Dermatoporosis as a target for senotherapy

Skin aging is traditionally viewed through the lens of aesthetic changes; however, in 2007, the term "dermatoporosis" was proposed to describe a syndrome of chronic cutaneous insufficiency and fragility [1]. This condition goes beyond cosmetic defects and represents a serious medical problem associated with the loss of skin protective functions.

Dermatoporosis usually manifests around age 70, primarily affecting sun-exposed areas of the body. However, symptoms can appear earlier, for instance, due to chronic systemic or topical corticosteroid therapy. The clinical presentation includes prominent skin atrophy (thinning), non-inflammatory senile purpura (bruising), and characteristic stellate pseudoscars. In severe cases, dermatoporosis can lead to the formation of deep, dissecting hematomas.

Morphologically, dermatoporosis is characterized by significant epidermal thinning and degradation of the dermal matrix. One of the main drivers of these changes is cellular senescence. Senescent cells stop dividing but remain metabolically active, acquiring a senescence-associated secretory phenotype (SASP). They begin to secrete pro-inflammatory cytokines, chemokines, and proteases that destroy surrounding tissues and disrupt the functions of neighboring healthy cells [2].

A marker for such cells is the p16Ink4a protein—a cell cycle inhibitor whose level in the skin correlates with biological age. Cells in which this protein is detected (p16Ink4a-positive cells) are considered definitively "senescent": they have permanently lost the ability to divide and have altered their shape and physiological activity. Studies have shown that in dermatoporosis, the number of such cells in the epidermis increases significantly compared to healthy skin [1].

Understanding the role of senescent cells has led to the emergence of senotherapy—a field of medicine aimed at selectively removing aging cells or suppressing their harmful secretions. Senotherapeutic agents are divided into two groups:

1. Senolytics — agents that induce death in senescent cells.
2. Senomorphics — agents that suppress SASP, shifting cells into a state of "rest" (senostasis) and reducing their negative impact on tissues.

In systemic medicine, clinical trials of senolytics are already being conducted for the treatment of age-related diseases [3]. In dermatology, the search for effective and safe senotherapeutics for topical use is one of the most pressing tasks.

Study: synergy of retinaldehyde and hyaluronate

The choice of retinaldehyde and hyaluronic acid for this study was not accidental. Both substances are "gold standards" in skincare with proven anti-aging properties when applied topically. Retinaldehyde is known for its ability to stimulate cell renewal and collagen synthesis, while hyaluronic acid is a critical component for maintaining tissue volume and hydration. It was important for scientists to test whether these popular ingredients could demonstrate synergy in a condition as severe as dermatoporosis and whether they could target the root cause of the pathology—senescent cells.

Methodology and objective
The objective of the study was to determine whether a combination of 0.05% retinaldehyde and 1% hyaluronate fragments (50–400 kDa) possesses senotherapeutic activity. The study included patients with dermatoporosis (mean age 78 years) who applied a cream containing these components to their forearms twice daily for 30 days. Skin biopsies were performed before treatment and one month after completion.

Results and explanation
The analysis showed impressive results:

• Reduction in senescence markers: the number of p16Ink4a-positive cells in the epidermis and dermis was significantly reduced after just one month of therapy.
• Increase in skin thickness: ultrasonography showed a significant increase in skin thickness.
• Clinical improvement: signs of atrophy, purpuric lesions, and the prominence of pseudoscars were visually reduced.
• Histological changes: significant epidermal hyperplasia, decreased elastosis, and increased collagen content and dermal vascularity were observed.

The explanation for the synergy lies in the complex effect on the CD44 receptor—the main cell surface receptor for hyaluronic acid, which is part of the "hyalurosome" molecular complex on the surface of keratinocytes. It was previously proven that hyaluronate fragments (50–400 kDa) restore atrophic skin by directly binding to the CD44 receptor [4]. Retinaldehyde, in turn, enhances this process indirectly by increasing the expression of genes responsible for the functioning of the entire hyalurosome. The synergistic effect is manifested by the fact that the combination of these components induces more significant epidermal hyperplasia and dermal restoration than either component alone, and also promotes the active elimination of senescent cells [5].

Practical perspectives

The study results confirm that the combination of retinaldehyde and hyaluronate fragments (50–400 kDa) is an effective senotherapeutic agent. This opens new possibilities for the development of specialized cosmetic and parapharmaceutical products.

For skincare practitioners, this represents a shift from simple matrix-stimulation to pathogenetically grounded correction of age-related changes. Using products containing retinaldehyde and hyaluronate fragments (50–400 kDa) not only prevents dermatoporosis in older patients but also actively restores skin that already shows signs of clinical fragility. It is important to note that the effect of this combination exceeds that of each component alone, making it a promising tool for the treatment of thinned and damaged skin.

References 

1. Kaya A., Saurat J.-H., Kaya G. Senotherapeutic effect of retinaldehyde and hyaluronate fragments in dermatoporosis. Dermatopathology 2023; 10(2): 168–172.
2. Naylor R.M., Baker D.J., van Deursen J.M. Senescent cells: a novel therapeutic target for aging and age-related diseases. Clin Pharmacol Ther 2013; 93(1): 105–116.
3. Justice J.N., Nambiar A.M., Tchkonia T et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine 2019; 40: 554–563.
4. Kaya G., Tran C., Sorg O. et al. Hyaluronate fragments reverse skin atrophy by a CD44-dependent mechanism. PLoS Med 2006; 3(12): e493.
5. Barnes L., Tran C., Sorg O. et al. Synergistic effect of hyaluronate fragments in retinaldehyde-induced skin hyperplasia which is a CD44-dependent phenomenon. PLoS ONE 2010; 5(12): e14372.