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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 17 of 24

The hydrolysed collagen has 2 distinct, but complimentary, functions. Firstly, the amino acids from
hydrolysis of collagen in the GI tract are the building blocks used by the fibroblast cell to make more
collagen. As collagen is uniquely rich in glycine, proline (and hydroxyproline, which is derived by post-
translational modification during collagen synthesis), this represents an enriched supply of the specific
amino acids required to make new collagen fibrils. Secondly, unique oligopeptide sequences, especially
dipeptides containing hydroxyproline, are known to stimulate fibroblasts via receptor-mediated activation
[95]
pathways to induce new collagen fibre synthesis . Although present at lower levels than amino acids,
the peptides can stimulate fibroblast receptors and are thus biologically potent even at lower absolute
concentrations.

The biological potency and clinical efficacy of hydrolysed collagen can be linked to both its unique amino
acid profile and specific oligopeptide sequences, which underlines the key characteristics contributing to
the major success of hydrolysed collagen as a supplement for health benefits in the body. Other proteins,
for example from casein, peanuts or tofu, have a different amino acid composition and are lower in relative
contribution of specific amino acids required for ribosomal synthesis of protein (which uses the enzyme,
aminoacyl tRNA synthase, to attach the appropriate amino acid via an ester bond). The appropriate tRNA
complex is used to synthesise the protein on the ribosomes of the endoplasmic reticulum of the cell [96,97] .
As collagen is the most abundant ECM protein the tRNA species need to be enriched with the appropriate
proteinogenic precursors for collagen synthesis. However, this situation is complicated by the fact that
amino acids such as glutamine, glutamate and aspartate are highly metabolized in the gut and do not
[98]
appear in appreciable amounts in the bloodstream. A comprehensive review by Albaugh et al. explores
the research whereby supplementation with specific amino acids such as proline was carried out in order to
stimulate collagen synthesis, but proof of superior efficacy to hydrolysed collagen requires further studies.

During digestion many di- and tri-peptides are produced in situ. In principle, from 18 proteinogenic amino
acids it is possible to derive 324 dipeptides or 5,832 tripeptides. Even if we account for an enrichment
of glycine, proline and hydroxyproline species, the number of peptides which can potentially stimulate
fibroblasts to synthesis new collagens is too large to test in vivo. Research has shown that significant
amounts of the di- and tri-peptide species, Pro-Hyp, Ala-Hyp, Ala-Hyp-Gly, Pro-Hyp-Gly, Leu-Hyp,
Ile-Hyp and Phe-Hyp were measurable in human blood following oral ingestion of different collagen
hydrolysates [95-100] . Some of these di- or tri-peptides have been shown to stimulate fibroblasts in vitro [101,102] .
However, superior efficacy of individual or synthetic peptides over the complex mix of oligopeptides
generated by digestion of collagen has not been shown to date. Until such proof is provided, it is a better
option to continue to use hydrolysed collagen, as processed through the digestive system, as a source of
fibroblast-stimulating peptides. Likewise, topical products using collagen peptides cannot provide this wide
spectrum of bioactive peptides, in addition to the problems of transcutaneous absorption of oligopeptides
across the stratum corneum being limited.

The expression “Beauty Vitamins” has been applied to several vitamins, but the importance of Vitamin C to
skin is unique in that ascorbic acid can act as a co-factor to several enzymes in the production of collagen,
in addition to its role as an antioxidant in protecting against free radical damage. The importance of vitamin
C in the production of functional collagen fibres has been shown to be dependent on its use as a cofactor
in hydroxylation of proline residues in procollagen (which stabilises the triple helix structure) and lysine
residues (which are used to cross-link fibres imparting structural rigidity and stability). Hydroxylation
is catalysed by Fe(II)-dependent dioxygenases in the case of prolyl and lysyl hydroxylases [103] . Collagen
prolyl-4-hydroxylase enzymes (C-P4H) catalyse the formation of 4-hydroxyproline (4-Hyp) on collagens
2+
by modifying proline residues in the Y position (of the X-Y-Gly sequence), in a process that requires Fe ,
molecular oxygen and ascorbic acid [104] . This modification takes place in the endoplasmic reticulum before
collagen triple helix formation. The content of 4-Hyp is a key determinant of the stability of the collagen
triple helix, without which conditions such as scurvy can become manifest.