Thorn therapy: cutaneous hormetic-immunostimulatory intervention as an evolutionary mismatch correction — a hypothesis
Medical Hypotheses, cilt.216, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 216
- Basım Tarihi: 2026
- Doi Numarası: 10.1016/j.mehy.2026.112112
- Dergi Adı: Medical Hypotheses
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CINAHL, EMBASE
- Anahtar Kelimeler: Cutaneous immunostimulation, Evolutionary mismatch, Hormesis, Microneedle, Old Friends hypothesis, Trained immunity
- Van Yüzüncü Yıl Üniversitesi Adresli: Evet
Özet
Throughout human evolutionary history, cutaneous micro-trauma from thorns, splinters, and abrasions likely occurred frequently alongside subdermal exposure to non-pathogenic environmental microorganisms and plant-derived antigens. Modern urban living has substantially reduced both stimuli. The Old Friends hypothesis attributes rising rates of allergies, autoimmune diseases, and chronic inflammatory conditions to the loss of immunoregulatory inputs from co-evolved organisms, while the hormesis literature demonstrates that low-dose mechanical stress activates cytoprotective pathways — including heat shock proteins, heme oxygenase-1, and Nrf2 — that promote stress resistance and longevity. Here, a concept termed “Thorn Therapy” is proposed: the chronic-repetitive cutaneous application of single-use dissolving microneedle patches coated with defined non-pathogenic antigens (mycobacterial cell wall components, β-glucan, helminth excretory-secretory products, saprophyte extracts, and plant polysaccharides). This intervention is designed to simultaneously restore both the mechanical hormetic stimulus and the antigenic immunostimulatory input that plausibly co-occurred in ancestral environments. Supporting evidence draws on stress hormesis and lifespan extension data, BCG-induced trained immunity (which reduces all-cause infant mortality by approximately 30%), and the demonstrated synergy between cutaneous mechanical pre-treatment and intradermal vaccine responses. Traditional cutaneous therapies (acupuncture, cupping, Gua Sha) are proposed as partial evolutionary analogs addressing only the mechanical component. A four-arm factorial experimental design using trained immunity markers, heat shock protein levels, and infection incidence as endpoints is outlined to test the central prediction: that combined mechanical-antigenic stimulation produces synergistic immunological benefits exceeding either stimulus alone.