to be able to embed itself within a cellular membrane due to its lipophilicity (similar to other carotenoids^[17]) reaching both the cytoplasmic and external sides of the membrane^[18] where it may interact with Vitamin C in a recycling manner.^[19]

Relative to other carotenoids (β-carotene, lutein/zeaxanthin, lycopene), astaxanthin fails to increase membrane width and was the only carotenoid that failed to induce peroxide formation (prooxidative effects) under periods of autooxidation;^[18] lutein/zeaxanthin were minimally oxidative while lycopene and β-carotene were more so.^[18]

Like most carotenoids, astaxanthin can incorporate itself in cellular membranes where it can reach both the cytoplasmic (intracellular) side as well as the external side.

Humans cannot synthesize astaxanthin in the body, nor does it appear to act as a pro-vitamin for Vitamin A (retinol) in mammals under normal conditions^[5][20] although it appears that in states of Vitamin A deficiency astaxanthin (in rats) can be forced into a provitamin role.^[21]

Astaxanthin may be able to act as a provitamin for Vitamin A in rats under conditions of dietary Vitamin A deficiency, but this capacity does not appear to exist under normal dietary conditions (and thus, astaxanthin is unlikely to cause Vitamin A toxicity symptoms)

Like all carotenoids such as β-carotene or lutein, astaxanthin is absorbed alongside fatty acids via passive diffusion into the intestinal epithelium; thus astaxanthin should be consumed with some dietary fat for absorption.^[22][23] It is more dependent on fat for absorption, as a cartinol ester, than other carotenes^[24] and as such bioavailability can be increased by either consuming with fatty meals or by making a lipid-containing delivery system.^[25]

Astaxanthin is approximately 40% less bioavailable in smokers, although this is more related to peripheral metabolism of astaxanthin rather than intestinal absorption.^[26]

Astaxanthin is fat soluble and has its absorption enhanced in the presence of fatty acids

Astaxanthin is absorbed via micelles made from dietary fat and then travels through the blood as a component of both LDL and HDL cholesterol. As a xanthophyll, it is more evenly spread between the two relative to carotenes (which favor LDL for transportation).^[13][27][28]

Astaxanthin is absorbed from the intestines via micelles made from dietary fatty acids, which is similar to all other carotenoid structures and thus requires coingestion with fatty acids (to make the micelles) to absorbed appreciable levels of astaxanthin

In mice, superloading astaxanthin as a disodium disuccinate ester (500mg/kg; human estimated equivalent being 40mg/kg) has resulted in a peak concentration (C_max) of 400nM.^[29]

According to one study, Astaxanthin had a plasma elimination half-life of 52 hours with a standard deviation of 40.^[13] That being said, there appears to be large differences between individuals and non-linear kinetics of astaxanthin. Doses as small as 10mg can persist in the body for upwards of a day whereas superdoses of 100mg can persist for 72 hours.^[30]

Saturation effects may also occur, as doses as low as 1mg can build up in the body given they are consumed continuously for 4 weeks.^[31] Within the first three weeks of supplement ingestion, 20mg astaxanthin results in higher serum concentrations (0.4µg/mL) than does 5mg astaxanthin (0.2µg/mL) from a baseline value of 0.03-0.04µg/mL.^[32]

Astaxanthin appears to be primarily metabolized by CYP1A (aromatase) following oral ingestion in the rat.^[33]

Astaxanthin appears to accumulate in most body tissues of the rat (except cardiac tissue) following oral ingestion of 100-200mg/kg in the rat.^[33]

One study suggests that farmed salmon (fed astaxanthin from bacterial synthesis) have a greater relevance to human health relative to wild salmon (obtain astaxanthin via consumption of their food sources) as the astaxanthin is more bioavailable.^[34] As mentioned in the structure section, this may be due to a higher concentration of Z-isomer Astaxanthin relative to All-E configuration; the latter of which is less orally bioavailable but more prominent in nature.

Astanxathin appears to have the potential to activate the Nrf2 signalling pathway in isolated HepG2 cells, with low concentrations being synergistic with the fish oil fatty acids EPA and DHA.^[35]

In neural progenator cells, astaxanthin is able to increase proliferation and colony formation at 1-10ng/mL with 10ng/mL showing a two-fold increase associated with PI3K and MEK signalling pathways eventually increasing the activity of proteins involved in proliferation (Rex1 mostly).^[36]

Appears to stimulate stem cell proliferation at a very low concentration relevant to oral supplementation

In Caenorhabditis elegans (Nematodes, used to research metabolic pathways of longevity^[37][38]), 0.1-1mM of astaxanthin is able to increase lifespan by 16-30% in all nematodes except the DAF-16 deficient ones.^[39] This enhanced lifespan was associated with increased nuclear accumulation of DAF-16 (the nuclear target of the Ins/IGF-1 signalling pathway^[40]) and increased antioxidant defenses which were thought to be due to DAF-16 gene product expression (superoxide dismutase enzymes in particular^[41]).^[39]

Astaxanthin may be able to promote cellular longevity secondary to boosting antioxidant defenses, which may be due to enhancing signalling through the Caenorhabditis elegans growth hormone pathway (DAF-16 nuclear accumulation)

Astaxanthin is known to be a more potent antioxidant than Vitamin E in regards to sequestering singlet oxygen (dioxide; O₂) in particular^[49][50] which is known to produce superoxide (O₂^-) that can sequester nitric oxide by forming peroxynitrate (ONOO^-);^[51] as high superoxide concentrations are known to impair blood flow by interfering with nitric oxide signalling, it is thought that astaxanthin could preserve signalling by nitric oxide.^[5]

Astaxanthin is thought to promote blood flow in part secondary to its antioxidant properties, since excessive oxidation (via superoxide) can impair proper blood flow

In rats, 50mg/kg astaxanthin oil (2.25-2.75mg/kg astaxanthin) was able to reduce both systolic and diastolic blood pressure in SHR/mrc-cp rats (a model for metabolic syndrome).^[52]

Astaxanthin is thought to play a role in atherosclerosis in part due to acting as an antioxidant and an antiinflammatory agent in endothelial cells,^[53] dysfunction of both systems in these cells underlying a pro-atherogenic state.^[54][55]

Red blood cell (RBC) concentrations of astaxanthin have been noted to be increased following 4 and 12 weeks of 3mg astaxanthin but not 1mg astaxanthin; RBC concentrations of other measured carotenoids (lutein, β-carotene, zeaxanthin, and β-cryptoxanthin) were not affected by astaxanthin content.^[56] This study failed to find a significant different in basal concentrations of phospholipid hydroperoxide in the RBCs^[56] although a previous study using 6-12mg found a reduction in total lipid peroxidation associated with astaxanthin being acummulated up to 86-109nM (relative to 8nM at baseline)^[57] also failing to find altered levels of other carotenoids in RBCs or tocopherols (Vitamin E).^[57] These two studies assessed lipid peroxidation via the content of phospholipid hydroperoxides (PLOOHs) and phosphatidylcholine hydroperoxides (PCOOHs)^[56][57] which carotenoids are known to reduce in vivo.^[58]

Oral ingestion of 6mg astaxanthin or higher appears to reduce membrane oxidation in red blood cells, although lower doses (in the 1-3mg range) do not appear to be effective despite possibly increasing the levels of astaxanthin in red blood cells

Oral ingestion of 6mg astaxanthin nightly for 10 days has been noted to improve (reduce) blood transit time to 90% of baseline values which was significantly better than placebo which saw no change.^[59]

In overweight subjects given 20mg astaxanthin daily for 12 weeks supplementation was associated with a reduction in LDL cholesterol (10.4%) and Apolipoprotein B (7.59%), with the latter causing a reduction in the ApoB/ApoA1 ratio by 8.22%;^[60] Apolipoprotein A1, HDL-C, and total cholesterol were unaffected^[60] and elsewhere in hyperlipidemic adults LDL has failed to be reduced over 12 weeks with 6-18mg astaxanthin, although these subjects were of normal BMI.^[61]

HDL-C has been found to be increased in persons with mild hyperlipidemia of 120-200mg/dL (triglycerides)^[61] while the aforementioned lack of increase was noted in persons without hyperlipidemia.^[60] 6-18mg of astaxanthin daily for 12 weeks was associated with an 8-14% increase in HDL-C with 12mg being most effective, and this change was associated with increases in adiponectin.^[61]

20mg of astaxanthin daily for 12 weeks in overweight adults has failed to reduce serum triglycerides relative to placebo,^[60] but a study in hyperlipidemic persons (120-200mg/dL baseline triglycerides) noted a reduction of 17-26% in a dose-dependent manner between 6-18mg daily for 12 weeks.^[61]

In a rat model of metabolic syndrome (SHRmrc-cp rats), 2.25-2.75mg/kg astaxanthin oral ingestion was able to reduce glucose and improve insulin sensitivity although not to the levels of the healthy control of Wistar rats.^[52]

Astaxanthin may be able to reduce blood sugar levels which, paired with its anti-inflammatory and anti-oxidative actions, might reduce stress on diabetic kidneys.^[62][63]

Supplementation of 12-18mg of astaxanthin daily for 12 weeks in persons with mild hyperlipidemia but of normal weight was able to increase circulating adiponectin by approximately 20-25%, while the increase seen with 6mg (of approximately 14%) was not statistically significant while 12mg nonsignificantly outperformed 18mg;^[61] this change was assocaited with benefits seen in HDL cholesterol^[61] of which the two are well known to be positively correlated.^[64] Adiponectin is also thought to partially underlie the triglyceride reducing effects of astaxanthin in the hyperlipidemic^[61] due to it being able to increase vLDL uptake and LDL expression in skeletal muscle.^[52][65]

Astaxanthin has once been noted to increase adiponectin in normal weight adults with hyperlipidemia, and this increase in thought to underlie the reductions in triglycerides and increase in HDL-C seen in these adults

Astaxanthin, due to its anti-oxidant abilities, can preserve the CPT-1 enzyme's function when faced with an oxidative insult by the lipid peroxide HEL.^[66]

Astaxanthin also showed a trend of using more body fat during exercise relative to glucose, as measured by Respiratory Exchange Ratio; and may explain the longer time to exhaustion in the astaxanthin group relative to control (as the measure was submaximal cardiovascular exercise).^[66] The dose of astaxanthin used in these studies was 0.02% feed intake, with the final feed intake not disclosed.

In otherwise healthy elite soccer players where activity was measured over the course of supplementation (4mg astaxanthin daily for 90 days) there was no notable change in workout volume conducted during exercise.^[67]

In trained cyclists who were subject to a pre-exhaustive test (2 hour exercise below VO₂ max) and then performed a 20km time trial, it seems that supplementation of 4mg astaxanthin for 28 days prior was associated with a greater improvement in time trial performance (121s reduction) relative to placebo (19s)^[68]

In a VO₂ max test, 4mg astaxanthin supplementation for about four weeks prior to testing appears to be associated with an increase in power output relative to baseline and placebo.^[68]

In otherwise healthy elite soccer players given 4mg of astaxanthin daily for 90 days was unable to change baseline oxidative biomarkers and changes in oxidation associated with exercise, but significantly reduced the exercise-induced increases in biomarkers of muscle damage (creatine kinase and ALT).^[67]

Astaxanthin might exert some of its anti-inflammatory actions through inhibition of the Cyclooxygenase-2 enzyme (COX-2).^[69]

Various in vivo studies show reduced inflammation with supplemented astaxanthin.^[70][71][72]

Astaxanthin can act in a protective manner against lipid peroxidation^[73] and, due to its polar nature, has no adverse effect on membrane structure.^[18] Apolar xanthophylls, on the other hand, may cause some degree of membrane disruption.^[18]

In one human study, consumption of astaxanthin at doses ranging from 1.8-21.6mg daily had lower levels of LDL oxidation.^[74] These results have been somewhat replicated in smokers.^[75]

In isolated ARPE-19 (retinal) cells, astaxanthin (5-20µM) is able to reduce H₂O₂ induced losses in cell viability and reactive oxygen species (ROS) production secondary to activating the PI3K/Akt pathway, which then induced the proteins NQO1, HO-1, GCLC, and GCLM.^[76] In these cells, the PI3K/Akt pathway regulate Nrf2^[77] which is known to induce the aforementioned antioxidant enzymes and it was confirmed that Nrf2 was localized to the nucleus.^[76]

Astaxanthin can increase Nrf2 activity and antioxidant enzymes in retinal cells secondary to activating the PI3K/Akt pathway

Obesity and overweight (according to BMI in persons of which lean mass is not a confound) is known to be associated with higher lipid peroxidation than lean controls^[78] which is exacerbated when looking at the morbidly obese.^[79]

In overweight adults given 20mg astaxanthin daily for 12 weeks, there appears to be an increase in total antioxidant capacity of the blood (20%) seen at a minimum of four weeks (34.5%) which is associated with reductions in the lipid peroxidation biomarker MDA at both four (10%) and 12 (33%) weeks of supplementation.^[60] This has been noted previously with 5mg and 20mg astaxanthin over three weeks in the same demographic,^[32] and it appeared that the large increasss in superoxide dismutase (193-194%) and total antioxidant capacity (121-125%) were merely being normalized to normal weight control while the reduction in lipid peroxidation (34.6-35.2% reduction, down to 1.72-1.77µM) failed to be normalized to normal weight control (0.265µM).^[32] Both studies noted a reduction in another biomarker of lipid peroxidation known as isoprostane^[60][32] but the reduction is different than MDA where the reduction is large (64.7-64.9%; down to 1.64-1.88ng/mL from 4.63-5.34ng/mL) yet normalizes the parameter relative to normal weight controls (2.54ng/mL).

Studies in overweight persons have noted significant improvements in general oxidation and the superoxide dismutase enzyme which seem to be normalized to the levels seen in lean controls; biomarkers of lipid peroxidation are either normalized (isoprostane) or are reduced but not to the level of normalization (MDA)

A combination of Astaxanthin and Saw Palmetto has been shown to increase testosterone while decreasing Dihydrotestosterone via inhibiting the 5-alpha reductase enzyme, at a dose of 800mg.^[80] Both compounds seem to be able to inhibit 5-AR independently.^[81]

A study in infertile men (16mg astaxanthin for three months) has failed to note an increase in serum testosterone relative to baseline and placebo treatments.^[82]

Astaxanthin has been implicated in reducing serum levels of estradiol in humans when supplemented in conjunction with Saw Palmetto at 2000mg daily.^[80]

Astaxanthin is known to be an antioxidant that can bioaccumulate in eye tissues, similar to the known macular pigments lutein and zeaxanthin; similar to the other carotenoids, astaxanthin may also play a protective role and particularly against age-related macular degeneration.^[83]

In the eyes, astaxanthin has been noted to protect cellular DNA from UV(A) radiation,^[84] bright light in general,^[85] reactive nitrogen species,^[86] and hydrogen peroxide (H₂O₂).^[87]

While astaxanthin can be active at concnetrations as low as 1-10nM,^[87] the protective effect of 100nM astaxanthin is nonsignificantly less than 1mM N-acetylcysteine^[87] and neither of these agents are inherently prooxidative without any oxidative stressor in retinal cells.^[87] The increase in antioxidant enzymes or genetic transcription (SOD, MT-II, and MT-III) seen with light-induced oxidation is not ablated with astaxanthin.^[87]

Astaxanthin appears to have general antioxidant properties in eye tissue. While it is not as potent in vitro as the reference drug of NAC, it is active at a level which is known to occur following low dose oral administration and does not appear to cause pro-oxidative effects under any circumstance

Choroidal neovascularization (CNV) in mice appears to be attenuated with injections of astaxanthin associated with antiinflammatory effects^[88] similar to lutein^[89] and EPA from fish oil.^[90] CNV is known to be a pathological factor in age-related macular degeneration (AMD)^[91] and is promoted by standard angiogenic factors such as VEGF^[92] and inflammatory factors such as macrophage infiltraton,^[93][94] and the effects of astaxanthin (10-100mg/kg injections) appear to be mediated by attenuating the increase in inflammatory factors (ICAM-1, IL-6) resulting in less macrophage accumulation and VEGF receptor expression (VEGF itself unaffected).^[88]

Since these effects were traced back to NF-kB activation being prevented by astaxanthin^[88] and this inflammatory mediator is known to be positively influenced by oxidative stress^[95][96] it is possible that the above mechanisms are secondary to an antioxidant effect of astaxanthin.

Astaxanthin appears to be implicated in preliminary research for reducing age-related choroidal neovascularization, which is due to an antiinflammatory effect which may be secondary to the known antioxidative properties of astaxanthin

In mice exposed to white light, 100mg/kg astaxanthin (one dose prior to, and five doses afterwards) is able to partially (47-63%) inhibit oxidative damage relative to control and attenuate retinal cell apoptosis^[85] with the protective effect at this dose extending to excitotoxins.^[87]

When looking at more practical lower doses, 5mg/kg astaxanthin in rats can attenuate oxidative damage caused by an increase in intraocular pressure.^[97]

Rodent studies have noted a large degree of protection seen with astaxanthin superloading, but some studies using more moderate doses (being similar to human supplementation) have also noted protective effects

In humans given 12mg of astaxanthin daily for four weeks, choroidal blood flow to the eye (assessed by laser speckle flowgraphy) was increased relative to placebo although there were no differences in intraocular pressure.^[98] This increase was time-dependent (10.3% at two weeks being lesser than 15.3% at four weeks), and was not associated with any changes

Astaxanthin may increase ocular blood flow without any significant changes in ocular blood pressure measurements

In smokers given a dose of 48mg astaxanthin, the C_max (peak absorption) does not appear to be significantly different from nonsmokers although the halflife of astaxanthin was reduced from around 30 hours to 18 hours^[26] causing overall bodily exposure to astaxanthin (MRT; Mean Residence Time) to be reduced 25% and elimination rate to be doubled.^[26] Reduced exposure to carotenoids has been noted previously (with β-carotene)^[99] and smokers tend to have lower carotenoid levels at baseline due to this increaed elimination^[99] thought to be related to higher oxidative stress causing more rapid elimination of antioxidants from the blood.

Smokers appear to have less overall exposure to astaxanthin following oral supplementation which is not related to impairments in absorption

Astanxathin is thought to be beneficial for the skin due to its lipid soluble properties and accumulation in the skin following oral administration, and some studies noting that a 'side-effect' of treatment is increased reports of skin quality enhancement with astaxanthin.^[60]

Topical application of a cream containing 5% of an astaxanthin containing oil (0.094% astaxanthin within the oil; 78.9µM final concentration) in otherwise healthy women at 1mL twice daily to the face for eight weeks was sufficient to reduce wrinkle and 'Crows feet' formation associated with improved elasticity of the skin.^[100] Age spots were also reduced as assessed by normal and UV lamp photographs, and while there was no overall moisturizing effect a subgroup with dry skin appeared to see some benefits and TEWL (whole group) was reduced.^[100]

Topical application of astaxanthin appears to improve elasticity and symptoms of skin aging, and there may be a moisturizing effect only present in those with dry skin

Oral ingestion of 3mg astaxanthin via an oil product in otherwise healthy men noted reductions in total area and volume of wrinkles, and similar to topical appliation there was a trend to improve moisture only in those with dry skin and there was a signficant improvement in elasticity of the skin in the 'Crows feet' after eight weeks relative to control.^[100]

Oral supplementation of the standard doses of astaxanthin also appear to be beneficial for the skin in the same ways that topical application is

Dietary antioxidants and carotenoids in general appear to be positively correlated with fertility^[101] and the state of fertiltiy being a prooxidative one,^[102][103] suggesting a role for antioxidants such as astaxanthin.

A pilot study using 16mg of astaxanthin in a double blind manner has reported a decrease in seminal reactive oxygen species and a reduction in serum inhibin B (known to inhibit follicle stimulating hormone and may suppress spermatogenesis when elevated^[104][105]) with treatment and this was associated with improved seminal motiltiy and a trend towards improved morphology (no influence on concentrations);^[82] these parameters were associated with greater monthly (23.1%) and total (54.5%) pregnancy rates relative to placebo (11.1% and 3.6%).^[82]

One study has used astaxanthin (0.27mg) alongside other ingredients such as lycopene, calcium, vitamin D, and citrus bioflavonoids (ie. hesperidin) relative to placebo noted that treatment was associated with a 48% reduction in symptoms as assessed by the MSSQ relative to the 10% increase seen in placebo.^[106] Symptoms improved were mostly related to hot flashes, libido, depression/anxiety, incontinence, and vaginal dryness.^[106]

One study using astaxanthin among many other compounds; astaxanthin may not be the major component due to its low levels ingested suggesting it is underactive

Consumption of 6mg daily of Astaxanthin for a prolonged period does not seem to adversely affect any blood parameter in humans according to one study^[107] a dose which effectively improves blood rheology.^[59]

In vitro studies with higher dosages have suggested a very high therapeutic threshold,^[108] but interventions with more than 6mg have yet to be conducted for a prolonged period of time. A study known as the Xanthin study is currently being undertaken to assess whether 8mg daily is effective in post-kidney transplantation patients.^[109][6] a dose that has been shown to be safe and effective in a study lasting 8 weeks.^[110]

One human study noted no side effects with 21.6mg daily for two weeks^[74] or 20mg for 12 weeks^[60] as well as a single dose of 48mg is well tolerated (except for red coloration of the feces, seen as due to the pigmentation of astaxanthin and medically benign).^[26]

Similar to how beetroot, via consumption of the betalain molecules, can cause feces to turn a reddish hue following oral supplementation it seems that high doses of astaxanthin (48mg acutely) can cause feces to turn a reddish hue^[26] also seen with 20mg over a period of weeks, albeit not in all subjects.^[60][32] This is seen as medically benign, but may be confused for colonic bleeding.