proteins in the cells and ECM. These proteins are modified by various post-translational mechanisms common with age such as oxidation, glycation, and conjugation with products from lipid
peroxidation. In young healthy skin, the proteolytic systems can effectively prevent the accumulation of damaged proteins both intracellularly and within the ECM.
Cross linkages between collagen and elastin provide essential stabilization to these important proteins when organized enzymatically,
while non-enzymatic spontaneous cross linkages can prove extremely detrimental to function and form of these proteins. The collagen matrix is very susceptible to modifications
that occur with aging due to the nature of the normal slow process of collagen turnover and low levels of MMPs, which slow collagen turnover and remodelling. These cross-linkages prevent the complete removal of collagen fragments, disrupting
repair or incorporation into newly made collagen fibrils. The result is the formation of voids in the three dimensional collagen
matrix and continuation of the ECM disruption.4
Oxidative Stress
Oxygen free radicals, the chemically reactive forms of molecular
oxygen (reactive oxygen species-ROS), have long been considered the primary cause of skin aging. The theory is that ROS, generated during aerobic energy metabolism within mitochondria,
oxidize cellular constituents and impair cellular function.4 Previous reports have established the link between ECM collagen fragmentation and oxidative stress.5 In support of this concept, it has been demonstrated that when fibroblasts are removed from this fragmented collagen ECM milieu, they significantly improve their capacity to produce new collagen.4 This provides a foundation for therapeutic intervention. One of the consequences of fragmented collagen is a decrease of focal adhesion points between the fibroblast and the collagen fiber. This results in less stretch on the fibroblast and change in form and function of the fibroblast from a spindle shaped active fibroblast to a rounded shaped senescent fibroblast that produces less collagen and elastin.5 The “loss of cell shape and mechanical tension is closely associated with increased transcription
factor AP-1,†which stimulates MMP production and decreases type 1 collagen expression.6
Neutrophil elastase, secreted by stress induced neutrophils, has also been implicated in elastin degradation and photodamage.
7 Exposure of human skin to a certain threshold of UV radiation and heat leads to an influx of proteolytic enzyme packed neutrophils. In fact, some authors have hypothesized that neutrophils are major contributors to the photoaging process, which they claim is primarily represented by elastic fiber degeneration.7 The most obvious changes seen histologically
in photodamaged skin relate to elastosis and elastic fiber network rather than that related to collagen. Unlike collagen degradation, sun damage does not lead to a loss of elastic
fibers but rather a loss of functional elastin primarily related to microfibrillar destruction.3,8 In humans, neutrophil-derived proteolytic enzymes are responsible for the ECM damage observed
in lung emphysema, rheumatoid arthritis, and wound infection. Similarly neutrophilderived proteolytic enzymes may be contributors to the ECM damage seen in photoaged skin.7
Fisher et al. have proposed that the combination of collagen fragmentation, oxidative stress, and MMP-1 up-regulation forms a self-perpetuating cycle representing human skin aging. This extends the oxidative theory of aging beyond the focus on cellular aging to include changes to the ECM.5
Reduced Proteasome Function
Aside from ECM degradation related to oxidative stress and neutrophil infiltration, aging, and photodamage can result in the accumulation of unfolded, misfolded, or aggregated proteins
from the process of reduced proteasome function.9 The ubiquitin protease system (UPS) plays a fundamental role in a large number of biological processes predominantly involving
the removal of intracellular protein degradation products. Any reduction in the function of the UPS pathway can result in intra- and extracellular accumulation of damaged proteins.9 Efficient removal of these protein fragments has significant impact on cellular mechanisms such as DNA repair, gene expression, neosynthesis of protein, and immune response modulation.10
Advanced Glycation End Products
Some modified proteins, specifically advanced glycation end products (AGEs) that accumulate on collagen and elastin in the skin, are the result of reactive sugars in the blood and lymph binding to the proteins in extensive cross linkages, especially during the process of aging and after UV irradiation.1 Glycation
does not occur to a major effect in the dermis before age 35 but once it begins, along with intrinsic aging, it progresses rapidly.11 Proteins are not the only targets, lipids such as phosphatidylethanolamine
and phosphatidylserine offer the amino groups required for initial linking of a sugar.11
Thus, skin aging and photodamage contribute to a series
of biological processes that result in ECM and cellular degradation with an accumulation of abnormal proteins, amorphous elastotic material, and a non-compliant stiffened
