Recent Advancements of Astaxanthin from an Animal Feed to a Therapeutic Agent in Humans—A Meta-Analysis Overview

Abstract

Astaxanthin is a well-known antioxidant; however, it is mostly used in aquafeed to enrich the animal flesh color. Its antioxidant properties are undervalued and underutilized in human applications. This antioxidant has many potential benefits in improving the human immune system functions including Alzheimer’s disease, treating aging problems, etc. However, there is minimal scientific evidence to justify these claims. This meta-analysis investigates the available literature in relation to the direct application of astaxanthin in humans for various health benefits. This article mainly focuses on the clinical research conducted directly on human subjects testing various health benefits of astaxanthin over the past ten years. Some research articles published during this period may have been missed unintentionally.

1. Introduction

The well-known powerful antioxidant often called the ‘King of carotenoids’, astaxanthin (3, 3′ – dihydroxy – β, β′ – carotene – 4, 4′ – dione), is mainly sourced from microalgae such as Haematococcus Pluvialis (recently renamed as H. lacustris [1]), Phaffia rhodozyma, Chlorella vulgaris, etc., and from crustaceans [2, 3, 4, 5, 6]. The antioxidant activity of this red carotenoid pigment is 10-fold greater than other carotenoids such as zeaxanthin, lutein, canthaxanthin, and β-carotene and 100-fold greater than that of α-tocopherol [7]. This antioxidant pigment has attracted considerable research attention recently because of its strong antioxidant properties [8, 9, 10, 11].

Astaxanthin has three stereoisomers namely (3R, 3′R), (3R, 3′S; meso), and (3S, 3′S) (Figure 1), and it presents in free- and esterified forms often called as astaxanthin complex together (Figure 2). It gets the antioxidant capability from its special functional groups [14, 15]. Although, it is prone to light, temperature, and oxidative deterioration [16]. The astaxanthin complex extracted from only natural resources is preferred over the synthetic one because of the high cost and consumer resistance toward the use of synthetic astaxanthin [3, 17, 18, 19, 20]. Natural astaxanthin is biologically more active than the chemically synthesized astaxanthin because of its different composition, and natural astaxanthin esters show better bioavailability than its free form [21]. Natural astaxanthin from microalgae has more than 50 times stronger singlet oxygen quenching ability and about 20 times stronger free radical elimination capacity than the synthetic astaxanthin, which contains all three stereoisomers of astaxanthin (1:2:1). But the natural Haematococcus astaxanthin has only the (3S, 3′S) stereoisomer [12].

Figure 1.

Structure of astaxanthin stereoisomers [12].

Figure 2.

Structure of free astaxanthin (2A); astaxanthin monoester (2B); astaxanthin diester (2C) [13].

This article collectively refers ‘free astaxanthin’ and ‘astaxanthin esters’ as ‘astaxanthin’. In the United States, astaxanthin is allowed to be used as a colorant in aquaculture to improve the fish color [14, 22]. The European Commission treats natural astaxanthin as a pigment to be used in foods [2]. So far, only the natural astaxanthin sourced from the microalgae, Haematococcus Pluvialis is permitted for direct human consumption; astaxanthin from other sources is used in animal feed [6]. The US Food and Drug Administration (FDA) has allowed a maximum of 12 mg of astaxanthin per daily serving. However, this recommended upper safe limit is meant for only healthy human individuals [23]. In Europe, natural astaxanthin is marketed at a daily dose of 12 mg and up to a maximum daily dose of 24 mg around the world [24, 25]. Natural astaxanthin intake ranging from 8 to 45 mg per day for 4–12 weeks has shown low adverse effects in humans [26]. The latest research reports astaxanthin can be consumed at any dose over any length of time in animals and humans without any adverse events [27].

Evidence-based research shows, when taken orally, astaxanthin does not get converted to Vitamin A, and hence, it is totally safe to humans [28]. However, there is no evidence to say that synthetic astaxanthin is unsafe to humans or animals. But the United States does not generally recognize the synthetic astaxanthin as safe [29]. Astaxanthin is proved to be effective even at low concentrations because of its polar features [7]. This article outlines the research articles that investigated the direct applications of astaxanthin in human clinical trials for a wide range of human health benefits.

2. Astaxanthin as a potential therapeutic agent: research overview

To produce this work, peer-reviewed online research articles were searched between 2013 to 2024 mainly from PubMed Central and ProQuest Central databases that were accessed through La Trobe University’s library portal. Some articles were sourced from other online journal databases as well. Search terms included the phrases such as ‘astaxanthin as an antioxidant in human application’ and ‘astaxanthin in human trials’. Close to one hundred research articles were reviewed, screened, and filtered to meet the required parameters to publish this work. The articles that did not study the direct application of astaxanthin in human models or only in the abstract form or with ambiguous research methodology were omitted. Cross-referenced articles were not reviewed from the selected journal articles. It is understood that all human clinical trials are conducted using natural astaxanthin sourced from Haematococcus Pluvialis as it is the only source permitted for human consumption. In human clinical trials, astaxanthin benefits humans mostly on cardioprotection, immune modulation, skin and cosmetic benefits, sports performance, ophthalmology, and consumption safety [30].

Some of the recent research articles that conducted clinical trials in humans have been listed below.

2.1 Anti-cancer activity

Recently, the anti-cancer activity of astaxanthin has been investigated as a potential treatment aid because of the severity of this incurable disease. A systematic review published in 2020 stated: ‘there are no clinical trials or well-defined clinical studies assessing the efficacy of astaxanthin administration reported in patients suffering of any kind of cancer’ [5]. In 2023, it is found that alone or in combination with other chemotherapeutics, astaxanthin can act as an auxiliary therapeutic agent in treating prostate cancer [31]. Although in vitro trials proved that astaxanthin could be used in colon cancer, gastric cancer, lung cancer, and breast cancer treatments, no human clinical trials are reported to justify these findings in the current literature [23, 32, 33].

Astaxanthin can also help preventing skin damage caused by ultraviolet (UV) radiation [2]. Photodamage caused by UV is the major factor for skin cancer. According to FDA, the Minimal Erythemal Dose (MED) is defined as “the smallest UV dose that produces perceptible redness of the skin (erythema) with clearly defined borders at 16 to 24 hours after UV exposure”. Consuming 4 mg of astaxanthin for 9 weeks significantly increased MED and reduced the dryness caused by UV in healthy humans. However, more structural clinical studies are recommended to fully understand the photoprotective property of astaxanthin in human subjects [34].

2.2 Anti-diabetic activity

Diabetes mellitus is a very common and serious public health condition affecting many people worldwide. The long-term complications of diabetes include retinopathy, cataract, neuropathy, and nephropathy, which can lead to permanent disability or death if left untreated. Diabetic nephropathy can be prevented by astaxanthin in addition to its beneficial role in controlling diabetic retinopathy progression in animal models [3]. Later human clinical trial has indicated astaxanthin (8 mg per day for 8 weeks) lowers blood pressure and improves glucose metabolism in type 2 diabetic patients [35]. Until 2020, there were only few studies in humans testing the effects of astaxanthin on diabetes [20]. A study conducted in 2021 showed astaxanthin significantly reduced the pain caused by diabetic neuropathy in 36 patients at a dose of 6 mg per day for 8 weeks [36]. The efficacy of astaxanthin is poorly investigated in diabetic patients; hence, more human clinical research is needed to explore this area further.

2.3 Anti-inflammation activity

As a powerful antioxidant, astaxanthin acts against inflammation. It has the potential to stop the onset of inflammation in humans. In young healthy female adults, astaxanthin enhanced the immune response by reducing the DNA oxidative damage biomarker inflammation [2]. In animal studies, astaxanthin has a strong potential to alleviate chronic obstructive pulmonary disease that obstructs the airflow in lungs; but no human studies were reported on this [23].

2.4 Cardiovascular disease (CVD) prevention

CVDs are mainly caused by atherosclerosis and hypertension, and it accounts for up to one third of all deaths globally. People with metabolic abnormalities such as glucose intolerance, dyslipidemia, and diabetes are potentially at risk of getting CVDs. Astaxanthin was beneficial in preventing atherosclerosis and hypertension in animal models, but no human subjects were examined [3]. Supplementing 12 mg of astaxanthin per day for 3 months improved cardiac contractility and exercise tolerance by reducing the oxidative stress of heart failure patients with left ventricular systolic dysfunction [37]. There are only a few published research articles found online on the direct human application of astaxanthin for various cardiovascular health benefits [1, 27]. More in-depth research is needed to investigate this further.

2.5 Neuroprotective activity

It is estimated that neurodegenerative diseases will take over cancer to be the second biggest cause of death among the elderly people by 2040s [3]. A preliminary clinical trial on 50 to 69-year-old males proved that a daily supplementation of 20 mg of astaxanthin for 12 weeks improved their cognitive performance [38]. Astaxanthin has been suggested as a therapeutic agent in treating various brain disorders because of its benefits in brain functioning, cognitive disorders, anti-stress, anti-fatigue, traumatic brain injury, dementia, and other psychiatric diseases such as schizophrenia, and autism. Human clinical trials conducted between 2009 and 2019 indicate that astaxanthin (maximum of 12 mg per day) helped healthy humans and/or people with mild cognitive impairment in treating brain diseases [27]. These studies indicate that astaxanthin alone or in combination with other compounds shows promise in improving cognitive performance processes and brain health [1, 27].

2.6 Sports performance enhancer

There had been many in vitro and in vivo animal studies reported to support the use of astaxanthin as a dietary supplement for humans, who exercise for recreational purposes and for athletes. However, the results were unclear when applied in exercising humans because of the limited number of well-controlled scientific research [39]. Without a doubt, severe mental and physical fatigue caused by oxidative stress can negatively impact our lives. Taking 6 mg of astaxanthin as a dietary supplement per day for 4 weeks promoted mental and physical fatigue in healthy volunteers. This may be due to its antioxidative effect on the oxidative stress that causes the exercise-induced fatigue and mental stress [40]. In addition, 12 mg of astaxanthin intake for 4 weeks improved the temporary reduction of antioxidant capacity in humans [41].

Later investigation using 12 mg of astaxanthin supplementation a day for a week improved the exercise performance of trained male cyclists by reducing the time to complete the 40 km cycling trial. It also enhanced fat oxidation in the final stages of the trial in the cyclists. More research is recommended to determine the optimal astaxanthin supplementation intake strategy and to understand the mechanics of how astaxanthin is exerting its ergogenic effect in exercising humans [42].

Lowering the daily supplementation of astaxanthin to 6 mg for 4 weeks significantly increased the concentration of glutathione (an antioxidant self-produced within the body) in 18–39 years old active young men; however, this dose may not be effective in oxidizing fat during exercise [43]. On the other hand, increasing the dose of astaxanthin supplementation to 24 mg a day for 16 weeks not only increased the walking endurance of healthy elderly adults living in a nursing home but also reduced the oxidative stress in them. But it did not significantly improve their muscle mass or their strength [44].

2.7 Skin aging prevention

Human skin ages fast due to the oxidative stress. Astaxanthin being an antioxidant may help humans with aging problems by reducing the oxidative stress. Numerous studies were conducted on the anti-aging potential of astaxanthin on human skin between 1995 and 2021, and the results were summarised by different authors [1, 27, 45, 46, 47, 48]. Some of these trials are also included in this overview article as individual research.

Dietary supplementation of 4 mg of astaxanthin a day for four weeks resulted in facial skin rejuvenation in middle-aged men and women because of its strong antioxidative properties [49]. Also, dietary supplementation of 12 mg of astaxanthin a day for 16 weeks improved skin elasticity in healthy females [50]. It is found that the major cause of aging is the oxidative damage in the mitochondria according to the mitochondrial aging theory [28]. Applying astaxanthin containing cream (0.7 mg/g) twice a day for 3 weeks reduced skin dryness and increased skin moisture in 11 females. Also, the dermatologist assessment confirmed that astaxanthin significantly improved the skin moisture content and elasticity in 28 middle-aged healthy women at a dose of 4 mg/day for 6 weeks [1]. The comprehensive meta-analysis conducted in 2021 has concluded that astaxanthin application either orally and/or topically may delay and improve skin aging signs. Oral supplementation of astaxanthin is proved to be effective than the topical application [48]. However, most of these investigations are carried out on healthy males and/or females. Further investigation is needed to test the efficacy of astaxanthin on skin aging on unhealthy human volunteers.

2.8 Eye health promoter

Astaxanthin has the potential in promoting eye health [1, 27]. This carotenoid pigment showed selective improvement of central retina function when a group of patients were supplemented with astaxanthin (4 mg per day) for 12 months. Nevertheless, further controlled studies on clearly defined population groups are suggested to define the appropriate dosage and exact composition to be used in human applications [4]. Also, 6 mg of astaxanthin was immediately administered to patients who underwent cataract surgery in one eye for 2 weeks before they underwent the surgery on the other eye. Aqueous humor samples were collected immediately after the surgery for analysis. The analytical results showed astaxanthin intake significantly reduced total hyperoxides in younger patients because of its antioxidative scavenging effect [51].

2.9 Other health-related benefits

In addition to the above-mentioned human health benefits, astaxanthin has been tested for some other human health benefits. It is claimed that astaxanthin plays beneficial role in the prevention of male infertility, but no human trials reported [3]. Similarly, astaxanthin restores the defense mechanism of the immune system in an animal study, but there is no clinical research to prove this in humans [30]. A daily intake of 4 mg of astaxanthin for 40 days not only increased serum antioxidant features but also improved oocyte maturation and rates of high-quality embryos. Nevertheless, it did not affect the pregnancy outcome in women with polycystic ovarian syndrome [52]. Astaxanthin is proved to be effective in cryopreservation of human sperm from the normal semen samples of 30 individuals by decreasing chromatin condensation and increasing the motility in human sperm before clinical application [53].

In blood rheology, astaxanthin decreased the blood transit time from 52.8 s to 47.6 s in adult men when it was administered at the rate of 6 mg per day for 10 days. Also this antioxidant is one of the few compounds that can cross the blood-brain barrier [3]. Astaxanthin administered at the doses of 5 mg and 20 mg for 2 weeks effectively protected against the obesity-induced oxidative stress in overweight and obese young adults [54]. Daily supplementation of astaxanthin (12 mg a day) for a year had no significant effect on arterial stiffness, oxidative stress, or inflammation in renal transplant recipients. The author declared that this research data might be a false-negative and suggested these findings to be used for further research and meta-analyses [55]. In 26–60-year-old adults, astaxanthin significantly increased high-density cholesterol, sometimes called as ‘good cholesterol’ without affecting the low-density cholesterol [56]. Daily supplementation of krill oil containing astaxanthin for six months improved knee pain, stiffness, and physical function in mild-to-moderate knee osteoarthritis patients [57].

Cisplatin-induced hearing loss has negative impact on the children’s academic development and social integration. Cisplatin ototoxicity happens because of the excessive production of reactive oxygen species. Astaxanthin is proved to be powerful in treating this type of hearing loss by scavenging these excess reactive oxygen radicals. Further clinical studies are recommended [7].

Carotenoids like astaxanthin are less bioavailable because of its high hydrophobicity, which makes them insoluble in digestive fluids. Up until October 2020, there was no clear data studied about the astaxanthin distribution in human tissues; however, it had been extensively studied in animals [20]. Bioavailability depends on many factors such as the food matrix nature, its structure, and the presence of other dietary agents. Therefore, more research is needed to study about the human bioavailability of astaxanthin to understand the complex digestion and absorption processes involved [28].

The above-mentioned potential therapeutic health benefits of astaxanthin are summarized in Table 1.

Potential therapeutic health benefits of astaxanthin in humans	Human clinical trials investigated
2.1 Anti-cancer activity	Potential auxiliary therapeutic agent alone or in combination in treating prostate cancer [31]; Helped with skin cancer by reducing the dryness caused by UV and increased MED [34]
2.2 Anti-diabetic activity	Lowered blood pressure and improves glucose metabolism in type 2 diabetic patients [35]; Significantly reduced the pain caused by diabetic neuropathy [36]
2.3 Anti-inflammation activity	Enhanced the immune response [2]
2.4 CVD prevention	Improved cardiac contractility and exercise tolerance [37]
2.5 Neuroprotective activity	Improved cognitive performance and brain health [27, 38]
2.6 Sports performance enhancer	Promoted mental and physical fatigue [40]; Improved the temporary reduction of human antioxidant capacity [41]; Improved exercise performance and enhanced fat oxidation [42]; Increased walking endurance and reduced oxidative stress [44]
2.7 Skin aging prevention	Reduced skin dryness and increased skin moisture [1]; Enhanced facial skin rejuvenation [49]; Improved skin elasticity [1, 50]
2.8 Eye health promotor	Improved central retina function [4]; Reduced total hyperoxides [51]
2.9 Other health benefits	Improved oocyte maturation and rates of high-quality embryos [52]; Effective in cryopreservation of human sperm [53]; Decreased blood transit time [3]; Protected against the obesity-induced oxidative stress [54]; Increased good cholesterol [56]; Improved knee pain, stiffness, and physical function [57]; Powerful in treating cisplatin-induced hearing loss [7]

Table 1.

Summary of potential therapeutic health benefits of astaxanthin in humans.

3. Recommendations

The meta-analysis of recent human clinical trials using daily astaxanthin supplementation is promising that it has the great potential to treat and/or prevent many severe and chronic diseases in humans. However, numerous human clinical trials need to be carried out to fully understand how astaxanthin gets distributed in human tissues as studying the human bioavailability of astaxanthin is a complex process. Once this mechanism is understood, it may help to understand the possible side effects and toxicity of prolonged intake of astaxanthin in the human body.

Similarly, more clinical research using a wide range of human subjects (both healthy volunteers and ill patients) is recommended to justify the claims on astaxanthin’s photoprotective, anti-cancer, anti-diabetic effects, and its preventive effects on various lung, renal, brain, eye, and cardiovascular diseases, just to name a few. Although there are numerous studies on the positive effects of astaxanthin on human skin aging, more human clinical trials are recommended to test this property on different human races to work out the variations of this preventive effect on different skin colors and compositions. As mentioned above, detailed and thorough clinical research using a wide range of human subjects is recommended before implementing the commercial therapeutic application of astaxanthin in treating and/or preventing various acute and long-lasting diseases in humans.

4. Conclusion

Based on this meta-analysis and collected research evidence, natural astaxanthin has a strong potential to be a therapeutic agent in treating or preventing various diseases in humans because of its powerful antioxidant properties. Daily supplement of astaxanthin as a dietary supplement may improve the human health by reducing morbidity and help to prevent many serious and chronic health conditions. This way astaxanthin may help the humankind to have a better quality of life. It may not be too far to see this ‘King of carotenoids,’ currently undervalued as an animal colorant, to be sold as a therapeutic agent in preventing and/or treating various human diseases in the commercial market.

Acknowledgments

I thank La Trobe University, Australia, for giving me Alumni access to the university’s library database to browse and download the journal articles. I also thank IntechOpen Limited for the invitation to prepare this article for publication in the book “Chemistry of Food Additives”, ISBN 978-0-85014-430-7.

Notes/thanks/other declarations

The author declares no conflict of interest as this meta-analysis was conducted in the absence of any professional, commercial, or financial relationships with any academic institutions or commercial organizations that could be interpreted as a potential conflict of interest.