QUESTIONS • CHALLENGES • CONTROVERSIES

Section Editor: James Q. Del Rosso, DO, FAOCD

products, and failure to discern “fiction

How Much Do We Really

from fact” related to unsubstantiated
claims made by some OTC anti-aging
skin care products. A cosmeceutical

Know About Our Favorite

product by definition is a cosmetic
product in which the active ingredient
is meant to have a beneficial

Cosmeceutical Ingredients?
physiological effect due to an
enhanced pharmacological action
when compared with an inert
Jacquelyn Levin, DO; James Q. Del Rosso, DO, FAOCD; cosmetic.1
Every day in clinical practice,
Saira B. Momin, DO dermatologists see patients who ask
them if cosmeceutical products are
beneficial. Accurate advice is a
challenge that requires knowledge of
clinicians are able to adequately the structure and function of human
Abstract answer questions about permeability, skin and the available scientific data,
To date, we are unaware of a review mechanism, and clinical effect. Both which may or may not support the
that has investigated common green tea and soy have been efficacy of a given cosmeceutical
cosmeceutical ingredients in order to popularized commercially based on product. As dermatologists, it is very
answer the three specific questions their antioxidant effects, yet there is a hard for us to keep up with the latest
proposed by the father of paucity of clinical studies concerning evidence on the popular cosmeceutical
cosmeceuticals, Dr. Albert Kligman. It their efficacy as topical anti-aging ingredients due to the vastness of
is the goal of this review to gather all agents. It may be that soy and green ingredients, the multitude of
the published scientific data on five tea are better at preventing the signs commercially available products and
common cosmeceutical ingredients, and symptoms of skin aging than their efficacy claims, and the validity
answer the three major questions actually reversing them. Since or accuracy of data gleaned from in-
about the scientific rationale for their cosmeceutical products are claiming to vitro and clinical studies, if available.
use, and ascertain how much we really therapeutically affect the structure
know about consumers’ favorite and function of the skin, it is rational What questions need to be asked
cosmeceutical ingredients. and necessary to hold them to when scientifically evaluating the
Most of the research concerning specified scientific standards that potential therapeutic merits of a
cosmeceutical retinoid ingredients is substantiate efficacy claims. cosmeceutical?
based upon the effects of retinoic acid According to Dr. Albert Kligman,
on the skin. Clinical trials concerning Introduction when asked to evaluate a new
retinol and retinaldehyde are scant Increasingly, patients are looking for cosmeceutical product that claims a
and lacking in statistical evaluation for cost-effective noninvasive methods to beneficial physiological effect, it is
significance. There is research improve the appearance of their skin. important to ask three questions:
substantiating the effects of kinetin in Many patients are turning away from 1. Can the active ingredient penetrate
plants and also in-vitro antioxidant prescription medications and medical the stratum corneum (SC) and be
effects. However, proof of anti-aging procedures and are instead delivered in sufficient
activity remains elusive, and the considering over-the-counter (OTC) concentrations to its intended
clinical efficacy of kinetin is based on treatments, such as cosmeceuticals. target in the skin over a time course
limited data. Niacinamide is the Factors that cause patients to switch consistent with its mechanism of
ingredient investigated that most to OTC products include lack of action?
closely upholds the “Kligman adequate insurance coverage for 2. Does the active ingredient have a
standards” of cosmeceutical-ingredient prescription products used to treat known specific biochemical
analysis. With the available scientific photoaging, the need to pay for mechanism of action in the target
evidence on topical niacinamide, physician visits to obtain prescription cell or tissue in human skin?

QUESTIONS • CHALLENGES • CONTROVERSIES

22 [ February 2010 • Volume 3 • Number 2]

3. Are there published, peer-reviewed, have mechanisms of action on cellular reviews the evidence on penetration of
double-blind, placebo-controlled, components that regulate the SC, the mechanism of action, and
statistically significant, clinical trials physiological functions (i.e., inhibition the anti-aging effects on skin based on
to substantiate the efficacy claims?1 or activation of enzymes involved in clinical studies.
(Table 1.) signal transduction or gene
To date, we are unaware of a review expression).2 Surprisingly, some What background information is
that has investigated common popular cosmeceutical ingredients available on cosmeceutical
cosmeceutical ingredients in order to have mechanisms that are currently retinoids?
answer these three specific questions. unknown and require further research. Retinoids consist of natural and
It is the goal of this review to gather If a viable biochemical or synthetic derivatives of vitamin A that
the available published scientific data pharmacological mechanism of action can be found in both prescription
on five common cosmeceutical exists, and the product can reach its medications and OTC cosmeceuticals.
ingredients, to answer the three major target at sufficient concentrations for a Retinoic acid (RA) as well as the
questions described above, and to long enough duration, the product synthetic napthalene derivatives
ascertain how much we really know deserves further clinical adapalene, tazarotene, and bexarotene
about our consumers’ favorite experimentation, preferably a are registered prescription drugs. The
cosmeceutical ingredients. randomized, double-blind, vehicle- topical cosmeceutical retinoids include
The first question addresses controlled clinical trial. retinyl esters, retinol, retinaldehyde,
whether the active ingredient Clinical trials should include the use and the group of oxoretinoids.4
penetrates the SC. The SC is an of noninvasive instrumentation, which RA has been extensively studied
effective barrier to transepidermal measures characteristics such as and used as an effective topical
water loss (TEWL) and to the TEWL, corneometry, skin elasticity, treatment for photoaging, acne, and
penetration of exogenous substances. colorimetry, surface replica analysis, numerous other dermatological
Typically, the substances that cannot and other techniques that can be used disorders. RA can, however, be
penetrate the SC easily include: to assess efficacy claims. Pretreatment irritating to the skin, limiting its use in
proteins, sugars, peptides and nucleic and post-treatment photography alone some patients. Retinol (ROL) and
acids with molecular weights greater are not adequate because there are retinaldehyde (RAL) are of interest to
than approximately 1000kDa, and major pitfalls in standardized clinical the scientific community and cosmetic
highly charged molecules.1 photography. In addition, it is difficult industry as gentler yet still effective
In addition, it is important to to measure appearance clinically alternatives to RA. However, the other
determine if the ingredient is delivered because it is highly subjective and cosmeceutical retinoids, retinyl
in sufficient concentrations to its endpoints are difficult to establish. palmitate and retinyl-acetate, are
intended target in the skin to produce The pitfalls of published clinical trials retinoid esters and are not considered
the desired effect. The minimum to date are that many of the reports effective against photoaging and
concentration of ingredient required to are anecdotal, have been performed therefore are not discussed in this
produce the desired effect is termed on small groups of patients, and review.4,5
the threshold concentration and is statistical significance has not been In the skin, ROL is oxidized into
important for evaluating cosmetic well established. RAL, which in turn is oxidized into
formulas. Another way to demonstrate the RA, the biologically active form of
If the agent meets the first effects of a product is histology. The vitamin A. Topical cosmeceuticals
criterion, that is penetration of the SC histological changes of photoaged skin containing ROL and RAL are
in an amount exceeding the threshold are well documented. Demonstration theoreticized to work because once
concentration, the second question of reversal of histological features of absorbed they are metabolized to RA,
follows intuitively. The second photoaging is another approach to which induces pharmacological
question asks if there is a known substantiate efficacy claims for the activity. Given this consideration, not
biochemical or pharmacological reversal of photoaging.3 only is the percutaneous absorption
mechanism of action for this active This next section presents a profile of ROL and RAL important to
ingredient to substantiate the summary of the published scientific its effectiveness, but the metabolism
marketing claim. Most data of five popular cosmeceutical of ROL and RAL to RA is just as
pharmacologically active ingredients ingredients. Specifically, this article important.

QUESTIONS • CHALLENGES • CONTROVERSIES

23 [ February 2010 • Volume 3 • Number 2] 23

TABLE 1. Three major questions used to evaluate cosmeceutical ingredients1 formation of RA from these substances
constitutes a small proportion of the
Can the active ingredient penetrate the stratum corneum and be metabolites formed. However, whether
QUESTION 1
delivered in sufficient concentrations to its intended target in the skin? this conversion is sufficient for
pharmacological activity is unknown.
Does the active ingredient have a known specific biochemical
QUESTION 2 In-vivo studies may better quantify
mechanism of action in the target cell or tissue in human skin?
both metabolism and dose-response
Are there published, peer-reviewed, double-blind, placebo-controlled, relationships.6
QUESTION 3
statistically significant, clinical trials to substantiate the efficacy claims?
What are the potential mechanisms
of action of retinoids?
What data is available on the also be considered that concentrations ROL and RAL are metabolized to
percutaneous absorption and above 0.025% may not induce greater RA in the skin and therefore, are
metabolic activity of retinoids? penetration or metabolism to RA. assumed to exhibit the same
In general, retinoids are lipophilic In another experiment, metabolism mechanism and clinical effects as RA
molecules that can penetrate the of ROL, RAL, and RA was studied (Table 2B). Of these effects, the
epidermis.6 One study demonstrated utilizing in-vitro human skin and surface roughness, mottled
the specific penetration characteristics dermal fibroblasts.8 Radiolabeled ROL hyperpigmentation, and fine wrinkles
of ROL and RAL in human skin in and RAL were applied either topically demonstrate the most significant
vivo by measuring levels of the skin to the skin biopsies or to the culture improvement with RA therapy.9
enzyme cytochrome P-450-dependent media of the fibroblast suspension and Although ROL- and RAL-containing
RA 4-hydroxylase (CP450-RAH) the metabolites were identified by cosmeceuticals have not been shown
(Table 2A).7 The enzyme CP450-RAH high-performance liquid to produce the magnitude of clinical
is induced by presence of RA in the chromatography (HPLC) after 24 results obtained with the prescription
skin and therefore its induction can be hours of incubation. The skin cultures products that are approved and used
used as an indicator of ROL and RAL demonstrated a gradient distribution to treat photoaging (tretinoin,
penetration and metabolism to RA. of the retinoids within the skin: 75 tazarotene), many consumers appear
The study found a significant percent of absorbed activity was in the to be pleased with their cosmetic
induction in this enzyme following epidermis, 20 percent in the dermis, results anecdotally.
topical application of ROL and RAL to and 2 to 6 percent in the culture Hyperpigmentation. RA is
human skin in vivo. After 48 hours of medium for the three retinoids tested. thought to reduce mottled
occlusion, both ROL and RAL (0.025% Of the epidermal extracts, 60 percent hyperpigmentation by enhancing
and greater) increased the enzyme of applied ROL remained epidermal cell turnover. Enhancing
activity significantly while lower unmetabolized. The main ROL epidermal cell turnover decreases the
concentrations did not cause metabolites in the epidermis were contact time between keratinocytes
significant induction.7 Interestingly, the retinyl esters (18.5%), RA (2%), RAL and melanocytes and promotes a rapid
increase in enzyme induction was not (1.6%), 13-cis-retinoic acid (1%), and loss of pigment through
linear and higher doses of ROL and polar compounds. The dermis yielded epidermopoiesis.10
RAL only caused small increases in similar metabolites, but a higher Fine lines and wrinkles. RA
enzyme activity. However, it should be proportion of polar compounds. RAL therapy reduces fine lines and
noted that at lower doses (0.01% and was also metabolized in the epidermis, wrinkles by increasing the capacity of
0.025%), RAL was a greater inducer of with 43 percent of the absorbed the epidermis to hold water through
CD450-RAH than ROL.7 Given the radioactivity being RAL, 9 percent stimulation of glycosaminoglycan
results of this study, it seems the retinyl esters, 14 percent ROL, and 0.8 (GAG) synthesis and by stimulating
threshold concentration for adequate percent RA.8 collagen synthesis through increases in
penetration and metabolism of RAL Collectively, several studies have transforming growth factor (TGF-
and ROL into RA is 0.025%. Hence, it therefore demonstrated an absorption beta) and procollagen.9–12 Furthermore,
is important that the concentration of and metabolic capacity for topical ROL it is believed that RA may also retard
RAL and ROL in cosmetic formularies and RAL.7,8 Retinyl esters appear to be or prevent further dermal matrix
be at least 0.025%. However, it must the major metabolite, while the degradation by inhibiting the enzymes

QUESTIONS • CHALLENGES • CONTROVERSIES

24 [ February 2010 • Volume 3 • Number 2]

that break down collagen and TABLE 2A. Summary of penetration data
preventing oxidative stress.11,13–17
Roughness. RA therapy reduces INGREDIENT DOES IT PENETRATE?*
skin roughness by modulating the
expression of genes involved in cellular • Retinoids are lipophilic molecules that penetrate the epidermis.6
differentiation and proliferation, hence • Penetration of ROL and RAL investigated in vivo by measuring
levels of the skin enzyme CP450-RAH with results showing
promoting epidermal cell turnover.9,11
significant penetration and metabolism of ROL and RA.7
The effects are believed to be • Metabolism of ROL, RAL, and RA was studied using in-vitro
mediated through binding to retinoic Retinoids human skin and dermal fibroblasts. Radiolabeled ROL and RAL
acid receptors (RAR) and subsequent were applied to skin biopsies or to a culture media of the
binding of these complexes to specific fibroblasts. Metabolites were identified by HPLC. Analyses
genes affecting gene transcription.18,19 demonstrated a gradient distribution of the retinoids within the
skin and metabolism of ROL and RAL to RA (2% and 0.8%,
What clinical studies are available respectively).8
on cosmeceutical retinoids? Kinetin • No published studies found to date on permeation alone.
There are extensive clinical trials
investigating the anti-aging effects of • Studies demonstrate significant penetration into human skin.48,49
topical RA (Table 2C). RA is Niacinamide • Increased levels of NAD have been used as evidence of
considered to be one of most effective percutaneous penetration.50
and well-substantiated compounds for
treating the signs and symptoms of • Results demonstrate that the ionized form of soy isoflavone
aging and/or photodamaged skin, has lower percutaneous absorption compared to non-ionized
including fine lines, hyperpigmented Soy isoflavones form of soy.98,99
spots, and wrinkles.10,20,21 However, few • Results showed that soy can permeate through the SC and can
studies have been reported for the reach viable layers of the epidermis and dermis.95,96
OTC retinoids. Here, the authors
Soy protease
present the results of studies • No published studies found to date on permeation alone.
inhibitors
investigating the anti-aging effects of
RAL and ROL. • EGCG is inherently hydrophilic, limiting its penetration in
Some studies have reported that Green tea human skin.113
RAL can produce significant clinical • No published studies found to date on permeation alone
improvement in the appearance of fine *Common abbreviations: AGE (Advanced glycation end products), BBI (Bowman-Birk
and deep wrinkles.10,22 In one study, the Inhibitor), CP450-PAH (cytochrome P-450-dependent RA 4-hydroxylase), DNA
efficacy of RAL 0.05% cream for the (deoxyribonucleic acid), EGCG (epigallocatechin gallate), GAG (glycosaminoglycans), GSH
treatment of photoaging was (glutathione), GST (glutathione-S-tarnsferase), H2O2 (hydrogen peroxide), HPLC (high
compared to 0.05% RA and vehicle performance liquid chromatography), NAD (niacinamide adenosine dinucleotide), RA
creams over an 18-week time period.22 (retinoic acid), RAL (retinaldehyde), ROL (retinol), ROS (reactive oxygen species), SC
A total of 125 patients (40 in the RA (stratum corneum), SOD (superoxide dismutase), STI (soybean trypsin inhibitor), TEWL
group, 40 in the RAL group, and 45 in (transepidermal water loss), TGF-B (transforming growth factor-beta), UV (ultraviolet light)
the vehicle group) were studied. This
study demonstrated that RAL can showed a significant improvement in arm comparison study.10 The study
produce clinical improvement in fine fine wrinkles after 12 and 24 weeks of population comprised 36 elderly
and deep wrinkles.22 However, treatment with the use of ROL versus subjects (mean age 87 years) residing
statistical significance was not placebo.10,23 One of the randomized, in two senior citizen facilities. Topical
reported and no intra-individual controlled trials was completed by 0.4% ROL lotion or its vehicle was
comparisons were made. Sorg et al10 who evaluated the applied at each visit by study
Topical ROL has been shown in effectiveness of topical ROL in personnel to either the right or the left
vivo to have only a modest effect improving the clinical signs of naturally arm, up to three times a week for 24
compared with topical RAL and RA aged skin in a randomized, double- weeks. Clinical assessment was made
while two randomized controlled trials blind, vehicle-controlled, left and right by using a semiquantitative scale and

QUESTIONS • CHALLENGES • CONTROVERSIES

25 [ February 2010 • Volume 3 • Number 2] 25

TABLE 2B. Summary of mechanisms of action and clinical significance

INGREDIENT WHAT IS THE MECHANISM?* DOES IT SHOW CLINICAL SIGNIFICANCE?*

• 0.05% RAL vs. 0.05% RA vs. vehicle in 125 patients over 18

1. Decrease fine lines and wrinkles
weeks in a nondouble-blind and nonrandomized study. This
• By decreasing the activity of enzymes that break down
study reported that RAL can produce significant clinical
collagen, increasing GAG synthesis, and increasing collagen
improvement in fine and deep wrinkles however specific
synthesis by increasing TGF-B and procollagen synthesis9–17
significance (the p value) was not reported and no
2. Decrease hyperpigmentation
intra-individual comparisons were made.22
• By increasing epidermal cell turnover which decreases the
RETINOIDS • 0.4% ROL vs. vehicle in a randomized, double-blind, vehicle-
amount of contact between melanocytes and keratinocytes10
controlled, left and right arm comparison study in 36 elderly
3. Decrease skin roughness
patients three times a week for 24 weeks. Clinically, ROL
• By promoting epidermal cell turnover. RA binds to retinoic
improved fine wrinkling with significance (p<0.001).
acid receptors (RAR) which then binds to specific genes. This
Histologically, biopsies showed ROL significantly increased
affects the transcription of genes which promote epidermal
GAG expression (p=0.02 [n = 6]) and procollagen I (p=0.049
cell turnover18–19
[n=4]).10

1. Delay aging in fibroblasts

• Delays alteration in cell size and shape, growth rates,
• Kinetin lotion (0.01%–0.1%) used twice daily for 24 weeks
cytoskeletal structure, macromolecular synthesis, and
on 96 subjects. Results showed improvement in skin texture,
quantity of lipofuscin associated with aging in in-vitro human
color, blotchiness, fine wrinkles, and skin barrier function.
fibroblasts. However, the exact mechanism remains elusive. 23
Average improvements ranged from 17–63% over baseline.39
2. Antioxidant effects
• Kinetin 0.03% + niacinamide 4% vs. niacinamide 4% on
KINETIN • By inhibiting the formation of ROS and acting as free radical
Asian skin. Both products showed an improvement in
scavenger. Specifically, it activates both SOD and catalase
hyperpigmentation, blotchiness, and hydration status, but the
expression and mimics SOD’s antioxidant activity. Also,
combination product had significantly better results.
prevents the oxidation of unsaturated fatty acids and DNA
Therefore, possibly indicating the role of kinetin in the
and prevents the oxidation and glycation/glycoxidation of
formula.26,27
proteins. Therefore inhibiting the formation of AGE
products.28,29,35–38

1. Antioxidant effects
• Niacinamide increases the reduced forms of NAD(P), which
have potent antioxidant properties.53–55
2. Improves epidermal barrier function
• Evidenced by reduced TEWL and an increase in the skin’s
resistance to potential harmful topical agents. Proposed • Analysis by multiple angle reflectance spectrophotometer
mechanisms include increased synthesis of ceramides via demonstrated that 2.5% niacinamide resulted in smoother
upregulation of serine palmitoyltransferase, the rate-limiting skin surface compared to vehicle alone (p<0.05).59
enzyme in sphingolipid synthesis, and stimulating • 3.5% niacinamide cream was compared with placebo for four
keratinocyte differentiation via an influence on keratin K1, weeks and demonstrated a 14.8% reduction in skin
which results in an increase in epidermal turnover.56–59 roughness (p=0.05).56,74,75
3. Decreases yellowing of skin • In a randomized, double-blind, split-face, placebo-controlled,
• Through its antioxidant capabilities, niacinamide inhibits clinical trial, 50 white females applied 5% niacinamide and
oxidative processes, such as protein oxidation, glycation, and vehicle twice daily for 12 weeks. Results showed significant
the Maillard reaction, which produces Amadori products. improvement in fine lines and wrinkles, hyperpigmentation,
NIACINAMIDE Amadori products are yellowish-brown in color and redness, yellowing, and skin elasticity (p<0.05).51
accumulate in skin matrix components, like collagen, • This study using niacinamide 5% and niacinamide 2% +
in response to oxidative stress as we age.65–68 UVB/UVA sunscreen moisturizer reported reduced facial
4. Decreases erythema and blotchiness hyperpigmentation in Japanese women.56
• Increasing barrier function may result in less irritation when • In a randomized, split-faced trial, 5% niacinamide was used
the skin encounters environmental insults and hence less on 18 Japanese women vs. vehicle. Pigmentation change was
redness. This theory has not been substantiated.50,60–61 evaluated qualitatively and quantitatively using high resolution
5. Decreases fine lines and wrinkles digital images and subjective judgments. After 8 weeks, there
• By reducing GAGs and increasing dermal collagen and was significant lightening of hyperpigmentation on the side
protein production (i.e., keratin, fillagrin, and treated with niacinamide compared to vehicle (p<0.05).56
involucrin).51,58,66,69
6. Hyperpigmentation
• Reduces melanosome transfer from melanocytes to
surrounding keratinocytes. One study showed that 5% niaci-
namide moisturizer provided 35–68 percent inhibition of
melanosome transfer from melanocytes to keratinocytes.71

QUESTIONS • CHALLENGES • CONTROVERSIES

26 [ February 2010 • Volume 3 • Number 2]

TABLE 2B (Continued). Summary of mechanisms of action and clinical significance

INGREDIENT WHAT IS THE MECHANISM?* DOES IT SHOW CLINICAL SIGNIFICANCE?*

1. Antioxidant effects
• By raising cellular GSH content (p<0.05) and GST activity (p<0.05),
decreasing H2O2 formation (p<0.05), and preventing DNA degradation
(p<0.01).101
2. Phytoestrogen effect
• Couples with estrogen receptors in the cell’s nucleus.104 Therefore may
have a similar potential to retard skin thinning and collagen loss
No published in-vivo human clinical trials
SOY ISOFLAVONES comparable to topical estrogen formulas.116
found to date with greater than 50 patients.
3. Increases collagen synthesis
• One study demonstrated in vitro that genistein was able to increase
collagen (COL1A2) gene expression in human fibroblasts.112
• One study showed genistein was able to stimulate collagen levels in
human dermal fibroblasts.111
4. Increases glycosaminoglycans (GAG)
• Increases levels of GAG, specifically hyaluronic acid, in aging skin.114,115

• STI and BBI was used on 65 women with

moderate facial photodamage in a 12-week
vehicle-controlled study. Efficacy was
1. Decreases hyperpigmentation measured by clinical evaluation, colorimetry,
• STI and BBI inhibit the keratinocyte protease-activated receptor 2 digital photography, and self assessment.
SOY PROTEASE (PAR-2). Inhibition of PAR-2 decreases Results showed improved mottled
INHIBITORS keratinocyte-melanocyte contact hence decreasing the pigmentation, blotchiness, dullness, fine
transfer of melanosomes into the keratinocytes.116–121 lines, overall texture, overall skin tone, and
overall appearance. Differences were
significant (p<0.05) from Week 2 to Week 12
for all above parameters (except dullness
which started at Week 4).83

1. Antioxidant effects
• By quenching the following ROS: singlet oxygen, superoxide radical,
hydroxyl radical, hydrogen peroxide, and peroxyl radical.133–138 In addition, • Randomized, double-blind, 8-week trial on 40
by limiting UV-induced lipid peroxidation and reducing the oxidation of women with moderate photoaging used
proteins in vitro.139,140 300mg green tea supplements and applied
2. Anti-inflammatory effects green tea cream twice daily vs. placebo.
• By down regulating nuclear transcription factor-kappa B (NF-kB). Subjects were graded based on wrinkling,
NF-kB up-regulates transcription of pro-inflammatory mediators, such as roughness, skin laxity, and pigmentation.
GREEN TEA
interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor-alpha.143 There were no statistically significant clinical
3. Decreases collagen breakdown improvements; however, an improvement in
• Down-regulates transcription factors activator protein 1 (AP-1). the elastic tissue content of treated
AP-1 is responsible for production of metalloproteinases, which break specimens (p<0.5) was observed upon
down collagen.132 histological examination of skin biopsies.152
4. Photoprotectant effect
• Green tea shows dose-dependent inhibition of UV-induced erythema
likely due to its antioxidant and anti-inflammatory effects.150

*Common Abbreviations: AGE (advanced glycation end products), BBI ( Bowman-Birk Inhibitor), CP450-PAH (cytochrome P-450-dependent
RA 4-hydroxylase ), DNA (deoxyribonucleic acid), EGCG (epigallocatechin gallate), GAG (glycosaminoglycans) , GSH (glutathione), GST
(glutathione-S-tarnsferase) , H2O2 (hydrogen peroxide), HPLC (high performance liquid chromatography), NAD (niacinamide adenosine
dinucleotide), RA (retinoic acid), RAL (retinaldehyde), ROL (retinol), ROS (reactive oxygen species), SC (stratum corneum), SOD (superoxide
dismutase), STI (soybean trypsin inhibitor), TEWL (transepidermal water loss), TGF-B (transforming growth factor-beta), UV (ultraviolet light)

QUESTIONS • CHALLENGES • CONTROVERSIES

[ February 2010 • Volume 3 • Number 2] 27

 TABLE 2C. Levels of evidence for substantiation of clinical data What data is available on the
INGREDIENT LEVEL OF EVIDENCE*
percutaneous absorption of kinetin?
The authors were unable to find
Retinoids B
any studies investigating the
Kinetin B percutaneous absorption of kinetin.
Niacinamide A However, kinetin has been shown to be
Soy isoflavones – nonirritating to the skin, easily
formulated, chemically stable, and
Soy protease inhibitors A
compatible with other formulation
Green tea B components.27
*Level A: High-quality randomized, controlled trial (RCT) that considers all important
outcomes. High-quality meta-analysis using comprehensive search strategies. Level B: A What are the potential mechanisms
well-designed, nonrandomized, clinical trial. A nonquantitative systemic review with of action of kinetin?
appropriate search strategies and well-substantiated conclusions. Includes lower quality Kinetin is shown to exert its anti-
RCTs, clinical cohort studies, and case-controlled studies with nonbiased selection of study aging effects in different systems
participants and consistent findings. Level C: Consensus viewpoint or expert opinion including plants, fruit flies, and
cultured human skin fibroblasts.28–31
biochemical measurements from skin concerning OTC retinoids, RAL seems Studies on human fibroblasts in vitro
biopsy specimens. After 24 weeks, to be the most efficacious.10,22 have demonstrated that kinetin may
there were significant differences Therefore, those patients who are have the ability to delay the onset of
between ROL-treated and vehicle- looking to decrease and or prevent the age-related changes as well as
treated sides for fine wrinkling scores signs of aging without use of a decrease the severity of these
(p<0.001). In addition, histology prescription product should use RAL changes.23 These age-related changes
showed ROL treatment significantly containing cosmeceuticals as they include the alteration in cell size and
increased GAG expression (p=.02 [n = have the best scientific evidence shape, growth rates, cytoskeletal
6]) and procollagen I (p=0.049 [n = 4]) supporting their efficacy in reducing structure, macromolecular synthesis,
compared with vehicle. This data the signs and symptoms of aging. and quantity of lipofuscin. The delay of
provided support that topical ROL So what do we tell our patients age-related cellular characteristics
improves fine wrinkles via its concerning retinoid cosmeceuticals? were most pronounced in cultures
metabolism to RA and subsequent The authors have presented sufficient where kinetin was continuously
increases in GAGs and collagen evidence on cutaneous penetration present. It was noted that some aging
production. and concerning mechanism of action characteristics began to reappear upon
and semi-sufficient evidence on the removal of kinetin, and youthful
What conclusions can be drawn clinical anti-aging effects of ROL and characteristics in general were better
from data on cosmeceutical RAL. They believe it is important to maintained in younger cells compared
retinoids? remind the patients that while the to older cells. This suggests that
After sunscreens, many believe most effective anti-aging treatment is continued use of kinetin is necessary
topical retinoids are the most achieved with prescription retinoids, to maintain results and that there may
important drug class to combat and there is some evidence to support the be additional benefit to starting kinetin
reverse the signs of aging. With more use of RAL and ROL to decrease fine at a younger age.32 However, the
than two decades of experimentation, lines and wrinkles. mechanism by which kinetin exerts its
there is a vast amount of evidence that effects on human fibroblasts remains
regular retinoid use over several What is kinetin (N-furfuryladenine elusive.
months results in clinical improvement growth factor)? Antioxidant effects. Investigators
in skin texture, wrinkles, and Kinetin is an essential plant growth have surmised that the mechanism of
pigmentation.24 However, most of this hormone that regulates aspects of action that results in age retardation
knowledge and experience is about growth and differentiation, retards leaf may involve the genes that influence
prescription products containing RA yellowing and senescence, and slows aging and may involve kinetin acting as
and not about OTC retinoids, ROL and down fruit ripening and both an inhibitor of reactive oxygen
RAL. Of the limited data available degeneration.25,26 species (ROS) formation and a

QUESTIONS • CHALLENGES • CONTROVERSIES

28 [ February 2010 • Volume 3 • Number 2]

scavenger of ROS.28,33 Many studies TABLE 3. Summary for ingredient substantiation: Answering the three major questions
have shown kinetin to be a powerful
antioxidant. Kinetin has the ability DOES IT SHOW
DOES IT DO WE KNOW HOW
to mimic superoxide dismutase INGREDIENT CLINICAL
PENETRATE? IT WORKS?
(SOD) activity, activate both SOD SIGNIFICANCE?
and catalase expression, and quench
ROS.28,29,35,36 Also, kinetin has been Retinoids Yes Yes Limited data
shown to prevent the oxidation of
unsaturated fatty acids and inhibit Kinetin No Partially Partially
the in-vitro oxidation of DNA.36,37
Also, Verbeke et al38 demonstrated Niacinamide Yes Yes Yes
that kinetin can inhibit the oxidation
and glycation/glycoxidation of Soy isoflavones Limited Data Yes No
proteins. By inhibiting the oxidation
and glycation/glycoxidation of Soy protease inhibitors No Yes Yes
proteins, kinetin inhibits the
formation of advanced Green tea Limited Data Yes No
glycation/glycoxidation end
products (AGE). These results
strengthen the view that kinetin is a suggest that kinetin improves barrier as an adjunctive therapy for anti-aging
powerful antioxidant with significant function of the SC, as evidenced by a purposes of the skin.27
biological properties and useful mean decrease in TEWL after 14
potential for the prevention of weeks of use. Hence, this What conclusions can be drawn
oxidative damage.38 demonstrated that topical kinetin from data on kinetin?
Other effects. Although clinical (0.01%–0.1%) can partially improve In summary, kinetin is a relatively
studies of topical kinetin have some of the clinical signs of mild-to- new ingredient in the cosmeceutical
suggested improvement in skin moderately photodamaged skin, such world with anti-aging potential given
texture, a decrease in as skin texture, fine wrinkles, skin its anti-aging role in plants and its in-
hyperpigmentation, and a decrease in color, and blotchiness, and can help vitro antioxidant effects. In order to
TEWL, there appears to be no restore normal skin barrier function recommend kinetin, the authors feel
reported mechanisms for how kinetin with 12 to 24 weeks of topical that the scientific evidence supporting
improves skin texture, fine wrinkles, application.39 kinetin is still lacking in permeation
hyperpigmentation, and/or the SC Another study investigated the anti- studies and mechanistic discoveries as
permeability barrier. aging effects of topical kinetin 0.03% to how this growth factor reduces
in combination with niacinamide 4% hyperpigmentation, improves skin
What clinical studies are available versus niacinamide 4% alone in Asians. barrier function, and improves skin
on kinetin? Amasino et al26 found that the texture. There is modest support of its
One open-label study about the combination of kinetin and efficacy based on clinical studies.
clinical safety and efficacy of kinetin niacinamide and niacinamide alone
0.1% lotion on human skin was effectively improved many of the facial What background information is
published by McCullough et al.39 aging signs in Asians. This combination available on niacinamide and
Ninety-six subjects with of ingredients reduced the number of nicotinic acid?
photodamaged skin showed hyperpigmented spots and red While the nutritional value of
improvement in the categories of skin blotchiness as well as increased SC niacin (vitamin B3) may be well
texture, color, blotchiness, and fine hydration status with more persistence recognized, the skin care benefit of
wrinkles after 24 weeks of twice-daily than the formula containing topically applied niacin is a recent
application of 0.01%, 0.05%, or 0.10% niacinamide alone. The authors believe discovery based on recently published
kinetin. Average improvements ranged that this indicates a decisive role for studies. Niacin (vitamin B3) has two
from 17 to 63 percent over baseline. In kinetin in the formulation and that potential forms that can be used in
addition, the results of this study kinetin plus niacinamide may be used cosmeceuticals: niacinamide

QUESTIONS • CHALLENGES • CONTROVERSIES

[ February 2010 • Volume 3 • Number 2] 29

(nicotinamide) and nicotinic acid. It is promising anti-aging cosmeceutical differentiation.56,57 Ceramides and other
debatable as to whether these two ingredient. intercellular SC lipids are known to
forms of niacin are interchangeable as play a central role in the structural and
topical cosmeceuticals. Some studies What data is available on the functional integrity of the epidermal
claim that niacinamide and nicotinic percutaneous absorption of barrier function. The responsible
acid are readily converted into each niacinamide? mechanism for the increase of
other in vivo40 while other studies Feldmann et al48 highlighted the ceramide synthesis in niacinamide-
speculate that niacinamide and possibilities for the topical application treated, cultured keratinocytes was
nicotinic acid may have very different of niacinamide because they were able found to be based on the upregulation
pharmaceutical activities despite to prove sufficient percutaneous of serine palmitoyltransferase, the
having identical vitamin activities.41 In penetration into human skin.48,49 In rate-limiting enzyme in sphingolipid
other words, nicotinic acid may have addition, several other studies have synthesis. The increase in ceramide
more benefits than topical used increased levels of NAD in skin synthesis has been confirmed in an in-
niacinamide on the skin due to the cells after the topical application of vivo trial after topical application of
fact that in addition to having the niacinamide as evidence of 2% niacinamide emulsion for four
vitamin effects on skin (increasing percutaneous penetration.50 weeks applied twice daily.56 The
levels of niacinamide adenosine elevation of ceramides after treatment
dinucleotide [NAD]), it may also have What are the potential mechanisms with niacinamide is associated with an
drug-mediated effects on skin via of action of niacinamide? improved barrier function as
interacting with nicotinic acid Studies have shown that evidenced by a reduced TEWL and an
receptors present in the skin.41–44 Yet, niacinamide has the potential to act as increase in the cutaneous resistance to
the disadvantage of using nicotinic an antioxidant, can improve epidermal potential harmful topical agents.56 The
acid as a topical cosmeceutical is its barrier function, decrease skin second mechanism likely responsible
unpleasant side effect of vasodilation hyperpigmentation, reduce fine lines for improved barrier function is a
that results in skin flushing. This is an and wrinkles, decrease stimulation of keratinocyte
effect that is not harmful but redness/blotchiness, decrease skin differentiation seen both in cell
intensely disliked by most patients.45,46 yellowness (sallowness), and improve cultures in vitro and in-vivo studies
In contrast to nicotinic acid, skin elasticity.51,52 The mechanisms by conducted by Tanno et al.56,57 In cell
niacinamide does not cause skin which niacinamide provides this array cultures, more rapid keratinocyte
flushing nor does it cause changes in of skin benefits is not completely differentiation following treatment
blood pressure, pulse, or body understood, but the role of with niacinamide was established.56 In
temperature.47 Due to the decreased niacinamide as a precursor to the particular, it was possible to determine
number of side effects of topical NADP family of coenzymes may play a an influence on keratin, K1. K1 is a
niacinamide compared to nicotinic significant role in all of these basic keratin synthesized mainly in the
acid, the effects of niacinamide as a improvements.50 lowest layers of the stratum spinosum.
topical cosmeceutical agent have Antioxidant capacity. The functional limitations of aging skin
been studied more to date. Niacinamide increases the antioxidant include reduced “turnover of the
Niacinamide, also known as capacity of skin after topical epidermis” (i.e., a slower epidermal
nicotinamide, is the precursor of application by increasing the reduced cell cycle) due to a deficiency of
important cofactors niacinamide forms (NADPH), which have potent NADP in aging cells.58,59 Tanno et al
adenosine dinucleotide (NAD) and its antioxidant properties.53–55 This is also demonstrated an in-vivo
phosphate derivative, niacinamide probably the most well-studied anti- improvement in epidermal barrier
adenosine dinucleotide phosphate aging effect of niacinamide. function with improved keratinocyte
(NADP). These cofactors and their Epidermal barrier function. differentiation after the application of
reduced forms (NADH and NADPH) Niacinamide may improve the skin topical niacinamide. Once again, the
serve as reduction-oxidation (redox) barrier function in two ways: first, by improved barrier function was evident
coenzymes in more than 40 cellular its ability to upregulate the synthesis by a decrease in TEWL and increase in
biochemical reactions. Thus, of ceramides as well as other SC SC moisture content. Similar results
niacinamide has the potential to exert intercellular lipids, and second, by were also obtained by Ertel et al.57 In
multiple effects on skin and is a stimulating keratinocyte conclusion, it seems that topical

QUESTIONS • CHALLENGES • CONTROVERSIES

30 [ February 2010 • Volume 3 • Number 2]

application of niacinamide increases increase dermal collagen and protein of this mechanism in reducing the
NADP levels, which in turn stimulates production. The development of appearance of fine lines and
keratinocyte differentiation. This wrinkles is a result of the decrease in wrinkles.51,70 Given the above analysis
results in a thicker SC, which is not epidermal cell layers and dermal and scientific data, it seems more
only associated with an improved components from a reduction in likely that an increase in dermal
barrier, but is also associated with protein and collagen synthesis. proteins (including collagen) may play
greater hydration retention capacity in Reduced protein synthesis is reflected a bigger role in reducing fine lines and
the SC.59 in the levels of keratin, fillagrin, and wrinkles than decreasing the level of
Erythema and blotchiness. The involucrin in the skin. Keratin GAGs.
mechanism by which deficiency has an effect on the Hyperpigmentation. Topical
redness/blotchiness is improved may epidermal cell structure and its water- niacinamide may be effective in
be related to the improved skin barrier binding capacity. Fillagrin is an decreasing epidermal
function for reasons discussed antecedent of natural moisturizing hyperpigmentation and reducing
above.50,60,61 Increased barrier function factor (NMF) and hence affects skin pigmented spots as we age.71
may mean less irritation and redness hydration. Involucrin is seen as Hakozaki et al71 showed that the
when the skin encounters significant for the cell envelope and reduction of cutaneous pigmentation,
environmental insults, such as structure of the SC. In summary, the surprisingly, was not due to the direct
detergents and soaps, and hence less effects of reduced collagen and protein influence of niacinamide on melanin
reddening of the skin. However, this synthesis are poor skin structure and synthesis by melanocytes. Instead,
theory has not been substantiated. reduced skin elasticity as well as a they showed that niacinamide
Yellowing of skin. The yellowing decrease in epidermal barrier function reduced melanosome transfer from
of skin that comes with aging may be a with a reduction in SC hydration. In melanocytes to surrounding
result of glycation of proteins in the studies on cell cultures, Oblong et al58 keratinocytes in a co-culture system,
skin called the Maillard reaction. The found that in aging cells it was possible although the specific mechanism
Maillard reaction is a spontaneous to prove that niacinamide, as a remains unknown.71 This was
oxidative reaction between protein precursor of NAD/NADP, stimulated supported by a study using 5%
and sugar that results in cross-linked collagen synthesis and the epidermal niacinamide moisturizer, which
proteins (Amadori products) that are proteins keratin, fillagrin, and provided 35 to 68 percent inhibition
yellowish-brown in color and are involucrin.51,58 In addition, another of melanosome transfer from
fluorescent.62–64 These proteins can study was able to show niacinamide’s melanocytes to keratinocytes.71
accumulate in the skin matrix ability to increase dermal matrix
components, similar to collagen, in collagen production.66 What clinical studies are available
response to oxidative stress as we age. The second mechanism that may be on niacinamide?
Published data show a fivefold relevant to decreasing the appearance Tanno et al56 showed a reduction in
increase in collagen oxidation products of wrinkles is the ability of niacinamide pigmentation as a result of
in human skin from age 20 to 80.65 to reduce excess dermal niacinamide. Eighteen Japanese
Since NADH and NADPH are glycosaminoglycans (GAGs). This is a women with hyperpigmentation were
antioxidants and their levels can be controversial theory because both the treated on one side of the face with
increased with niacinamide, a possible elevation and depletion of dermal 5% niacinamide and on the other side
effect of topical niacinamide is GAGs are associated with with vehicle only. The pigmentation
inhibition of oxidative processes, such photodamaged or wrinkled skin.52,69 change was evaluated qualitatively
as protein oxidation, glycation, and the What is known is that the presence of and quantitatively using high-
Maillard reaction, and hence the GAGs is required for normal structure resolution digital images and
inhibition of skin yellowing.66–68 and function of the dermal matrix and subjective judgments. In both forms
Fine lines and wrinkles. Multiple increasing the levels of GAGs can of evaluation, it was found that after
mechanisms may be involved in the increase the moisture content of skin. eight weeks of treatment there was
ability of niacinamide to reduce the Testing has indicated that niacinamide significant lightening of
appearance of fine lines and wrinkles. reduces excess production of GAGs in hyperpigmentation on the side
The first to consider is that old human dermal fibroblasts, thus treated with niacinamide when
niacinamide may have the ability to supporting the potential involvement compared with the effect of the

QUESTIONS • CHALLENGES • CONTROVERSIES

[ February 2010 • Volume 3 • Number 2] 31

vehicle (p<0.05).56 hyperpigmented spots, red blotchiness, Nicotinic acid receptors are G protein
In a separate study also reported by skin sallowness, and improvement in coupled receptors that when
Tanno et al performed with 120 skin elasticity.51 Matts and Solenick stimulated lead to an increase in skin
Japanese women, comparisons were later confirmed the results of Bissett et leptin, which in turn activates several
made among a sun protection factor al with 5% and 2% niacinamide.59 The signaling pathways to enhance
(SPF) 15 cream with and without 2% results also demonstrated that the anti- epidermal differentiation and stimulate
niacinamide and the relevant vehicle. aging effects of niacinamide were dose wound healing.78,82
As a result of niacinamide treatment, dependent. In a clinical study by Jacobson et
there was a lightening of the skin after al,76 MN increased skin cell NAD by 25
four and six weeks, which was noted What conclusions can be drawn percent (p=0.0001) demonstrating
to be markedly better than the formula from data on niacinamide? effective delivery. Relative to placebo,
without niacinamide.56 The topical use of niacinamide for MN treatment of photodamaged facial
It is theoreticized that niacinamide anti-aging has proven to be effective skin increased SC thickness by
may improve the texture of skin by not only when there are signs of a approximately 70 percent (p=0.0001)
speeding up epidermal turnover hence niacin deficiency. Despite the recent and increased epidermal thickness by
functioning as a mild exfoliant.72 Using discovery of the cosmetic benefit of approximately 20 percent (p=0.001).
a multiple angle reflectance niacin for the skin, there have been In two separate studies, MN treatment
spectrophotometer in an in-vivo test sufficient studies completed to answer increased rates of epidermal renewal
of the back of the hand, Matts and all three “Kligman questions.” It is the by six (p=0.003) to 11 percent
Solenick73 established a beneficial opinion of the authors that (p=0.001) and increased the minimal
effect for the topical application of niacinamide is one of the best studied erythemal dose by 8.9 (p=0.07) and
niacinamide in smoothing the skin cosmeceutical ingredients for anti- 10 percent (p=0.05) relative to
surface structure. This study aging. However, further research is placebo. MN treatment also resulted
demonstrates that the long-term required to uncover the specific in reductions in the rates of TEWL of
application of 2.5% niacinamide can mechanisms of niacinamide in the skin approximately 20 percent relative to
correct the skin surface damage that and to optimize the concentration of placebo on cheeks and arms of study
results from aging. These results were niacinamide in cosmeceutical subjects.
statistically significant compared with formulations. The above data demonstrates that
the influence of the vehicle alone topical nicotinic acid preparations
(p<0.05).59 In agreement with the Is there additional information on can enhance epidermal
above, another clinical trial using 3.5% nicotinic acid? differentiation and barrier function,
niacinamide cream was compared with As mentioned earlier, a major suggesting that it may be effective in
placebo for four weeks and obstacle in the topical delivery of the treatment of photodamaged skin
demonstrated a 14.8-percent therapeutic amounts of nicotinic acid and other conditions (such as atopic
reduction in skin roughness to any tissue is its ability to cause a dermatitis) with skin barrier
(p=0.05).56,74,75 peripheral vasodilation that leads to a impairments. However, it is hard to
One of the best randomized, double- skin flushing response. While this compare these results with the
blind, split-face, placebo-controlled, effect is not harmful, it is intensely results presented above on
clinical trials published on the anti- disliked by most patients.45,46 This issue niacinamide since not all of the same
aging effects of topical niacinamide was may be avoided by using the long attributes were monitored (such as
done by Bissett et al.51 In this study, 50 chain ester derivative of nicotinic acid, redness, yellowing, wrinkling, etc).
white females with clinical signs of myristyl nicotinate (MN), which is able Further investigation is needed to
photodamage applied 5% niacinamide to deliver large amounts (in compare the efficacy of MN to
to half of the face and its vehicle concentrations near 5%) of nicotinic niacinamide. Both niacinamide and
control to the other half twice daily for acid without flushing.76,77 nicotinic acid have significant
12 weeks. Analyses of the data The advantage of using nicotinic numbers of published studies to
revealed a variety of effects related to acid over niacinamide is its drug- answer all three major questions to
improvements in skin appearance for mediated effect on skin as a result of date. However, there is more data
topical niacinamide including its ability to interact with nicotinic acid available on the anti-aging effects and
reductions in fine lines and wrinkles, receptors present in the skin.42–44 mechanisms of topical niacinamide.

QUESTIONS • CHALLENGES • CONTROVERSIES

32 [ February 2010 • Volume 3 • Number 2]

What background information is may correlate with topical treatment structure; however, this was not the
available on soy? of photoaging. case in this present study.102 Thus, the
Soybeans are known to contain Antioxidant effects. Free radical authors conclude that soy isoflavones
many components with biological formation plays a crucial role in aging may have inhibitory activity against
activity in the skin.83 The major skin.100 A clinical study by Sharma et oxidative damage and may be capable
components of soy are phospholipids al101 found that soy isoflavones of preventing the biochemical
(45–60%) and essential fatty oils (genistein and daidzein) have a alteration associated with aging.101
(30–35%) while the minor fourfold mechanism of action to fight Phytoestrogen effects. The
components include the most active oxidative process in the skin.101 In this primary metabolites of soy isoflavones,
compounds, such as isoflavones and study, soy isoflavones were shown to genistein and daidzein, have been
the proteases soybean trypsin inhibitor raise cellular glutathione (GSH) identified in various studies in animal
(STI) and Bowman-Birk inhibitor content and glutathione S-transferase and human cell cultures as
(BBI).84–86 In this review, the authors (GST) activity (p<0.05), prevent phytoestrogens. Phytoestrogens are
will focus on the effects of topical antioxidant enzyme depletion, plant compounds with a weak
isoflavones and their ability to reduce decrease H2O2 formation (p<0.05), estrogenic effect. In soy, genistein and
ROS, stimulate collagen synthesis, and prevent ornithine decarboxylase daidzein are present as glycosides,
increase moisture in the skin and also (ODC) induction and DNA which do not have estrogenic activity,
the proteases STI and BBI,83,87–94 and degradation (p<0.01). Given the wide and only upon conversion to their free
reduce skin hyperpigmentation. array of antioxidant effects, the isoflavone form do they demonstrate
authors speculate that soy isoflavones phytoestrogen activity.103
What data is available on the may not act as antioxidants Phytoestrogens, just like estrogen,
percutaneous absorption of soy? themselves but instead affect cell work by coupling with estrogen
The most plentiful isoflavones in signaling processes that increase the receptors (ERs) in the cell’s nucleus.
soy are genistein and daidzein. The skin’s own antioxidant capabilities. Two types of receptors, alpha and
permeation of isoflavonoids through However, there is a lack of evidence beta, have been identified and both are
the skin barrier is poorly investigated. supporting soy isoflavones as a cell- present in the skin.104 One study
However, the data that is available signaling molecule, and the antioxidant demonstrated a higher affinity of
indicates that the compounds of this nature of soy isoflavones cannot be genistein for ER-beta;105 however,
group can permeate through the SC sidelined completely because of the another study reported a higher
and can reach viable layers of the polyphenolic structure. Given its affinity of genistein for ER-alpha
epidermis and dermis.95,96 The structure, genistein can donate agonist activity.106 In comparison with
permeation rate of soy through the SC hydrogen atoms to deleterious oxygen genistein, estradiol has 700-fold more
is dependent upon the isoflavonoid’s free radicals and form less reactive ER-alpha and 45-fold more ER-beta
structure and vehicle composition.97 In phenoxy radicals in the process. activity.107 Even though phytoestrogens
general, the ionized form of a Further research is required to are weak estrogens, soy may contain
compound has lower percutaneous determine soy’s true antioxidant as much as 1/1000 of its content as
absorption compared to non-ionized mechanism in skin. However, the phytoestrogens. Therefore, circulating
form. This is due to the lipophilic topical application of soy isoflavones levels of phytoestrogens may be high
nature of the SC.98,99 This theory has been shown to increase the and the subsequent biological effect
explains why genistein in a completely antioxidant capability of skin may be great.
neutral condition (pH 6) shows higher compared to control via increases in Several studies have shown that
skin accumulation compared to the the four mechanisms mentioned postmenopausal women have a
ionized form (pH 10.8). The same above. In one study, genistein was able measurably thinner dermis and less
result was observed for permeation to decrease the H2O2 increment in collagen compared to premenopausal
profiles of daidzein. human keratinocytes caused by women.108,109 Topical estrogen is able to
ultraviolet B rays by 71 percent and retard skin thinning and collagen loss
What are the potential mechanisms daidzein almost completely inhibited in postmenopausal women because
of action of soy? H2O2 production by UVB. Daidzein was estrogen receptor levels are highest in
Soy has been purported to exhibit a expected to be a less effective the granular layer of skin. Therefore,
few potential modes of action, which antioxidant due to its chemical the phytoestrogens, genistein and

QUESTIONS • CHALLENGES • CONTROVERSIES

[ February 2010 • Volume 3 • Number 2] 33

daidzein, have a similar potential to cancer and uterine cancer with the use prevent UV-induced pigmentation in
retard skin thinning and collagen loss of soy products. However, data vitro and in vivo. It has been shown
due to estrogenic stimulation.116 concerning this risk is contradictory. that STI and BBI inhibit the
Further research is needed to compare On one hand, the majority of breast keratinocyte protease-activated
the estrogenic activity of whole soy cancers are estrogen dependent and receptor 2 (PAR-2), which is involved
versus genistein and daidzein in their the use of phytoestrogens could in the regulation of pigmentation.116–121
free isoflavone form. potentiate cancer cell growth, while on PAR-2 is expressed on keratinocytes
Collagen synthesis effects. In the other hand, epidemiological data and has been shown to increase
other studies, soy isoflavones were suggest a protective effect of soy keratinocyte phagocytosis.117,118 Several
investigated for their potential to against the development of cancer in-vitro and preclinical investigations
stimulate collagen synthesis.111,112 One (including breast cancer).113 The have demonstrated that the
study demonstrated in vitro that authors of this review speculate that modulation of PAR-2 activation
genistein was able to increase collagen soy’s protective effect may be due to facilitates keratinocyte-melanocyte
(COL1A2) gene expression in in-vitro its antioxidant abilities while potential contact and therefore enhances the
human fibroblasts.112 Another study carcinogenic ability may be related to transfer of melanosomes into the
tested four different formulas in terms binding to estrogen receptors. keratinocytes and produces reversible
of their capacity to stimulate de novo Although the amount of depigmentation.116,119
collagen synthesis.111 Depending on the phytoestrogens that are systemically
respective method of extraction, the absorbed from a topical preparation is What clinical studies are available
four formulas contained different likely very low, it would be prudent to on soy?
amounts of isoflavones. The isoflavone avoid these products in a person with Recently, a topical soy formulation
daidzein did not elicit any effect, but active breast cancer.116 was developed containing
genistein was able to stimulate Glucosaminoglycan effects. nondenatured STI and BBI.122 This is
collagen levels in human dermal Finally, it has been shown that soy important because STI in particular is
fibroblasts (HDF). Interestingly, the isoflavones can increase levels of GAG inactivated by heat and the processing
effect on collagen status did not and specifically hyaluronic acid (HA) of soybeans and soy milk can destroy
correlate with the isoflavone content in aging skin although the exact their therapeutic effects, including
of the respective formulas. In other mechanism of action, as far as we are depigmenting activity.123 Preliminary
words, the formula with the highest aware, has not been discovered. HA is in-vivo human studies support the
amount of isoflavones did not display an anionic, nonsulfated GAG skin-lightening effect of nondenatured
the highest efficacy in terms of distributed widely throughout the skin. soy extracts.122,124–126 A study by Wallo et
collagen stimulation. In this study, the Hyaluronic acid is important for tissue al83 investigated the efficacy of a novel
specific soy extract that was the most repair and maintaining skin soy moisturizer containing
effective contained 10 to 12 percent hydration.111 It is widely accepted that nondenatured STI and BBI for the
genistein. The authors speculate that the HA content in skin, as well as all improvement of skin tone,
compounds other than isoflavones may the GAG content, declines with pigmentation, and other photoaging
play an important role for the collagen age.114,115 Given the importance of HA attributes.83 Sixty-five women, with
stimulatory effect. This fits well with for connective tissue overall, and the moderate facial photodamage, were
their observation that purified proven decline of HA in aged skin, enrolled in the 12-week, parallel,
isoflavones stimulated collagen there appears to be a necessity for vehicle-controlled study. Efficacy was
synthesis to a lesser extent than whole compounds that stimulate HA measured by clinical evaluation,
topical soy. Therefore, it appears that production in aging skin. More colorimetry, digital photography, and
the pronounced collagen stimulation of research needs to be completed to self assessment. Improvement of skin
soy is only in part because of the demonstrate the efficacy of soy in tone was clinically defined as a
isoflavones genistein and daidzein and stimulating HA synthesis and how reduction in mottled
other ingredients in soy, such as clinically this increase in HA affects hyperpigmentation, lentigines, and
saponins, may play a larger role.111 the appearance of skin. blotchiness, with an increase in skin
Potential effects on breast Hyperpigmentation. Soybean brightness (i.e., reflection of light from
cancer. Due to soy’s potential as a trypsin inhibitor (STI) and Bowman- skin’s surface). Improvement of skin
phytoestrogen, there is some concern Birk protease inhibitors (BBI) in soy texture was defined as a reduction in
regarding an increased risk of breast milk exhibit depigmenting activity and the surface roughness and/or an

QUESTIONS • CHALLENGES • CONTROVERSIES

34 [ February 2010 • Volume 3 • Number 2]

improvement in fine lines and evaluating a product, it is important to antioxidants, are highly unstable and
wrinkling. The results showed that the know whether the product contains easily oxidized in an ambient
novel soy moisturizer was significantly whole soy, the isoflavones genistein environment. Equally difficult is
more efficacious than the vehicle in and daidzein, or soy protease ensuring that the active ingredient
improving mottled pigmentation, inhibitors STI and BBI in the penetrates the epidermis and that it
blotchiness, dullness, fine lines, overall nondenatured form. stays in the skin long enough to exert
texture, overall skin tone, and overall its desired effect. EGCG is inherently
appearance. Differences were marked What background information is hydrophilic, limiting its penetration in
from Week 2 to Week 12 for all above available on green tea? human skin. Thus, green tea extract is
parameters (except dullness, which White, green, and black teas are among the more difficult botanicals to
started at Week 4).83 derived from the leaves and buds of formulate.132 Only when these
Given STI and BBI’s efficacy for the tea plant (camellia senensis), with formulation challenges are met can
treating hyperpigmentation, one might different varieties dependent on the this topical antioxidant be effective.
consider using whole soy for the type of processing and antioxidation or After reviewing available product
treatment of melasma. Currently, there fermentation.128,129 Black tea is the most information, it appears that there is
are conflicting views as to whether soy processed (fermented), while white tea little standardization regarding the
should be used to treat patients with recently replaced green tea as the least minimal concentration of green teas in
melasma. On the one hand, one study processed. The main active ingredients cosmeceuticals, and many products
found that treatment with topical soy in green tea are polyphenols, also lack active ingredient characterization.
twice daily for 12 weeks was shown to known as catechins, which include Some authors feel that 5% green tea
be effective for the treatment of epicatechin, epicatechin-3-gallate extract is an effective concentration.132
melasma.127 On the other hand, high (ECG), and epigallocatechin-3-gallate However, the flaw in this logic is that it
levels of estrogen have been shown to (EGCG).128,129 The largest catechin and is the amount of green tea polyphenols
cause melasma and since soy has most active antioxidant in any tea is and not the amount of green tea in a
estrogen receptor bind capacity, it may EGCG. Green tea has the highest product that should be considered
be advisable to avoid soy in patients concentration of EGCG.130 when evaluating a product. Many
with melasma. Obviously further Polyphenols comprise 30 to 35 authors recommend products that
research is required; however, it percent of the dry weight of the green contain polyphenols in the 90-percent
should be noted that the isolated tea leaf.107 These polyphenols are range, which turns the product brown.
constituents of soy STI and BBI do not believed to have anti-aging effects This brown color does not indicate
contain phytoestrogenic abilities and through decreasing inflammation and that the product has oxidized, as is the
may be a good option for the acting as a scavenger of free radicals. case when vitamin C products
treatment of melasma. In addition, compounds found in green darken.53,116
tea have been shown to influence
What conclusions can be drawn biochemical pathways important in cell What are the potential mechanisms
from data on soy? synthesis and responses of tumor of action of green tea?
All three of the “Kligman questions” promoters.131 In this review, the Tea polyphenols have been shown
are adequately answered for soy’s authors focus on the antioxidant and to exhibit antioxidant and anti-
protease inhibitor depigmentation anti-inflammatory attributes of green inflammatory activities, which may
effects. However, soy isoflavones, tea, as these are the factors that most potentially exert clinical benefits.
despite all the research into its contribute to green tea’s potential as Antioxidant activity. Tea
antioxidant effects is lacking in-vivo, an anti-aging cosmeceutical. polyphenols are strong antioxidants.133
human, clinical trials with greater than The polyphenols in tea have
50 patients to prove the efficacy of soy What data is available on the demonstrated the ability to quench the
isoflavones efficacy as an anti-aging percutaneous absorption of following ROS: singlet oxygen,
topical cosmeceutical. green tea? superoxide radical, hydroxyl radical,
Given that there are two active The formulary of green tea hydrogen peroxide, and peroxyl
ingredients in soy, isoflavones and polyphenols as active ingredients in radical.133–138 In addition, tea
protease inhibitors, there appears to topical products remains a challenge in polyphenols have been shown to limit
be a need for specific labeling of the cosmeceutical industry. Green tea UV-induced lipid peroxidation in skin
topical soy products. As a physician polyphenols, as with most and reduce the oxidation of proteins in

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[ February 2010 • Volume 3 • Number 2] 35

a free radical-generating system in tea extract and/or one of its pigmentation, and other stigmata
vitro.139,140 constituents resulted in dose- associated with photoaging at baseline
Anti-inflammatory and collagen dependent inhibition of UV-induced and at eight weeks. At the end of eight
synthesis effects. Free radicals are erythema. EGCG and ECG were the weeks, investigators found no
known to promote oxidation of nucleic most efficient components in statistically significant clinical
acids, proteins, and lipids and can suppressing UV-induced erythema improvements in women using the
damage intracellular structures when tested individually. It was also green tea products. Because trends
including DNA.141,142 Free radicals also shown that green tea extract can toward improvement were seen in the
up-regulate transcription factors, such reduce the DNA damage that occurs green tea group, investigators
as activator protein 1 (AP-1) and after UV radiation through postulate that a longer study might be
nuclear transcription factor-kappa B mechanisms discussed above.107,132 necessary to demonstrate efficacy.
(NF-kB).132 AP-1 is responsible for Thus, it appears that topical However, an improvement in the
production of metalloproteinases that application of green tea extract and elastic tissue content of treated
breakdown existing collagen, some of its components may be useful specimens (p<0.5) was observed upon
contributing to skin wrinkling.132 NF-kB for mitigating the adverse effects of histological examination of skin
up-regulates transcription of pro- sunlight on human skin, such as biopsies.152
inflammatory mediators, such as photoaging.
interleukin (IL)-1, IL-6, IL-8, and In another study, topical green tea What conclusions can be drawn
tumor necrosis factor-alpha.143 Acting was shown to provide photoprotection from data on green tea?
through the cell surface, these pro- anywhere from 24 hours up to 72 Although it has been shown that
inflammatory mediators further hours. It reduced the number of green tea is able to influence
activate AP-1 and NF-kB, resulting in sunburned cells by 66 percent when mechanisms on skin that are beneficial
more damage. It is the sum of these applied 30 minutes prior to UVB for anti-aging, via its antioxidant and
events that are responsible for skin exposure and when applied at 1- to 10- anti-inflammatory properties, there
aging.144 percent concentrations. A dose- has yet to be a clinical trial to show a
We now know that green tea and dependent inhibition of ultra-violet- significant clinical improvement in the
EGCG in addition to being effective induced erythema was evident.150 signs of aging with the topical
free-radical scavengers, down-regulate Green tea extract also prevented application of green tea. Even so,
UV-induced expression of AP-1 and psoralen-UVA photodamage with pre- green tea products are widely used by
NF-kB and suppress metalloproteinase and post-treatment by reducing consumers despite the lack of
and age-related collagen cross-linking erythema, hyperplasia, and evidence. For this reason, a healthy
in mice.139,145–149 In addition, it has been hyperkeratosis.151 dose of skepticism is appropriate for
shown in vitro that green tea dermatologists regarding the
polyphenols inhibit the activity of What clinical studies are available usefulness of many cosmeceuticals
collagenase and increases collagen on green tea? touting green tea until a split-face,
biosynthesis rate of human To date, we are only aware of one double blind, randomized trial
fibroblasts.91 randomized, double-blind, controlled, involving several concentrations of
Photoprotectant effects. Thus clinical trial involving topical green tea green tea extract or EGCG is
taken together, a multitude of extract. This study was completed by conducted.
scientific evidence exists supporting Chiu et al152 and consisted of 40
the notion that green tea extract may women with moderate photoaging. Conclusion
improve aging skin through its Eighteen subjects took 300mg green The term cosmeceutical was
antioxidant and anti-inflammatory tea supplements twice a day and created to define a subgroup of topical
capabilities. These scientific theories applied green tea cream twice daily; products with “drug-like” effects on
were put to the test in studies whereas, the other 18 subjects used a skin and to differentiate this subgroup
published by Elmets et al.150 In their placebo cream and a placebo from purely cosmetic products and
study, human skin was pretreated with supplement twice daily. All subjects topical prescription drugs. Since
either green tea extract or one of its used the same sunscreen and cleanser. cosmeceutical products are claiming to
constituents and then exposed to two Experts were blinded and subjects affect the structure and function of
minimal erythema doses of solar were graded based on wrinkling, skin it makes sense then to hold
stimulated light. Application of green roughness, course rhytids, skin laxity, cosmeceutical products to higher

QUESTIONS • CHALLENGES • CONTROVERSIES

36 [ February 2010 • Volume 3 • Number 2]

standards of scientific substantiation When evaluating a cosmeceutical 107(2):178–182.
than cosmetic products. In our ingredient, it is important for 8. Baily J, Cretaz M, Scifflers MH, Marty JP.
opinion, these higher standards should physicians to access the scientific In vitro metabolism by human skin and
include at minimum being able to literature, not only in medicine, but fibroblasts of retinol, retinal and retinoic
substantiate the three major questions also in basic pharmacology and acid. Exp Dermatol. 1998;7:27–34.
proposed by Dr. Albert Kligman, as biochemistry, to verify that the claims 9. Kang S, Fisher GJ, Voorhees JJ.
discussed earlier. Thus, there needs to made for active cosmeceutical Photoaging and topical tretinoin: therapy,
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Dr. Levin is from the Mohave Skin & Cancer Clinics, Dermatology Research Center, Las Vegas, Nevada; Dr. Del Rosso is
Dermatology Residency Director, Valley Hospital Medical Center, Las Vegas, Nevada; Dr. Momin is Chief Dermatology
Resident (PGY-4), Valley Hospital Medical Center, Las Vegas, Nevada.
Disclosure: Dr. Levin was a previous employee of and is a consultant to Guthy-Renker Corporation.
Drs. Del Rosso and Momin report no relevant conflicts of interest.

QUESTIONS • CHALLENGES • CONTROVERSIES

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