What are the causes of skin ageing?

Skin ageing primarily results from a series of internal processes programmed by our biology. These mechanisms, collectively termed intrinsic ageing, occur naturally over time, independently of our environment. They reflect a gradual decline in essential cellular functions : epidermal renewal, collagen production, maintenance of hydration, antioxidant defence... This endogenous ageing, encoded in our genes, progressively and inevitably alters the skin’s structure and physiology.

Genetic and cellular senescence.

Skin ageing is before all else associated with cellular senescence, a gene-programmed process that leads to a gradual reduction in the proliferation of skin cells. This loss manifests as thinning of the epidermis, reduced skin elasticity and a diminished capacity to repair damaged tissue. Senescence was first described in 1961 by Hayflick and Moorhead, who demonstrated that somatic cells irreversibly lose their ability to divide after a finite number of divisions. This limitation is largely linked to the progressive shortening of telomeres, the ends of chromosomes which, when they become too short, activate a DNA repair signal leading to cell-cycle arrest.

Senescent cells, although unable to divide, remain metabolically active and adopt a particular phenotypic profile, known as the Senescence-Associated Secretory Phenotype (SASP). This phenotype is characterised by the release of pro-inflammatory cytokines, growth factors, metalloproteinases and other bioactive molecules that, over time, degrade the extracellular matrix, disrupt the functioning of neighbouring cells and promote chronic inflammation, a phenomenon also known as inflamm'aging. Senescent cells gradually accumulate in the skin, hastening the appearance of signs of ageing.

Oxidative stress.

The oxidative stress is a major factor in skin ageing, resulting from an imbalance between the production of free radicals and the skin’s antioxidant defence mechanisms. With age, mitochondria become less efficient, producing more free radicals during cellular respiration, which damage proteins, lipids and DNA in skin cells. Excess free radicals in the skin trigger two senescence signalling pathways: the MAPK and NF-κB pathways. These pathways induce activation of the AP-1 complex, leading to increased TNF-α and matrix metalloproteinases (MMPs), enzymes capable of degrading the dermal extracellular matrix. In particular, AP-1 stimulates MMP1, MMP3 and MMP9, which fragment type I and III collagen into disorganised fibrils, reducing the skin’s density and integrity.

The skin, however, has endogenous antioxidant systems to limit these effects. Among these are enzymes, such as superoxide dismutase and catalase, which neutralise free radicals, while non-enzymatic antioxidants such as glutathione, coenzyme Q10, vitamin C and vitamin E protect the skin’s proteins and lipids and contribute to collagen synthesis and stabilisation. Nevertheless, with age, the efficacy of these defences diminishes : for example, catalase activity in the aged dermis is reduced, leading to an accumulation of hydrogen peroxide, and levels of vitamins C and E fall, rendering the skin more vulnerable to external aggressions.

Hormonal fluctuations.

Skin ageing is also influenced by hormonal fluctuations, particularly the decrease in oestrogens. In women, menopause marks a sudden drop in the production of oestradiol, a hormone hitherto synthesised by the ovaries. Oestrogen acts on keratinocytes, fibroblasts, melanocytes, hair follicles and sebaceous glands, thereby contributing to skin hydration, elasticity and wound healing. This hormonal deficiency causes a progressive atrophy of the cutaneous tissue, observable as skin thinning, a loss of collagen, reduced vascularisation and increased dryness.

Fibroblasts, less stimulated, produce less type I and III collagen, while elastic fibres become increasingly disorganised. Indeed, oestrogens act by binding to the nuclear ERα and ERβ receptors, which activate transcription of genes involved in the production of collagen and dermal regeneration. Their deficiency alters the expression of these genes and concurrently promotes the activation of matrix metalloproteinases, responsible for the degradation of supporting fibres. This imbalance between collagen synthesis and breakdown accelerates skin laxity and the formation of wrinkles.

But oestrogens are not the only hormones involved. As we age, the production of dehydroepiandrosterone (DHEA), a hormone secreted by the adrenal cortex, also declines. DHEA is involved in the peripheral synthesis of oestrogens and androgens, serving as a hormonal precursor for the skin. It stimulates dermal fibroblast proliferation, promotes sebum production, improves skin hydration and supports the skin’s barrier function. The decline in DHEA thus exacerbates intrinsic skin ageing.

Disruption of the skin barrier and immune function.

Intrinsic ageing of the skin is not limited to a decline in metabolic or hormonal functions. It is also accompanied by a progressive disorganisation of the skin barrier and by an impairment of the immune mechanisms that defend it. Long regarded as a passive target of circulating inflammatory mediators, the skin is now recognised as a organ that initiates inflammation. Langerhans cells, immune sentinels, detect danger signals and activate T lymphocytes, while the keratinocytes themselves secrete cytokines such as IL-1, TNF-α or GM-CSF.

However, when the epidermal barrier is compromised, these cytokines rise rapidly, leading to epidermal hyperplasia and local inflammation. This response, advantageous during a single insult, becomes harmful when it recurs over time. Continuous lymphocyte activation and the release of pro-inflammatory mediators then sustain a vicious cycle of inflammation and tissue degradation, with inflammation disrupting keratinocyte differentiation.

Stem cell exhaustion.

Cutaneous ageing is accompanied by a progressive reduction in the reservoir of epidermal and dermal stem cells, which are nevertheless essential for the renewal of the skin. They ensure the continuous replacement of keratinocytes and the repair of tissues after injury. With age, their capacity for proliferation and differentiation becomes impaired. Several mechanisms account for this depletion: the accumulation of DNA damage, telomere erosion and increased oxidative stress disrupt the genetic and metabolic stability of these cells. At the same time, reduced growth signals, such as Wnt, and chronic inflammation impair the ability of stem cells to reactivate when the skin is damaged.

Disruption of proteostasis.

Maintaining proteostasis, that is the balance between protein synthesis, folding, repair and degradation, is crucial for cellular health. In young skin, a complex network of molecular chaperones, proteasomes and autophagic systems continuously monitors damaged or misfolded proteins. However, with age, this system becomes dysregulated, particularly under oxidative stress, leading to an accumulation of oxidised or denatured proteins within keratinocytes and fibroblasts. This triggers a low-grade inflammatory response and endoplasmic reticulum stress, resulting in increased apoptosis and reduced cell viability. Ultimately, the skin loses its suppleness, density and regenerative capacity.

Intrinsic skin ageing arises from a series of interconnected biological processes: heightened oxidative stress, hormonal alterations, immune weakening, cellular exhaustion and proteostasis imbalance. These mechanisms act slowly but inevitably, compromising the skin’s capacity to regenerate and maintain its structural integrity.

In addition to the internal mechanisms described above, the skin is exposed to various external factors that accelerate its ageing.

Ultraviolet (UV) rays.

The detrimental effects of the sun on the skin and its role in skin ageing, referred to as photoageing in this specific case, need no further demonstration. Chronic exposure to ultraviolet rays (UVA and UVB) is one of the main factors accelerating skin ageing. UVB, which are primarily absorbed in the epidermis, cause genotoxic damage by altering cellular DNA, disrupting the organisation of collagen fibres and leading to their degradation. The more penetrating UVA rays reach the dermis and stimulate the expression of matrix metalloproteinases, weakening the dermal structure and contributing to skin laxity.

Meanwhile, UV radiation induces an excessive production of free radicals, intensifying the oxidative stress that gradually accumulates over time. This imbalance fosters the development of telangiectasias, the stiffening of blood vessels and the formation of pigment spots. In fair-skinned individuals or carriers of genetic variants, such as mutations in the MC1R receptor, free radical production is amplified, heightening the skin’s susceptibility to oxidative stress and accelerating photoageing.

Pollution.

Chronic exposure to air pollution is a major factor in extrinsic skin ageing. Environmental pollutants, such as hydrocarbons, oxides, fine particles and ozone, induce significant oxidative stress. Ozone, in particular, causes oxidative damage to the stratum corneum and depletes enzymatic and non-enzymatic antioxidant reserves, notably vitamins C and E, while impairing mitochondrial function and reducing ATP production and sirtuin-3 levels, which are essential for free radical clearance. Exposure to pollutants also disrupts the skin barrier and compromises immunity, thereby promoting skin ageing.

Tobacco.

In addition to dulling the complexion, tobacco is associated with accelerated skin ageing. Indeed, components of cigarette smoke promote oxidative stress and chronic inflammation. These substances stimulate the production of matrix metalloproteinases, leading to the degradation of collagen and elastin of the dermis. Tobacco also reduces cutaneous vascularisation, resulting in decreased oxygen and nutrient delivery to the tissues. Moreover, smoking alters the function of keratinocytes and fibroblasts, compromising the skin’s ability to repair itself and retain moisture.

FIROOZ and its team studied the characteristics of smokers’ and non-smokers’ skin. To this end, 52 participants were assessed to measure the elasticity, thickness and density of their epidermis and dermis. The depth of the nasolabial folds, those creases running from the wings of the nose to the corners of the mouth, was also analysed. The results showed that smokers exhibited a reduced elasticity on the forehead, an increased dermal thickness on the cheek, as well as a lower density of the epidermis on the forehead and of the dermis on the arm. The tobacco is therefore an important factor in skin ageing.

Stress.

Stress, like lack of sleep, can affect skin ageing. When the body perceives a threat, several physiological pathways are activated: the autonomic nervous system, the renin–angiotensin system and the hypothalamic–pituitary–adrenal (HPA) axis. This activation leads to the release of stress hormones such as adrenaline, noradrenaline and cortisol. In the short term, these mediators allow the body to adapt to a one-off danger. However, their prolonged stimulation plunges the organism into a state of metabolic and immune imbalance which increases the production of free radicals.

Studies have shown that catecholamines released during periods of stress can induce direct DNA damage and reduce the expression of the p53 protein, which plays a key role in preserving genomic integrity. This decrease undermines the cells’ ability to repair such damage. Furthermore, an excess of cortisol disrupts the skin barrier, reduces collagen production by fibroblasts and promotes chronic inflammation — three processes closely associated with premature skin ageing.

The lack of sleep, often co-occurring with stress, amplifies these phenomena by exacerbating inflammation. A study carried out by KIM and colleagues assessed the effects of restricting sleep to four hours per night over six consecutive nights in 32 participants in their forties. The researchers measured skin elasticity (parameter R2) and wrinkle depth (parameter Ra) around the eyes and on the forehead. Notably, the closer R2 is to 1, the more elastic the skin. The results showed a progressive decrease in skin elasticity and a rapid increase in wrinkle depth from the very first day of sleep deprivation.

An unbalanced diet.

Diet can also play a role in skin ageing. Diets rich in antioxidants help reduce oxidative stress, inflammation and promote collagen synthesis, thus limiting the appearance of wrinkles, dryness and skin atrophy. Conversely, a diet high in fats, refined sugars and trans fatty acids promotes the formation of advanced glycation end products, which damage the skin’s structure and diminish its elasticity. An excessively rich diet also has pro-inflammatory and oxidative effects on the skin. High-fat diets increase oxidative stress and reduce protein synthesis, resulting in less firm skin.

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

Cutaneous aging is also caused by external factors, which alter the structural proteins of the skin, promote oxidative stress and inflammation, and accelerate tissue degradation.

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