New therapeutic approaches for a healthy aging of the skin: epigenetics

If from the moment we are conceived a genetic code tells us how we will grow older, why is not the conquest of seniority in full health and beauty elementary, quick and assertive? The answer imposes some complexity, since the causes of aging are not independent.

From the first day of birth, we age. Through a complex system, our body chronologically renews cells and changes their shape (phenotype), that is, they adjust the conditions of aging. However, it is not only the intrinsic factors of our body that lead us down this path. Extrinsic factors and our interaction with the environment in which we live - diet, stress, pollution and sun exposure, etc. - are also determinants in the sense of "how" we age. That is, although hereditary factors may dictate how we will pass through time, it will be the environment that will determine if any traits are to be altered, and then begin a whole process of transformation that begins at the genetic level. So does the surroundings interfere with how we evolved? The answer is yes.

It will be more closely assessing this phenomenon that we will find the epigenetic factors as main responsible for regulating the environment under our genes. Epigenetics - a phenomenon capable of modifying some genes by external factors such as pollution and stress - changes the way our cells read the original genes and function as "gene switches," stimulating or silencing genes. It occurs without any alteration of the DNA sequence, but regulating gene expression through different mediators is essential to justify, for example, the reason why the aging pattern is different between two genetically identical individuals as identical twins.

Among the known epigenetic mechanisms we have: 
1. Methylation of DNA (addition of a methyl group to DNA) 
2. Modifications of histones (proteins in which our DNA is packaged) 
3. Non-coding RNAs (ncRNAs) generated from DNA regions that do not have genes 

DNA methylation is perhaps the best known epigenetic marker, but the challenge of using it in skin aging treatments relays in the difficulty of identifying its triggers as well as the genes involved during this chemical bonding, which affects its control.

While DNA methylation is associated with repression and gene silencing, histone modifications can act both in suppression and in gene activation. Histones are proteins in which our DNA associates in a way to compact its size, forming a DNA-protein complex known as a nucleosome. Any change in the natural balance of this structure interferes with gene expression. However, the understanding and elucidation of all mechanisms that act on the functionalities of histones, is not yet fully uncovered due to the intense exchange of information that occurs during the process of modifications. In this way, it is not possible to perform the activation and deactivation of genes in a controlled manner.

Another mechanism that has been studied, and which has gained greater relevance in epigenetics, is the presence of microRNAs, a species of ncRNA (non-coding RNA, that is, that does not produce a protein) in the process of gene expression. This is because, miRNAs appear to be the most indicated for a therapeutic approach to skin aging since more than 800 miRNAs have already been identified, including its impact on protein metabolism. RNA (ribonucleic acid) is the main molecule involved during the process and control of cellular protein synthesis. Composed of a single strand, the RNA is produced in the nucleus of the cell (mimicking one of the strands of the DNA), and then is routed to the cytoplasm for protein production. The ncRNAs are not translated into proteins, but many of them are able to regulate gene expression or even protein production, thus being a kind of "genetic switch".

In order to explore possible epigenetic mechanisms to be regulated, Chemyunion has developed a new active ingredient that through the regulation of miRNA (micro-RNAs) acts in an effective way in reducing signs of skin aging: Agen. The inspiration for the creation of this innovation has emerged in the natural nutritional components known to affect health and aging, since epigenetics seems to be one of the mechanisms by which these components have their effect. Apple and ginger were the foods chosen from scientific bases related to the millenarian knowledge of both health and reduction of age-related phenotypes. Thus, Agen is composed of the synergistic blend of apple extract (Malus domestica) and supercritical ginger extract (Zingiber officinale).


• Regulation by epigenetic routes of 5 miRNA essential to reduce and decelerate the appearance of signs of aging; 
• Significant improvement in skin firmness and elasticity after 14 days; 
• Redensification of the dermis in 29% (1/3 more extracellular matrix) and improvement of epidermal thickness in 40% after 60 days; 
• Significant improvement in skin tone uniformity; 
• Wrinkle reduction; 
• Improved skin resistance, integrity and regeneration; 
• Stimulation of cell renewal and differentiation providing a younger and healthier skin. 


1. miRNA profile of target proteins in skin fragments treated with 1% Agen

Expression of miRNA. (EGFR: Epidermal Growth Factor receptor, COL1A2: Collagen Type I Alpha 2 Chain, COL4A3: Collagen Type 4 Alpha 3 Chain, COL4A4: Collagen Type 4 Alpha 4 Chain, COL4A6: Collagen Type 4 Alpha 6 Chain, DCN: Decorin, FN1: Fibronectin1). 

2. Extracellular Matrix Expression after 72 hours of treatment with 2% Agen 

Evaluation by immunofluorescence of collagen type I, collagen type IV, decorin and fibulin-5 (green) and counterstaining with DAPI (blue, marker of cell nuclei). Images of microscope with magnification of 40x. 10 μm histological sections on human skin fragments (ex vivo) incubated in culture medium (basal control) or treated with 2% Agen or placebo for 72 hours. Collagen type I comprises the extracellular matrix of the dermis (85-90%), being essential for the firmness and elasticity of the skin, whereas type IV collagen, present in the dermis (2-4%), composes the basal membrane being the main responsible for tissue integrity and stability. Decorin aids in the formation of collagen fibers and modulates growth factors that act directly on cell proliferation. Fibrinin-5 is also a glycoprotein essential to the elasticity of the cutaneous tissue, capable of regulating the deposition of elastin.

3. Wrinkles evaluation by VisiaCR in a clinical study

Photographic registration of volunteers using 2% Agen for 60 days.