2025-10-29 08:22:17
Presenters: Thornfeldt CR1
Affiliations: 1Episciences, Boise, Idaho.
Background: Chronic exposure to natural sunlight is the major driver of photoaging1 although airborne pollution and tobacco smoke have also been proven.2,3 Variation of Fitzpatrick skin types I through VI also impacts the speed and severity of visible aging. Sunscreens used daily significantly reduce photoaging in as little as four years.1 Vitamin A and its metabolites are considered the gold standard to reverse and prevent photoaging to a significant degree although they rarely completely reverse all visible signs. One problem with vitamin A metabolic products is photosensitivity to a variable degree. This is due primarily to thinned compromised stratum corneum barrier integrity and function as well as reduction in sebum production. These anomalies induce the commonly seen erythema, scaling, irritation and burning with topical application. The incidence is up to 40%, lasting 2 to 6 weeks.4,5 Tretinoin (Tr) is the final metabolite of vitamin A used in human cells. The topical products incorporating this bioactive are all prescription. Its precursors of retinol, beta carotene and retinaldehyde do not require prescription due to significantly less efficacy, irritation reactions and photosensitivity. These are frequently incorporated into cosmeceuticals. Users must assume the compromised epidermis can synthesize normal amounts and normal structure of tretinoin induced mediators, exosomes and second messengers. Tretinoin is the bioactive molecule used in the first FDA product be approved to treat wrinkles about two decades ago.
Increasing interest in herbal topical therapies has resulted in nearly a thousand studies published since 2017 for reversing skin aging.6 The herbal extract product was designed to reverse photoaging by repairing and optimizing stratum corneum barrier function, mitigate cutaneous inflammatory reactions, prevent photosensitivity while upregulating all five epidermal strata structure and function.
Objective: The purpose of this trial is to compare the effect upon molecular biomarkers indicating severity of photoaging and ability to repair the epidermis damaged from environmental insults. HE and Tr were compared in a 12-day occlusive patch followed by biopsy in a paired comparison clinical trial. HE was previously documented to have a negative Repeat Insult patch test indicating no sensitization nor irritation with this product. Higher concentrations of Tr were not used due to significantly increased risk of irritation with occlusion.
Methods: Institutional Review Board approval was conducted for Ethical Considerations. The volunteer subjects all consented to this study and its publications. The IRB was conducted by Advarra: #Pro00068962. Eight subjects aged 62 to 74 years old that were post or peri-menopausal were selected. All subjects were Caucasian with skin type I to III with moderate to severe photoaging on their forearms. The two test products were applied to mirror images in a paired comparison manner with occlusion by Fin chamber affixed with Scanpor tape. Each subject had HE applied to one forearm and Tr to the other forearm. The patches were changed every other day for HE for 6 applications total. Tr was applied every 3 days for 3 applications total. About 80 microliters of test product were applied to each site. On day 12, punch biopsies were performed at each test site on each subject. The biomarker scales and definitions compared between the two topical treatments include: 1) Fibrillin Ab measures protein that assembles microfibrils to form elastin fibers. It uses a scale of 0=normal skin, to 3= marked diffuse fibrillin staining; 2) Procollagen I immunostain measures cytoplasmic stain in dermal fibroblasts with scale of 1=<5% positive cells to 5=>30% positive cells; 3) PPAR gamma measures nuclear staining and reported as number of positive nuclei/mm2 for keratinocyte terminal differentiation while down regulating keratinocyte proliferation.
The test products were occluded which increases cutaneous penetration of topically applied products from 3 to 15-fold. This accelerates reparative processes, enhancing visible results but also increases risk of adverse reactions.
Statistical analysis used Wilcoxon signed rank test. This trial was conducted by SGS, an international contract research organization at their facilities. It was sponsored by Episciences, Inc. of Boise, Idaho.
Results: No statistical significant difference was observed between HE and Tr after measuring the two biomarkers for photoaging. However, PPAR gamma achieved a trend for statistical significance (p=0.075) superior of HE to Tr. Despite occlusion, no adverse reactions were noted including erythema, edema, scaling with either test product.
Discussion: Peroxisome Proliferator Activated Receptor (PPAR) gamma is a nuclear receptor that regulates gene expression for lipid, glucose and amino acid metabolism. PPAR is a prominent biomarker for evidence of epidermal repair. Its activation triggers keratinocyte differentiation while reducing its proliferation. It is essential for maintaining epidermal integrity for functioning skin permeability barriers by promoting in terminal differentiation. PPAR gamma also regulates skin inflammation. It is additionally critical for pilosebaceous unit homeostasis by protecting follicular epithelial stem cells. Increased levels indicate increase in metabolic processes needed for epidermal rejuvenation and optimization.9 The positive impact upon HE by PPAR gamma was numerically superior with a trend toward statistical significant (p=0.075) superiority over prescription Tr 0.02%. This data supports other clinical trials’ greater efficacy and safety when compared to prescription strength Tr.
Two bioactive markers studied in this trial assess the impact of topical ingredients on key structural and functional anomalies that occur early in development of photoaging.
The first, fibrillin, is a glycoprotein secreted by fibroblasts into the extracellular matrix. It is incorporated into insoluble microfibrils to provide the scaffold for elastin deposition. Fibrillin is a major component of a sheath surrounding amorphous elastin. Increased Fibrillin antibody levels indicate increased synthesis of this critical protein.7
The second, procollagen 2, is the initial 3-dimensional stranded structure for collagen I assembly. Its principal peptides are glycine, proline and lysine. Procollagen is modified by adding hydroxyl groups to proline and lysine. This allows for glycosylation and formation of collagen’s triple helix. Procollagen is shipped from endoplasmic reticulum to Golgi apparatus then secreted into the extracellular space. This is the site of completion of formation of collagen fibrils. Increase of Procollagen 2 is one of the earliest markers indicating upregulation of collagen synthesis.8
The limitation of this in vivo pilot study is small sample size and short duration of treatment product usage. This data strongly suggests a longer duration clinical study to evaluate other biomarkers such as elastin and with a larger number of subjects (N of 36 or more) is warranted. The suggested clinical trial should include mechanical instrumentation and imaging assessments.
Conclusion: The unique herbal blend of HE appears to be equally effective to prescription Tr 0.02% upon biomarkers, Fibrillin and Procollagen 2 that indicate photo damage to moderate and severe degrees. Herbal based (HE) appears likely to be superior to prescription Tr 0.02% in regenerating epidermis and stratum corneum as evidenced by the biomarker PPAR.
Disclosures: Dr. Carl R Thornfeldt is the CEO and founder of Episciences in Boise, Idaho. Clinical study was recruited and completed by SGS International. It was reviewed and approved by the IRB.
Funding: Episciences, Inc. of Boise, Idaho.
References
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6 Cho S-Y, Lee H-G, Kwon S, et al. A systematic Review of In Vivo Studies of the Efficacy of Herbal Medicines for Anti-aging in the Last Five Years. Pharmaceuticals. 2023;16 (448).
7 Kumra H, Reinhardt DP. Methods in Extracellular Matrix Biology in Methods In Cell Biology. Mecham RP eds. 2018(143):223. Science Direct. Elsevier.
8 Hulmes DJS. Roles f Procollagen C Propeptides in Health and Disease. Biochem. 2019, Sep. 13;63(3):313-323.
9 Yuval R et al. Role of PPAR gamma-medicated signaling in skin biology and pathology. Exp Dermatol. 2015(April)24(4):245-251.
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