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The effect of oral collagen peptide supplementation on skin moisture and the dermal collagen network: Evidence from an ex vivo model and randomized, placebo-controlled clinical trials

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  • Rousselot BVBA
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The effect of oral collagen peptide supplementation on skin moisture and the dermal collagen network: Evidence from an ex vivo model and randomized, placebo-controlled clinical trials

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Background: Skin dryness and an accelerated fragmentation of the collagen network in the dermis are hallmarks of skin aging. Nutrition is a key factor influencing skin health and consequently its appearance. A wide range of dietary supplements is offered to improve skin health. Collagen peptides are used as a bioactive ingredient in nutricosmetic products and have been shown in preclinical studies to improve skin barrier function, to induce the synthesis of collagen and hyaluronic acid, and to promote fibroblast growth and migration. Our aim was to investigate the effect of oral supplementation with specific collagen peptides on skin hydration and the dermal collagen network in a clinical setting. Methods: Two placebo-controlled clinical trials were run to assess the effect of a daily oral supplementation with collagen peptides on skin hydration by corneometry, on collagen density by high-resolution ultrasound and on collagen fragmentation by reflectance confocal microscopy. Human skin explants were used to study extracellular matrix components in the presence of collagen peptides ex vivo. Results: Oral collagen peptide supplementation significantly increased skin hydration after 8 weeks of intake. The collagen density in the dermis significantly increased and the fragmentation of the dermal collagen network significantly decreased already after 4 weeks of supplementation. Both effects persisted after 12 weeks. Ex vivo experiments demonstrated that collagen peptides induce collagen as well as glycosaminoglycan production, offering a mechanistic explanation for the observed clinical effects. Conclusion: The oral supplementation with collagen peptides is efficacious to improve hallmarks of skin aging.
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Journal of Cosmetic Dermatology,0, 1--11
The effect of oral collagen peptide supplementation on skin moisture
and the dermal collagen network: evidence from an ex vivo model
and randomized, placebo-controlled clinical trials
J
erome Asserin, PhD,
1
Elian Lati, PhD,
2
Toshiaki Shioya, B.Eng.,
3
& Janne Prawitt, PhD
4
1
COSderma Laboratory, Bordeaux, France
2
BIO-EC Laboratory, Longjumeau, France
3
Unitec Foods, Tokyo, Japan
4
Rousselot BVBA, Gent, Belgium
Summary Background Skin dryness and an accelerated fragmentation of the collagen network in
the dermis are hallmarks of skin aging. Nutrition is a key factor influencing skin
health and consequently its appearance. A wide range of dietary supplements is
offered to improve skin health. Collagen peptides are used as a bioactive ingredient in
nutricosmetic products and have been shown in preclinical studies to improve skin
barrier function, to induce the synthesis of collagen and hyaluronic acid, and to
promote fibroblast growth and migration. Our aim was to investigate the effect of
oral supplementation with specific collagen peptides on skin hydration and the
dermal collagen network in a clinical setting.
Methods Two placebo-controlled clinical trials were run to assess the effect of a daily
oral supplementation with collagen peptides on skin hydration by corneometry, on
collagen density by high-resolution ultrasound and on collagen fragmentation by
reflectance confocal microscopy. Human skin explants were used to study
extracellular matrix components in the presence of collagen peptides ex vivo.
Results Oral collagen peptide supplementation significantly increased skin hydration
after 8 weeks of intake. The collagen density in the dermis significantly increased and
the fragmentation of the dermal collagen network significantly decreased already after
4 weeks of supplementation. Both effects persisted after 12 weeks. Ex vivo experiments
demonstrated that collagen peptides induce collagen as well as glycosaminoglycan
production, offering a mechanistic explanation for the observed clinical effects.
Conclusion The oral supplementation with collagen peptides is efficacious to improve
hallmarks of skin aging.
Keywords: collagen peptides, fragmentation, anti-aging, reflectance confocal
microscopy, glycosaminoglycan, hyaluronic acid
Introduction
Nutrition is known to have a major influence on skin
physiology. Thus, a good nutritional status is reflected
in good skin health perceived as a surrogate for the
person’s well-being. A wide range of nutritional supple-
ments have reported to exert benefits on skin health
Correspondence: Janne Prawitt, Rousselot BVBA, Meulestedekaai 81, Gent
9000, Belgium. E-mail: janne.prawitt@rousselot.com
Accepted for publication July 23, 2015
This is an open access article under the terms of the Creative Commons
Attribution-NonCommercial-NoDerivs License, which permits use and
distribution in any medium, provided the original work is properly cited,
the use is non-commercial and no modifications or adaptations are made.
©2015 The Authors. Journal of Cosmetic Dermatology Published by Wiley Periodicals, Inc. 1
Original Contribution
claiming to lead to a more youthful appearance.
1
Unfortunately, the scientific evidence for those claims
is often preliminary.
2
While young skin is firm, smooth and of radiant
appearance, profound changes occur in the structure of
the dermis and epidermis over time through processes of
intrinsic and extrinsic aging. The collagen density of the
dermis decreases with age and is associated with a
reduction in dermal thickness.
3
The dermal collagen
network becomes increasingly fragmented presenting
shorter and less organized fibers and accumulating
degraded collagen fragments.
4
An increase in matrix
metalloproteinase (MMP) expression accounts for the
accelerated collagen degradation.
5
In parallel, the syn-
thesis of new extracellular matrix components by dermal
fibroblasts slows down, failing to adequately replace the
degraded matrix.
6
The elastic fibers of the papillary der-
mis loose integrity during aging and reach less far into
the dermalepidermal junction. This overall loss in elas-
ticity and strength leads to sagging and wrinkling.
7,8
The amount of hyaluronic acid, which is abundant in
both epidermis and dermis, decreases with age.
9
This is
reflected in the reduced capacity to retain moisture, lead-
ing to the typically dry skin of aging people and most
importantly impairing the epidermal barrier function.
10
Collagen peptides are natural bioactive ingredients
used in many nutricosmetic products, orally taken
nutritional supplements which provide skin health and
beauty benefits. Collagen peptides present as a mix of
specific peptides of different length with high abun-
dance of the amino acids hydroxyproline, glycine, and
proline, which are produced by enzymatic hydrolysis of
native collagen extracted from animal connective tis-
sues. Hydroxyproline is unique to collagen and can be
used analytically to differentiate collagen from other
proteins. Collagen peptides are efficiently digested into
di- and tripeptides, which are resistant to further intra-
cellular hydrolysis.
11
The peptides are transported
across the intestinal mucosa by the transporter PEPT-
1.
12
In humans, hydroxyproline containing di- and
tripeptides have been shown to appear one hour after
ingestion of collagen peptides at nanomolar concentra-
tions in the blood.
13
Investigations using radioactively
labeled collagen peptides have demonstrated that the
absorbed peptides reach the skin
14
and are retained in
the tissue for up to 2 weeks.
15
A growing body of evidence demonstrates the effi-
cacy of collagen peptides to improve parameters of skin
physiology in preclinical studies. Collagen peptides
were shown to increase hyaluronic acid production in
dermal fibroblasts
16,17
and to improve skin barrier
function by increasing the water content of the stra-
tum corneum.
16,18,19
Further, collagen peptides induce
the synthesis of collagen on the mRNA and protein
level
20,21
as well as the production of stronger collagen
fibrils,
22
promote growth of skin fibroblasts,
23
and
induce fibroblast migration.
24,25
In contrast, clinical
evidence for the efficacy of collagen peptides on human
skin is still scarce.
2630
Therefore, we have conducted two clinical trials
showing the increase of skin hydration and the quanti-
tative and qualitative improvement of the collagen der-
mal network upon oral supplementation of collagen
peptides. Investigations in human ex vivo skin biopsies
demonstrated that collagen peptides induce collagen as
well as hyaluronic acid production. To the best of our
knowledge, this is the first report of clinical evidence
for the efficacy of collagen peptides to improve the der-
mal collagen fragmentation and thus to counteract a
hallmark of skin aging.
Materials and methods
Test products
The studies were performed using specific collagen
peptides of fish origin (Peptan
â
F) and porcine origin
(Peptan
â
P) with an average molecular weight of
20005000 Da. All products were provided by Rous-
selot.
Clinical study 1
A minimized, placebo-controlled, parallel-group, dou-
ble-blind, monocentric study was performed in 2008 at
SOUKEN Laboratories in Tokyo, Japan. The protocol
was conducted according to the guidelines of Good
Clinical Practice and the Helsinki declaration. All par-
ticipants gave their informed consent.
Participants were selected from the SOUKEN labora-
tory database according to the following eligibility cri-
teria: Japanese women, 4059 years old, low skin
water content, not pregnant, no systemic disease, no
intolerance to fish or gluten, no medications, and no
food supplements. Sixty women were screened, and 33
were allocated to either a placebo (dextrin) or one of
two treatment (Peptan
â
F [fish] or Peptan
â
P [porcine])
groups minimizing for variation in skin water content.
Participants took a formulated drink at bedtime which
contained either 10 g placebo or 10 g Peptan. Treat-
ment took place on 56 consecutive days. Assessment
of facial skin parameters was performed at baseline
and after 4 and 8 weeks of treatment in a controlled
environment with a room temperature of 22 1°C
2©2015 The Authors. Journ al of Cosmetic Dermatology Published by Wiley Periodicals, Inc.
Anti-aging effect of orally taken collagen peptides .J Asserin et al.
and a relative humidity of 50 10% after 30 min of
acclimatization. Skin moisture level was measured by
conductance with a Corneometer
®
device (CK elec-
tronic, K
oln, Germany) at three different application
points per subject. The rate of transepidermal water
loss (TEWL) was assessed with a Tewameter
®
device
(CK electronic) on the line between the ear lobe and
mouth edge at 3 cm distance from the earlobe.
Clinical study 2
A randomized, placebo-controlled, parallel-group, dou-
ble-blind, monocentric study was performed in 2012 at
COSderma Laboratories in Bordeaux, France. The pro-
tocol was approved by a French Ethics Committee fol-
lowing the guidelines of the French authorities
(AFSSAPS). The study was performed according to the
guidelines of Good Clinical Practice and the Helsinki
declaration. All participants gave their informed con-
sent.
Participants were selected from the COSderma labo-
ratory database according to the following eligibility
criteria: Caucasian women, 4065 years old, BMI of
1825 kg/m
2
, Fitzpatrick phototype IIV, all skin
types, not pregnant, no systemic disease, no intoler-
ance to fish or gluten, no medications, no food supple-
ments, no changes in dietary habits or hormonal
treatment in the last 3 months, no beauty care in the
last month, and no extensive sun exposure just before
or during the study. One hundred and six women were
randomly allocated to either a placebo (maltodextrin)
or a treatment (Peptan
®
F) group. Participants took a
formulated powder drink in the morning before break-
fast which contained either 10 g placebo or 10 g Pep-
tan. Treatment took place on 84 consecutive days.
Assessment of skin parameters was performed at base-
line and after 4 and 12 weeks of treatment in a con-
trolled environment with a room temperature of
20 2°C and a relative humidity of 45 5% after
20 min of acclimatization. Single measurements were
performed at the forearm with the same location dedi-
cated to one type of measurement for the duration of
the study. Collagen density of the dermis was mea-
sured by high-frequency real-time ultrasound of the
skin with a Dermcup
®
device (Atys Medical, Soucieu
en Jarrest, France). The echogenic collagen and elastic
fibers of the dermis were visualized in a vertical cross
section. The echogenicity was quantified by visual
scoring on a 10-point scale. The fragmentation of col-
lagen in the reticular dermis was assessed by reflec-
tance confocal microscopy using a Vivascope3000
®
device (MAVIG GmbH, Mu
¨nchen, Germany) which
provides horizontal optical cross sections of 5lmof
the epidermis and the dermis with a maximal depth of
200 lm visualizing the cellular microstructure. The
image of the stack positioned 25 lm below the papil-
lary dermis provides information on the fragmentation
of the reticular dermis. The images were quantified
with the Software CONFOSCAN (NIDEK Technologies Srl,
Padova, Italy). Briefly, the collagen fibers were identi-
fied by binarization within a defined region of interest
with the same threshold used for all time points per
subject. The fragmentation was calculated as the num-
ber of objects/average object surface.
Ex vivo experiments
Human skin explants with an average diameter of
10 mm were prepared from a thighplasty sample of a
49-year-old Caucasian woman. Explants were kept in
culture at 37 °C and 5% CO
2
in BIO-EC’s Explants
Medium containing 5% serum for 9 days and incu-
bated with 0.01, 0.1, or 1 mg/mL specific collagen
peptides of fish origin (Peptan
®
F). Experiments were
performed in triplicates. Culture medium containing
the product was renewed on day 2, 5, and 7. On day
9, the explants were harvested, fixed in Bouin solution,
dehydrated, and embedded in paraffin. Sections of
5lm were prepared, mounted on silanized glass slides,
and submitted to different stainings. For the observa-
tion of general skin morphology, slides were stained
with Masson’s Trichrome, Goldner variant. Acidic gly-
cosaminoglycans were stained with Alcian Blue and
total collagen with picro-Sirius Red. Microscopic obser-
vations were made using a Leica DMLB microscope at
a209magnification. Ten pictures were taken of each
sample of the triplicate with a DP 72 Olympus camera
(Olympus Life Science, Hamburg, Germany). For each
condition, 15 representative pictures were selected and
quantified with the OLYMPUS CELL
D
software (Olympus
Life Science).
Statistical analysis
Statistical analysis was performed with SPSS version
17.0 (SPSS Inc., Chicago, IL, USA) or GRAPHPAD PRISM
version 5.04 (GraphPad Software, La Jolla, CA, USA).
Normality was tested with the ShapiroWilk test.
Homogeneity between groups at baseline was tested by
ANOVA. Differences intragroup over time and between
treatment groups per time point were calculated by
ANOVA or ANCOVA with a post hoc analysis using the
Dunnett’s test. Statistical significance was considered
when P<0.05.
©2015 The Authors. Journal of Cosmetic Dermatology Published by Wiley Periodicals, Inc. 3
Anti-aging effect of orally taken collagen peptides .J Asserin et al.
Results
Peptan improves skin hydration in humans
Aging of the skin is associated with a decrease in water
content. In a first clinical pilot study, we evaluated the
effect of oral Peptan intake on skin hydration. Thirty-
three women were distributed equally on a placebo and
two treatment groups by minimizing for variation in
skin water content (Fig. 1). The participants took 10 g
of placebo or Peptan of fish (Peptan
®
F) or porcine (Pep-
tan
®
P) origin orally per day for a duration of 8 weeks.
All participants finished the study according to the pro-
tocol and no adverse events were reported.
Two parameters of skin hydration were assessed,
skin moisture level measured as a function of conduc-
tance and TEWL. While there was no change in the
placebo group, the oral intake of Peptan F over
8 weeks led to a significant increase of skin moisture
level by 12% (Fig. 2). Peptan P significantly increased
skin moisture level by 16% already after 4 weeks of
treatment and as much as 28% after 8 weeks
(P=0.003 vs placebo at 8 weeks). TEWL was not dif-
ferent between both Peptan groups and the placebo
(data not shown). Thus, the oral intake of Peptan
seems to effectively improve skin hydration without
affecting TEWL.
Peptan increases collagen density in the human dermis
To gain extended insight on the efficacy of Peptan to
improve skin aging parameters, we performed a ran-
domized, placebo-controlled, double-blind trial. One
hundred and six women were screened for eligibility
and randomly allocated to take 10 g placebo (n=52)
or Peptan (n=54) per day as a flavored powder drink
for a duration of 12 weeks. One hundred and one par-
ticipants completed the study according to the proto-
col, with 18 subjects (placebo n=7, Peptan n=11)
presenting minor deviations from the protocol regard-
ing the product administration (Fig. 3). No adverse
events were reported. Three subjects were withdrawn
from the placebo group, two on their own request and
one for noncompliance. Two subjects were lost to fol-
low-up from the Peptan group. Reflectance confocal
microscopy data on collagen fragmentation was not
Randomized
(n=33)
Assessed for eligibility
(n=60)
Allocated to Peptan F
(n=11)
Allocated to Peptan P
(n=11)
Allocated to Placebo
(n=11)
Analyzed
(n=11)
Analyzed
(n=11)
Analyzed
(n=11)
Figure 1 Flowchart of the clinical pilot study performed at SOU-
KEN laboratories, Japan.
Figure 2 Effect of the daily oral intake of 10 g Peptan compared
to placebo on skin hydration determined by Corneometer in
women (n=11/group). Values are presented as mean SEM.
Statistical differences were calculated by ANOVA and Dunnett’s post
hoc test with *P<0.05, **P<0.01, ***P<0.001; *comparison
with baseline, §comparison with placebo.
Randomized
(n=106)
Assessed for eligibility
(n=106)
Allocated to Peptan
(n=54)
Allocated to Placebo
(n=52)
Discontinued (n=2)
Lost to follow-up (n=2)
Completed (n=52)
Discontinued (n=3)
Withdrawn on own request (n=2),
for non-compliance (n=1)
Completed (n=49)
Analyzed (n=51)
Data non-analyzable (n=1)
Analyzed (n=48)
Data non-analyzable (n=1)
Figure 3 Flowchart of the clinical study performed at COSderma
laboratories, France.
4©2015 The Authors. Journ al of Cosmetic Dermatology Published by Wiley Periodicals, Inc.
Anti-aging effect of orally taken collagen peptides .J Asserin et al.
analyzable for one subject in each group. Hence, the
results from 48 subjects of the placebo group and of
51 subjects of the Peptan group are presented below.
As shown in Table 1, there were no differences
between both groups at baseline regarding age, the dis-
tribution of phototype as well as skin type.
A major structural skin parameter that is altered
during aging is the density of the collagen layer in the
dermis. We evaluated the effect of Peptan intake on
this parameter by measuring echogenicity using high-
frequency ultrasound. Echogenicity of the dermis did
not change in the placebo group during the course of
the study. The oral intake of Peptan resulted in a
highly significant increase of the dermal echogenicity
as early as 4 weeks after the start of the treatment
when compared to the baseline value and this effect
persisted after 12 weeks of treatment, indicating a con-
sistent increase in collagen density in the dermis over
time. After 12 weeks of Peptan intake, the treatment
effect (12w-0w) was significantly higher than in the
placebo group (8.83% vs. no change, respectively,
P=0.007) (Fig. 4).
Peptan reduces collagen fragmentation in the human
dermis
During aging, not only the amount of collagen
changes in skin but also the quality of the collagen
network. Therefore, in the same clinical study (Fig. 3),
we investigated the degree of fragmentation of collagen
fibers in the reticular dermis using reflectance confocal
microscopy by Vivascope. This state-of-the-art tech-
nique delivers a stack of confocal images over a stretch
of 150 lm from the stratum corneum down with col-
lagen fibers appearing as white structures.
Figure 5a shows exemplary images of the reticular
dermis of two subjects at baseline and 12 weeks
after the oral intake of placebo or Peptan, respec-
tively. At 12 weeks, the epidermis of the subject tak-
ing placebo (Fig. 5a.C) clearly exhibited smaller
collagen structures than at baseline (Fig. 5a.A). In
contrast, the subject taking Peptan displayed larger
collagen fragments after 12 weeks of intake
(Fig. 5a.D) compared to baseline (Fig. 5a.B). Thus,
the collagen fibers were less fragmented after Peptan
intake compared to placebo.
The quantitative analysis of the confocal images con-
firmed that the collagen fragmentation in the reticular
dermis did not change under placebo intake (Fig. 5b).
In contrast, intake of Peptan significantly reduced the
fragmentation by 17.8% already at 4 weeks and even
further, by 31.2%, at 12 weeks. These data clearly
demonstrate the efficacy of Peptan to reduce the frag-
mentation of the dermal collagen layer.
Peptan increases collagen and glycosaminoglycan
content in human skin explants
The above presented data show that oral intake of Pep-
tan in humans improves skin hydration and the qual-
ity and quantity of the dermal collagen network. To
better understand how Peptan exerts these actions, we
analyzed the general morphology, glycosaminoglycan,
and collagen content of human skin explants in
response to different concentrations of Peptan.
The general morphology of the skin explants was
not affected by the incubation with Peptan. Both
control and Peptan-treated explants exhibited a slight
Table 1 Baseline characteristics of women randomly allocated to
the placebo and the Peptan group. Data are presented as means
(SD) or numbers (%).
Placebo (n=49) Peptan (n=52)
Age (year) 52.4 (2.6) 54.8 (2.6)
Phototype (Fitzpatrick)
I 0 2 (4%)
II 19 (39%) 18 (35%)
III 29 (60%) 31 (60%)
IV 1 (2%) 1 (2%)
Skin type
Normal 13 (27%) 13 (25%)
Dry mixed 0 1 (2%)
Dry 36 (73%) 38 (73%)
Figure 4 Effect of the daily oral intake of 10 g Peptan compared
to placebo on collagen density in the dermis (n=4851) deter-
mined by high-frequency ultrasound. Values are presented as
mean SEM. Statistical differences were calculated by ANOVA and
Dunnett’s post hoc test with **P<0.01, ***P<0.001; *compar-
ison with baseline, §comparison with placebo.
©2015 The Authors. Journal of Cosmetic Dermatology Published by Wiley Periodicals, Inc. 5
Anti-aging effect of orally taken collagen peptides .J Asserin et al.
parakeratosis, no evidence of stimulation in the epider-
mis, and a well-cellularized collagen network in the
papillary dermis (data not shown).
As depicted in Figure 6, the glycosaminoglycan level
in the basal epidermis increased in skin explants in
response to Peptan incubation, visible as blue staining
in the histological slides (Fig. 6a). The quantification of
the images (Fig. 6b) shows that this increase was dose-
dependent within the range of 0.010.1 mg/mL Pep-
tan with a fivefold and a highly significant 18-fold
increase, respectively. At 1 mg/mL Peptan, saturation
of the effect was reached with a significant 17-fold
increase compared to the control.
In line with the glycosaminoglycan content, Sirius
Red staining of human skin explants revealed that the
collagen content of the papillary dermis increased in
response to incubation with Peptan (Fig. 7a). This
increase was dose-dependent with 3% more collagen in
the presence of 0.01 mg/mL Peptan and a significant
maximal increase of 9% in the presence of 0.1 mg/mL
Peptan (Fig. 7b). Again, saturation of the effect was
reached at 1 mg/mL Peptan with a significant increase
of 5.4%. Given the high basal amount of collagen in
the papillary dermis, a 5% increase is considered to be
a clear biological difference.
Thus, Peptan is highly efficacious to increase the
amount of water-binding glycosaminoglycans and the
collagen content of human skin. These effects might
underlie the increase in skin moisture (Fig. 2) and col-
lagen density (Fig. 4) observed in the clinical studies.
Discussion
Collagen peptides are a bioactive ingredient used in
functional foods and dietary supplements, such as
nutricosmetics, to help improve parameters of skin
physiology. In the present study, we report that the
oral supplementation with specific collagen peptides
(Peptan
®
) improves skin hydration as well as the
density and the structure of the collagen network of
the dermis. To our knowledge, this is the first clini-
cal study showing an effect of collagen peptides on
dermal collagen fragmentation. Analysis of human
skin explants cultured ex vivo in the presence of
specific collagen peptides (Peptan
(R)
) indicated that
an increase in dermal collagen and epidermal GAG
content might be responsible for the observed physio-
logical effects.
The properties of skin are defined by the complex
architecture of its different layers, which are increas-
ingly degraded during aging. Skin contains up to 70%
of collagen, which provides the tissue with tensile
strength. However, the collagen content declines with
age and this process is accelerated in women by the
0 weeks 4 weeks 12 weeks
Fragmentation Δvs 0w pΔvs 0w p
Placebo
Peptan
12.4 (1.9)
18.8 (2.4)§
13.4 (1.7)
15.5 (2.9)
+8.0%
-17.8%
0.929
0.036*
13.1 (1.8)
12.9 (2.4)
+5.9%
-31.2%
0.933
0.001**
(a)
AB
CD
ab
cd
(b)
12w 0w
Placebo Peptan Placebo Peptan
Figure 5 Effect of the daily oral intake of 10 g Peptan compared to placebo on the collagen network fragmentation of the reticular der-
mis (n=4851). (a) Exemplary confocal images showing the collagen network of the reticular dermis before and after 12 weeks of daily
oral intake of 10 g Peptan compared to placebo. (b) Quantification. Values are presented as mean (SEM). Statistical differences were cal-
culated by ANOVA and Dunnett’s post hoc test with *P<0.05, **P<0.01, ***P<0.001; *comparison with baseline, §comparison with
placebo.
6©2015 The Authors. Journ al of Cosmetic Dermatology Published by Wiley Periodicals, Inc.
Anti-aging effect of orally taken collagen peptides .J Asserin et al.
hormonal changes of the menopause.
31
In the first
4 years of menopause, the synthesis of collagen
decreases by up to 30%.
32
A weakening of the dermis
measured as decreased echogenicity has been related
to increased skin wrinkling.
33
We found that oral sup-
plementation with fish collagen peptides (Peptan
â
F) in
women increased the collagen density in the dermis by
9%, as measured by high-frequency ultrasound. In
addition, collagen peptides (Peptan
â
F) dose-depen-
dently increased the amount of collagen in the dermis
of human skin explants by up to 5% which can be
considered an important biological increase in light of
the high basal amount of collagen in the papillary der-
mis. This finding strongly indicates that collagen pep-
tides strengthen the dermis by inducing collagen
synthesis and might thereby reduce skin wrinkling.
Our results are in line with two recent studies that
have directly shown an induction of collagen synthesis
100μm100μm
100μm100μm
OthP Objecf 40 OthP Objecf 40
OthP Objecf 40 OthP Objecf 40
(a)
AB
CD
(b)
0
5
10
15
20
25
30
Control 0.01 mg/mL
Peptan
0.1 mg/mL
Peptan
1 mg/mL
Peptan
Acidic GAGs (surface %)
***
***
Figure 6 Glycosaminoglycan (GAG) content of the basal epidermis in human skin explants (a) visualized by Alcian Blue staining after
incubation with (A) control, (B) 0.01 mg/mL Peptan, (C) 0.1 mg/mL Peptan, (D) 1 mg/mL Peptan for 9 days (representative images).
(b) GAG content was quantified using OLYMPUS CELL
D
Software and expressed as surface %. Values are presented as mean SEM. Statisti-
cal differences were calculated by ANOVA and Dunnett’s post hoc test with *P<0.05, **P<0.01, ***P<0.001.
©2015 The Authors. Journal of Cosmetic Dermatology Published by Wiley Periodicals, Inc. 7
Anti-aging effect of orally taken collagen peptides .J Asserin et al.
in response to oral collagen peptide administration.
Zague et al.
21
reported that bovine collagen peptide
feeding to rats increased collagen type I and IV protein
content in the skin. Liang et al.
20
could link an induc-
tion of collagen type I and III mRNA and protein levels
upon fish collagen peptide feeding to an increased der-
mal thickness and hydroxyproline content in rats. Fur-
ther, porcine collagen peptides were demonstrated to
increase the diameter of collagen fibrils in the skin of
pigs.
22
Recently, a pilot trial using a fish collagen pep-
tide (Peptan
â
F) containing formulation showed that
collagen density increased after 12 weeks of collagen
peptide treatment.
26
Another clinical trial has detected
an increase of procollagen and elastin in skin lymph
fluid after 8 weeks of oral porcine collagen peptide sup-
plementation indicating an induction of extracellular
(a)
(b)
50
60
70
80
90
100
Control 0.01 mg/mL
Peptan
0.1 mg/mL
Peptan
1 mg/mL
Peptan
Total collagen (surface %)
*** **
A
B
C
D
100
m
O
t
h
P
Ob
j
e
c
f
2
5
100
μ
m
O
t
h
P
Ob
j
e
c
f
2
5
100
m
O
t
h
P
Ob
j
e
c
f
2
5
100
μ
m
O
t
h
P
Ob
j
e
c
f
2
5
Figure 7 Total collagen content of the papillary dermis of human skin explants (a) visualized by Sirius Red staining after incubation
with (A) control, (B) 0.01 mg/mL Peptan, (C) 0.1 mg/mL Peptan, (D) 1 mg/mL Peptan for 9 days (representative images). (b) Total col-
lagen content was quantified using OLYMPUS CELL
D
Software and expressed as surface %. Values are presented as mean SEM. Statistical
differences were calculated by ANOVA and Dunnett’s post hoc test with *P<0.05, **P<0.01, ***P<0.001.
8©2015 The Authors. Journ al of Cosmetic Dermatology Published by Wiley Periodicals, Inc.
Anti-aging effect of orally taken collagen peptides .J Asserin et al.
matrix synthesis.
27
However, no data were assessed
regarding structural changes in the dermal collagen
network.
During skin aging, the fragmentation of the dermal
collagen network by MMPs has been described to have
major consequences not only for the skin’s structure
but also for the microenvironment of the dermal
fibroblasts.
34
The cells detach from the loosening and
increasingly disorganized network of shorter and thin-
ner collagen fibers and lack the mechanical stimulus
which is a key factor to induce collagen synthesis.
4,32
The induction of different MMPs has been described to
be linked to collagen fragmentation.
5
In a model of
fibroblasts cultured in a collagen lattice, MMP1 diges-
tion mimicked the negative effect of collagen fragmen-
tation on fibroblast function described for aged skin
in vivo.
35
In the above reported clinical study, we used
a state-of-the-art technology, reflectance confocal
microscopy, to assess the effect of oral fish collagen
peptide (Peptan
â
F) supplementation on dermal colla-
gen fragmentation in human skin. Collagen peptide
supplementation significantly decreased the fragmenta-
tion of the collagen in the reticular dermis. To our
knowledge, this is the first clinical evidence for such an
anti-aging effect. One previous investigation demon-
strated that fish collagen peptide feeding to rats could
decrease the collagen fragmentation in skin in accor-
dance with our results.
20
This effect was linked to a
reduced expression of MMP1 and an induction of its
inhibitor TIMP1.
The water content of the skin depends on the cuta-
neous evaporation rate and the hydration level of the
epidermis, contributing to maintain skin health and a
youthful appearance.
7
In the above presented clinical
trial, we observed a significant increase in skin mois-
ture level after porcine and fish collagen peptide (Pep-
tan
â
) supplementation when compared to placebo.
However, the TEWL, a measure of stratum corneum
integrity, was not affected. As the presence of water-
binding glycosaminoglycans, mainly hyaluronic acid,
determines the hydration level of skin, we assessed the
effect of collagen peptides on glycosaminoglycans in
the epidermis of human skin explants. Collagen
peptides (Peptan
â
F) very clearly and significantly
increased the amount of glycosaminoglycans in the
epidermis in a dose-dependent manner suggesting that
an increase in glycosaminoglycan synthesis is responsi-
ble for the moisturizing effect. In line with our results,
fish collagen peptides in combination with glucosamine
and vitamin C have been reported to increase skin
moisture and elasticity after 6 weeks in women with
dry skin in a noncontrolled study.
30
Another trial
showed a dose-dependent increase of skin moisture but
not TEWL after fish or porcine collagen peptide supple-
mentation for 4 weeks, comparable to our findings.
29
Interestingly, a recent open-label study with a formula-
tion containing 5 g fish collagen (Peptan
â
F) reported
an improvement in skin dryness and face wrinkles,
indicating that a dose of 5 g of collagen peptides might
be effective.
26
A recent clinical trial failed to see an
effect of porcine collagen peptide supplementation on
skin hydration or TEWL after 8 weeks; however, the
baseline values of skin hydration were rather low and
some of the administered doses were very weak (2.5 g/
day).
28
A set of in vivo studies further demonstrated
that fish collagen peptides and collagen peptide-derived
dipeptides could prevent the decrease in water content
and the increase in TEWL in mouse models of photoag-
ing
16,18,19
with one study making the link to an
increase of the dermal hyaluronic acid content.
16
This
proposed mechanism of action is further substantiated
by data from an investigation studying the effect of
prolinehydroxyproline, one of the major dipeptides
present in human blood after collagen peptide inges-
tion, on human dermal fibroblast function.
36
An
increase in hyaluronic acid secretion was observed in
response to prolinehydroxyproline, which was linked
to an increased expression of hyaluronic acid synthase
(HAS)2, the key enzyme of hyaluronic acid synthesis.
17
A link between induced HAS expression and improved
skin hydration in humans has been recently estab-
lished.
37
The exact mechanisms of action whereby collagen
peptides modulate fibroblast function is poorly charac-
terized to date, but certain peptide sequences within
the collagen peptides may be specifically recognized by
the cell membrane of the fibroblast. A number of stud-
ies have been performed on other cell types such as
osteoblasts, osteoclasts,
38
and chondrocytes, which
originate from the same stem cell line and share cer-
tain characteristics, such as the capacity to produce
collagen. Further, the dipeptides prolinehydroxypro-
line and hydroxyprolineglycine, which are abundant
in the circulation after collagen peptide ingestion,
might contain a certain level of bioactivity in fibrob-
lasts.
17,18
In conclusion, we provide clinical evidence for the
efficacy of specific collagen peptides (Peptan
â
)to
improve skin moisture and, for the first time, to pre-
vent and reduce the fragmentation of the dermal colla-
gen network, thus counteracting one of the hallmarks
of skin aging. The improvement of those physiological
skin parameters is likely linked to an increase of colla-
gen and glycosaminoglycan synthesis in the respective
©2015 The Authors. Journal of Cosmetic Dermatology Published by Wiley Periodicals, Inc. 9
Anti-aging effect of orally taken collagen peptides .J Asserin et al.
skin layers. These data demonstrate that the oral sup-
plementation with specific collagen peptides can
improve skin structure and health from within.
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Anti-aging effect of orally taken collagen peptides .J Asserin et al.
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Various dietary supplements are claimed to have cutaneous anti-aging properties; however, there are a limited number of research studies supporting these claims. The objective of this research was to study the effectiveness of collagen hydrolysate (CH) composed of specific collagen peptides on skin biophysical parameters related to cutaneous aging. In this double-blind, placebo-controlled trial, 69 women aged 35-55 years were randomized to receive 2.5 g or 5.0 g of CH or placebo once daily for 8 weeks, with 23 subjects being allocated to each treatment group. Skin elasticity, skin moisture, transepidermal water loss and skin roughness were objectively measured before the first oral product application (t0) and after 4 (t1) and 8 weeks (t2) of regular intake. Skin elasticity (primary interest) was also assessed at follow-up 4 weeks after the last intake of CH (t3, 4-week regression phase). At the end of the study, skin elasticity in both CH dosage groups showed a statistically significant improvement in comparison to placebo. After 4 weeks of follow-up treatment, a statistically significantly higher skin elasticity level was determined in elderly women. With regard to skin moisture and skin evaporation, a positive influence of CH treatment could be observed in a subgroup analysis, but data failed to reach a level of statistical significance. No side effects were noted throughout the study. © 2013 S. Karger AG, Basel.
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With worldwide expansion of the aging population, research on age-related pathologies is receiving growing interest. In this review, we discuss current knowledge regarding the decline of skin structure and function induced by the passage of time (chronological aging) and chronic exposure to solar UV irradiation (photoaging). Nearly every aspect of skin biology is affected by aging. The self-renewing capability of the epidermis, which provides vital barrier function, is diminished with age. Vital thermoregulation function of eccrine sweat glands is also altered with age. The dermal collagenous extracellular matrix, which comprises the bulk of skin and confers strength and resiliency, undergoes gradual fragmentation, which deleteriously impacts skin mechanical properties and dermal cell functions. Aging also affects wound repair, pigmentation, innervation, immunity, vasculature, and subcutaneous fat homeostasis. Altogether, age-related alterations of skin lead to age-related skin fragility and diseases. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
Article
Oral supplementation with collagen hydrolysate (CH) has been shown to improve the condition of the skin in humans and experimental animals. Several hydroxyproline-containing oligo-peptides were previously detected in human peripheral blood after the ingestion of CH, and the two dipeptides, prolyl-hydroxyproline (PO) and hydroxyprolyl-glycine (OG), have been proposed to have beneficial effects on human health. When HR-1 hairless mice were fed a HR-AD diet, which lacked magnesium and zinc, transepidermal water loss (TEWL) increased and water content of stratum corneum decreased. In the present study, we investigated the effects of dietary PO and OG on skin barrier dysfunction in HR-1 hairless mice. Mice were fed a HR-AD diet with or without PO (0.15%) and OG (0.15%) for 35 consecutive days. The administration of PO and OG significantly decreased TEWL, and significantly increased water content of stratum corneum. A DNA microarray analysis of the dorsal skin revealed differences in gene expression between the group administered PO and OG and the control group. We also identified muscle-related Gene Ontology as a result of analyzing the up-regulated genes. These results suggested that the administration of PO and OG improved skin barrier dysfunction and altered muscle-related gene expression. Copyright © 2014. Published by Elsevier Inc.
Article
The presence of hydroxyproline (Hyp)-containing peptides in human blood after collagen hydrolysate ingestion is believed to exert beneficial effects on human health. To estimate the effective beneficial dose of these peptides, we examined the relationship between ingested dose and food-derived Hyp levels in human plasma. Healthy volunteers (n = 4) ingested 30.8, 153.8 and 384.6 mg per kg body weight of collagen hydrolysate. The average plasma concentration of Hyp-containing peptides was dose-dependent, reaching maximum levels of 6.43, 20.17 and 32.84 nmol/ml following ingestion of 30.8, 153.8 and 384.6-mg doses of collagen hydrolysate, respectively. Ingesting over 153.8 mg of collagen hydrolysate significantly increased the average concentrations of the free and peptide forms of Hyp in plasma. The Hyp absorption limit was not reached with ingestion of as much as 384.6 mg of collagen hydrolysate. These finding suggest that ingestion of less than 30.8 mg of collagen hydrolysate is not effective for health benefits.
Article
Collagen atrophy is a major factor in skin ageing. A strong correlation exists between skin collagen loss and oestrogen deficiency caused by the menopause. Skin ageing is associated with a progressive increase in extensibility and a reduction in elasticity. With increasing age, the skin also becomes more fragile and susceptible to trauma, leading to more lacerations and bruising. Furthermore, wound healing is impaired in older women. Oestrogen use after the menopause increases collagen content, dermal thickness and elasticity, and it decreases the likelihood of senile dry skin. Large-scale clinical trials are necessary to help make informed recommendations about postmenopausal oestrogen use and its role in preventing skin ageing.
Article
Ultraviolet B (UVB) irradiation induces serious damage to the skin. Collagen hydrolysate and collagen-derived peptides have effects on skin function in vivo and in vitro. However, few studies have investigated changes in the epidermal barrier or dermal elasticity caused by UVB. Here, we investigated the loss of epidermal barrier function and skin elasticity induced by UVB irradiation in hairless mice fed collagen hydrolysate. Mice were orally administered collagen hydrolysate, in a single dose (20 mJ/cm(2) ) or repeated doses (10-30 mJ/cm(2) , 3 times/week for 6 weeks), and the dorsal skin was exposed to UVB. Skin measurements and histological and analytical studies were performed. In control mice, a single UVB irradiation induced epidermal barrier dysfunction including an increase in transepidermal water loss (TEWL), epidermal hyperplasia, and a decrease in stratum corneum water content. Administration of collagen hydrolysate significantly decreased TEWL and epidermal thickness and increased stratum corneum water content. Repeated UVB irradiation decreased skin elasticity and dermal hyaluronic acid (HA) content in control mice, whereas collagen hydrolysate significantly suppressed both the increase in TEWL and the decrease in stratum corneum water content and improved skin elasticity and dermal HA content. Collagen hydrolysate administration affects epidermal barrier function and dermal skin elasticity.
Article
We conducted a placebo-controlled, double-blind 4-week study on the oral intake of either 3 doses of scaled collagen hydrolysate (2.5 g, 5g and 10 g), pig skin collagen hydrolysate (10 g) or placebo in 214 healthy female volunteers (mean age, 34.1 pSD 5.9 years). The volunteers were divided randomly into 5 groups and their skin condition was measured before and after ingestion. The moisture content of the stratum corneum of the cheek showed a significant increase after 4 weeks in all the groups taking the hydrolysates, while it showed a dose-dependent improvement in groups taking collagen hydrolysate (2.5g-10g). A stratified statistical analysis of subjects >30 years old showed significant differences in the groups taking 5g or 10g of hydrolysates (P<0.05), compared with the placebo group. There were no significant differences in transepidermal water loss, viscoelasticity or cutaneous findings between any of the groups. These results indicate that the major change following oral intake of collagen hydrolysate is an improvement in the moisture content of the stratum corneum.