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Hyaluronic acid supports health inwards and outwards

Article
August 14, 2022
By
Olena Mokshyna, PhD.

Hylauronic acid is widely popular in various forms (oral, intravenous, and subcutaneous) for multiple medical and aesthetical purposes.

Hyaluronic acid (HA), despite the name (derived from the Greek word for glass “gyalos”), by its structure presents a glycosaminoglycan – a long linear polysaccharide molecule, each unit of which consists of two sugar residues. Another well-known compound from this group is chondroitin sulfate, which is responsible for the health and flexibility of joints. 

HA occurs in multiple tissues in the human body, including connective tissue, skin, joints, and tendons. HA is widely popular in various forms (oral, intravenous, and subcutaneous) for multiple medical and aesthetical purposes. HA formulations can be prepared in low (500-730 kDa), intermediate (800-2,000 kDa), and high (~6,000 kDa) molecular weight, which influences their efficacy (1). HA efficacy can also depend on its origin and method of production

Properties

The physiological roles of HA are ubiquitous and, mostly, well-studied. By rough estimates, a body weighing 70 kg contains 15 g of HA (2). Due to its polymer structure, long HA molecules have high viscosity and act as a lubricant, shock absorber, joint stabilizer, and water balance regulator. 

In skin, HA is involved in tissue repair, saves skin elasticity, and prevents the formation of wrinkles. Decreased production of HA is one of the mechanisms connecting excessive ultraviolet exposure and accelerated skin aging (3). In joints, HA is crucial for their normal structure and function (4). It is abundantly naturally present in the synovial fluid (viscous fluid located in joints), joint capsule, and cartilage. Joint diseases, such as osteoarthritis and rheumatoid arthritis, are particularly characterized by an imbalance in HA levels. 

Besides the abovementioned processes, HA plays a role in a plethora of processes, including inflammation response and wound healing (5), ovulation and fertilization (6), signal transduction, and tumor development (having both pro- and anti-tumor effects) (7). 

In every case, the precise biological effect heavily depends on molecular weight. Short hyaluronan chain fragments can have an inflammatory and immune-stimulatory effect while suppressing the effects of larger HA chains (7). On the other hand, high molecular weight HA possesses lubricant properties, has anti-angiogenic activity (inhibition of blood vessel formation, particularly in cancers), and acts as a natural immunosuppressant (8). It has also been shown that HA of very high molecular weight, which is produced by naked mole-rats, alters the expression of the p53 gene (gene crucial to preventing cancer formation) and protects cells from stress-induced cycle arrest and death (9)

Medical, cosmetical, and supplement uses 

The multiple roles of HA in humans led to ubiquitous studies and applications. First and foremost, those are medical applications intended to alleviate the burden of joint diseases. Several HA-based injection therapies were FDA approved, and a meta-analysis of the available research shows that the injections of high molecular weight HA tend to improve function and ease pain in patients with knee osteoarthritis (10). A few clinical studies demonstrated that oral administration of HA had similar effects (11,12).

Another well-known application of HA is for cosmetic purposes. In topical skin care, HA cannot penetrate the upper skin layers and serves more as a protective “coating” maintaining the skin moisture (13). However, the effect differs in the case of oral administration or injections. In a double-blind placebo-controlled study, oral supplementation with HA led to a significant decrease in wrinkles and an increase in skin luster and suppleness (14). HA also shows potential not only in cosmetic skin repair but in the treatment of wounds, burns, and diabetes-related skin conditions (15).

Other uses of HA include ophthalmology (dry eye disease) (16), dentistry (oral ulcers and inflammation) (17), tumor-targeted drug delivery (18), tissue engineering, and regenerative medicine (19).

Oral HA supplements have become increasingly popular due to the endogenous nature of the compound and its good safety profile. HA addresses multiple age-related issues (such as slower wound healing, joint stiffness, chronic mucus membrane inflammation, and skin aging) and potentially has anti-cancer and cytoprotective properties. Thus, it has a high potential as an anti-aging and longevity-promoting supplement. However, not all these properties have been confirmed in the case of oral HA administration, and intestinal absorption may lead to the HA breakdown altering its other properties (20).

Dosage, recommendations, and side effects

Since it is synthesized in the human body, HA has high biocompatibility and negligible side effects. No long-term adverse effects are expected. However, one must pay attention to the source of HA in the supplements as it might be isolated from animal tissues, and accompanying proteins might cause adverse immune reactions.

The possible contraindications might include HA-sensitive individuals, pregnant or nursing women, people with infections, and kidney or liver diseases. In case of any doubts, one should consult the registered health care provider.

In our Marketplace, you can find pure high molecular weight HA from the DoNotAge vendor with a recommended dosage of 200 mg/serving (one capsule).

References

 

1.         Berenbaum F, Grifka J, Cazzaniga S, D’Amato M, Giacovelli G, Chevalier X, et al. A randomised, double-blind, controlled trial comparing two intra-articular hyaluronic acid preparations differing by their molecular weight in symptomatic knee osteoarthritis. Ann Rheum Dis. 2012 Sep;71(9):1454–60.

2.         Fraser JRE, Laurent TC, Laurent UBG. Hyaluronan: its nature, distribution, functions and turnover. J Intern Med. 1997 Jul;242(1):27–33.

3.         Averbeck M, Gebhardt CA, Voigt S, Beilharz S, Anderegg U, Termeer CC, et al. Differential Regulation of Hyaluronan Metabolism in the Epidermal and Dermal Compartments of Human Skin by UVB Irradiation. J Invest Dermatol. 2007 Mar;127(3):687–97.

4.         Chernos M, Grecov D, Kwok E, Bebe S, Babsola O, Anastassiades T. Rheological study of hyaluronic acid derivatives. Biomed Eng Lett. 2017 Feb;7(1):17–24.

5.         Neuman MG, Nanau RM, Oruña-Sanchez L, Coto G. Hyaluronic Acid and Wound Healing. J Pharm Pharm Sci. 2015 Jan 29;18(1):53.

6.         Kovacs P, Kovats T, Sajgo A, Szollosi J, Matyas S, Kaali SG. The role of hyaluronic acid binding assay in choosing the fertilization method for patients undergoing IVF for unexplained infertility. J Assist Reprod Genet. 2011 Jan;28(1):49–54.

7.         Stern R, Asari AA, Sugahara KN. Hyaluronan fragments: An information-rich system. Eur J Cell Biol. 2006 Aug;85(8):699–715.

8.         Snetkov P, Zakharova K, Morozkina S, Olekhnovich R, Uspenskaya M. Hyaluronic Acid: The Influence of Molecular Weight on Structural, Physical, Physico-Chemical, and Degradable Properties of Biopolymer. Polymers. 2020 Aug 11;12(8):1800.

9.         Takasugi M, Firsanov D, Tombline G, Ning H, Ablaeva J, Seluanov A, et al. Naked mole-rat very-high-molecular-mass hyaluronan exhibits superior cytoprotective properties. Nat Commun. 2020 Dec;11(1):2376.

10.       Phillips M, Vannabouathong C, Devji T, Patel R, Gomes Z, Patel A, et al. Differentiating factors of intra-articular injectables have a meaningful impact on knee osteoarthritis outcomes: a network meta-analysis. Knee Surg Sports Traumatol Arthrosc. 2020 Sep;28(9):3031–9.

11.       Tashiro T, Seino S, Sato T, Matsuoka R, Masuda Y, Fukui N. Oral Administration of Polymer Hyaluronic Acid Alleviates Symptoms of Knee Osteoarthritis: A Double-Blind, Placebo-Controlled Study over a 12-Month Period. Sci World J. 2012;2012:1–8.

12.       Nelson FR, Zvirbulis RA, Zonca B, Li KW, Turner SM, Pasierb M, et al. The effects of an oral preparation containing hyaluronic acid (Oralvisc®) on obese knee osteoarthritis patients determined by pain, function, bradykinin, leptin, inflammatory cytokines, and heavy water analyses. Rheumatol Int. 2015 Jan;35(1):43–52.

13.       Kogan G, Šoltés L, Stern R, Gemeiner P. Hyaluronic acid: a natural biopolymer with a broad range of biomedical and industrial applications. Biotechnol Lett. 2006 Dec 8;29(1):17–25.

14.       Oe M, Sakai S, Yoshida H, Okado N, Kaneda H, Masuda Y, et al. Oral hyaluronan relieves wrinkles: a double-blinded, placebo-controlled study over a 12-week period. Clin Cosmet Investig Dermatol. 2017 Jul;Volume 10:267–73.

15.       Voigt J, Driver VR. Hyaluronic acid derivatives and their healing effect on burns, epithelial surgical wounds, and chronic wounds: A systematic review and meta-analysis of randomized controlled trials: Hyaluronic acid and wound healing. Wound Repair Regen. 2012 May;20(3):317–31.

16.       Lee D, Lu Q, Sommerfeld SD, Chan A, Menon NG, Schmidt TA, et al. Targeted delivery of hyaluronic acid to the ocular surface by a polymer-peptide conjugate system for dry eye disease. Acta Biomater. 2017 Jun;55:163–71.

17.       Casale M, Moffa A, Vella P, Sabatino L, Capuano F, Salvinelli B, et al. Hyaluronic acid: Perspectives in dentistry. A systematic review. Int J Immunopathol Pharmacol. 2016 Dec;29(4):572–82.

18.       Huang G, Huang H. Hyaluronic acid-based biopharmaceutical delivery and tumor-targeted drug delivery system. J Controlled Release. 2018 May;278:122–6.

19.       Hemshekhar M, Thushara RM, Chandranayaka S, Sherman LS, Kemparaju K, Girish KS. Emerging roles of hyaluronic acid bioscaffolds in tissue engineering and regenerative medicine. Int J Biol Macromol. 2016 May;86:917–28.

20.       de Souza AB, Chaud MV, Santana MHA. Hyaluronic acid behavior in oral administration and perspectives for nanotechnology-based formulations: A review. Carbohydr Polym. 2019 Oct;222:115001.

Hyaluronic acid (HA), despite the name (derived from the Greek word for glass “gyalos”), by its structure presents a glycosaminoglycan – a long linear polysaccharide molecule, each unit of which consists of two sugar residues. Another well-known compound from this group is chondroitin sulfate, which is responsible for the health and flexibility of joints. 

HA occurs in multiple tissues in the human body, including connective tissue, skin, joints, and tendons. HA is widely popular in various forms (oral, intravenous, and subcutaneous) for multiple medical and aesthetical purposes. HA formulations can be prepared in low (500-730 kDa), intermediate (800-2,000 kDa), and high (~6,000 kDa) molecular weight, which influences their efficacy (1). HA efficacy can also depend on its origin and method of production

Properties

The physiological roles of HA are ubiquitous and, mostly, well-studied. By rough estimates, a body weighing 70 kg contains 15 g of HA (2). Due to its polymer structure, long HA molecules have high viscosity and act as a lubricant, shock absorber, joint stabilizer, and water balance regulator. 

In skin, HA is involved in tissue repair, saves skin elasticity, and prevents the formation of wrinkles. Decreased production of HA is one of the mechanisms connecting excessive ultraviolet exposure and accelerated skin aging (3). In joints, HA is crucial for their normal structure and function (4). It is abundantly naturally present in the synovial fluid (viscous fluid located in joints), joint capsule, and cartilage. Joint diseases, such as osteoarthritis and rheumatoid arthritis, are particularly characterized by an imbalance in HA levels. 

Besides the abovementioned processes, HA plays a role in a plethora of processes, including inflammation response and wound healing (5), ovulation and fertilization (6), signal transduction, and tumor development (having both pro- and anti-tumor effects) (7). 

In every case, the precise biological effect heavily depends on molecular weight. Short hyaluronan chain fragments can have an inflammatory and immune-stimulatory effect while suppressing the effects of larger HA chains (7). On the other hand, high molecular weight HA possesses lubricant properties, has anti-angiogenic activity (inhibition of blood vessel formation, particularly in cancers), and acts as a natural immunosuppressant (8). It has also been shown that HA of very high molecular weight, which is produced by naked mole-rats, alters the expression of the p53 gene (gene crucial to preventing cancer formation) and protects cells from stress-induced cycle arrest and death (9)

Medical, cosmetical, and supplement uses 

The multiple roles of HA in humans led to ubiquitous studies and applications. First and foremost, those are medical applications intended to alleviate the burden of joint diseases. Several HA-based injection therapies were FDA approved, and a meta-analysis of the available research shows that the injections of high molecular weight HA tend to improve function and ease pain in patients with knee osteoarthritis (10). A few clinical studies demonstrated that oral administration of HA had similar effects (11,12).

Another well-known application of HA is for cosmetic purposes. In topical skin care, HA cannot penetrate the upper skin layers and serves more as a protective “coating” maintaining the skin moisture (13). However, the effect differs in the case of oral administration or injections. In a double-blind placebo-controlled study, oral supplementation with HA led to a significant decrease in wrinkles and an increase in skin luster and suppleness (14). HA also shows potential not only in cosmetic skin repair but in the treatment of wounds, burns, and diabetes-related skin conditions (15).

Other uses of HA include ophthalmology (dry eye disease) (16), dentistry (oral ulcers and inflammation) (17), tumor-targeted drug delivery (18), tissue engineering, and regenerative medicine (19).

Oral HA supplements have become increasingly popular due to the endogenous nature of the compound and its good safety profile. HA addresses multiple age-related issues (such as slower wound healing, joint stiffness, chronic mucus membrane inflammation, and skin aging) and potentially has anti-cancer and cytoprotective properties. Thus, it has a high potential as an anti-aging and longevity-promoting supplement. However, not all these properties have been confirmed in the case of oral HA administration, and intestinal absorption may lead to the HA breakdown altering its other properties (20).

Dosage, recommendations, and side effects

Since it is synthesized in the human body, HA has high biocompatibility and negligible side effects. No long-term adverse effects are expected. However, one must pay attention to the source of HA in the supplements as it might be isolated from animal tissues, and accompanying proteins might cause adverse immune reactions.

The possible contraindications might include HA-sensitive individuals, pregnant or nursing women, people with infections, and kidney or liver diseases. In case of any doubts, one should consult the registered health care provider.

In our Marketplace, you can find pure high molecular weight HA from the DoNotAge vendor with a recommended dosage of 200 mg/serving (one capsule).

References

 

1.         Berenbaum F, Grifka J, Cazzaniga S, D’Amato M, Giacovelli G, Chevalier X, et al. A randomised, double-blind, controlled trial comparing two intra-articular hyaluronic acid preparations differing by their molecular weight in symptomatic knee osteoarthritis. Ann Rheum Dis. 2012 Sep;71(9):1454–60.

2.         Fraser JRE, Laurent TC, Laurent UBG. Hyaluronan: its nature, distribution, functions and turnover. J Intern Med. 1997 Jul;242(1):27–33.

3.         Averbeck M, Gebhardt CA, Voigt S, Beilharz S, Anderegg U, Termeer CC, et al. Differential Regulation of Hyaluronan Metabolism in the Epidermal and Dermal Compartments of Human Skin by UVB Irradiation. J Invest Dermatol. 2007 Mar;127(3):687–97.

4.         Chernos M, Grecov D, Kwok E, Bebe S, Babsola O, Anastassiades T. Rheological study of hyaluronic acid derivatives. Biomed Eng Lett. 2017 Feb;7(1):17–24.

5.         Neuman MG, Nanau RM, Oruña-Sanchez L, Coto G. Hyaluronic Acid and Wound Healing. J Pharm Pharm Sci. 2015 Jan 29;18(1):53.

6.         Kovacs P, Kovats T, Sajgo A, Szollosi J, Matyas S, Kaali SG. The role of hyaluronic acid binding assay in choosing the fertilization method for patients undergoing IVF for unexplained infertility. J Assist Reprod Genet. 2011 Jan;28(1):49–54.

7.         Stern R, Asari AA, Sugahara KN. Hyaluronan fragments: An information-rich system. Eur J Cell Biol. 2006 Aug;85(8):699–715.

8.         Snetkov P, Zakharova K, Morozkina S, Olekhnovich R, Uspenskaya M. Hyaluronic Acid: The Influence of Molecular Weight on Structural, Physical, Physico-Chemical, and Degradable Properties of Biopolymer. Polymers. 2020 Aug 11;12(8):1800.

9.         Takasugi M, Firsanov D, Tombline G, Ning H, Ablaeva J, Seluanov A, et al. Naked mole-rat very-high-molecular-mass hyaluronan exhibits superior cytoprotective properties. Nat Commun. 2020 Dec;11(1):2376.

10.       Phillips M, Vannabouathong C, Devji T, Patel R, Gomes Z, Patel A, et al. Differentiating factors of intra-articular injectables have a meaningful impact on knee osteoarthritis outcomes: a network meta-analysis. Knee Surg Sports Traumatol Arthrosc. 2020 Sep;28(9):3031–9.

11.       Tashiro T, Seino S, Sato T, Matsuoka R, Masuda Y, Fukui N. Oral Administration of Polymer Hyaluronic Acid Alleviates Symptoms of Knee Osteoarthritis: A Double-Blind, Placebo-Controlled Study over a 12-Month Period. Sci World J. 2012;2012:1–8.

12.       Nelson FR, Zvirbulis RA, Zonca B, Li KW, Turner SM, Pasierb M, et al. The effects of an oral preparation containing hyaluronic acid (Oralvisc®) on obese knee osteoarthritis patients determined by pain, function, bradykinin, leptin, inflammatory cytokines, and heavy water analyses. Rheumatol Int. 2015 Jan;35(1):43–52.

13.       Kogan G, Šoltés L, Stern R, Gemeiner P. Hyaluronic acid: a natural biopolymer with a broad range of biomedical and industrial applications. Biotechnol Lett. 2006 Dec 8;29(1):17–25.

14.       Oe M, Sakai S, Yoshida H, Okado N, Kaneda H, Masuda Y, et al. Oral hyaluronan relieves wrinkles: a double-blinded, placebo-controlled study over a 12-week period. Clin Cosmet Investig Dermatol. 2017 Jul;Volume 10:267–73.

15.       Voigt J, Driver VR. Hyaluronic acid derivatives and their healing effect on burns, epithelial surgical wounds, and chronic wounds: A systematic review and meta-analysis of randomized controlled trials: Hyaluronic acid and wound healing. Wound Repair Regen. 2012 May;20(3):317–31.

16.       Lee D, Lu Q, Sommerfeld SD, Chan A, Menon NG, Schmidt TA, et al. Targeted delivery of hyaluronic acid to the ocular surface by a polymer-peptide conjugate system for dry eye disease. Acta Biomater. 2017 Jun;55:163–71.

17.       Casale M, Moffa A, Vella P, Sabatino L, Capuano F, Salvinelli B, et al. Hyaluronic acid: Perspectives in dentistry. A systematic review. Int J Immunopathol Pharmacol. 2016 Dec;29(4):572–82.

18.       Huang G, Huang H. Hyaluronic acid-based biopharmaceutical delivery and tumor-targeted drug delivery system. J Controlled Release. 2018 May;278:122–6.

19.       Hemshekhar M, Thushara RM, Chandranayaka S, Sherman LS, Kemparaju K, Girish KS. Emerging roles of hyaluronic acid bioscaffolds in tissue engineering and regenerative medicine. Int J Biol Macromol. 2016 May;86:917–28.

20.       de Souza AB, Chaud MV, Santana MHA. Hyaluronic acid behavior in oral administration and perspectives for nanotechnology-based formulations: A review. Carbohydr Polym. 2019 Oct;222:115001.

Article reviewed by
Dr. Ana Baroni MD. Ph.D.
SCIENTIFIC & MEDICAL ADVISOR
Quality Garant
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Dr. Ana Baroni MD. Ph.D.

Scientific & Medical Advisor
Quality Garant

Ana has over 20 years of consultancy experience in longevity, regenerative and precision medicine. She has a multifaceted understanding of genomics, molecular biology, clinical biochemistry, nutrition, aging markers, hormones and physical training. This background allows her to bridge the gap between longevity basic sciences and evidence-based real interventions, putting them into the clinic, to enhance the healthy aging of people. She is co-founder of Origen.life, and Longevityzone. Board member at Breath of Health, BioOx and American Board of Clinical Nutrition. She is Director of International Medical Education of the American College of Integrative Medicine, Professor in IL3 Master of Longevity at Barcelona University and Professor of Nutrigenomics in Nutrition Grade in UNIR University.

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