At the Roots of the Skin Aging Process

Like other organs, the skin also undergoes functional decline during aging, making it more fragile and susceptible to external agents, including infections, with an increasing accumulation of cellular damage, DNA mutations, protein damage, and alterations in cellular functionality.

The accumulation of alterations results in a buildup of dysfunctional cells, which (1) hinders the process of homeostasis, (2) limits the skin’s regenerative potential, and (3) triggers what is known as low-grade inflammation or inflammaging. This dysfunction results in an alteration not only of intercellular communications but especially of inter-tissue communications, which, in the skin – an organ formed by two distinct tissues (dermis, epidermis/hypodermis) – are indispensable for the proper functionality between the epidermal layers.

The hallmarks of aging, therefore, prove to be strongly interrelated: different types of molecular damage alter organelles, cellular functions, and their fates, creating an imbalance in cutaneous homeostasis. The alteration of cellular functions and consequent tissue dysfunction occurs through the progression of cellular heterogeneity: over time, the stem cell pool (in green on the left) is replaced by senescent cells (in red on the right), creating a pro-inflammatory microenvironment that alters neighboring cells and triggers a self-perpetuating process.1

Principles of the Molecular and Cellular Mechanisms of Aging.
Journal of Investigative Dermatology, 2021

Skin aging is the result of two distinct processes: “intrinsic aging”’, the normal genetic aging process that occurs over time and is influenced by endogenous stress factors (e.g., diet, medications, emotional states, pathological states, lifestyle), and “extrinsic aging” or accelerated aging resulting from exposure to external factors (e.g., pollution, sun exposure, climatic factors). 2

It is important to emphasize how all these “skin exposome factors” ‘often act with each other in synergy to accelerate the skin aging process.3

Hence the importance of a holistic approach in successfully addressing the challenge of healthy aging skin.

The skin aging exposome. J Dermatol Sci. 2017

The Research Underlying Deep Transversal Action

As life expectancy lengthens, the challenge is maintaining healthy skin well into very old age, and the most efficient strategy known to date is to act on the process underlying tissue change: chronic low-grade inflammation or inflammaging.

This condition is characterized by an increase of pro-inflammatory cytokines, leading to premature senescence, and is now considered the underlying basis for aging-related pathologies.

As senescent cells increase, the inflammation level (“inflammatory skin microenvironment”) also increases, interfering with normal tissue function and leading to an alteration in the so-called adaptive immunity, resulting in a breakdown of the extracellular matrix (ECM) and a diminished ability to regenerate it. This consequently impairs the skin’s resilient characteristics and external appearance.

Furthermore, extracellular matrix fragments can, in turn, be pro-inflammatory and produce ulterior disorganization of the ECM, creating a self-perpetuating vicious cycle.4

Inflammaging and the Skin. Journal of Investigative Dermatology. 2021.

Controlling cutaneous homeostasis primarily means controlling skin hydration, which is essentially carried out by the epidermis, the skin layer in direct contact with the external environment.

The epidermal lipids that control TEWL and the cell-cell junction system (Tight Junction or Tight Junctions) between keratinocytes perform the barrier function.5-7

Cutaneous dryness, due to the continuous exposure of the skin to the external environment, results not only in a loss of extracellular water present in the stratum corneum but also in the loss of water from the keratinocytes of the vital layers due to the osmotic gradient created and that generates a flow that moves water from the cells outward and can lead to cell death.6,8-10

The primary defense mechanism to maintain cell volume is the presence of natural substances defined as osmolytes, such as betaine, myo-inositol, and taurine. 9,11 These osmolytes can be transported into the cells experiencing stress caused by dehydration and can accumulate at high concentrations without causing side effects, thereby preventing water loss from the cells themselves. On the other hand, if cells have too much water, osmolytes can pumped outside the cell.9, 12-14

A reduction in keratinocyte volume is observed in the aging process as a consequence of both intrinsic and extrinsic aging, corresponding to a decreased osmolyte transport capacity as observed in vitro. 15

Osmolyte transporter expression is reduced in photoaged human skin:
Implications for skin hydration in aging. Aging Cell. 2020

Scientific research on skin aging is the basis for developing the formulation of Skin 3:3 face cream, which aims for deep transversal action, thanks to a pool of specific active ingredients for the 3 main actions needed for healthy skin over time.

To learn more about the selected active ingredients and their functions, read our article 


  1. Da Silva et al., Principles of the Molecular and Cellular Mechanisms of Aging. Journal of Investigative Dermatology, 2021, 141(4): 951-960,
  2. Draelos Z, Cosmetic Dermatology Products and Procedures, 2022 Cap 7 pag 72.
  3. Krutmann J et al. The skin aging exposome. J Dermatol Sci. 2017, 85(3):152-161.
  4. Pilkington et al., Inflammaging and the Skin. Journal of Investigative Dermatology, 2021, 141:1087-1095
  5. Brandner et al., Organization and formation of the tight junction system in human epidermis and cultured keratinocytes. European Journal of Cell Biology, 2002, 81(5):253-263
  6. Denda et al., Low humidity stimulates epidermal DNA synthesis and amplifies the hyperproliferative response to barrier disruption: implication for seasonal exacerbations of inflammatory dermatoses. Journal of Investigative Dermatology, 1998, 111(5):873-8.
  7. Kirschner et al., Contribution of Tight Junction Proteins to Ion, Macromolecule, and Water Barrier in Keratinocytes. Journal of Investigative Dermatology, 2013, 133(5):1161-1169
  8. Denda et al., Effects of Skin Surface Temperature on Epidermal Permeability Barrier Homeostasis. Journal of Investigative Dermatology, 2007, 127(3): 654-9
  9. El-Chami et al., Role of organic osmolytes in water homoeostasis in skin. Exp Dermatol. 2014, 23(8):534-7
  10. Verdier-Sévrain et al., Skin hydration: a review on its molecular mechanisms. J Cosmet Dermatol. 2007, 6(2):75-82
  11. Strange, Cellular volume homeostasis. Advances in Physiology Education, 2004, 28: 155-9
  12. Burg and Ferraris, Intracellular organic osmolytes: function and regulation. J Biol Chem. 2008, 283(12):7309-13
  13. Ito et al., Potential Anti-aging Role of Taurine via Proper Protein Folding: A Study from Taurine Transporter Knockout Mouse. Adv Exp Med Biol. 2015, 803:481-7
  14. Kroemer et al., Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ. 2009, 16(1):3-11
  15. April R. Foster et al. Osmolyte transporter expression is reduced in photoaged human skin: Implications for skin hydration in aging. Aging Cell, 2020, 19(1)


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