Issue 47 — July 2011

Issue 47
Category		Title		Authors
Guest Article		Anti-Aging - Where Do We Stand? Theories and Hypotheses on Skin Aging		Petra Huber, Karin Hess

Abstract
This article presents current theories, often referred to in the literature, concerning skin aging processes. To date, more than 300 molecular biological mechanisms have been described in an effort to explain human aging. Some of these mechanisms affect not only evidence-based and individual treatment approaches in anti-aging medicine, but also concepts in the field of cosmetics. [1], [2], [3]

The most discussed and scientifically established theories are those concerning free radicals (ROS), mitochondrial dysfunction, altered hormone levels and the telomere theory. The theory of glycation processes (AGEs) is known in medicine mainly due to the impact of diabetes and offers interesting potential for cosmetics.

Introduction
The scientist Leonard Hayflick discovered in the 60s that human cells, such as fibroblasts in cell cultures, have only a limited lifetime and will not divide indefinitely, as pluri- or unipotent stem cells do (the so-called "Hayflick phenomenon") [3]. The causes lie in the genetic material of cells. This fatalism is now being replaced by theses that the "aging programs" encoded in genes are co-determined by external factors. There are therefore high expectations in the cosmetics sector that it may be possible to intervene in these control loops with signalling molecules, as a first step. "Cosmetic gene therapy" remains a pipe dream, however [2].

Both modern anti-aging medical research, involving individual treatment approaches for each client, and classical aging research, which attempts to deduce general, so called evidence-based approaches, have attempted to find out how an organism can age more gracefully or even more slowly [4]. The modern zeitgeist, with its expectations of beauty and health, has significantly contributed to the rediscovery of prophylactic approaches and relativized the high demands of "anti-aging", at least in linguistic terms, with expressions such as "better aging" or "smart aging". Transhumanists, grouped around the British biogeneticist and age researcher Aubrey de Grey, are extremely optimistic [3]. They hope that scientific advances will soon turn mankind's ancient dream of stopping the aging process, or combating the disease of aging, into reality. Until then, the experimentally inclined (and financially strong) transhumanists have arranged that they will be preserved in thermos tanks with liquid nitrogen after their death.

The statements of various market research institutions, confirmed by the market strategies of smaller and larger cosmetic companies, demonstrate that the anti-aging market segment has in recent years shown the highest - sometimes disproportionately high - growth rates in the cosmetics sector. Demographically, sales of products promising anti-aging effects are growing thanks to the growing population of over 50 year olds (the 50+ generation or "best agers"). But even the younger generation appears to be showing increasing interest in such products. [5], [6]

Characteristics of mature skin (skin aging)
The aging process has many factors. The typical, visible and measurable characteristics of mature skin have various origins and have been described in detail in the literature [7], [8].

In general terms, the characteristics of mature skin are wrinkles and a loss of elasticity. The dermo-epidermal junction flattens in old age. The intrinsic aging of the skin leads to thinner, atrophic skin. Fine wrinkles and visible blood vessels are further characteristics. The dryness is caused by the qualitative and quantitative decrease of skin lipids. Aging skin also tends to increased irritation and redness, due to its impaired barrier function [9].

Extrinsic irritation factors lead to increased cell metabolism in the epidermis, so that irregular keratinisation is seen on the stratum corneum. An uneven skin surface with a yellowish skin tone is the result. This leather-like skin develops age spots and uneven pigmentation on areas exposed to the sun. UV radiation triggers increased enzyme activity in the matrix metalloproteinases (MMP), amongst other effects. Even a tenth of the minimum erythema dose (MED) induces higher activity of these collagen and elastin-forming enzymes [10]. More prominent wrinkles and "elastosis cutis" characterise faces whose aging is predominantly extrinisic. Tissue infiltration indicates inflammation processes.

Figure 1:  Visual representation of skin changes over a lifetime (Skin Care Forum 39)

Enlarged version

In addition to wrinkles, attentive cosmetic users may notice that from forty years of age the skin becomes thinner; this reduction in thickness takes place at the rate of 1 percent a year, while the elasticity of the collagen and elastin decreases by 2 percent [2].

Theories and hypotheses on skin aging
The aging characteristics of the skin are the result of intrinsic, and above all, extrinsic causes. Most of the theories listed below describe intrinsic changes which determine the rhythm of the "biological clock". As a border area the skin is exposed more than any other organ to aging processes caused by extrinsic factors (especially to the additional burden of reactive oxygen species (ROS)). These can accelerate the intrinsic processes. Aging is the result of complex processes, the causes and effects of which are unlikely to be exclusively intrinsic or extrinsic. This makes research on this topic all the more exciting and provides hope of further discoveries, such as molecular communication processes between skin cells. All the indicators suggest that in future it will be possible to have a lasting influence the aging process of the skin by measures other than behavioural changes.

Research findings, from the statement by Leonard Hayflick in the sixties quoted above up to today, indicating that aging is in extreme cases a disease, or rather “the accumulation of unfavourable and adverse changes that increase the risk of death” [11], suggest that the biological complexity of aging will require many more years of intensive research in all the life sciences.

This publication looks at the theories in turn, focusing on their relevance to anti-aging medicine and to the cosmetics sector.

The theory of free radicals (ROS = Reactive Oxygen Species)
This well-known theory assumes that the organism is constantly exposed to free oxygen radicals. Free radicals are incomplete, highly reactive molecules which rob intact molecules of electrons in their striving for completeness, and so can damage cell membranes, chromosomes and tissue. Free radicals occur naturally through mitochondrial cell respiration and can be fostered by external influences such as ozone, nicotine, or stress [12]. Human skin has developed protective mechanisms against ROS over the course of evolution. Enzymes such as superoxide dismustase, catalase and glutathione peroxidase act as radical scavengers and may reduce oxidative damage. With age, the adaptability and the reaction capability of these mechanisms decreases, and the balance between pro-and anti-oxidative systems alters; increasing cell damage is caused by ROS. This is called oxidative stress. The oxidation reactions induced by free radicals mainly affect unsaturated fatty acids, which are components of membrane phospholipides. The cell membrane is damaged; intracellular components and thus functionality are lost. The lipids are altered by the radicals in such a way that they themselves begin to act as radicals. In this way, a chain reaction begins that can only be interrupted by antioxidants.

In the connective tissue collagen is oxidised and hyaluronic acid is depolymerised. Thus degenerative pathological changes occur in the dermis [14]. When radicals are not deflected, the body “collects” more and more ROS-induced damage, which over time affects a variety of body functions. Excessive UV radiation further stimulates the secretion of signalling molecules such as cytokines. These cause, among other effects, a cascade of chronic inflammation with an increase in the concentration of mastocytes in the connective tissue [2]. The result can be, for example, increased secretion of enzymes such as elastase, which attack the structure of matrix proteins. Antioxidants such as vitamins and polyphenolic compounds (grape seed, green tea extracts, etc.) in particular are useful as cosmetic protection against free radicals.

The theory of mitochondrial dysfunction
This theory is closely connected to the radicals theory. Mitochondria are regarded as "molecular clocks", whose high mutation rate is believed to limit the lifespan of mtDNA (messenger, transfer DNA), and of nRNA (nuclear RNA) [16] [17].

The main function of mitochondria is to provide adenosine triphosphate (ATP) through cellular respiration; they are the energy centres of each cell. In this process electrons are transported, and from these electrons, free radicals are generated. Mutations in mitochondrial DNA can be induced when neutralisation processes are overburdened. Functional disorders of mitochondria occur and the impulse for cell metabolism collapses. This promotes enzyme activities of matrix metalloproteinases (MMP), which break down the dermal collagen and greatly accelerate aging of the skin.

The role of changes in hormones
This theory of aging is based on the assumption that hormones substantially affect the aging process. Hormones are considered to regulate the activities of all enzymes in the body, which are required for repair, protection against and elimination of cellular damage [18]. With age, the levels of certain hormones in the body decrease. The hormonal balance changes dramatically in women during and after menopause, but hormone levels also change in men as they age (andropause). The hormonal theory assumes that people age because of declining hormone levels. Important hormones that decline with advancing age include the sex hormones such as estrogens and androgens, but also hormones such as melatonin, the adrenal hormones known as DHEA (dehydroepiandrosterone) and other growth hormones such as somatotropin.

Hormonal skin aging leads to changes in the epidermis and dermis which cause increased skin dryness in advanced years, and a decrease in epidermal thickness of up to 50%, or up to 30% in dermal thickness.

The hormonal changes accompanying aging have a direct effect on the skin and are treated in dermatology by oral or local-topical substitution. However, systemic estrogen substitution may lead to a slightly increased risk of breast cancer, while supplementation with testosterone and DHEA may increase the risk of prostate cancer [3]. Replacing melatonin has so far produced no positive effects on the skin.

The telomere theory
Each cell division requires the precise replication of DNA. In this process, the end caps stored on the DNA, called telomeres, play a crucial role. They function as protective caps on the chromosome ends, comparable to the dust jacket of a book. DNA cannot be entirely read at the outer ends when it is replicated. Thus, each cell division results in a reduction of these telomere areas. After numerous cell divisions the readable range of the DNA reaches a critical length, and the cell division process of the cell ceases [3]. The enzyme telomerase repairs and extends the telomeres, so that the cell remains endlessly capable of division; unfortunately cancer cells also contain this enzyme [3]. Regular movement slows aging by preserving telomeres, according to research at the University of Homburg, Germany. The three U.S. scientists Carol W. Greider, Jack W. Szostak, Elizabeth Blackburn shared the 2009 Nobel Prize for Medicine for their work on the role played by telomerase in arresting cell aging.

The theory of glycation
In this theory glucose is held to be responsible for the increasing number of rigid collagen compounds in older persons. In the glycation process, sugar molecules that have not been utilised by the body, such as sugar aldehydes or sugar ketones, connect in a non-enzymatic reaction with the free amino acid groups of lysine molecules in the collagen fibres of the dermis (so-called cross-linking). In two reaction steps, this leads to irreversible end products, so-called AGEs (Advanced Glycation End-products). These lead to a gradual stiffening and loss of firmness and elasticity of the skin, blood vessels and other protein types. Oxidative processes play a role in the formation of AGEs via a reaction path. In general, therefore, antioxidants also appear to inhibit the formation of these end products. Acetylsalicylic acid (aspirin), aminoguanidine, vitamins of the B group and other vitamins are used in medicine and experimental biochemistry to protect other possible weak points in the reaction cascade [3].

Figure 2: The various reaction steps which lead to the formation of AGEs [22] (Image provided courtesy of Cosmetics & Toiletries magazine)

Enlarged version

Which anti-aging concepts are relevant to the cosmetics sector?
The translation of the theories described into the language of cosmetics takes many forms. Based on the findings from skin research, a variety of research approaches to anti-aging agents have been established, and further proposals for future product development and launches are being made. For legal reasons, certain treatment concepts are (so far) reserved exclusively for dermatology.

Locally applied cosmetic agents must above all have excellent compatibility, be toxicologically safe and show no other systemic side effects. The current sphere of activity in cosmetics is therefore limited to protecting, activating and regulating the skin (stem) cells, and optimising a healthy skin environment. Essential building materials can be supplied topically, locally or orally. (Dietary supplements or functional foods have also been discovered by the cosmetics sector. Together with selected foods that are rich in biologically active ingredients, these constitute useful complementary anti-aging measures.) In addition, as many innovative and interesting examples show, there is a whole range of naturally and synthetically derived cosmetic active ingredients that provide a good alternative to treating signs of aging before aesthetic dermatology measures need to be taken. Further areas for current research ought to include questions about how the skin as a closed loop (homeostasis) reacts to external changes, both positive and negative, and whether active ingredients are better applied individually or as a complex with complementary attack mechanisms.

Anti-aging agents are divided into generations, each depending on the author's point of view [9]. A selection is shown in Table 1. This division, similar to pharmaceutical drug research, follows a chronological development which is linked to the progress made in skin research, and thus only provides a snapshot of the prevailing markets. Naturally, the active ingredients from the first generation have received the most attention. Ideally, there are evidence-based statements for these ingredients, based on double-blind, placebo-controlled efficacy studies.

Table 1: Anti-aging ingredients (according to [9])
First generation	Vitamins A, C, E Coenzyme Q10 Alpha lipoic acid Flavonoids Phytoestrogens
Second generation	Growth factors Copper tripeptide Palmitoyl pentapeptide N6-furfuryladenine
Third generation	DMAE Acteyl hexapeptide 3

Some drug groups and their mode of action are described below as examples (not evaluative!). Based on the theories and hypotheses of aging mentioned above, various approaches and applications are possible for anti-aging agents. The active compounds may have preventive effects and may also mitigate existing visible signs of aging. It can certainly be advantageous if the same drug acts at different molecular levels. Nevertheless, in cosmetics virtually all formulations contain a combination of several active ingredients, used synergistically, and their benefits are promoted in these terms.

A large, well-studied class of active compounds is antioxidants. Vitamins such as tocopherol (vitamin E) or retinoids (vitamin A) can convert free radicals into less aggressive forms of the molecule and thus protect the skin. One particular antioxidant is the coenzyme Q10, known as CoQ10 or ubiquinone. As one ages, the content of CoQ10 in the cells decreases. In vitro studies have shown that topically applied CoQ10 protects cells from UVA-induced DNA damage, preserves the body's own glutathione and suppresses the secretion of collagenase. If the body is supplied with enough ubiquinone, it supports the production of vitamin E and can reactivate forms that have been inactivated by free radicals [3].

Another important group of active ingredients for use in cosmetic formulations are the peptides, which are all compounds that consist of amino acids (AA). Due to the number of peptide-linked monomers, these oligopeptides are referred to as di-, tri-, penta- and so on. Among the anti-aging peptides used in cosmetics, a distinction is made between signal peptides and neurotransmitter-blocker peptides. The signal peptides mimic protein sequences from collagen and elastine structures. They thus stimulate the production of new collagen and elastin. The second category of peptides can block neurotransmission, and thus act as muscle relaxants (“botox-like”). Examples available for sale are soya peptides, other amino-peptide complexes and the neurotransmitter-blocking peptide acetyl hexapeptide-8.

Further active compounds of interest for cosmetics are glycation inhibitors such as dipeptide carnosine or aminoguanidine. The latter has been shown to significantly reduce the cross-linking of sugars and proteins, but only in vitro [22] or by oral ingestion. Animal studies have shown that older groups that received aminoguanidine as a food supplement showed the same elastic tissue structures as young animals [3]. The exact processes involved in the prevention of glycation by the chemical substance aminoguanidine are still not entirely clear.

Outlook
Health is a mega-trend that will bring additional important impulses in the coming years for the cosmetics sector and will be of great economic interest.

The current understanding of aging mechanisms is reflected in the efficacy testing carried out by the producers of raw material and in the cosmetics sector’s products and advertising. Both basic and applied skin research will also generate further potential for active substances and their methods of application. New (or rediscovered) agents will be isolated or synthesized, and their effectiveness verified by increasingly specific in vitro cell culture tests. The trend toward research into natural substances is cost-effectively supported by skin models or organotypic models. However, it would be useful to investigate a larger number of active ingredients for their “anti-aging” potential in the near future. Innovative active compounds, combined with an ideal basic formula that guarantees the penetration and preservation of the compounds, will continue to ensure constant replenishment of the anti-aging product pipeline. At the same time, increasing demands will be made of both the basic formulation and the accompanying auxiliary materials (“functionals”) to deliver not only good penetration but also precisely targeted delivery of the active ingredients.

In addition to creative product concepts, corresponding reformulations of product descriptions will also be necessary. The term anti-aging has been already extended from the face to areas of the body and hair care, and even to decorative cosmetics. The challenge will be to continue harmonising descriptions of product benefits with complex mechanisms of action and to communicate these in a way customers can understand. Thanks to a steadily increasing demographic demand, the area of anti-aging skin care will continue to be the sector with the highest growth, as it has been in recent years.

Figure 3: Anti-aging is also “better-aging”

The basis of this article, which has been extended for the present publication, was provided by the introductory theoretical part of a Bachelor's bachelor thesis written in the summer of 2009 in cooperation with the ZHAW in Wädenswil (CH) (supervised by Petra Huber, Lecturer in Cosmetics and Toxicology) and with Mibelle Cosmetics AG (CH) (Dr. Bernhard Irrgang, Head of the Business Unit Face & Body Care).

Note
This article was originally published as follows:
Petra Huber, Karin Hess; Anti-Aging - Wo stehen wir? Theorien und Hypothesen zur Hautalterung, SOFW-Journal 136, 10-2010, S.2-10
Petra Huber, Karin Hess; Anti-Aging - Where Do We Stand? Theories and Hypotheses on Skin Aging, SOFW-Journal 136, 10-2010, pp. 2-10

References
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[3] Schmitt, R., Homm, S. (2008), Handbuch Anti-Aging und Prävention, Verlag im KILIAN, Marburg
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[16] Wiesner RJ, Zsurka G, Kunz WS (2006), Mitochondrial DNA damage and the aging process; facts and imaginations, Free Radic Res. Dec 40(12), 1284-94
[17] Kunz WS (2009), Mitochondriales Altern, Vortrag anlässlich des VII. Internationaler Kongress für Anti Aging- und Präventivmedizin; Von der Evidenz-basierten zur Individual-Medizin, Sept. 2009
[18] Umbach, W. (2004), Kosmetik und Hygiene von Kopf bis Fuss. 3. vollständig überarbeitete Auflage. Wiley-VCH Verlag GmbH & Co, Weinheim
[19] Zouboulis, Ch. C. (2003), Intrinsische Hautalterung. Eine kritische Bewertung der Rolle der Hormone. Der Hautarzt 9 / 2003, S. 825 - 832
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Author


Petra Huber, federally certified pharmacist, MAS ETH MTEC, is lecturer in Cosmetics and Toxicology at the ZHAW School of Life Sciences and Facility Management in Wädenswil, Switzerland, Zurich University of Applied Sciences. Among her projects are the exploration of the feasibility of nutritional ingredients and skin appearance/beauty for product innovations like nutricosmetics for the Swiss market. She is member of the Swiss Society for Anti-Aging Medicine and Prevention (SSAAMP), of the Association of Soap, Perfume and Detergent Experts (SEPAWA), the Swiss Federation of Pharmacists (Pharmasuisse) and the Swiss Society of Cosmetic Chemists (SWISS SCC), where she has been elected member of the steering committee at the beginning of 2011.

Contact address:
Petra Huber, federally certified pharmacist, MAS ETH MTEC, is lecturer in Cosmetics and Toxicology
ZHAW Zurich University of Applied Sciences
School of Life Sciences und Facility Management
Institute of Food and Beverage Innovation
Grüental Campus, Post Box
CH-8820 Wädenswil

E-mail: petra.huber@zhaw.ch.
Phone +41 (0)58 934 57 28
Fax +41 (0)58 934 50 01
Internet: www.lsfm.zhaw.ch www.lebensmittel.zhaw.ch



Karin Hess, Bachelor in Food Technology (ZHAW Zurich University of Applied Sciences, Wädenswil, Switzerland), has completed her Bachelor’s thesis in the field of cosmetics and has been trainee for leading various projects in the enterprises of Migros since Fall 2009. As per November 2011, she will assume the position of product developer in Research & Development at Mifa AG.

Contact address:
Karin Hess, Bsc in Lebensmitteltechnologie Trainee M-Industriemanager Ab November Forschung & Entwicklung bei der Mifa AG
Rheinstrasse 99
CH-4402 Frenkendorf
Email: karin.hess@mifa.ch
Internet: http://www.mindustry.com/de/home.html
www.mifa.ch