Free radicals: how can antioxidants fight them?

The free radicals are unstable molecules naturally produced by the body during physiological processes such as cellular respiration or enzymatic activity. They carry an unpaired electron in their outer orbital, making them highly 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 primary reactive oxygen species (ROS), a category of free radicals, is 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 conditions, free radical production is regulated; it even plays a beneficial role in certain biological functions, such as immune defense or cellular signaling. However, when their formation exceeds the skin’s antioxidant capacity, an imbalance arises: oxidative stress. This state promotes lipid peroxidation, damages structural proteins like collagen and elastin, and disrupts DNA repair mechanisms. The consequences of oxidative stress on the skin are numerous, manifesting in a dull complexion, reduced firmness, and accelerated skin aging.

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

Antioxidants act as a molecular shield by neutralizing free radicals before they can damage cellular structures. Their main strategy is based on the gift of an electron: they compensate the free radical’s missing electron without becoming unstable themselves. This capacity stems from the chemical structure of antioxidants, which is often rich in conjugated double bonds or phenolic groups capable of delocalizing electronic charge. Thus, the antioxidant molecule absorbs the radical’s reactive energy, stabilizing it and halting the chain of oxidative reactions. This is the case, for example, of the vitamine E or of the vitamine C.

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

Finally, some antioxidants act by enhancing natural antioxidant enzymes of the skin, such as superoxide dismutase, catalase, or glutathione peroxidase, which break down radicals into harmless molecules like water or oxygen. For example, one can cite 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 constitute the skin’s first line of defense against free radicals. They are produced naturally by the body and enable the detection, neutralization, and repair of oxidative damage before it alters cellular structures. There are two types of antioxidants: 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 having a specific and complementary mode of action. These enzymes are especially concentrated in the epidermis, the outermost layer of the skin. Superoxide dismutases act by converting the superoxide radical (O2•-), produced notably by mitochondrial respiration, into hydrogen peroxide (H2O2), less reactive. Three forms exist: SOD1, located in the cytosol and nucleus, SOD2, located in the mitochondria, and SOD3, present in the extracellular space. These enzymes prevent the propagation of chain reactions initiated by superoxide radicals.

Catalase, primarily located in corneocyte peroxisomes, then degrades the hydrogen peroxide generated by superoxide dismutases into water and oxygen. Its concentration in the skin exceeds that of other antioxidant enzymes. Glutathione (GSH) and its associated enzymes, glutathione peroxidase (GPx) and glutathione reductase (GR), are also important. GSH directly neutralizes free radicals through its thiol group and regenerates other antioxidants such as vitamin E. When oxidized, it forms a dimer (GSSG), which glutathione reductase converts back to GSH using NADPH. Selenium-dependent glutathione peroxidase, in turn, reduces H2O2 and prevents lipid peroxidation, preventing the destruction of cell membranes.

As we age, the skin’s antioxidant defenses tend to diminish.

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

Non-enzymatic antioxidants, molecular allies for the skin.

Besides enzymes, the skin contains other non-enzymatic antioxidants. These compounds, often supplied through the diet, complement the action of enzymatic defenses. 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 synthesized by the human body, it must be supplied through the diet. Its mechanism is based on the direct donation of electrons to free radicals, converting them into stable, nonreactive forms. Present primarily in the dermis, vitamin C also functions as an enzymatic cofactor in the synthesis of collagen, contributing to the stability of the extracellular matrix.

• Vitamin E : Fat-soluble, it incorporates 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 hydrophilic and lipophilic antioxidants. Beyond its radical-scavenging role, vitamin E influences certain intracellular signaling pathways, notably protein kinase C, contributing to the modulation of inflammatory and photoinduced responses.

• Beta-carotene : A precursor to vitamin A, beta-carotene supports the skin’s antioxidant defenses by intercepting peroxyl radicals and inhibiting lipoxygenases that produce reactive species. Its conjugated double-bond structure enables it to absorb excess energy and stabilize radicals via the formation of transient epoxides.

• Uric acid : It is capable of neutralizing hydroxyl radicals, singlet oxygen, and certain metal oxidants. In the skin, its role remains limited due to low tissue vascularization, but it contributes notably to systemic protection against oxidation.

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

The NRF2 regulatory system, a complement to cutaneous antioxidant defense.

Beyond enzymatic and non-enzymatic antioxidants, the skin possesses transcriptional regulatory systems capable of modulating its response to oxidative stress. Among these, the pathway of the transcription factor NRF2 (nuclear factor erythroid 2–related factor 2) plays a central role. Indeed, NRF2 controls the expression of a large number of genes involved in neutralizing free radicals and restoring redox balance.

Under 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 oxidized, modifying its conformation and releasing NRF2. NRF2 then translocates to the nucleus, where it binds to antioxidant response elements (ARE) and initiates 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.

If the skin has its own antioxidant defense systems, these mechanisms weaken over time and with repeated exposure to environmental stressors such as UV rays. Therefore, it is important to support them with an external supply of antioxidants, whether through dietary intake or cosmetic application.

Nutrition, an internal lever to strengthen antioxidant defenses.

The first way to support the skin’s antioxidant defenses, and more broadly those of the body, is to maintain a balanced diet rich in antioxidants. Foods such as fruits, vegetables, vegetable oils, nuts, and fatty fish provide a broad spectrum of protective molecules, including vitamins A, C, and E, as well as polyphenols. Once absorbed, these compounds are distributed throughout the body via the bloodstream and contribute to the neutralization of free radicals. Carotenoids, for example, integrate into cell membrane structures, while water-soluble vitamin C acts within intracellular aqueous environments.

A randomized, double-blind study evaluated the efficacy of a dietary supplement enriched with polyphenols (unspecified concentration) in 100 workers exposed to urban pollution. Composed of four standardized plant extracts (Olea europaea, Lippia citriodora, Rosmarinus officinalis and Sophora japonica), the supplement was administered to assess its impact on skin oxidative stress. The latter was evaluated by measuring the content of lipid peroxides (LPO), represented by malondialdehyde (MDA), in the stratum corneum.

The results demonstrated a statistically significant reduction in malondialdehyde content in the stratum corneum of subjects who received the dietary supplement, as early as 4 weeks, with further reductions at 8 and 12 weeks. No changes were observed in the placebo group, which appears to confirm the supplement’s effect on cutaneous oxidative stress. Concurrently, skin elasticity, firmness, and hydration improved, transepidermal water loss decreased, and dark spot pigmentation was reduced, whereas the placebo showed no effect. The study thus confirms the benefit of oral antioxidant intake in limiting pollution-induced oxidative stress and supporting the skin’s antioxidant defenses.

Topical antioxidant care: a barrier against oxidative stress.

The topical application of antioxidants allows for direct targeting of the skin. Unlike oral intake, which depends on systemic bioavailability, cosmetic formulations offer localized action. The most commonly used active ingredients include vitamin C, vitamin E, resveratrol, ferulic acid, and green tea extracts, rich in polyphenols. Combined with a systematic sun protection, topical antioxidants are now a cornerstone in the strategy of photoprotection and skin-aging prevention, complementing the skin’s endogenous antioxidant defenses.

Several studies have evaluated the effects of topical antioxidants on the skin, including one conducted by ROSSI and colleagues. The researchers assessed 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 exposed to a controlled dose of UVA (5 J/cm² for 2 minutes), and skin oxidative stress was assessed 4 and 24 hours after exposure on 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 to prevent UV-induced oxidative damage.

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