Interactions of Astaxanthin and Omega-3 Fat in Health and Disease

Abstract

Elevated oxidative stress and chronic inflammation are major pathological factors underlying numerous diseases, including cardiovascular and neurodegenerative diseases. Astaxanthin, an antioxidant carotenoid, and very long-chain omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid and docosahexaenoic acid, are commonly found in seafood and exhibit beneficial effects on a myriad of diseases. The two powerful nutrients often work together, and this interaction is particularly beneficial for various aspects of health, primarily due to their complementary antioxidant and anti-inflammatory properties. The current understanding of the molecular and cellular mechanisms by which powerful duos exhibit protective effects, and their potential interactive effects on cardiometabolic and neurodegenerative diseases, is discussed.

1. Introduction

Diet and dietary factors are key modifiable factors that influence health and disease risks. Bioactive food components, including carotenoids, polyphenols, phytosterols, fiber, and very long-chain omega-3 polyunsaturated fatty acids (omega-3 PUFAs), are known to provide beneficial effects [1]. Astaxanthin (Ast), an oxygenated carotenoid, and omega-3 PUFAs are frequently found in several seafoods, and the intake of both is known to be protective against various diseases [2,3,4]. This literature review examines current understanding of how Ast and omega-3 PUFAs act together to reduce oxidative stress and inflammatory responses through complementary mechanisms, providing beneficial effects on health and disease, particularly in cardiometabolic and neurodegenerative conditions. The distinctive roles of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the two most common omega-3 PUFAs contained in seafood, are also discussed.

2. Methods

This narrative review examined potential interactive effects of Ast and omega-3 PUFAs on health and diseases. The relevant literature was searched on PubMed, ResearchGate, and Web of Science using search terms that included Ast, omega-3 fat, oxidative stress, and inflammation. Health benefits of Ast and omega-3 PUFAs on cardiometabolic diseases were examined using terms such as hyperlipidemia, cardiovascular diseases, fatty liver, hepatic steatosis, insulin resistance, and type 2 diabetes. Their benefits on neurodegenerative conditions were searched using terms that included Alzheimer’s disease, Parkinson’s disease, and dementia. Effects of different omega-3 PUFAs were searched using terms that included EPA, docosapentaenoic acid (DPA), and DHA.

3. Food Sources of Ast and Omega-3 PUFAs

3.1. Dietary Sources of Ast

Ast is a xanthophyll carotenoid that is responsible for the characteristic reddish-orange color in certain marine organisms such as Antarctic krill, shrimp, crab, lobster, trout, and salmon. These organisms obtain their Ast by consuming specific types of microalgae, yeast, or smaller fish. Ast is also commonly used in aquaculture for pigmentation as well as for the health of aquatic animals [5]. Ast has a long polyene chain with two terminal beta-ionone rings with hydroxyl groups and keto groups at both ends. The hydroxyl groups can be esterified with various fatty acids (FAs), and Ast is present as free, mono-esters or di-esters. Additionally, various geometric and meso isomers of Ast are also present in foods and supplements, with different forms exhibiting distinctive stability, bioavailability, and functions [6].

Antarctic krill and shrimp contain 30–40 mg/kg Ast, primarily in the form of Ast-esters. The common esterified FAs are myristic acid (C14:0), palmitic acid (PA, C16:0), oleic acid (C18:1), EPA (C20:5), and DHA (C22:6) [7]. Salmon and trout contain mostly free Ast in their muscle tissues in the range of 6–38 mg/kg flesh. Wild-caught salmon contains higher amounts of Ast, with Sockeye salmon containing 26–38 mg/kg of flesh and Atlantic farmed salmon containing 6–8 mg/kg of flesh [4]. In contrast to wild-caught salmon mostly containing free forms of Ast, farm-raised salmon contains Ast-ester forms in addition to the free forms, most likely due to their diets [8]. Additionally, different isoforms of Ast are present between the wild-caught and farm-raised salmon [8]. Various dietary supplement products, containing 2–12 mg per capsule, are available. They are mostly derived from microalgae [Haematococcus pluvialis (H. pluvialis)], yeast (Phaffia rhodozyma), or chemical synthesis. H. pluvialis mostly contains Ast-esters, while free Ast is found in yeast and synthetic form [9]. It has been shown that Ast-esters, especially diester forms, are more stable than free Ast [6]. The Food and Drug Administration has placed Ast, H. pluvialis extract containing Ast-esters, on the GRAS (Generally Recognized As Safe) list.

3.2. Dietary Sources of Omega-3 PUFAs

FAs are not only energy substrates but also provide important functional roles, such as structural components and precursors for signaling molecules. FA synthesis is not a major pathway in adult humans consuming typical Western diets; FAs are mainly derived from dietary lipids, which are mostly present as triacylglycerols (TAGs) and a small fraction as phospholipids (PLs) [10]. FAs are classified based on the carbon chain length as well as the presence, number, and stereochemistry of double bonds. Humans need to consume two essential FAs: omega-6 linoleic acid (C18:2) and omega-3 alpha-linolenic acid (ALA, C18:3). These can be further elongated and desaturated into omega-6 arachidonic acid (ARA, C20:4) and omega-3 EPA (C20:5), DPA (C22:5), and DHA (C22:6), respectively. Genetic differences in elongases and desaturases influence the functionality and metabolism of PUFAs [11]. ALA conversion into EPA, DPA, and DHA in the human body is not efficient. Consequently, FA composition in cellular TAGs and PLs mostly reflects dietary FA intake, especially for the omega-3 PUFAs [10]. Depending on the types of FAs consumed, they have differential impacts on health such that a high intake of omega-3 PUFAs is beneficial, while saturated FAs cause harmful effects [12].

In general, cold-water, oily fish such as mackerel, herring, salmon, and sardines are the richest sources of omega-3 PUFAs. These fish, however, do not produce omega-3 PUFAs. Rather, they accumulate omega-3 PUFAs by consuming microalgae, phytoplankton, smaller fish, and crustaceans. Other sources of omega-3 PUFAs include seaweeds and crustaceans. Omega-3 PUFA content in fish varies mainly due to their diets; for example, wild-caught salmon contains a greater amount of EPA and DHA, while farm-raised salmon contains a higher amount of omega-6 PUFAs [4]. Cooked Atlantic salmon provides 1.57–1.83 g of EPA plus DHA per three ounces, while canned sardines contain approximately 1.19 g per three ounces. For more detailed information, please refer to the U.S. Department of Agriculture, FoodData Central Website.

Current intake of seafood, a primary source of omega-3 PUFAs, falls below recommended levels in most countries [13,14], and dietary supplements are available. While fish oil has been the main source of omega-3 PUFAs, the use of alternatives, such as krill oil and algae oil, has been on the rise [15,16]. Algae oil, notably, provides an excellent omega-3 PUFA source for vegetarians and vegans. These oils typically contain 20% to 40% of omega-3 PUFAs out of their total FAs [17,18]. Beyond supplements, a high-purity prescription form of an ethyl ester of EPA, icosapent ethyl, is available due to its well-documented health benefits [19].

3.3. Stability and Bioavailability of Ast and Omega-3 PUFAs

The conjugated double bonds in omega-3 PUFAs are susceptible to oxidation by light, temperature, oxygen, and other oxidants during processing, storage, and cooking, producing oxidized lipids that can be harmful [20]. While the polyene chain in Ast may also be oxidized, leading to its degradation, Ast is known to reduce the oxidation of omega-3 PUFAs in foods [21]. Although cooking generally increases their bioavailability, these two nutrients are sensitive to heat, oxygen, and light and can be degraded during high-temperature cooking for prolonged periods [8]. It has been reported that cooking 85 g of salmon to an internal temperature of 71 °C did not impact Ast levels in both wild-caught and farm-raised salmon [4]. However, Ast levels were lower in processed (canned/pouch) compared to unprocessed (fresh/frozen) forms of salmon. While baking and steaming are mostly recommended, frying fish and shellfish, especially with margarine, is strongly discouraged [22]. Among different forms of Ast, Ast-esters are known to be more stable than free forms [23]. Additionally, the Z-isomers, which are present in wild salmon, have been shown to be less stable than the all-E-isomer. However, the Z-isomers are known to have greater bioavailability than the all-E-isomer [24]. FAs, including omega-3 PUFAs, have higher bioavailability. It has been shown that omega-3 PUFAs in the PL form, as found in krill oil, may offer superior bioavailability compared to the TAG forms in fish oil [25].

4. Digestion, Absorption, and Transport of Ast and Omega-3 PUFAs

Ast is a lipid-soluble compound, and its digestion, absorption, and transport are closely related to lipids and lipoprotein metabolism. Dietary lipids enhance both digestion and absorption of Ast [26]. TAGs are digested by lipases and colipases into FAs and MAGs, and PLs by phospholipases and esterases into FAs and lysophospholipids (lyso-PLs) in the stomach and small intestine (Figure 1). Ast-esters are digested into FAs and Ast, potentially by esterases, which are then incorporated into the micelles. Bile salts assist the digestion and absorption of both nutrients by acting as emulsifiers and aiding micelle formation. Micelles bring lipid-soluble nutrients close to the brush border membrane across the unstirred water layer, enabling the subsequent absorption of the digestion products—FAs, MAGs, lyso-PLs, and Ast—into the enterocytes mostly via passive diffusion [27]. Several transporter proteins, such as cluster-determinant 36 and scavenger receptor class B type 1, have been suggested to mediate the absorption of FAs and Ast via the facilitative diffusion process [28,29]. FAs and MAGs are esterified into TAGs, and lyso-PLs are re-esterified with FAs to form PLs. TAGs, PLs, and other lipid-soluble nutrients, including fat-soluble vitamins and carotenoids, are then packaged into chylomicrons within the enterocytes. Ast is incorporated into chylomicrons, most likely in the PL monolayer enveloping the lipoprotein particles. Chylomicrons exit into the lymphatic system and are slowly released into the systemic blood through the thoracic duct, initially bypassing the liver.

Lipoprotein lipase (LPL) hydrolyzes TAGs in TAG-rich lipoproteins into FAs, MAGs, and glycerol, which are taken up by cells. LPL is mainly expressed in adipose tissues and skeletal muscle. However, adipose LPL activity is increased in the post-prandial condition; hence, the majority of dietary lipids are stored in the adipose tissues [30]. After LPL-mediated hydrolysis of TAGs, chylomicrons become chylomicron remnants, which are taken up by the liver. The liver packages lipid-soluble nutrients, including vitamin E and carotenoids, into very low-density lipoprotein (VLDL), an endogenous lipid transport mechanism. VLDL becomes low-density lipoprotein (LDL) after LPL-mediated TAG hydrolysis. It is estimated that 60% of FAs in hepatic TAG are derived from circulating FAs, with lesser contributions from de novo lipogenesis (25%) and diet (15%) in humans [31]. Adipose tissue is the major storage site of energy, where FAs and MAGs, derived from LPL-mediated hydrolysis of TAG in chylomicron and VLDL, are re-esterified into TAGs and stored in lipid droplets of adipocytes. When systemic energy demands increase during fasting or exercise, adipocytes hydrolyze TAG through lipolysis and release FAs and glycerol to the systemic blood. In adults consuming a typical Western diet, the majority of FAs in adipose TAG are derived from dietary sources and therefore, FAs in the blood reflect mostly FA compositions in the diet [10].

Ast is incorporated into the PL monolayer that surrounds the hydrophobic core of the lipoprotein particles, and studies have reported that 36–64% of blood Ast is found in TAG-rich lipoproteins (chylomicrons/VLDLs), 28–29% in LDL, and 21–24% in HDL [27,32]. Cells acquire Ast by taking up LDL particles through LDL receptor-mediated endocytosis or from HDL particles, possibly via passive diffusion or a receptor-mediated facilitated diffusion process. Ast is known to inhibit oxidation of LDL and other lipoprotein particles [33], a mechanism through which Ast provides beneficial impacts on atherosclerotic cardiovascular diseases.

5. Mechanisms Involved in the Beneficial Actions of Ast and Omega-3 PUFAs

5.1. Antioxidant Action of Ast

The unique structure of Ast, a series of conjugated double-bond chains with polar ionone rings at both ends, allows it to act as a strong antioxidant, effectively scavenging free radicals and reactive oxygen and nitrogen species (RONS). Studies have shown that Ast is a more potent antioxidant than other carotenoids (alpha-carotene, beta-carotene, and lutein) and vitamin E [34,35,36]. Ast is relatively more polar than other carotenoids and spans PL monolayers in lipoproteins and bilayers in cellular membranes, where Ast effectively detoxifies free radicals and other RONS in both the hydrophobic core (FA tails) and surface [35] (Figure 2). Additionally, Ast activates the natural antioxidant defense systems by inducing the expression and activity of antioxidative enzymes through nuclear factor erythroid 2-related factor 2 (NRF2), a key transcription factor that mediates cellular defense systems against oxidative stress and induces the expression levels of antioxidant enzymes, including glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase (CAT) [37,38].

Ast may also exert beneficial impacts on cellular functions by maintaining membrane integrity through the prevention of peroxidation of PUFAs in membrane PLs. While beta-carotene and lycopene (nonpolar carotenoids) disordered the membrane bilayer and increased lipid peroxidation in model membranes enriched with PUFAs, Ast preserved membrane structure and decreased membrane lipid peroxidation [39]. This is crucial in the prevention of numerous diseases, including atherosclerosis and neurodegenerative diseases, where the accumulation of oxidized lipids plays a crucial role. Additionally, studies have shown that Ast can counteract ferroptosis, a novel form of iron-mediated lipid peroxidation in PUFAs in membrane PLs and cell death, thereby decreasing cardiotoxicity and atherosclerosis, as well as neurotoxicity [40,41].

5.2. Omega-3 PUFA-Mediated Suppression of Oxidative Stress

Although conjugated double bonds in omega-3 PUFAs may react with RONS, acting as a sink for oxidative damage, they are also susceptible to lipid peroxidation. Upon incorporation into membrane PLs, omega-3 PUFAs increase membrane fluidity and lipid raft formation and therefore affect the localization, function, and signaling of membrane-bound proteins, including insulin receptors and those involved in oxidative stress responses [12] (Figure 2). Further, omega-3 PUFAs can reduce oxidative stress through suppression of inflammation, activation of NRF2, and induction of antioxidant enzymes [42].

5.3. Anti-Inflammatory Actions of Ast

Ast is known to inhibit the inflammatory responses through multiple mechanisms, including suppression of the canonical proinflammatory signaling pathways by directly scavenging RONS, inducing NRF2 activity and the expression of antioxidant genes, and decreasing mitochondrial dysfunction. Ast inhibited phosphorylation and degradation of inhibitor of kappa B (IκB) by activating IκB kinase, which prevented nuclear translocation of nuclear factor kappa B (NF-κB), the canonical transcription factor that increases the expression of proinflammatory genes [43]. Additionally, Ast suppressed mitogen-activated protein kinases (MAPKs) [44]. Through these actions, Ast decreased the expression of proinflammatory cytokines [tumor necrosis factor-alpha (TNFα), interleukin-1 beta (IL-1β), interleukin-6 (IL-6)] and other genes [cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS)] in various cell types such as macrophages [43,44]. There is an antagonistic crosstalk between the two transcription factors such that NRF2 activation suppresses NF-κB activity and vice versa, especially in the context of oxidative stress and inflammation [45]. Studies have shown that Ast suppressed the expression levels of proinflammatory cytokines through NRF2-dependent and -independent mechanisms [46,47].

Ast is also present in organelle membranes, including mitochondria, where ROS are generated during oxidative metabolism, and high levels of ROS cause mitochondrial dysfunction. In macrophages, Ast blocked endotoxin-induced mitochondrial dysfunction and proinflammatory responses [48]. Furthermore, Ast not only decreased proinflammatory M1 macrophages but also induced macrophage polarization toward more anti-inflammatory phenotypes in peritoneal macrophages [49] and in the liver of mouse models with metabolic dysfunction-associated steatohepatitis [47], improving insulin resistance and hepatic steatosis, respectively.

5.4. Anti-Inflammatory Actions of Omega-3 PUFAs

Different types of FAs have distinctive roles in health and disease, and the health benefits of omega-3 PUFAs are at least in part mediated by their anti-inflammatory actions. Multiple mechanisms are involved in omega-3 PUFA-mediated suppression of inflammation. EPA, DPA, and DHA are used for the synthesis of lipid mediators, including specialized proresolving mediators (SPMs; resolvins, maresins, and protectins) that play crucial roles during the resolution of inflammatory responses [12]. Lipid mediators, including eicosanoids and SPMs, are generated from omega-3 and omega-6 PUFAs through cyclooxygenases, lipoxygenases, and cytochrome P450 oxidases. Omega-3 PUFAs not only compete with omega-6 arachidonic acid (ARA) for the same enzymatic systems, thereby reducing the production of proinflammatory eicosanoids from ARA, but also increase the production of less inflammatory or even anti-inflammatory eicosanoids from EPA [12]. Anti-inflammatory lipid mediators reduce inflammation by decreasing further immune cell infiltration, enhancing the phagocytic activity of macrophages, or inducing a switch to more resolutory M2-macrophages. They also reduce inflammatory responses by suppressing the expression of proinflammatory cytokines (TNFα, IL-1β, and IL-6) and chemokines.

FAs also affect cellular signaling pathways by directly acting as ligands for the membrane receptors. It is well known that saturated FAs, especially PA, activate the canonical proinflammatory signaling pathways via Toll-like receptors (TLRs). Upon activation by PA, TLR4 activates nuclear translocation of NF-κB through stimulation of IκB kinase and degradation of IκBα and IκBβ, which results in the liberation of NF-κB [12]. TLR4 also acts through p38, ERK_1/2, and JNK MAPKs that mediate the proinflammatory responses by phosphorylating transcription factors such as activator protein 1. Omega-3 PUFAs have been shown to suppress proinflammatory responses by inhibiting TLR4 or antagonizing PA-mediated stimulation of TLR4 [50,51].

Omega-3 PUFA-mediated activation of free fatty acid receptors (FFAR4), a member of G-protein coupled receptors, is also known to be involved in their beneficial anti-inflammatory actions. FFAR4 is abundantly expressed in immune cells and adipocytes. In macrophages, omega-3 PUFAs act through the FFAR4 to inhibit the canonical proinflammatory signaling pathways, including NF-κB and JNK MAPKs [52]. Omega-3 PUFA-mediated stimulation of FFAR4 has been shown to reduce vascular inflammation and thrombus formation [53].

5.5. Interactive Effects of Ast and Omega-3 PUFAs in Reducing Oxidative Stress and Inflammation

Both AST and omega-3 PUFAs individually contribute to reducing oxidative stress and inflammatory responses. Further, Ast not only prevents oxidation of omega-3 PUFAs in foods, increasing their storage stability, but also suppresses peroxidation of omega-3 PUFAs in lipoproteins and PLs in cellular membranes [21]. When combined, they can provide a more robust defense against free radicals, protecting cells and tissues from damage, and potentially can have additive or synergistic antioxidant effects via the NRF2 pathway, as shown in a hepatic cell line [54]. The antagonistic crosstalk between NF-κB and NRF2 suggests that the two nutrients potentially work together to reduce inflammation.

5.6. Other Mechanisms Mediating the Beneficial Actions of Ast and Omega-3 PUFAs

In addition to providing health benefits by reducing oxidative stress and inflammation, both Ast and omega-3 PUFAs are known to confer beneficial effects through modulation of gut microbiota and gut-derived metabolites. Ast-mediated increases in the abundance of beneficial Akkermansia muciniphila and short-chain FAs are thought to be involved in the beneficial effects of Ast [55,56,57]. Similarly, omega-3 PUFAs also exert protective actions at least in part by improving gut microbiome: increased richness, diversity, and abundance of short-chain FA-producing genera, Bifidobaterium, Roseburia, and Lactobacillu while decreasing LPS-producing Bacteroidetes [58,59].

AST has been shown to enhance transcriptional activity of peroxisome proliferator-activated receptor-gamma [60], a nuclear receptor that plays a fundamental role in adipocyte development and their metabolic and endocrine properties, insulin sensitivity, and the regulation of inflammatory responses [61]. Therefore, Ast may enhance the thermogenic capacity and secretory profiles in adipose tissues, providing protection against cardiometabolic diseases. Omega-3 PUFAs are also known to enhance the browning of white fat through the FFAR4 as well as the production of bioactive lipid species, which in turn exert beneficial impacts on obesity and its associated metabolic diseases [62].

Both Ast and omega-3 PUFAs are known to suppress endoplasmic reticulum stress, leading to a reduction in the proinflammatory responses, oxidative stress, and apoptosis in several models [63,64]. Other mechanisms involved in the beneficial effects of Ast and omega-3 PUFAs include their regulation of autophagy through activation of AMP-activated protein kinase and insulin signaling activities [65,66].

6. Health Benefits of Ast and Omega-3 PUFAs

6.1. Beneficial Impacts of Ast

Oxidative stress and chronic inflammation are the major pathological factors in various diseases such as cardiometabolic diseases, neurodegenerative diseases, and ageing-associated macular diseases. Numerous studies, mostly in preclinical animal models, have shown that Ast provides protection against cardiometabolic diseases by alleviating hyperlipidemia, hepatic steatosis, and insulin resistance through reducing oxidative stress and inflammation [67,68,69]. Ast also reduced hepatic injuries through downregulation of MAPK-mediated apoptosis and autophagy [44,70]. Another study, using a diet-induced model of fatty liver disease, found that Ast reduced liver inflammation, improved insulin sensitivity, and was more effective than vitamin E [49]. Ast also exerted a protective effect on cardiac dysfunction and necrosis caused by sepsis by inhibiting inflammation [71].

Chronic neuroinflammatory response involving neuronal and immune cells occurs in the central nervous system (CNS) during the development of neurodegenerative diseases. Proinflammatory mediators (TNFα, IL-6, and NO) released by immune cells, including the tissue-resident macrophage microglia, increase oxidative stress, causing cytotoxicity in the CNS [72]. Ast has a unique ability to cross the blood–brain barrier and exerts neuroprotective effects directly within the CNS through its potent antioxidative and anti-inflammatory actions [72]. Ast also enhances mitochondrial function, while suppressing neuronal cell death. Therefore, Ast has garnered significant interest for its potential therapeutic role in neurodegenerative diseases. For the efficacy of Ast in neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and ageing-associated decline in cognitive function and dementia, readers are referred to recently published reviews [73,74].

6.2. Beneficial Impacts of Omega-3 PUFAs: Distinctive Roles of EPA and DHA

Omega-3 PUFAs also exert beneficial impacts on various diseases. Their health benefits for cardiometabolic and neurodegenerative diseases are well known, and for further information, readers are referred to previous reviews on these topics [12,62,75]. While generally positive associations between the intake of omega-PUFAs and reduced disease risks have been reported, whether increasing their intake provides protective effects on health and the underlying mechanisms that mediate their beneficial impacts remains uncertain. Moreover, although EPA (20:5) can be converted into DHA (C22:6), the two omega-3 PUFAs are known to exhibit distinct tissue distribution patterns, metabolism, functional properties, and contribution to disease risks [76]. Current understanding of the differential roles of EPA and DHA, the two omega-3 PUFAs enriched in seafood, is discussed below.

DHA is the most abundant PUFA in the nervous system, especially the brain and retina, constituting up to 60% of the total omega-3 PUFAs [76]. DHA contributes to the structural formation and functional capabilities during the development of the CNS. Studies using model membranes have shown that EPA and DHA associate with distinct regions of the membrane, and DHA is more incorporated into lipid rafts than EPA [77]. In the brain, DHA enhances and stabilizes lipid rafts containing high levels of cholesterol and sphingomyelin. Moreover, DHA and its derivatives, including D-class neuroprotectins, provide neuroprotective actions against neurodegenerative diseases and injuries [78]. Preclinical studies in neuronal cell culture models have shown that differential impacts of EPA, DHA, and the ratio of EPA to DHA on amyloid accumulation, cellular stress signaling, and apoptosis [79,80,81]. However, a recently published systematic review and meta-analysis reported that although omega-3 PUFA supplementation reduced the progression of cognitive decline among patients with Alzheimer’s disease, there were no differences among EPA, DHA, and EPA/DHA mixed formulations [82], and more studies are needed to assess potential distinct roles of DHA compared to EPA in neurodegenerative diseases.

In the retina, a high concentration of DHA is essential for maintaining the fluidity, integrity, and correct morphology of photoreceptor cell membranes [83]. The rapid motion of DHA is thought to be necessary for rapid conformational changes in rhodopsin during light perception. Accordingly, a recent systematic review on randomized controlled clinical trials supports a crucial role of omega-3 PUFA supplementation, especially DHA, in visual health during early life [84]. The results from animal studies showed that a PL form of DHA (lysophosphatidylcholine-DHA), but not omega-3 PUFA supplements in TAG forms, increased retinal DHA, indicating its higher bioavailability [85]. However, whether it leads to improvement in visual functions in humans requires further investigation.

Despite a similar reduction in TAG levels, EPA alone, compared to the combined use of EPA and DHA, showed a further significant risk reduction in cardiovascular diseases, an implication of distinctive roles between EPA and DHA [86,87]. While DHA, compared to EPA, creates a more fluid membrane, EPA has been shown to suppress membrane cholesterol crystalline domain formation more effectively through a potent antioxidant mechanism in hyperglycemia [88]. Further, EPA, compared to DHA, more effectively suppressed oxidation of HDL, small-dense LDL, and model membranes [89]. Different lipid mediators generated from EPA, compared to DPA and DHA, may also contribute to the better actions of EPA than mixed formulations of omega-3 PUFAs.

6.3. Interactions of Ast and Omega-3 PUFAs in Reducing Disease Risks

The complementary actions of Ast and omega-3 PUFAs to counteract oxidative stress and inflammatory responses suggest that combined intake of both nutrients may be better than each (Figure 3). Accordingly, several studies have shown that combinations of Ast and DHA exhibit better protective effects than each in animal models of neurodegenerative diseases [90,91]. Moreover, Ast and DHA exhibited potential synergistic beneficial effects on dysregulated plasma metabolic profiles induced by undernutrition during the gestation and lactation periods [92]. Krill oil contains both Ast and omega-3 PUFAs. However, krill oil contains omega-3 PUFAs in PL forms compared to the TAG forms in fish oil, and it also contains variable amounts of EPA and DHA per serving [93]. Whether supplementation of krill oil is better than fish oil in reducing disease risks remains undetermined.

7. Conclusions

Ast and omega-3 PUFAs are commonly present in selected seafood, and they are known to exert beneficial impacts on health. The interactions of Ast and omega-3 PUFAs are manifold. Dietary lipids, such as FAs esterified in the forms of TAG and PLs, enhance the digestion and absorption of Ast. The transport of Ast is also closely related to lipoprotein metabolism. Therefore, dietary lipids enhance the bioavailability of Ast. Furthermore, the polyene chain in omega-3 PUFAs can be oxidized and degraded, and Ast, as a strong antioxidant, can prevent this oxidation both in foods and the body.

Both Ast and omega-3 PUFAs inhibit oxidative stress and inflammation, the major pathological factors underlying various diseases, including cardiometabolic and neurodegenerative diseases, through complementary mechanisms. Ast is relatively polar compared to other carotenoids and can span the PL monolayers of lipoprotein particles and bilayers of cellular membranes, preventing lipid peroxidation by scavenging free radicals and RONS. Ast also suppresses oxidative stress by stimulating the transcriptional activity of NRF2, thereby increasing expression levels of antioxidant enzymes. Omega-3 PUFAs suppress inflammation through multiple mechanisms. Upon incorporation into membrane PLs, omega-3 PUFAs increase membrane fluidity and lipid raft formation, affecting cellular signaling activities. Additionally, they serve as precursors for the production of anti-inflammatory lipid mediators and reduce the production of proinflammatory eicosanoids by competing with omega-6 ARA for the same enzymes. Omega-3 PUFAs also suppress inflammation by antagonizing the proinflammatory TLR4 signaling pathways and by acting as ligands for FFAR4. Through these various mechanisms, omega-3 PUFAs suppress the canonical proinflammatory NF-κB and MAPK signaling pathways. An antagonistic crosstalk exists between NRF2 and NF-κB, the two primary transcription factors that mediate antioxidant responses and proinflammatory responses, respectively. Therefore, Ast activation of NRF2 can suppress inflammation while omega-3 PUFA inhibition of NF-κB can enhance antioxidant capacity, clearly indicating complementary actions of the two bioactive food components.

The interactive actions of Ast and omega-3 PUFAs create a powerful duo, working in concert to exert profound antioxidative and anti-inflammatory effects throughout the body. While numerous studies have shown beneficial impacts of each in various disease models, most results are derived from preclinical models, and studies that have examined the interrelationships of their beneficial effects, especially in humans, are limited. Various isomers of Ast and omega-3 PUFAs, EPA and DHA in the form of TAG or PLs, are present in food, and they are known to exhibit distinctive bioavailability or functional roles. Moreover, food sources also contain many other components, and future studies to understand the complexity of the food matrix on health and disease are warranted. The potential additive or synergistic effects of Ast and omega-3 PUFAs extend to various other areas, including eye health, skin health, and ageing-associated health issues, where oxidative stress and chronic inflammation play crucial roles in their pathogenesis.