Hyaluronidase, the enzyme killing skin´s own hyaluron

It is widely known that skin´s own hyaluron is a precious molecule keeping our skin hydrated as it is a powerful humectant (attracting and binding water), hence giving the skin a natural plumpness and bounce. What many don´t know is that skin´s own hyaluronic acid content needs to be replenished continuously, as it´s half-life is only several hours up to one day 1. It´s degradation is fastened by 2 different pathways: an external influence via free radical activity or physical degradation and an internal pathway via enzymatic or biological degradation by a family of enzymes called hyaluronidase or abbreviated HYAL.

There are 6 different ones identified and HYAL 1 is the most active one. HYAL 1 “cuts” large size hyaluron molecules (the most capable of binding water) into smaller molecules, which are eliminated even faster. One of the strategies to maintain skin´s own hyaluron content is to inhibit the HYAL enzymes, especially HYAL1. Comparing photo-exposed skin to photoprotected skin showed significant increase in the expression of L-HA (low molecular weight HA) which are smaller or broken hyaluronic acid molecules. An increase of degradated hyaluron was associated with a significant expression of HYAL-1 (2)..UV, ROS or free radical activity leads to the activation of hyaluronidase (3,4).

You may now wonder how it is possible that hyaluron filler injections can have a lasting effect of several months or even longer than a year. This is because in those injectable gels the hyaluron molecules are stabilized to protect them from the impact of free radicals and HYAL enzymes. Often this is done with chemical crosslinks (BDDE). Manufacturers of those hyaluron injectable gels use different stabilizing or crosslink technologies and different number of crosslinks, which impacts the gels consistency and longevity. They aren´t completely resistant to hyaluronidase, as it can be used to dissolve injected hyaluron. As hyaluron is anyway depleted and replenished every day, this dissolving procedure hardly affects skin´s own hyaluronic acid content. This is a common misconception.

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In skin care however, the use of crosslinked hyaluron (hence lasting for months or longer) does not make a lot of sense as we usually cleanse our skin twice daily and thus wash it away. It is too large to penetrate. There are some benefits for crosslinked hyaluron, but it does not impact the longevity of skin´s own hyaluronic acid content. One ingredient derived from the roots of Chinese Licorice plant called Enoxolone (also known as Glycyrrhetinic acid) however, has proven to decrease the HYAL1 activity by 54% (in vitro) (5.6). This is a novel and safe topical way to protect skin´s own hyaluronic acid content from fast degradation and elimination.
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However, as mentioned before free radicals increase HYAL1 activity and as we age our skin becomes less resilient against accumulated oxidative stress. Therefore, the most optimal approach to inhibit increasing break down of hyaluronic acid is to combine HYAL1 inhibition with powerful anti-oxidants. In the illustration, which I created professionally, it is Saponin. Saponin is next to a powerful anti-oxidant, also a potent bio-stimulator of the fibroblast for hyaluron (+256%) and collagen (+49%) (6). Furthermore, Enoxolone stimulates melanin production, supports the skin's own repair mechanism against UV-induced DNA damage and inhibits enzymatic elastin degradation. What a power-couple to have in dermo-cosmetic products to manage the biological degenerative process of ageing skin. 
 
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1. HA: a key molecule in skin aging E. Papakonstantinou
2. Dermatoendocrinol. 2012 Jul 1; 4(3): 253–258. doi: 10.4161/derm.21923 Hyaluronic acid: A key molecule in skin aging Eleni Papakonstantinou, 1 Michael Roth, 2 and George Karakiulakis 1 
3. BMC Complementary and Alternative Medicine December 2013, 13:304| In vitro determination of the anti-aging potential of four southern African medicinal plants Authors Gugulethu NdlovuEmail, Gerda Fouche, Malefa Tselanyane, Werner Cordier, Vanessa Steenkamp
4. Bioorg Chem. 2018 Apr;77:159-167. doi: 10.1016/j.bioorg.2017.12.030. Epub 2018 Jan 4. In-vitro evaluation of antioxidant, anti-elastase, anti-collagenase, anti-hyaluronidase activities of safranal and determination of its sun protection factor in skin photoaging. Madan K1, Nanda S2.
5. EADV Poster 2021 A holistic hyaluron-centric anti-aging concept to improve static and dynamic wrinkles Geloven van A, Harbig S, Stuhr A, Dunckel J, Kuhn A, Dippe R, Warnke K, Beiersdorf AG, Hamburg, Germany 
6. EADV Poster 2021 Multifaceted novel approach to increase skin’s own epidermal & dermal hyaluron content Bussmann T, Warnke K, Krüger A, Möller N, Harbig S, Stuhr A, Dunckel J, Geloven van A, Weise J, Beiersdorf AG, Hamburg, Germany
7. Hong et al. Glycyrrhetinic Acid: A Novel Modulator of Human Skin Pigmentation and DNA-Repair September 2009Journal of Investigative Dermatology Conference: 39th Annual European-Society-for-Dermatological-Research Volume: 129

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