CPD: Reviewing Collagen Supplements

Reviewing Collagen Supplements

Independent nurse prescriber Caroline Hall explores the literature around collagen supplementation in aesthetics

There has been a huge rise in the use of nutraceuticals over the last five years.1 Collagen supplementation has been particularly popular,2 and we are seeing an increase in patient interest due to media and raised awareness and usage of lifestyle supplements. The use of supplements remains somewhat controversial given the lack of regulation regarding over-the-counter supplements and the quantity and quality of ingredients.2 There’s also the question: do they actually work? As more evidence begins to emerge supporting the use of supplementation, more practitioners are using a holistic approach and combining non-surgical treatments with cosmeceutical skincare products and nutraceutical supplements to give optimum results for patients. At the time of writing this article I did not use, nor recommend, any collagen supplements in my practice. Despite being asked by my patients on a regular basis if I recommend collagen supplementation and if so, what brands could I recommend, I felt that my lack of knowledge surrounding the products and any associated evidence prevented me from feeling confident in doing so. As medical professionals, an evidence-based approach should be at the core of our practice and I feel it is important we look at the evidence base of a product before we recommend it to our patients. I have therefore decided to write this CPD article to look at the evidence surrounding collagen supplementation, to understand its mechanism of action and what evidence there is to support its use in skin rejuvenation.

Nutraceuticals It is widely accepted and supported within the literature that diet has a profound effect on the skin and so does good nutrition.3,4 Nutrition is needed for all biological processes of the skin and the quality of nutrition will have an impact of overall skin health and ageing.4 With this in mind, I will be exploring the evidence to see if supplementing the diet with collagen has a proven effect on skin health/ageing. So, what exactly is a nutraceutical? The Cambridge dictionary defines a nutraceutical as a ‘functional food’ and a food to which vitamins, minerals, or drugs have been added to make it healthier. For this article I will be specifically focusing on collagen supplements. These are most commonly seen either in capsule, powder or ready mixed liquid form.5 The global nutraceutical market is rapidly growing and is projected to reach US $722.49 billion by 2027,2 so as more and more products are developed, and more consumers take interest, it is more important than ever to understand the best, most effective types to offer types to offer in clinic. Collagen and ageing Collagen is a major protein that is found in the extracellular matrix and it accounts for approximately 80% of the dry weight of skin composition.6 Within the skin you will find as many as 14 different collagens, the most common are Type I (80%) and Type III (15%). Collagen degradation starts in our mid-20s and we lose around 1% per year from this point.7 It is expected that women will lose up to 30% of their collagen in the first five years following the menopause, and the rate at which collagen degrades in the years after menopause raises to 2% per year.8-10 The reduction in collagen due to the menopause is linked to the reduction of oestrogen in the body.11 Ageing of the skin is caused by intrinsic and extrinsic factors. Young skin is smooth and supple, often radiant, given its regular cell renewal process. As we age, changes occur within the structure of the dermis and epidermis and the density of the collagen decreases, and in turn the thickness of the dermis also decreases.7 Collagen fibres begin to fragment, become shorter, irregular and less organised. As a result, the collagen fibres lose their ability to retain moisture and the skin loses elasticity and becomes more wrinkled6 (Figure 1). Alongside this, an increase in the production of matrix metalloproteinase (MMP) causes accelerated collagen degradation. In addition, the synthesis of new extracellular matrix components by dermal fibroblasts slows, thus failing to adequately replace the degraded matrix.11-14

Collagen in nutraceuticals There are four main types of collagen used in the production of nutraceutical supplements: bovine, porcine, poultry and marine.15 Although bovine collagen is often cheaper to produce, there are limitations due to dietary requirements or religious constraints and carbon footprint.15 Marine collagen, although more expensive to produce has fewer dietary restrictions, and a high rate of absorption due to its low molecular weight, typically 3-5KDa, although seafood allergies need to be taken in to account. Collagen is mainly formed by the amino acids glycine (33%), proline and hydroxyproline (22% combined)15– see Figure 2.

Cuticle Epidermis Hyaluronic acid

Dermis Hypodermis Muscles Elastic fibre (broken) Collagen (atrophy) Fat cells

Hydroxyproline

Amino acid sequence

Collagen molecule

Collagen fibre

Glycine

Proline

A-chains

Collagen fibrils

Figure 2: The structure of collagen fibres15

Vegan collagen doesn’t exist in nature, the precise mix of amino acids found in animal collagen cannot be found in plants. Most vegan collagen supplements contain some amino acids such as leucine and contain collagen precursors such as vitamin C, which helps the body to synthesis its own collagen. Native collagen refers to collagen in its purest form, i.e. tendons, cartilage, bones and other animal tissue. It consists of a triple helix structure of the amino acids glycine, proline and hydroxyproline, and has a high molecular weight of 300kDa.16 This makes it very difficult for the body to absorb, meaning any collagen used in supplementation must first be degraded into hydrolysed collagen which consists of smaller segmented proteins of around 1kDa to 10kDa. This lower molecular weight gives a higher bioavailability as it is more easily absorbed by the body (Figure 3).16

It was previously thought that collagen, when ingested, was hydrolysed into amino acids in the gastrointestinal tract (GI) prior to being absorbed. However, increasing evidence suggests that collagen peptides are absorbed directly into the blood stream.17 A 2018 study included five female volunteers in good health who fasted for 12 hours and were then given 5g of porcine collagen hydrolysate mixed with 200ml of water. 10ml venous blood samples were taken at 30, 60, 120, 240, 360, and 480 minutes. The results indicated that the dipeptide prolyl-hydroxyproline was found in the blood stream following ingestion of collagen peptide supplements and was noted to peak at two hours and decrease after four hours.18 A further study in 2010 where a sample size of 48 rats were given poultry collagen, indicated that orally-administered hydrolysed collagen is absorbed into the blood stream via the small intestine, both in the form of free amino acids and small collagen peptides. Through the network of blood vessels, these collagen peptides and free amino acids are then distributed throughout the body, in particular to the dermis, where it has been proven they can remain up to 14 days.19

Once in the dermis, hydrolysed collagen has a dual action mechanism; firstly, free amino acids provide building blocks for the formation of collagen and elastin fibres. Secondly, hydrolysed collagen has been shown to increase growth and the overall number of fibroblasts produced. Collagen peptides also work as chemoattractants for fibroblasts which is thought to play a role in stimulating the cells that synthesise new collagen fibres, hyaluronic acid and elastin.18

Studies linking collagen supplementation and skin changes Now we have seen there is evidence that collagen is absorbed into the blood stream and the positive effect it has on the cells that produce collagen, we must look if there is evidence that the collagen supplementation has a visible effect or shows structural changes within the skin. A 2008 study of 66 women aged 40-59 were involved in a randomised, placebo controlled clinical trial. They were randomly split into three groups – a placebo group, a group given porcine collagen peptides 10g, and a group given 10g of marine collagen for 56 consecutive days. Facial assessment was carried out at baseline, four weeks and eight weeks in a controlled environment. Assessment was done by using a Corneometer device to assess skin moisture levels at three different points per subject. Transepidermal water loss (TEWL) was recorded using a Tewameter 3cm from the earlobe on the line between the ear and mouth. At eight weeks the results showed an increase of 12% in the skin’s moisture level in the group using marine collagen and an increase of almost 28% in the group using porcine collagen in comparison to the placebo group. No increased TEWL was noted in any of the groups, so therefore it was established that using a collagen supplement could effectively increase the levels of hydration in the skin without increasing the moisture lost.20 In a randomised, blind, placebo-controlled study in 2019, 72 healthy women aged 35-73 were given either a food supplement containing 2.5g of collagen peptides, acerola fruit extract, vitamin C, zinc, biotin, and a native vitamin E complex or a placebo for 12 weeks.21 The study used objective skin assessment tools for testing such as, cutometry (elasticity), the use of silicone skin replicas with optical 3D phaseshift rapid in-vivo measurements (roughness), corneometry (skin

Native collagen Hyrdrolysed collagen peptides

Regular molecular weight (300,000 dalton)

Low molecular weight (2,000 dalton)

Difficult to absorb Excellent absorption

Collagen is a major protein that is found in the extracellular matrix and it accounts for approximately 80% of the dry weight of skin composition

hydration) and skin sonography (density). The subjects were tested at day zero, day 84 and day 112. No significant differences were found in skin hydration at day zero, but by week 12 there was noted to be a significant difference in skin hydration when compared to the placebo group. Skin elasticity was also found to be increased and this increase was statistically significant at week 12 when compared to the placebo group. Alongside a significant difference in skin hydration and skin elasticity, a significant change in skin roughness was noted in the supplemented group, both groups started at similar levels and reduction in wrinkle depth was noted in the verum group and the maximum improvement of skin roughness was 41%. Skin density was sonographically measured and, interestingly, an increase in skin density was found in both the test group and the placebo group at week 12. The thickness of the dermis and corresponding skin density showed an increase of 34.8% in the test group, and 6.8% in the placebo group. The increase in the placebo group was attributed to the ‘placebo effect’ of unconscious lifestyle changes by the subjects during the study.

The same assessment tools were used four weeks after stopping the supplements and skin hydration levels were still increased significantly when compared to the initial hydration levels at day zero. Although skin hydration levels decreased by 48% between week 12 and 16, skin hydration levels still remained 15% higher than the baseline levels taken at week zero. Skin density continued to show a significant increase four weeks later when compared to day zero levels and the study revealed a significant improvement to the collagen structure of the skin in response to the test product.21 Skin density showed a decline of 31.3% at week 16 when compared to week 12, however this was still an increase of 18% above baseline. For all skin parameters, the improvement percentage remained higher at four months than at the beginning of the study. A further randomised, placebo-controlled, triple-blind trial in January 2020 of 60 females between 40 and 70, confirmed the positive cosmetic effects of the collagen-containing food supplement on the quality and appearance of the skin.22 The study randomly split the participants into two equal groups and they were either given the placebo drink or the supplement containing 2.5g of specific short-chain collagen oligopeptides, 666mg acerola fruit extract, 80mg vitamin C, 3mg zinc citrate, 2.3mg vitamin E, and 50μg biotin. Each participant had one drink per day for 84 days. The study used objective, blinded, and validated image analyses using confocal laser scanning microscopy and showed a significant improvement of the collagen structure of facial skin after intake of the collagen supplement, while no improvements were found after intake of the placebo. A visual analogue scale was used to assess the images from the VIVASCOPE showing the collagen structure of the subcutis. The images were taken before and after 85 days of the test product. The expert grader assessed the after image as clearly better with a score of +27, with zero equaling no difference. The results of the study confirmed a positive effect on condition and appearance of the skin following collagen peptide supplementation.22 In 2019, a review of the literature was carried out on 11 studies, totaling 805 patients. Of these studies, two used collagen peptides 3g per day for four to 12 weeks and saw notable improvements in skin elasticity and hydration. Eight studies used between 2.5g-10g for eight to 24 weeks for the treatment of skin ageing, pressure ulcers and cellulite and those studies found promising results for wound healing and ageing when using oral collagen supplementation. The review also showed no adverse effects from collagen supplementation in any of the studies.23

There doesn’t appear, from the studies, to be a recommended dosage for optimum results or even a minimum recommended amount, although most studies appear to have used a minimum of 2.5g and a maximum of 10g of hydrolysed collagen per day. A study in 2016 of 56 women compared two groups of patients given two types of collagen hydrolysates, which were made up of different amounts of the bioactive dipeptides Pro-Hyp and HypGll.24 The group with the higher concentration of collagen peptides showed significantly more improvement in skin elasticity, moisture and wrinkles than those in the lower concentration and the placebo group. This trial suggests that a higher concentration of hydrolysed collagen gives greater effect, and although the trial measured safety of the supplementation by carrying out blood tests, and reported no adverse events, there appears to be no published data on a safe upper amount.

A study in 2019 set out to determine the maximum level of dietary collagen peptides that can be incorporated in the Western pattern diet while maintaining its indispensable amino acid balance.25 Calculations based on the protein digestibility-corrected amino acid score, a method for assessing the indispensable amino acids within a food by comparing its amino acids to what our bodies can use,26 showed that a level as high as 36% of collagen peptides can be used as protein substitution in the daily diet while ensuring indispensable amino acid requirements are met. This study suggests that the effective amounts of functional collagen peptides (2.5-10g per day) observed in the literature are below the maximum level of collagen that may be incorporated in the standard US diet. This shows a dosage of between 2.5-15g of hydrolysed collagen per day may be safe and effective. Although there are no published recommended upper limits, most preparations do not exceed a recommended dose of 15g per

Given that there is limited evidence for a safe upper dose, there is scope to research this further

day and as with any supplement we can guide our patients to follow the recommended instruction on the particular supplement given.

Conclusion From the literature we can see that there is now growing evidence to support improvements in skin elasticity, texture and improvement in collagen structure when using a daily collagen supplement. This evidence may give practitioners confidence to offer collagen supplementation within their clinics and expect evidence-based results for their patients. A range of collagens were used in the studies, but liquid based marine collagen was shown to be superior in terms of bioavailability and absorption and is overall accepted to have fewer dietary limitations for patients when compared to bovine/porcine.24 In terms of dosage, it was difficult to find any recommended minimum or maximum dose as the dosage of supplementation varied between the studies. It was suggested in one study that higher doses of hydrolysed collagen led to increased improvement in the skin when compared to lower dose and a placebo. Improvement in skin health, elasticity and hydration was shown in three studies when 2.5g per day of hydrolysed collagen was ingested which gives a good baseline of a minimum amount a supplement should contain, and one study showed that up to 15g per day was considered safe and effective.24 Given that there is limited evidence of a safe upper dose, there is scope to research this further. Some studies included other ingredients such as vitamins or fruit extracts in the test drinks but not in the placebo. This should be taken into consideration as it wasn’t clear when reading the studies if this could have an impact on the absorption of the supplements or results of the studies. I would like to research this area further to establish the link between efficacy of results and the addition of other ingredients. Collagen supplements come in different flavours and forms; powders or ready mixed liquids. It may be down to personal taste which is preferred by patients. To conclude, I believe it appears there is enough evidence in which to support using collagen supplements in practice. Based on what I have found, I will be recommending a marine collagen-based supplement in dissolvable powder/liquid form however, this area would benefit from further research.

Caroline Hall is an independent nurse prescriber and the owner of R&R Aesthetics in Leeds. She worked as a nurse and midwife within the NHS for 14 years before becoming a full-time aesthetic practitioner in 2016. Qual: RGN, RM, Bsc Hons, INP

Test your knowledge! Complete the multiple-choice questions below and go online to receive your CPD certificate!

Questions

1. Collagen peptides are absorbed into the body…

2. What is thought to be the minimum recommended dosage of collagen per day?

3. What is thought to be the most bioavailable type of collagen?

4. What is the recommended kDa of a collagen peptide supplement?

5. What limitations are to be considered when using bovine collagen supplements?

Possible answers

a. Sublingually b. Transdermally c. Via the small intestine d. Are not absorbed at all

a. 5g b. 2.5g c. 10g d. 250g

a. Marine b. Bovine c. Porcine d. Plant based

a. 1-10kDa b. 300kDa c. 1,000kDa d. 500kDa

a. Taste b. Cost c. Availability d. Dietary/religious requirements Aesthetics Clinical Advisory Board Member and nurse prescriber Jackie Partridge says... The decision as to whether to promote collagen supplements remains a somewhat controversial one. As this article demonstrates, there appears to be no evidence to support minimum or maximum dosages and as medical practitioners, I feel this leaves many of us with unanswered questions to support promoting collagen supplements to our patients. While, as the author states, marine collagen appears to offer a superior outcome, the lack of scientific data on dosage remains a concern. Cost is another factor that patients will be interested in, and as the supplement market is so crowded with high street and online special offers, this remains a topic requiring further investigation.

REFERENCES

1. Grand View Research. The Nutraceutical Market Size, Share & Trends Analysis Report by Product

Region, and Segment Forecasts, Dietary Supplements, Functional Foods, Functional Beverages, 2020-2027, USA, Research and Markets 2020 2. Department of Health and Social Care, Food supplements: summary information on legislation relating to the sale of food supplements DOH, 2011, <https://assets.publishing.service.gov.uk/ government/uploads/system/uploads/attachment_data/file/204303/Supplements_Summary__

Jan_2012__DH_FINAL.doc.pdf> 3. Mordor Intelligence LLP, Europe Collagen Supplements Market - Growth, Trends and Forecasts (2020 - 2025), India: Report Linker, 2020 <https://www.reportlinker.com/p05903714/Europe-

Collagen-Supplements-Market-Growth-Trends-and-Forecasts.html?utm_source=GNW> 4. S Schagen, et al., Discovering the link between nutrition and skin aging, Dermato-endocrinology, (4) 298-307, 2012 5. CambridgeDictionary, Nutraceutical, 2021, <https://dictionary.cambridge.org/dictionary/english/ nutraceutical>. Accessed 25/03/21 6. C Cao, et al., Diet and Skin Aging-From the Perspective of Food Nutrition, Nutrients, 12(3) 870, 2020 7. K Gelse, et al., Collagens Structure, Function, and Biosynthesis, Adv Drug Deliv Rev, 55 (12) 1531 – 46, 2003 8. S Shuster et al., The influence of age and sex on skin thickness, skin collagen and density, British

Journal of Dermatology, 93 (639–43), 1975 9. M Brincat , CJ Moniz, JW Studd, A Darby, A Magos, G Emburey, E Versi. ‘Long-term effects of the menopause and sex hormones on skin thickness’. British Journal of Obstetrics and Gynaecology. (1985) 92 (3) (p256-9). 10. M Brincat, E Versi, CF Moniz, A Maggos J De Trafford, JW Studd. ‘Skin collagen changes in postmenopausal women receiving different regimens of estrogen therapy.’ Obstetrics and

Gynecology. (1987) 70(1) (p123-127). 11. P Affinito et al., Effects of postmenopausal hypoestrogenism on skin collagen, Maturitas, 15;33(3) 239-47, 1999 12. J Varani, MK Dame et al., Decreased collagen production in chronologically aged skin: roles of age dependent alteration in fibroblast function and defective mechanical stimulation, The

American Journal of Pathology, 168 (1861–8), 2006 13. T Quan, E Little et al., Matrix metallo-proteinases and collagen fragmentation in photodamaged human skin: impact of altered extracellular matrix microenvironment on dermal fibroblast function,

Journal of Investigative Dermatology, 133 (1362–6), 2013 14. JH Chung, JY Seo, et al., Modulation of skin collagen metabolism in aged and photoaged human skin in vivo, Journal of Investigative Dermatology, 117 (p1218–24), 2001 15. A León-López, A Morales-Peñaloza, et al., Hydrolyzed Collagen-Sources and Applications,

Molecules, 24 (22) 4031, 2019 16. GY Li, S Fukunaga, e al., Comparative study of the physiological properties of collagen, gelatin and collagen hydrolysate as cosmetic materials, International journal of cosmetic science, 27 (p101–106), 2005 17. D Liu, M Nikoo, et al., Collagen and Gelatin,Annual Review of Food Science and Technology, 6:1 (527-557), 2015 18. Y Shigemura Y, K Iwai, et al., Effect of prolyl-hydroxyproline (Pro-Hyp), a food-derived collagen peptide in human blood, on growth of fibroblasts from mouse skin, Journal of Agricultural Food

Chemistry, 57 (444–449), 2018 19. M Watanabe-Kamiyama, M Shimizu et al., Absorption and effectiveness of orally administered low molecular weight collagen hydrolysate in rats, Journal of Agricultural Food Chemistry, 58 (2) (835-41), 2010 20. J Asserin, E Lati, et al., The effect of oral collagen peptide supplementation on skin moisture and the dermal collagen network: evidence from an ex vivo model and randomized, placebocontrolled clinical trials, Journal of Cosmetic Dermatology, 14(4) (291-301), 2015 21. L Bolke, G Schlippe, et al, Collagen Supplement Improves Skin Hydration, Elasticity, Roughness, and Density: Results of a Randomized, Placebo-Controlled, Blind Study, Nutrients, 11(10) (2494), 2019 22. S Laing, S Bielfeldt, et al., A Dermonutrient Containing Special Collagen Peptides Improves Skin

Structure and Function: A Randomised, Placebo-Controlled, Triple-Blind Trial Using Confocal

Laser Scanning Microscopy on the Cosmetic Effects and Tolerance of a Drinkable Collagen

Supplement, Journal of Medicinal Food, 23(2) 147-152, 2020 23. FD Choi, CT Sung, et al., Collagen Supplementation: A Systematic Review of Dermatological

Applications, Journal of Drugs in Dermatology, 118 (1) 9-16, 2019 24. N Inoue, F Sugihara, et al., Ingestion of bioactive collagen hydrolysates enhance facial skin moisture and elasticity and reduce facial ageing signs in a randomised double-blind placebocontrolled clinical study, Journal of the Science of Food and Agriculture, 96 (12) (4077-81), 2016 25. C Paul, S Leser, et al., Significant Amounts of Functional Collagen Peptides Can Be Incorporated in the Diet While Maintaining Indispensable Amino Acid Balance, Nutrients, 11(5) (1079), 2019 26. Food and Agriculture Organization (FAO) Dietary protein quality evaluation in human nutrition: report of an FAO Expert Consultation, FAO Food Nutr. Pap, 92 (1-79), 2013