Original Paper

Skin Pharmacol Physiol 2017;30:146–158 Received: October 25, 2016

Accepted after revision: February 24, 2017
DOI: 10.1159/000464470
Published online: May 20, 2017

An Insight into the Changes in Skin Texture and

Properties following Dietary Intervention with
a Nutricosmeceutical Containing a Blend of
Collagen Bioactive Peptides and Antioxidants
Licia Genovese a Andrea Corbo b Sara Sibilla a
a
Minerva Research Labs Ltd., London, UK; b Master II livello Università degli Studi di Camerino, Camerino, Italy

Keywords daily oral consumption of the nutricosmeceutical. We also

Nutricosmeceutical · Skin aging · Collagen peptides · obtained a positive patient feedback through the self-as-
Antioxidants · GOLD COLLAGEN® sessment questionnaires. Taken together these results show
that this nutricosmeceutical supplement may have photo-
protective effects and help improve skin health.
Abstract © 2017 S. Karger AG, Basel
Background: Skin aging is a multifactorial phenomenon
which causes alterations in skin physiological functions and,
most visibly, phenotypic changes. In particular, during the Introduction
aging process, hyaluronic acid, collagen, and elastin fibers
undergo structural and functional changes. Aims: This study Intrinsic and extrinsic aging act simultaneously and
aimed to give an insight into the photo-protective benefits are associated with structural and functional alterations
and efficacy of an oral liquid nutricosmeceutical containing in the skin which lead ultimately to the formation of phe-
collagen bioactive peptides and antioxidants to counteract notypic changes such as increased skin frailty, fine lines
the signs of aging. Methods: A double-blind, randomized, and wrinkles. Collagen and elastin are long-life proteins
placebo-controlled clinical trial was conducted by an inde- predisposed to intrinsic molecular aging. As a conse-
pendent esthetic clinic on 120 healthy volunteer subjects for quence, they accumulate damages over time and this de-
90 days. Subjects were divided into 2 groups: 60 subjects creases their ability to function correctly. Intrinsically
consumed 1 bottle (50 mL) of the nutricosmeceutical daily aged skin is generally characterized by dermal atrophy
and the other 60 consumed 1 bottle (50 mL) of the placebo. with reduced density of collagen fibers, elastin and hyal-
Outcome measures were related to skin elasticity (expressed uronic acid [1–3].
as Young’s elasticity modulus) and skin architecture (histo- Structural changes in the dermis are even more severe
logical analysis). In addition, the subjects recruited in this when the skin is both intrinsically old and photo-aged
study underwent observational assessments through self- (chronically exposed to sunlight [4, 5]). Extrinsically aged
assessment questionnaires. Results and Conclusions: Over- skin is characterized by the degradation and the alteration
all, we demonstrated a significant increase in skin elasticity of collagen fibers and by the accumulation of disorga-
(+7.5%), p ≤ 0.001 and an improvement in skin texture after nized elastin proteins throughout the dermis, a process
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Univ. of California San Diego

© 2017 S. Karger AG, Basel Sara Sibilla

Minerva Research Labs Ltd.
1-6 Yarmouth Pl.
Downloaded by:

E-Mail karger@karger.com
London W1J 7BU (UK)
www.karger.com/spp
E-Mail ssibilla @ minervalabs.com
known as elastosis. The degradation of existing collagen of the collagen peptides and/or proline during a period of
fibers leads to a reduction in the mechanical tension pro- 6 h and until 14 days. The results were very promising in
vided by the fibroblasts, reflected by a decrease in their terms of residence in the skin and showed that the radio-
activity [6]. activity remained elevated up to 14 days [27].
Chronic exposure to sunlight can also cause actinic Another study, performed in human subjects, ana-
keratosis (thickening of the stratum corneum), acantho- lyzed the absorption and distribution of specific peptides
sis (increased cell number in the stratum spinosum of the after consumption of hydrolyzed collagen derived from
epidermis), vascular ectasia (enlargement of the vessels), cartilage, chicken feet and porcine skin after 12 h of fast-
and general skin inflammation [7–9]. ing. It was shown that after hydrolyzed collagen intake,
In the aging process, an accumulation of oxidative the amount of hydroxyproline-containing peptides in the
damage in cells and tissues is also observed [10, 11]. This blood increased, reaching a peak after 2 h, followed then
is caused by a disturbance in the balance between the by a decrease to half the maximum level at 4 h after inges-
production of reactive oxygen species (ROS) and the tion. A small peptide formed by proline and hydroxypro-
natural antioxidant defenses. In the skin, free radical line (Pro-Hyp) was found in the blood after ingestion of
damage can cause deterioration of the stratum corneum hydrolyzed collagen. More specifically, the amount of
[12] and supportive connective tissue, resulting in de- Pro-Hyp present in human plasma after ingesting 9.4–
creased elasticity and resilience [13]. Sun damage, in- 23 g of hydrolyzed collagen was 25–60 nmol/mL [28]. The
creasing ROS production, can cause both skin cancer higher levels of Pro-Hyp found in the blood after hydro-
and photo-aging [14] and affects the skin through wrin- lyzed collagen consumption could be partly explained by
kling, scaling, dryness, and mottled pigmentation [15]. the higher quantity of the Pro-Hyp sequence in collagen.
In addition, the activation of matrix metalloproteinases These results suggest that Pro-Hyp can be considered an
(MMPs) can occur. These enzymes, induced by UVA indigestible peptide as more than 75% of Pro-Hyp was
and UVB rays, play a major role in the pathogenesis shown to persist in the blood for 24 h after in vitro reac-
of photo-aging by exerting a proteolytic activity that tion with human serum. Similar results were obtained by
results in the degradation of collagen and elastin fibers Ohara et al. [29].
[16, 17]. In addition, it has been shown that collagen-derived
Nowadays, there are continuously new insights into peptides (proline-hydroxyproline and glycine-proline-
the effects of orally administered biologically active com- hydroxyproline) are absorbed through PEPT1 transport-
pounds (such as antioxidants) on skin function, and this er [30].
has led to the development of nutritional supplements to Topical application of products containing collagen
benefit human skin [18–20]. For example, some dietary does not significantly improve the skin texture, as the col-
components with antioxidant properties could have an lagen molecules cannot penetrate the epidermis, due to
indirect effect on the skin via secondary messengers, or their high molecular weight (130–300 kDa) [31]. The oral
during digestion they can pass down the gastrointestinal intake of collagen bioactive peptides instead, due to their
tract, cross the intestinal barrier, and then (through the low molecular weight, permits a systemic absorption and
blood stream) reach the different tissues of the body, distribution of these peptides in the different tissues [27,
among which skin, potentially in an active form. The 28, 32]. Collagen peptides activate fibroblasts, leading to
blood can continuously replenish the skin with these bio- the production of collagen [33], elastin [33] and hyal-
active compounds, which are then distributed to all skin uronic acid [29].
compartments (epidermis, dermis, subcutaneous fat) and We investigated here the capacity of an oral liquid sup-
also to the sebum [20]. plement containing both collagen bioactive peptides and
Similarly, there is extensive literature showing the ben- antioxidants to benefit the cutaneous tissue.
efits of hydrolyzed collagen-based nutraceutical supple-
ments on human skin [21–26].
The absorption and distribution of hydrolyzed colla- Materials and Methods
gen has been analyzed in several different studies. An in
Test Product
vivo study performed in Wistar rats analyzed the distri-
The product considered in this study is GOLD COLLAGEN®
bution of orally administered 14C-labeled proline and/or FORTE (referred in the text as test product) and it is taken orally.
collagen peptides to the skin and other tissues. Radioac- It is manufactured by MINERVA Research Labs (London, UK).
tivity was measured in the different tissues after ingestion This nutricosmeceutical contains a European patented complex
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Health DOI: 10.1159/000464470
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(EP2532252 B1: beverage to ameliorate skin condition), which in- Table 1. Ingredients in test product and placebo
cludes the following bioactive ingredients: hydrolyzed collagen
type I (5,000 mg), with a molecular weight of 0.3–8 kDa, hyaluron- Ingredients in test product
ic acid, borage oil and N-acetylglucosamine. The product also con- European patented complex1
tains vitamins and minerals for the maintenance of skin, hair and Hydrolyzed collagen, hyaluronic acid, N-acetylglucosamine,
nails and a blend of antioxidants (L-carnosine, resveratrol, lyco- borage oil
pene, coenzyme Q10, pomegranate, acai berry) for the protection
against oxidative damage. The test product is stable at room tem- Minerals
perature and has a shelf-life of 21 months starting from the day it Zinc, copper
has been manufactured. The best before date is indicated on the Vitamins
bottle label and on the packaging box. Vitamins C, E, B6, A, D, biotin
Study Design Antioxidants
A double-blind, randomized, placebo-controlled study was Resveratrol, acai berry, coenzyme Q10, pomegranate, lycopene,
conducted by an independent esthetic clinic in Rome (Italy). Sub- L-carnosine
jects participating in the trial were divided into 2 groups: 60 volun- Additional active ingredients
teer subjects (57 females and 3 males) consumed 1 bottle (50 mL) Bioperine®, evening primrose oil (in combination with borage oil)
of the test product daily over a period of 90 days, and similarly
other 60 volunteer subjects (54 females and 6 males) consumed 1 Other ingredients
bottle (50 mL) of the placebo. The sample size was chosen after Water, citric acid, soybean polysaccharide, malic acid, stevia,
consultation with a statistician in order to reach statistically sig- flavoring (peach and lychee)
nificant results for each group when final analysis was performed.
Ingredients in placebo
Ingredients for the test product and placebo are listed in Table 1.
Water, stevia, peach and lychee flavoring , citric acid, malic acid,
This trial was conducted during summer time in order to evaluate
soybean polysaccharide
the efficacy of the test product to protect the skin against UV-in-
duced photo-aging. Some of the subjects recruited in this study 1
Patent No. EP2532252 B1.
underwent a cosmetic treatment on the face (i.e., botox, filler) dur-
ing the trial period.

Inclusion and Exclusion Criteria

The inclusion criteria were as follows: healthy female and male
volunteers between 40 and 60 years, with any body mass index (BMI), There was no distinction in the boxes and bottles given to the
of all ethnic types, with a balanced diet, able to understand the study subjects except for the batch number written on the box side and
related information and to give a written informed consent. on the bottle cap.
The exclusion criteria were as follows: female subjects who All participants in the trial were randomly assigned to either
were pregnant, had a recent pregnancy (past 6 months), were plan- the test product or placebo group, received the corresponding
ning a pregnancy or breastfeeding, subjects with allergies to fish or treatment and were analyzed for the outcome measurements. The
soy, subjects with a significant past medical history which in the primary outcome measure was related to skin elasticity. Addition-
opinion of the investigator would compromise the safety of the al secondary outcome measurements included the qualitative anal-
subjects, subjects with severe skin-related pathologies (i.e., skin ysis of skin structure through histological examination and self-
cancer, psoriasis, eczema, melasma), subjects who were using col- assessment questionnaires completed by the subjects.
lagen-based food supplements.
Subjects with the characteristic hallmarks of skin photo-aging Outcome Measures
(i.e., wrinkling, orthokeratotic hyperkeratosis, irregular acantho- Skin Elasticity
sis, vascular ectasia and dermal elastosis) were also recruited in the Skin elasticity (expressed as Young’s elasticity modulus) was
study. assessed with SkinLab USB Elasticity Module (DermaLab® Series,
Subjects continued to use their usual facial skin cleansing and Cortex Technology, Hadsund, Denmark).
moisturizing products, and make up for the duration of the entire Young’s elasticity was measured in the inner part of the ventral
study. forearm, at 10 cm from the wrist of each subject recruited in the
trial. The test site was the same for all participants and areas with
Blinding and Randomization any type of skin lesion were disregarded (i.e., moles, scars).
This research study was a double-blind, randomized, placebo-
controlled trial. A total of 120 subjects who met the inclusion cri- Skin Biopsies and Histological Examination
teria were recruited by the investigator(s) into the study. They were This exam was performed by incisional biopsy (Punch 4.0 mm)
allocated randomly and they ingested 1 dose (50 mL) of the test at the level of the surface of the right buttock. The histological ex-
product or the placebo on a daily basis for 90 days. MINERVA Re- amination was performed by staining the sections with hematoxy-
search Labs generated the random allocation sequence using lin and eosin for the assessment of skin structures and, in particu-
GraphPad QuickCalcs, a widely used method for random alloca- lar, of collagen and elastin fibers.
tion into equal-sized groups (http://www.graphpad.com/quick-
calcs/randomize1/).
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Table 2. Subjects’ demographics All subjects recruited in the trial compiled self-assessment
questionnaires comprised of 2 parts: the first section was complet-
Test product Placebo ed by the subjects at baseline (day 0), while the second section was
(n = 60) (n = 60) completed at the end of the trial (day 90).
The photographic assessment was done at the beginning (day
Mean age (SD), years 47.72 (6.5) 49.65 (6.5) 0) and at the end of the trial (day 90).
Sex, n (%) The test product used in this study is an over-the-counter nu-
Female 57 (95) 54 (90) traceutical which has been in the market since 2014. It has been
Male 3 (5) 6 (10) assigned a notification number in several European countries and
Ethnic background, n (%) MHRA confirmed this product should not be considered a me-
Caucasian 56 (93.3) 56 (93.3) dicinal. All procedures carried out in this study were in accordance
Asian 1 (1.6) 3 (5) with the ethical standards of the responsible committee on human
Latin-American 2 (3.3) / experimentation (institutional and national) and with the Helsin-
Middle-Eastern 1 (1.6) / ki Declaration of 1975, as revised in 2000 and 2008. The procedures
Mean BMI (SD) 21.78 (2.06) 22.97 (3.88) were explained and an informed written consent was signed by all
Subjects smoking, n (%) 29 (48.3) 28 (46.6) participants included in the study.
Subjects drinking alcohol, n (%) 24 (40) 23 (38.3)
Statistical Analysis
The mean values of the measurements for skin elasticity were
calculated and analyzed at each time point. All data were tested for
Table 3. Subjects’ skin baseline characteristics normal distribution by the Shapiro-Wilk normality test and vari-
ances among data groups were tested for homogeneity by the Lev-
Test product Placebo ene’s test.
(n = 60) (n = 60) Statistical analysis was carried out by differently combining and
comparing the test product and placebo results at day 0 with the
Fitzpatrick, n (%) test product and placebo results obtained at day 90. In a second
I 3 (5) 7 (11.6) analysis, skin elasticity was evaluated filtering the data according to
II 13 (21.6) 14 (23.3) the subjects who underwent a cosmetic treatment or not. Although
III 30 (50) 23 (38.3) a cosmetic treatment is mainly a topical treatment and might not
IV 13 (21.6) 12 (20) act to increase skin elasticity systemically, we have decided to pro-
V 1 (1.6) 4 (6.6) ceed with this type of data filtering because the treatment could
Glogau, n (%) represent an influencing factor which can lead the subjects to have
I 31 (51.6) 28 (46.6) a higher self-esteem and a better care of their own skin.
II 20 (33.3) 28 (46.6) The Student paired-samples t test was used for before-and-after
III 8 (13.3) 3 (5) observations (day 0 vs. day 90) on the test product subjects and for
IV 1 (1.6) 1 (1.6) before-and-after observations on the placebo subjects (day 0 vs.
Skin elasticity, n (%) day 90). Student t test for 2 unpaired samples was used to compare
High 5 (8.3) 6 (10) the mean values between the test product and placebo at day 0 and
Medium 17 (28.3) 21 (35) between the test product and placebo at day 90. Data were consid-
Low 8 (13.3) 10 (16.6) ered significant when p was ≤0.05 and are presented here as mean
± SEM.

Observational Self-Assessment Questionnaires

Self-assessment questionnaires (with a verbal rating scale) con-
sisted of questions related to skin, hair, nails, joints, mood, and pho- Results
to-aging conditions and questions regarding the subject’s apprecia-
tion of the product. Questionnaires were filled by each participant. Subject Demographics and Baseline Skin Characteristics
A photographic record of the face of all subjects who gave their The subjects recruited in the trial were equally distrib-
consent was taken and particular focus was given to the crow’s feet uted between the test product and the placebo groups on
area and nasolabial folds.
the basis of the following characteristics: age, sex, ethnic
Measurements Schedule background (mainly Caucasian), BMI, smoking habits,
Skin elasticity was measured at baseline (day 0) and at the end and weekly alcohol use (Table 2). Among all subjects, the
of the treatment (day 90) in all subjects recruited in the trial, allo- most represented Fitzpatrick skin classification was type
cated with either the test product or placebo. III and the most represented photo-aging score was I/II.
Biopsies were taken at the beginning (day 0) and at the end of
the trial (day 90) from 4 subjects who took the test product and Most of the subjects had a medium level of skin elasticity
who did not undertake any other cosmetic treatment during the at day 0 (Table 3).
trial period. No adverse events were reported in this study.
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 Increase in Skin Elasticity
Placebo Test product
Skin elasticity was measured before (7.90 ± 0.2 mm;
*** n = 60) and after placebo treatment (7.52 ± 0.2 mm; n =
9
*** 60) with a significant difference in the averages of –0.38
8 mm (p ≤ 0.001, t test paired samples), which resulted in
a –5% decrease from day 0 (Fig. 1). The elasticity param-
7
eter was also measured before (7.51 ± 0.2 mm; n = 60) and
6 after the treatment with the test product (8.07 ± 0.2 mm;
Young’s elasticity

n = 60), with a difference of +0.56 mm (Fig. 1). This +7.5%

5 increase in skin elasticity was statistically significant (p ≤
4
0.001, t test paired samples).
Skin elasticity was compared between test product and
3 placebo at day 0 and between test product and placebo at
day 90 and the difference was not significant in both cases.
2
As 57.5% of the total subjects recruited in this study
1 underwent a cosmetic treatment in the face, we further
investigated the effect of the placebo and the test product
0
Day 0 Day 90
on skin elasticity by analyzing the subjects separately re-
garding who had or did not have a cosmetic treatment.
Skin elasticity was first compared between test product
Fig. 1. Skin elasticity measurements (expressed as Young’s elastic- and placebo at day 90 by filtering subjects with and
ity modulus). A significant increase of +7.5% in skin elasticity was
seen in subjects consuming the test product for 90 days (*** p ≤
without a cosmetic treatment. A significant increase in
0.001, t test paired samples). A significant decrease (–5%) in skin skin elasticity was detected in the test product group
elasticity was seen in placebo subjects at day 90, when compared compared to the placebo group, in subjects who did
to day 0 (*** p ≤ 0.001, t test paired samples). not undergo a cosmetic treatment (+13.9% increase;

Without cosmetic treatment With cosmetic treatment

Test product supplementation Placebo supplementation

** **
9 *** 9 ***
8 8

7 7

6 6
Young’s elasticity
Young’s elasticity

5 5

4 4

3 3

2 2

1 1

0 0
a Day 0 Day 90 b Day 0 Day 90

Fig. 2. Skin elasticity measurements (expressed as Young’s elastic- out (+5.4% increase) (** p ≤ 0.01, t test paired samples). b Placebo:
ity modulus) by analyzing subjects with and without cosmetic skin elasticity was significantly reduced of –3.7% for the subjects
treatment. a Test product: a significant increase in skin elasticity with cosmetic treatment (*** p ≤ 0.001, t test paired samples) and
was seen both in the subgroup with a cosmetic treatment (+9.1% of –6.5% for the ones without (** p ≤ 0.01, t test paired samples).
increase) (*** p ≤ 0.001, t test paired samples) and in the one with-
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7.17 ± 0.3 mm, placebo n = 24; 8.17 ± 0.3 mm, test prod- reduction was of –3.7% (8.06 ± 0.3 mm, day 0; 7.76 ± 0.3
uct n = 27; t test unpaired samples, p ≤ 0.05) (online mm, day 90; n = 36, p ≤ 0.001, t test paired samples) and
suppl. Fig. 1; for all online suppl. material, see www. for the subjects without cosmetic treatment, the reduc-
karger.com/doi/10.1159/000464470). A similar compari- tion was of –6.5%, (7.67 ± 0.4 mm, day 0; 7.17 ± 0.3 mm,
son was performed at day 90 considering only subjects day 90; n = 24, p ≤ 0.01, t test paired samples) (Fig. 2). No
who underwent a cosmetic treatment and in this group significant difference was observed in the baseline condi-
the increase in skin elasticity failed to reach significance. tion at day 0 between both subgroups, neither for the ones
When the subgroup analysis was performed by com- treated with the test product nor for the ones treated with
paring day 90 to day 0, among the subjects taking the test placebo.
product, there was a statistically significant increase in
skin elasticity both in the subgroup with a cosmetic treat- Histological Analysis
ment (+9.1% increase; 7.32 ± 0.3 mm, day 0; 7.99 ± 0.4 Histological biopsies of healthy skin from 2 female
mm, day 90; n = 33, p ≤ 0.001, t test paired samples) and subjects before treatment with the test product showed
in the one without (+5.4% increase; 7.75 ± 0.3 mm, day 0; the following skin characteristics: orthokeratotic hyper-
8.17 ± 0.3 mm, day 90; n = 27, p ≤ 0.01, t test paired sam- keratosis, irregular acanthosis, vascular ectasia, and der-
ples) (Fig. 2). Moreover, skin elasticity was significantly mal elastosis. After 90 days of treatment, there was an
reduced in the placebo subjects for both subgroups. In improvement in the structure and stratification of the
particular, for the subjects with cosmetic treatment the epidermal layers (absence of the architectural disorder of

Color version available online

Epidermal-dermal Orthokeratotic Irregular Orthokeratotic
junction hyperkeratosis acanthosis hyperkeratosis
Papillary
dermis Irregular
acanthosis

Vascular
ectasia
Day 0

Dermal elastosis

Reticular dermis

Multi-stratified squamous epithelium Epidermal layers

Stratum corneum Epidermis

Stratum granulosum
Hyaline papillary
Epidermis Stratum spinosum dermis

Papillary Stratum basale

Dermal
Day 90

dermis
collagen
fibers

Reticular
dermis Normal collagen Normal collagen
structure structure

Patient I (test product) Patient II (test product)

Fig. 3. Histological examination of skin biopsies in 2 subjects (left elastosis were observed. At day 90: improvement in the structure
and right panel) consuming the test product for 90 days. Day 0 is of the dermis and in the stratification of the epidermal layers, im-
compared to day 90 for both subjects. Arrows in all pictures indi- provement in collagen structural architecture within the dermis
cate skin structure and characteristics. At day 0: orthokeratotic hy- (increase in fiber width and parallel collagen running fibers).
perkeratosis, irregular acanthosis, vascular ectasia, and dermal
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 Color version available online
Subject I
Subject II

Fig. 4. Evidence of improved skin texture in

the crow’s feet area and nasolabial folds
when comparing the pictures before (day
0) and after the treatment (day 90) with the Day 0 Day 90
test product.

the Malpighian layer) and an improvement in the colla- more elastic; 91.7% agreed their hair was stronger and
gen fibers structural architecture within the dermis (in- 81.7% agreed it was thicker; 91.7% agreed their nails
crease in the fiber width and parallel collagen running were stronger and 93.3% agreed their nails were health-
fibers) (Fig. 3). Importantly, these subjects did not un- ier; 76.7% had an improvement in joint comfort and
dergo any other cosmetic procedures at that time. 98.3% had an improvement in their general wellbeing.
For the same 2 subjects, a photographic record of their Overall, most of the subjects gave a very positive feed-
face was acquired before and after treatment with the test back after treatment with the test product. The analysis
product; these images are shown in Figure 4. of the results related to the placebo group revealed a sig-
Similar histological results, relative to the biopsies of nificant lower appreciation for all parameters consid-
other 2 subjects included in this trial, have been published ered.
as preliminary data from a pilot study [26]. The questionnaire results related to the skin at day 90,
from subjects who took the test product or the placebo,
Self-Assessment Questionnaires Results were further analyzed filtering and comparing those sub-
A first analysis was performed to compare placebo jects who underwent a cosmetic procedure and those who
and test product questionnaire results at day 0 for skin, did not. Importantly, a first analysis revealed that both of
hair, nails, joints, mood, photo-aging, and product ap- these subgroups (considering only the ones allocated with
preciation. The analysis showed that at baseline both the test product) had a similar perception of all skin param-
groups reported similar perceptions for the parameters eters at day 90 (online suppl. Fig. 2, upper panel). Second,
considered (data not shown). A summary of the most considering the ones allocated with the placebo, the per-
significant feedbacks from the test product group versus ception of skin parameters was similar between both sub-
the placebo group at the end of the treatment (day 90) is groups and the values percentages were generally lower
shown in Figure 5 and further complete results are compared to the ones of the correspondent skin param-
shown in the online supplementary Tables and Photo- eters in the test product group analysis (online suppl. Fig. 2,
aging Table. It is worth mentioning here some results for lower panel). Moreover, the analysis of the test product
the test product group: 95% of the subjects agreed their versus placebo, considering separately the subjects who
skin was more hydrated and 91.6% agreed their skin was underwent a cosmetic procedure and the ones without,
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 Placebo Test product

Skin Hair Nails

100 100 100
80 80 80

People, %

People, %
People, %

60 60 60
40 40 40
20 20 20
0 0 0
at re

as e

er

ag s

lin ess

er

er

st s

le ut

er

er

r
ie
m Les

fa ow
el or

ick

ck
dr o

th

ng

ng
o

th
ed

es

er
Sm ic

ss
L
hy M

Gr

lls
oo

ui
t

l
ro

ro
Th

ea
sq
Fa
St

St

H
e
da

ow
fin

Gr
Joints Mood Appreciation
100 100 100

80 80 80

People, %
People, %
People, %

60 60 60
40 40 40
20 20 20
0 0 0
fo in

er re

ge l

er

pr wo duc o

da e

a uct nd
un ee

st
ry th
t
en Mo

pi
om se

e
pr ue

y
rt

gy

en o
ta
yo F

od m
ap

ve e

fri t
t c rea

t e tak
is in

d
pr m
H

th
th nt
o
c

is co
uc d
In

e co

e
l

th re
ik
od u
us ill
in

Il

ld
Iw
jo

ou
I

Iw
Fig. 5. Results of the self-assessment questionnaires compiled by the subjects (placebo vs. test product) regarding their skin, hair, nails,
joints, mood, and appreciation of the product after 90 days of treatment.

showed that in both cases the treatment with the nutricos- ity of +7.5% after 90 days of treatment. We hypothesize
meceutical enhanced the perception of skin condition ben- that this increase may be due to the dual action mecha-
efits compared to placebo (online suppl. Fig. 3). nism of collagen bioactive peptides in the dermis: (1) free
The results related to the photo-aging analysis (part of amino acids provide support for the formation of colla-
the overall skin and hair analysis) also showed improve- gen fibers [34]; (2) bioactive peptides bind to fibroblasts
ments in skin and hair parameters both when comparing membrane receptors and stimulate their proliferation
test product vs. placebo at day 90 (i.e., 95 vs. 50% of peo- [35] and the production of new collagen [33, 36, 37], elas-
ple who agreed their skin was more hydrated; 91.7 vs. 35% tin [33], and hyaluronic acid [29].
of people who agreed their hair was stronger) and when This increase in skin elasticity was detected both in
comparing day 90 vs. day 0 in the test product group only subjects who had a cosmetic treatment and in those who
(i.e., 95% of the subjects agreed their skin was more hy- did not. More specifically, the statistically significant in-
drated at day 90 vs. 48.3% who agreed their skin was dri- crease in skin elasticity in subjects taking the nutricosme-
er at day 0 and 91.7% agreed their hair was stronger at day ceutical supplement alone, without undertaking any oth-
90 vs. 71.6% who agreed their hair was weaker at day 0; er cosmetic treatment in conjunction, excludes the pos-
Fig. 6 and online suppl. photo-aging Table). sibility that the cosmetic treatment could increase skin
elasticity on its own. The combination of the dietary sup-
plement together with a cosmetic treatment induces a
Discussion greater significant increase in skin elasticity (+9.1%)
when compared to the dietary supplement alone, which
In this study, we show that the oral consumption of a suggests that this nutricosmeceutical could work syner-
nutricosmeceutical containing a blend of collagen pep- gistically in combination with a cosmetic treatment to
tides and antioxidants significantly increases skin elastic- improve skin elasticity.
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 Placebo Test product
Skin photo-aging Hair photo-aging
100 100

80 80

People, %
People, %
60 60

40 40

20 20

0 0
More Youthful Less Less Grows Stronger Thicker
hydrated damage fine lines faster

Day 0 Day 90
Skin photo-aging Hair photo-aging
100
100

80 80

60
People, %

People, %
60

40 40

20 20

0 0
Dry/more Pigmented/ Cracks/ Fine lines/ Grows Weak/ Thin/
hydrated youthful less damage less fine lines slowly/ stronger thicker
grows faster

Fig. 6. Results of the self-assessment questionnaires compiled by the subjects by analyzing skin and hair param-
eters related to photo-aging after 90 days of treatment. Upper panel: skin and hair analysis by comparing placebo
versus test product. Lower panel: skin and hair analysis by comparing day 90 to day 0 in subjects who took the
test product only.

The reduction in skin elasticity observed only in the 25, 33]. However, the supplements used in these studies
placebo group was expected and might have been caused were mainly formulated with hydrolyzed collagen and
by the summer climatic conditions during the trial period ingredients that boost collagen production or prevent
(sun damage in particular) [2, 38]. its degradation (such as vitamins C and E) [39]. In this
Although skin elasticity did not overall significantly study, we suggest that the increase in skin elasticity might
increase when all the subjects taking the test product were be due not only to the presence of the collagen bioactive
compared to placebo at end of the trial, the subgroup peptides, but also to the presence of a mix of antiox-
analysis revealed that there was a significant improve- idants: L-carnosine, resveratrol, lycopene, coenzyme
ment in skin elasticity in those subjects taking the nutri- Q10, pomegranate, and acai berry. The beneficial prop-
cosmeceutical without undergoing any other cosmetic erties of these ingredients are well known and have been
treatment. First, this is an indication of the efficacy of this extensively studied in the literature. Carnosine is a scav-
nutricosmeceutical in improving skin elasticity, when enger of ROS and reactive nitrogen species [40]; resvera-
compared to placebo. Second, the reason the significant trol is an antioxidant polyphenol from red wine with well
improvement is related only to a subgroup might be ex- reported anti-aging properties [41]; lycopene is a carot-
plained by the fact that a bigger sample size is required to enoid present in human blood and tissues [42]; CoQ10
reach overall significance. plays a key role in mitochondrial bioenergetics and can
Other studies have reported an increase in skin elas- function as an antioxidant [43]; pomegranate is a source
ticity after supplementation with collagen peptides [23, of numerous phenolic compounds [44] and acai berry
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154 Skin Pharmacol Physiol 2017;30:146–158 Genovese/Corbo/Sibilla

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has been reported as a food with significantly high anti- physiological balance of collagen and elastin synthesis
oxidant capacity [45]. and degradation.
The bioavailability of these antioxidants has been The significant increase in skin elasticity and the im-
widely, yet not in-depth, studied in the literature. For ex- provement in several histological photo-aging param-
ample, in humans it was shown that carnosine is rapidly eters after consumption of the test product indicate also
cleared from the plasma and sequestered in some com- its potential photo-protective role on skin.
partments before it is excreted in the urine. It appears that Our results are in line with other studies which have
carnosine could be distributed to the muscles, which are also given a useful insight into the epidermal and dermal
the major repository of endogenous carnosine [46]. Res- ultra-structural changes after either antioxidant topical
veratrol has a good absorption but low bioavailability application [56] or antioxidant oral supplementation
(around 10% of ingested dose being bioactive) when oral- [57–59].
ly administered to man [47]. Interestingly, its absorption In line with our results, epidermal and dermal ultra-
appears to follow a circadian rhythm being more bio- structural improvements can be obtained also following
available in the morning when compared to the afternoon consumption of collagen based supplements both in mice
[48]. Lycopene, a carotenoid, is absorbed in the intestine [21] and in humans [26, 60].
and then transported through the bloodstream by lipo- Results from the self-assessment questionnaires
proteins to various target tissues, including skin [49]. The showed an overall significant perceived improvement in
absorption of CoQ10 is poor because of its insolubility in skin, hair, nails, mood, product appreciation, and joints
water and large molecular weight. Solubilized formula- condition in the test product group at the end of the
tions of CoQ10 have been shown to have enhanced bio- treatment. A question about joint comfort was included
availability [50]. Pomegranate is rich in polyphenols such in the self-assessment questionnaires as dietary supple-
as ellagitannins which are able to hydrolyze into ellagic mentation with hydrolyzed collagen could help in allevi-
acid and other small polyphenols. Ellagic acid metabolites ating the joint pain, which typically arises with age-relat-
in plasma vary very much among subjects as the metabo- ed diseases such as osteoarthritis and rheumatoid arthri-
lism of polyphenols is known to vary in human subjects tis [61, 62].
[51]. Only few studies have been performed to determine Importantly, the improvements in the above parameters
the absorption of polyphenols from acai berry specifical- were not observed to the same extent in the placebo group
ly. However, in the literature there are several results re- (also when comparing the 2 subgroups of subjects who un-
garding the intestinal absorption of polyphenols from dertook a cosmetic treatment or not). Having any kind of
different plants and their plasma absorption is highly cosmetic treatment during the trial period may have con-
variable [52, 53]. tributed to improve subjects’ psychological self-esteem and
Therefore, the combination of these powerful active to exclude the possibility that the positive perception of
ingredients, present in the test product, might help coun- skin condition was due to the cosmetic treatment, the com-
teract age-related ROS damages and inhibit the activation parison of these subjects with the ones who did not under-
of MMPs. Further studies are ongoing to investigate this go any cosmetic treatment (both subgroups using the test
mechanism of action. product) resulted in a similar positive perception in all skin
The histological examinations in the test product parameters. This confirms that the test product generates a
group revealed an improvement in the structure and similar perception in skin condition regardless if the sub-
stratification of the epidermal layers and in the collagen ject undertook a cosmetic treatment or not.
and elastin fibers network in addition to a reduction in The analysis performed considering both the test
the photo-aging parameters (such as solar elastosis, epi- product and placebo subjects who underwent a cosmetic
dermal acanthosis, vascular ectasia, and phlogosis) [54, procedure and the ones who did not revealed that in both
55]. Importantly, as these subjects did not undergo any cases the test product enhances in a similar way the per-
other cosmetic treatment, the histological parameters an- ception of a better skin condition, when compared to pla-
alyzed were not influenced by these procedures. More- cebo.
over, the biopsies were taken from areas that could be af- The test product group also felt an improvement in
fected by sun damage, especially in summer time. those parameters directly linked to photo-aging.
These results suggest that the oral intake of this nutri- In conclusion, the results herein provided give an im-
cosmeceutical supplement can help improve skin health portant insight into the anti-aging and photo-protection
by restoring the correct thickness of skin layers and the benefits that can be achieved when both collagen bioac-
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Nutricosmeceutical Intervention on Skin Skin Pharmacol Physiol 2017;30:146–158 155

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tive peptides and antioxidants are blended together and Statement of Ethics
supplemented daily. Further in depth studies are needed All procedures carried out in this study were in accordance
to have a better understanding of the structural changes with the ethical standards of the responsible committee on human
happening within the epidermis and dermis after this experimentation (institutional and national) and with the Helsin-
type of intervention. ki Declaration of 1975, as revised in 2000 and 2008. The procedures
were explained and an informed written consent was signed by all
participants included in the study.
Acknowledgments
All authors contributed to the design of the clinical trial, which Disclosure Statement
was carried out at Roma Medica Srl, Rome (Italy) by A.C., who
analyzed the data and presented it to L.G. and S.S., removing any This research was carried out at Roma Medica Srl, Rome (Italy).
perceived conflict of interest. All authors contributed to the writ- The nutricosmeceutical supplement used in this study, GOLD
ing and preparation of the manuscript. COLLAGEN® FORTE, was provided by MINERVA Research
The nutricosmeceutical supplement (GOLD COLLAGEN® Labs (London, UK). The authors certify that there is no conflict of
FORTE) and placebo used in this study were provided by MINER- interest regarding the material discussed in this manuscript.
VA Research Labs (London, UK). The study was funded by MINERVA Research Labs (London,
The study was funded by MINERVA Research Labs (London, UK).
UK).

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