Cosmetics and genetics: what do they have in common?

Hernandez Elena, Биомолекула.гиThe cosmetics industry, free from prejudices related to the correctness of the use of scientific terms, has long been juggling words such as "DNA", "genes", "signaling molecules", "genetic code" and others.

However, the subtle mechanisms of gene regulation — alas — are still too poorly understood even at the level of experiments "in vitro", not to mention being used in real cosmetic preparations that will be used by millions of people. This article contains several examples illustrating the complexity of the mechanisms involved in the regulation of life processes.

Let's start with what this article should actually end with: cosmetics that would be able to "intelligently" influence the genetic mechanisms of skin cells are still as far from real embodiment as gene therapy of diseases. Of course, progress in the field of molecular biology is obvious, and scientists have made great progress over the past decade in terms of understanding the most subtle mechanisms of gene regulation. But every step forward opens up new horizons, and it becomes clear that the process of cognition is infinite, just as nature itself is infinite.

If we ignore the philosophical lyrics and, based on the facts already available, imagine how complex the mechanism of gene control is, it becomes clear that in many cases we still cannot consciously interfere with it. But while medicine is taking the first timid steps in this direction, hedging and even reinsuring itself, the cosmetics industry, not constrained by strict legislative frameworks, is already freely juggling words such as "DNA", "genes", "signaling molecules", "genetic code", etc.

My personal attitude to this stems from basic biological education, which, alas, leaves an imprint on the worldview and does not allow me to join the general euphoria. I will give just a few examples — illustrative illustrations of how complex the issue of regulation of gene activity is.

Fibroblast fibroblast discordIn July 2006, the results of a study conducted by a group of scientists from the Stanford School of Medicine were published in the journal PLoS Genetics [1].

Fibroblasts, the main cells of connective tissue, were taken as the object of study, in which the activity of 337 genes was determined. 47 fibroblast populations from 43 body sites were studied (see figure). It turned out that genes manifest themselves differently depending on the localization of cells in the body. But if the difference between a fibroblast located in the connective tissue septum of the alveoli in the lungs and a skin fibroblast is not surprising, then the difference in gene activity between dermal fibroblasts located in different areas (for example, the forearm (blue circles) and the lower leg (turquoise circles)) makes you think. In the light of these studies, it is worth taking a fresh look at the problem of creating dermatotropic drugs with signaling activity for the skin on different parts of our body.

Differences in gene expression in human fibroblasts [1]. A. 47 primary fibroblast populations from 43 different parts of the body. The populations are numbered, the corresponding numbers are in circles of different colors. Dermal fibroblasts: forearm (blue), lower leg (turquoise), abdomen, chest and face (pink), foreskin (yellow); fibroblasts of internal organs (red). Cells were obtained from 20 autopsy (cadaver) materials (letter A) or from tissue samples removed as a result of surgical intervention (letters B-T). B. Diversity of gene expression programs in 47 fibroblast populations. Each row represents one gene, each column corresponds to one fibroblast population. The expression level of each gene is displayed in color relative to the average activity level: green is below average, red is above average, black is average. c. Similarity between different populations of human fibroblasts. Populations (circles with numbers) that are similar in terms of gene expression form clusters.

Regulate regulatoryThe following example shows that the gene control system consists of many levels.

In this regard, enzymes from the sirtuin group are of interest, which exercise control over proteins that regulate cellular activity. Sirtuins are enzymes found in both prokaryotic (bacteria) and eukaryotic (animal, plant) cells. They affect the life of the cell through the expression of certain genes. For example, sirtuin Sirt-1 regulates the transcription of genes responsible for the synthesis of the following proteins:

• FoxO1, Fox03 and Fox04 are transcription factors of genes involved in cellular defense mechanisms and glucose metabolism;
• H3, H4, and H1 are histone proteins required for DNA packaging in a chromosome;
• Ku70 is a transcription factor that stimulates DNA repair and increases cell viability;
• MyoD is a transcription factor that stimulates the development of muscle cells and tissue repair;
• NCoR is a regulator of many genes, including those involved in fat metabolism, inflammatory processes and the work of other regulators, such as the PGC-1a protein;
• P300 is a regulator responsible for the adhesion of acetyl groups to histones;
• p53 is a transcription factor that initiates programmed death of a damaged cell;
• PGC-1a is a regulatory protein that controls cellular respiration and, apparently, plays a role in the development of musculature;
• NF-kB is a transcription factor that controls the inflammatory process and the survival of growing cells.

"Regulators of regulators" — sirtuins — are most likely able to control age-related pathological processes, such as aging, obesity, metabolic syndrome, type II diabetes, Parkinson's disease. Normally, the activity of sirtuins is inhibited by nicotinamide (a derivative of vitamin B3), also known as niacin. Drugs that compete with nicotinamide for the binding site to the receptor activate sirtuins. It is known that resveratrol, found in red wine, has a similar property [2]. However, its content in wine is much lower than the therapeutic dose required for the activation of sirtuins. So the use of resveratrol in the composition of this wonderful natural source in order to influence the sirtuins, unfortunately, will not lead to the desired effect. Today, a number of laboratories around the world are developing medicinal agents and drugs that specifically block the binding site of nicotinamide to the receptor and thereby increase the activity of sirtuins. It is possible that substances acting in this way will be useful in the treatment of degenerative diseases such as diabetes, atherosclerosis and gout [3]. It is possible that in the future dermatotropic drugs will be created that selectively affect the activity of sirtuins in skin cells.

The problem of nutritionAnother issue that has been actively discussed recently concerns skin nutrition.

It should be borne in mind that everything that we "let" into our body along with food can affect the activity of genes and direct it in one direction or another. Substances absorbed through the intestinal wall into the blood pass through the "filter" — the liver — then spread throughout the body, exit the bloodstream into the intercellular fluid and only then get to the cells. These substances can be an energy and/or metabolic substrate for the cell. The first are "fuel" that is "burned" in cellular "furnaces" — mitochondria — and supplies the cell with energy. The latter are the building material from which the cell builds the structures it needs. But there is another category of substances — these are the so-called signaling molecules, whose role is to transmit a command to the cell for further actions. Some of these compounds implement their signal at the gene level, activating or, conversely, inhibiting their expression.

Of course, the nutrition of skin cells occurs in the same way as the nutrition of other cells of the body, i.e. through the blood. However, substances applied to the skin as part of dermatotropic agents and passed through the barrier structures of the stratum corneum can reach living cells and get inside. And here it is very important to know how they will behave in a cage. A textbook example was ascorbic acid (vitamin C), which activates fibroblast genes responsible for the synthesis of collagen types I and III [4]. The issue of dosages is very important, as, for example, in the case of retinol (vitamin A), which regulates the genes responsible for the proliferation and differentiation of keratinocytes. The penetration of toxic substances into the cell, on the contrary, can negatively affect the functioning of the well-functioning mechanism of gene regulation, and then the cell dies or degenerates into a malignant one [5].

These and other examples lead us to reconsider the attitude towards cosmetics, designated as "nutritious".

As for the effect of food on genes, it was seriously talked about not so long ago. Scientists pin great hopes on this direction. It is very likely that in the future, the preparation of an individual diet in order to correct the mechanisms of gene regulation will become part of the gene therapy of a number of diseases [6]. However, this is a topic for a separate conversation.

The examples given are only isolated fragments, but even from them it is possible to imagine how complex the problem of gene regulation really is. Work in this area is actively carried out in many laboratories around the world. Every year, research tools and methods are becoming more sophisticated and accurate, and this expands the capabilities of molecular biologists and geneticists in terms of understanding the life of cells [7].

It is possible that in a few years it will be possible to develop dermatotropic agents that will actually be able to work at the level of the genetic apparatus, namely, to carefully and meaningfully interfere in the subtle processes of regulation of cellular vital activity and direct them in the right direction. If this happens, then we can rightfully talk about a new generation of cosmetics — cellular cosmetics. But will it really be COSMETICS in the sense in which we understand it today? This question remains open.

Literature Rinn J.L., Bondre C., Gladstone H.B., Brown P.O., Chang H.Y. (2006).

• Anatomic demarcation by positional variation in fibroblast gene expression programs. PLoS Genetics 2, 1084–1096;
• Stefani M., Markus M.A., Lin R.C., Pinese M., Dawes I.W., Morris B.J. (2007). The effect of resveratrol on a cell model of human aging. Ann. N.Y. Acad. Sci. 1114, 407–418;
• Olaharski A.J., Rine J., Marshall B.L., et al. (2005). The flavoring agent dihydrocoumarin reverses epigenetic silencing and inhibits sirtuin deacetylases. PLoS Genetics 1, 689–694;
• Tajima S., Pinnell S.R. (1996). Ascorbic acid preferentially enhances type I and III collagen gene transcription in human skin fibroblasts. J. Dermatol. Sci. 11, 250–253;
• Waldecker M., Kautenburger T., Daumann H., Busch C., Schrenk D. (2007). Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon. J. Nutr. Biochem. (doi: 10.1016/j.jnutbio.2007.08.002);
• Mattson M.P. (2007). Dietary factors, hormesis and health. Ageing Res. Rev. (doi: 10.1016/j.arr.2007.08.005);
• Holtz R., Vitz W. (2006). DNA Microarray: application to personal health care and cosmetic industries. Cosmet. Sci. Tech.

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27.02.2008