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Reilly et al. Plast Aesthet Res 2021;8:2 I http://dx.doi.org/10.20517/2347-9264.2020.153 Page 7 of 24

Type I collagen content is approximately 70%-75%, compared to type III collagen which is approximately
18%-21%, of the total of collagen content at all gestational ages. This level of Type I collagen is lower than
measured in adult skin (~ 85%-90%), whereas the Type III is higher than that observed in adult skin (~
8%-11%). It is believed that this difference reflects the higher requirements of collagen production to
support the developing vasculature and innervation of the foetus. The activities of the enzymes required to
synthesise collagen fibres have been reported to vary with age, e.g., the enzyme activities of hydroxylases
and glucosyltransferase were expressed maximally in foetal skin, retaining a higher level of activity in the
[35]
skin of young children compared to adults .

During childhood, through prepubertal growth stages and pubertal changes caused by the production of
sex hormones in adolescents, there is rapid and extensive collagen turnover. The majority of publications
on collagen production in prepubertal and pubertal adolescents is concerned with Type I collagen used
as the organic support matrix which is mineralized for the development of bone. Collagen is constantly
being synthesised, laid down in the ECM, only to be degraded by enzymes, in particular the MMPs, in
a balanced cycle which allows growth. This turnover of collagen is rapid during development and then
quiescent during adult years but increases again in later life to compensate for cumulative deleterious
damage associated with chrono-ageing and photo-ageing [36,37] . Thus, collagen synthesis and degradation are
precisely controlled and biochemically complex processes, which is pivotal to tissue development, tissue
repair following damage and tissue maintenance in varied anatomical and physiological systems.

Skin ageing results from a series of divergent processes which affect many constituents of the skin and
hence its appearance. There are two primary skin ageing mechanisms, referred to as intrinsic and extrinsic.
These intrinsic processes are controlled predominantly by genetic and hormonal variations, whereas
extrinsic components include smoking, alcohol consumption, chronic sun exposure, stress, and several

other factors. Extrinsically aged skin is characterised by several clinical manifestations including the
presence of fine lines and increased wrinkle formation, reduced recoil capacity, increased fragility of the
skin and altered melanogenesis and skin pigmentation.

[38]
The proportion of the collagen types in skin change with age . Young skin is composed of 80% type I
[39]
collagen and about 15% collagen type III . With age, the ability to replenish collagen naturally decreases
by about 1.0%-1.5% per year. This decrease in collagen is one of the characteristic hallmarks associated with
the appearance of fine lines and deeper wrinkles [Figure 5]. Moreover, deep inside in the dermis, fibrillar
collagens, elastin fibres and hyaluronic acid, which are the major components of the extracellular matrix,
undergo distinct structural and functional changes.

Collagen and elastin are stable proteins with a half-life measured in years (t for skin collagen is
1/2
[40]
approximately 15 years) and hence are predisposed to long term cellular stress . In considering the
collagen bundle it is obvious that the bulk of the collagen protein is inaccessible due to the close packing
of individual fibrils. Even in the outer sheath the proteins are chemically cross-linked to the fibres inside
the bundle and are thus not readily cleaved by proteases. This highlights the importance of MMP enzymes
which can cleave the collagen triple helix and make the fibre accessible to degradation enzymes and cellular
[41]
recycling .
In the family of MMPs, it is the collagenases that are required to carry out the first degradation step, in
which the fibres are cleaved into characteristic ¼ and ¾ fragments [Figure 6]. According to the Lauer-
Fields model, cleavage occurs at the border of a tight triple helix region (high in imino acid content) and a
loose triple helix region (low in imino acid content), where the enzyme can unwind the triple helix strands
and initiate hydrolysis of the individual strands . Following this first step, other proteinases continue the
[42]
degradation of the collagen fibres, including gelatinase (MMP-2), serine proteinases, cysteine proteinases,
and aspartic proteinases.