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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-
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).
© 2016 Wiley Periodicals, Inc. 3
A contemporary review of cosmeceuticals . C-M Lee
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.
4 © 2016 Wiley Periodicals, Inc.
A contemporary review of cosmeceuticals . C-M Lee
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.
© 2016 Wiley Periodicals, Inc. 5
A contemporary review of cosmeceuticals . C-M Lee
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
6 © 2016 Wiley Periodicals, Inc.
A contemporary review of cosmeceuticals . C-M Lee
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
© 2016 Wiley Periodicals, Inc. 7
A contemporary review of cosmeceuticals . C-M Lee
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.
8 © 2016 Wiley Periodicals, Inc.
A contemporary review of cosmeceuticals . C-M Lee
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).
© 2016 Wiley Periodicals, Inc. 9
A contemporary review of cosmeceuticals . C-M Lee
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
10 © 2016 Wiley Periodicals, Inc.
A contemporary review of cosmeceuticals . C-M Lee
products as one formulation of a mix of ingredients
remain an area to explore.
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