Nutraceuticals The Future of Age Management BOLEY NUTRACEUTICALS

“Nutraceuticals: The Future of Age Management? ” BOLEY NUTRACEUTICALS LTD. DISTRIBUTORS OF TOTALLY DERMA

What happens with ageing ? Ø Ø Ø Ø Ø Reduction in hyaluronic acid, collagen and elastin fibres Atrophy and laxity of the skin and mucous membranes Painful and stiff joints Hormonal imbalance Vaginal dryness Dyspareunia Urinary symptoms Poor body image Low self-esteem IAAGSW London 27 -29 October 2017

Nutraceuticals: The Future of Age Management? Can Oral Supplements Really Address Aesthetic and Physiological Ageing Processes? Is it possible to increase collagen and hyaluronic acid internally through nutraceuticals? IAAGSW London 27 -29 October 2017

NUTRACEUTICALS Term coined in 1989 by Stephen L. De. Felice, founder and chairman of the Foundation of Innovation Medicine A foodstuff (as a fortified food or dietary supplement) that provides health benefits in addition to its basic nutritional value Global Nutraceutical Market: 259 Billion in 2012 Projected to be $ 424 Billion in 2017 ENA (European Nutriceutical Association)

Nutraceuticals: COLLAGEN DRINKS Claim to boost the body’s natural collagen production. Marine collagen based ? Of absorption since nutritional supplement ? If absorbed, are the amino acids utilized for boosting collagen production in the body or for general energy production Clinical studies show a particular Hydrolysed BOVINE Collagen branded ARTHRED® does absorb through the small intestine and does stimulate collagen production in the body.

ARTHRED® Patented Hydrolysed bovine collagen 2 -3 kilodaltons (k. Da) vs. 70 k. Da for collagen / gelatine products. Digestible, highly absorbable, hypoallergenic Contains amino acids: glycine, proline, hydroxylysine, lysine and hydroxyproline. Comprise 50% of the substance by weight. Bovine Hydrolysed Collagen peptides resemble human collagen more closely than marine collagen. Gelatine origination by Gelita AG

Bioavailability of ARTHRED® Hydrolysed means ‘pre-digested’, a MINUTE molecular size that reaches the small intestine undamaged by digestive enzymes and is optimally absorbed there. The benefits of an enzymatic hydrolysis are smaller short chain amino acid peptides which are uniform and consistent in size thereby guaranteeing a 95% absorption rate. Arthred’s guaranteed small short chain amino acid content, takes the burden off the digestive system. The product is already in the form needed for straight absorption through the small intestine – therefore the stomach does not need to break it down. This is particularly useful in clients who have compromised digestive systems as the protein in Arthred® does not need to be broken down by the digestive system.

Bioavailability of ARTHRED® Superior absorption and bioavailability due to low molecular weight. Greiling et al. 1998, showed 10 g Arthred® significantly increased collagen amino acids in blood serum. Hydroxyproline rose in blood serum by 550% after Arthred® ingestion.

Serum Amino Acid Concentration After Oral Administration Of ARTHRED® Hydroxyproline Hydroxylysine Glycine Proline

Skin Studies Using Bovine Hydrolysed Collagen Proksch et al. (2014) conducted a double blind placebo controlled trial with 69 women aged 3555 yrs old with Bovine hydrolysed collagen or placebo for 8 weeks. The bovine hydrolysed collagen group showed significant improvement in skin elasticity, Skin moisture, and skin evaporation over placebo group.

Skin Studies Using Bovine Hydrolysed Collagen (cont…. ) 1 2 Proksch et al. (2014) conducted another double blind placebo controlled trial with 114 women aged 45 -65 yrs old with Bovine hydrolysed collagen or placebo for 8 weeks. After 8 weeks the bovine hydrolysed collagen group significantly reduced eye wrinkles between 2049. 9%. 3 Pro-collagen type I increased by 65% 4 Elastin increased by 18% 5 A positive longlasting effect was also observed 4 weeks after the last bovine hydrolysed collagen administration.

Hyaluronic Acid Major component of dermis and cartilage Major injectable filler for skin N-acetyl glucosamine + D-glucuronic acid=HA Commonly found in nutritional supplements, moisturizers, and anti-aging creams Problem: HA is not absorbed through skin or from GI tract due to high molecular weight

Synovoderma: Hyaluronic Acid Highly absorbable, highly bioavailable form of oral HA Very Low molecular weight hyaluronic acid 50 -200 k. Da (HA usually 1200 -1500 k. DA) An animal study with radiolabelled Synovoderma: Radiolabeled Hyaluronic Acid was detected in blood, muscles, salivary glands and bone within 30 mins of ingestion. Less than 5% of radioactivity appeared in faeces after 72 hours, showing a high absorption rate.

Introducing: Collagen/HA/nutrient Powder: boosts collagen production, HA and hydration New Collagen / HA / Nutraceutical Collagen Drink Supplement addresses both the aesthetic (physical) signs of ageing and the underlying physiological processes. Optimises not only for the skin but the entire body and its systems at the cellular level aiming to deliver visible improvements in overall skin, hair, nails, joints, gut health, general well-being and gynaecological menopausal dryness. once daily, pleasant tasting, easy to digest

Collagen/HA Drink Supplement technology The ingredients in Collagen Drink Supplement® are digested and absorbed in the small intestine and distributed via the blood vessels into the deeper layer of the dermis, where they multiply & stimulate fibroblast cells to produce more collagen and hyaluronic acid in the dermis Collagen Drink Supplement® is shown to deliver benefits not only for skin, but for joints, hair, nails, bone, gut inflammation, bladder, urethra, vagina and therefore is also a valuable supplement for peri-post menopausal women.

Collagen/HA Drink Technology - COLLAGEN • 10, 000 mg. of Arthred™, a proven hydrolysed bovine powdered collagen • pharmaceutical grade, patented, clinically proven ingredients • to support, maintain and promote cartilage tissue and collagen throughout the body • digestible, highly absorbable and well tolerated

Collagen/HA Drink Technology - COLLAGEN Bovine collagen is BEST FORM of collagen – identical to human 3 Studies show FOURFOLD stimulation of fibroblasts, significant increase in collagen synthesis and decreased MMP 2 activity 4 After 1 dose Arthred™ Collagen – Hydroxyproline levels rise by 550% (not possible through diet alone)5 After 1 dose Collagen/HA drink® – Hydroxyproline levels rise between 1500% and 3500% as we will see later* Clinical evidence for therapeutic 10, 000 mg dose to boost collagen all over. 6 3. Cheryl M. Burgess. Cosmetic Dermatology p 99 -100 ISBN 3 -540 -23064 -5 Springer 4. JOURNAL OF MEDICINAL FOOD J Med Food 14 (6) 2011, 618– 624 Collagen Hydrolysate Intake Increases Skin Collagen Expression and Suppresses Matrix Metalloproteinase 2 Activity. Vivian Zague, Vanessa de Freitas, Marina da Costa Rosa, Georgia Alvares de Castro, Ruy G. Jaeger, and Glaucia M. Machado-Santelli. 5. Greiling, H and HW Stuhlsatz. 1998. Personal Communication. 6. Beuker, F, P Stehle, M Ritsch, and H Theel. 1993. The influence of regular gelatin substitution at the amino acid levels in blood plasma. Ernährungs-Umschau. 40: 64. * Based on 12 week clinical skin trials in 2015 in US for Totally Derma formulation

Collagen/HA Drink technology – HYALURONIC ACID • HA is not a component of most ‘collagen drinks’ • Contains Synovoderma - Superior Patented HA powder, 210 g per serving • Molecular weight of just 50 k. Daltons, proven 95% absorption in studies 8 • Increased dermal HA leads to improved skin volume, optimal hydration, increased Collagen Synthesis, stimulation of fibroblasts, toxin elimination • Double blind studies show significant improvements in dryness, itchiness and redness for 100% of subjects over 6 weeks 9 8. Life Sciences Division, American Institute for Biosocial and Medical Research. Absorption, distribution and excretion of labeled hyaluronan after single oral doses in rats and beagle dogs. Alexander G Schauss, 1 Lajos Balogh, 2 Andras Polyak, 2 Domokos Mathe, 2 Reka Kiraly, 2 Gyozo Janoki 2 9. Aesthetic Dermatology Vol. 12 109 -120, 2002: Clinical Effects of dietary hyaluronic acid on dry, rough skin. Sato T, Sakamato O, Odanaka W, Yoshida K, and Urishibata, O

Collagen/HA Drink Composition: • Hydrolyzed Collagen 10, 000 mg • Hyaluronic Acid • Zinc • Vitamin C 210 mg 5 mg 250 mg • Grape Seed Extract 160 mg • Green Tea Extract 160 mg

USEFUL INGESTED ANTIOXIDANTS TO HELP ADDRESS AGEING TISSUE Zinc Co-factor needed for Collagen synthesis procollagen, N-Proteinase & pro-collagen C-Proteinase Green tea extract Contains Catechins (polyphenol) A 12 -week, double-blind, placebo controlled study of 60 women found that Green Tea Catechins were able to clinically improve skin elasticity, roughness, scaling, density, and water content Grape seed extract Powerful antioxidant Contains phenols (proanthocyanidins) Protects cells Alpha Lipoic Acid is a water- and fat-soluble antioxidant that is capable of regenerating other antioxidants, such as vitamins C and E. It therefore exerts numerous anti-ageing effects in the body and skin. Alpha lipoic acid research was done on human dermal fibroblasts in vitro (test tube) in cell-culture systems. The results showed that, when taken orally, Alpha Lipoic Acid helps to prevent cellular damage via its antioxidant properties. By protecting fibroblasts this helps to slow down the ageing process in the skin and stimulate repair.

The Collagen/HA Drink® technology – Co-Factors Seven different Co-Factors included to MAXIMISE the effects of the Collagen and HA synthesis and repair. Ascorbic Acid (Vit C) Copper Manganese Zinc Green Tea Extract Grape Seed Extract Alpha Lipoic Acid All work synergistically.

12 Week Evidence for Collagen/HA Drink SUPPLEMENT® Study Design and Subjects 12 -week usage study assessing the absorption of daily Nutraceutical Drink ingestion examining absorption levels of the key ingredients, collagen and hyaluronic acid, in blood serum and skin biopsies. Study Population: 6 women aged 46– 65 years with mild to moderate general facial lines and coarse wrinkles in the eye area, skin dehydration and mottled pigmentation on the face. Subjects continued their regular skin care regimen alongside consumption of the nutraceutical beverage.

12 Week Evidence for Collagen/HA Drink SUPPLEMENT® Assessments Blood serum was assessed at baseline (fasting) and 2 hours after beverage consumption for levels of hydroxyproline (as a marker for collagen serum absorption) and HA Skin biopsies from non-sun exposed skin (hip region) were collected at baseline and after 12 weeks of daily use of the beverage, and were sectioned and immunofloressence stained for hematoxylin and eosin (H&E, control) and for the following markers: − Elastin as a marker for collagen absorption − Colloidal iron as a marker for HA absorption Visia Skin Analysis Machine facial assessment at baseline and 12 weeks Retrospective self-reporting questionnaire

Results (1) Absorption levels of serum hydroxyproline (HP) Blood serum levels of HP (nmol/ml) 160 140 120 100 80 60 40 20 0 Subject 1 Subject 2 Baseline HP Subject 3 Subject 4 Subject 5 HP 2 hrs post-consumption Subject 6

Results (2) see explanation Absorption levels of serum hyaluronic acid (HA) Blood serum levels of HA (ng/ml) 120 100 80 60 40 20 0 Subject 1 Subject 2 Baseline HA Subject 3 Subject 4 Subject 5 HA 2 hrs post-consumption Subject 6

Results (3) Percentage increase in blood serum HP and HA, 2 hours after consuming the formulation contained in Nutraceutical Drink Supplement Subject Subject 1 2 3 4 5 6 Increase in HP +2250% +1500% +3500% +2325% +3150% +2700% Increase in HA +47. 5% +173% +83% No change − 23. 2% − 13. 8%

Results (4) Skin biopsy sections – elastin staining (marker for collagen absorption) Baseline 12 weeks

Results (5) Skin biopsy sections – colloidal iron staining (marker for HA absorption) Baseline 12 weeks

Visia Skin Study Results – 10 week daily consumption Aged 47 - Nasolabial Fold Baseline Aged 47 - Nasolabial Fold 10 weeks

Visia Skin Study Results – 10 week daily consumption Aged 52 - Crows Feet Baseline Aged 52 - Crows Feet 10 weeks

Skin Study Conclusion These studies support the notion that ingesting specific ingredients can result in an anti-ageing and ‘health-boosting’ effect on the skin and body. The right balance of specific, optimal quality and high purity ingredients is crucial in order to ensure therapeutic levels are absorbed and are bioavailable for body utilisation. The specific formulation of TOTALLY DERMA Nutraceutical Drink works from within to stimulate the body’s own production of collagen, elastin and HA, thus addressing the underlying physiological ageing process. Optimisation not only for the skin but the entire body and its systems at the cellular level aiming to deliver visible improvements in overall skin, hair, nails, joints, gut health, general well-being and gynaecological menopausal dryness.

Testimonials Prof E. Briden - Dermatologist US “We are really excited by the results we are getting in our scientific study. The results include markedly elevated blood serum levels for Hydroxyproline post consumption, which shows the impressive absorption levels. The study group are happy with the improvements in their skin so far. ” “The skin biopsies are truly remarkable! They show increased elastin and GAG's and a marked decrease in periocular wrinkles”. “Two of the patients on the study commented that the product really helped their joints - they commented that their knees did not hurt when running and now they have been finished for a week, their knees hurt. “

Testimonial from Consumer September 2017 Totally Derma - totally over the moon. . . This is it, this is the one product that works - for me. No marine collagen (a must for me), just a clever combination of ingredients that when combined, work magic. First trial - wary of results, all too quickly my body responded and I felt 'good'. Within weeks my hair, nails and skin had benefited, even my bones and muscles felt stronger. I felt energised and in tune with my whole self, both physically and emotionally. Whatever was missing, my body found it in the product. I became a worshiper, never missing my daily fix and convinced that my improved appearance and improved energy was down to this pot of powder. I could never explain how scientifically it works for me - it just does - I only hope it never goes away again in my lifetime. Nikki M. Reigate, Surrey

Totally Derma® I months supply = 1 tub RRP = £ 105. 00 Cost to patient = £ 3. 50 /day