Evidence implicates nutrition as important for connective tissue health

Connective tissue is a predominantly non-cellular material that serves to cushion, stretch, bend, mold, support and connect other tissues/organs to one another in the body including muscle tissue, bone and skin.  For instance, connective tissue provides the structural and functional components in joints and skin that must be made and deposited over the course of our lifetime in order for us to remain healthy, mobile and looking youthful.  However, the production of these tissues progressively decline over time, resulting in deterioration of existing connective tissues and manifesting into visible signs of aging, such as wrinkles and joint discomfort. The question then becomes, can we help or supplement our body in order to extend the health of these tissues? Connective tissue is perhaps the most diverse and abundant of the four major tissue types (epithelial, nervous, muscle and connective). It is roughly defined as any tissue that is found between (connecting) two of the other remaining tissue types, or adjacent bone. Connective tissue is composed of three main components: (1) fibrous components that impart structure to the tissue or space, (2) a matrix or “ground” component that imparts flexibility and hydration to the tissue, and (3) cells that are required for the biosynthetic homeostasis (continued production) of the tissue overall. 

Dietary supplements and Connective tissue fibers​​

The fibrous component of connective tissue is derived from either elastic or collagen-based proteinaceous fibrils. Elastic fibrils, which are made from the amorphous protein elastin as well as ancillary proteins, are as their name implies able to stretch up to 1.5 times their original length, while maintaining the ability to recover their original morphology without significant deformations. 

Collagen fibrils, on the other hand, are long helical strands of individual collagen peptides, which provide a somewhat less flexible structure to connective tissues in our bodies, but serve an equally if not more important role in human health. Collagen peptides are best recognized as being rich in hydroxyproline, which is a modified form of the common amino acid proline. Hydroxyproline, which is present in collagen to help promote the unique triple helical structure that is the hallmark of this structural fiber, can make up anywhere from 10-20% of the peptide's amino acid composition.  Collagen types are differentiated by their location and function(s), and can be classified into two main groups (Fibrillar, non-fibrillar). Most common are the fibrillar collagens, which are Type I (found in skin, tendons, organs, bone and vascular ligature), Type II (found in cartilage), Type III (form the fibrous component of reticulate and typically found with Type I collagens), Type IV (forms the basal lamina) and Type V (found at cell surfaces, in hair and in the placenta). Needless to say, maintaining adequate levels of fibrillar collagen throughout our lifetimes is a key ingredient to maintaining our health in almost every aspect of human physiology, but in particular in healthy joints and youthful looking skin.  One well-researched strategy for maintaining connective tissue components is through the dietary supplementation of their pre-cursors as potential molecular building blocks. In fact, evidence suggests that oral supplementation of collagen products can indeed have a profound influence over the body's content of connective tissue components (including Types I and II collagen and glycosaminoglycans) as well as biochemical markers of their increased synthesis by cellular components.

Most collagen sources for commercial products are derived from animal skin or bone tissues (Types I/III collagens), and from the joints (Type II collagen) of chicken. However, collagen-based supplements can range from non-hydrolyzed high molecular weight forms of Type I/III and II, to their pre-digested lower molecular weight hydrolyzed forms, and finally to a product like  BioCell Collagen, that is a patented enzymatically hydrolyzed extract of chicken sternal cartilage providing low molecular weight bioavailable Type II collagen, hyaluronic acid (HA) and chondroitin sulfate.  Current research, encompassing in vitro​, animal model and multiple clinical studies, indicate that bioavailability of collagen peptides, the ability to be absorbed from the intestine and accumulate in the blood and connective tissue, favors smaller peptide fragments over larger forms of collagen.  There is also strong evidence that ingestion of peptides containing the quintessential collagen hydroxyproline-proline dipeptide motif are many fold better than free amino acids in promoting the incorporation of supplemented materials into newly synthesized connective tissue components[2]​. Likewise, this same dipeptide has been shown to promote the synthesis of other non-proteinaceous connective tissue components in cells, even in the absence of supplementation of those components[2]​. In all, oral ingestion of hydrolyzed collagen appears to promote connective tissue production.  

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 Improving non-proteinaceous connective tissue contents through diet​​

When considering the two main collagen rich organs associated with decline during aging, our skin and joints, collagen fibrils are complimented by a non-proteinacious matrix of components known as the glycosaminoglycans (GAG). This complex interconnected framework, rich in GAG molecules, helps to maintain hydration in the skin and cushioning in the joints while ensuring that each organ maintains the necessary elasticity for function during our lifetime. In both cases, the primary component is the non-sulfated GAG, HA, which forms the backbone of the web-like matrix in connective tissues. HA is further interwoven and crosslinked in each tissue by additional sulfated glycosaminoglycan components, including chondroitin sulfate (and the aminosugar glucosamine) in the joints and dermatan sulfate and keratin in the skin. As with collagen peptides, it is thought that delaying the decline in the GAG components of our skin and joints is a necessary strategy if one wants to maintain a desirable skin appearance and optimal joint health.       

The nature and ubiquity of HA in our connective tissue has led to its wide spread use in connective tissue health. In fact, forms of HA are commonly used as prescribed injectable lubricants for our joints and filler for our eyes during cataract procedures. However, HA is also utilized as a supplement by itself, but has suffered in its overall efficacy from intrinsic limits due to its bioavailability. Namely, HA is naturally found as long acidic linear mucopolysaccharides, having regularly alternating units of N​-acetylglucosamine and D​-glucuronic acid linked by 1, 4- or 1, 3-β-glycosidic bonds. This means it has a high molecular weight and its excessive charge limits its crossing lipid membrane barriers easily.  Thus, like collagen, HA needs to be broken down into smaller molecular weight fragments or hydrolyzed prior to ingestion for optimal uptake and absorption.

There is evidence, however, that a synergistic effect of increased bioavailability occurs when connective tissue components found together in a native matrix are hydrolyzed enzymatically and ingested. Specifically, ingestion of BioCell Collagen, which again is a patented extract of chicken sternal cartilage that provides a naturally occurring matrix of hydrolyzed type II collagen (60%), chondroitin sulfate (20%) and hyaluronic acid (HA) (10%), caused a three to eight fold higher content in blood than non-HA containing collagen (type I/III) products from bovine or porcine sources and non-collagen containing products derived from rooster comb. Additional double blind placebo controlled clinical studies also found that supplementation with BioCell Collagen significantly improved joint comfort and mobility[5]​ as well as skin appearance[1]​ indicative of increased HA content.     

Dietary regulation of connective tissue cellular components​​

The final ingredients of the connective tissue are the cells that constantly strive to produce the proper levels of all of the non-cellular components (predominantly collagen and GAG’s) in the connective tissue. In the case of skin dermal tissue and joint articular cartilage, these cells are termed fibroblasts and chrondroblasts, respectively. Fibroblasts are found in the dermis proper, which is the middle and thickest layer of our skin (the largest organ in the body), and primarily serve to secrete collagen peptides, HA and dermatan sulfate/keratin to maintain skin thickness, hydration and elasticity. Chrondroblasts, likewise, are found in the cartilagenous tissues and serve to secrete Type II collagen peptides, HA, chondroitin sulfate and glucosamine. To say that these cells are the targets of most healthy aging ingredients, “chondroprotectants“ and “fibroprotectants”, would be an understatement, as their function is imperative to maintaining healthy levels of collagen and GAGs in skin and joints.    

Here again, there is a growing body of evidence that the introduction of hydrolyzed collagen can stimulate chondrocytes to synthesize new collagen. For instance, feeding chondrocytes hydrolyzed collagen, Types I/III from skin or Type II from chicken sternum, has been shown to increase Type II collagen production in vitro​[2]​. Oral supplementation of collagen has also been shown to increase collagen content in skin[3]​,[1]​,[4]​.  Even more clinical evidence indicates that that the unique combination of hydrolyzed Type II collagen, HA and chondroitin sulfate found in BioCell Collagen may also stimulate connective tissue cellular health during active recovery from exercise challenges.[5]​   

Overall, a growing body of evidence indicates that supplying our bodies with proportionate pre-digested building blocks of connective tissue components, such as the hydrolyzed Type II collagen, HA, and chondroitin sulfate found in the patented BioCell Collagen products, hold the potential to promote natural synthesis of connective tissue components such as collagen, HA and sulfated GAGs in our body, which may lead to improved longevity of connective tissue health. 

Sources:

[1]​ Schwartz SR and Park J. Clin Interv Aging. 2012;7:267-73.
[2]​ Oesser S and Seifert J. Cell Tissue Res. 2003 Mar;311(3):393-9.
[3]​ Asserin J, et al.​ J Cosmet Dermatol. 2015 Dec;14(4):291-301.
[4]​ Proksch E et al.​ Skin Pharmacol Physiol. 2014;27(3):113-9.
[5]​ Lopez HL. et al.​ Integr Med (Encinitas). 2015 Jun;14(3):30-8.