The Collagen

Collagen in the body

The skin [6]

The skin represents 16% of the human body, which is the largest organ in the human body. It is our first line of defence against the external environment. Three layers make up the skin:

• The epidermis: in direct contact with the outside, it is very thin and ensures the barrier function of the skin.
• The dermis: connective tissue of the skin, it is considerably thicker than the epidermis and extremely resistant thanks to its richness in type I collagen and elastin that give the skin its firmness and elasticity. It is the fibroblasts, specific cells of the dermis, that produce these major compounds of the dermis, including precisely the type I collagen.
• The hypodermis: the deepest layer, it is rich in lipids (with its characteristic cells, the adipocytes) playing a nourishing and protective role (especially against the cold) and contains collagen to a lesser extent.

The figure below outlines the structure of the skin and the arrangement of collagen fibres within the dermis. One can thus easily visualize its function of structure and maintenance of the skin.

The joints [7]

Cartilage is a specialized connective tissue that covers both ends of the bones to form the joint. It plays a key role in ensuring the proper sliding between the bones and limiting the intensity of friction, ensuring cushioning and controlling joint pressure. Cartilage has specific cells, the chondrocytes, which synthesize its constituents such as collagen, the majority component. There are three types of cartilage: hyaline cartilage, elastic cartilage and fibrous cartilage. Hyaline cartilage is the most abundant, it is this one which is at the articular level and which is essentially made up of type II collagen.

The muscles [8]

Skeletal muscles (majority muscles, long before the heart muscle and smooth muscles) are composed of bundles of fibres themselves formed by myofibrils (i.e. fibrils having a contractile power). The muscles consist of the alternation of these fiber bundles with connective tissue mainly composed of collagen types I and III (other fibrillary collagen) and giving the muscle its elasticity and flexibility during contraction. This extracellular matrix containing collagen thus plays a protective role around the muscle.

Other key compounds in the extracellular matrix [9]

The dermis and cartilage are two connective tissues whose extracellular matrices are not only composed of collagen, but also of carbohydrate molecules, glycosaminoglycans, such as hyaluronic acid (or hyaluronane) for skin, and chondroitin sulfate for cartilage. Glycosaminoglycans are, for some, composed of glucosamine sulfate present in large quantities in the joints. Less abundant than collagen, glycosaminoglycans are however essential to maintain the dermis and cartilage by helping to retain water, and thus ensuring the hydration of the skin and joints.They are found in different proportions in the body: hyaluronic acid is more present in the dermis while chondroitin sulfate is more abundant in cartilage.

Collagen in the Course of Life [10–12]

During physiological aging, the decrease in collagen production leads to a weakening of the structure of the dermis, and consequently, of the skin. It is estimated that an adult loses an average of 1% dermal collagen per year. This natural aging process also affects motor function in bone and cartilage. Overall at 80, we would have lost 75% of our body collagen.

In addition, these collagen-rich tissues are particularly subject to external aggressions such as UV rays and pollution for the skin, or more or less intense physical activity for the joints (bones and cartilage).

The figure below presents a histological and schematic view of the evolution of the skin over time. Old skin, young skin, shows a low density of collagen in the dermis and sagging in the epidermis, revealing characteristic marks: wrinkles. These can be more or less visible. They are particularly favored by the photo-exposure of the skin over the course of life: the greater the exposure to UV, the more wrinkles become.

Collagen hydrolysates [5–14]

So-called “native” collagen has a triple helix structure with a high molecular weight of around 300 kDa (kilodaltons). As with most proteins, ingesting it directly to compensate for the loss of our own collagen would be ineffective because, with this molecular weight, it is not assimilated by our body. In other words, native collagen does not have good bioavailability.

To overcome this problem, Nutra has developed so-called “hydrolyzed” forms, also called “collagen hydrolysates”. They are of porcine, bovine, avian and marine origin. This latter source is increasingly popular for health, cultural and industry traceability reasons.

The enzymatic hydrolysis of native collagen produces a set of small peptides (chains of amino acids), the weight of which can vary between 0.3 and 8 kDa, which is 40 to 1000 times smaller than that of native collagen. Thanks to their new form of reduced size, collagen hydrolysates (or collagen peptides) have better bioavailability to act in two potential modes of action:

• Assimilated during digestion, they provide, in exogenous contributions, the constitutional “blocks” (glycine, hydroxyproline, proline) essential for the formation of collagen. Due to their small size, certain peptides such as tripeptides (formed by three amino acids) can pass the intestinal barrier without undergoing enzymatic hydrolysis. They then directly provide the constitutional blocks and ligands, and optimize the production of collagen.
• By binding to receptors on fibroblast membranes, peptides stimulate the production of new endogenous collagen, but also other components of the skin such as elastin and hyaluronic acid.

In summary, hydrolyzed collagen is a highly digestible form of collagen, and it is readily absorbed by the human body. Its amino acids and peptides are distributed via the bloodstream to target tissues, such as the dermis and cartilage.

Ultimately, for an effective Nutraceutical supplementation with collagen, it is important to take into account the parameters of high bioavailability:

• A contribution in the form of low molecular weight hydrolysates: the lower the peptides are, the more effective the collagen hydrolyzate would be,
• An intake mainly composed of glycine then hydroxyproline-proline.

Clinical efficacy of collagen hydrolysates in Nutra

Collagen in hydrolyzed form has been widely studied: its tolerance and efficacy have been clinically demonstrated in several areas.

Collagen and skin
The appearance of the skin is a major beauty concern. Over time, its collagen capital decreases and signs of aging appear: wrinkles, sagging, loss of elasticity ... A 2019 review [15] identified different clinical studies that can be compared on hydrolyzed collagen supplementation and its impact on the skin. In this published work, 11 studies were selected, counting a total of 805 subjects. Collagen dosages varied between 2.5g and 10g per day over periods of 56 days (8 weeks) to 180 days (24 weeks). On average, the collagen hydrolysates used were 2 kDa. All the studies have shown significantly positive effects on various parameters linked to the aging of the skin: thickness of the dermis, wrinkles, elasticity… Through these studies, hydrolyzed collagen has therefore been shown to be effective (and safe) for improving the appearance of the skin. Supplementation with collagen hydrolysates therefore appears to be an asset in preventing skin aging and the appearance of signs of aging [16].

Collagen and Joints

Joint pain can affect many of us and affect certain more specific populations, such as athletes and the elderly. In these people, erosion of the cartilage caused by shock or the effect of time leads to osteoarthritis or arthritis. It is in fact within the framework of these issues that clinical studies are widely carried out. Compilations of results from clinical work highlight the significantly positive effects of taking hydrolyzed collagen to relieve joint pain (sensation and structure) [17,18]. These data are, however, and as always, to be considered in the clinical conditions in which they were observed. Most of these clinical studies have been performed at doses of 10g per day of collagen and type I peptides, and more recently at doses of 5g at a molecular weight of 3kDa [19,20]. Other studies have used doses of 1.2g of low molecular weight collagen peptides (<1kDa) [21–23]. The important parameter of these studies is the duration of collagen supplementation. Indeed, this work has revealed that significant positive effects appear with a duration of 24 weeks. Associated with the articular problem arises the question of the bone-collagen relationship. Improvement in bone mineralization through collagen supplementation is not yet sufficiently documented [24]. In contrast, a clinical study has shown promising effects in postmenopausal women (131 subjects). In these studies, supplementation with collagen peptides (5g per day) demonstrated better bone mineral density and improved bone plasma markers [25].

The Nutri&Co choice

After understanding the essential characteristics of good collagen, we have selected two high quality ingredients for our Collagen:

• Collagen HMGTM: a type I collagen dosed at 5g / day, and with an average molecular weight consistent with the efficacy data in the literature on improving the appearance of the skin (firmness and wrinkles).
• Cartydiss® Collagen: a type II collagen dosed at 0.5 g / day and clinically studied. The study carried out on 23 women aged 45 to 59 years taking 500 mg per day for 90 days demonstrated visible effects on:
  - reduction of wrinkles,
  - the increase in the density of the dermis,
  - improving the smooth appearance of the skin.

Our formula guarantees:

• A combination of hydrolysates of types I and II collagen, the two most abundant fibrillar collagens in the body.
• An aminogram of collagens rich in glycine (the majority), hydroxyproline and proline, the three main amino acids that make up collagen.
• A broad spectrum of molecular weights, with a majority of low weights (see table below), for good assimilation and an interesting variety in proteins. Indeed, if collagens I and II provide relatively similar peptides, type II collagen allows a supply of specific constituents of the extracellular matrix of cartilage such as chondroitin sulfate (about 150 mg per day for a dose of our Collagen) and glucosamine (about 80 mg per day for a dose of our Collagen).
• Impeccable traceability: our raw materials used come from controlled and committed fish by-product lines.
• Convenience of use: the high quality of our collagens makes it possible to obtain a powder with good solubility, while a natural peach aroma provides a fine and delicate flavor. These organoleptic characteristics allow easy and daily use of our Marine Collagen in different types of hot or cold preparations and drinks.

Publications

1. Sorushanova, A.; Delgado, L.M.; Wu, Z.; Shologu, N.; Kshirsagar, A.; Raghunath, R.; Mullen, A.M.; Bayon, Y.; Pandit, A.; Raghunath, M.; et al. The Collagen Suprafamily: From Biosynthesis to Advanced Biomaterial Development. Adv. Mater. 2019, 31, 1801651, doi:10.1002/adma.201801651.
2. Mouw, J.K.; Ou, G.; Weaver, V.M. Extracellular Matrix Assembly: A Multiscale Deconstruction. Nat. Rev. Mol. Cell Biol. 2014, 15, 771–785, doi:10.1038/nrm3902.
3. Arseni, L.; Lombardi, A.; Orioli, D. From Structure to Phenotype: Impact of Collagen Alterations on Human Health. Int. J. Mol. Sci. 2018, 19, 1407, doi:10.3390/ijms19051407.
4. Fligiel, S.E.G.; Varani, J.; Datta, S.C.; Kang, S.; Fisher, G.J.; Voorhees, J.J. Collagen Degradation in Aged/Photodamaged Skin In Vivo and After Exposure to Matrix Metalloproteinase-1 In Vitro. J. Invest. Dermatol. 2003, 120, 842–848, doi:10.1046/j.1523-1747.2003.12148.x.
5. Sibilla, S.; Godfrey, M.; Brewer, S.; Budh-Raja, A.; Genovese, L. An Overview of the Beneficial Effects of Hydrolysed Collagen as a Nutraceutical on Skin Properties: Scientific Background and Clinical Studies. Open Nutraceuticals J. 2015, 8, 29–42, doi:10.2174/1876396001508010029.
6. Haydont, V.; Bernard, B.A.; Fortunel, N.O. Age-Related Evolutions of the Dermis: Clinical Signs, Fibroblast and Extracellular Matrix Dynamics. Mech. Ageing Dev. 2019, 177, 150–156, doi:10.1016/j.mad.2018.03.006.
7. Sophia Fox, A.J.; Bedi, A.; Rodeo, S.A. The Basic Science of Articular Cartilage: Structure, Composition, and Function. Sports Health Multidiscip. Approach 2009, 1, 461–468, doi:10.1177/1941738109350438.
8. Csapo, R.; Gumpenberger, M.; Wessner, B. Skeletal Muscle Extracellular Matrix – What Do We Know About Its Composition, Regulation, and Physiological Roles? A Narrative Review. Front. Physiol. 2020, 11, 253, doi:10.3389/fphys.2020.00253.
9. Gandhi, N.S.; Mancera, R.L. The Structure of Glycosaminoglycans and Their Interactions with Proteins. Chem. Biol. Drug Des. 2008, 72, 455–482, doi:10.1111/j.1747-0285.2008.00741.x.
10. Shuster, S.; Black, M.M.; McVITIE, E. The Influence of Age and Sex on Skin Thickness, Skin Collagen and Density. Br. J. Dermatol. 1975, 93, 639–643, doi:10.1111/j.1365-2133.1975.tb05113.x.
11. Shoulders, M.D.; Raines, R.T. Collagen Structure and Stability. Annu. Rev. Biochem. 2009, 78, 929–958, doi:10.1146/annurev.biochem.77.032207.120833.
12. Varani, J.; Dame, M.K.; Rittie, L.; Fligiel, S.E.G.; Kang, S.; Fisher, G.J.; Voorhees, J.J. Decreased Collagen Production in Chronologically Aged Skin. Am. J. Pathol. 2006, 168, 1861–1868, doi:10.2353/ajpath.2006.051302.
13. Naylor, E.C.; Watson, R.E.B.; Sherratt, M.J. Molecular Aspects of Skin Ageing. Maturitas 2011, 69, 249–256, doi:10.1016/j.maturitas.2011.04.011.
14. León-López, A.; Morales-Peñaloza, A.; Martínez-Juárez, V.M.; Vargas-Torres, A.; Zeugolis, D.I.; Aguirre-Álvarez, G. Hydrolyzed Collagen—Sources and Applications. Molecules 2019, 24, 4031, doi:10.3390/molecules24224031.
15. Choi, F.D.; Sung, C.T.; Juhasz, M.L.; Atanaskova Mesinkovska, N. Oral Collagen Supplementation:A Systematic Review of Dermatological Applications. J. Drugs Dermatol. 2019, 18.
16. Aguirre-Cruz, G.; León-López, A.; Cruz-Gómez, V.; Jiménez-Alvarado, R.; Aguirre-Álvarez, G. Collagen Hydrolysates for Skin Protection: Oral Administration and Topical Formulation. Antioxidants 2020, 9, 181, doi:10.3390/antiox9020181.
17. Honvo, G.; Lengelé, L.; Charles, A.; Reginster, J.-Y.; Bruyère, O. Role of Collagen Derivatives in Osteoarthritis and Cartilage Repair: A Systematic Scoping Review With Evidence Mapping. Rheumatol. Ther. 2020, 7, 703–740, doi:10.1007/s40744-020-00240-5.
18. de Almagro, M.C. The Use of Collagen Hydrolysates and Native Collagen in Osteoarthritis. Am. J. Biomed. Sci. Res. 2020, 7, 530–532, doi:10.34297/AJBSR.2020.07.001217.
19. Zdzieblik, D.; Oesser, S.; Gollhofer, A.; König, D. Improvement of Activity-Related Knee Joint Discomfort Following Supplementation of Specific Collagen Peptides. Appl. Physiol. Nutr. Metab. 2017, 42, 588–595, doi:10.1139/apnm-2016-0390.
20. Zdzieblik, D.; Brame, J.; Oesser, S.; Gollhofer, A.; König, D. The Influence of Specific Bioactive Collagen Peptides on Knee Joint Discomfort in Young Physically Active Adults: A Randomized Controlled Trial. Nutrients 2021, 13, 523, doi:10.3390/nu13020523.
21. Feliciano, D.SL.; Gonzalez-Suarez, C.B.; Bernardo-Bueno, M.M.; Malvar, A.K.G.; Cua, R.C.A.; Tan-Sales, B.G.K.; Aycardo, S.M.O.; tan-Ong, M.; Chan, R.; De Los Reyes, F. Effect of Collagen Hydrolysate as Adjuvant Treatment to Excercise for Knee Osteoarthritis. PARM Proc. 2017, 9.
22. Bruyère, O.; Zegels, B.; Leonori, L.; Rabenda, V.; Janssen, A.; Bourges, C.; Reginster, J.-Y. Effect of Collagen Hydrolysate in Articular Pain: A 6-Month Randomized, Double-Blind, Placebo Controlled Study. Complement. Ther. Med. 2012, 20, 124–130, doi:10.1016/j.ctim.2011.12.007.
23. Bernardo, M.L.R.; Azarcon, A.C. A Randomized Controlled Trial on the Effects of Oral Collagen Treatment on the Media) Knee Joint Space Aod Functional Outcome among Veterans Memorial Medical Center Patients Diagnosed with Osteoarthritis of the Knee. PARM Proc. 2012, 4, 9.
24. Daneault, A.; Coxam, V.; Wittrant, Y. Biological Effect of Hydrolyzed Collagen on Bone Metabolism. Crit. Rev. Food Sci. Nutr. 2015, 00–00, doi:10.1080/10408398.2015.1038377.
25. König, D.; Oesser, S.; Scharla, S.; Zdzieblik, D.; Gollhofer, A. Specific Collagen Peptides Improve Bone Mineral Density and Bone Markers in Postmenopausal Women—A Randomized Controlled Study. Nutrients 2018, 10, 97, doi:10.3390/nu10010097.