Free radicals: how can antioxidants combat them?

The free radicals are unstable molecules naturally produced by the body during physiological processes such as cellular respiration or enzymatic activity. They possess an unpaired electron in their outer orbital, rendering them extremely reactive. To regain stability, these chemical species seek to capture or donate an electron, triggering a cascade of oxidation reactions that can damage membrane lipids, proteins and DNA. Among the main reactive oxygen species (ROS), a category of free radicals, are superoxide (O2•-), the hydroxyl radical (•OH) and hydrogen peroxide (H2O2). Other reactive nitrogen species (RNS), such as nitric oxide (NO•) and peroxynitrite (ONOO⁻), also contribute to oxidative imbalance.

Under normal circumstances, free radical production is regulated: it even plays a beneficial role in certain biological functions, such as immune defence or cellular signalling. However, when their formation exceeds the the skin’s antioxidant capacity, an imbalance arises: the oxidative stress. It promotes lipid peroxidation, damages structural proteins such as collagen and elastin, and disrupts DNA repair mechanisms. The consequences of oxidative stress on the skin are manifold, manifesting in a dull complexion, loss of firmness and accelerated skin ageing.

In addition to metabolism, various environmental factors contribute to the generation of free radicals in skin cells, such as exposure to ultraviolet radiation, pollution or tobacco smoke.

Antioxidants act as a molecular shield by neutralising free radicals before they can damage cellular structures. Their primary strategy relies on electron donation: they compensate for the free radical’s missing electron without becoming unstable themselves. This capability arises from the chemical structure of antioxidants, often rich in conjugated double bonds or phenolic groups capable of delocalising the electronic charge. Thus, the antioxidant molecule absorbs the radical’s reactive energy, stabilising it and interrupting the chain of oxidative reactions. This is the case, for example, with vitamin E or vitamin C.

Other antioxidants, such as ferulic acid, operate via chelation mechanisms, capturing transition metals like iron (Fe²⁺) or copper (Cu²⁺) that catalyse the generation of particularly toxic hydroxyl radicals via the Fenton reaction. Some polyphenolic compounds, such as flavonoids, also act by stabilising free radicals through resonance, dissipating their excess energy as heat or light.

Finally, some antioxidants act by strengthening the skin’s natural antioxidant enzymes such as superoxide dismutase, catalase or glutathione peroxidase, which decompose radicals into harmless molecules like water or oxygen. One example is niacinamide, which increases NADPH levels, an essential cofactor for glutathione reductase, contributing to the regeneration of reduced glutathione (GSH), the main intracellular antioxidant.

Endogenous antioxidants form the first line of defence of the skin against free radicals. They are produced naturally by the body and enable the detection, neutralisation and repair of oxidative damage before it alters cellular structures. Two types of antioxidants are distinguished: enzymatic antioxidants and non-enzymatic antioxidants.

Enzymatic antioxidants, catalysts against oxidative stress.

Among the main enzymatic antioxidants are superoxide dismutases (SOD), catalase, glutathione peroxidase, glutathione reductase, peroxiredoxins and ferritin, each acting by a specific and complementary mechanism. These enzymes are particularly concentrated in the epidermis, the outermost layer of the skin. Superoxide dismutases work by converting the superoxide radical (O2•–), notably produced by mitochondrial respiration, into hydrogen peroxide (H2O2), less reactive. Three forms exist: SOD1, located in the cytosol and nucleus; SOD2, found in the mitochondria; and SOD3, present in the extracellular space. These enzymes prevent the propagation of chain reactions initiated by superoxide radicals.

Catalase, located primarily in the peroxisomes of the stratum corneum, subsequently degrades the hydrogen peroxide formed by SOD into water and oxygen. Its concentration in the skin surpasses that of other antioxidant enzymes. Glutathione (GSH) and its associated enzymes, glutathione peroxidase (GPx) and glutathione reductase (GR), are also important. GSH directly neutralises free radicals via its thiol group and regenerates other antioxidants, such as vitamin E. When oxidised, it forms a dimer (GSSG), which glutathione reductase reconverts into GSH using NADPH. Selenium-dependent glutathione peroxidase, in turn, reduces H2O2 and stops lipid peroxidation, preventing the destruction of cell membranes.

With age, the skin’s antioxidant defences tend to diminish.

Note : Other enzymes supplement this antioxidant barrier, such as ferritin, an iron-storage protein, and peroxiredoxins (PRDX), which neutralise peroxides.

Non-enzymatic antioxidants, molecular allies for the skin.

In addition to enzymes, the skin contains other antioxidants that are non-enzymatic. These compounds, often supplied through the diet, complement the action of enzymatic defences. The most important are vitamins C and E, beta-carotene, uric acid and coenzyme Q10.

• Vitamin C : It is the most abundant water-soluble antioxidant in the skin. Unable to be synthesised by the human body, it must be supplied via the diet. Its mechanism relies on the direct donation of electrons to free radicals, converting them into stable, non-reactive forms. Present mainly in the dermis, vitamin C also serves as an enzymatic cofactor in the synthesis of collagen, contributing to the stability of the extracellular matrix.

• Vitamin E : Lipid-soluble, it is incorporated into cell membranes and sebum, where it protects lipids from peroxidation. It intercepts peroxyl radicals before they propagate the oxidative reaction. The resulting tocopheroxyl radical is then regenerated by vitamin C or glutathione, illustrating the synergy between water-soluble and lipid-soluble antioxidants. Beyond its radical-trapping role, vitamin E influences certain intracellular signalling pathways, notably protein kinase C, contributing to the modulation of the inflammatory and photo-induced response.

• Beta-carotene : A precursor of vitamin A, beta-carotene enhances the skin’s antioxidant defences by intercepting peroxyl radicals and inhibiting lipoxygenases responsible for generating reactive species. Its conjugated double-bond system enables it to absorb excess energy and stabilise radicals via the transient formation of epoxides.

• Uric acid : It can neutralise hydroxyl radicals, singlet oxygen and certain metallic oxidants. In the skin, its role remains limited due to low tissue vascularisation, but it contributes significantly to systemic protection against oxidation.

• Coenzyme Q10 : Also known as ubiquinone, coenzyme Q10 is a lipid-soluble molecule located in mitochondrial membranes. It plays a dual role: as a cofactor in the respiratory chain and as a scavenger of lipid radicals. In its reduced form (ubiquinol), it interrupts the propagation of peroxidation reactions while protecting other lipid antioxidants, such as vitamin E.

The NRF2 regulatory system, a complement to the skin’s antioxidant defence.

Beyond enzymatic and non-enzymatic antioxidants, the skin is equipped with transcriptional regulatory systems capable of fine-tuning its response to oxidative stress. Among these, the NRF2 (nuclear factor erythroid 2–related factor 2) transcription factor pathway occupies a central role. Indeed, NRF2 controls the expression of a large number of genes involved in the neutralisation of free radicals and the restoration of redox balance.

In normal conditions, NRF2 remains inactive in the cytoplasm, bound to the KEAP1 protein and cullin 3, which promote its degradation via ubiquitination. However, when oxidative stress increases, the cysteine residues of KEAP1 become oxidised, altering its conformation and releasing NRF2. NRF2 then migrates to the nucleus, where it binds to antioxidant response elements (ARE), initiating the transcription of protective enzymes such as catalase, superoxide dismutase and glutathione reductase. NRF2 also regulates the production of non-enzymatic proteins with antioxidant potential, such as ferritin.

Although the skin possesses its own antioxidant defence systems, these mechanisms weaken over time and with repeated exposure to environmental stressors, such as UV radiation. It is therefore important to support them with an external supply of antioxidants, whether dietary or cosmetic.

Diet, an internal lever to strengthen antioxidant defence.

The first way to support the skin’s antioxidant defences, and more broadly those of the body, is to follow a balanced diet rich in antioxidants. Foods such as fruit, vegetables, vegetable oils, nuts and oily fish supply a wide spectrum of protective molecules, including vitamins A, C and E and polyphenols. Once absorbed, these compounds are distributed throughout the body via the bloodstream and help neutralise free radicals. Carotenoids, for example, integrate into the structure of cell membranes, while the water-soluble vitamin C acts in intracellular aqueous environments.

A randomised, double-blind trial assessed the effectiveness of a polyphenol-enriched dietary supplement (concentration not specified) in 100 workers exposed to urban pollution. Comprising four standardised plant extracts (Olea europaea, Lippia citriodora, Rosmarinus officinalis and Sophora japonica), the supplement was administered to evaluate its effect on skin oxidative stress. This was measured by determining the lipoperoxide (LPO) content, represented by malondialdehyde (MDA), in the stratum corneum.

The results showed a statistically significant decrease in MDA content in the stratum corneum of subjects who took the dietary supplement from 4 weeks onwards, with further reductions at 8 and 12 weeks. No change was observed in the placebo group, which appears to confirm the supplement’s effect on cutaneous oxidative stress. Meanwhile, skin elasticity, firmness and hydration improved, transepidermal water loss decreased and dark-spot pigmentation was reduced, while the placebo showed no effect. The study thus confirms the value of oral antioxidant supplementation to limit pollution-induced oxidative stress and support the skin’s antioxidant defences.

Topical antioxidant treatments, a barrier against oxidative stress.

Topical application of antioxidants allows direct targeting of the skin. Unlike oral intake, which relies on systemic bioavailability, cosmetic formulations deliver a localized effect. The most commonly used active ingredients include vitamin C, vitamin E, resveratrol, ferulic acid, and green tea extracts, which are rich in polyphenols. Combined with a systematic sun protection, topical antioxidants now constitute a cornerstone in photoprotection and prevention of skin ageing by complementing the skin’s endogenous antioxidant defences.

Several studies have assessed the effects of topical antioxidants on the skin, including one conducted by ROSSI and colleagues. The researchers evaluated the antioxidant activity in situ of a product containing three antioxidants: a vitamin E precursor, retinaldehyde and glycylglycine oleamide. Twenty volunteers applied this formulation or its vehicle daily for 30 days to skin areas subjected to a controlled dose of UVA (5 J/cm2 for 2 minutes), and skin oxidative stress was assessed 4 and 24 hours after exposure at day 0, then after 15 and 30 days of application by measuring lipid peroxidation (LPO) in the stratum corneum. The results, presented below, show that the antioxidant formulation significantly increased the skin's antioxidant capacity and confirm the value of topical antioxidant application in preventing UV-induced oxidative damage.

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