Does Skin Immunosenescence Hold the Key to Unlocking Systemic Age-Related Diseases?

🔍 Key Finding Skin immunosenescence, a decline in immune function with age, plays a key role in various skin diseases like infections, inflammatory disorders, and cancers, and may also have systemic implications for conditions like neurological and respiratory diseases due to shared inflammatory pathways and cytokine signaling. Further research is needed to understand the complex interplay between skin and systemic immunity in aging to develop personalized preventative and therapeutic strategies.

🔬 Methodology Overview

• Design: Narrative review (state-of-the-art review)
• Data Sources: Not explicitly stated, but implies use of international scientific literature.
• Selection Criteria: Implicit focus on studies related to immunosenescence and its impact on skin health, skin diseases, and systemic conditions. Includes studies on melanoma, squamous cell carcinoma, atopic dermatitis, psoriasis, infectious skin diseases, and the skin microbiome.
• Analysis Approach: Qualitative synthesis and summarization of findings from selected studies. Discussion of shared mechanisms and emerging trends.
• Scope: Examines the etiopathogenetic role of skin immunosenescence in various dermatological conditions and its systemic implications, highlighting the interplay between skin immunity and overall health.

📊 Results

• Melanoma: Loss of T cell surface markers CD27 and CD28, or expression of Tim-3 and CD57, is associated with resistance to immune checkpoint inhibitors.
• Cutaneous Squamous Cell Carcinoma (cSCC): Incidence in organ transplant recipients (OTRs) is up to 200 times that of the general population. The percentage of CD8+ T cells expressing CD57 is the strongest immunological predictor of future cSCC in OTRs. Approximately 90% of cSCCs in OTRs contain HPV DNA, compared to 11-32% in immunocompetent skin.
• Atopic Dermatitis (AD): Affects up to 10% of adults, with increasing incidence in the elderly. Extrinsic AD (80% of adult cases) is associated with high IgE levels and allergen sensitization. Intrinsic AD (20% of cases, more common in elderly) has normal/low IgE and no allergen sensitization.
• Pruritus (Itching): Xerosis is the most common cause in the elderly (38-85% prevalence). Reduced ceramide levels and alkaline skin pH contribute to xerosis and itching.
• Psoriasis: Late-onset psoriasis (after age 65) is increasing in incidence but often milder than early-onset. Higher proportions of terminally differentiated/senescent CD8+ T cells are found in patients with longer disease duration (over 15 years). Higher frequency of CD57+CD4+ and CD57+CD8+ T cells in nonlesional skin of psoriasis patients compared to lesional skin.
• Cutaneous Infections: Immunosenescence is a risk factor for various infections, including leishmaniasis, herpes viruses, and bacterial infections. Sestrin-driven immunosenescence of NK cells and CD8+ T cells negatively impacts cutaneous leishmaniasis prognosis.

💡 Clinical Impact Skin immunosenescence plays a crucial role in various dermatological conditions and has systemic implications, particularly for allergic inflammation and neurological disorders, necessitating a more comprehensive assessment of immune status in older patients with skin conditions. This may lead to personalized approaches to disease prevention and treatment, including more diligent screening for comorbidities and careful consideration of treatment risks in elderly patients with inflammatory skin diseases or those receiving immunosuppressive therapy.

🤔 Limitations

• No confirmed chronological parallelism between immunosenescence and skin senescence.
• Inadequate data to confirm the causal role of HPV in cSCC.
• Unclear role of IL-17 in AD.
• Limited data on long-term safety of biological drugs in elderly psoriasis patients.
• Limited understanding of the mutual influence between skin microbiome and host immunity, and the impact of interindividual variability on immunosenescence/inflammaging.
• Limited understanding of cytokine patterns involved in the skin-other organ pathogenetic shift.
• Limited characterization of binding proteins and their role in healthy centenarians.

✨ What It Means For You Doctors should be aware of the heightened risk of infections and certain cancers in elderly patients with inflammatory skin conditions like psoriasis, especially when considering immunosuppressive treatments like biologics. Additionally, clinicians should consider the impact of immunosenescence on the diagnosis and treatment of skin conditions in the elderly, as it can alter immune responses and disease presentation, particularly with pruritus and autoimmune diseases. Early detection and careful monitoring are crucial for effective management of these conditions in older populations.

Reference Papa, V.; Li Pomi, F.; Borgia, F.; Vaccaro, M.; Pioggia, G.; Gangemi, S. Immunosenescence and Skin: A State of Art of Its Etiopathogenetic Role and Crucial Watershed for Systemic Implications. Int. J. Mol. Sci. 2023;24:7956. https://doi.org/10.3390/ijms24097956