Hyaluronic acid, anti-ageing and cellulite | Part I

• What is hyaluronic acid, what does it do, how can it help me look younger - and does it make me put on weight?

• Skin hydration, anti-ageing, wound healing, water retention, cellulite

• Introducing hyaluronic acid

• Hyaluronic acid: what is it exactly?

• The different sizes (molecular weights) of hyaluronic acids

• Hyaluronic acid molecular weights in the context of the human body - how big are they?

• Hyaluronic acid and silicon

• Appearance and biological effects

• Size does matter but larger is not necessarily better: hyaluronic acid and cellulite / water retention

• Neither too small, nor too big

• Diet, lifestyle and HA

• Hyaluronic acid synthesis decreases with age

• Cosmetic hyaluronic acid skin absorption

• Which molecular weights of hyaluronic acid penetrate the skin better?

• My professional experience with different molecular weights of hyaluronic acid

• What hyaluronic acid is used in filler injections?

• Hyaluronic acid in serums, gels and creams

• Beware of those £230 hyaluronic acid serums - in reality they are not worth more than £20 - max

• Hyaluronic acid-boosting actives in serums, gels and creams

• Hyaluronic acid-protecting actives in serums, gels and creams

• Where does HA in cosmetics come from?

• Hyaluronic acid, hyaluronidase and cellulite

• Other uses of hyaluronic acid: eye drops, intimate gels, shaving gels, hair products

• Is hyaluronic acid safe?

• Do hyaluronic acid supplements help with skin hydration and anti-ageing?

• Does hyaluronic acid cause weight gain?

• Does hyaluronic acid make you retain water?

• In summary

• Human skin penetration of hyaluronic acid of different molecular weights as probed by Raman spectroscopy

• Have a skin tightening/cellulite treatment in London with the experts

• Check our professional consultancy in cellulite, skin tightening, ultrasound and radiofrequency

For more fascinating information on the "molecule of youth" also check the second part of our detailed and extensive article.

What is hyaluronic acid, what does it do, how can it help me look younger - and does it make me put on weight?

I have been formulating hyaluronic acid (HA) skin products since 2003 and I have seen HA starting to gain wider popularity from 2010 onwards.

In the last 5-10 years hyaluronic acid has become the most well-known cosmetic active ingredient. All the new skincare products must have it. Everyone claims to be using the best type of hyaluronic acid in their products.

But what is hyaluronic acid, what does it do, how does it work and what is really the best type of hyaluronic acid?

Here is all the detailed information you need to know about hyaluronic acid.

Skin hydration, anti-ageing, wound healing, water retention, cellulite

Hyaluronic acid (also known as hyaluronate or hyaluronan) is the most important moisturising molecule in the human body, an essential component of skin and connective tissue, and an invaluable anti-ageing and connective tissue restructuring active ingredient.

For all these reasons hyaluronate is ideal for use in skin hydration, anti-ageing, wound healing, anti-water retention and anti-cellulite creams, gels and serums.

Hyaluronic acid comes in various sizes (molecular weights), with the higher sizes forming a film on the skin and the smaller ones penetrating in the deeper dermal layers.

Low molecular weight (LMW) hyaluronic acid comprises small size hyaluronic acid molecules and can penetrate deeper than normal hyaluronate.

In addition, LMW hyaluronan itself is a penetration absorber for other active ingredients in body / face creams. 

Introducing hyaluronic acid

Hyaluronic acid is a “gooey” carbohydrate molecule found on most body tissues, especially in the eye, joints and skin.

Hyaluronan plays an important lubricating, cushioning, hydrating, immune, antioxidant, wound healing and skin repair role.

More specifically:

• Hyaluronic acid is the skin’s most important hydration factor. It’s molecule forms a three-dimensional network that acts like a sponge that literally traps water around and inside its folds.

• In addition, HA is used by the body as a lubricant in joints, as a padding in earlobes, fills the vitreous space in the eye, stimulates or inhibits inflammation, stimulates healing and wound repair and is an important component of literally all extracellular matrix (= the fluid between cells) throughout the body.

• On skin hyaluronic acid is found mainly on the base of the epidermis (skin’s uppermost layer), maintaining the space between cells, hydrating the skin and facilitating the passage of nutrients there.

An average 60 kg woman has about 13g of HA in her body, 4.3g of which is recycled every single day. This means that all hyaluronic acid in our bodies is completely recycled and renewed every three days.

However before discussing how hyaluronic acid works and what it can do for your skin, it would be good idea to first present an 101 on hyaluronic acid, so that we can better understand its mode of action.

Hyaluronic acid: what is it exactly?

Hyaluronic acid (HA) is a natural polymer, i.e. a large molecule composed of many repeating smaller "subunit” molecules.

In the case of hyaluronic acid, the individual molecules are the sugars D-glucuronic acid and N-acetyl-D-glucosamine, linked together to form a disaccharide. This disaccharide has a molecular weight of 401.1 Dalton (Da).

The length of the hyaluronic acid molecule can range from 2 to 50,000 disaccharides, with a molecular weight ranging from 802 to ~20,000,000 Da.

The average molecular weight of hyaluronic acid is 4 MDa in joints and about 2 MDa in skin. Hyaluronic acid purified from human umbilical cord is about 3 MDa.

As the body continuously creates and breaks down hyaluronic acid (as mentioned above, it replaces all its HA every three days) and as the degradation of hyaluronic acid happens gradually, we can have HA fragments of all sorts of molecular weights at any given moment in normal tissues, anything from 800Da-4MDa.

The different sizes (molecular weights) of hyaluronic acids

Hyaluronic acid sizes are divided in different categories:

• Extra high molecular weight HA: 3-20 MDa

• High molecular weight HA: ~2 MDa

• Medium molecular weight HA: ~1 MDa

• Low molecular weight HA: ~300 kDa

• Very low molecular weight HA: ~60 kDa

• Oligomeric HA / HA oligomers: anything from 800Da - 10kDa

Hyaluronic acid molecular weights in the context of the human body - how big are they?

The number of repeat disaccharides in a completed hyaluronan molecule can reach up to up to 20,000,000 Dalton (20 MDa) in vivo.

A typical hyaluronic acid polymer that is found in the human joint synovial fluid, i.e. one with 10,000 repeat disaccharides, has a molecular mass of 4 MDa daltons (each disaccharide is ~400 daltons).

The average length of a disaccharide is ~1 nm. Thus, such a hyaluronan molecule of 10,000 repeats could extend to 10 µm if stretched from end to end, a length approximately equal to the diameter of a human erythrocyte (red blood cell).

Hyaluronic acid and silicon

Hyaluronic acid also contains silicon, ranging between 350μg/g to 1900μg/g depending on location in the organism.

Appearance and biological effects

Obviously, molecules which range in size up to 25,000x times are bound to have both quite different appearance and quite different biological effects. And more and more studies show exactly that.

It is commonly said that HA can absorb 1,000 times its own weight in water - but that only applies to high molecular weight HA. The lower molecular weights can obviously absorb much less water.

So in practice, if you dilute high molecular weight HA 1% in water you will get a quite thick liquid or thin gel. A low molecular weight HA with 1% water would be a much thinner liquid or very thin gel, while an oligomer with 1% water would be as runny as water.

I have formulated with all these types of hyaluronate and indeed this is the exact appearance ands viscosity of all these dilutions.

Needless to say, an 1% dilution of 20 MDa HA would be an extremely gooey, thick, almost solid gel.

Size does matter but larger is not necessarily better: hyaluronic acid and cellulite / water retention

You may wonder why the long introduction about the sizes and the gel appearance. The answer is quite interesting.

The larger 3-20MDa HA, i.e. the extra high molecular weight HA, is the type of HA found in cellulite and severe water retention.

This abnormally large size of HA is what retains water in hypodermal tissues and contributes to the appearance of cellulite and overall tissue puffiness on the calves and thighs.

So the ‘water retention’ is your legs is not just ‘water’, it is water trapped in very high molecular weight (VHMW) hyaluronic acid.

This VHMW HA is produced by the body as a result of pathological processes and has nothing to do with HA in food, supplements or skincare gels, serums and creams.

Neither too small, nor too big

So we don’t want to have too high molecular weight in our tissues, as it is a sign of a pathological process.

On the other hand, we do not want to have too many HA fragments on the tissues either, i.e. not too many oligomers or even 200DA-10kDa HA, as these are known to stimulate inflammation.

(Of course, inflammation has its place and it is sometimes necessary.)

All other molecular weights (50 kDa-2 MDa) seem to be neutral or beneficial, with 2 MDa being considered to be the most “normal” (if such a thing exists) and to inhibit inflammation.

Molecular weights below 50 kDa have to be used carefully, as they have quite varying biological effects, according to size.

So we could argue that the only really bad type of HA in anything other than joints and padding tissues (e.g. earlobe) is the extremely high molecular weight one (>>20 MDa), which also contributes to fibrosis.

Diet, lifestyle and HA

A diet rich in vegetables (magnesium) and fruit (ascorbic acid) is supposed to help boost natural HA production, although evidence is thin.

Also some foods naturally contain HA or HA precursors. Examples of such foods are bone broth, organ meats and joint cartilage.

Hyaluronan can also be taken orally, in the form of a nutritional supplement, and it actually does reach skin and joints and does help with hydration/anti-ageing and with joint health, respectively.

This is similar to taking hydrolysed collagen orally, which does help with skin anti-ageing, firmness and tendon/ligament health. The only difference with collagen is that HA should be taken whole, i.e. 2 MDa, as opposed to collagen, which should be taken hydrolysed.

UV radiation from the sun tends to diminish hyaluronic acid, leading to skin dryness and inflammation. By ensuring the skin has plenty of HA in the summer it can stay hydrated and protected from sun damage.

Drinking loads of water can boost the other important molecule for hydration, the one without which hyaluronan is totally useless: water. Ideally you should drink two litres of water a day.

So you can combine oral HA and loads of water for improved skin hydration and anti-ageing. For maximum maximum results, you can use a quality serum, gel or cream containing HA.

Hyaluronic acid synthesis decreases with age

From the age of 45 or so, levels of HA begin to decline significantly, with 50% less produced at age 60 and a whooping 75% less at age 70. The effect of the decrease is looser, drier skin that does not heal well and that shows wrinkles more easily.

As HA stimulates skin repair and hydration, and as our skin produces less and less as we age, it goes without saying that we would like to add some HA into the skin in the form of a serum, cream or gel.

Cosmetic hyaluronic acid skin absorption

As you can understand, the large, 2MDa, molecular weight HA (the one the body itself produces) would find it impossible to even penetrate the epidermis, while different sizes (molecular weights) below 400 kDa can go all the way into the dermis and even hypodermis. The lower the molecular weight, the deeper HA can penetrate into the skin.

However, things are not so simple. As we mentioned above, we must really know what we are doing with lower molecular weight HA, so shoving a 20 kDa HA into the skin is not the solution to everything, as this may prove either beneficial or irritating. Things are complicated with extremely low molecular weight HA.

However, most research papers have shown that anything between 50 kDa ~ 400 kDa penetrates well and has beneficial effect on the skin and my personal formulating and clinical experience is that this is the best range of molecular weight to use.

Which molecular weights of hyaluronic acid penetrate the skin better?

This question has been answered by the 2016 study titled: Human skin penetration of hyaluronic acid of different molecular weights as probed by Raman spectroscopy (please see further below).

The results of the study are quite clear and quite enlightening: anything up to 300 kDa offers a good degree of penetration, with 50-300 kDa being ideal for anti-ageing and lower molecular weights (800-10 kDa) being ideal for cellulite removal and water retention reduction.

On the other hand, anything above 1,000 kDa (1MDa) stays on the surface of the epidermis, with the skin’s native 2,000 kDa (2MDa) hyaluronan being totally unable to penetrate the epidermis.

"Our results show a difference of skin permeation of the three HA. Indeed, HA with low molecular weight (20-300 kDa) passes through the stratum corneum in contrast of the impermeability of high molecular weight HA (1000-1400 kDa)."

Note: this is some food for thought for those ignorant “experts” in the media who claim that active ingredients do not penetrate the epidermis to reach the dermis for therapeutic purposes. The evidence is ample, one just needs to open a book from time to time and study it…

My professional experience with different molecular weights of hyaluronic acid

I have been formulating hyaluronic acid serums, gels and creams for cosmetic applications since 2003 - at different concentrations and of different molecular weights, all the way from 800 Da to 2 Mda.

1 MDa HA can hydrate the epidermis itself, without penetrating further, while 2 MDa just sits on top of the epidermis and goes nowhere else.

On the other hand, I have found that 10 kDa, although it absorbs really well, is not that beneficial and in high concentrations can actually irritate the skin - exactly as research predicts. 

This differential absorption capability of HA depending on its molecular weight is the reason why more and more cosmetic companies these days use more than one size of HA.

Sometimes they randomly put all sorts of molecular weights to cover the full spectrum, sometimes the formulation is well thought out. Sometimes they use huge concentrations, which are unnecessary or even counterproductive. More is not always better.

Filler injections contain cross-linked hyaluronic acid

Hyaluronic acid can also be linear or cross-linked.

Linear is the standard HA found in the body and in nature.

Cross-linked HA is a man-made invention to create a more stable and more hydrating HA, but it unfortunately has poorer penetration capability, as the molecule is “fatter” and cannot cross the epidermis very easily.

Cross-linked HA is what is used in filler injections, but these days it is also available in some anti-ageing creams too.

Hyaluronic acid in serums, gels and creams

As HA forms a stable gel, it is quite easy to produce a serum or a gel just by using HA and water. Creams however, are a different matter, and HA can actually increase the instability of a cream. This is the reason most HA products on the market are the easy to produce gels and serums.

Many HA serums and gels contain about 0.1% HA, i.e. 1 part HA and 999 parts water and perhaps some other active or inactive ingredients.

However, more concentrated products can contain up to 2% HA. More than that is simply too much, making the cream or gel too thick and uncomfortable. As we said previously, when it comes to hyaluronan, more is not better. Personally I find anything above 1% superfluous, with the best concentrations being 0.2-1%, depending on the type of HA used.

Hyaluronic acid is now of the most important anti-ageing actives in face skin care creams and serums - and is also found in some body products. Unfortunately, unless the type and concentration of HA is specifically mentioned on the packaging, it is very difficult to know what quality and how much of it is used in skin formulations.

However, this is a problem with all skincare ingredients.

Our LipoTherapeia Celluence® cellulite creams make use of the benefits of low molecular weight hyaluronic acid at optimum concentrations.

Beware of those £230 hyaluronic acid serums - in reality they are not worth more than £20 - max

Combine people’s ignorance, extreme marketing hype and greedy skincare companies and what do you get? Hyaluronic acid serums costing £230 for 30ml, which in essence should not sell more than £20 - even with all the expensive packaging taken into account.

Of course it’s a free world and no-one is committing a crime here.

Charging £230 for 30ml of hyaluronic acid (plus couple of other token ingredients, usually very cheap ones) is obscene. But spending £230 for such a product is just stupid.

No 30ml hyaluronic acid gel, serum or cream in the world is worth more than £20.

Hyaluronic acid-boosting actives in serums, gels and creams

On the other hand, some skincare products also include actives that boost the skin’s own production of HA.

This offers a more delayed result but bypasses the problem of HA absorption, as the HA is synthesised inside the skin by the skin itself and it is not added externally.

Hyaluronic acid-protecting actives in serums, gels and creams

Other actives inhibit the action of the body’s enzymes that break down HA, called, hyaluronidases.

Most polyphenols can do that: they prolong the useful life of HA in the skin and inhibit its early or excessive degradation by hyaluronidases.

Where does HA in cosmetics come from?

In the past HA used to be sourced from pigs’ ears or cocks’ combs. I remember the first HA we bought to use in our products in 2002 was of porcine origin. I am not happy to use animal products in cosmetics, but there was nothing else those days.

Today all HA is made by bacterial fermentation to produce the standard size of 2 MDa HA.

That is then “cut down”, either by enzymes or by hydrolysis, into smaller sizes (molecular weights). The body itself does the same thing by breaking down 2MDa HA into “smaller pieces” with enzymes called hyaluronidases.

We mentioned hyaluronidases above, in reference to active ingredients that inhibit their action, in order to protect hyaluronic acid. In small amounts they are necessary for normal function but in high amounts they can cause damage.

As with everything, balance and moderation is the key.

Hyaluronic acid, hyaluronidase and cellulite

Sometimes doctors inject hyaluronidase into tissues to break down the excessively high molecular weight HA (>> 2 MDa), that we mentioned above in reference to cellulite.

In cellulite, that type of hyaluronan is what maintains the water retention in the interstitial spaces, creates the puffy, congested appearance and eventually leads to fibrosis (fibrosis is built on a hyaluronic acid “scaffolding”).

One of those uses is the temporary reduction of cellulite. I use the word “temporary" because the body can rebuild loads of fresh 10 MDa or 20 MDa HA in just a few days, as we mentioned above.

So the long-term solution to cellulite cannot be hyaluronidase injection. A real solution has to comprise comprehensive measures to stop the water retention / production of 20MDa HA in the first place. But that’s another story for another article.

Other uses of hyaluronic acid: eye drops, intimate gels, shaving gels, hair products

In addition to skincare creams/gels/serums, injectable fillers and oral supplements, hyaluronic acid is also used in eye drops, helping moisturise the eyes, on condoms, in vaginal lubricant gels and creams, as shaving gel lubricants and in hair products.

Is hyaluronic acid safe?

In skincare products, supplements and all the other other non-injectable uses mentioned above, hyaluronic acid is extremely safe.

Of course, you can overdo it it if you use too much, as with anything else - even water kills if drunk in high amounts. But generally speaking, HA is one of the safest skincare actives.

Furthermore, there is absolutely no reason to use excessive amounts of hyaluronic acid, either in skincare or in supplement form, as more does not equal better.

For example, there are quite a few example of hyaluronic acid serums that apparently contain 5% HA or more.

• Firstly, those companies intentionally mislead about the content of HA in their products - none of those products contain so much HA

• And secondly, even if a product contained such high percentages that would be utterly stupid, as there are no extra benefits from such extreme concentrations. Plus the final product would be extremely thick and gooey and would not absorb and/or clog the pores.

In injectables, hyaluronic acid is much less safe, sometimes causing semi-permanent or permanent scar tissue or other damage, depending on the skill of the person who injects and individual skin reactions of the person who is injected.

There is a big difference between applying a product on the skin and injecting it.

Do hyaluronic acid supplements help with skin hydration, joint health and anti-ageing?

Absolutely. Just make sure you buy high molecular weight hyaluronic acid (2 MDa), i.e. complete / not hydrolysed HA, which is the best form to take orally.

Does hyaluronic acid cause weight gain?

It would be easy to infer from the above that if very high molecular weight hyaluronic acid is a hallmark of cellulite / water retention, then taking HA supplements by mouth could also cause weight gain or even cellulite.

This is, however, a very naive thought, based on several misunderstandings:

• Supplements contain the proper hyaluronic acid, i.e. 2 MDa, not the “bad” one (20 MDa) that gathers in tissues with water retention / cellulite

• The body breaks this 2 MDa HA down to smaller fragments (< 2 MDa) via the digestion process and later reassembles it, as needed

• 50 kDa - 2MDa hyaluronic acid acts as an anti-inflammatory and in fact, HA supplements have been proven beneficial for joint as well as skin problems

• The 20 MDa HA found in cellulite / water retention is actually produced by the body itself, without any external help, due to uncontrolled inflammation in those tissues. As we mentioned above, even if you temporarily remove it, your body can rebuild new 20 MDa HA in a matter of days, if inflammation exists in a tissue.

Plus, hyaluronic acid contains no calories, so it cannot directly lead to weight gain either.

All in all, no, you will not get fatter if you take an hyaluronic acid supplement, neither will you get more cellulite. Most probably in fact, it may help, to a small extent, to reduce cellulite.

Neither if you take a multivitamin or indeed a protein supplement, will you put on weight.

What makes you fat is sugar, alcohol, excess carbs, excess fat and inactivity, not supplements or vitamins.

Does hyaluronic acid make you retain water?

As mentioned above, dietary hyaluronic acid (in food or capsule form) can actually help improve water retention.

On the other hand, medical conditions such as lymphoedema can cause the body to produce extremely high molecular weight hyaluronic acid and thereby retain body water, especially on the thighs.

Of course, hyaluronic acid you apply on your face or body skin does NOT cause water retention - it just hydrates your skin.

In summary

As we age we produce less and less HA and we are in need of protecting and boosting the levels of HA in our skin.

This can be done by avoiding excessive sun exposure; with a diet rich in vegetables, herbs and bone broth / organ meats; by drinking loads of water; and by applying a good HA skincare product, with multiple molecular weights of HA, ideally 50-300kDa.

Hyaluronic acid supplements also help, as the HA in them does find its way into the skin (and joints), helping hydrate and nourish the body from within.

Human skin penetration of hyaluronic acid of different molecular weights as probed by Raman spectroscopy

• Research paper link: https://onlinelibrary.wiley.com/doi/abs/10.1111/srt.12228

• Abstract: Background: Topical delivery of molecules into the human skin is one of the main issues in dermatology and cosmetology. Several techniques were developed to study molecules penetration into the human skin. Although widely accepted, the conventional methods such as Franz diffusion cells are unable to provide the accurate localization of actives in the skin layers. A different approach based on Raman spectroscopy has been proposed to follow-up the permeation of actives. It presents a high molecular specificity to distinguish exogenous molecules from skin constituents. Methods: Raman micro-imaging was applied to monitor the skin penetration of hyaluronic acids (HA) of different molecular weights. The first step, was the spectral characterization of these HA. After, we have determined spectral features of HA by which they can be detected in the skin. In the second part, transverse skin sections were realized and spectral images were recorded. Results: Our results show a difference of skin permeation of the three HA. Indeed, HA with low molecular weight (20–300 kDa) passes through the stratum corneum in contrast of the impermeability of high molecular weight HA (1000–1400 kDa). Conclusion: Raman spectroscopy represents an analytical, non-destructive, and dynamic method to evaluate the permeation of actives in the skin layers.

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