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Hyaluronic acid: Skin matrix health is not just about proteins

The skin matrix is what would remain if you took the dermis (the fibrous middle layer of the skin) and removed all cells from it. The skin matrix is responsible for structural integrity, mechanical resilience, stability and many other properties of the skin. The degradation of the skin matrix plays an important role in the development of wrinkles and other signs of skin aging. The best known components of the skin matrix are structural proteins (notably collagen and elastin), which are vital to skin health and youthfulness. However, just like steal beams and rebar are necessary but insufficient for building a skyscraper, structural proteins are necessary but insufficient for a healthy skin matrix. In addition to the framework of structural proteins, the skin matrix also needs appropriate fillers, which provide mechanical cushioning, hold moisture, enhance barrier function, and so forth. The principal skin matrix fillers are glycans, a class of glucose-based polymers that includes glycosoaminoglycans and proteoglycans. As far as skin rejuvenation is concerned, the most important glycan may be hyaluronic acid (a.k.a. hyaluronan, hyaluronate or HA).

Chemistry of hyaluronic acid

Hyaluronic acid is a polymer whose unit consits of D-Glucuronic acid and N-Acetyl Glucosamine. Hyaluronic acid chains can be up to 25,000 units long or even longer; their molecular weight ranging from about 5,000 to 20,000,000 Da.

Hyaluronic acid is synthesized by the enzymes called hyaluronan synthases. Humans have at least three types of hyaluronic acid synthases: HAS1, HAS2, and HAS3. HAS1 and HAS2 synthases produce high molecular weight HA whereas HAS3 produces low molecular weight HA. Hyaluronic acid is degraded by the enzymes called hyaluronidases, of which there also appear to be several types.

Hyaluronic acid and skin physiology

Hyaluronic acid has many functions throughout the body, especially in the connective tissue. In the skin, some of its known roles are the following:

  • Holding moisture
  • Increasing viscosity and reducing permeability of extracellular fluid
  • Contributing to mechanical resilience and suppleness of the skin
  • Regulation of tissues repair
  • Regulation of movement and proliferation of cells
  • Regulation of immune and inflammatory responses

It is important to note that physiological effects of hyaluronic acid depend to a large degree on the size (molecular weight) of its chains. In particular, relatively small HA molecules (weighing less than about 20,000 Da) appear to trigger the early phases of wound healing, including activation of various types of immune cells and inflammatory responses. This is understandable. Considering that tissue injury would typically result in increased degradation of extracellular matrix (and HA in particular), it makes sense that the degradation fragments (i.e. small size HA fragments) would act as indicators of injury and trigger wound healing. On the other hand, large HA molecules appear to suppress local immune response and inflammation. By the similar logic, the predominance of large HA molecules sends a signal that the skin is intact and defense and/or repair are not required.

Hyaluronic acid and aging

The skin content of hyaluronic acid decreases with age (after peaking in adolescence or early adulthood). This contributes to the loss of moisture; the skin becomes thinner and less supple. The loss of HA may also impair the skin's ability to repair itself and possibly affects the synthesis and deposition pattern of other skin matrix components.

Can you boost hyaluronic acid in your skin?

Reversing the age-related decline in the skin content of hyaluronic acid is an increasingly visible topic in skin care. It would complement other steps to preserve the health of the skin matrix (such as replenishing collagen and elastin). Unfortunately, as of the time of this writing, there is no simple, inexpensive and broadly effective way to preserve/restore HA levels in the skin. Below, we discuss what options are currently available or hold promise for the future.

Topical hyaluronic acid

Topical hyaluronic acid in the form of gels, serums and so forth is widely available but its usefulness is limited.

HA can provide effective skin surface moisturizing, either alone or in combination with other moisturizing ingredients. However, there is a controversy whether concentrated HA formulas should be used as a moisturizer in dry climate. When air humidity is very low, HA may preferentially pull water from the skin rather than from the air, thus producing the opposite effect. The optimal use of HA as a moisturizer needs further research.

But can topical HA go beyond moisturizing? Can it penetrate into the dermis and help rebuild the skin matrix? Generally, large molecules do not penetrate the skin or do so in very small amounts. Most likely, medium-to-large size HA molecules (perhaps with molecular weight above 20,000 Da) won't penetrate sufficiently to have an impact on the skin matrix. However, small size HA (5,000 - 20,000 Da) may penetrate into the dermis in significant amounts. However, this may not necessarily be a good thing. Assuming small size HA molecules penetrate into the dermis, they are likely to trigger some elements of the wound healing response (as we discussed above), such as immune activation, inflammation, cell division, blood vessel growth, new skin matrix synthesis and so forth. The net effect might be either matrix degradation and accelerated skin aging or matrix remodeling and improved skin texture. Studies are required to answer this question.

Hyaluronic acid-based fillers

Considering that medium and large hyaluronic acid molecules cannot penetrate the skin in significant amounts, one alternative is to deliver HA via injection. This approach may improve localized imperfections (e.g. wrinkles, furrows, depressed scars) but cannot revitalize the skin overall. For details, see our article on HA-based fillers.

Stimulating synthesis of hyaluronic acid

One way to increase the skin content of HA would be to stimulate its synthesis in the skin. Unfortunately, there is little data on practically useful ways to do it. One approach to explore would be to provide the body with more building blocks for hyaluronic acid, such as glucosamine and N-acetyl-glucosamine. Research is needed to determine whether oral or topical administration of the HA building blocks increases its synthesis in the skin - particularly the synthesis of medium-to-large size molecules. (This approach has been shown to work for cartilage but each tissue is different.) Another approach is to find agents that stimulate the activity of hyaluronan synthases, the enzymes producing HA. Presumably, the ideal agent should preferentially activate HAS1 and HAS2, the enzymes producing high molecular weight HA. Unfortunately, no such agent suitable for practical use appears to be available as of the time of this writing.

Inhibiting the degradation of hyaluronic acid

If stimulating HA synthesis is problematic or insufficient, an alternative could be to inhibit its degradation. Plugging the drain instead of pouring more, so to speak. One way to do it would be to inhibit the HA-degrading enzyme hyaluronidase. Unfortunately, practically useful hyaluronidase inhibitors appear as hard to come by as hyaluronan synthase activators. There are a few leads, however. One candidate is escin, a saponin extracted from horse chestnut. In a few clinical trials, it was shown to strengthen veins and improve venous insufficiency, presumably via inhibiting hyaluronidase and elastase in vein walls. It may (or may not) be able to inhibit these matrix-degrading enzymes in the skin. The other candidate, surprisingly, is a variant of a well-known skin care ingredient ascorbyl palmitate. Ascorbyl palmitate is often considered inferior (as a skincare ingredient) to other common vitamin C derivatives because it is a poor activator of collagen synthesis. A variant (isomer) of ascorbyl palmitate called L-Ascorbic Acid 6-Hexadecanoate was shown to inhibit hyaluronidase in some species, including mammals. Whether this effect can be reproduced in the human skin remains to be seen. If it is, the skin care reputation of ascorbyl palmitate may get a boost.


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