Review
Revisiting the Omega-3 Paradox in Cardiovascular Prevention: A Precision Medicine Perspective within the discipline of Mind-Body-Medicine
by J George Landers1, Anna Görkes1, Karla Vogelsang1, Tobias Esch1, and Nicole Jankovic1
1Institute for Integrative Health Care and Health Promotion, School of Medicine, Witten/Herdecke University, 58455 Witten, Germany
Cite as: Landers, J.G., Görkes, A., Vogelsang, K., Esch, T. & Jankovic, N. (2026). Revisiting the Omega-3 Paradox in Cardiovascular Prevention: A Precision Medicine Perspective within the discipline of Mind-Body-Medicine. THE MIND Bulletin on Mind-Body Medicine Research, 10(1), 31-37. https://doi.org/10.61936/themind/202603137
Abstract
Omega-3 fatty acids are considered cardioprotective, but large population-based studies show a contradictory picture. Omega-3 supplementation benefits those with established heart disease, but in
heart-healthy older adults, it may increase the risk of atrial fibrillation and stroke. This article develops a mechanistic hypothesis to resolve this paradox. Polyunsaturated fatty acids (PUFAs)
increase the susceptibility of cell membranes to lipid peroxidation and ferroptosis. Whether this results in damage or protection depends crucially on age, gender, genetic factors, fatty acid
desaturase (FADS1/FADS2), inflammatory status and the integrity of the nuclear factor erythroid 2–related factor 2 (NRF2) system. Omega-3 fatty acids therefore do not have a beneficial or
detrimental effect per se, but rather act as context-dependent modulators of a sensitive redox biological balance, with relevant implications for prevention and integrative medicine.
Keywords: PUFA, lipid peroxidation, ferroptosis, NRF2 and atrial fibrillation
Teaser
Omega-3 fatty acids can both protect and, under certain conditions, promote atrial fibrillation. We propose that FADS genotypes, age, sex, NRF2 function and mind body factors determine whether
increased PUFA availability yields adaptive antioxidant signaling or pathological lipid peroxidation and ferroptosis, making omega 3 a context dependent biological modulator rather than a
universally applicable supplement.
An epidemiological paradox
The analysis of the UK Biobank by Chen et al. (2024) showed in a multi-state model that regular intake of fish oil supplements was associated with an increased risk of incident atrial
fibrillation (AF) in individuals without known cardiovascular disease at baseline (hazard ratio (HR) 1.13; 95% confidence interval (CI): 1.10–1.17, adjusted for potential confounding factors
including dietary intake) and stroke HR 1.05 (95% CI: 1.00-1.11). In contrast, fish oil was associated with a lower risk of subsequent serious cardiovascular events and cardiovascular
mortality in individuals with pre-existing AF (HR 0.92; 95% CI 0.87–0.98).In contrast, the large randomized VITAL trial (Manson et al. 2019) found that supplementation with vitamin D₃
(cholecalciferol) at a dose of 2000 IU per day and marine n-3 (omega-3) fatty acids at 1 g per day did not result in a significant association with major cardiovascular events among middle aged
men and women living in the United States without a history of cancer or cardiovascular disease.
The crucial question, therefore, is not whether omega-3 fatty acids are inherently beneficial or harmful, but rather under which biological conditions their effects may vary. We address this
distinction in the following sections.
Polyunsaturated fatty acids (PUFAs): essential – but prone to oxidation
PUFAs, both n-3 and n-6, are structurally particularly susceptible to oxidative modifications due to their multiple double bonds. Zheng et al. (2024) describe that PUFA-rich membrane
phospholipids are preferred substrates for lipid peroxidation. Under certain conditions, this process can lead to regulated cell death programmes such as ferroptosis. Further studies support this
correlation (Mortensen et al. 2023). Hassannia et al. (2019) express this particularly clearly: ``Supplementing cells with PUFAs promotes ferroptosis.“
The ambivalence is important here: ferroptosis is associated with pathogenic processes in the cardiovascular system, but at the same time plays a tumour-suppressive role. This is precisely where
the tension surrounding omega-3 supplementation begins.
Ferroptosis and AF
For a long time, AF was primarily considered an electrophysiological problem. Now, however, oxidative stress, mitochondrial dysfunction and iron-dependent processes are increasingly coming into
focus. Zhou et al. (2024) discuss ferroptosis as a potential mechanism in the development of AF and emphasize the role of disturbed calcium homeostasis.
This allows the UK Biobank signal to be reinterpreted: it is not necessarily omega-3 itself that has an arrhythmogenic effect, but rather an excess of easily peroxidable membrane lipids combined
with insufficient antioxidant counter regulation that could increase vulnerability.
Why healthy hearts may show increased AF and stroke risk with omega‑3 supplementation
The hypothesis put forward here is as follows:
In people with healthy hearts, omega-3 supplementation initially increases the peroxidation-prone lipid load. At the same time, antioxidant protection systems, particularly NRF2, are still
sufficiently active to prevent major structural damage. The result can be a comparatively "mild" manifestation: AF without immediate heart failure or myocardial infarction.
Ferroptosis is thought to be a gradual and self-reinforcing process. As long as NRF2 effectively counter regulates, oxidative damage remains limited. However, with increasing age, the
NRF2-mediated antioxidant response weakens (Schmidlin et al. 2019). Under these conditions, an identical PUFA load could result in higher toxic vulnerability.
NRF2 – the underestimated switch
NRF2 is the central transcription factor of the cellular antioxidant response. Dodson et al. (2019) describe NRF2 as a central regulator of ferroptotic vulnerability, among other things through
the regulation of glutathione metabolism and iron homeostasis.
The current literature suggests that n-3 PUFAs can modulate NRF2-dependent signaling pathways (Davinelli et al. 2022). In a myocardium that is already under oxidative stress, omega-3 may therefore act less primarily as a peroxidisable substrate and more as a signal transmitter that activates antioxidant and anti-inflammatory programmes. This could explain why protective effects are observed in certain contexts in patients with existing heart disease. Importantly, NRF2 activity is dynamically regulated and responsive to behavioral and environmental inputs, therefore providing a direct bridge to Mind Body Medicine interventions.
FADS1/FADS2 genetics, ancestry and individual response
Variants of the fatty acid desaturase 1 (FADS1) and FADS2 genes determine how efficiently PUFAs are converted into long-chain fatty acids (EPA, DHA, ARA). Chilton et al. (2021) show that these
variants correlate strongly with ancestry and influence the formation of bioactive lipid mediators. Many African Americans have high-activity haplotypes, which can promote increased formation of
pro-inflammatory metabolites in a Western diet. In contrast, Inuit carry almost fixed FADS variants with reduced desaturase activity, which is an adaptation to their traditionally very
omega-3-rich diet. Less endogenous conversion is required here.
Machine learning (ML) analysis of VITAL data confirms that the benefits of omega-3 supplements are genetically heterogeneous, showing that some subgroups benefit, others hardly at all. Therefore,
a heart-healthy Briton who takes fish oil is not automatically "like an Inuit" (Hamaya et al. 2025). Protective effects depend on FADS genotype and ancestry, there are also relevant differences
within Europe
Bronze Age migration, intra European FADS variation
Recent ancient DNA studies indicate a substantial Bronze Age influx into Britain from e.g. north western German coastal populations with marine oriented subsistence patterns (Olalde et al. 2026).
These migrants — archaeologically and isotopically consistent with elevated marine/fish consumption — plausibly introduced allele frequencies and metabolic adaptations favoring higher tissue
incorporation of long chain marine n 3 PUFAs. By analogy with Arctic populations adapted to omega 3–rich diets, a Bronze Age gene flow from a “waterworld” cultural complex could create regional
gradients of FADS1/FADS2 haplotypes within Britain. This raises the possibility that a subset of UK Biobank respondents carrying Bronze Age–derived alleles may biologically resemble historical
fish eating populations (greater baseline EPA/DHA membrane incorporation and altered mediator profiles), and therefore respond differently to exogenous omega 3 supplementation than individuals
whose ancestries carry high activity FADS haplotypes of African origin (Chilton et al. 2021). These intra European differences are hypothesis generating but relevant: they suggest that
interpreting UK Biobank associations between fish oil use and AF should consider fine scale ancestry and historical migration patterns as potential modifiers of PUFA metabolism and
supplementation effects.
Gender makes a difference
Biological sex influences fat metabolism: women convert α linolenic acid more efficiently into long chain n 3 fatty acids—particularly EPA and, to a lesser extent, DHA (Burdge and Wootton 2002).
Consequently, with comparable intake, women tend to have higher DHA levels than men (Lohner et al. 2013). Women also showed greater incorporation of omega 3s into muscle and erythrocyte membranes
(Pufahl et al. 2025). After menopause however, changes in anti inflammatory lipid mediators are linked to a less favorable cardiovascular risk profile (So et al. 2024). Consequently, identical
omega 3 doses do not produce the same biological effects in women and men and also changes with age.
When the carrier increases the risk
Not only the quantity, but also the molecular form of fatty acids is relevant. DHA in the form of lysophosphatidylcholine is absorbed particularly efficiently in the brain (Nguyen et al. 2014;
Sugasini et al. 2019). Under conditions of limited antioxidant counterregulation, increased tissue availability could theoretically also influence the peroxydable substrate load. Billman (Billman
2013) discussed the possible rhythmogenic effects of higher omega-3 doses early on, long before current population-based data was available.
Mind‑Body Medicine: behavioral modulators of NRF2 and ferroptotic risk
Chronic psychosocial stress and sleep deprivation elevate systemic inflammation and glucocorticoid signaling, which can suppress NRF2 activity and antioxidant defenses (Davinelli et al. 2024).
Exercise (Narasimhan and Rajasekaran 2016) and nutritional factors such as dietary antioxidants (vitamin C, E, polyphenols, selenium) (Andrés et al. 2024) are well-documented activators of
NRF2. Vitamin D shows NRF2 activating effects in preclinical models and may augment antioxidant resilience in humans in specific contexts. The combination of omega-3, vitamin D, and exercise, as
investigated by Bischoff-Ferrari et al. (2022), could conceptually help to stabilize the balance between increased PUFA availability and antioxidant counter regulation – an approach with
potential relevance for prevention and integrative medicine. Meditation practices reduce sympathetic tone and systemic inflammation and have been associated with improved redox biomarkers in some
studies, thereby potentially shifting individuals toward a protective phenotypic response to increased PUFA availability (Black and Slavich 2016). Integrating these mind‑body levers into omega‑3
prescribing could convert a marginally risky exposure into one that provokes adaptive NRF2 induction and cardio protection. This frames omega‑3 use as an intervention embedded within behavioral
and psychosocial context. A practical approach how to reduce the own risk profile through stress regulation has been published earlier by Esch and Esch (2024).
Fig. 1. Conceptual framework illustrating the hypothesized pathways linking omega-3 supplementation to cardiovascular disease risk.
Falsifiability
The hypothesis would be refuted if:
• NRF2 dysregulation did not explain a relevant proportion of the variance in cardiovascular disease,
• or PUFA supplementation were consistently harmful or beneficial regardless of NRF2 status.
For the time being, it applies to populations with a risk profile similar to that of the UK Biobank.
Conclusion
Omega-3 fatty acids are not a trivial dietary supplement, but rather an intervention in a sensitive redox biological balance. The actual risk may lie less in omega-3 itself than in the contextual
blindness with which we use it. This finding underscores the need for context- and person-oriented nutritional medicine. Omega-3 supplementation should not be recommended across the board, but
rather considered individually in terms of "precision nutrition" based on genetic profile (FADS), age, gender, antioxidant capacity, and modifiable mind body factors that regulate oxidative
stress. The apparent paradox of harm in heart healthy older adults versus benefit in those with established disease can be reconciled by recognizing that PUFAs increase peroxidation substrate
while simultaneously acting as signaling molecules that may activate NRF2 mediated defenses when those defenses are intact or can be
upregulated. Mind body medicine provides feasible, non pharmacologic tools to shift the balance toward protection, supporting an integrated precision nutrition strategy.
Author Contributions: Conceptualization, N.J.; investigation, J.G.L., A.G., K.V.; writing, N.J.; idea and review, J.G.L., and editing, N.J.; All authors have read and agreed to this version of the manuscript. J.G.L. collaborates with IGVF as a senior consulting scientist.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: No data was used in this commentary article.
Acknowledgments: The first draft of the current article was an AI-generated summary of information and hypothesis formulated by J.G.L. Further literature research was performed and integrated by
K.V., A.G. and N.J. All authors read, edited and approved the final version of the manuscript.
Conflicts of Interest: The authors declare no conflicts of interest.
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