Autophagy aids dermocosmetic evaluation

As will be discussed here, all of these mechanisms are now known to reflect the underlying decline in macroautophagy, a fundamental degradative pathway which is responsible for removal of damaged proteins and dysfunctional organelles. Stem cells are essential for replenishing the various cell types of human skin. Macroautophagy at a high level is characteristic of stem cells and is necessary for them to retain their ‘stemness’ since declining macroautophagy leads to gradual end-differentiation. Recently, it has become clear that macroautophagy declines spontaneously in skin during ageing. The effects of substances which reverse the decline in autophagy, with a corresponding delay in the loss of stem cells and ageing in skin, can now be studied using simplified in vitro models for skin. 

hat cells produce reactive oxygen species (ROS) such as oxygen free radicals (O-) which contain an extra electron. These are produced normally as a very minor byproduct of energy production in the mitochondrial electron transport chain.1 ROS attack cellular proteins and nucleic acids, especially locally in the mitochondria, where they gradually degrade protein function and elicit mutations in mitochondrial DNA, over time leading to destruction of these energy powerhouses of the cell.1 Unfortunately, debilitated mitochondria produce ever increasing levels of ROS as their electron transport chain degrades.  Furthermore, especially cells of the skin are doubly threatened by injury because they are additionally exposed to UV from sunlight and the action of various environmental agents which also act to produce ROS. 

The most important mechanisms of skin ageing are stem cell exhaustion, genomic instability, mitochondrial dysfunction with oxidative stress and senescence. The main underlying cause of all these debilities lies in the damage to mitochondria.1 Of course, irreversibly damaged cells can kill themselves with apoptosis and be replaced with new cells, but such selfrenewal depends on having pools of stem cells. Stem cells are slowly dividing cells which in each round of division always produce two kinds of progeny, one new stem cell and one differentiationcompetent, highly proliferative daughter cell which can be used to replace damaged cells.2 Particularly in the epidermis, the proliferative daughter cell is important in the hierarchical pathway. They are progenitor cells for the epidermis, also called ‘Transient Amplifying Cells’. As shown in Figure 1, these divide again and again, making progeny that can amplify for several generations, thus providing the mass of cells which finally, when end-differentiated, provide the barrier function of skin.  Note that autophagic activity and proliferative activity normally decline gradually over the many generations, while differentiation increases. However, though much less active in cell division, the maintenance of stem cells is crucial2 since they are needed over the whole lifespan of the organism for replenishing the various cell types in skin. They are few, located in specialised niches in the basal layer of the inter-follicular epidermis, in the ‘bulge’ of the hair follicles, as well as in dermal adipose tissue (adipose mesenchymal stem cells), and they are exposed to the same risks, UV light and toxic environmental agents, as are all cells, especially in the skin. Fortunately, self-renewal has another dimension – selfrepair. Cells have repair systems that can correct many mutations in nuclear DNA while oxidised, damaged proteins and lipids can be just replaced with new synthesis. However, if an individual damaged organelle such as a mitochondrion continues to spew out ROS, exacerbating the damage, it has to be eliminated. This represents no major problem for energy metabolism because cells have hundreds to many thousands of mitochondria and, at any one time, only a few will have suffered damage. And, to carry out this elimination, the cell can trigger an evolutionally ancient pathway called macroautophagy.