Review
“Therapeutic uses of natural astaxanthin: An evidence-based review focused on human clinical trials”

https://doi.org/10.1016/j.phrs.2021.105479Get rights and content

Abstract

Astaxanthin is a natural C40 carotenoid with numerous reported biological functions, most of them associated with its antioxidant and anti-inflammatory activity, standing out from other antioxidants as it has shown the highest oxygen radical absorbance capacity (ORAC), 100–500 times higher than ⍺-tocopherol and a 10 times higher free radical inhibitory activity than related antioxidants (α-tocopherol, α-carotene, β -carotene, lutein and lycopene). In vitro and in vivo studies have associated astaxanthin's unique molecular features with several health benefits, including neuroprotective, cardioprotective and antitumoral properties, suggesting its therapeutic potential for the prevention or co-treatment of dementia, Alzheimer, Parkinson, cardiovascular diseases and cancer. Benefits on skin and eye health promotion have also been reported, highlighting its potential for the prevention of skin photo-aging and the treatment of eye diseases like glaucoma, cataracts and uveitis. In this review, we summarize and discuss the currently available evidence on astaxanthin benefits, with a particular focus on human clinical trials, including a brief description of the potential mechanisms of action responsible for its biological activities.

Introduction

Antioxidants can be defined as molecules that, at low concentrations, delay or prevent oxidation, acting at biological membranes, or at intracellular levels, therefore protecting the cells of different organs and diverse biological systems [11], [60]. Among natural antioxidants, carotenoids and their derivatives stand out as a broad group of molecules that are naturally produced by plants and other photosynthetic organisms. These molecules are capable of protecting cells from oxidative processes mediated either by light, free radical-mediated peroxidation, or singlet oxygen [49]. Given these properties, the effects of carotenoids on health and their cosmetic benefits have been under investigation for a long time [73]. Among them, astaxanthin, a red C40 molecule, is one of the most abundant aquatic carotenoids, standing out among its chemical family as it has been shown to have the highest oxygen radical absorbance capacity, with a 100–500 times more antioxidant capacity than ⍺-tocopherol (Vitamin E), a well-known and commonly used antioxidant [42], [63]. Several sources of natural astaxanthin have been reported, including the microalgae Haematococcus pluvialis (recently renamed as H. lacustris according to the taxonomy study carried by [61]), Chlorella vulgaris, Chlorella zoofingiensis and Chlorococcum sp. It is also naturally synthesized by the red yeast Phaffia rhodozyma [28]. Among these, H. pluvialis is currently the only natural source of astaxanthin approved for human consumption [4], [75]. Astaxanthin can also be included indirectly in our diet by consuming crustaceans (e.g., copepods, shrimp, and krill) and Salmonidae (e.g., salmon, rainbow trout) species, whose diets include natural sources of astaxanthin.

The astaxanthin molecule has two asymmetric carbon atoms at positions 3 and 3' (Fig. 1). Consequently, there are different possible optical isomers or enantiomers: 3S, 3'S; 3R, 3'R; and 3R, 3′S. In nature, isomers with a chirality 3S, 3'S, or 3R, 3'R are the most abundant, among which, the former has the highest reported antioxidant activity [4], [63], [97]. Synthetic astaxanthin consists in a combination of 3R,3'R; 3R, 3′S; and 3R,3'R isomers (1:2:1) [46]. Astaxanthin contains conjugated double bonds, hydroxyl, and keto groups, showing both lipophilic and hydrophilic properties [28]. The conjugated double bonds at its center are responsible for its red color and, most important, for its high antioxidant capacity, as it donates the electrons that react with free radicals to convert them into more stable products, blocking free radical chain reactions [4]. Astaxanthin can also trap free radicals in its terminal ring moiety, in which the hydrogen atom at the C3 methine has been suggested to be a radical trapping site [92]. As astaxanthin shows both lipophilic and hydrophilic properties, this molecule is exposed to both the inside and outside of the cell, where it can scavenge radicals from the surface of the cell and at the interior of the phospholipid membrane (Fig. 2). This feature makes astaxanthin unique when compared to other antioxidants, such as β-carotene or vitamin C, which can only reside within or outside the lipid bilayer membrane, respectively [92]. Indeed, studies have demonstrated that astaxanthin shows the highest antioxidant activity when compared to related carotenoids, being 10 times stronger. Miki [50] studied the scavenger effect of astaxanthin and related carotenoids (zeaxanthin, lutein, tunaxanthin, canthaxanthin and β-carotene) against free radicals, using the thiobarbituric acid reactive substances (TBARS) assay with α-tocopherol as control. The results showed that astaxanthin has the highest scavenger effect, with an ED50 of aproximately 200 nM, whereas other carotenoid samples were in the range of 200–1000 nM. In vivo assays carried in the same study also demonstrated that astaxanthin shows the lowest ED50 values (2 µM) when assessing its inhibitory activity against the action of free radicals on rat blood cells and mithochondria. More specific fluorometric assays, based on BODIPY fluorescent probes that are susceptible to oxidation by peroxyl radicals, have also demonstrated that astaxanthin shows the highest relative antioxidant activity (1.3 ± 0.2) when compared to the antioxidant Trolox (1.0) and the carotenoids α-tocopherol (0.9), α-carotene (0.5), β -carotene (0.2), lutein (0.4) and lycopene (0.4) [59], [60].

Given its unique features, astaxanthin has been widely studied in the last years, both in animal and human models, showing neuroprotective, cardioprotective and antitumoral properties, together with promising results on skin and eye health promotion, suggesting its therapeutic potential for the prevention or co-treatment of diseases such as dementia, Alzheimer, Parkinson, cardiovascular diseases, cancer and glaucoma, among others. Here, we provide an updated view of natural astaxanthin's benefits and its therapeutic uses, focusing on those that have shown evidence or promising results in human clinical trials.

Section snippets

Pharmacokinetics of astaxanthin

Like all carotenoids, astaxanthin is absorbed by the organisms alongside fatty acids via passive diffusion into the intestinal epithelium. Briefly, astaxanthin mixes with bile acid after ingestion and forms micelles in the intestine. The micelles containing astaxanthin are partially absorbed by intestinal mucosal cells, which are incorporated into chylomicrons to be delivered to the liver. Then, astaxanthin is assimilated with lipoproteins and transported to different tissues. Importantly,

Biological activities of astaxanthin

Different studies have shown a wide range of potential mechanisms through which astaxanthin might exert its benefits, including photoprotective, antioxidant, anti-inflammatory, and anti-apoptosis effects, which act at different levels, including benefits to the skin, cardiovascular system, and eyes. In addition, several studies have demonstrated its neuroprotective capacity and antitumoral activity (Fig. 3). In the following sub-sections, we review the latest and most relevant studies regarding

Discussion

Growing evidence of astaxanthin benefits on human health has been reported, validating its consumption for the prevention or co-treatment of several diseases, especially those related to oxidative stress and aging. Its demonstrated benefits, together with an important part of the world population interested in leading healthier lifestyles, have made astaxanthin a highly demanded antioxidant, with a global market size that is expected to grow from $USD 600 million in 2018 to 880 million by 2024

Aknowledgements

We especially appreciate the illustrations made for this review by Brenda Bout, Jorge Dagnino, and Sergio San Martín. PAG is supported by grants FONDECYT 1190864 (ANID, Chile) and the Millennium Institute on Immunology and Immunotherapy (P09/016-F; ICN09_016) of the ANID – Millennium Science Initiative Program.

Conflict of interest

The authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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