Viewpoint 5
2008-02-02

Cancer and ageing, two processes, originally seen as completely independent, now show more and more common mechanisms, a development that is also true for skin cancer induced by ultraviolet (UV)-radiation (photocarcinogenesis) and premature ageing of the skin by UV (photoageing). In fact, it has been the normal human fibroblast, a cell particularly important for photoageing, which allowed the central observation in this context. In 1961 Leonard Hayflick described that normal human fibroblasts in culture showed exponential growth until they ultimately entered a state of irreversible growth arrest. Now called the Hayflick phenomenon (1), over the following years intensive research in either the field of carcinogenesis or ageing unravelled a number of underlying mechanisms that play a role in this process [Summarised in (2) and 3)]. So called ‘Hayflick factors’ such as derepression of the INK4a/ARF locus, attrition of telomeric chromosome ends and DNA damage to the genome (4) are now known to be involved in a process called senescence, which occurs in tissue culture as well as during the normal ageing process of replicating cells and which prevents benign but damaged cells with remaining proliferative potential from transformation into malignant cancer cells. While it is clear that malignant transformation ultimately leading to cancer is definitely unwanted, the situation is less clear with senescence. As a process protecting from cancer, senescence is important and beneficial. With regards to longevity, however, senescence appears more like a necessary burden to avoid far greater dangers. With this respect, it would be desirable to benefit from senescence associated growth control but have it occur at a slower rate in order to age more slowly. But how is this best achieved? A possible way may be opened by a process linking the two processes cancer and ageing, cellular metabolism. Already before the Hayflick phenomenon has been described in 1961, it has been proposed by Denham Harman in 1956 that highly reactive oxygen species (ROS) are the key mediators of the ageing process (5), a hypothesis that has been confirmed by a large body of research. Even earlier than that, in 1930, Otto Warburg described changes in the energy metabolism of tumors (6), where oxidative phosphorylation by the respiratory chain was decreased in favour of glycolysis. Interestingly, evidence increases supporting the notion that these processes are connected with each other, thus also linking ageing and cancer. But how are these processes connected and what is the relevance for photoageing of the skin? The answer to this question may be oxidative stress. The role of ROS in ageing is well accepted. The highest turnover of ROS occurs in the mitochondria (7) and it is estimated that 1–4% of the O2 uptake into the cell is turned into ROS (8). As a result of elegant mouse studies, the impact of mitochondria and mutations of the mitochondrial genome on ageing is now generally accepted (9, 10). The same is true for UV-induced skin ageing where several groups could demonstrate the involvement of ROS-induced mitochondrial DNA mutations in the pathogenesis of photoageing (11-19). In line with the notion that ageing and cancer are closely intertwined, mitochondrial DNA mutations have not only been implicated in ageing but also in different tumor entities including skin cancer (20-27). The fact that mitochondria are the locus with the highest ROS production in the cell and the fact that mitochondria are also the locus of energy production through the respiratory chain, strengthen the link between energy metabolism and ageing in general and UV-induced skin ageing in particular. With regards to cancer, it has been generally assumed that respiration is decreased in tumors, while glycolysis is increased because tumors grow under conditions of hypoxia and energetic restraints. However, it has been shown that the Warburg effect is also active under normoxia and when ample energy precursors are present (28). Therefore, increasing the less effective energy production via glycolysis may be a protective measure of tumor cells from oxidative stress (28). Interestingly, evidence also indicates that this Warburg associated reduction of the respiratory chain may also be a way the cancer cells employ to evade ROS-induced senescence (28). Although, of course, evasion of senescence is not an option in the attempt to reduce photoageing. Yet, increasing the efficacy of the respiratory chain with the aim to reduce endogenous ROS production may well be. Since photoageing is mainly induced by chronic oxidative stress with the known consequences of matrixmetalloproteinase-1-induction and collagen degradation, improvement of the respiratory chain efficacy may reduce endogenous ROS production to a level which can be quenched by cellular ROS-detoxifying systems (Fig. 1). Oxidative stress and the Warburg effect. Reactive oxygen species (ROS) play a role in cancer, normal and UV-induced skin ageing. The induction of mitochondrial DNA mutations with subsequent impairment of mitochondrial function has been reported previously (9, 19). In addition, oxidative stress can have two different effects: (i) Induction of ROS can lead to senescence associated growth control directly through activation of checkpoint genes and (ii) decreased respiration and increased glycolysis, associated with the Warburg effect can also be mediated by ROS. This appears to be a new escape mechanism of tumor cells to evade senescence. Improving the efficacy of the respiratory chain may be a possible way to postpone, not prevent, ROS-mediated senescence without the risk of malignant transformation. This strategy may open new possibilities in prevention or delay of UV-induced skin ageing. The creatine kinase system may be a promising target to improve the cell’s energy metabolism in this way. In fact, the involvement of this system in UV-damaged skin cells has been reported previously (29). Furthermore, co-incubation of UV-irradiated normal fibroblasts with the energy precursor creatine, did indeed normalise mitochondrial function, paralleled by reduction of photoageing-associated mitochondrial DNA mutations (17). Thus, initial reports exist, indicating that improvement of the energy metabolism may also improve UV-induced skin ageing. However, whether senescence-associated growth control or the Warburg effect is also affected by these strategies has to be shown by future studies. Furthermore, to merely offer of energy precursors may be too simplistic an approach. Possibly, other compounds will improve cellular energy metabolism on levels previously unrecognised in the field of photoageing. With processes such as derepression of the INK4a/ARF locus, DNA repair or the Warburg effect and all their known modulators, some interesting developments in this field should be possible.