Everything you need to know about oxidative stress and its effects on the skin.

Oxidative stress corresponds to an imbalance between the production of free radicals, whether reactive oxygen species (ROS) or reactive nitrogen species (RNS), and the skin’s ability to defend itself against them. Under normal circumstances, these molecules play a physiological role in cellular communication, immune defence, and wound healing. However, when their production exceeds the body’s antioxidant capacity, they become toxic to skin cells and compromise their proper functioning.

Free radicals are extremely unstable molecules possessing one or more unpaired electrons in their outer shell. Under normal circumstances, electrons occur in pairs, ensuring energy balance. When an electron is alone, the molecule seeks to restore this stability by capturing or donating an electron to another molecule. This drives free radicals to react with their environment, notably with lipids, proteins and the DNA of skin cells, causing structural and functional alterations.

To prevent this damage, the skin has an endogenous antioxidant system comprising enzymes such as superoxide dismutase (SOD), catalase and glutathione peroxidase, as well as non-enzymatic antioxidants like vitamin E, vitamin C, glutathione and coenzyme Q10. These antioxidants act as a defensive shield, neutralising free radicals before they can react with cellular constituents. However, when this shield is overwhelmed due to a overproduction of free radicals or to a failure of the antioxidant system, the redox balance shifts, leading to a state of oxidative stress.

Oxidative stress in the skin results from a combination of internal and external factors. Internal factors stem from the body’s normal functioning and its metabolic processes, while external factors relate to the environment and lifestyle. Thus, free radicals naturally accumulate in the skin, but certain habits can increase their number and amplify their effects.

An internal production of free radicals via metabolism.

The production of free radicals in the skin largely originates from internal mechanisms, notably cellular metabolic processes. Mitochondria represent a major source of reactive oxygen species, generated as by-products of normal metabolism via the respiratory chain. The superoxide ion (O2•−), initially produced in the mitochondrial matrix, the intermembrane space and the outer membrane, can be converted into hydrogen peroxide (H2O2) by the action of superoxide dismutase (SOD) or react with nitric oxide (NO•) to form peroxynitrite (ONOO−), a particularly reactive RNS.

Beyond mitochondria, several intracellular enzymes contribute to the production of ROS and RNS: NADPH oxidases, xanthine oxidoreductase, certain peroxisomal oxidases, cytochrome P450 enzymes, cyclooxygenases and lipoxygenases. These enzymes often rely on iron and its derivatives, such as heme or iron–sulfur clusters, to function properly. A phenomenon known as “ROS-induced ROS release” (RIRR) can occur when the ROS produced stimulate the formation of additional ROS via the opening of the mitochondrial permeability transition pore, thereby exacerbating intracellular oxidative stress.

The normal metabolism of the skin, essential for its survival and renewal, constitutes a constant source of free radicals.

An imbalance of the skin microbiota may lead to oxidative stress.

The human skin harbours a complex and dynamic community of microorganisms, the cutaneous microbiota, which plays a crucial role in maintaining the skin's barrier function, its immunity and in preventing certain dermatoses. Indeed, alterations of the skin microbiota have been associated with conditions such as psoriasis, eczema or acne, hence the importance of protecting it. However, the microbiota's balance can be destabilised by environmental factors, such as exposure to UV rays or to organic pollutants, such as polycyclic aromatic hydrocarbons, which induce oxidative stress in the skin.

The cutaneous microbiota also influences the balance of oxidative stress via interactions with the gut microbiota as part of the gut–skin axis. Disturbances in the skin flora can promote the build-up of free radicals and inflammation. Several studies have demonstrated a correlation between the severity of certain skin diseases, partly attributable to an imbalance in the cutaneous microbiota and blood oxidative stress markers, such as malondialdehyde and nitric oxide (NO). These data suggest that maintaining a balanced microbiota is essential for regulating oxidative stress in the skin.

A study conducted among 25 patients with atopic dermatitis and 25 healthy subjects illustrated this link. The investigators assessed levels of malondialdehyde (MDA), a marker of oxidative stress, and both enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxidase) and non-enzymatic antioxidants (reduced glutathione, vitamins A, E and C) in patients and healthy controls. The findings revealed in the eczematous patients a significant rise in MDA, accompanied by a marked reduction in antioxidants. These findings indicate an increased vulnerability to free radicals. In the case of eczema, where the cutaneous microbiota is unbalanced with elevated staphylococci and the skin barrier is disrupted, this oxidative stress helps perpetuate chronic inflammation and lesions.

Exposure to UV rays, visible light and infrared radiation contributes to oxidative stress.

Ultraviolet rays are the primary external source of free radical production within the skin. Under solar exposure, photons from UVA rays (320–400 nm), and to a lesser extent UVB rays (280–320 nm), are absorbed by endogenous photosensitising molecules such as cytochromes, riboflavin, haem or porphyrin. Once excited, these molecules react with oxygen to generate various reactive oxygen species, notably the superoxide anion (O2•–) and singlet oxygen (¹O2).

These free radicals then trigger a cascade of deleterious chemical reactions : the superoxide is converted by superoxide dismutase (SOD) into hydrogen peroxide, a molecule capable of diffusing across cell membranes. In the presence of transition metals such as iron (Fe2+) or copper (Cu2+), H2O2 then generates the hydroxyl radical, one of the most toxic to skin cells. This process contributes to lipid peroxidation, to the alteration of structural proteins such as collagen and elastin and to DNA damage.

In addition to UV rays, visible light (400–700 nm) and the infrared radiation (700–4000 nm) also contribute to the formation of reactive oxygen species (ROS) in the skin. Visible light can generate hydroxyl radicals (•OH), perhydroxyl radicals (•OOH) and singlet oxygen, exacerbating oxidative stress. Infrared radiation primarily acts at the mitochondrial level, where it stimulates the production of ROS, which are then converted into heat, notably activating the heat shock protein MP-1. These mechanisms contribute to the progressive deterioration of the skin barrier and promote the onset of oxidative stress.

Pollution has oxidising effects on the skin.

Daily exposure to air pollution is another significant external source of oxidative stress for the skin. Fine particles from fuel combustion contain polycyclic aromatic hydrocarbons. These molecules, which are highly photo-reactive, become activated by UV radiation and trigger a massive production of reactive oxygen species. This synergy between pollutants and solar radiation considerably intensifies oxidative stress.

Nitrogen oxides (NO and NO₂), mainly emitted by road traffic and the combustion of solid fuels, also contribute to this oxidation. By reacting with the skin’s photoactivated chromophores, these gases promote the formation of superoxides and nitrated radicals, which alter the lipids and proteins of the hydrolipidic film. This repeated oxidation gradually erodes the skin’s protective barrier, rendering it more permeable and reactive.

Another major pollutant, ozone (O₃), perfectly illustrates the complexity of cutaneous oxidative stress. Although it does not penetrate the skin, it acts at the surface, where it rapidly reacts with sebum to form lipid peroxidation products and reactive aldehydes. These pro-oxidant compounds trigger local inflammation and accelerate the loss of essential antioxidant vitamins in the skin, such as vitamin E and vitamin C.

Smoking, a direct source of oxidative stress.

Smoking is a potent external factor in the generation of cutaneous oxidative stress. Cigarette smoke contains over 4,000 chemical compounds, including a high proportion of free radicals and oxidising species. These reactive substances, such as nitric oxide (NO•) and the peroxynitrite radical (ONOO–), penetrate the skin directly from inhaled air or via cutaneous contact. They trigger an oxidative cascade that destabilises cell membrane lipids and depletes the skin’s antioxidants, thereby impairing its ability to defend against ROS. Concurrently, tobacco impairs cutaneous microcirculation, reducing the supply of oxygen and nutrients to cells, a process that favours the internal production of superoxide radicals (O2•⁻).

Diet can influence oxidative stress.

Diet, particularly sugar consumption, directly influences oxidative stress in the body. When glucose is present in excessive amounts in the bloodstream, it reacts spontaneously with proteins, lipids or nucleic acids to form advanced glycation end-products (AGEs). This process, known as glycation, alters the structure and function of skin proteins, particularly collagen and elastin, rendering the skin more rigid and less resilient. AGEs also promote the generation of free radicals such as superoxide (O₂•⁻) and peroxynitrite (ONOO⁻), thus amplifying oxidative stress within the skin.

Moreover, AGE formation is accompanied by a activation of the transmembrane receptor RAGE (Receptor for Advanced Glycation End Products), present in keratinocytes and fibroblasts. Its activation stimulates the release of pro-inflammatory cytokines and increases mitochondrial ROS production, creating an oxidative and inflammatory vicious circle. Conversely, a diet rich in natural antioxidants, notably from fruits, vegetables, nuts and polyphenol-rich oils, helps to neutralise free radicals and limit glycation.

Psychological stress, a driving force behind oxidative stress.

Chronic psychological stress is often an underappreciated internal factor in the development of cutaneous oxidative stress. Once established, it simultaneously activates the autonomic nervous system, the renin–angiotensin system and the hypothalamic–pituitary–adrenal axis. These mechanisms lead to the release of angiotensin II, a molecule capable of stimulating the production of NADPH oxidase-dependent ROS within neutrophils. At the same time, angiotensin II inhibits the synthesis of heme oxygenase-1, an antioxidant enzyme, thereby reducing the cells’ capacity to defend themselves against oxidation.

Furthermore, several studies have highlighted a link between depressive disorders and an increased oxidative state. Notably, the work carried out by Gibson and colleagues involved 32 individuals, 16 of whom were experiencing depression. The researchers demonstrated that fibroblasts derived from depressed patients exhibit elevated protein carbonylation and an overexpression of glutathione reductase, both of which are markers of intensified cellular oxidative stress.

Oxidative stress has multiple effects on skin physiology. Indeed, free radicals disrupt cellular structures, proteins, lipids and DNA and trigger inflammatory responses. These disruptions manifest as visible and functional alterations in the skin, notably skin laxity, pigmentation disorders and compromised barrier function.

Oxidative stress accelerates skin laxity.

Oxidative stress directly affects collagen and elastin fibres, essential components of the dermal structure. Free radicals oxidise these proteins, causing their fragmentation and a reduction in their ability to maintain skin firmness and elasticity. Furthermore, ROS activate enzymes such as matrix metalloproteinases (MMPs), which further degrade collagen and elastin, thus accelerating skin laxity and wrinkle formation.

Meanwhile, oxidative stress disrupts the function of fibroblasts, the cells responsible for synthesising collagen and elastin, as well as glycosaminoglycans like hyaluronic acid. Fibroblasts exposed to ROS exhibit reduced proliferation and activity, limiting the dermal regeneration capacity. This combination of enzymatic breakdown and decreased cellular production leads to a gradual loss of skin density and tone, promoting premature skin ageing.

Oxidative stress can lead to pigmentation disorders.

Oxidative stress strongly influences skin pigmentation, particularly through the action of free radicals on melanocytes, the skin cells that produce melanin. The mechanisms regulating pigmentation are complex, but it is now established that UV exposure and the resulting oxidative damage to DNA induce cellular signals that stimulate melanogenesis. Nitrogen radicals, particularly nitric oxide (NO•), are notably involved. The NO produced by keratinocytes exposed to UV light stimulates the α-MSH/MC1R pathway, activating tyrosinase, the key enzyme in melanin synthesis. ROS, such as H₂O₂, also play a role in regulating tyrosinase via activation of proteins such as MITF and signalling pathways including ERK and JNK.

Oxidative stress serves as a bona fide intracellular messenger, triggering melanin production and accentuating the emergence of pigmentary imbalances.

Oxidative stress compromises the skin’s barrier function.

Oxidative stress impairs the integrity of the skin barrier, essential for protecting the skin against environmental aggressors and limiting water loss. ROS and RNS can oxidise the lipids of the stratum corneum, resulting in a loss of corneocyte cohesion and disruption of intercellular lipids. This process weakens the skin barrier and increases transepidermal water loss, which can lead to skin dehydration.

Meanwhile, oxidative stress can disrupt the synthesis of structural proteins, such as filaggrin and loricrin that help maintain the skin barrier. The accumulation of free radicals also triggers local inflammatory responses via activation of pro-inflammatory cytokines, which amplifies the loss of barrier function and contributes to the appearance of irritation and redness.

Note : By altering DNA and mitochondrial activity in keratinocytes, oxidative stress can disrupt their proliferative capacity and cause a slowdown in cellular renewal. This manifests as an accumulation of dead cells on the surface of the epidermis that can prevent light from reflecting properly, giving the skin a dull appearance.

To counteract oxidative stress, the balance between antioxidants and free radicals must be restored through external antioxidant supplementation.

Indeed, the antioxidants neutralise free radicals and thereby limit the oxidation of lipids, proteins and DNA. Among the antioxidants most studied for the skin are vitamin C, vitamin E, beta-carotene and selenium, found in fruits, vegetables, nuts and oily fish. The vitamin C, for example, is involved in collagen synthesis while protecting cells against ROS. The vitamin E, being fat-soluble, acts primarily at the level of cellular membranes, limiting lipid peroxidation and stabilising the skin barrier. A varied diet, rich in berries, citrus fruits, green vegetables and oilseeds, thus helps support the skin’s natural defence against oxidative stress.

Good to know : The ORAC index (Oxygen Radical Absorbance Capacity) measures the antioxidant power of foods. The higher a food’s ORAC index, the greater its antioxidant power.

In addition to diet, antioxidant-enriched cosmetics are effective tools for protecting the skin. Serums containing stabilised vitamin C, resveratrol or coenzyme Q10 act by reducing the accumulation of free radicals in the skin. At the same time, it is essential to protect the skin daily from UV rays, which generate oxidative stress and are the primary cause of skin ageing.

Finally, a balanced lifestyle (avoiding tobacco, adopting sun-protection measures, managing psychological stress, etc.) helps to limit oxidative stress.

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