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. Author manuscript; available in PMC: 2026 Jul 31.
Published in final edited form as: Food Chem. 2025 Mar 27;482:144024. doi: 10.1016/j.foodchem.2025.144024

Characterization of astaxanthin isomers in different types of salmon filets and human plasma after salmon consumption

Peiran Lu 1, Nichole Reisdorph 2, Audrey E Hendricks 3, Richard Reisdorph 2, Kevin Quinn 2, Michael Armstrong 2, Cole Michel 2, Katrina A Doenges 2, Daniel N Frank 4, Wayne W Campbell 5, Emily B Hill 6, Nancy F Krebs 6, Yashu Tang 1, Dingbo Lin 1, Minghua Tang 7,*
PMCID: PMC13422621  NIHMSID: NIHMS2195085  PMID: 40179560

Abstract

Astaxanthin, a marine carotenoid with antioxidant and anti-inflammatory properties, exists in various isomers in salmon. Despite salmon being a key dietary source of astaxanthin in American diets, the isomer contents across salmon types, processing methods, and human plasma post-consumption remains underexplored. Using mass spectrometry, we analyzed astaxanthin isomers, EPA, and DHA in wild and farmed salmon, processed salmon products, and human plasma following a feeding study. Results showed higher levels of 3S,3′S-all-trans-astaxanthin, EPA, and DHA in wild versus farmed salmon. Cooking did not affect 3S,3′S-all-trans-astaxanthin levels, but they were lower in processed forms like canned salmon. Plasma concentrations of 3S,3′S-all-trans-astaxanthin increased significantly in humans after consuming a Mediterranean diet with two servings of farmed salmon per week for five weeks. Notably, 13-cis-astaxanthin, but not 9-cis-astaxanthin, was detected in plasma. These findings demonstrate that food processing and farming practices affect astaxanthin levels, and that plasma astaxanthin concentrations reflect dietary salmon intake.

Keywords: Alpha-linolenic acid, Arachidonic acid, Astaxanthin isomer, EPA, DHA, Human consumption, Mediterranean diet, Mass spectrometry

Introduction

Seafood, particularly oily fish, such as salmon, is rich in several high quality, essential nutrients that benefit human health. According to the Food and Agriculture Organization of the United Nations’ salmon market reports, global salmon production has increased consistently over the years [1]. However, the average intake of seafood (including fish and shellfish) in the U.S. is only 33% of the current recommended amount [2]. Lower seafood intake correlates with greater metabolic disease development [3–5].

Two types of fresh/frozen salmon are commonly available on the US market: wild and farmed. Salmon yield and nutritional values rely highly on the environment and feeding regimes [6,7]. Farmed salmon feeds are rich in proteins and fats, thereby altering their nutrient composition compared with wild salmon diets [6–9]. For example, astaxanthin is added to farmed salmon feed to augment color and bolster nutritional value while wild salmon consume astaxanthin through algae, plants, and small fish [10]. Astaxanthin is a red, fat-soluble pigment primarily generated by bacteria, yeast, and some plants and can be found in fish and birds that consume these products [11]. In typical American diets, salmon is the main food source of astaxanthin [11]. However, due to limited dietary intake, astaxanthin is not a primary carotenoid in human plasma [12,13].

Pre-clinical studies have demonstrated that astaxanthin has antioxidant and anti-inflammatory properties that act by reducing mitochondrial damage, oxidative stress, and inflammatory cytokines [14]. Astaxanthin also drives interleukin-10 (IL-10) production as an anti-inflammatory agent in inflammatory rodent models [15–17]. Research conducted using a hypertensive rat model showed that astaxanthin reduces blood pressure, improves vascular remodeling, and reduces reactive oxidative species [18]. Our research group has reported that astaxanthin alters the gut microbiome and regulates metabolic homeostasis in mice [19].

While more studies are focusing on the health benefits of astaxanthin, its complex chemistry and metabolism make understanding the specific mechanisms behind astaxanthin’s health-promoting effects challenging. Astaxanthin is a xanthophyll carotenoid with a unique molecular structure that allows several geometrical (cis/trans, E/Z) and optical [(3S,3’S), (3R,3’R), and (3R,3’S)] isomers, all with the same mass (596.4 g/mol) and molecular formula (C40H52O4). Most astaxanthin found in nature and in salmon is the 3S,3’S-all-trans-astaxanthin form, meaning that the two hydroxy substituents are on the same side of the molecule, at positions 3 and 3’ (Supplemental Figure 1); this isomer is commonly referred to as “astaxanthin” [20]. In contrast, various optical isomers and significant amounts of the cis-isomers, primarily 9-cis-astaxanthin (also called 9-Z-astaxanthin) and 13-cis-astaxanthin (also called 13-Z-astaxanthin), have been found in humans because E-isomers, after ingestion, are transformed into Z-isomers [20–22]. In addition to differences based on isomeric forms of astaxanthin, several other factors impact astaxanthin composition in marine products. For example, total astaxanthin content (all astaxanthin isomers) in Pacific shrimp was reduced after boiling, with greater losses as cooking time increased [21]. Freeze drying, heat drying, microwave cooking, and boiling Antarctic krill also reduced total astaxanthin [24]. Importantly, to our knowledge, no study has examined the levels of astaxanthin isomers in various types and forms of salmon or human plasma following the consumption of salmon.

Our primary objective was therefore to compare astaxanthin content, including its isomers, between types and forms of salmon and to evaluate their abundance in human plasma after salmon consumption. We hypothesized that the astaxanthin content would be higher in wild-caught versus farmed salmon and fresh versus canned or pouch-stored salmon. Based on previous work, we expected levels of astaxanthin to decrease after cooking [24]. Furthermore, we expected plasma concentrations of 3S,3’S-all-trans-astaxanthin, 9-cis-astaxanthin, and 13-cis-astaxanthin isomers to increase following salmon consumption. Because polyunsaturated fatty acid contents also tend to vary between wild versus farmed salmon [25], polyunsaturated fatty acids were measured in our salmon samples as a secondary objective. To test these hypotheses, salmon filets from various sources and undergoing different processing methods were used for astaxanthin assessment by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). To test astaxanthin concentration after consumption, astaxanthin isomers were measured in plasma using samples from a Mediterranean-style controlled feeding study [26].

Material and methods

Salmon samples

Two groups of salmon samples were gathered and processed separately to investigate whether the quantity of astaxanthin differed by type or processing of salmon. Group 1: To determine the quantities of astaxanthin and polyunsaturated fatty acids in wild versus farmed salmon, three frozen, uncooked wild Atlantic skinless salmon filets and three frozen, uncooked farmed Atlantic skinless salmon filets were purchased from US Foods®. The three Atlantic wild and three Atlantic farmed salmon samples, each weighing 170 g wet weight, were divided in half to yield a total of 12 samples for processing. For each filet, 85 g was kept raw, and 85 g was heated on a steel pan to an internal temperature of 71°C (160 °F) without adding oil or seasoning. Both raw and cooked halves were cut into one-inch cubes and refrozen. In a commercial blender, each sample was blended with an equal volume of dry ice until a powder was formed. The powder was then placed in test tubes for processing. All samples (n=6 filets, 3 wild and 3 farmed each with a cooked and uncooked portion) were stored at −80 °C until analysis.

Group 2: To determine quantities of astaxanthin in a variety of processed forms, farmed Atlantic and wild Pacific salmon filets were purchased locally at King Soopers and Sprouts stores in the Denver, CO, USA metro area, as fresh (uncooked and never frozen), frozen, canned, and pouch packaged forms. Astaxanthin was investigated by processing (i.e., processed: canned, pouch vs. not processed: fresh, frozen) as well as by type (i.e., Pacific wild vs. Atlantic farmed) and preparation (i.e., cooked vs. uncooked).

Specifically, a total of 8 sample types were analyzed for this portion of the study as follows: 1) farmed Atlantic fresh (cooked), 2) farmed Atlantic fresh (uncooked), 3) wild Pacific frozen (Sockeye, cooked), 4) wild Pacific frozen (Sockeye, uncooked), 5) Store brand foil lined pouch, 6) brand name foil-lined pouch, 7) brand name smoked, and 8) brand name canned. The cooking method for the farmed Atlantic fresh and farmed Pacific frozen salmon samples involved heating over medium heat in an Instant Pot Multi Cooker (Downers Grove, IL) with no oil or additives for 1.5 minutes, with continual stirring. All salmon samples were chopped into small pieces and placed in 15 mL Eppendorf tubes at −80° C prior to lyophilization for the purpose of freezing. Frozen salmon samples were lyophilized for 72 hours at −40 °C and stored at −80° C until analysis. Prior to analysis, 100 mg of each sample was weighed into 3 separate microcentrifuge tubes to obtain n=3 technical replicates per sample type. Hence a total of 24 (8 types × 3 samples per type) samples were analyzed for this portion of the study.

Dietary salmon intervention

Fasting plasma samples obtained from participants in a previously published clinical trial (registered at clinicaltrials.gov as NCT025731290) [26] were used. All procedures were performed in compliance with applicable laws and institutional guidelines, as approved by the IRB. Informed consent was obtained from all participants. In brief, participants (n=39) classified as being overweight or having moderate obesity and who scored low on a Mediterranean diet compliance checklist underwent two 5-week controlled feeding dietary interventions (portioned quantities of all foods provided) with a 4-week self-chosen dietary wash-out period. Both controlled feeding interventions were Mediterranean-style diets, differing in the amounts of red meat. The amount of red meat (~500 g or ~200 g of lean, unprocessed beef and pork per week) consumed during each intervention period was compensated for predominantly with poultry, along with modest differences in dairy, egg, and grains. Salmon intake (two 168 g servings of fresh, farmed salmon per week) was the same between the two intervention diets, and no other seafood was consumed. For the astaxanthin analysis, fasting plasma samples were compared before and after each intervention for astaxanthin contents. All food items consumed during the dietary intervention besides salmon were also analyzed for astaxanthin.

Sample preparation, LC-MS and LC-MS-MS instrumental analysis of astaxanthin

For all salmon and plasma samples, a modified liquid-liquid extraction method was used to separate hydrophobic and hydrophilic fractions as previously described [27–29]. Briefly, following lyophilization, salmon samples were bead homogenized in ice cold methanol at 100 mg/mL; 100 μL of supernatant was removed for use in subsequent steps. For preparation of participants’ plasma samples, 50 μL was used from pre- and post-intervention samples, with no homogenization performed. An internal standard mix was spiked into each sample (Avanti Polar Lipids, Alabaster, AL) for the purpose of quality control. Samples were then subjected to liquid-liquid extraction with methyl tert-butyl ether (MTBE). After drying using nitrogen gas, lipid fractions were resuspended in methanol. Only lipid fractions were analyzed due to the lipid soluble nature of astaxanthin.

Plasma and salmon samples were analyzed by liquid chromatography mass spectrometry (LC-MS) using an Agilent 6545 quadrupole time-of-flight mass spectrometer (QTOF, Agilent Technologies, Santa Clara, CA, USA) as previously described [30]. Samples were injected onto an Agilent Zorbax SB-C18 Rapid Resolution High Definition, 1.8 μm (2.1 mm × 100 mm) analytical column attached to an Agilent 1290 series LC pump. LC flow rate was 700 μL/min with a maximum pressure of 1000 bar. The mobile phases for separation consisted of A) water with 0.1% formic acid and B) isopropyl alcohol/acetonitrile/water (60:36:4) with 0.1% formic acid as the aqueous and lipid phases, respectively. Initial composition was 30% B then increased linearly using the following gradient: 0.00–1.00 minutes to 70% B, 1.00–7.92 minutes to 100% B, then held at 100% B from 7.92–10.40 minutes. Composition was re-equilibrated to initial conditions through 10.50 minutes with a total run time of 15.1 minutes. The autosampler tray temperature was 4 °C and the column temperature was maintained at 60 °C.

LC flow was introduced into an Agilent 6545 QTOF mass spectrometer via electrospray ionization (ESI) and MS-only (no fragmentation) was performed in positive ionization mode. MS parameters for plasma and salmon samples were as follows: scan rate of 2 spectra/second, mass range 75–1700 m/z, drying gas temperature of 300 °C with flow rate of 12 L/min, nebulizer pressure 35 psi, sheath gas temperature of 275 °C with flow rate of 12 L/min, skimmer voltage 65 V, capillary voltage 3.5 kV, nozzle voltage 250 V, and fragmentor voltage 100 V. A reference mix with masses of 121.0509 and 922.0098 was used for external calibration (Agilent Technologies, Santa Clara, CA, USA). Sample preparation blanks were run prior to analytical samples. Analytical samples were analyzed in random order with QC samples injected every 5 samples. Total ion chromatograms (TIC) were monitored for retention time reproducibility.

Fragmentation data (LC-MS/MS) was collected using the same parameters as the LC-MS method with the following exceptions: the instrument was operated in Auto MS/MS mode utilizing a preferred ion list only containing the m/z value of 597.39439 at charge state 1 with a 15 ppm error window for the proton adduct (MH+) of astaxanthin, MS scan rate was set to 3 spectra/s, MS/MS scan rate was set to 3 spectra/s and scan range to 50–1700 m/z, Quad isolation width was set to narrow (~1.3 amu), and MS/MS spectra were collected at separate CID collision energies of 10, 20, and 30V.

Preparation and analysis of authentic astaxanthin standards

Authentic astaxanthin standards [3S,3’S-all-trans-astaxanthin, 9-cis-astaxanthin, and 13-cis-astaxanthin; MilliporeSigma, Burlington, MA, USA] were dissolved in chloroform at a concentration of 2 μg/μL then diluted to a concentration of 2 ng/μL in methanol. One μL of each standard was injected for LC-QTOF-MS analyses to obtain individual retention times for each isomer. Note that all three isomers have a molecular formula of C40H52O4, molecular weight of 596.3866 g/mol, and proton adduct (MH+) of m/z 597.3944. Standards were mixed 1:1:1 and 2 μL of the mix was injected for LC-MS/MS analysis to determine retention times for astaxanthin isomers and to obtain MS/MS spectra for each isomer. A set of plasma and salmon samples were analyzed separately using LC-MS/MS to confirm the identification of 3S,3’S-all-trans-astaxanthin, 9-cis-astaxanthin, and 13-cis-astaxanthin isomers by mass (597.3944 m/z), retention time, and MS/MS spectral matching to that of authentic standards.

LC-MS and LC-MS-MS data analysis

Relative quantitation, whereby peak areas of compounds are compared across samples, of 3S,3’S-all-trans-astaxanthin, 9-cis-astaxanthin, and 13-cis-astaxanthin was conducted based on previous methods [30]. Briefly, molecular formula, isotope ratios, and retention time are used to extract target compounds using Find by Formula in MassHunter Profinder version 10 (Agilent Technologies). Peak areas of 3S,3’S-all-trans-astaxanthin, 9-cis-astaxanthin, and 13-cis-astaxanthin were compared to determine fold-change differences across plasma samples and salmon samples using Mass Profiler Professional software (Agilent Technologies). An MS/MS spectral library using Personal Compound Database and Library Manager (PCDL) in Mass Hunter (Agilent Technologies) was created from data acquired from the analysis of authentic standards (3S,3’S-all-trans-astaxanthin, 9-cis-astaxanthin, and 13-cis-astaxanthin). Identification of isomers in plasma was accomplished by matching acquired spectra to the library using Mass Hunter.

Salmon polyunsaturated fatty acid analyses

Gas chromatography mass spectrometry (GC-MS) was performed to analyze eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and arachidonic acid (AA) in salmon samples [31]. Briefly, ~100 mg pre-blended salmon tissues were combined with 1 mL of acetonitrile:6N HCL 9:1 prior to homogenization in a bead homogenizer for 2 minutes at 50 Hz. Samples were then centrifuged at 14,000 RPM for 5 minutes at 4 °C. Supernatants were removed, heated at 100° C for 45 minutes, then added 1.0 mL of methanol:10N NaOH 9:1 for alkaline hydrolysis at 100° C for 45 minutes. Fatty acids were extracted in hexane. Finally, samples were analyzed by negative chemical ionization (NICI) GC-MS (Agilent Technologies).

Statistical analyses

Data processing, QC, and statistical analyses for the plasma data were performed using R v.4.4.1 (R Core Team 2021).

For the evaluation of salmon samples by type and processing, two groups of salmon samples were gathered and processed separately (see Materials and Methods, Salmon Samples) to investigate whether the quantity of astaxanthin differed by these characteristics. For group 1, three astaxanthin isomers were investigated by salmon type (i.e., Atlantic wild vs. Atlantic farmed) and preparation (i.e., cooked vs. uncooked). For group 2, astaxanthin was investigated by processing (i.e., processed: canned, pouch vs. not processed: fresh, frozen) as well as by type (i.e., Pacific wild vs. Atlantic farmed) and preparation (i.e., cooked vs. uncooked). Note that while both groups of salmon samples assessed wild vs. farmed, the location of the salmon samples differed (i.e., only Atlantic for group 1 and Pacific or Atlantic for group 2).

Given the small sample sizes for each group of salmon samples, we used the nonparametric Kruskal-Wallis test. For the group 1 analyses, we adjusted for three isomers using false-discovery rate (FDR) and subsequently, for a global FDR<0.05, we used the Wilcoxon Rank Sum test to compare salmon type and preparation method also using FDR over all pairwise tests. For group 2, only astaxanthin was assessed removing the need to adjust for multiple testing in the global test. Wilcoxon Rank Sum tests were used to compare processed vs. not processed and then processing type (i.e., canned vs. pouch) and not processed groups (i.e., fresh vs. frozen) adjusting using FDR.

Statistical analysis on the plasma samples was also performed. Plasma was obtained at 4 time points (2 pre- and 2 post-intervention) for 39 individuals. Due to two missing observations, 162 observations remained for analysis. Astaxanthin values were adjusted for analytical batch and processing order effects through linear regression with astaxanthin as the outcome and batch, order, and batch-by-order interaction as the predictor terms. The regression was refit removing residuals outside of 3 times the inter quartile range. The updated regression was used to adjust all observations and adjusted values were then ranked. Linear mixed-effect models (LMEs) with the lmer function in the lmerTest package were used to assess change in rank (outcome) (post – pre) after each Mediterranean-style intervention period using the intercept term with participant ID included as a random intercept to control for repeated measures from the 2 intervention periods [32]. Thirty-nine participants had complete data for both intervention periods, and 2 participants had complete data for 1 intervention period, resulting in 80 change observations. In accordance with the NIH best practices for sex as a biological variable, sex stratified models were also assessed [33]

Results

Astaxanthin isomers are identified using authentic standards

Authentic astaxanthin reference standards were analyzed to determine mass, isotopic distribution, MS/MS fragmentation pattern, and retention time (Figure 1A, top panel). The 3S,3’S-all-trans-astaxanthin, 9-cis-astaxanthin, and 13-cis-astaxanthin were detected at 2.413, 2.707, and 2.822 min, respectively, and all at 597.394 m/z, as expected. Compounds eluting with the same m/z and with retention times 2.401, 2.712, and 2.812 min were detected in salmon samples (Figure 1A, middle panel). Similarly, two compounds were detected in human plasma samples with 597.394 m/z and retention times 2.419 and 2.827 min (Figure 1A, bottom panel). Based on matching retention times and m/z values of the authentic standards, these were presumed to be 3S,3’S-all-trans-astaxanthin and 13-cis-astaxantin, respectively. Indeed, the m/z values for each compound detected in plasma and salmon matched the authentic standards within 0.5 ppm mass error (Figure 1B, Supplemental Figure 1). MS/MS fragmentation spectra in both salmon and plasma matched that of the authentic 3S,3’S-all-trans-astaxanthin standard, further confirming that this astaxanthin isomer was detected in plasma (Figure 1C). As expected, the three isomers were indistinguishable by MS/MS analysis, as the spectra were identical for all three. However, based on retention times measured for each standard, the MS/MS analysis provided confirmation of the identities of 9-cis-astaxanthin, and 13-cis-astaxanthin in salmon (Supplemental Figure 2). Due to the low signal intensity of the 9-cis-astaxanthin isomer in plasma, MS/MS spectra of sufficient quality could not be acquired to match to the spectral library.

Figure 1. Salmon astaxanthin isomers are identified by LC-QTOF-MS.

Figure 1.

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A, The 3S,3’S-all-trans-astaxanthin (3S,3’S-all-trans), 9-cis-astaxanthin (9-cis), and 13-cis-astaxanthin (13-cis) authentic reference standards are resolved using LC-QTOF-MS with 597.394 m/z and retention times of approximately 2.4, 2.7, and 2.8 minutes (top panel), respectively. The three compounds were also detected in salmon at the same m/z and retention times (middle panel). Two peaks were detected in plasma at the same m/z and ~2.4 and 2.8 minutes (bottom panel). B. The m/z values for the peaks at 2.4 minutes in plasma and salmon match that of the 3S,3’S-all-trans-astaxanthin standard within 3 ppm mass error. The m/z values for the peaks at 2.7 and 2.8 minutes in salmon and at 2.8 minutes in plasma, also match those of the 9-cis-astaxanthin and 13-cis-astaxanthin standards (supplemental Figure 1). C. MS/MS mirror spectra of 3S,3’S-all-trans-astaxanthin in salmon (top) and plasma (bottom). Red spectra were acquired from sample analysis, black spectra are from a spectral library created from an authentic 3S,3’S-all-trans-astaxanthin reference standard. Spectral match quality scores are 94.2 and 82.5 for salmon and plasma, respectively, indicating high quality matches. Matching MS/MS spectra for 9-cis-astaxanthin and 13-cis-astaxanthin isomers in salmon are shown in supplemental Figure 2.

Salmon samples differ in astaxanthin content by type and processing

Following confirmation of the identity of all three astaxanthin isomers, we used the LC-MS data to compare the peak areas of the isomers in farmed Atlantic versus wild Atlantic salmon (i.e., relative quantitation). All astaxanthin isomers had FDR=0.0378 for the global test. Further, while Atlantic wild salmon had significantly higher compound values than Atlantic farmed (FDR=0.0043), astaxanthin values did not differ significantly or considerably by preparation (i.e., cooked vs uncooked; FDR>0.464) (Figure 2A-C).

Figure 2. Salmon samples differ in astaxanthin contents by type and cooking status.

Figure 2.

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Group 1 salmon sample astaxanthin results of all three isomers: A. 3S,3’S- all-trans-astaxanthin; B. 9-cis-astaxanthin; and C. 13-cis-astaxanthin are presented. Cooking/heating did not affect astaxanthin contents for any isomers, and wild salmon samples had significantly higher astaxanthin contents than farmed salmon samples for all three isomers (FDR=0.0043).

For the group 2 salmon analysis, the relative abundance of 3S,3’S-all-trans-astaxanthin in several forms of salmon was also determined using the LC-MS data. Astaxanthin was significantly associated with processing type (pglobal = 6.069e-4) with significantly higher levels (FDR=3.916e-06) seen in unprocessed (i.e., fresh/frozen) vs. processed (i.e., canned/pouch). Within a processing type, no significant or considerable differences were seen between fresh vs. frozen (p=0.3823) or canned vs. pouch (p=0.1667) (Figure 3).

Figure 3. Salmon samples differ in astaxanthin content by processing.

Figure 3.

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Group 2 salmon sample astaxanthin results of 3S,3’S-all-trans-astaxanthin are presented. Unprocessed salmon (frozen/fresh) had significantly higher 3S,3’S-all-trans-astaxanthin contents than processed (canned/pouch) (FDR=3.916e-06).

Polyunsaturated fatty acids are higher in wild salmon compared to farmed salmon, regardless of cooking conditions

Gas chromatography mass spectrometry was used to measure PUFAs in wild versus farmed salmon, with results expressed in μmol/L. Wild salmon contained higher EPA and DHA but lower alpha-linolenic acid (ALA) and arachidonic acid (AA) compared to the farmed salmon (Figure 4 A-D, p<0.01).

Figure 4. Wild salmon has high polyunsaturated fatty acids EPA and DHA but is low in ALA and AA compared to farmed salmon, and cooking does not cause significant changes in PUFA content.

Figure 4.

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A. C20:5n3 EPA; B. C22:6n3 DHA; C. C18:3n3 ALA; and D. C20:4n6 AA. Values are means ±SDs, n=3 with 2 technical replicates. Labeled means without a common letter differ, p<0.05. EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; ALA, alpha-linolenic acid; and AA, arachidonic acid.

Plasma astaxanthin levels are elevated in humans after a Mediterranean-style dietary intervention with salmon

The relative abundance of 3S,3’S-all-trans-astaxanthin was determined in plasma samples from participants before and after each 5-week dietary intervention as described above. Normalized and ranked astaxanthin increased in plasma after consumption of a Mediterranean-style diet including salmon (p=7.64e-13). This result was seen in both females (p=2.99e-8) and males (p=1.3e-3) although the increase appeared to be more consistent in females than males (Figure 5). Further analysis of all foods the participants consumed (not shown) confirmed that astaxanthin was detected in salmon only, validating the source of plasma astaxanthin in the dietary intervention.

Figure 5. Plasma astaxanthin content increases after dietary consumption of salmon.

Figure 5.

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Plasma 3S,3’S- all-trans-astaxanthin changes over two dietary interventions (trial 1, trial 2). Each trial included 2 servings of salmon per week with no other seafoods and each trial was a 5-week intervention. Normalized and ranked plasma astaxanthin concentrations increased after each trial in A. males only, B. females only. and C. all participants combined (p=7.64e-13).

Discussion

Astaxanthin is a carotenoid that, when consumed in whole foods (i.e., salmon), may exhibit anti-inflammatory properties beneficial for human health. Yet, neither the major astaxanthin in salmon, 3S,3’S-all-trans-astaxanthin, nor two of its main isomers, 9-cis-astaxanthin and 13-cis-astaxanthin, have been well studied [21]. This study investigated the relative abundance of 3S,3’S-all-trans-astaxanthin in farmed versus wild salmon, in processed versus unprocessed salmon, and in cooked versus uncooked salmon. Further, we examined the relative abundance of 3S,3’S-all-trans-astaxanthin in human plasma following consumption by participants in a dietary intervention that included salmon. Results demonstrated, for the first time, that a lower abundance of 3S,3’S-all-trans-astaxanthin was found in processed salmon products compared to fresh or frozen salmon. An increase in the relative abundance of 3S,3’S-all-trans-astaxanthin was found in human plasma following salmon consumption in a rigorous controlled feeding trial with salmon as the only astaxanthin food source.

Salmon is a common nutritious food available to consumers in fresh, pre-frozen, or packaged forms. Food processing (such as pouch and canned) could possibly decrease the nutritional value of salmon, including its total astaxanthin content, as shown in the present study and previous research [34, 35], as we demonstrated that fresh varieties contained higher astaxanthin content than those packaged in a pouch and/or can. Pouched packaging often includes vacuum sealing and removing access liquid, which could potentially affect astaxanthin content. In this study, heating/cooking salmon did not significantly diminish astaxanthin content, which contrasts with other studies [36] and may be due to the different cooking times and/or cooking styles used in prior research. In addition, others have reported that astaxanthin stability is influenced by the matrix in which extracted astaxanthin is heated; for example, extracted astaxanthin is more stable in orange juice compared to skim milk[10]. The cooked salmon from group 1 was cooked to 71 °C (160 °F), higher than the USDA recommended salmon cooking temperature of 63 °C (145 °F) and astaxanthin was still stable. Further, the current study focused on the independent analysis of the 3S,3’S-all-trans-astaxanthin, 9-cis-astaxanthin, and 13-cis-astaxanthin isomers, while most previous studies measured total astaxanthin contents or a single isomer.

The metabolism of astaxanthin isomers in humans is not well understood [20–22]. Because of the different chemical structures, there may be differences in metabolic efficiency and/or transformation among isomers. The predominant astaxanthin isomers found in salmon filets were comparable to the 3S,3’S-all-trans-astaxanthin and 13-cis-astaxanthin isomers detected in humans. The charge carriers in plasma 13-cis-astaxanthin are slightly different than in salmon, with the M+NH4 and M+K species missing in plasma. This may be due to the lower abundance of the plasma 13-cis-astaxanthin isomer compared to plasma 3S,3’S-all-trans-astaxanthin, since the NH4+ and K+ species were low abundance to begin with. Intriguingly, the 9-cis-astaxanthin isomer present in salmon was not detectable in plasma after the dietary intervention.

The absence of 9-cis-astaxanthin in human plasma, despite its presence in salmon tissues, is likely due to species-specific differences in metabolism, lipid transport, and isomer stability and modification. In humans, β-carotene oxygenase 2 (BCO2) possibly preferentially cleaves cis-isomers of carotenoids, including 9-cis-astaxanthin, at the 9,10 or 9”,10” positions, leading to its degradation before it can accumulate in plasma [37]. In contrast, salmon may have lower BCO2 activity or different enzyme specificity, allowing for the retention and storage of 9-cis-astaxanthin in tissues [38, 39]. Additionally, astaxanthin transport via lipoproteins (e.g., chylomicrons, HDL, LDL) in humans varies depending on isomeric structure, potentially leading to lower plasma levels of 9-cis-astaxanthin compared to all-trans or 13-cis isomers. In contrast, salmon have evolved efficient mechanisms to incorporate and store astaxanthin directly in muscle tissues, which may explain why 9-cis-astaxanthin persists in salmon but not in human plasma [40]. These findings suggest that BCO2 enzymatic activity, lipid transport mechanisms, and differential isomer stability contribute to the selective loss of 9-cis-astaxanthin in humans. Further research is warranted to clarify the species-specific metabolism of astaxanthin isomers and the potential functional impacts of carotenoid metabolism on human health.

Plasma 3S,3’S-all-trans-astaxanthin accumulation after the dietary intervention confirms that this form of astaxanthin can be absorbed and stably transported in human circulation like other carotenoids [41]. Additional isomers identified in human plasma samples support previous work showing that astaxanthin can be metabolized or transformed and modified post-absorption [20–22]. Matching the authentic reference standard for 3S,3’S-all-trans-astaxanthin to both the MS/MS library and the compound we detected in salmon provides strong confirmatory evidence for the identification of this compound in plasma. While the identities of the 9-cis-astaxanthin and 13-cis-astaxanthin isomers in plasma could not be confirmed due to low abundance, their masses and previous work by Yang, et. al. (2015), Coral-Hinostroza, et. al. (2004), and others suggest that these compounds are likely 9-cis-astaxanthin and 13-cis-astaxanthin [20, 21, 27].

Generally speaking, farmed salmon is in many respects nutritionally similar to wild (caught) salmon. However, for farmed salmon, its feed is commonly rich in fats, proteins, antibiotics, and other ingredients that make it grow faster and larger than its wild-caught counterpart [42]. Astaxanthin is typically added to the food of farmed salmon, while wild salmon obtain astaxanthin from their diet, which includes Crustacea[43, 44]. Besides higher astaxanthin contents, results from this study also suggested that wild salmon may be more beneficial for increasing dietary PUFA consumption because it had higher contents of EPA and DHA, but lower levels of ALA and AA. High ALA and AA in farmed salmon may be due to the salmon feed having higher ALA and AA contents [45, 46]. AA is the precursor for pro-inflammatory oxylipins [47]. ALA can be metabolically converted to longer-chain omega-3 fatty acids like EPA and DHA, but not very efficiently [45, 46]. Greater intake of dietary ALA and/or AA may be associated with a greater prevalence of several metabolic disorders, including but not limited to obesity, insulin resistance, and fatty liver diseases [48–52].

Besides the aforementioned strengths, this study has several limitations. First, the dietary intervention study was a secondary analysis and thus only farmed salmon was consumed. Future controlled feeding studies comparing farmed vs. wild salmon and evaluating astaxanthin absorption are warranted. Second, salmon was fed at 2 servings per week for all participants in both intervention periods, and thus it was not possible to determine whether plasma astaxanthin followed a dose-response pattern. Future research could consider a controlled feeding intervention targeting wild versus farmed salmon with frequent sampling to study kinetics and different quantities to study dose response. The sample sizes used here for salmon were small and often only represented subsamples of one or two fish for each characteristic and do not cover all geographical or environmental factors. As such, many conclusions from these results should be considered preliminary. For instance, it was unknown if all farmed salmon from different farms or even within the same farm would have similar astaxanthin levels as that seen here or if wild salmon from the same or different locations would also be consistent. More research is needed to assess consistency of astaxanthin levels within and across salmon sources and types. Nonetheless, this study provides initial insights into the variability (and lack of variability) of astaxanthin across salmon characteristics. Due to a paired study design comparing cooked and uncooked samples of the same fish, we found that the cooking performed here appeared to not have a considerable effect on astaxanthin levels.

Overall, astaxanthin metabolism, including its different isomers, in the format of whole foods such as salmon, is not well investigated. This study was among the first to compare astaxanthin isomers in salmon from different sources and processing methods, demonstrating different astaxanthin contents across sample types. Furthermore, this study also demonstrated that consumption of salmon increases circulating human plasma astaxanthin with different isomer accumulation compared to salmon, suggesting the potential application of different astaxanthin isomers that can be used as biomarkers of different salmon consumption in human feeding studies.

Supplementary Material

1

Appendices

Two supplemental figures are available.

Highlights.

  • Three astaxanthin isomers in salmon, predominantly 3S,3′S-all-trans-astaxanthin

  • 9-cis- and 13-cis-astaxanthin found in salmon; but only 13-cis in human plasma

  • Higher levels of three astaxanthin isomers in wild salmon than farmed salmon

  • Astaxanthin levels unchanged by cooking but lowered in processed salmon

  • Elevation of plasma 3S,3′S-all-trans-astaxanthin in humans consuming a salmon diet

Acknowledgments

Design study: WWC, NFK, DL, DNF, MT

Data Collection and Analyses: NR, RR, KQ, MA, CM, DNF, EH, PL, DL, YT, MT

Manuscript preparation and Revision: PL, NR, DL, MT, RR, WWC, EH, AEH, NFK

Funding sources

This work was supported by the National Institutes of Health [2T32DK007658-31] and foodomics R01 [5R01DK113957-05], NIH CoBRE [1P20GM152333], USDA NIFA [2020-67017-30842], CSU Lillian Fountain Smith Endowed Professorship (MT), and OSU John and Sue Taylor Professorship (DL). The original randomized controlled feeding trial was supported by the National Cattlemen’s Beef Association, a contractor to the Beef Checkoff, and the Pork Checkoff (to WWC) with additional support by the NIH’s Ingestive Behavior Research Center at Purdue University [5T32DK076540-08] and the NIH’s Indiana Clinical and Translational Sciences Institute [UL1TR001108]

Footnotes

Declaration of interests

The authors have nothing to declare

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