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Skin might be able to close the translation gap

Karin Scharffetter-Kochanek, dermatologist and head of the Department of Dermatology and Allergology at the University Hospital of Ulm, has spent a long time investigating skin ageing. Her specific focus on skin has not, however, restricted her understanding of ageing to barely deterministic or mechanistic details. Quite the opposite is true. Scharffetter-Kochanek takes an open and broad approach that attempts to place the ageing of individual organs into a systemic relationship that takes all organs into account.

Atrophic brain of an Alzheimer’s patient. © Dep. of Neurology, University Hospital Ulm
A DFG-funded clinical research group at Ulm University, coordinated by Dr. Scharffetter-Kochanek, is working on developing preventive and therapeutic measures based on the molecular and cellular mechanisms of ageing. The approach is so special because the group of researchers are looking at the issue from a broad range of different angles – some of them focus on the individual organ (skin), others on the immune system and some on the central nervous system (CNS).

The researchers hope to be able to explain, understand – and subsequently also treat – infectious and autoimmune diseases, the neuronal degeneration of the CNS, defective wound healing, osteoporosis, arthrosis and arteriosclerosis, diseases that mainly occur in old age. The overall aim of the Ulm researchers, in common with many other research groups, is to find ways for people to remain healthy as they age.

Increasing knowledge requires flexible researchers

Prof. Karin Scharffetter-Kochanek © University Hospital Ulm
Scientists working on the phenomena of ageing need to be curious and flexible, two adjectives that describe Dr. Scharffetter-Kochanek well. Progress in scientific knowledge has overturned quite a few long-standing hypotheses, including for example, the assumption that genes that are switched on will inevitably kick-start the ageing process.

Since research into this issue began, signalling pathways that are even able to prevent ageing have been discovered in mice. Experts refer to these as anti-ageing pathways; they are evolutionarily conserved and are most likely also found in humans. In a EU-funded project (Proteomage), Scharffetter-Kochanek and her team have been working with European colleagues on the analysis of gerontogenes and their gene products.

Over the course of the last year, Scharffetter-Kochanek has realised that it is necessary to focus on another field of research that up until recently has only received scant attention. Experiments have shown that skin also contains pluripotent stem cells that are of great importance for tissue renewal and/or organ development.

Many findings support the free radical theory

Scharffetter-Kochanek is convinced that ageing depends to a large extent on the generation of free radicals and their damaging effect on mitochondrial and nuclear genes. The relationship has not yet been clarified in detail. Does such damage lead to the generation of free radicals in the cell, leading in turn to growth arrest or apoptosis (cell death), or must the chain of molecular events be read the other way round?

“Private” ageing must be better understood

It is very difficult to work out such correlations. Scharffetter-Kochanek explains that tissue has its “private” ageing pathways; there are also “general” systemic ageing pathways, which are relatively well understood compared to organ-specific pathways.

Although knowledge relating to cellular and molecular mechanisms underlying ageing has grown considerably, it still cannot be applied because there is a big gap between laboratory data and living organisms, particularly in highly developed mammals such as mice and humans.

Research into skin: much more than just a stopgap

Simplified schematic detailing the differences between young, intrinsically aged and photoaged skin. The cells of the young skin and extracellular matrix are regular and equally distributed. In intrinsically aged skin, tissue loss and damaged molecules of the extracellular matrix affect the equilibrium. In photoaged skin, the tissue is enlarged, the thickness of the skin has increased considerably, the skin cells are untypically distributed, and the function and structure of components of the extracellular matrix are impaired. © Scharffetter-Kochanek / University Hospital Ulm
According to Scharffetter-Kochanek, the investigations into skin ageing have many plus points: skin is an easily accessed organ that can be analysed using non-invasive techniques. In addition, there are indications that the mechanisms of action of skin ageing are also of importance for other organs that are rich in connective tissue, for example bones, joints and the cardiovascular system.

The skin is therefore an ideal organ for studying the differences between intrinsic and extrinsic ageing. Immanent skin ageing is mainly characterised by the degradation of connective tissue (which can be partially reversed). Extrinsic ageing, i.e. skin ageing through external cues, is mainly caused by UV irradiation (artificial and natural), pollutants such as tobacco smoke or polluted air.

Morphological overlaps

While intrinsically aged skin does not change considerably on a morphological level, UV-irradiated skin reveals great changes: wrinkles, deep furrows, tissue loss, changes in the pigment net with irregular pigmentation and even early signs of spinocellular carcinomas (white melanomas) which are referred to as acinetic keratoses and predominantly occur on exposed skin areas such as the face, the back of the hand and the forehead.

Extrinsically aged skin is also characterised by malignant skin tumours such as basal cell carcinoma and malignant melanomas. There is a higher incidence of serious skin tumours in extrinsically aged skin, but, according to Scharffetter-Kochanek, the morphological alterations of intrinsically and extrinsically altered skin overlap.
Young fibroblasts in cell culture © Scharffetter-Kochanek
Whether extrinsically or intrinsically aged – the skin in any case loses its function as an effective barrier and homeostatic organ. The DNA repair and immune response abilities of the skin decrease and the reduced quantity of melanocytes (pigment cells that protect the skin against UV irradiation) increases the risk of epidermal DNA damage, which leads to a strong increase in skin cancer risk.

The “geronto-organ” skin is also an excellent model for the investigation of ageing processes due to its complex composition and the large number of different cells involved. The connective tissue of the dermis plays a central role in the highly complex structure of the skin. The homeostasis of the dermis is regulated by the dermal fibroblasts, which in turn affect other skin cells that influence the epidermal keratinocytes and melanocytes.

Once the cells ‘retire’ they lose their regenerative potential

Old, enlarged fibroblasts in cell culture
In cell culture, fibroblasts develop typical morphological and functional signs of ageing. For example, increased proteolytic degradation and the increased inability to divide accompany a reduction in regenerative potential. Scharffetter-Kochanek believes that these phenomena also occur in the living organism.

Like many researchers on ageing, Scharffetter-Kochanek also believes that ageing can only be explained by a combination of several theories taken together, including the genetic theory, according to which so-called gerontogenes affect the ageing process on the level of cells, organs and organisms. This also includes genes that are involved in the organisms’ stress response which play a role in energy consumption, and genes that function as molecular clocks and are involved in cell division and organ development processes.

Significance of the free radical theory on connective tissue

Femur bones with age-based bone density (Photo: University Hospital Ulm)
Gerontogenes also include antioxidative enzymes such as the enzymes superoxide dismutase and catalase. In an ongoing project, the dermatologist from Ulm is investigating how much the enzyme manganese superoxide dismutase (SOD2) – i.e. the first antioxidant defence against highly reactive oxygen species – is involved in tissue and organism ageing.

This enzyme occurs mainly in mitochondria and, if overexpressed, has a life-prolonging effect in Caenorhabditis elegans, a model of post-mitotic ageing. According to Scharffetter-Kochanek little is still known about whether the function of this enzyme is conserved during evolution and whether the enzyme also influences or controls the ageing of higher organisms.

It had previously been impossible to investigate this, because mice that lacked this protective enzyme usually died before birth. In order to analyse the importance of this enzyme for ageing in vivo in the skin of higher organisms, Scharffetter-Kochanek’s research team has created mice in which the antioxidative enzyme is selectively suppressed in both histogenetic areas of the skin.

What connective tissue might have in common with osteoporosis

Old, osteoporotic femur bone (Photo: Scharffetter-Kochanek)
According to Scharffetter-Kochanek, these specially developed mouse models make it possible for the first time ever to study the effect the loss of this antioxidative enzyme has on ageing. The phenotype of such knock-out mice suffers from atrophic skin, heavy osteoporosis, is hunchbacked and has diseased muscles. The researcher from Ulm concludes that the connective skin tissue, including the fibroblasts and the numerous structural proteins of the extracellular matrix, is of overall importance for bones and other organs that are rich in connective tissue (skin and the vascular system).

The theory that highly reactive oxygen species play a role in cellular (intrinsic and extrinsic) ageing was developed using many cell biology methods, both natural genetic modifications and transgenic organisms. Numerous observations support this theory on ageing, according to which the destructive effect of free oxygen radicals is responsible for age-related disorders in cells and tissues.

Oxidative metabolism speeds up the ageing process

Scharffetter-Kochanek and the other members of the clinical research group are undertaking a second project where they hope to substantiate the hypothesis that the oxidative metabolism speeds up ageing. The researchers’ work is based on the influence of UV irradiation on skin ageing. UV irradiation enables the researchers to considerably increase the proportion of cell-damaging by-products of cell respiration in intrinsically aged skin.

Scharffetter-Kochanek has investigated this effect in a recently identified gene that plays a role in the long-term elevated concentrations of free oxygen radicals. The researchers induced the early ageing of fibroblasts by making them more sensitive to UV irradiation at the same time as irradiating them with long-wave UVA light, which is able to intrude deeper into the connective tissue. Scharffetter-Kochanek will tell us more about the results of her investigation once they have been published.

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/skin-might-be-able-to-close-the-translation-gap