Structural activity relationship analysis (SAR) and in vitro testing reveal the anti‐ageing potential activity of acetyl aspartic acid

Abstract

Synopsis Background Acetyl aspartic acid (A‐A‐A) was discovered through gene array analysis with corresponding connectivity mapping (Cmap), aiming for identification of new compounds with anti‐ageing properties. Objective The aim of this study was to use structural activity relationship (SAR) analysis to identify a predictive mechanism of action of A‐A‐A. The findings from SAR will be further characterized by in vitro activity testing. Furthermore, we aimed to investigate the role of polymerized filamentous F‐actin in ageing fibroblasts and to evaluate the effect of A‐A‐A on this model. Methods To predict the mode of action of A‐A‐A, we used the PASS computer program as a SAR model. In vitro, scratch motility tests with immortalized keratinocytes were used as a model for wound healing potential. Matrix metalloproteinase 1‐3 (MMP 1‐3) was analysed using multiplex protein assays (Luminex), and polymerized actin was detected by phalloidin staining in dermal fibroblasts (HDF). Results SAR analysis predicted that A‐A‐A would possess both epidermal and dermal activities with identification of wound healing and MMP inhibition potential. Further in vitro studies confirmed the wound healing potential using keratinocyte scratch motility assays. We were also able to confirm the dermal activities predicted by inhibition of MMP (MMP 1–3) in HDF by A‐A‐A. In addition, we found a positive relationship between age and F‐actin expression. We also discovered that stimulation of HDF with A‐A‐A for 72 h significantly reduced the polymerized cytoskeletal network as visualized by inhibition of F‐actin expression. In fact, A‐A‐A leveraged the expression of F‐actin in middle‐aged female fibroblasts (50 years of age) to the level of young female fibroblasts (30 years of age), corresponding to a 40% reduction in F‐actin expression. Conclusion Using an in silico and in vitro approach, we were able to demonstrate that A‐A‐A has the capacity to target different compartments of the skin through keratinocyte regeneration, MMP inhibition and relief in fibroblasts stiffness by reduction of F‐actin cytoskeletal network in HDF.

In vivo topical application of acetyl aspartic acid increases fibrillin‐1 and collagen IV deposition leading to a significant improvement of skin firmness

“…Gene array investigation of 30 000 genes with corresponding connectivity mapping after 7‐day topical application of RA, a gold standard for treatment of photoaged skin revealed A‐A‐A as a potential retinoid mimicking agent . The epidermal and dermal activity of A‐A‐A was also demonstrated in vitro showing (i) increased keratinocyte regeneration, (ii) relief of fibroblast stiffness and (iii) MMP inhibition .…”

“…Clinical effects on skin firmness and elasticity in both naturally aged skin and photodamaged skin have been documented [7][8][9]. Secondly, A-A-A increased keratinocyte migration in a wound healing model, which gave an important indication that this amino acid could possess regenerative epidermal activity in aged skin [2]. Thirdly A-A-A relieves stiffness of aged dermal fibroblast (HDFs), which was demonstrated using the age-related cytoskeleton stress marker, F-actin.…”

Evaluation of skin firmness by the DynaSKIN, a novel non‐contact compression device, and its use in revealing the efficacy of a skincare regimen featuring a novel anti‐ageing ingredient, acetyl aspartic acid

“…The ability of AAA to positively influence the skin components associated with a loss in skin biomechanics, including a relief in fibroblast stiffness, has previously been demonstrated (38). Biomarker analysis following topical application of AAA revealed an upregulation of the skin elasticity proteins collagen IV and fibrillin at the basement membrane of the dermo-epidermal junction of photoaged skin (38). Furthermore, this effect on the skin structure translated to have clinical significance.…”

“…Given that the initial magnitude of the improvement was 11% to almost 13% for the different parameters, there was little room for incremental benefit for the duration of application, sometimes observed following 12-week application regimens. The ability of AAA to positively influence the skin components associated with a loss in skin biomechanics, including a relief in fibroblast stiffness, has previously been demonstrated (38). Biomarker analysis following topical application of AAA revealed an upregulation of the skin elasticity proteins collagen IV and fibrillin at the basement membrane of the dermo-epidermal junction of photoaged skin (38).…”

Computer-aided prediction of biological activity spectra for chemical compounds: opportunities and limitation

“…Компанией «Oriflame Skin Research Institute» (Швеция) было показано, что ацетил аспарагиновая кислота (AAA) проявляет омолаживающие кожу свойства (anti-ageing action), однако механизм этого действия оставался неясным [60]. Прогноз спектра биологической активности с использованием PASS показал, что AAA может стимулировать регенерацию кератиноцитов благодаря ингибированию действия матричных металлопротеиназ 1-3 и экспрессии F-актина.…”