In 1994, a large trial in 29,133 Finnish smokers set out to test whether two antioxidants, including beta-carotene, reduced lung cancer. Among those taking beta-carotene, it showed the opposite: 18% more lung cancers. This failure captures the paradox of oxidative stress: a very real phenomenon, central to biology, but not something we control simply by swallowing antioxidants. Definition, the useful role of free radicals, causes, the difficulty of measurement, trial findings and genuinely authorised claims: here is what you need to know.
Key takeaways
- Oxidative stress is an excess of oxidants relative to defences, disrupting cell signalling or damaging lipids, proteins and DNA.
- At low levels, free radicals are useful: they act as messengers and trigger adaptations, particularly to exercise.
- Across 78 trials, antioxidant supplements did not reduce mortality; beta-carotene and vitamin E slightly increased it.
- Seven nutrients, including vitamins C and E, zinc and selenium, can claim to contribute to protecting cells from oxidative stress.
What is oxidative stress?
Our bodies use oxygen to produce energy. In doing so, they continuously form reactive oxygen species: the superoxide anion, hydrogen peroxide or the hydroxyl radical. Some are free radicals, highly reactive molecules with an unpaired electron.
The concept of oxidative stress was formulated in 1985. It describes an imbalance between these oxidants and antioxidant defences, in favour of the oxidants. Researchers now distinguish two situations. At low levels, they refer to “oxidative eustress”: oxidants act as signals. At high levels, “oxidative distress”: they damage lipids, proteins and DNA.
Are free radicals always bad?
No. More than 40 enzymes produce them in a controlled way, notably NADPH oxidases and the mitochondrial respiratory chain. At tiny concentrations, in the nanomolar range, hydrogen peroxide acts as a messenger. It regulates metabolism and helps cells adapt. Our white blood cells also use these molecules to destroy microbes.
Exercise offers a striking example. In a trial in 39 young men, four weeks of training improved insulin sensitivity, but only without antioxidants. With 1,000mg vitamin C and 400 IU vitamin E per day, this benefit disappeared, as did activation of antioxidant defence genes. A small, temporary oxidative stress stimulates defences: this is the principle of hormesis.
What causes oxidative stress?
Some oxidant production is normal and continuous. An imbalance appears when production rises sharply or defences weaken. Commonly cited factors include:
- smoking;
- air pollution and excessive UV exposure;
- alcohol;
- chronic inflammation;
- persistently high blood glucose;
- intense, unfamiliar physical exertion.
Smoking provides a well-documented example. In 10 smokers, blood F2-isoprostanes, products of lipid oxidation, were more than twice as high as in 10 non-smokers (242 versus 103 pmol/L). After two weeks without smoking, levels fell markedly, from 250 to 156 pmol/L.
What are the symptoms of oxidative stress?
There are no specific symptoms. Oxidative stress is a biochemical state, not a disease: it has no recognisable symptoms of its own. It does, however, accompany many diseases, such as atherosclerosis, chronic obstructive pulmonary disease and Alzheimer's disease, without always being their cause.
The researcher who formulated the concept warns against using the term “without a clear relationship to redox chemistry”. Be wary of vague symptom lists associated with tests or “anti-free-radical” products.
Can you measure your oxidative stress?
It is difficult. Numerous markers exist, but many rely on non-specific methods. Reliable methods are too complex for routine use, and no marker is validated as a diagnostic tool. In its health claim guidance, EFSA reviewed the main markers:
| Marker | What it reflects | Reliability according to EFSA |
|---|---|---|
| Urinary F2-isoprostanes (mass spectrometry) | Lipid oxidation | Accepted direct measurement |
| MDA, TBARS | Lipid oxidation | Unreliable on their own |
| 8-OHdG | DNA damage | Prone to artefacts |
| Total antioxidant capacity (ORAC, FRAP…) | Plasma antioxidant capacity | Benefit not established |
| Reduced/oxidised glutathione ratio | State of defences | Useful only if protection is demonstrated |
In other words, a laboratory “oxidative stress” panel provides a partial snapshot that is difficult to interpret for an individual.
Antioxidant supplements: what large trials show
The results are disappointing, and sometimes concerning. A 2012 Cochrane review pooled 78 randomised trials and 296,707 healthy or ill participants. Overall, antioxidant supplements (beta-carotene, vitamins A, C and E, selenium) did not change mortality. In the 56 higher-quality trials, they even slightly increased it (+4%). The increase concerned beta-carotene (+5%) and vitamin E (+3%); vitamin C and selenium had no significant effect.
Two trials made a strong impression. In Finnish smokers, 20mg beta-carotene daily increased lung cancers by 18% and mortality by 8%. In 35,533 men, 400 IU vitamin E daily increased prostate cancer risk by 17%. In 2022, the US expert group USPSTF recommended not using beta-carotene or vitamin E to reduce the risk of cardiovascular disease or cancer.
An exception: AMD
One area is an exception. In people already affected by age-related macular degeneration (AMD), a 2023 Cochrane review (26 studies) concluded that supplements combining several antioxidant vitamins probably slow progression to a severe form (risk reduced by around one quarter). This finding relies mainly on a large US trial and concerns patients under ophthalmological care, not the general population.
Why these failures?
First, because according to the researcher who defined the concept, the main defence rests on antioxidant enzymes, much more than small antioxidant molecules such as vitamins. Second, because oxidants also act as signals: indiscriminately neutralising them may block useful adaptations. Finally, clinical trials did not confirm the hopes raised in the laboratory. Researchers are now pursuing more targeted approaches.
Antioxidants made by the body
Our cells have a genuine defence network. It includes enzymes such as superoxide dismutase, catalase and glutathione peroxidases, the latter requiring selenium. It also includes molecules, foremost among them glutathione.
Glutathione is the most abundant small sulphur-containing molecule in our cells. Its production depends mainly on the availability of cysteine, an amino acid, and an enzyme regulated by the Nrf2 factor. This is why N-acetylcysteine, which provides cysteine, is studied as a precursor. To learn more, read our articles on glutathione and N-acetylcysteine (NAC). These oxidation-reduction reactions occur throughout metabolism, as illustrated by the NAD+ and NADH pair.
Which claims are authorised?
In the European Union, only seven nutrients can display the claim “contributes to the protection of cells from oxidative stress”, provided the product is at least a significant source. The exact wording is:
- “Vitamin C contributes to the protection of cells from oxidative stress”
- “Vitamin E contributes to the protection of cells from oxidative stress”
- “Riboflavin contributes to the protection of cells from oxidative stress” (vitamin B2)
- “Zinc contributes to the protection of cells from oxidative stress”
- “Selenium contributes to the protection of cells from oxidative stress”
- “Copper contributes to the protection of cells from oxidative stress”
- “Manganese contributes to the protection of cells from oxidative stress”
Only one other claim concerns oxidative stress: “Olive oil polyphenols contribute to the protection of blood lipids from oxidative stress”, restricted to olive oil providing at least 5mg hydroxytyrosol and its derivatives per 20 g. Glutathione, NAC, resveratrol and other polyphenols have no such claim. For EFSA, antioxidant capacity measured in a test tube does not prove a benefit in the body. We also explain this in our article on resveratrol myths and realities.
Frequently asked questions
Is there a difference between the French terms “stress oxydatif” and “stress oxydant”?
No: both describe the same phenomenon. “Stress oxydant” is often preferred in French scientific publications, and “stress oxydatif” in everyday language.
Is oxidative stress related to psychological stress?
Despite the name, these are two different concepts. Oxidative stress is a chemical imbalance in cells; psychological stress is the body's response to pressure. For the latter, see our article on stress and ingredients studied for it.
Which foods provide antioxidants?
Fruit, vegetables, pulses, nuts, tea and cocoa provide vitamins, carotenoids and polyphenols. But their laboratory-measured “antioxidant capacity”, such as the ORAC index, does not tell us what they do in the body. The value of a varied diet cannot be reduced to that number.
Does exercise increase oxidative stress?
Temporarily, yes, especially during intense or unfamiliar exertion. However, regular training stimulates expression of the body's antioxidant defences. This is a beneficial adaptation that high doses of antioxidant vitamins may blunt.
Does oxidative stress cause ageing?
Oxidative damage does accumulate with age, and the idea that free radicals cause ageing is old. It has, however, been qualified: oxidants are also useful signals, and antioxidant supplements did not reduce mortality in trials.
Oxidative stress and inflammation: what is the link?
They reinforce one another. Inflammatory cells produce oxidants to destroy microbes, and excess oxidants in turn activate inflammatory signals. This is why both are associated in many chronic diseases.
Conclusion
Oxidative stress is a sound concept, but often misused. Free radicals are not only enemies: at low levels they act as signals and stimulate our own defences, especially enzymes and glutathione. Large trials show that high-dose antioxidant supplements do not protect and may sometimes harm. The safest approaches remain simple: do not smoke, move regularly and eat a varied diet. Among supplements, only a few nutrients have an authorised oxidative stress claim.
Sources
- Sies H (2015). Oxidative stress: a concept in redox biology and medicine. Redox Biology, 4, 180-183. doi:10.1016/j.redox.2015.01.002
- Sies H, Jones DP (2020). Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nature Reviews Molecular Cell Biology, 21(7), 363-383. doi:10.1038/s41580-020-0230-3
- Forman HJ, Zhang H (2021). Targeting oxidative stress in disease: promise and limitations of antioxidant therapy. Nature Reviews Drug Discovery, 20(9), 689-709. doi:10.1038/s41573-021-00233-1
- Ristow M et al. (2009). Antioxidants prevent health-promoting effects of physical exercise in humans. Proceedings of the National Academy of Sciences, 106(21), 8665-8670. doi:10.1073/pnas.0903485106
- Morrow JD et al. (1995). Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers. Smoking as a cause of oxidative damage. New England Journal of Medicine, 332(18), 1198-1203. doi:10.1056/NEJM199505043321804
- Frijhoff J et al. (2015). Clinical relevance of biomarkers of oxidative stress. Antioxidants & Redox Signaling, 23(14), 1144-1170. doi:10.1089/ars.2015.6317
- EFSA NDA Panel (2018). Guidance for the scientific requirements for health claims related to antioxidants, oxidative damage and cardiovascular health (Revision 1). EFSA Journal, 16(1), e05136. doi:10.2903/j.efsa.2018.5136
- Bjelakovic G et al. (2012). Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database of Systematic Reviews, (3), CD007176. doi:10.1002/14651858.CD007176.pub2
- Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group (1994). The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. New England Journal of Medicine, 330(15), 1029-1035. doi:10.1056/NEJM199404143301501
- Klein EA et al. (2011). Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA, 306(14), 1549-1556. doi:10.1001/jama.2011.1437
- US Preventive Services Task Force, Mangione CM et al. (2022). Vitamin, mineral, and multivitamin supplementation to prevent cardiovascular disease and cancer: US Preventive Services Task Force recommendation statement. JAMA, 327(23), 2326-2333. doi:10.1001/jama.2022.8970
- Evans JR, Lawrenson JG (2023). Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration. Cochrane Database of Systematic Reviews, 9, CD000254. doi:10.1002/14651858.CD000254.pub5
- Lu SC (2013). Glutathione synthesis. Biochimica et Biophysica Acta, 1830(5), 3143-3153. doi:10.1016/j.bbagen.2012.09.008
- Commission Regulation (EU) No 432/2012 of 16 May 2012 establishing a list of permitted health claims made on foods. Official Journal of the European Union, L 136, 1-40. eur-lex.europa.eu
Food supplements do not replace a varied, balanced diet or a healthy lifestyle. Ask a healthcare professional for advice if you are taking medication, pregnant or breastfeeding.
