Month: December 2025

Discovering a new NAD+ precursor

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A 2025 rodent study investigated dynamics of organ and circulating nicotinamide:

“Liver-derived circulating nicotinamide from nicotinamide adenine dinucleotide (NAD+) catabolism primarily feeds systemic organs for NAD+ synthesis. We surprisingly found that, despite blunted hepatic NAD+ and nicotinamide production in liver-specific nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) deletion mice (liver-specific knockout [LKO]), circulating nicotinamide and extra-hepatic organs’ NAD+ are unaffected.

Metabolomics reveals a massive accumulation of a novel molecule in the LKO liver, which we identify as nicotinic acid riboside (NaR). The liver releases NaR to the bloodstream, and kidneys take up NaR to synthesize NAD+ through nicotinamide riboside kinase 1 (NRK1) and replenish circulating nicotinamide.

Serum NaR levels decline with aging, whereas oral NaR supplementation in aged mice boosts serum nicotinamide and multi-organ NAD+, including kidneys, and reduces kidney inflammation and albuminuria. The liver-kidney axis maintains systemic NAD+ homeostasis via circulating NaR, and NaR supplement ameliorates aging-associated NAD+ decline and kidney dysfunction.

While this study provides evidence of hepatic production and renal consumption of NaR for NAD+ homeostasis in mice, future human works are warranted to confirm these findings. In addition, genetic studies will be necessary to fully understand NaR metabolism at cellular and organismal levels.

While this study shows the oral availability of NaR and its effect on systemic NAD+ metabolism in mice, human studies testing NaR safety, oral availability, pharmacokinetics, and pharmacodynamics should be performed to test potential clinical usage of NaR supplements. Additionally, future studies are needed to investigate physiological significance of NT5C2-mediated hepatic production of NaR in healthy mice and identify NaR transporter(s).”

https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00217-7 “Nicotinic acid riboside maintains NAD+ homeostasis and ameliorates aging-associated NAD+ decline” (not freely available) Thanks to Dr. Dorota Skowronska-Krawczyk for providing a copy.

An elaborating commentary was published along with this study:

“Nicotinamide (NAM), nicotinamide riboside (NR), nicotinic acid (NA), and NAR are the salvageable precursors that feed into production of nicotinamide mononucleotide (NMN) and nicotinic acid mononucleotide (NAMN) to regenerate NAD coenzymes. NAMN is at an interesting juncture in NAD metabolism because it is formed in de novo synthesis and in salvage synthesis from both NA and NAR.

Song and coworkers did not specifically set out to determine endogenous sources of NR and/or NAR. Rather, they wanted to see what would happen when they deleted the major Nmnat isozyme, Nmnat1, in liver.

With depression of hepatic NAD+, they saw elevation of liver NMN and NAMN and discovered a huge increase in hepatic and circulating NAR. By viral knockdown, the step of conversion of accumulated NAMN to NAR was found to be catalyzed by a 5′ – nucleotidase encoded by the Nt5c2 gene, and the major tissue receiving the NAR was found to be the kidney.

Further, they showed that levels of NAR decline in aging while provision of supplementary NAR supports a newfound ability of the mouse kidney to circulate NAM. Of potential translational significance, supplementary NAR also supported mouse kidney function in aging.”

https://www.brennerlab.net/curriculumvitae/ “The NARly side of whole-body NAD homeostasis” (*pdf at page bottom)

Human studies of astaxanthin – Part 2

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Continuing Part 1, here are four more 2025 human studies of the Nrf2 activator astaxanthin, starting with a randomized, double-blind, placebo-controlled trial of its effects on reducing oxidative stress and inflammatory responses following eccentric exercise:

“This study investigated effects of astaxanthin supplementation on plasma MDA and HMGB1 levels following acute eccentric exercise in recreationally active male students. Fifty-four students were assigned to receive either 12 mg/day of natural astaxanthin (AST, n = 27) or placebo (PLA, n = 27) for 14 days.

A key consequence of eccentric-induced muscle damage is overproduction of reactive oxygen species (ROS). When ROS production exceeds the capacity of endogenous antioxidant systems, lipid peroxidation can occur. Malondialdehyde (MDA) is a stable end-product of lipid peroxidation and serves as a widely recognized biomarker for oxidative stress and cell membrane damage.

In parallel, muscle cell damage results in release of damage-associated molecular patterns (DAMPs) into the extracellular space. Among these, High Mobility Group Box-1 (HMGB1) plays a central role in inflammation when passively released from the nucleus. HMGB1 acts as a potent pro-inflammatory signal by activating innate immune receptors, recruiting immune cells, and upregulating cytokines such as IL-6 and TNF-α.

This heightened immune activity contributes to delayed-onset muscle soreness, which typically peaks 24–72 hours post-exercise, and is associated with impaired recovery. Sustained elevations in oxidative and inflammatory biomarkers, including MDA and HMGB1, may further impair recovery and contribute to long-term muscle pathology.

Astaxanthin’s antioxidant effects are mediated through both direct and indirect mechanisms. Structurally, astaxanthin is a xanthophyll carotenoid with a unique polar–nonpolar–polar configuration that enables it to span the phospholipid bilayer of cell membranes. This positioning allows it to neutralize ROS both at the membrane surface and within the lipid bilayer.

In addition, astaxanthin enhances endogenous antioxidant defenses by upregulating enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) through activation of the Nrf2–ARE signaling pathway. This dual mode of action provides both immediate and sustained protection against oxidative stress during and after exercise.

The placebo group showed substantial increases in MDA and HMGB1 after exercise, whereas the astaxanthin group experienced attenuated rises (~22% and ~27% smaller, respectively) and faster recovery toward baseline within 24 hours. These findings suggest that astaxanthin supplementation can be incorporated into recovery strategies for athletes and active individuals, especially during periods of heavy training or repeated bouts of intense eccentric exercise. By reducing oxidative damage and inflammation, astaxanthin may shorten recovery time, limit performance loss, and support overall training adaptations—benefits that are particularly valuable in sports requiring frequent high-intensity efforts.

Several limitations should be acknowledged in this study.

  1. Sample size was relatively small and limited to recreationally active young males, which may restrict generalizability of findings to other populations such as females, older adults, or elite athletes.
  2. Supplementation period was limited to 14 days; although this duration is sufficient to achieve plasma saturation of astaxanthin, longer interventions may produce different or more pronounced effects.
  3. Only two biomarkers were assessed (MDA and HMGB1), which provide important but incomplete insights into broader oxidative stress and inflammatory response. Including additional markers such as enzymatic antioxidants, cytokine profiles, and muscle damage indicators (e.g., creatine kinase) could yield a more comprehensive understanding.
  4. Dietary intake and physical activity outside the intervention were self-reported and not strictly controlled, which may have introduced variability in results.”

https://tmfv.com.ua/journal/article/view/3664/1922 “Taking Astaxanthin Supplementation Attenuates MDA and HMGB1 Following Eccentric Exercise: A Randomized Controlled Trial in Recreationally Active Students”

A clinical trial investigated astaxanthin’s effects with exercise in diabetic women:

“This study examined whether combined aerobic and resistance training (CT) and astaxanthin (AST) supplementation synergistically improve oxidant and inflammatory status as well as metabolic indices in T2DM, focusing on the mediatory role of Humanin (HN) and microRNAs (miRNA-122, miRNA-126-3p, and miRNA-146a).

Ninety women with T2DM were randomly assigned to six groups (n = 15 each):

  • Control (C), placebo (P), AST supplementation (S), combined training (CT), CT + placebo (CT + P), and CT + AST supplementation (CT + S).
  • CT, CT + P and CT + S groups underwent an 8-week training program (eight exercises, three sessions per week).
  • S and CT + S groups received 8 mg/day of AST.

This study only enrolled female participants age between 30 and 60 years old to minimize inter-individual biological variability arising from sex differences in hormone regulation, fat distribution, and gene expression related to inflammation and oxidative stress. Oxidative stress (OS) markers, inflammatory cytokines, HN levels, miRNAs expression, fasting blood glucose (FBG), insulin resistance (HOMA-IR), lipid profile, and hemoglobin A1c (HbA1c) were assessed.

HN is a member of a class of novel mitochondrial-derived peptides released during mitochondrial dysfunction. HN reduces ROS production, enhances antioxidant protein expression, maintains redox balance, and suppresses TNF-α, IL-1β, and IL-6 to inhibit inflammation. Furthermore, resistance and endurance training has shown to increase HN expression in patients with prediabetes. Exercise – aerobic and endurance – has been shown to increase circulating and skeletal muscle levels of HN, correlating with improved insulin sensitivity and mitochondrial function.

Our results showed:

  • CT and AST supplementation both improved antioxidant defense and reduced inflammation, and their combination was more effective than either intervention alone.
  • CT and AST supplementation increased blood concentration of HN, and their combination showed greater effects than AST supplementation, but not CT.
  • CT and AST supplementation increased blood levels of miRNAs-126-3p, and -146a and decreased miRNA-122, with their combination being slightly more effective in decreasing miRNA-122.
  • Both interventions improved lipid profile, with their combination being more effective in improving HDL and TG levels, although not total cholesterol.
  • FBG, HOMA-IR, and HbA1c were reduced by CT but not by AST supplementation.

Our data suggest that combining exercise with AST supplementation might improve oxidative status and inflammation through mechanisms involving HN and miRNAs 122, 126-3p, and 146a. Alleviating OS and inflammation could, in turn, lead to improvements in lipid profiles (e.g., TG, and HDL), IR, and reductions in HbA1c and FBG, as observed in our study. Furthermore, the combined approach seems to be more effective at improving cholesterol and TG levels.“

https://www.nature.com/articles/s41598-025-23914-y “Redox-sensitive miRNAs and Humanin could mediate effects of exercise and astaxanthin on oxidative stress and inflammation in type 2 diabetes”

A meta-analysis of randomized controlled trials reported until May 2025 assessed astaxanthin’s effects on lipid profiles. Neither of the two trials covered here nor the three trials covered in Part 1 were included in this meta-analysis.

“Astaxanthin, a xanthophyll carotenoid, has garnered significant interest due to its benefits with regard to dyslipidemia. This multifaceted functional food ingredient modulates several key enzymes associated with lipid regulation, including HMG-CoA reductase, CPT1, ACCβ, and acyl-CoA oxidase. It influences key antioxidant molecular pathways like Nrf2, limiting dyslipidemia occurrence and regulating liver cholesterol uptake through modulation of liver lipid receptors.

Astaxanthin daily doses and durations of analyzed studies: 12 mg for 8 weeks; 12 mg for 4 weeks; 20 mg for 12 weeks (two trials); 12 mg for 12 weeks; 8 mg for 8 weeks; 6 mg and 12 mg for 12 weeks; 6 mg, 12 mg, and 18 mg for 12 weeks.

This meta-analysis concludes positive effects of astaxanthin (6–20 mg/d) on HDL-C and triglyceride levels. Astaxanthin (6–20 mg/d) does not appear to significantly influence LDL-C and total cholesterol levels.

Regarding HDL-C, improvements were observed from 55 ± 8 mg/dL (pre-intervention) to 63 ± 8 mg/dL (post-intervention) (p < 0.01) in the 12 mg/d of astaxanthin groups. In triglyceride levels, results show a decrease from 151 ± 26 mg/dL (pre-intervention) to 112 ± 40 mg/dL (post-intervention) (p < 0.01) for 18 mg/d astaxanthin supplementation.

Further research is necessary to fully harness the potential of astaxanthin, which includes assessing astaxanthin in different subsets of patients, and in combination with other nutraceuticals to understand the compound’s effectiveness with regard to varying health conditions, genetic and epigenetic factors, and synergistic effects with other compounds.”

https://www.mdpi.com/1424-8247/18/8/1097 “Assessing the Effects of Moderate to High Dosage of Astaxanthin Supplementation on Lipid Profile Parameters—A Systematic Review and Meta-Analysis of Randomized Controlled Studies”

This same group of researchers assessed that in nine RCTs, astaxanthin had no effects on either body weight or BMI per https://www.mdpi.com/1424-8247/18/10/1482 “Therapeutic Potential of Astaxanthin for Body Weight Regulation: A Systematic Review and Meta-Analysis with Dose–Response Assessment”

Human studies of astaxanthin – Part 1

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Here are three 2025 clinical trials of the Nrf2 activator astaxanthin’s effects. Let’s start with a clinical trial of inflammation-related diabetic complications and insulin resistance:

“We investigated effects of 10 mg/day astaxanthin (ASX) supplementation for 12 weeks on microRNAs (miRNAs), lysophosphatidylcholine (LPC), and α-hydroxybutyrate (α-HB) as novel factors in development of a variety of diabetes-related complications.

  • LPC is believed to play a significant role in atherosclerosis and inflammatory diseases by modifying functions of multiple cell types, including smooth muscle cells, endothelial cells, monocytes, macrophages, and T cells. LPC can interfere with glucose-stimulated insulin secretion by impairing calcium homeostasis and other signaling pathways that are crucial for the proper functioning of beta cells. This impairment exacerbates hyperglycemia in diabetic patients. LPCs may impede insulin signaling pathways, thereby contributing to insulin resistance (IR).
  • α-HB is also an indicator of IR and impaired glucose regulation, both of which appear to result from excessive lipid oxidation and oxidative stress. The European population cohorts in 2016 identified α-HB as a selective biomarker for decreased glucose tolerance and prediabetes, which was independent of age, sex, BMI, and fasting glucose.
  • A number of studies have established a link between miR-21, miR-34a, and miR-155 and diabetic complications such as retinopathy and nephropathy.

In the ASX group, participants were divided into 2 subgroups according to the urinary albumin-to-creatinine ratio (ACR) (< 30 mg/g or ≥ 30 mg/g, an indicator of diabetic kidney disease).

  • The level of fasting plasma glucose before and after 12 weeks of treatment with ASX was 139.27 ± 21.18 vs. 126.43 ± 18.97 (p = 0.002), demonstrating a significant reduction compared to the placebo group.
  • In the ASX group, the mean HbA1c level at baseline was 7.89 ± 0.79 and declined to 7.05 ± 0.35 after the supplementation period, which was statistically significant.
  • Supplementation with ASX resulted in a statistically significant drop in HOMA-IR levels, whereas this parameter was not altered significantly in the placebo group.
  • The ASX group, in comparison with the placebo group, demonstrated marked changes in lipid profile factors such as TC, TG, and LDL (p = 0.011, p = 0.043, and p = 0.022, respectively).

Clinical studies indicate that rigorous diabetes management does not substantially diminish appearance of complications. Modifications in oxidative stress and IR markers, as well as miRNA expression, must be analyzed to identify biological markers with sufficient predictive power for development of complications in diabetic patients.

Supplementation with ASX substantially diminished the levels of α-HB, LPC, and inflammation-related miRNAs in diabetic patients with and without complications.”

https://onlinelibrary.wiley.com/doi/10.1155/ije/5878361 “Astaxanthin Modulates Inflammation in Type 2 Diabetes via Regulation of microRNAs, Lysophosphatidylcholine, and α-Hydroxybutyrate”

Another clinical trial investigated astaxanthin’s effects in heart failure patients:

“Chronic heart failure (HF) is often linked to increased oxidative stress and metabolic issues like high uric acid, which can worsen outcomes.This study aimed to investigate the effects of ASX supplementation on oxidative stress markers as the primary outcome and clinical symptoms in patients with HF.

80 patients with HF were enrolled and randomly assigned to receive either ASX (20 mg/day) or a placebo (20 mg/day of maltodextrin) for 8 weeks. Biomarkers including total antioxidant capacity (TAC), malondialdehyde (MDA), superoxide dismutase (SOD), serum uric acid (UA), and clinical symptoms (dyspnea, fatigue, appetite) were assessed pre-and post-intervention.

Daily supplementation with 20 mg of ASX for eight weeks in patients with HF resulted in significantly greater improvements in oxidative stress biomarkers compared to placebo group. This improvement included reductions in uric acid and MDA, along increases in TAC and SOD.

In our study, participants received the cis-isomer form of ASX. The cis-isomer of ASX demonstrates greater anti-inflammatory and antioxidant properties than the trans-isomer, along with enhanced bioavailability. Inconsistencies among studies may be attributed to differences in participants’ baseline antioxidant status, underlying medical conditions, dosage, isomeric form and formulation of ASX used, and the duration of intervention.

One of the strengths of this study is that it represents the first randomized clinical trial to evaluate the effects of ASX supplementation on oxidative stress markers, UA levels, and clinical symptoms in patients with HF. Additionally, potential confounding factors were controlled as much as possible. However, several limitations were identified, including the relatively short intervention duration, limited sample size, limited generalizability of the findings due to the single-center design, absence of blood ASX level measurements, and lack of long-term follow-up.”

https://link.springer.com/article/10.1186/s12872-025-05260-z “Impact of astaxanthin on oxidative markers, uric acid, and clinical symptoms in heart failure: a randomized clinical trial”

A third clinical trial evaluated astaxanthin’s effects as an adjunct to standard treatment of community-acquired pneumonia:

“Adult patients diagnosed with community-acquired pneumonia (CAP) were enrolled and assigned to receive either 12 mg/day ASX or a placebo in addition to standard antibiotic therapy for 7 days. Inflammatory markers, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-10 (IL-10), were measured at baseline and post-treatment. Secondary outcomes included Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores.

A total of 80 patients (40 per group) completed the study. Patients receiving ASX exhibited significant reductions in pro-inflammatory cytokines compared to the placebo group. IL-6 and TNF-α levels were significantly lower in the ASX group at the end of the study (P < 0.05). Additionally, SOFA and APACHE II scores showed greater improvements in ASX-treated patients, suggesting a potential role in mitigating disease severity.

These findings suggest that ASX may help preserve organ function, limit the progression of inflammatory injury, and reduce overall disease severity in hospitalized patients with CAP.

ASX is widely regarded as the most potent carotenoid, owing to its unique molecular structure. Its polar-nonpolar-polar configuration enables it to span lipid bilayers and neutralize ROS both within and outside cellular membranes—an advantage not shared by other carotenoids that tend to localize at the membrane surface.

Despite the positive findings of this study, some limitations should nevertheless be considered.

  • The relatively small sample size may have limited the statistical power to detect differences in some outcomes and affects the generalizability of the findings.
  • Microbiological data on CAP pathogens were not collected. As different microorganisms can trigger distinct inflammatory responses, this limits our ability to assess pathogen-specific variations in ASX efficacy.
  • A notable limitation of this study is the short follow-up duration, with outcomes assessed only over a 7-day period. While this timeframe offers insight into the acute effects of ASX on inflammatory and OS markers, it does not clarify whether these benefits are sustained beyond the immediate treatment window.
  • The fixed dose of 12 mg once daily may not have maintained optimal therapeutic levels throughout the day. Dose-ranging studies and evaluations of alternative regimens are needed to determine the most effective strategy.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1621308/full “The anti-inflammatory and antioxidant effects of astaxanthin as an adjunctive therapy in community-acquired pneumonia: a randomized controlled trial”

Part 2 continues with four more 2025 human studies of astaxanthin.