Abstract
Background. European Food Safety Authority (EFSA) health claims permit statements that specific nutrients "contribute to the normal function of the immune system", "contribute to the reduction of tiredness and fatigue", and "contribute to the protection of cells from oxidative stress". Despite the regulatory clarity of these three claim categories, their underlying biochemistry is highly interconnected: the same metabolic hubs — mitochondrial bioenergetics, the KEAP1–NRF2 redox axis, glutathione turnover, one-carbon metabolism, NAD+/sirtuin signalling, immunometabolic substrate switching in lymphocytes, and diet-derived microbial metabolites — recur across all three physiological domains.
Objective. To synthesize post-2020 mechanistic and clinical evidence on the human metabolic pathways and biochemical mechanisms that jointly support immune function, reduce fatigue, and protect cells from oxidative stress; to expose their integrative structure; and to appraise translational implications.
Methods. A structured narrative review of ~300 peer-reviewed papers indexed in 2020–2026 in Elicit's academic corpus, of which 86 were retained after multi-criterion curation for depth, methodological quality, and thematic coverage. Findings were extracted per source with a large-language-model pipeline that recorded exact source-sentence quotations, then integrated.
Results. Three master axes emerge: (1) the KEAP1–NRF2 pathway and the glutathione/glutaredoxin, selenoprotein and coenzyme Q10 (CoQ10) systems constitute an integrated cytoprotective network against oxidative stress; (2) micronutrients (vitamins A, C, D, zinc, selenium), specialized pro-resolving mediators derived from omega-3 polyunsaturated fatty acids (EPA/DHA), microbiota-derived short-chain fatty acids (SCFAs) and dietary polyphenols shape both innate and adaptive immunity primarily through T-cell immunometabolic reprogramming, dendritic cell/Treg polarization, and NRF2–NF-κB cross-talk; (3) fatigue is causally linked to mitochondrial bioenergetic insufficiency, iron- and B-vitamin–dependent oxygen transport and one-carbon flux, magnesium-dependent ATP handling, NAD+ decline, and carnitine-dependent long-chain fatty-acid β-oxidation, with converging evidence from randomized trials of CoQ10+NADH, iron, B-complex, carnitine and adaptogenic plants.
Conclusion. The mechanistic overlap between the three EFSA claim domains is not coincidental: mitochondrial function, redox tone, and immunometabolic substrate allocation are the shared substrate on which "energy", "immunity" and "cellular protection" are all built. Rational nutrition and pharmaco-nutritional strategies should exploit this convergence rather than target each domain in isolation.
Keywords: immunometabolism; NRF2; glutathione; coenzyme Q10; NAD+; oxidative stress; fatigue; mitochondrial bioenergetics; short-chain fatty acids; vitamin D; zinc; selenium; omega-3.
1. Introduction
Human physiology maintains three tightly coupled homeostatic properties that are commonly separated in regulatory and nutritional discourse: an immune system that discriminates and resolves threats, a bioenergetic system that delivers ATP at demand, and a redox system that keeps reactive species within a signalling window. All three properties depend on shared molecular machinery — the mitochondrion, the thiol-disulfide network, and the transcription factors that sense electrophilic and inflammatory stress. Nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcriptional regulator that induces antioxidant, detoxifying and cytoprotective genes to maintain redox homeostasis and simultaneously modulates innate and adaptive immunity via cross-talk with NF-κB and MAPKs[1]; recent 2025 reviews explicitly frame this pathway as therapeutically actionable across inflammatory and autoimmune diseases[1, 2].
In parallel, since 2020 the field has consolidated the concept of immunometabolism: effector T cells and M1 macrophages preferentially use aerobic glycolysis to deliver rapid ATP and biosynthetic precursors, whereas memory T cells and M2 macrophages rely on oxidative phosphorylation and fatty-acid oxidation for durable energy and tolerance, integrated by mTORC1–AMPK signalling, glutaminolysis and the kynurenine pathway[3]. Nutrient availability is not a passive backdrop to this reprogramming — activated T cells run glycolysis and OXPHOS concurrently and allocate glucose, amino acids and lipids to distinct biosynthetic and effector fates[4]. Thus, at the cellular level, "immune support", "energy" and "oxidative protection" are not three independent phenomena but three read-outs of the same substrate-and-redox economy.
Fatigue, in the operational sense used by the EFSA "reduction of tiredness and fatigue" claim, is the systemic manifestation of that economy failing to keep pace with demand. Scoping reviews across 2022–2024 report that mitochondrial transport and respiratory-chain markers, mitochondrial DNA mutations, and immune-cell energy disorders are consistently associated with clinical fatigue phenotypes[5]. Case–control studies of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) show lower mitochondrial coupling efficiency and proteome changes centred on pyruvate dehydrogenase and coenzyme A metabolism, reducing intracellular ATP-generating capacity in peripheral immune cells[6]; post-COVID syndrome and CFS share reduced complex-I OXPHOS activity in skeletal muscle[7].
The purpose of this review is to consolidate the post-2020 evidence on the metabolic pathways and biochemical mechanisms by which the human body: (i) supports the immune system; (ii) reduces tiredness and fatigue; and (iii) protects cells from oxidative stress; and to expose the deep mechanistic overlap between them.
2. Methods
Search and corpus.
Twenty structured queries were executed in parallel against the Elicit academic index (a Semantic Scholar-derived corpus with year and citation filters), covering the following domains: NRF2/KEAP1 signalling, glutathione biosynthesis and redox, selenium/selenoproteins, mitochondrial bioenergetics and chronic fatigue, coenzyme Q10, B vitamins and one-carbon metabolism, iron and erythropoiesis, magnesium, NAD+ and sirtuins, dietary polyphenols/flavonoids, omega-3 PUFA, microbiota-derived SCFAs, vitamin A/retinoic acid, T cell immunometabolism, mitochondrial ROS, L-carnitine, and adaptogens (Rhodiola rosea, Withania somnifera). Queries were restricted to publication year > 2020.
Screening and extraction.
Three hundred candidate sources were retrieved. A curated set of 86 was retained through hand-selection prioritizing (a) systematic reviews and meta-analyses, (b) randomized controlled trials with reported effect sizes and (c) mechanistic reviews from established journals since 2021. Findings were extracted from each source's peer-reviewed abstract via a typed LLM pipeline, capturing thematic area, mechanistic summary, key evidence and translational relevance, with exact-sentence citations propagated from source text.
Scope limits.
This is a narrative review. Full-text retrieval was attempted for every curated paper but succeeded for a minority — the review therefore rests on peer-reviewed abstracts of high-quality sources and does not replace individual reading of the primary methods sections. Effect sizes are transcribed only where explicitly stated in abstracts.
3. Cellular Protection Against Oxidative Stress
3.1 The KEAP1–NRF2 axis: the sensor-response backbone of cellular redox
The KEAP1–NRF2 system is the sulfur-utilizing cytoprotective defense against oxidative stress: KEAP1 acts as a biosensor for electrophiles via reactive thiols, while NRF2 is a transcription factor that regulates antioxidant and detoxification genes and simultaneously exerts anti-inflammatory activity and regulates cellular metabolism and mitochondrial function[8]. Under basal conditions, a KEAP1–Cullin3–RBX1 E3 ubiquitin ligase complex ubiquitinates NRF2 for continuous proteasomal degradation, keeping NRF2 activation transient; oxidative or electrophilic modification of KEAP1 cysteines disrupts NRF2 ubiquitination, permitting nuclear translocation and induction of detoxifying, metabolic and repair genes[9]. The downstream target set includes thioredoxin (TXN), glucose-6-phosphate dehydrogenase (G6PD), glutathione-S-transferase A2 (GSTA2), NAD(P)H:quinone oxidoreductase 1 (NQO1), and heme oxygenase 1 (HMOX1), covering both direct antioxidant defenses and the NADPH regeneration required to sustain them[10].
Two properties of the pathway are particularly important for the "cellular protection" claim. First, NRF2 activity has explicit anti-inflammatory as well as antioxidant consequences: it suppresses pro-inflammatory cytokine gene induction and its activation in myeloid and endothelial cells represses proinflammatory cytokine and adhesion-molecule expression, mitigating organ damage[11, 12]. Second, NRF2 activity is context-dependent — transient activation is protective, whereas persistent activation (e.g., via KEAP1 or NFE2L2 mutations) drives tumorigenesis, chemoresistance, metabolic reprogramming and immune evasion[9]. Reviews from 2024–2025 explicitly caution that general antioxidant-scavenger approaches have largely failed clinically, and that pharmacological targeting of the KEAP1/NRF2 axis (dimethyl fumarate is an approved example) is a more mechanistically grounded strategy[10].
3.2 Glutathione and the glutaredoxin/S-glutathionylation network
Glutathione (GSH) is the central intracellular antioxidant, present at millimolar intracellular concentrations, that maintains redox homeostasis, detoxifies xenobiotics, and supports immune defense; its levels depend on the coordinated activity of γ-glutamyl-cysteine ligase (GCL), glutathione-S-transferase (GST) and γ-glutamyl-transferase (GGT), and on the availability of amino-acid substrates (cysteine, glutamine, glycine, serine, taurine)[13]. Mechanistically, GSH acts through several complementary routes:
- (i) glutathione peroxidases (GPxs) scavenge H2O2 and lipid hydroperoxides using GSH as reducing equivalent;
- (ii) GSH forms thioether S-conjugates with electrophiles (often GST-catalysed) for excretion; and
- (iii) GSH engages in reversible S-glutathionylation of protein thiols catalysed by glutaredoxins (Grx), which converts protein-SSG into a bona fide reversible signalling switch[14, 15].
The connection to immunity is direct. Altered GSH levels track with aberrant NLRP3 inflammasome activation across infections and autoimmune/neurodegenerative disorders, placing GSH as a redox brake on innate inflammatory activation[16]. Reviews published in 2023–2026 converge on GSH as a "universal biomarker" of health that supports immune-cell function through redox balance and detoxification[17, 18]. Translationally, restoration of GSH pools via precursors — N-acetylcysteine (NAC), S-adenosylmethionine (SAMe), 2-oxothiazolidine-4-carboxylate (OTC), or direct glycine + cysteine supplementation — is proposed as a personalized-medicine strategy integrating nutrigenetics and redox biomarkers, though randomized outcome data remain limited[13].
3.3 Selenium, selenoproteins and glutathione peroxidase-1
Selenium exerts its biological effects almost exclusively via its incorporation as selenocysteine into ~25 mammalian selenoproteins, most of which are oxidoreductases participating in antioxidant defense, redox signalling, and immune/inflammatory regulation[19]. Glutathione peroxidase-1 (GPx1) is a paradigmatic selenoenzyme that reduces H2O2 and soluble lipid hydroperoxides using GSH as reductant, thus directly translating selenium status into modulation of cytoplasmic and mitochondrial ROS balance[20]. GPx4, the phospholipid-hydroperoxide-specific isoform, in addition governs susceptibility to ferroptosis and shapes granulocyte and dendritic-cell functions; selenoprotein K and MSRB1 are further examples of selenoproteins that participate in initiation and resolution of inflammatory responses[21]. Optimal selenium status is associated with restoration of immune functions, particularly antioxidant protection of intestinal lymphoid tissue and enterocyte membranes, whereas selenium deficiency is associated with immunosuppression[22].
3.4 Mitochondrial ROS, coenzyme Q and the redox-signalling window
Mitochondria produce reactive oxygen species during oxidative phosphorylation and simultaneously manage them via a dedicated antioxidant system, functioning as both source and sink of ROS[23]. mtROS act as genuine second messengers regulating differentiation and cell-fate decisions rather than being purely toxic byproducts[24]. Their generation at complexes I and III depends on two variables — the redox state of the coenzyme Q (CoQ) pool and the proton motive force — and defective mitochondria that accumulate with age produce more mtROS, disrupting redox signalling and impairing homeostasis[25].
Recent 2025 reviews on muscle and cardiovascular disease consolidate the position that mitochondrial dysfunction and oxidative stress are jointly emerging as convergent mechanisms in myopathic and cardiometabolic conditions[26]. The relevance for the "cellular protection" claim is that CoQ10 sits at the biochemical junction where energy production and antioxidant defense meet: as ubiquinone it accepts electrons in the electron transport chain, and as ubiquinol it acts as a lipid-phase antioxidant that neutralizes ROS and terminates lipid peroxidation chains[27, 28].
4. Support of the Immune System
4.1 T-cell immunometabolism as the integrating framework
Any modern account of "immune support" must be built on immunometabolism. Effector T cells and M1 macrophages preferentially use glycolysis for rapid ATP and pro-inflammatory signalling; memory T cells and M2 macrophages depend on OXPHOS and fatty-acid oxidation for sustained energy and tolerance; the switch is orchestrated by mTORC1–AMPK signalling, glutaminolysis and the kynurenine (tryptophan) pathway[3]. A 2025 synthesis argues that the classic "Warburg-only" model is oversimplified: activated T cells run glycolysis and OXPHOS concurrently and allocate glucose, amino acids and lipids to distinct biosynthetic and bioenergetic fates depending on nutrient availability[4]. Metabolic pathway architecture — not merely nutrient concentration — determines proliferation, differentiation and effector-response programs across T-cell subsets[29, 30].
This is the reason nutritional immunology behaves as it does. When a micronutrient supports immunity, the mechanism is rarely "boosting" a static pool of cells; it is usually enabling substrate switching, cofactor supply, or receptor signalling within this immunometabolic architecture.
4.2 Vitamin C (ascorbate)
Ascorbate supports immunity through two distinct biochemical routes. The classical one is the reducing environment it maintains in immune-cell cytoplasm. The more recently characterized one is epigenetic: ascorbate is a required cofactor for Fe2+- and α-ketoglutarate-dependent Jumonji-C domain histone demethylases (JHDMs) and for TET (ten-eleven translocation) methylcytosine dioxygenases, thereby driving active DNA demethylation events that instruct T-cell development and differentiation[31, 32]. In monocyte-derived dendritic cells (moDCs), vitamin C induces extensive demethylation at NF-κB/p65 binding sites and upregulates antigen-presentation and immune-response gene expression; p65–TET2 interaction mediates these effects and vitamin C additionally increases TNFβ production and enhances DC-driven autologous T-cell proliferation[33]. In tumour models, TET2 promotes antigen-presentation machinery gene expression and this is potently enhanced by vitamin C, with correlations between TET activity, antigen-presentation gene expression and patient outcome[34].
4.3 Vitamin D
The active hormone 1,25-dihydroxyvitamin D (calcitriol) binds the vitamin D receptor (VDR) expressed on innate and adaptive immune cells and regulates hundreds of target genes governing antimicrobial peptide expression, cytokine secretion, epithelial and endothelial barrier integrity, and a tolerogenic T-helper phenotype[35, 36]. Direct in vivo mechanistic evidence in humans comes from the VitDHiD study: in 25 healthy adults given a single 80,000 IU vitamin D3 bolus, analysis of 452 VDR target genes in PBMCs identified 61 genes in eight major innate-immunity KEGG pathways, with five pathways silenced, two stabilized, and one increased, consistent with vitamin D acutely restraining acute inflammation and keeping cytokine release under control[37]. Vitamin D also induces CYP27B1 at sites of infection, enabling local 1,25(OH)2D production that directly drives antimicrobial peptide genes (including CAMP/LL37) and autophagy for control of intracellular pathogens[38]. Deficiency is epidemiologically linked to increased susceptibility to respiratory tract infections and sepsis and to autoimmunity (multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus), with 25(OH)D3 above 30–50 ng/mL considered essential for optimal immune function[36, 39].
4.4 Zinc
Zinc is best understood as an ionic second-messenger micronutrient. Beyond its role as a catalytic and structural cofactor in >300 metalloenzymes, it acts intracellularly as a signalling ion analogous to calcium in T-cell receptor, Toll-like receptor and cytokine pathways in monocytes/macrophages and T cells[40]. In HUT78 T cells, zinc deficiency reduces focal adhesion kinase (FAK) and ezrin–radixin–moesin (ERM) phosphorylation, lowers LFA-1 and elevates CD49d expression, compromising cytoskeletal remodeling and impairing T-cell motility and immunological synapse formation[41]. Zinc status also modulates the metabolic switch of T-cell activation, influencing glucose uptake and insulin-receptor signalling and thereby biasing polarization toward effector or regulatory phenotypes[42].
Clinically, a 2025 randomized pilot trial in older adults (>65 years) with serum zinc below 70 μg/dL showed that 30 mg/day zinc for 3 months raised serum zinc by a mean of 18.1 μg/dL (vs +1.2 μg/dL controls; adjusted β = 20.91 ± 2.35 μg/dL, P<0.001), increased T-cell counts (β = 219.75 ± 40.67 cells/μL, P<0.001) and improved anti-CD3/CD28 and phytohemagglutinin proliferative responses (P = 0.010 and P<0.001, respectively)[43]. In aged mouse models, zinc supplementation reduces MCP-1 and dampens T-cell activation–induced IFN-γ, IL-17 and TNF-α while increasing naïve CD4+ T-cell frequency, supporting zinc status as a modulator of age-related T-cell dysfunction and inflammaging[44].
4.5 Selenium in immune regulation
Selenium's immune role goes beyond antioxidant coverage. Selenoprotein K and GPx4 modulate granulocyte pro-inflammatory response initiation and resolution; MSRB1 facilitates LPS-stimulated macrophages toward anti-inflammatory IL-10 and IL-1RA production; and selenium metabolism in solid tumours regulates GPx4-mediated ferroptosis resistance and autophagy-driven immunomodulation[21]. Optimal selenium status also protects intestinal lymphoid structure and enterocyte membranes and regulates transcription factors involved in inflammation resolution (NF-κB, PPARγ)[22].
4.6 Vitamin A and retinoic acid
All-trans retinoic acid (atRA), the bioactive vitamin A metabolite, binds retinoic-acid receptors (RARs) and orchestrates mucosal immune programs. It induces regulatory T cells (Tregs), upregulates gut-homing adhesion molecules CCR9 and α4β7 integrin on lymphocytes, enhances dendritic-cell retinal dehydrogenase (RALDH) expression to amplify local RA synthesis, and maintains Th17/Treg balance and appropriate Th-cell responses[45, 46]. A 2025 mechanistic study elucidates a three-day epithelial→myeloid→T-cell retinoid transfer axis in mesenteric lymph nodes: microbial-associated molecular patterns induce epithelial serum amyloid A (SAA), retinol-binding proteins transfer retinoids to myeloid cells, and microbial antigen drives retinoid transfer to developing T cells — coupling gut microbiota directly to intestinal adaptive-immune programming[47].
4.7 Dietary polyphenols and flavonoids
Polyphenols support immunity primarily as NRF2 activators. They increase endogenous antioxidant enzyme expression (SOD, CAT, HO-1, NQO1) and suppress NF-κB-dependent proinflammatory transcription, effectively rebalancing the redox–immune interface[48]. Beyond radical scavenging, they inhibit phospholipase A2, cyclooxygenase and lipoxygenase in the arachidonic-acid cascade, reducing prostaglandin and leukotriene generation and lymphocyte/macrophage cytokine release[49]. Mechanistic reviews from 2025–2026 also emphasize NRF2 activation by flavonoids and even flavonoid + mesenchymal stromal-cell combinations as strategies for chronic inflammatory disease[50, 51]. A 2026 synthesis of clinical and preclinical evidence catalogues the polyphenol → Keap1–NRF2/ARE + mitochondrial quality control mechanism but also stresses that bioavailability and gut-microbiota-driven biotransformation remain the dominant translational barriers[52].
4.8 Omega-3 polyunsaturated fatty acids (EPA/DHA)
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) modulate immunity by four converging mechanisms:
- altering immune-cell membrane fluidity and lipid-raft signalling;
- inhibiting NF-κB activation, lowering proinflammatory cytokine expression;
- activating PPAR-γ; and
- serving as precursors to specialized pro-resolving mediators (SPMs) — resolvins, protectins and maresins — that actively drive resolution of inflammation rather than merely suppressing it[53].
Meta-analytical evidence has hardened around these mechanisms. A 2026 meta-analysis of 41 RCTs on EPA/DHA in exercise contexts reported that IL-6, TNF-α, creatine kinase and delayed-onset muscle soreness were significantly reduced (SMD = −0.4 to −0.7), with the strongest effects at ≥2 g/day mixed EPA+DHA for ≥6 weeks, particularly in recreational athletes[54]. A separate 2026 dose- and ratio-dependent meta-analysis of 96 clinical trials found that daily doses of 1–3 g/day produced the most consistent reductions in C-reactive protein, TNF-α and IL-6; EPA:DHA ratios <1.0 gave the greatest cytokine reductions, whereas ratios ≥1.0 more effectively raised blood EPA:DHA ratio and reduced arachidonic acid[55]. Broader translational reviews support these observations in autoimmune (T1D, RA, SLE, MS) and viral diseases[56].
4.9 Short-chain fatty acids and the gut microbiota
Gut-microbial fermentation of dietary fibre yields short-chain fatty acids (SCFAs) — mainly acetate, propionate and butyrate — that regulate epithelial barrier function and mucosal/systemic immunity through two conserved mechanisms: signalling via G-protein-coupled receptors (GPR41, GPR43, GPR109A) and inhibition of class I and II histone deacetylases (HDACs)[57, 58]. Butyrate is the best-characterized effector: HDAC inhibition drives differentiation of intestinal epithelial cells, phagocytes, B cells and plasma cells, and biases T cells toward regulatory over effector phenotypes, with anti-inflammatory activity extending to extra-intestinal sites[57, 59]. Reviews from 2025–2026 explicitly frame SCFA dysregulation as a driver of autoimmune, metabolic and inflammatory disease risk and position SCFA-based interventions (dietary fibre, fermentation-enhancing microbiome engineering) as precision-nutrition strategies[60].
5. Reduction of Fatigue and Tiredness
5.1 Mitochondrial bioenergetic dysfunction as the core mechanism
A 2022 scoping review of 17 adult clinical studies concluded that markers of mitochondrial respiratory chain and transport function, mitochondrial DNA mutations, and immune-cell energy disturbances (e.g., natural-killer cells) are consistently associated with clinical fatigue, and that interventions targeting these markers could reduce or prevent fatigue[5]. In ME/CFS peripheral blood mononuclear cells, mitochondrial coupling efficiency is significantly lower than in matched controls, and the proteome shows disturbances centred on pyruvate dehydrogenase and coenzyme A metabolism — a mechanistically coherent explanation for the reduced ATP-generating capacity that tracks with fatigue severity[6]. Muscle-biopsy evidence extends this: complex-I OXPHOS activity is significantly reduced in post-COVID syndrome relative to healthy controls, with morphological cristae differences between CFS and post-COVID syndrome consistent with virus-linked mitochondrial injury[7]. A 2024 review by Ross reinforces that mitochondrial dysfunction is central to CFS[61].
5.2 Coenzyme Q10 (and NADH)
CoQ10 sits at the shared node of energy and redox metabolism: as ubiquinone it accepts electrons in the electron transport chain and supports ATP synthesis; as ubiquinol it terminates lipid-peroxidation chains[27]. Reviews consistently propose it as a candidate against oxidative stress, age-related decline, cardiovascular disease and mitochondrial dysfunction[27]. In exercise physiology, CoQ10 reduces lipid peroxidation and biomarkers of muscle damage (creatine kinase, LDH-M, myoglobin), and accelerates recovery, although effects on peak performance depend on dose, duration, exercise modality and individual characteristics[28].
The most rigorous single trial in ME/CFS is a 12-week randomized, double-blind, placebo-controlled study in 207 patients receiving 200 mg CoQ10 + 20 mg NADH once daily: the experimental group showed significant reductions in cognitive-fatigue perception and overall FIS-40 score (P<0.001 and P=0.022, respectively) and improved SF-36 health-related quality of life (P<0.05), with sleep-duration and habitual sleep-efficiency improvements at 4 and 8 weeks[62]. The picture is nevertheless not uniformly positive across all fatigue populations. A 2025 systematic review and meta-analysis of five RCTs (n=474) reported that CoQ10 significantly reduced depressive symptoms (SMD −0.68; 95% CI −1.02 to −0.33; P<0.01; I² = 58%), but that the evidence for fatigue reduction was inconclusive (SMD −0.33; 95% CI −1.38 to 0.72; P=0.54) based on only two eligible trials, largely reflecting heterogeneity in populations and fatigue instruments rather than a definitive null[63].
5.3 B vitamins and one-carbon metabolism
Folate (B9) and cobalamin (B12) are cofactors in folate-mediated one-carbon metabolism (FOCM), driving methyl transfer for methionine regeneration and de novo thymidylate and purine synthesis; deficiency causes megaloblastic anemia, and B12 deficiency in particular produces neurocognitive impairment[64]. B-complex vitamins (B1, B2, B3, B5, B6, B7, B9, B12) function as cofactors for glycolysis, the TCA cycle, β-oxidation, neurotransmitter synthesis and immune regulation, providing a mechanistic basis for a role in fatigue reduction[65]. A 2025 systematic review and meta-analysis of six studies (3 RCTs, 2 observational, 1 open-label) found a significant reduction in fatigue severity when all studies were pooled (SMD −0.42; P = 0.002) but not when restricted to the two RCTs with sufficient quantitative data (SMD −0.12; P = 0.48), with heterogeneity (I² = 42%) attributable to variation in formulation, duration and outcome measures[65]. In fibromyalgia, retrospective analysis of 2,142 patients showed a 42.4% prevalence of B12 deficiency and a significant association between B12 deficiency and fatigue after adjustment for vitamin D (odds ratio 1.39; 95% CI 1.11–1.75; P = .004)[66]. Broader reviews position B vitamins as central to brain-health and metabolic-syndrome contexts as well[67].
5.4 Iron and oxygen delivery
Iron deficiency impairs skeletal-muscle metabolism through mechanisms co-dependent on oxygen and iron availability, including the hypoxia-inducible-factor (HIF) pathway[68]. In a controlled 31P-MRS study of iron-deficient (n=13) versus iron-replete (n=13) individuals, submaximal exercise lactate clearance was significantly reduced in the iron-deficient group (P=0.005), corrected by intravenous iron; IV iron additionally increased maximal-exercise lactate threshold by ~10%, regardless of baseline iron status[68]. In the IRONWOMAN RCT (n=26 iron-deficient non-anemic recreationally active females), intravenous iron therapy significantly improved serum ferritin, serum iron and transferrin saturation, improved running economy at 4 weeks, and reduced fatigue scores versus placebo, without changes in VO₂peak or hemoglobin mass[69]. Reviews in endurance disciplines document a similar pattern of ferritin- and hemoglobin-related fatigue in athletes[70]; recent 2025 clinical reviews emphasize the prevalence of iron deficiency in adults and the shift toward IV iron for symptomatic non-anemic patients[71].
5.5 Magnesium
Magnesium is required as an essential cofactor for over 300 enzymatic reactions, including all reactions involving ATP (which biochemically operates as Mg-ATP), and is central to calcium-channel gating and skeletal-muscle contraction[72]. It is required across myogenesis, fibre-type composition, contractile function and performance[73]. Deficiency associates epidemiologically with muscle weakness and fatigue, and adequate magnesium intake is proposed as a straightforward, mechanistically grounded intervention for reducing fatigue-related symptoms[72].
5.6 NAD⁺ and sirtuin signalling
NAD⁺ operates as a redox coenzyme in glycolysis, TCA cycle and oxidative phosphorylation, and simultaneously as a co-substrate for sirtuins (SIRT1–7), PARPs and CD38/CD157 ectoenzymes; it links energy metabolism to genomic maintenance and mitochondrial homeostasis[74]. Cellular NAD⁺ declines with age, driven by increased consumption by CD38 and PARP1 under chronic inflammation and genomic stress; this decline is causally linked to mitochondrial and homeostatic dysfunction underlying aging phenotypes[75]. Approaches to restore cellular NAD⁺ include the vitamin B3 precursors nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), caloric restriction, exercise, and pharmacological inhibition of NAD⁺-catabolizing enzymes, with preclinical models showing rejuvenated mitochondrial function, improved glucose and lipid handling, cardioprotection, and reduced diet-induced weight gain[76]. Early human trials confirm safety and bioavailability with signals of benefit on vascular and metabolic parameters, prevention of nonmelanotic skin cancer, modest blood-pressure and lipid effects in older overweight adults, kidney-injury prevention in at-risk patients, and suppressed inflammation in Parkinson's disease and SARS-CoV-2 infection[77]. Long-term safety, optimal dosing, tissue-specific delivery and possible pro-tumorigenic effects remain open translational questions[74].
5.7 L-carnitine
L-carnitine is required for mitochondrial import of long-chain fatty acids for β-oxidation and for efflux of acyl groups when substrate flux exceeds demand, preventing lipid accumulation that reduces energy production and can trigger cytotoxicity[78]. Beyond its transport role, L-carnitine upregulates SOD, GPx and catalase activities, reduces ROS, and suppresses TNF-α and IL-6, interrupting the feedback loop between oxidative stress and chronic inflammation[79]. Prevention of L-carnitine deficiency is proposed as a route to maintain metabolic flexibility in age- and metabolic-disease contexts[80]. Clinically, in a 120-patient open comparative study of arterial hypertension and/or coronary heart disease with asthenic syndrome, sequential intravenous levocarnitine (1000 mg/day for 10 days) followed by oral acetyl-L-carnitine (500 mg twice daily for 2 months) significantly reduced asthenia scores on the MFI-20 and VAS-A instruments versus baseline and versus basic-therapy controls, and improved endothelial parameters[81].
5.8 Adaptogens: Rhodiola rosea and Withania somnifera
Adaptogens are plant-derived substances that enhance systemic resilience to physical and psychological stress. Two recent systematic reviews consolidate the RCT evidence base for Rhodiola rosea (rosavin- and salidroside-mediated modulation of central neurotransmission and HPA-axis output) and Withania somnifera (multi-dimensional effects on stress, sleep, cognition and hormonal signalling)[82, 83]. A 2024 review reports Rhodiola-associated reductions of mental fatigue under stress and improved mental and physical performance, with a favourable safety profile[84]. A 2023 12-week RCT in 200 mg-BID ashwagandha (Witholytin®) in overweight/mildly obese adults (aged 40–75) with self-reported stress and fatigue reported no significant between-group effect on perceived stress (P=0.867) but a significant reduction in fatigue on the Chalder Fatigue Scale (P=0.016) and an increase in heart-rate variability (P=0.003) in the ashwagandha group; men receiving ashwagandha additionally showed significant increases in free testosterone (P=0.048) and luteinizing hormone (P=0.002)[85].
6. Integrative Discussion: Convergence Across the Three Domains
Three levels of convergence justify treating the "immune", "energy" and "cellular-protection" claim domains as views of one biology.
Level 1 — Redox: the NRF2–GSH–selenoprotein–CoQ axis.
NRF2 induces GSH-synthetic and GSH-utilizing genes (GCL subunits, NQO1, HMOX1, TXN), while selenocysteine-containing GPx1 and GPx4 use GSH to detoxify ROS; CoQ10 supplies the lipid-phase antioxidant pool and terminates lipid peroxidation. This is the biochemical substrate of "protection from oxidative stress"[8, 13, 20, 27]. The same axis is simultaneously immunoregulatory: NRF2 activation in myeloid and endothelial cells suppresses proinflammatory cytokine and adhesion-molecule expression[12]; GSH controls NLRP3 inflammasome activation[16]; and selenoprotein-mediated redox tone shapes granulocyte, macrophage and dendritic-cell function[21].
Level 2 — Bioenergetics and immunometabolism.
Fatigue is fundamentally a mismatch between ATP supply and demand: ME/CFS PBMCs show reduced coupling efficiency[6], post-COVID muscle shows reduced complex-I activity[7], and iron deficiency shifts systemic metabolism toward glycolysis[68]. But the same OXPHOS machinery underlies memory T-cell and M2 macrophage tolerance[3]. NAD⁺, CoQ10, L-carnitine, magnesium, iron and B vitamins all support this shared machinery, and are the reason why the EFSA-endorsed nutrients for "energy-yielding metabolism" and "reduction of tiredness and fatigue" overlap so heavily with those for immunity[72, 77, 80].
Level 3 — Nutritional inputs shape both.
Diet-derived signals — polyphenols (NRF2 activation), omega-3 PUFA (SPM biosynthesis and PPAR-γ), SCFAs (GPCR/HDAC signalling), vitamin A/RA (mucosal Treg and gut-homing), zinc (immunometabolic switching), vitamin D (VDR/CAMP), vitamin C (TET/JHDM cofactor for epigenetic programming) — sit at nodes that jointly modulate immunity, energy metabolism and redox tone[34, 37, 42, 47, 48, 55, 57].
The therapeutic implication is that combination interventions targeting several nodes are mechanistically justified. The most compelling clinical example is CoQ10 + NADH: the combination raises both electron-carrier substrates simultaneously and shows measurable clinical benefit in a rigorously conducted RCT in ME/CFS[62]. Similarly, the co-administration of vitamin D with vitamin C in dendritic-cell contexts[86] and the integration of polyphenols with mesenchymal stromal-cell therapy in inflammatory disease[50] illustrate a broader design principle: exploit the convergence.
Two caveats matter for translation. First, bioavailability limits the translation of many polyphenol-based interventions from bench to clinic, and gut microbiota critically shapes metabolite profiles[52]. Second, NRF2, NAD⁺ and other pathways discussed above have dose- and context-dependent effects — persistent NRF2 activation contributes to tumorigenesis and immune evasion in the presence of KEAP1/NFE2L2 mutations[9], and long-term safety and optimal dosing of NAD⁺ precursors remain unresolved[74]. Any "support" strategy must respect these context dependencies.
7. Conclusions and Future Directions
Post-2020 evidence supports the following consolidated positions:
- Cellular protection from oxidative stress is not delivered by generic radical scavengers but by an integrated system: KEAP1–NRF2 as the master transcriptional switch, GSH/glutaredoxin as the operational thiol network, selenoproteins (particularly GPx1/GPx4) as substrate-specific detoxifiers, and coenzyme Q10 as the lipid-phase antioxidant coupled to the electron-transport chain[8, 13, 20, 27].
- Immune support proceeds through immunometabolic reprogramming and epigenetic-metabolic cofactor supply rather than through simple "boosting". Vitamins C, D, A, zinc, selenium, omega-3 PUFA, polyphenols and SCFAs each intervene at specific nodes of this reprogramming — TET/JHDM cofactor supply (vitamin C), VDR–antimicrobial-peptide axis (vitamin D), RAR-driven mucosal programming (vitamin A), immunometabolic switching (zinc, selenium), NF-κB / SPM axis (omega-3), and HDAC/GPCR-mediated regulation (SCFAs)[21, 31, 37, 42, 47, 53, 57].
- Fatigue reduction is mechanistically underwritten by mitochondrial bioenergetics: adequate substrate supply (iron, B vitamins, L-carnitine, magnesium), adequate electron-carrier pools (CoQ10, NAD⁺) and preserved OXPHOS capacity. Recent RCT-level evidence supports iron correction (IRONWOMAN trial), CoQ10+NADH (Castro-Marrero trial), B-complex supplementation in CFS (2025 systematic review), and adaptogens (Rhodiola rosea, Withania somnifera) as evidence-informed adjuncts[62, 65, 69, 85].
These three domains share biochemistry. Mitochondrial ROS management, immunometabolic substrate switching, and NRF2-driven cytoprotection are the same architecture viewed from three angles. Rational nutritional and pharmaco-nutritional strategy should therefore prioritize combination interventions that exploit this convergence.
Key open questions for future research include:
- definitive long-term safety and dose-response of NAD⁺ precursors in humans[74];
- optimal EPA:DHA ratios and doses for specific inflammatory phenotypes[55];
- formulation strategies to overcome the bioavailability ceiling of polyphenols[52];
- individualized SCFA-directed dietary and probiotic interventions[60];
- adequately powered RCTs of adaptogens with standardized extract composition and long-term outcomes[82]; and
- mechanistic biomarkers that integrate the redox, energetic and immune axes rather than reporting them separately.
Funding
None declared.
Conflicts of Interest
The authors declare no conflict of interest.
Data Availability
All extracted data and the underlying search corpus are available from the corresponding author upon reasonable request.
References are provided as inline <citations> tags throughout the text. Each tag resolves to the corresponding peer-reviewed source and the specific sentence(s) supporting the claim.
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