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.