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Page 4 of 6 Sparavigna. Plast Aesthet Res 2020;7:14 I http://dx.doi.org/10.20517/2347-9264.2019.73

a matter of intense study, not only for the identification of all component proteins but also, for defining
[16]
the molecular mechanisms regulated by the ECM . To date, about 300 matrisome proteins have been
identified including: 43 types of collagen subunits in fibrillar and non-fibrillar form (the most common
is type 1 representing 80%-90%); 36 types of proteoglycans dispersed amongst collagen fibers to take
up the interstitial space and maintain hydration; growth factors linked to glycosaminoglycans that are
retained in the extracellular space to increase functionality; about 200 soluble proteins, which not only
promote assembly of the ECM but are also involved in cell-ECM interactions, and act as ligands with
[17]
receptors (integrins); and enzymes such as lysil-oxidase, transglutaminase and hydroxylase . To simplify,
the matrisome is composed of 3 main molecular groups: structural proteins, adhesion proteins and
proteoglycans. Among structural proteins, collagen is most abundant. Its peculiar amino acid sequence
[18]
provides essential functions . Aging reduces collagen synthesis and alters its structure (collagen fibers
become fragmented and stiff). Amino acids are fundamental to the structure and thus, function of collagen
- for example, the interaction of specific amino acids with potassium ions favors non-covalent binding
and binding to proteoglycans. There is less elastin overall but it is still essential for maintaining the elastic
properties of skin. Elastin fibers stretch under traction but with mechanical stress, can be restored to their
original conformation. This process is due to the presence of hydrophobic amino acids such as valine and
alanine, both of which are exposed to the hydrophilic components of ECM during mechanical stress. When
the mechanical force is removed, elastin folds back on itself and its fibers become shortened. It goes without
[19]
saying that the optimal functionality of elastin would also be dependent on adequate tissue hydration .
Therefore, the aging process would undoubtedly influence the ECM and matrisome as a whole. All 300
matrisome proteins are affected and their turnover is related to their individual half-lives. To illustrate,
the half-life of collagen is about 3 years and that of elastin is 70, which means that post-translational
modifications like glycation have an essential role in skin elasticity and structure. The increase in MMPs is
also part of aging and correspondingly, structural proteins such as collagen and elastin lose function and
contribute towards a loss of skin tone. The imbalance of peptide content has to be taken into account as
well, in terms of cellular cross-talk alterations.

TREATMENT OF ECM ALTERATION IN SKIN AGING
Given the above discussion, the most advanced antiaging treatments would therefore be those that are able
to rebuild the ECM, which is responsible for both physical support and the exchange of nutrients, cellular
mediators, and growth factors [20,21] . The most effective treatment would target cell metabolism, autophagy,
cell renewal and the production of new ECM. Such results can theoretically be obtained by providing the
right metabolic and structural support to cells (i.e., hyaluronic acid, specific amino-acids and peptides,
antioxidants) as well as mechanical stimulation which would, in turn, stimulate mechano-transduction
(that is the conversion of mechanical forces into biochemical signals) through the creation of a scaffold in
reduced volumes to enable stimulation of interstitial fluid circulation.

Low and/or high molecular weight, natural (not cross-linked) hyaluronic acid have been reported to
be capable of hydrating the ECM, thereby stimulating cellular activity when administered as injectable
formulas. Low molecular weight hyaluronic acid has the ability to stimulate cells thereby preventing aging,
increasing skin brightness, hydration, tone, reducing wrinkles and restoring volume. On the other hand,
high molecular weight forms exert powerful antioxidant activity by neutralizing free radicals and becoming
a scaffold for the skin. Hyaluronic acid however, must be continuously produced as they have particularly
short half-lives and are degraded by specific enzymes, hyaluronidases. To increase the consistency
and longevity of injected hyaluronic acid in the dermis, it is necessary to render it less susceptible to
hyaluronidases by chemical modification with cross-linking agents to bridge its filaments. The such
chemically-modified hyaluronic acid has a greater filling effect but its biological properties are drastically
reduced in favor of the filling capacity (filler) making fillers a different issue (they consist of cross-linked