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Page 12 of 24 Reilly et al. Plast Aesthet Res 2021;8:2 I http://dx.doi.org/10.20517/2347-9264.2020.153

OXIDATIVE DAMAGE AND REPAIR OF COLLAGEN
In the ageing process the long-term effects of oxidative damage to cells and tissues is a key mechanism
which can be targeted by intervention strategies so that we can attempt to slow the damaging effects of
ageing. In this context a disturbance in the balance between the production of reactive oxygen species (ROS)
and our cellular protection via antioxidant defences is defined as oxidative stress [11,70] . ROS are a specific
subset of free radical species that act by driving several molecular pathways that play important roles in
pathologic conditions such as cancer, heart diseases and diabetes. Sun damage (in particular UVA-radiation
mechanisms which regulate ROS production) can cause both skin cancer and photo-ageing, affecting the
[71]
skin through wrinkling, scaling, dryness and mottled hyperpigmentation . The ROS can cause damage
to intracellular constituents such as DNA, lipids and proteins. However, the skin possesses defence
mechanisms which interact with toxicants and counteract their damaging effect (including both non-
enzymatic and enzymatic molecules that function as potent antioxidants). These defences, although highly
effective, have limited capacity and can be overwhelmed, especially during ageing, leading to increased
ROS levels and to the associated increased risk of dermatological diseases.

Free radical species are defined by the presence of unpaired electrons in the outer shells of the atom, or
[72]
constituent atoms of molecules . This unstable configuration will seek to find an electron, either to take
(in the case of ionic bonds) or to share (in the case of covalent bonds). The high energy free radicals can
do a lot of damage to cellular structural components (such as lipid bilayer membranes) or subcellular
components (such as proteins, lipids or DNA) that they encounter. These high energy species react
rapidly with neighbouring molecular species, and thus have a very short half-life and a low steady state
concentration in situ. Free radical Initiation occurs when a high energy event, such as when a UVB or UVA
[73]
photon strikes a target atom, stripping an electron from an outer shell . Initiation may also occur as a
consequence of oxidative metabolism and mitochondrial respiration in the cell. When a free radical reacts
with another molecule it in turn generates another free radical, in what is referred to as the Propagation
stage. This causes a chain reaction which is inherently dangerous to any biological system. The final stage is
referred to as Termination, which ends the chain reaction.

The consequence and impact of ROS depends on the ability of the cell to limit the free radical attack
and repair the damage. In the case of DNA, specific enzymes such as NAD-dependent Poly ADP
Ribose Polymerase (PARP), can repair the damage to DNA, preventing coding errors or mutations in
[74]
the genetic code . Lipid turnover is typically high and ensures replacement of lipid peroxides. Protein
damage however can be difficult to repair, especially if the turnover rate of the protein is low. However,
it is important to note that damage to the collagen protein is likely via an indirect mechanism. The
main biological target of free radical damage in the case of proteins is that of sulphydryl-containing
species, including the tripeptide glutathione, which has a high sulphydryl content due to the presence
of cysteine [75,76] . Glutathione can be recycled using NADPH (the reduced form of nicotinamide adenine
dinucleotide phosphate) as a cofactor, thus making it a highly effective free radical scavenger. However,
the ensuing oxidative depletion of glutathione and consequent inflammation cascade leads to increased
[77]
transcription, translation and expression of MMP enzymes which can affect integrity of the ECM . As
explained earlier in this review, the matrix metalloproteinase family of enzymes (especially MMP-1 and
MMP-3) can degrade collagen fibres leading to a loss of functional ECM.

One approach to prevent or treat these ROS-mediated disorders is based on the administration of different
antioxidants in an effort to restore homeostasis. Free radical scavengers from dietary and supplemental
sources include water soluble ingredients such as Vitamin C (l-ascorbic acid), lipid soluble ingredients
such as Vitamin E (d-α-tocopherol), and a vast array of antioxidant species sourced from botanicals,
including flavonoids, carotenoids and numerous plant extracts. The antioxidant species protect the cell by
neutralizing the free radicals, but in the process themselves become free radical species. However, it is more