The role of UVA rays in skin aging

ARTICLE

Chronic sun exposure causes photoaging of human skin, a process that is characterized by clinical, histological and biochemical changes which differ from alterations in chronologically aged but sun-protected skin. Within recent years substantial progress has been made in unraveling the underlying mechanisms of photoaging [1]. A question of great importance has been: Which parts of the sunlight cause which feature of photoaging? Ultraviolet rays penetrate into the skin and according to their wavelength interact with different cells that are located at different depths. Ultraviolet radiation of the shorter wavelength (UVB; 290-320 nm) is mostly absorbed in the epidermis and affects predominantly epidermal cells, i.e. keratinocytes, while longer wavelengths (UVA; 320-400 nm) penetrate deeper and can interact with both epidermal keratinocytes and dermal fibroblasts. Once UV light has reached the cells of the skin, the different wavelengths exert their specific effects. UVA rays mostly act indirectly through generation of reactive oxygen species (ROS) which subsequently can exert a multitude of effects such as lipidperoxidation, activation of transcription factors and generation of DNA-strand breaks. While UVB light can also generate ROS, its main action is the direct interaction with DNA via induction of DNA damage [2].

Exposure of human skin to UVA rays has been shown to trigger two of the major pathways leading to photoaging: (i) induction of matrixmetalloproteinases and (ii) of mutations in mitochondrial DNA.

UVA rays and matrixmetalloproteinases

A wealth of evidence exists indicating that the induction of matrix metalloproteinases (MMP) plays a major role in the pathogenesis of photoaging [1]. While it has been demonstrated that ultraviolet radiation affects the posttranslational modification of dermal matrix proteins such as collagen it has been known for some years that ultraviolet rays also induce a wide variety of an ever increasing family of MMPs. These MMPs can be induced by both UVB and UVA radiation [1]. As indicated by their name MMPs show proteoloytic activity to degrade matrix proteins. Each MMP degrades different components of the dermal matrix proteins such as MMP-1 cleaving collagen type I, II, III and MMP-9, also called gelatinase, degrading collagen type IV, V and gelatin. For UVB radiation-induced MMP activation it has been nicely demonstrated that activation of transcription factors might be responsible and that this activation cascade can be counterregulated through retinoic acid. The precise role of transcription factors in UVA radiation-induced MMP activation is currently not known. Studies in human keratinocytes, however, indicate that UVA radiation-induced gene expression involves transcription factors different from those mediating UVB radiation induced gene regulatory effects. Recent studies have demonstrated that transcription factor AP-2, which is activated by UVA radiation through a mechanism involving the generation of singlet oxygen, appears to be of central importance for UVA radiation-induced gene expression in human keratinocytes [3].

In addition to activation of MMPs, a second pathophysiological pathway leading to photoaging of human skin has recently been identified. This pathway is initiated by alterations at the level of mitochondrial DNA.

UVA rays and mitochondrial DNA mutations

Mitochondria are cell organelles whose main function is to generate energy for the cell. This is achieved by a multistep process called oxidative phosphorylation (OXPHOS). Located at the inner mitochondrial membrane five multi-protein complexes generate an electrochemical gradient which is used in the last step of the process to turn ADP and organophosphate into ATP. In close proximity to this site lies the mitochondrion's own genetic material, the mitochondrial (mt) DNA. The human mtDNA is a 16,559 bp long, circular and double-stranded molecule of which four to ten copies exist per cell. Mutations of mtDNA have been found to play a causative role in degenerative diseases such as Alzheimer's disease, chronic progressive external ophthalmoplegia and Keams-Sayre syndrome. In addition to degenerative diseases it has been found that mutations of mtDNA may play a causative role in the normal aging process with an accumulation of mtDNA mutations accompanied by a decline of mitochondrial function. Also, recent evidence indicates that mtDNA mutations not only play a role in the normal aging process but that they may also be involved in the process of photoaging.

Accordingly, several groups have demonstrated that chronically sun-exposed skin showing clinical signs of photoaging has a higher mutation frequency of the mtDNA than sun protected skin [4]. Recent work has also established a direct link between UVA radiation induced oxidative stress and the generation of the most frequent mtDNA deletion, the so-called common deletion. Accordingly, we have recently developed an in vitro model in which human dermal fibroblasts were repetitively exposed to for three weeks to sublethal doses of UVA radiation in order to generate the common deletion [5]. By employing this in vitro model system for photoaging we have demonstrated that the UVA radiation-induced generation of the common deletion is mediated through the generation of singlet oxygen. Very recently, these in vitro studies have been extended in vivo where repetitive irradiation of normal human skin also lead to the induction of the common deletion. This in vivo model will prove to be extremely useful to assess the capacity of sunscreens and antioxidants to protect human skin against photoaging. The development of these combined in vitro/in vivo models will also help us to further unravel underlying mechanisms involved in UVA radiation-induced photoaging. This task is paramount to design effective therapeutic and protective strategies for a public that is increasingly exposing itself to UVA rays.

References

1. Berneburg M, Plettenberg H, Krutmann J. Photoaging of human skin. Photodermatology, Photoimmunology & Photomedicine 2000 (in press).

2. Stege H, Roza L, Vink A, Grewe M, Ruzicka T, Grether-Beck S and Krutmann J. Enzyme plus light therapy to repair immunosuppressive effects on human skin damaged by ultraviolet B-radiation. Proc Natl Acad Sci USA 2000; 97: 179-5.

3. Grether-Beck S, Oliazola-Horn S, Schmitt H, Grewe M, Jahncke A, Johnson JP, Briviba K, Sies H, Krutmann J. Activation of transcription factor AP-2 mediates ultraviolet A radiation- and singlet oxygen-induced expression of the human intercellular adhesion molecule-1 gene. Proc Natl Acad Sci USA 1996; 93: 14586-91.

4. Berneburg M, Gattermann N, Stege H, Grewe M, Vogelsang K, Ruzicka T, Krutmann J. Chronically ultraviolet-exposed human skin shows a higher mutation frequency of mitochondrial DNA as compared to unexposed skin and the hematopoietic system. Photochem Photobiol 1997; 66: 271-5.

5. Berneburg M, Grether-Beck S, Kurten V, Ruzicka T, Briviba K, Sies H, Krutmann J. Singlet oxygen mediates the UVA-induced generation of the photoaging-associated mitochondrial common deletion. J Biol Chem 1999; 274: 15345-9.