jocd_12261_final revised proof

Journal of Cosmetic Dermatology, 0, 1--13

Fifty years of research and development of cosmeceuticals: acontemporary review

Chun-Man Lee, MB BS, MRCP (UK)

Department of Dermatology, Frimley Park Hospital NHS Foundation Trust, Frimley, UK

Summary Facial rejuvenation can be categorized into skincare and facial contouring. Research

and development of cosmeceuticals is aimed at addressing the major signs of

photoaging: wrinkles, dyschromia, and sallowness. Assessment of photoaging comes

in clinical and photographic forms; a photonumeric scale developed by Griffiths et al.

has been assured of its validity and reliability for the assessment of severity of

photoaging in qualitative studies. Treatment of photoaging comes in two categories:

preventive and reversal of signs; whilst sunfactors are the most efficient and essential

in preventing photodamage, research and development of cosmeceuticals for facial

rejuvenation has been robust, thanks to several landmark studies in the last fifty

years, funded by some of the forerunners in contemporary cosmetic industry. Stem

cell research remains the current forerunner in research concerning

cosmeceuticals. Nevertheless, high-quality, randomized control trials remain

scarce within the contemporary literature, and more research and trials without

funding by the industry are required to give rise to impartial comparisons between

various cosmeceutical products. The “perfect cream” for facial rejuvenation remains

elusive.

Keywords: cosmeceutical, sunscreens, antioxidant, photoaging of the skin, facial

rejuvenation, alpha hydroxy acids

Introduction: facial aging and rejuvenation

A strong correlation exists between physical attrac-

tiveness and social status, where a youthful appear-

ance confers economic and social advantages.1 Facial

rejuvenation can be broadly categorized into alteration

of skin’s structure and functionality and facial con-

touring; within the literature, there is evidence for the

superiority of youthful-looking skin over facial symme-

try and proportions.2 Facial soft tissue changes associ-

ated with aging are well known for their effects on

facial morphology – from skeletal atrophy giving rise

to less anchoring support to overlying tissues, to the

loss of facial fat pad volume leading to the downward

migration of esthetic units that results in folds in

between two vertically adjacent units – the sequelae

of facial aging include deep wrinkles and folds, a

gaunt appearance with protrusion of infraorbital fat

pads, thinning of the lips as well as jowls; a triangular

facial shape gives the impression of an aging face, in

contrast to an “inverted triangle” that represents

youthfulness.3 Whilst facial contouring can be

addressed by means of surgical and such nonsurgical

procedures as injectables (of neurotoxins and synthetic

volumizing and/or stimulatory fillers) and thread-lift,

topical therapies have been developed to enhance the

effects of ablative procedures such as chemical peels,

microneedling, and CO2 ablative laser resurfacing: to

Correspondence: Chun-Man Lee, Speciality Doctor in Dermatology,

Department of Dermatology, Frimley Park Hospital NHS Foundation Trust,

Dermatology, Portsmouth Road, Frimley, GU16 7UJ, UK. E-mail: benjam-

[email protected]

Accepted for publication July 8, 2016

© 2016 Wiley Periodicals, Inc. 1

Review Article

improve the appearance of skin under the main pillars

of photoaging – wrinkles, dyschromia, and sallowness

– unlike nonsurgical procedures, the onset of action,

effectiveness, and tolerance for the latter are slow and

certainly not immediately observable, care has to be

taken when analyzing data purporting efficacy of

cosmetic products – data must be obtained from a

reliable assessment of photoaging when comparing

products.

Assessment of photoaging

Photoaging accounts for the largest proportion of cases

of extrinsic skin aging; it is characterized by its preco-

cious onset and such exaggerated characteristics as

coarse wrinkling, dyschromia, and sallowness that

form the basis of a descriptive grading scale used in

the assessment of cutaneous photodamage (Fig. 1).4

The earliest validated photonumeric scale described in

the literature was the Leeds scoring system for assess-

ing acne severity.5 Griffiths photonumeric scale

appears to be derived from a pre-existing facial acne

scale, with five high-quality, paired photographic stan-

dards (profile and oblique views) to which a photoaged

facial skin is graded against.6 It appears to be compre-

hensive and superior in consistency of getting the same

results amongst assessors/graders, and repeatability,

when compared against a basic descriptive scale – it

has been utilized in numerous studies aimed at com-

paring efficacies of “antiaging” cosmetic products are

available in the literature, in addition to the famous

Leiden Longevity Study that explored a link between

facial appearance and familial longevity.7 (Fig. 2)

Prevention and reversal of photoaging

Clinical signs of skin aging solely by the passage of

time rarely manifest prior to the seventh decade – pre-

mature skin aging result from the accumulative expo-

sure to environmental factors, amongst which

terrestrial UV radiation and sunlight has to be the

most important owing to it being the most ubiquitous

of all.8 Signs of photoaging can be categorized and

matched against histological changes of skin, in addi-

tion to examples of ingredients that have been

researched and developed to prevent, alleviate, or even

reverse these changes (Table 1) – this article will look

at these ingredients in greater details.

The scope of this article focuses on the prevention

and reversal of the process by the above-mentioned

cosmeceutical ingredients. The term “cosmeceutical” is

used to refer to skincare products formulated with

biologically active ingredients in the discussion. A

timeline of “land-mark” ingredients is illustrated below

(Fig. 3). Much of the available evidence comes from

the literature research – from manufacturers’ claims

with traceable references, to landmark studies refer-

enced by contemporary academic resources such as

textbooks.11 From the outset, the most direct approach

of photoprotection is sun avoidance (long-sleeves, sun-

hat, and avoidance of outdoor activities at peak UV

hours) and application of sunscreen.

Figure 1 Descriptive scale used in the assesment of cutaneous

photodamage*.

2 © 2016 Wiley Periodicals, Inc.

A contemporary review of cosmeceuticals . C-M Lee

Prevention

Sunscreens can be broadly categorized functionally

into absorbers and reflectors, which are comprised of

organic chemical compounds (benzophenones, avoben-

zone, ecamsule, methyl antranilate, salicylates, cinna-

mates, etc.) and the inorganic metal particles,

respectively. A summary of categories of some common

sunscreen ingredients used in cosmeceuticals is illus-

trated as follows11: (Fig. 4)

Organic compounds absorb solar UV radiation and

dissipate it by means of a series of exothermic reactions

or high wavelength (therefore low energy) irradiation

into the surrounds:

Benzophenones (benzophenone-3, oxybenzophe-

none) are predominant UVB absorbers (peak absorption

at 290 nm) with weak absorption of UVA that are

added as a secondary sunscreen ingredient in combina-

tion with other ingredients for several reasons:

• Benzophenones have the highest bioavailability out

of all sunscreen ingredients due to their being lipid

soluble and are readily absorbed systemically into

skin; there are reports of these compounds being

found in blood and urine samples of human sub-

jects following topical applications.17,18

• Because of its lipophilicity, high concentrations

may render the end product sticky and esthetically

unpleasant.

• They accounted for the highest incidence of photo-

dermatitis in the literature of the last decade.19

Avobenzone (also known as Parsol 1789) is a

highly effective UVA absorber with UVB coverage

(290-400 nm). It has the best safety profile amongst

all sunscreen ingredients but its photo-instability and

incompatibility with metal oxide sunscreen ingredients

renders it an unpopular choice until the issues are

negotiated by the combination with benzophenones

that confer photo-stability; such a formulation has

been marketed under the patent name of HelioplexTM:

Neutrogena division of Johnson & Johnson, New

Brunswick, NJ, USA (SPF70) by Neutrogena� (Neutro-

gena, Los Angeles, CA, USA).20

Ecamsule was another organic compound patented

by L’Oreal� (̂Ile-de-France, France) (1982) under the

trade name MexorylTM (L’Oreal�) to stabilize avoben-

zone.

Figure 2 CEM Griffiths et al. ©1992 “A photonumeric Scale for

the Assessment of Cutaneous Photodamage from Archives of Der-

matology”.4 Each of the five photographic standards (frontal and

oblique) is assigned a grade (even numbers) to indicate an inter-

val degree of photodamage. A nine-point scale is completed with

intermediate grades to fill in gaps (odd numbers) where 0 indi-

cates no photodamage and 8 being most severe. In this article, a

high degree of intergrader agreement illustrates reliability of the

scale upon comparison with a descriptive grading scale (see

below).



Methyl anthranilate is safe and effective organic

sunscreen ingredient frequently found in formulations

that confer photoprotection against UVA. Its stickiness

renders it esthetically unpleasant in higher concentra-

tions.21

Titanium dioxide and zinc oxide are metal oxides.

In the form of microparticles, these inorganic com-

pounds deflect and protect the skin beneath from solar

UV radiation. Nanoparticles have been developed in an

attempt to mitigate white streaks in cosmetically sensi-

tive areas on skin and/or clothing; for years, there

remained fear for possible systemic absorption through

the skin.20

Reversal of photoaging

All-trans retinoic acid acts as a hormone that is taken

up by cells to reach the nucleus, where it interacts

with the corresponding receptors, retinoic acid recep-

tors (RAR), and retinoid x receptors (RXR), to activate

or inhibit the transcription process of elements that

modulate keratinization of epidermis, synthesis of colla-

gen, and production of matrix metalloproteinases

(MMPs) – the antiwrinkle effect is therefore attributed

to the combined effect of stimulated pro-collagen I

synthesis, through a cell signaling pathway, and the

inhibition of UV-induced production of MMPs.12,22

Immunohistochemical evidence exists for the increase

in collagen content and thickening in epidermis in sec-

tions biopsied from all-trans RA-treated skin. In addi-

tion, for a mechanism not completely understood,

retinoic acid and derivatives seem to promote a rela-

tively minor lightening effect by suppressing expression

of the key enzyme tyrosinase in melanin (pigment)

synthesis.23,24 The current data available for molecular

mechanisms of all-trans RA’s effects on skin rejuvena-

tion have been summarized in a British journal article,

published in 2010 (extract, in Table 2).

Tretinoin has been the prescription only form of topi-

cal vitamin A since the beginning; it has been well

studied over the centuries, and its profile of side effects

has been predominately by irritability to skin – CEM

Griffiths (1992) illustrated the better of the two most

studied concentrations promoting similar effects on

photoaged skin. Based on an abundance of clinical evi-

dence, over-the-counter retinoids are developed from

such intermediate forms as retinol and retinyl esters

(the least irritating of two) that may produce the same

effects and side effects but to a lesser degree26; these

chemicals are unstable upon exposure to sunlight and

Table 1 A summary of main characteristics of photoaged skin with their histological correlates on which cosmeceutical products are

researched and developed

Characteristics of photoaging andunderlying mechanisms Additional information Examples of topical therapies/cosmeceutical ingredients

Sallowness and uneven texture due

to accumulation of elastotic material.

Poor quality of keratinization due to

slowing of differentiation process

and subsequently shedding of

squamocytes lead to enlarged and

clogged pores.

UVR induces reactive hyperproliferation of

keratinocytes at some sites and apoptosis

in others.9 An abundance of dystrophic

elastotic materials in place of healthy elastic

fibers that are now degraded and damaged

either directly by photochemical reaction or

indirectly via generation of reactive oxygen

molecules (RoS) and metalloproteinases

(MMP) 8 – in a process known as

solar elastosis.

Sunscreens (benzophenone, avobenzone, ecamsule,

methyl anthranilate, metal oxides) to block skin

interaction with UVR; hydroxyl acids (AHAs, PHAs,

bionic acids) to exfoliate in low concentrations

and induce renewal of keratinization by

epidermolysis in high concentrations; vitamin

B3 and its derivatives to regulate keratinization

whilst conferring antioxidative effects.

Coarse wrinkles secondary to loss

of major extracellular matrix (ECM)

components and as a consequence

the loss of firmness. Dehydrated

skin is marked with finer

wrinkles.

Photoaging is predominantlycharacterized by wrinkling

in Fitzpatrick skin types I-III.

Reduced density of dermal collagen as a

result of UVR induced breakdown either

directly or indirectly via generation of MMP;

thinning of epidermis and impaired barrier

function of skin results in profound

dehydration

Sunscreens as above. Retinoids (retinaldehyde,

retinol, retinyl propionate) to promote thickening

of epidermis, stimulate synthesis of procollagen

I and thence dermal collagen; peptides (pal-KTTKS)

stimulate collagen synthesis and improve barrier

function.10 Polyhydroxy/bionic acids are large

molecule hydroxyl acids that are strong humectants.

Dyschromia is the uneven skin tone

found in photoaged skin; it is

predominant in aging skin amongst

darker skin types. Such is the result

of clumping of melanocytes induced

by UVR exposure.

Lentigines result from a fundamental increase

in melanocytes in basal epidermis; ephilides

(freckles) due to accumulation of melanin

(pigment) in the more superficial layers,

more common in summer months and

in younger, fairer skin types.

Sunscreens as above. Antioxidants to enhance

photo-protective effects of sunscreens. Sugar

amines such as N-acetyle glucosamine (NAG)

and botanicals such as kojic acid, liquorice extract,

and arbutin are effective lightening agents to

skin tone.



atmospheric oxygen; therefore, extra caution must be

taken with storage. (Fig. 5)

Topical antioxidants

Antioxidants confer ability of the skin to ameliorate

oxidative stress in addition to the various molecular

components of skin with intrinsic antioxidant proper-

ties.29 Humans lack the ability to synthesize vitamin C

due to a mutated gene present in most mammals 29,30

and therefore are reliant on dietary source. Only a

small proportion of what is absorbed will end up in the

skin – topical vitamin C needs to be in high

concentration (15% L-ascorbic acid) in order to

achieve efficacy; it has an in vivo half-life of 4 days

when applied on skin, and any exposure to oxidative

stress would deplete its content in a neutralizing reac-

tion – the ideal pH for the stabilization of a solution of

pure vitamin C is acidic, at pH 3.5.31

Either vitamin C or vitamin E alone is ineffective in

preventing UV radiation-induced skin damage, as

manifested in skin erythema (sun burn); Halperin,

et al. (1993) demonstrated the lack of effect of topical

15% L-ascorbic acid alone on radiation dermatitis –topical 15% vitamin C (L-ascorbic acid) in combi-

nation with 1% vitamin E (alpha-tocopherol)

Figure 3 The popular use of the term cosmeceutical originates from the discovery of the antiaging effect of topical retinoic acid and

derivatives on skin by Dr Albert Kligman PhD in 1984.12 In 1989, two researchers Dr Eugene Van Scott and Dr Ruey Yu PhD presented

alpha hydroxyl acids as chemical compounds with cosmetic properties, 10 years after their discovery of their molecular effects on skin.13

This was followed by the development of topical antioxidants formulated with vitamins C and E.14 In 2009, a double-blind, randomized

controlled trial 15 that illustrated efficacy in some contemporary cosmeceutical created a shopping frenzy for that product, which was

hailed by the media as “the miracle ingredient”. The cosmetic companies behind these studies with or without historical affiliations with

the researchers have thrived in brand management in the name of science for the decades to come.

Figure 4 Representation of the ultraviolet (UV) component of the electromagnetic spectrum, copyright © 1997.16 Each organic com-

pound tends to have a specific target range of UV radiation for photochemical reaction/absorption, whilst inorganic compounds which

are largely tiny particles of minerals or metals would deflect UV beams indiscriminately – cosmeceuticals in today’s market are largely

formulated with not one but several ingredients to achieve broad spectrum photoprotection.



provide synergistic protection against oxidative stress

in skin32; 2 years later, the same authors suggested

that adding ferulic acid (a botanical chemical, a

potent phenolic antioxidant found in plants) to vita-

mins C+E results in a fourfold increase in protection

against UV-induced photodamage.33 In this study,

higher minimal erythematous doses (MED) are

required to activation of caspases that are markers of

cell death response to the exposure of UV radiation,

concluding that skin saturated in a solution of ferulic

acid added into a solution of vitamins C+E has

reduced clinical erythematous and immunological

response to UV-induced damage.

Vitamin B3, or niacin, is interconvertible with niaci-

namide. It is a precursor molecule to a vast number

of coenzymes that play a role in neutralizing oxidative

stress in over 40 cellular biochemical reactions.34

Studies are largely randomized controlled trials looking

at the in vivo effects of topical niacinamide (2-5%) of

using sophisticated specialized skin analysis imaging

systems that capture high-quality, standardized facial

images.35–37 The antiaging effects an overall improve-

ment of skin barrier (reduced TEWL and facial red

blotchiness) and skin tone (with reduced sallowness), a

reduction of fine wrinkles, and reduction of hyperpig-

mentation.38 Like most other antioxidants, niaci-

namide is chemically unstable when exposed to the

atmosphere. One author who is the leading figure in

research and development of topical niacinamide has

suggested formulating products in the pH range of 4–7to avoid hydrolysis (it converts niacinamide to nico-

tinic acid that is irritant to skin);38 nicotinate esters

such as tocopheryl nicotinate and methyl nicotinate

have been developed to address skin irritability but

evidence for efficacy is meager.

Hydroxy acids

Alpha hydroxyl acids (AHAs) are amongst the first to

be discovered (Table 1) and developed for skin rejuve-

nation in two formulations13: In high concentrations

(e.g., glycolic acid 35% and above), these promote epi-

dermolysis exfoliation and effectively producing a

chemical peel; in low concentrations, they normalize

epidermal layers by thinning stratum corneum whilst

promoting thickening of granular layer. Polyhydoxy

(PHA)/bionic acids were subsequently developed that

would rectify the irritating effect of alpha hydroxy

acids on skin, whilst retaining their skin rejuvenation

effects. One in vitro study used simulated solar radia-

tion (SSR) on cultured murine fibroblasts, treated with

gluconolactone (a PHA) in various concentrations, to

demonstrate some activity in suppressing solar elasto-

sis, via downregulating the gene responsible for the

UV-induced production of dystrophic elastic fibers.39 In

addition, antioxidative properties of gluconolactone

and lactobionic acid have been demonstrated with the

inhibition of oxidative discoloration of banana peels to

the atmosphere.11 (Table 3)

Peptide cellular messengers

Peptides are long-chain molecules made up of build-

ing blocks of protein, the amino acid molecules. In

Table 2 A schematic representation of retinoid effects on skin, courtesy of Medscape ©201025

Molecular mechanisms Histological/ultrastructural features Clinical effects

� Increased collagen synthesis:

o Inhibition of the UV-induced c-Jun

o Alteration in the TGF-beta expression

� Inhibition of collagen degradation:

o AP-1 mediated MMP inhibition

� Collagen rich “repair zone” in

upper papillary dermis

� Increased collagen I, III and VII (anchor fibrils)

� Reorganization of dermal collagen into

woven bundles of fibers� Normalization of elastic tissue organization

� Increased angiogenesis

Improvement of coarse wrinkling

� Initiation of increased epidermal proliferation

o EGF receptor activation via specific induction

of its ligands heparin-biding EGF

and amphiregulin

� Increased epidermal differentiation

� Stimulated transglutaminase, involucrin,

and fillagrin expression

� Epidermal hyperplasia

� Compaction of the stratum corneum

� Thickening of the granular layer

� Increased epidermal and dermal

intercellular mucin deposition

Increased skin smoothness and

decreased roughness

� Inhibition of tyrosinase activity

� Inhibition of melanosome transfer

� Physicochemical UV photoabsorption

� Decreased melanin content

� Enhanced keratinocyte shedding

� Reduced size of melanocytes’ Golgi

complex and endoplasmic reticulum

Improvement of skin

discoloration/dyschromia



cosmetics, peptides’ long-chain structures rendered

the molecules lipophilic: able to absorb water content

and confer hydration to the corneal layer of skin as

a strong humectant. However, in recent years, new

scientific interests have evolved into the use of pep-

tides as cellular messengers – cells communicate and

modulate activities by means of protein molecules

(peptides) being secreted from one cell and inserted

Figure 5 In this diagram, sourced from Bickers & Athar ©2006, reactive oxygen species, ROS (O2� and H2O2), and reactive nitrogen

species, RNS (NO), are generated to promote oxidative stress by lipid peroxidation.27 The cascades of reactions that promote the conver-

sion of these reactive species to the even more highly reactive groups of molecules are initiated by the exposure of skin cells to solar radi-

ation (UVA and UVB, bottom left) and chemicals (termed xenobiotics in this representation, top left) from the environment. Antioxidants

in skin include the soluble glutathione and ascorbic acid (vitamin C), in addition to the lipophilic alpha-tocopherol (vitamin E).28 Within

each skin cell enzymes, such as glutathione (GSH), GSH reductase, superoxide dismutases (SOD), GSH peroxidase, catalase, and quinone

reductases (QR, top left), act to neutralize reactive species by converting them to less reactive and/or nontoxic particles.

Table 3 Antiaging effects of hydroxyl acids

Hydroxy acids Histological effects Clinical effects Evidence

Alpha hydroxy acids (glycolic,

citric, lactic, mandelic acids)

Epidermal: low concentration ↓melanin

clumping, normalizing proliferation of

keratinocytes Dermal: ↑ collagen, ↑ GAGs

↓mottled pigmentation and

sallowness, ↓fine wrinkles,

↑skin firmness

40–43

Polyhydroxy acids (gluconolactone) Epidermal: ↑ thickness with normalized

stratum corneumDermal: ↑GAGs (HA) Antioxidativeactivity; minimizing solar elastosis;

A large molecule with slower

absorption and therefore ↓irritationand a humectant; ↓TEWL and

irritant erythema with ↑protectivebarrier

39

Polyhydroxy bionic acids

(lactobionic, maltobionic acids)

As above Also a strong humectant, nonirritant;

same action as alpha hydroxyl

acids at epidermal and dermal levels.

44

Alpha hydroxyl acids have been shown in in vivo studies to rebuild dermal extracellular matrix components, by stimulating syntheses of

procollagen I and glycoasminoglycans (GAGs) of which hyaluronic acid (HA) are predominant,40 and normalize cellular layers in the

epidermis,13 in addition to a reduction in uneven pigmentation illustrated in various in vivo studies that was illustrated by a dose-depen-

dent decrease in melanin deposition in vitro by mouse and human melanoma cells42; they are nonetheless highly irritating to skin. Poly-

hydroxy/bionic acids are referred to as the second- and third-generation hydroxyl acids, respectively. These acids have acquired a larger

molecular structure and thence properties of a strong humectant. Human studies performed with patch testing with 0.1% sodium lauryl

sulfate (SLS) solution demonstrated an anti-irritant property 11 on a par with an improvement of barrier protection by the skin. Evidence

is provided by selected randomized controlled studies utilizing clinical (digital imaging) and histological methods.45



into another – amongst many peptides that have

been developed to reduce wrinkles by targeting

fibroblasts and stimulating collagenesis, one of the

best known palmitoyl peptides has been developed by

French manufacturer Sederma� (Sederma, Croda

International Group, Le Perray-en-Yvelines, France),

made up of palmitoyl-lysine, threonine, threonine,

lysine, and serine (hence the abbreviated name pal-

KTTKS).46 At a molecular level, this peptapeptide is

a fragment of procollagen I; as long-chain polypep-

tides are poorly penetrated into skin, the more lipo-

philic compound has been developed by

palmitoylation; such is rooted in an in vivo study

demonstrating an enhanced absorption of a peptide

drug.47 In one in vitro experiment, KTTKS has

demonstrated efficacy in stimulating production of

collagen in cultured fibroblasts.10 In a double-blind,

randomized, placebo-controlled trial setup by

researchers in the United States, digital facial imag-

ing offered the best objective evidence of significant

improvement in skin texture with reductions in wrin-

kles at 8 weeks,48 without a report of skin intoler-

ance.

Growth factors and cytokines

These are naturally occurring signal protein molecules

involved in an inflammatory response in wound heal-

ing; such has triggered research and development of

applying physiologically balanced ingredients into topi-

cally applied products – cosmeceuticals.49 Such mini-

mally invasive procedures as dermabrasion and

microneedling are based upon the idea of simulating

wound healing to achieve skin rejuvenation; growth

factors and cytokines are secreted by various skin cells

to activate fibroblasts, stimulate collagenesis and colla-

gen remodeling, in order to aid tissue regeneration and

wound healing.50

Topical transforming growth factor (TGF)-beta 1 has

been extracted from neonatal dermal fibroblasts in an

in vivo study to develop a novel skin cream containing

a mixture of human growth factors and cytokines.52

Histology and ultrastructural analysis have demon-

strated evidence of skin rejuvenation with thickening

of epidermis, and reduced solar elastosis and neocolla-

genesis (Fig. 6), which correlates well with the

improved appearance of skin texture and wrinkles after

6 months of twice daily topical application of study

cream (PSPTM – processed skin cell proteins; Neocutis,

Inc., San Francisco, CA, USA). The authors have pur-

ported a positive correlation between an increased pro-

duction of thinner collagen fibers and fibroblast

density.49 However, whether the findings of an

increase in collagen III fibers being represented by the

appearance of thinner fibers in the papillary dermis,

and such an increase being truly representative of neo-

collagenesis, remains debatable. (Fig. 7)

In addition, TGF-beta 1 appears to mediate lighten-

ing effects effected by adipose tissue stem cells (ASC-

CM), through an increased degradation of such

important copper-containing enzymes for melanin

production as tyrosinase and tyrosinase-related pro-

tein 1.53 On that note, stem cells derived from Swiss

Uttwiler Spatlauber apple trees have been extensively

Figure 6 Extract, all rights reserved S Werner, R Grose. 2003 © Physiological Reviews 51 “Multiple functions of TFG-b during wound heal-

ing”. TFG-b is produced by skin cells including fibroblasts and keratinocytes during wound healing to stimulate formation of new blood

vessels, collagen fibers, and remodeling of ECM. TFG-b also regulates epithelial thickness by an inhibitory process.



studied in vitro for their potential effects of skin reju-

venation.54 Whilst cosmeceutical products that con-

tain Swizz apple stem cell extract have been

developed with purported antiwrinkle effects evident

in as little as 2 weeks,55 insufficient data are avail-

able as evidence of a plausible mechanism of action

and further research is needed.

Skin-lightening agents

For more than half a century, hydroquinone in low

concentrations (2%) had been the gold standard over-

the-counter (OTC) treatment for dyspigmentation; it

binds onto the pigment-producing enzyme tyrosinase

to inhibit its activity, thereby inhibiting melanosome

production. Due to controversies over the safety of

hydroquinone in cosmeceutical products – the most

fearsome of which was a possible association with

malignancies – numerous isolated reports have been

gathered from the literature, dated to the first decade

of this century.56 The need for an alternative skin-

lightening agent has led to enhanced research and

development of some of the currently widely available

ingredients in cosmeceuticals, such as topical retinoids,

vitamins C and B3, in addition to several others as out-

lined below: (Table 4)

Discussion

Photoaging remains the biggest contributing factor

for facial aging; three major signs of photoaging are

wrinkles, dyschromia, and sallowness. Whilst this is

only additional to the changes in facial contours

with aging, which would require surgical and

Figure 7 Courtesy of Dr Mussarrat Hussain, MD 52# 2008 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS); (top) electron

microscopy demonstrating a slight decrease in coarse type I collagen fibers (>60 nm) and a 58.4% increase in finer type III fibers were

evidence 6 months after treatment (b). (bottom) under light microscopy, an increased density of fibroblasts in the dermis beneath a

thickened epidermis is evident after treatment (b).



nonsurgical procedures to achieve a reversal of signs,

research and development into finding the “perfect

cream” has been robust, thanks to the major break-

throughs in the discovery of numerous botanical

ingredients that have subsequently led to develop-

ment of cosmeceutical products accumulated in the

market today. In addition, the methodology in assess-

ing severity of photoaging has evolved over the

years, from being descriptive and rather subjective,

to becoming reliably reproducible and objective, with

the help of digital imaging.

The prevention and reversal of photoaging come in

as part of a package in facial rejuvenation. Prevention

is achieved by sun avoidance and application of sun-

screen in regular intervals. Active ingredients of sun-

screens can be categorized into reflectors and

absorbers, with each of absorbers having a specific tar-

get range of UV radiation for photochemical reaction/

absorption and therefore would require combination

when formulating a broad spectrum, fit-for-all sun-

screen, whilst the largely broad spectrum inorganic

reflectors come with leaving the white streaks of metal

oxide particulates that remain much undesired. Cases

of photo-dermatitis, oily formulations, and the funda-

mental necessity for regular application may render it

unpopular for some.

Reversal of photoaging has unfortunately been

used excessively by the marketing in cosmetic indus-

try – much of the scientific basis and research back-

ing for most of cosmetic products remain meager,

with only a handful remain worthy of literature

research where materials are available – from ran-

domized controlled experiments illustrating in vitro

effects of a botanical ingredient, to the large-scaled

trials demonstrating in vivo efficacies with modifica-

tions to skin evident at the histological level. Herein,

I have listed and described the most promising ingre-

dients found in cosmeceuticals, with the backing of a

plausible mechanism of action, a valid in vivo

research evidence for efficacy at treatment the major

signs of facial photoaging: wrinkles, dyschromia, and

sallowness, whilst leaving room for imagination with

the potential of research in stem cell therapy for

facial rejuvenation.

Whilst there is no such “perfect cream” in one single

formulation for both the prevention and treatment of

photoaging available to date, research and develop-

ment for novel ingredients may lead to a change of

culture of the modern cosmetics industry to one that is

more scientific research, and less commercial market-

ing, driven. High-powered, good quality clinical studies

to look at efficacies and side effects of cosmeceutical

Table 4 A summary of the most common pigment-lightening cosmeceutical ingredients with mechanisms of action supported by in vitro

studies and available evidence of efficacy found in the literature

Cosmeceutical ingredients Mechanism of action Evidence

N-acetyl glucosamine (NAG), a precursor molecule

to hyaluronic acid, which is an ECM component

known collectively as glycoaminoglycans (GAGs)

Inhibition of the activation of melanin-producing

enzyme tyrosinase, also a strong humectant

due to its hydrophilic molecular structure

Mechanism of action is rooted in an invitro study.57 Topical use of 2% NAG

results in reduction in facial

hyperpigmentation 58 and more so when

combined with 4% niacinamide.59

Kojic acid, found as a by-product in malting rice,

derived from fungi (Aspergillus and Peniciliium

species) during fermentation process.

Chelation of copper (an important cofactor

constituent of the enzyme) and thereby inhibits

the production of melanin by tyrosinase.

A comparative study looking at

combinations of glycolic acid + kojic acid

versus glycolic acid + hydroquinone

indicates equivocal efficacies in the

treatment of melasma,60 but skin

irritability remains an issue; cases of

contact dermatitis exist for the topical

use of kojic acid 61

Liquorice extract contains a number of active

pigment-lightening agents known as flavonoids

that act to inhibit melanogenesis at various

levels of the pathway.

Liquirtin contained in the extract disperses

melanin; glabridin acts on tyrosinase and

inhibits melanogensis 62 other chemicals

within it confers an anti-inflammatory effect

and therefore render it nonirritating to skin 61

In vivo studies indicate some therapeutic

value in treating postinflammatory

hyperpigmentation 63 but efficacy

appears minimal in comparative

studies 64

Arbutin is a botanical ingredient extracted from

the bearberry plant and is used in a variety of

products manufactured in Japan and is a

common pigment-lightening ingredient in many

cosmeceutical formulations marketed in the

United States.65

It is glycosylated hydroquinone.66 It inhibits

activity of tyrosinase as well as melanosome

maturation via extracellular signal-related

protein kinase (ERK) activation67; tyrosinase

activity is inhibited without altering

intracellular RNA expression.

Efficacy is concentration-dependent,

with 3% being commonly used in

common cosmeceuticals, beyond which

concentration there are reports of

postinflammatory hyperpigmentation.61



products as one formulation of a mix of ingredients

remain an area to explore.

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