UNLOCKING the MELANIN MYSTERY...unique distribution of pigments throughout the body. More than 300 genes that affect pigmentation of skin, hair and/or eyes have been identified (Montoliu,

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UNLOCKING the MELANIN MYSTERY:AN EVOLUTION OF SKIN PIGMENTATION SOLUTIONS

A SCIENCE WRITER’S GUIDE

FOR INTERNAL AMWAY EMPLOYEE USE ONLY. NOT TO BE USED FOR ADVERTISING. DISTRIBUTOR EDUCATION LITERATURE OR MARKETING MATERIALS SUBJECT TO LOCAL LEGAL AND TECH REG REVIEW.

“Radiance” - both literally and figuratively - has taken on new meaning for

women around the world as the ultimate marker of youth. For skin,

radiance is manifested as a flawless complexion unmarred

by spots, freckles or discolorations. Indeed, the quest for

radiance has become a near obsession on a global scale,

as seen by a nearly 10% growth in the skincare brightening

category – with products promising that coveted boost – from

2010 to 2011 (Tyrimou, 2012).

To achieve the goal of improving skin radiance, cosmetic scientists

are applying complex methodologies from other fields of research, such

as drug discovery, to identify new biological targets for active cosmetic

ingredients (Burlando, 2010). These new targets include mediators

of inflammation, proteins involved in oxidative damage

and aging, as well as the proteins that cause skin

color (pigmentation) changes.

Plants provide a natural, safe and efficient source of active

cosmetic ingredients, many of which have been used for centuries

in skincare, and are now augmenting and in some cases gradually replacing

synthetic compounds in modern-day cosmetics (Burlando, 2010). Through advanced

scientific discoveries, the mechanisms behind how plant products improve the

appearance of skin, are coming to light.

Changes in the color, uniformity and texture of skin occur gradually with age,

hormone fluctuations, stress and environmental exposure. This guide will explore

the underlying internal and external factors involved in skin pigmentation and provide

an overview of the latest technology for brightening the skin.

INTRODUCTION


BASICS OF THE SKIN ………………………………………………………………… 1

SKIN PIGMENTATION BIOLOGY …………………………………………………… 1

MELANIN ………………………………………………………………………… 2

UNDERSTANDING CHANGES IN SKIN PIGMENTATION ……………………… 3

AGE-RELATED PIGMENTATION CHANGES AND HYPERPIGMENTATION …………………………………………………… 3

HYPERPIGMENTATION: AT THE CELLULAR LEVEL ……………….………… 4

RESTORING RADIANCE: ADVANCES IN RESEARCH AND TREATMENT OF HYPERPIGMENTATION …………………………………..…… 4

INNOVATIONS IMPACTING PRODUCT PERFORMANCE ……………………… 5

ARTISTRY™ IDEAL RADIANCE™ – A NEW SKIN BRIGHTENING SYSTEM ……… 7

CONCLUSION ……………………………………………………………………… 7

GLOSSARY ……………………………………………………………………………… 8

REFERENCES …………………………………………………………………………… 9

TABLE OF CONTENTS


The skin is the largest organ in the human body, accounting for approximately 16 percent of total body weight (Martini and Nath, 2009). It is a constant and dynamic interface between the body and its environment.

On a cosmetic level, the appearance of the skin is a reflection of health and a measure of age and beauty. The skin is the only organ continually exposed to the environment and on display for all to see (Fisher, et al. 2008). Skin changes are prompted not only by environmental factors such as sun exposure, but also by genetics, nutrition, psychological stress and the natural aging process (Medline Plus, 2010).

Every square centimeter of skin contains millions of cells, as well as hundreds of sweat glands, oil glands, nerve endings and blood vessels. This complicated pattern can be divided into two distinct compartments (Figure 1): the epidermis and the dermis.

SKIN PIGMENTATION BIOLOGYAll organisms, from starfish to humans, are made up of different colors and patterns, which arise from the unique distribution of pigments throughout the body. More than 300 genes that affect pigmentation of skin, hair and/or eyes have been identified (Montoliu, 2011; Yamaguchi and Hearing, 2009; Chi, 2006).

Among the millions of cells that make up human skin are pigment-producing cells called melanocytes, which reside in the epidermis (Figure 1). Melanocytes produce the pigment melanin; this process is called melanogenesis. Other cells in the skin called keratinocytes receive and distribute melanin into upper compartments of the skin (Yamaguchi, 2007) (Figure 1).

Internal factors that help regulate skin pigmentation include:• Cell behaviors that influence melanocyte and keratinocyte activity • Growth factors and hormones circulating in the bloodstream and through the layers of skin• Nervous system signals• Inflammation-related signals• Immune system responses

External factors that directly or indirectly affect skin pigmentation include:• Ultraviolet (UV) radiation• Pollution• Stress • Mechanical injury

UV radiation is particularly damaging because it increases the formation of free radicals, or unstable molecules, in the skin. Free radicals can cause UV-related aging, also known as photoaging, through a process called oxidative stress. Oxidative stress leads to signs of aging, including pigmentation changes, as the skin cells become damaged. UV radiation is also primarily responsible for immediate darkening, tanning, and retention of oxidized fatty tissue in the skin.

1

BASICS OF THE SKIN

Epidermis

Dermis

Melanocyte

Keratinocyte

Melanin

FIGURE 1 COMPARTMENTS OF THE SKIN

FOR INTERNAL AMWAY EMPLOYEE USE ONLY. NOT TO BE USED FOR ADVERTISING. DISTRIBUTOR EDUCATION LITERATURE OR MARKETING MATERIALS SUBJECT TO LOCAL LEGAL AND TECH REG REVIEW. 2

MELANIN

Melanin, a noticeable component of human cosmetic variation, is also an important defense mechanism against harmful environmental factors. To protect itself from the constant barrage of internal and external influences, the skin often reacts by altering pigmentation levels (Costin and Hearing, 2007), such as by ramping up melanin production to thwart the damaging effects of UV exposure.

Figure 2 depicts the process of melanin production and subsequent distribution to the skin surface. Melanin is produced with the help of an enzyme called tyrosinase, levels of which directly correlate with the amount and distribution of melanin produced. In turn, the amount and distribution of melanin determines the degree of pigmentation.

Melanosomematuration

Tyrosinaseproduction and activity

4Free radicals

2

Inflammation

1

Melanin transfer

6

Immediate darkening:melanin

polymerization

7Hormones

35

FIGURE 2 STEPS IN MELANIN PRODUCTION

1 Inflammatory molecules produced in epidermal keratinocytes in response to injury, acne, UV radiation, or various other environmental factors, signal melanin production.

2 Free radicals generated by pollution and sun exposure stimulate melanin production.

3 Epidermal cells bombarded by free radicals or undergoing inflammation activate melanocytes through various hormones, such as alpha-Melanocyte-Stimulating Hormone, (a-MSH).

4 Melanocytes then produce the enzyme tyrosinase and other proteins needed to synthesize melanin and build melanosomes. (Angelopoulou, 1999).

5 The maturity of the melanosomes also influences the amount of skin pigmentation.

6 For UV protection, melanin must be transferred from the melanocyte into keratinocytes. The melanin shields the genetic material of the keratinocyte to protect it from damage.

7 Immediate pigment darkening, triggered by UV radiation and free radicals, does not require tyrosinase. Instead, many melanin precursors join together (polymerize) in keratinocytes.


UNDERSTANDING CHANGES IN SKIN PIGMENTATIONVariation in skin color is one of the most noticeable human differences (Jablonski and Chaplin, 2010). Before the advent of novel analysis methods and the accumulation of vast consumer databases, the study of changes in skin pigmentation was severely limited. Recent advances have improved our understanding dramatically.

Over the past decade, new methods to examine changes in skin pigmentation and a deeper understanding of molecular mechanisms behind these changes, whether governed by genetic forces or the natural aging process, have led to development of better-quality products designed to reduce or reverse skin discoloration.

Recent research is exploring new techniques to analyze additional parameters of skin’s appearance, including evenness of skin color (unrelated to changes in pigmentation) and reflectance (light reflection) (Angelopoulou, 1999). This diverse research echoes the many nuanced terms women today use to describe the appearance of their skin.

AGE-RELATED PIGMENTATION CHANGES AND HYPERPIGMENTATIONWith aging comes a decrease in the number of melanocytes, a disruption in cellular activity and an increase in size of the remaining melanocytes. Aged skin thus appears paler, even to the point of seeming almost translucent in some cases. Large dark spots composed of the enlarged melanocytes (called age spots, liver spots, or lentigos) may appear in sun-exposed areas (Medline Plus, 2010).

As with lines and wrinkles, age-spots and hyperpigmentation, or the darkening of an area of skin, are indicators of accelerated aging. Age spots, a form of hyperpigmentation, are a result of excess production of melanin by melanocytes and a subsequent increase in melanin transfer to keratinocytes (Schwartz, 2012). In fact, age-spots and blotches are now a greater concern for those aged 55 and older than fine lines and wrinkles (data on file).

Hyperpigmentation is not only a result of aging; it can also be triggered by free radical damage, irritation and inflammation. The two most common types of hyperpigmentation unrelated to aging are melasma and post-inflammatory hyperpigmentation (PIH) (Linde, 2006). • Melasma is a dark skin discoloration that appears on sun-exposed

areas of the face; young women with brownish skin tones are at the greatest risk of developing this common skin disorder (Pubmed Health, 2010).

• PIH is a disorder in which excess melanin is produced in response to inflammation in the skin, which may be caused by infections, allergic reactions, injuries, reactions to medications, inflammatory diseases, acne, or burns (Schwartz, 2012).

While these conditions are not often associated with other physical symptoms, they can be of great cosmetic concern and thus have a major impact on a woman’s self-esteem and psychological well-being.

Maintaining youthful skin tone and

appearance has long been an import-

ant cultural concern for Asian wom-

en. For this reason, skin pigmenta-

tion research over the last decade

has increasingly focused on Asian

women. These women perceive age

spots and uneven skin tone as a fun-

damental flaw in their appearance

as well as an indicator of premature

aging. The latest consumer research

indicates that this concern is now a

rapidly growing global phenomenon

(data on file with ARTISTRY).

BOX 1 HYPERPIGMENTATION AND BEAUTY IN ASIAN CULTURE


HYPERPIGMENTATION: AT THE CELLULAR LEVELThe radiant appearance of skin that is free of dark spots and discolorations depends on two main factors: 1) the amount of melanin produced, and 2) the distribution of melanin to keratinocytes in the outer layers of the skin. Both can be disrupted on a cellular level by the following (Schwartz, 2012):• Increased levels of tyrosinase• Inflammation in the epidermis, which results in the release of inflammatory proteins that trigger: – Increased production of melanin by melanocytes – Increased transfer of melanin to the surrounding keratinocytes• Oxidative and psychological stress• Reduced exfoliation (cellular turnover) rate

RESTORING RADIANCE: ADVANCES IN RESEARCH AND TREATMENT OF HYPERPIGMENTATIONCurrent treatments for hyperpigmentation, including hydroquinones, retinoids and tyrosinase inhibitors, have had disappointing results (Hacker, 1996; Seiberg, 2000).

Ongoing research into skin pigmentation and skin coloration by ARTISTRY™ scientists, combined with state-of-the-art ingredient screening methods, has led to new discoveries that help improve skin complexion.

Armed with new understanding, particularly on the role of inflammatory pathways and targets, applied genetic patterns, and more sophisticated ingredient-screening tools, ARTISTRY scientists are now able to create even more powerful interventions by: • Mitigating chronic inflammatory signals sent by cells in and around

damaged, hyperpigmented regions• Inhibiting multiple cellular biochemical pathways involved in the

production of melanin, including: – The formation and maturation of melanosomes – Production and activity of tyrosinase – Transfer of melanin from melanocytes to keratinocytes• Improving skin’s natural protective mechanisms with more

effective nutrients and anti-oxidants to promote healthy, gentle skin turnover and increased production of the body’s own anti-oxidants.

To understand the impact of new, active cosmetic ingredients on melanin production, ARTISTRY scientists developed highly sensitive assays and skin tissue testing methods. These methods were then used to screen hundreds of potential ingredients, thereby identifying several unique new components from plants or other natural sources, which outperform previous technologies.

In 2012, ARTISTRY skincare scientists also uncovered a new way to measure the optical qualities of skin, identifying luminosity, translucency and evenness of skin tone as the primary qualities used in describing an ideal complexion (Box 3). They then further unraveled the mech-anisms contributing to hyperpigmentation triggered by internal and external factors to formulate better products.

Research in the areas of pigmen-tation and aging has accelerated greatly due to a partnership be-tween Amway and the ARTISTRY Scientific Advisory Board, in partic-ular Yale University senior research-er, Dr. John Pawelek, a leading skin cancer expert. This partnership has broadened scientists’ understand-ing of the biology behind pigmen-tation and the specific biochem-ical changes that occur as skin ages. In addition, great progress has been made in creating more accurate and predictive screening tools to assess and select func-tional ingredients that help prevent and reverse pigmentation issues.

The ARTISTRY Scientific Advisory Board set the stage to target age spots and hyperpigmentation much more systematically and effectively than ever before.

BOX 2 THE ARTISTRY SCIENTIFIC BOARD: PARTNERSHIP IN UNDER-STANDING PIGMENTATION AND AGING SKIN


INNOVATIONS IMPACTING PRODUCT PERFORMANCE

The skin serves as an excellent environmental barrier; as such, targeting ingredients to their intended destination is a challenge. ARTISTRY scientists therefore developed an exclusive delivery system using liposomes, or microspheres (or microcapsules) comprised of skin-mimicking lipids (fats) similar to cells on the skin surface, combined with encapsulated brightening cosmetic ingredients. They then demonstrated that this system helps deliver ingredients to the deepest surface layers of the skin, where critical steps in the process of melanin production occur (Figure 2), to reduce spots and hyperpigmentation.

This 3D Brightening Technology takes hydrating, brightening and soothing ingredients deep within the surface layers of the skin tissue. The three ingredients in the liposome are (Figure 3): • Licorice to help soothe and calm skin • Patented Acerola Cherry Ferment, a skin-brightening ingredient • Ceramide-3, a moisture-retaining lipid naturally present in the skin

The liposome enhances the ingredient delivery and targets the deepest surface layers to reduce melanin levels significantly.

ARTISTRY™ scientists pioneered the understanding of the unique skin characteristics and concerns of Asian

women. Their most recent and wide-ranging research, conducted over the past five years, yielded new

insight into how skin’s appearance changes with age. ARTISTRY scientists developed and fielded unique

research using sophisticated digital imaging and analysis instrumentation, generating more than 16,000

unique data sets from Asian women across multiple countries.

Newly developed and proprietary analysis methods led to the discovery that an “ideal complexion” is most

accurately described using three optical parameters – luminosity (brightness), translucency (ratio of surface

to sub-surface reflectance), and evenness of tone (color uniformity).

A poll of 2,000 women confirmed the notion that the perception of healthy, younger-looking skin correlates

closely with specific values of these measurable qualities (data on file). This new understanding significantly

improved the ability to develop technologies that target these critical skin qualities.

BOX 3 ADVANCING RESEARCH ON THE PERCEPTIONS OF SKIN COMPLEXION IN ASIAN WOMEN

3D BRIGHTENING TECHNOLOGY FIGURE 3

A. Empty liposomes, exclusive to Amway, are shown by microscopy.

B. Cutaway diagram of the liposome and components that form the delivery system for 3D Brightening Technology.


Additional powerful ingredients identified and developed by ARTISTRY™ scientists have also proven to diminish age spots effectively:

• Pearl protein (hydrolyzed conchiolin protein) – extracted from crushed pearls and renowned as a beauty treatment since ancient times, this form of pearl protein helps disrupt the sun-induced production of melanin to help diminish dark spot formation. (Figure 4)

• Multiflora blend – a blend of powerful anti-oxidants extracted from plants such as English Daisies, European Geraniums, Jasmine, Evening Primrose and Sophora Japonica. These powerful botanicals act at the skin’s surface to help shield it from free radicals, while boosting the skin’s natural ability to protect itself from pigment darkening; antioxidants help inhibit the formation of melanin in the uppermost surface layers of the skin.

• RedAlgaeandPlumextracts – prevent the transfer of melanin to keratinocytes

• Peaextract– helps prevent melanocytes from maturing, thereby reducing melanin production

• Ascorbylglucoside,PomegranateandChiaextracts – reduce activity of a gene called MC1R, which in turn dampens the activity of pigmentation factors such as tyrosinase

• Lecithin – reduces inflammatory signaling from keratinocytes

Per

cent

mel

anin

pro

duct

ion

Untreated Pearl protein

40

0

60

100

20

80

PEARL PROTEIN SUPPRESSES THE OVERPRODUCTION OF MELANIN BY MELANOCYTES

FIGURE 4

Untreated 2hr 6hr 12hr 24hr

40

0

60

100

20

80

% M

C1

R G

ene

Exp

ress

ion

Ascorbyl Glucoside + Chia + Pomegranate

EXTRACTS OF POMEGRANATE, CHIA AND ASCORBYL GLUCOSIDE WORK TOGETHER TO INHIBIT A GENE CALLED MC1R, THEREBY REDUCING MELANIN LEVELS

FIGURE 5


Together, these ingredients and targeted delivery system form the technology behind the ARTISTRY IDEAL RADIANCE skin care line, which was developed with pigmentation changes of Asian skin in mind. The components of this brightening skin care system diminish the appearance of dark spots and discolorations by targeting different steps in the process of melanin production. The ARTISTRY IDEAL RADIANCE system reduces the amount of melanin produced by surpressing melanocyte activity, as can be seen in cultures of tissue after 10 days of product use (Figure 6).

CONCLUSION

These carefully selected ingredients — backed by scientific advances in hyperpigmentation research and an understanding of ideal qualities in youthful looking skin — form a holistic, balanced approach to skin brightening. Clinical research by ARTISTRY scientists suggest that reduction of visible dark spots and hyperpigmentation can be reduced in 80 percent of women by 12 weeks.†

†After using the ARTISTRY IDEAL RADIANCE system.

ARTISTRY™ IDEAL RADIANCE™ – A New Skin Brightening System

MELANIN PRODUCTION BY MELANOCYTES (DARK STAINING, LEFT) IS DECREASED AFTER 10 DAYS OF TREATMENT WITH ARTISTRY™ IDEAL RADIANCE™ (RIGHT)

FIGURE 6

UNTREATED ARTISTRY IDEAL RADIANCE


3D Brightening Technology – a liposome delivery system that contains licorice, patented acerola cherry ferment and ceramide-3.

alpha-Melanocyte-Stimulating Hormone, orαa-MSH – a hormone that activates melanocytes to produce melanin.

Epidermis – the top compartment of the skin, which contains melanin, melanocytes and keratinocytes.

Evenness of Tone – a measure of skin color uniformity.

Free Radicals – unstable molecules, generated in response to UV radiation, that can result in oxidative stress in cells.

Hyperpigmentation – the darkening of an area of skin and a common sign of accelerated aging.

Liposomes – microspheres of skin-mimicking lipids similar to biological cells.

Luminosity – a measure of skin brightness.

Keratinocytes – the primary cells of skin tissue.

Melanin – natural pigment found in skin.

Melanocytes – skin cells in the epidermis that produce melanin.

Melanogenesis – process by which melanin is made.

Melanosomes – vesicles where melanin matures and is transported to keratinocytes.

Melasma – a dark skin discoloration that appears on sun-exposed areas of the face.

Multiflora Blend – a blend of powerful anti-oxidants extracted from plants such as English Daisies, European Geraniums, Jasmine, Evening Primrose and Sophora Japonica.

Oxidative Stress – damage to skin cells caused by free radicals that leads to signs of aging as the cells become damaged.

Pearl Protein – hydrolyzed conchiolin protein derived from crushed pearls.

Post-Inflammatory Hyperpigmentation (PIH) – a disorder in which excess melanin is produced in response to inflammation or injury to the skin.

Reflectance – measure of the light reflected by skin.

Translucency – a measure of the ratio of surface to sub-surface skin reflectance.

Tyrosinase – an enzyme essential to the production of melanin.

GLOSSARY


REFERENCESAnderson, PM. 2009. Composition and method for preparing stable unilamellar liposomal suspensions. US Patent Pending. Application 20120245528.

Angelopoulou E. The reflectance spectrum of human skin. 1999. http://repository.upenn.edu/cis reports/584. Accessed December 13, 2012.

Burlando B, Verotta L, Comara L, and Bottini-Massa E. Herbal Principles in Cosmetics: Properties and Mechanisms of Action. Boca Raton, FL: Taylor & Francis Group; 2010.

Chi A, Valencia JC, Hu ZZ, et al. Proteomic and bioinformatic characterization of the biogenesis and function of melanosomes. J Proteome Res. 2006;5:3135-3144.

Costin G-E and Hearing VJ. Human skin pigmentation: melanocytes modulate skin color in response to stress. FASEB J. 2007;21:976-994.

Dornoff, JM, O’Toole, DA, and Davies, MB. 1998. Skin whitener composition containing acerola cherry fermentate. US Patent 5,747,006.

Fisher GJ, Varani J, and Voorhees JJ. Looking older: Fibroblast collapse and therapeutic implications. Arch Dermatol. 2008;144:666-672.

Hacker SM. Common disorders of pigmentation: when are more than cosmetic cover-ups required? Postgrad Med. 1996;99:177–186.

Jablonski NG and Chaplin G. Human skin pigmentation as an adaptation to UV radiation. Proc Natl Acad Sci. 2010;107(Supplement 2):8962-8968.

Lynde CB, Kraft NJ and Lynde CW. Topical Treatments for Melasma and Postinflammatory Hyperpigmentation. Skin Therapy Letter. 2006;11:1-6. Available at http://www.medscape.com/viewarticle/549273_1. Accessed December 20, 2012.

Martini FH and Nath JL. Fundamentals of Anatomy & Physiology—8th Edition. Benjamin Cummings; 2008.

Mayne, JR. 2004. Composition containing oat extract for increase cell renewal rate. US Patent 6,753,020.

Medline Plus. Aging changes in skin. http://www.nlm.nih.gov/medlineplus/ency/article/004014.htm. Accessed December 13, 2012. Last updated August 15, 2010.

Montoliu L, Oetting WS, and Bennett DC. 2011 Color Genes. European Society for Pigment Cell Research. http://www.espcr.org/micemut. Accessed December 13, 2012.

Pubmed Health. Melasma. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001839/. Accessed December 13, 2012. Last updated October 3, 2010.

Rana, J. and Diwakar, G. 2011. Topical composition with skin lightening effect. US Patent 7,897,184.

Schwartz RA, Kihiczak NI and Hantash BM. Postinflammatory hyperpigmentation. http://emedicine.medscape.com/article/1069191-overview#a0101. Accessed December 13, 2012. Last updated July 10, 2012.

Seiberg M, Paine C, Sharlow E, et al. Inhibition of melanosome transfer results in skin lightening. J Invest Dermatol. 2000;115:162-167.

Tyrimou N. Skin Care Market Radiant for Foreseeable Future. GCI Magazine. September, 2012. Available at http://www.gcimagazine.com/marketstrends/segments/skincare/167697355.html. Accessed December 20, 2012.

Yamaguchi Y and Hearing VJ. Physiological factors that regulate skin pigmentation. Biofactors. 2009;35:193-199.

Yamaguchi Y, Brenner M, and Hearing VJ. The regulation of skin pigmentation. J Biol Chem. 2007;282:27557-27561.

Documents

UNLOCKING the MELANIN MYSTERY...unique distribution of pigments throughout the body. More than 300 genes that affect pigmentation of skin, hair and/or eyes have been identified (Montoliu,