Build your collagen from the ground up

Collagen is the most abundant structural protein in the body, constituting more than 25% of the body’s total proteins. Its main function is to provide strength, structure and support to all tissues and organs in which it is present. To give us an idea of its importance, it constitutes approximately 80% of tendons, 74% of skin, 64% of the cornea, 50% of cartilage, 23% of cortical bone, 12-24% of arteries, 10% of the lung and 4% of the liver.¹

Collagen is synthesized by connective tissue cells (fibroblasts) and is expelled into the extracellular space. With the passage of time the endogenous production of collagen decreases both in quantity and quality, resulting in a more unstable and brittle collagen network, bones weaken, joint pain appears due to the loss of cartilage, the skin loses firmness and elasticity causing the appearance of wrinkles, etc. It is estimated that from the age of 45 the loss of collagen accelerates, reaching losses of 35% from the age of 60.

Therefore, ensuring a correct synthesis of collagen is essential to improve the functioning of all the organs where it is present, whether to repair tissue, prevent disease or improve health in general. Among the most conventional treatments we find preparations based on pure collagen extracted for example from shark cartilage. Due to the complex structure of collagen our digestive system is not very efficient in hydrolysing this protein. Studies indicate that the absorption of unhydrolyzed collagen does not exceed 5%, so the health benefits are minimal. On the other hand, there are hydrolysed collagen supplements where part of the collagen is fragmented into small peptides, much more bioavailable. These small protein pieces can in turn be broken down and metabolized inside the body, giving rise to its essential components, the amino acids. The problem is that most hydrolysed collagens that we find in the market do not specify exactly the percentage of hydrolysis that they present, being able to be from 5% to 90%.

If what we are looking for is to optimize our collagen synthesis to the maximum, we must go to the origin and look for supplements that provide the amino acids and the most important nutrients involved in the synthesis of collagen. In this way we will achieve maximum bioavailability and efficiency.

Amino acids as collagen precursors

The collagen molecule presents a characteristic and unusual composition. Almost one third of its composition is glycine and 13% is proline. Of the derived amino-acids it contains 9% 4-hydroxyproline and 0.6% 5-hydroxylysine.² It also contains glutamate, arginine, alanine and other amino acids of lesser structural relevance. As we have indicated, glycine is limiting in the formation of collagen. Glycine residues occur repeatedly every three amino acids and its small size allows it to adopt the alpha helix structure. It is also necessary for triple helix conformation.

Glycine is considered a non-essential amino acid since it is synthesized endogenously from serine, but in many occasions the amount of serine we have is not enough to synthesize effectively all the glycine we need, since the requirement of glycine is very high due to the fact that it is involved in many important metabolic functions. An extra supply of serine through supplementation could increase the amount of glycine available to form collagen.

Glycine, in addition to participating in the synthesis of collagen, is involved in a multitude of processes such as the synthesis of haemoglobin, creatine, glutathione, nucleotides, bile salts, etc. Therefore, the lack of this amino acid can cause these processes to not function properly and have harmful repercussions on health. The main process affected by glycine deficiency is the synthesis of collagen, since more than 90% of the available glycine is used up in this process. A deficient supply of glycine means that not enough collagen is synthesized and this can cause weakness in the body’s mechanical system (joint weakness, osteoarthritis, broken bones, sprains, etc.) but it can also be the cause of anaemia, muscular dystrophies, excess cholesterol, and many other pathologies, which could be resolved by increasing the daily intake of glycine.³

It is estimated that the metabolic needs of glycine exceed 15 grams daily, however it has been seen that between endogenous synthesis and what is incorporated through the diet we only acquire about 6 grams of this nutrient so we approximately have a daily deficit of at least 10 grams a day. It is for this reason that glycine should be considered an essential amino acid that we should provide through diet or supplements.⁴

Another very important amino acid in the structural maintenance of collagen is proline.⁵ The pyrrolidine rings of the proline residues repel each other by spatial impedance in a way that forces the polypeptide chain to form a very stretched and thin levorotatory helix. As the collagen super helix is dextrorotatory and the three α-helices that form it are levorotatory, this prevents the unwinding of the three chains. Furthermore, in their hydroxylated form, both 4-hydroxyproline and 5-hydroxylysine confirm stability to the collagen triple helix, since the -OH groups of the residues form hydrogen bonds between the different chains.⁶ It is important to note that these hydroxyamino acids are not incorporated into collagen during protein synthesis; rather, once the lysine and proline are incorporated, they undergo hydroxylation by the action of two enzymes: lysyl hydroxylase and prolyl hydroxylase.⁷ These enzymes require the presence of α-ketoglutarate, iron, oxygen and ascorbic acid (vitamin C) to perform their function. These cofactors are essential for the maturation of the collagen matrix. For example, when there is a deficiency of iron or vitamin C, the hydroxylation of these amino acids is inhibited and the formation of the collagen triple helix is impeded. On the other hand, it should be noted that some hydroxylysine residues have carbohydrates (glucose and galactose disaccharides) covalently attached. Although the function of these saccharides is unknown, it is thought that they may act by directing the arrangement of the fibrillae.³

Arginine, although its percentage in the composition of collagen is lower than others, could be considered the fourth most important amino acid in the synthesis of this protein. It is encompassed within the non-essential amino acids since our organism produces large amounts of arginine in the urea cycle. Actually, all arginine is consumed in the same cycle as a consequence of an improvement in the kinetic performance of this route, so mathematically we can consider it as an essential amino acid and its intake is necessary.⁸ In turn, a consumption of citrulline and ornithine would also increase the availability of this amino acid to form collagen since they act as precursors and derivatives of arginine. Orally supplemented citrulline reaches the kidneys where it can be converted directly into arginine. In addition, some studies suggest that L-citrulline may act as an allosteric inhibitor of the enzyme arginase and may therefore also play a role in the positive regulation of arginine bioavailability.⁹ On the other hand, the importance of magnesium in protein synthesis should not be forgotten. Silicon is also vital in giving stability to the collagen triple helix as it forms bonds with the hydroxyl groups of the chains, making the collagen fi-strands more resistant.¹⁰

At this point it is important to note that collagen constitutes approximately 40% of the cartilage matrix and together with hyaluronic acid (HA) is a very important element for the maintenance of hyaline cartilage. An optimal supply of both nutrients could slow down the progression of diseases related to the degradation of articular cartilage, such as osteoarthritis. Hyaline cartilage is a resistant and elastic tissue formed by chondrocytes, which are the cells responsible for producing the extracellular matrix. responsible for producing the extracellular matrix (ECM), composed mostly of type II collagen and proteoglycans (PGs). The collagen fibres are responsible for giving integrity to the tissue while the PGs, being viscous and hydrophobic, generate great resistance to compression. To form the matrix, the PGs bind to HA, forming an aggrecan-HA complex. On the other hand, collagen binds to the side chains of glycosaminoglycans (GAGs), chondroitin sulphate being the most abundant. These joints is what gives firmness and elasticity to the ECM. For its part, HA due to its high viscosity retains water and acts as a joint lubricant, minimizing Friction and thus inflammation and pain. Regarding the mechanism of action, it is believed that HA acts by binding to the intestinal receptor TLR-4 increasing the production of anti-inflammatory cytokines such as IL-10 and decreasing the expression of pleiotrofina, thus reducing pain and inflamation.¹¹ In oral supplements a low molecular weight HA is usually used since the smaller Fragments facilitate its absorption and arrival in the intestine. Another protective nutrient with interesting properties is SAMe (S-adenosyl-L-methionine). It is an intracellular metabolite of amino acids, formed by adenosine triphosphate (ATP) and methionine. It exhibits analgesic and anti-inflammatory capacity and also stimulates the synthesis of PGs and phosphotilcholine. A double-blind, randomized, controlled study compared the efficacy of SAMe (1,200 mg) and celecoxib (Celebrex® 200 mg), an NSAID-type anti-inflammatory, in the reduction of pain associated with osteoarthritis of the knee. Although treatment with SAMe has a slower onset of action, the results obtained after 16 weeks with both treatments were comparable in terms of pain relief, with SAMe producing the least side effects.¹² As for the mechanism of action, everything seems to indicate that SAMe acts by reducing TNFα levels and modulates the expression of the enzyme nitric oxide synthase (NOS). It also restores glutathione levels by decreasing oxidative stress and inflammation. In summary and in conclusion, if we are looking for an extra supply of nutrients to boost the synthesis of endogenous collagen and help us maintain healthy skin, bones and joints for longer, we should look for supplements that provide us with the essential nutrients involved in the construction of collagen (amino acids) and that also contain lubricants and anti-inflammatories of natural origin.

Bibliographic references:

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