Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : September 27, 2021
Accepted : December 21, 2021
Published online : December 31, 2021
doi:10.24659/gsr.8. 4_190

Original article

Glycation and metabolic syndrome in the skin premature aging
Jana Janovska 1), Claude Dalle 2), Julija Voicehovska 3)1) Riga Stradins University, Department of Internal Disease, Riga, Latvia
2) World Society Interdisciplinary Anti-Aging Medicine, Paris, France3) Riga Stradins University, Department of Internal Disease, Riga, Latvia

Abstract

Purpose:In recent years, the role of advanced glycation end products (AGEs) in promoting and exacerbating metabolic andskin abnormalities has attracted much attention. In this study, we elucidated the relationship between AGE accumulation andskin characteristics, commonalities, and features in metabolic syndrome (MS) patients and controls.
Methods: Caucasian male and female patients (n = 296) living in Riga, Latvia, divided into MS (n = 149) and non-MS(n = 147), were analyzed by skin lesion (epidermoid nigricans, seborrheic keratosis, actinic keratosis, age-related wrinkles,
gravitational wrinkles, and facial telangiectasia). MS was diagnosed using IDF criteria. For glycative stress index, skinautofluorescence (SAF) was measured using AGE Reader, and skin AGE accumulation was evaluated. Skin findings wereassessed using Dermatoscopy Dermlite for facial teleangiectasia, dermatosis and dyspigmentation. Blood biochemical
analysis included oxidative stress indices (glutathione: GSH, selenoprotein: Se, superoxide dismutase: SOD, glutathione
peroxidase glutathione peroxidase: GPx, and malondialdehyde: MDA).
Results: The MS group showed higher body mass index (BMI) ( p < 0.001, Mann-Whitney test), higher triglyceride (TG)(p < 0.001, Mann-Whitney test), lower HDL-C (p < 0.001, Mann-Whitney test), and lower Vitamin D ( p = 0.05 comparedto the non-MS group. For inflammatory response and oxidative stress, the MS group showed higher C-reactive protein (CRP)( p = 0.007, Mann-Whitney test), higher MDA ( p = 0.006, Mann-Whitney test), and significantly equal SOD ( p = 0.291).
SAF, an index of glycative stress, was significantly equal in the MS group (p = 0.468). Next, we conducted a Spearman rankcorrelation analysis between SAF and each item. Significant correlations were found for the following items: FPG: r = 0.345( p = 0.036, n = 37), TC: r = 0.328 (p = 0.023, n = 48), HDL-C: r = − 0.399 (p = 0.019, n = 34), CRP: r = 0.372 (p = 0.028,
n = 37), and CRP: r = 0.372 ( p = 0.028, n = 37). No significant correlations were found with other items.
Skin lesions were classified as seborrheic keratosis (n = 109), actinic keratosis (n = 25), acanthosis nigricans (n = 16), aging
wrinkles (n = 126), gravity wrinkles (n = 34), facial telangiectasia (n = 242), and lentigo pigmentosa (n = 204). SAF was
positively correlated with skin aging parameters of seborrheic keratosis and lentigo pigmentosa (p < 0.05) and associatedwith the severity of skin aging on the face using the skin aging index ( p < 0.05). In skin biopsies, the expression of GLUT1 was increased, accompanied by a decrease in the number of regulatory T cells.
Conclusion: MS was associated with excess ROS and reduced antioxidant capacity. Accumulation of AGEs in the skin wasstrongly associated with clinical aging-related changes (seborrheic keratosis, telangiectasia, and skin wrinkles). The AGE
accumulation was associated with inflammatory processes, indicating that SAF may be closely related to skin health.

KEY WORDS: advanced glycation end products (AGEs), metabolic syndrome, oxidative stress, aging,		

premature skin aging.

Introduction.
Recently, the role of heredity and telomerase shortening
in the aging process has been recognized 1, 2). Theories of
biological aging are complicated and involve both internaland external factors. Theories of skin aging are cellularsenescence, decreased cellular DNA repair and telomerase,

point mutations, increased frequency of chromosomal
aberrations, single gene mutations, oxidative stress andglycation. In recent years, the role of advanced glycation end
products (AGEs) in promoting and exacerbating metabolicand skin abnormalities has received increasing attention.
AGEs are produced when reducing sugars are nonenzymatically bound to proteins and lipids. This process

Corresponding to: Jana Janovska, MD
Anti-Aging Institute, Baznīcas Street 18, Riga, LV-1010, Latvia
TEL : +371-25- 41-8181 e-mail: j.a.janovska@gmail.com
Co-authors: Dalle C, contacts@drclaudedalle.com; Voicehovska J, dr.julia.v@gmail.com_ 19 0 _Glycative Stress Research 2021; 8 (4 ): 190-200(c) Society for Glycative Stress ResearchGlycative Stress Research

is facilitated by the hyperglycemic and hyperlipidemic
environment characteristic of many metabolic disorders,
including diabetes, obesity, metabolic syndromes (MS),and their complications. In the skin, AGEs cause biologicalmodifications such as activation of molecular synthesis in
the extracellular matrix (ECM) 3) and matrix degradation(matrix metalloproteinase: MMP) 4). This review presents theidea that AGEs encompass the causes and consequences ofpremature skin aging and represent a "common background"
underlying skin pathophysiology and barrier changes 5, 6).
The aim of this study was to clarify the relationshipbetween AGE accumulation and skin characteristics, common
features and characteristics in MS patients and controls interms of glycative stress. Furthermore, accumulation of
AGEs and skin characteristics in MS patients were examined
and analyzed in comparison with controls.

Subjects and Methods
In thisprospective study, we included male and female
patients (n = 296) from our clinic living in Riga, Latvia, andperformed an intergroup analysis of patients with and without
MS. According to the International Diabetes Federation(IDF ), the inclusion criteria for MS are presence of central
obesity (defined by waist circumference with ethnic-specificvalues) plus one of the following four factors;- Elevated triglycerides (TG) of 150 mg/dL (1.7 mmol/L) or
more, or receiving specific treatment for this dyslipidemia.
- High-density lipoprotein cholesterol (HDL-C) (< 40 mg/dL[1.03 mmol/L] in men and < 50 mg/dL [1.29 mmol/L] inwomen) or receiving specific treatment for dyslipidemia.
- Elevated blood pressure (systolic pressure higher than 130
mmHg or diastolic pressure higher than 85 mmHg) ortreatment for previously diagnosed hypertension.
- Fasting plasma glucose (FPG) of 100 mg/dL (5.6 mmol/L)or higher, or previously diagnosed type 2 diabetes mellitus( T2DM).
The patient's clinical examination, blood pressure andwaist circumference were measured. Clinical examination of
the skin was performed using dermatoscopy (Dermlite DL;
Derma Medical Systems, Vienna, Austria) 7). The detectedskin manifestations (seborrheic keratosis, actinic keratosis,
acanthosis nigricans, and facial telangiectasia) were divided
into several subtypes (mild, expressive, and extreme
expressive).
Blood biochemical analysis included cholesterol,
HDL-C, LDL-C, vitamin D (Vit D) levels, C-reactive protein(CRP), and oxidative stress indices (glutathione: GSH,
selenoprotein: Se, superoxide dismutase: SOD, glutathione
peroxidase: GPx, malondialdehyde: MDA, and 4-hydroxy2, 3-trans-nonenal: HNE).
The AGE Reader TM (DiagnOptics B.V., Groningen,
The Netherlands) was used to evaluate glycative stress 8). The
AGE Reader TM is a non-invasive device that measures tissue
accumulation of AGEs in human skin on the forearm, andthe results are expressed as values of skin autofluorescence(SAF) (Diagnoptics).

The Skin Aging Index (SAI) was evaluated. Tissue
MDA and SOD was measured by using skin biopsy
specimens from lesion and non-lesion area.

Statistical analysis
All data were calculated using SPSS 22 version.
Descriptive statistics were used to show a normal distribution(p > 0.05). Means and standard deviations (SD) for age were
calculated and shown in error bar graphs separately for men
and women.
First, biserial correlation was calculated to determine
if there was a correlation between the quantitative data andthe dichotomous data (0 no, 1 yes). Since all the data involvedin the data analysis by the Kolmogorov-Smirnov test fit anormal distribution (p > 0.05), parametric statistics were used
to represent the descriptor statistics and the graphical data.
For quantitative data, groups were divided according
to dichotomous data where binomial correlations were
statistically significant and means and SD were calculated
and displayed in error bar graphs; Pearson correlation
between Age Reader T M and HDL was calculated, andstatistically significant results were obtained and displayed inscatter plots.
For immunohistochemical analysis in 32 patients,
parametric statistics were used for descriptor statistics
and graphical data representation, as all data analysis by
Kolmogorov-Smirnov test fitted a normal distribution ( p >0.05).

Ethical Standards

This study was conducted using existing materials
that were not linked to personal information. Our study was
designed in conformation to the Helsinki Declaration. The
study protocol was approved by the Committee of Ethics,
Riga Stradins University.

Results

MS group and glycative stress
Total 296 subjects (Age; 47.0 ± 11.2, BMI; 26.3 ± 4.8),
of which 149 (50.4 %) were MS (Age; 51.4 ± 9.8, BMI; 29.0
± 4.2) and 147 (49.6 %) were non-MS (Age; 42.4 ± 10.8,
BMI; 23.6 ± 3.6).
Comparing the MS and non-MS groups, the MS group
showed a significantly higher BMI (p < 0.001, Fig. 1-a),higher FPG (p < 0.001, Fig. 1-b), higher TC ( p < 0.001, Fig.
1-c ), higher LDL- C (p < 0.01, Fig. 1-d ), not significantly
lower HDL-C (p = 0.702, Fig. 1-e), and higher TG ( p = 0.019,
Fig. 1-f ). Vit D was not significantly lower (p = 0.063, Fig.
1-g ).
In terms of inflammatory response and oxidative
stress, CRP was significantly higher ( p = 0.007, Fig. 2-a),
MDA was higher (p = 0.006, Fig. 2-b), and SOD was not
significantly different ( p = 0.292, Fig. 2-c) in the MS group,and there was no significant difference in Se between the twogroups ( p = 0.382, Fig. 2-d ).

_ 191 _Glycation and Metabolic Syndrome in the Skin Premature Aging

a)

b)

44

***

36

FPG (mmol/L)

BMI (kg/m 2)

40

32
28
24
20
16

d)
TC (mmol/L)

LDL-C (mmol/L)

***

6.0

5.5

5.0

10

***

5

3.75

**

3.50
3.25
3.00
2.75

f)

3.4
3.2

12.5
10.0

2.8

TG (mmol/L)

HDL-C (mmol/L)

15

0

c)

e)

20

2.4
2.0
1.6

7.5
5.0

*

2.5

1.2
0.8

0

(- )

g)

(+ )

Vit. D (ng/mL)

Metabolic syndrome
35

30

25

(- )

(+ )

Metabolic syndrome

Fig. 1. Comparison with and without metabolic syndrome (MS): BMI and blood chemistry.
a) BMI,1 b) FPG, c) TC, d) LDL-C, e) HDL-C, f) TG, g) Vit. D. Results are expressed as mean ± 95% CI (box) and SD
Fig.
(bar). * p < 0.05, ** p < 0.01, *** p < 0.001, MS group (n = 149) vs non-MS group (n = 147) by Mann-Whitney test (a , b, e, f )or Student’s t test (c, d, g). BMI, body mass index; FPG, fasting plasma glucose; TC, total cholesterol; LDL- C, low-density
lipoprotein-cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; Vit. D, vitamin; CI, confidential
interval; SD, standard deviation.

_ 19 2 _Glycative Stress Research

b)

25
20

6

**

5

MDA (mM)

CRP (mg/L)

a)

15

**

10

4
3
2

0

1

c)

d)
2200

78

Se (mg/L)

SOD (U/g Hb)

2000
1800
1600
1400

74

70

1200
66

1000

(- )

(+ )

(- )

Metabolic syndrome(+ )Metabolic syndrome

Fig. 2. Comparison with and without metabolic syndrome (MS): Inflammation and oxidative stress.
a) CRP, b) MDA, c) SOD, d) Se. Results are expressed as mean ± 95% CI (box) and SD (bar). ** p < 0.01, MS group
Fig. 2(n = 149) vs non-MS group (n = 147) by Mann-Whitney test (a, b, c) or Student’s t test (d). CRP, C-reactive protein;
MDA, malondialdehyde; SOD, superoxide dismutase; Se, selenoprotein: CI, confidential interval; SD, standard deviation.

SAF, an index of glycative stress, was significantly
higher in the MS group (p = 0.024, Fig. 3-a), and there wasno difference in SAF between men and women ( p = 0.359,
Fig. 3-b ). Next, we conducted a Spearman rank correlation
analysis between SAF and each item. Significant correlations
were found for the following items: FPG: r = 0.345 ( p =0.036, n = 37, Fig. 4-a), TC: r = 0.328 (p = 0.023, n =48, Fig. 4-b), HDL-C: r = − 0.399 (p = 0.019, n = 34, Fig.
4-c), CRP: r = 0.372 (p = 0.028, n = 37, Fig. 4-c), and CRP:
r = 0.372 (p = 0.028, n = 37, Fig. 4-d ). No significant
correlations were found with other items.

MS and skin aging index (SAI)
The skin aging index, SAI, was significantly higher inthe MS group (p < 0.001, Fig. 5-a). SAI was also significantly
correlated with SAF (r = 0.203, p = 0.026, Fig. 5-b), Vit D (r= − 0.378, p < 0.001, Fig. 5-c), and systolic blood pressure (r= 0.181, p = 0.102, Fig. 5-d ).
There was no significant difference in GPx (p = 0.208,
Fig. 6 ) of the skin tissue between the two groups.

Analysis by skin lesions

The skin lesions were classified as seborrheic keratosis (n= 109), actinic keratosis (n = 25), acanthosis nigricans (n =16), aging wrinkles (n = 126), gravity wrinkles (n = 34), andfacial telangiectasia (n = 242).
The amounts of MDA and SOD in lesional and nonlesional areas are shown in Fig. 7-a, b. MDA amount was
higher in lesions of acanthosis nigricans (p = 0.341, MannWhitney test), but there were no differences in other parameters
between lesions and non-lesions. SOD levels were higher inlesions for lentigo and actinic keratosis and higher in nonlesional areas for seborrheic keratosis. Lentigo pigmentation( p = 0.332, Mann-Whitney test), seborrheic keratosis (p =0.355, Mann-Whitney test), actinic keratosis (p = 0.464, MannWhitney test).
When SAF was compared according to the presenceor absence of lesions, it was not significantly higher inthose with seborrheic keratosis (r = − 0.034, p = 0.588, Fig.
8 ). When compared by the presence of wrinkles, SAF was
not significantly higher in those with mimetic wrinkles (r =0.091, p = 0.378, Fig. 9-a), age-related wrinkles (r = 0.212, p= 0.001, Fig. 9-b ), and gravity wrinkles (r = 0.363, p < 0.001,
Fig. 9-c).
FPG tended to increase with depth of wrinkles but
it was not significant (p = 0.721, Kruskal-Wallis test, Fig.
10-a). Analysis of skin biopsy tissues revealed a marked
monocyte infiltration at the wrinkle formation site but thecorrelation with FPG was not significant (p = 0.360, KruskalWallis test, Fig. 10-b).

_ 193 _Glycation and Metabolic Syndrome in the Skin Premature Aging

a)

b)

80

*

70

Age (year)

Age (year)

70

80

60
50
40

60
50
40

30

30

20

20

(+ )

(- )

Male

Metabolic syndrome

FemaleGenderFig. 3. Age profile of the subjects.
a) MS and non-MS, b) gender difference. Results are expressed as mean ± 95% CI (box) and SD (bar). * p < 0.05,

MS group (n = 149) vs non-MS group (n = 147) by Mann-Whitney test. MS, metabolic syndrome; CI, confidential
interval; SD, standard deviation.

Fig. 3

HDL-C (mmol/L)

c)

b)
8.6

6.4

7.8

6.0

7.0

TC (mmol/L)

6.8

5.6
5.2
4.8

6.2
5.4
4.6

4.4

3.8

4.0

3.0

d)

3.0
2.6

CRP (mg/L)

FPG (mmol/L)

a)

2.2
1.8
1.4

20
16
12
8
4

1.0
0.6
1.0

2.0

3.0

4.0

SA F

0

1.0

2.0

3.0

4.0

SA F

Fig. 4. Relationship between SAF and blood chemistry data.
a) FPG, b) TC, c) HDL-C, d) CRP. By Spearman rank correlation analysis. SAF, skin autofluorescence; FPG,
fasting plasma glucose; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; CRP, C-reactive
protein.

Fig. 4_ 19 4 _Glycative Stress Research

a)

b)

12

***

3.5

8

SA F

SA I

10

4.0

6

3.0
2.5

4
2

2.0

0

1.5

--

(+ )

(- )

Metabolic syndrome

d)

12

10

8

8

6

6

4

4

2

2

0

10

20

30

40

50

60

+++

12

10

0

++

( -- = not present; + = some mild wrinkles; ++ =mild wrinkle reticle; +++ = rough fixed reticle)

SAI

SAI

c)

+

SAI / microrelief

070Vit. D (ng/mL)

80

100

120

140

160

180

Arterial systolic pressure (mm/Hg)

Fig. 5. Relationship with Skin aging index (SAI).
a) MS, b) SAF, c) Vit. D, d) CRP. Results are expressed as mean ± 95% CI (box) and SD (bar). *** p < 0.001,
MS group (n = 149) vs non-MS group (n = 147) by Mann-Whitney test (a). Spearman rank correlation analysis
is conducted (b, c, d). SAI (Y-axis in a, c, d), 0-2 = minimal, 2-8 = moderate, 8-15 = expressive; MS, metabolic
syndrome; SAF, skin autofluorescence; Vit. D, vitamin; CRP, C-reactive protein; CI, confidential interval; SD,
standard deviation.

9,100

GPx

8,100

7,100

6,100

(- )

(+ )

Metabolic syndrome

Fig. 6. Comparison with and without metabolic syndrome (MS): GPx in the skin tissue.

Results are expressed as mean ± SD (bar). MS group (n = 149) vs non-MS group (n = 147). GPx, glutathione
peroxidase; SD, standard deviation.

Fig. 6_ 195 _Glycation and Metabolic Syndrome in the Skin Premature Aging

a)

6.0

MDA (mM)

5.0
4.0
3.0
2.0
1.0

b)

SOD (U/g Hb)

2,400

2,000

1,600

1,200
numbers(- )(+ ) (- ) (+ ) (- )(+ ) (- ) (+ ) (- ) (+ ) (- ) (+ ) (- ) (+ )

64

3

38

11

61

34

64

8

29

43

43

31

15

57

a
Tele
n gie
ia

s

to s i

ic an

k les

c tas

wrin

k l esto s i

ni gr

kera

kera

ei c

sis

wrin

vit y

ng

ini c

Gra

Ag i

Ac t

orrh

tigo

nt h o

Se b

Len

Ac a

s

s

Fig. 7. MDA and SOD in lesion and non-lesion areasa) MDA, b) SOD. Results are expressed as mean values of triplets or doublets. MDA, malondialdehyde; SOD,
superoxide dismutase.

Fig. 7
4.1
3.7

SA F

3.3
2.9
2.1
2.5
1.7
1.3
0.9

(+ )

(- )

Seborrheic keratosis

Fig. 8. SAF and seborrheic keratosis.

Results are expressed as mean ± 95% CI (box) and SD (bar), lesion (+); n = 63, lesion (−); n = 75. SAF, skinautofluorescence; CI, confidential interval; SD, standard deviation.

Fig. 8_ 19 6 _Glycative Stress Research

a)

b)

3.5

3.7

3.0

3.3
2.9

2.5

SAF

SAF

4.1

2.0

2.5
1.7

1.5

1.3

1.0

0.9

(+ )

(- )

(+ )

(- )

Age-related wrinkles(Permanent elastic creases)

Mimetic wrinkles

c)

**

2.1

3.5

SAF

3.0

***

2.5
2.0
1.5
1.0

(+ )

(- )

Gravity wrinkles

Fig. 9. Relationship between Wrinkles and SAF.
a) Mimetic wrinkles, b) Age-related wrinkles, c) Gravity wrinkles. Results are expressed as mean ± 95% CI (box)and SD (bar). a) lesion (+); n = 50, lesion (−); n = 2, b) lesion (+); n = 63, lesion (−); n = 74, c) lesion (+); n = 25,

lesion (−); n = 27. ** p < 0.01, *** p < 0.001 by Spearman rank correlation analysis or Mann-Whitney test. SAF, skinautofluorescence; CI, confidential interval; SD, standard deviation.

Fig. 9

a)

b)

10.0

10.0

FPG (mmol/L)

9.0

FPG (mmol/L)

11.0

8.0
7.0
6.0

9.0
8.0
7.0
6.0

5.0

5.0

4.0

4.0

-

+

++

+++

None

SAI / microrelief(- = not present; + = some mild wrinkles; ++ =mild wrinkle reticle; +++ = rough fixed reticle)

SlightModerate

Monocyte infiltration

Fig. 10. FPG and wrinkles / monocyte infiltration.
a) Wrinkle depth, b) Monocyte infiltration in the wrinkle lesion. Results are expressed as mean ± 95% CI (box)and SD (bar), n = 160. FPG, fasting plasma glucose; SAI, Skin Aging Index; CI, confidential interval; SD, standard
deviation.

Fig. 10_ 19 7 _Glycation and Metabolic Syndrome in the Skin Premature Aging

Discussion

MS and AGEs in skin lesion

The present study showed the following;- The glycative stress index and oxidative stress index werestronger in MS patients.
- SAF, an indicator of glycative stress, showed good key
results regarding the correlation between endogenous skinaging factors and epigenetically induced reasons (exogenous
aging) 9, 10).
- The accumulation of AGEs is associated with inflammatory
processes in vivo ( increased CRP and oxidative stressindicators).
-AGEs were associated with presence of MS,
hypercholesterolemia, and increased BMI 11).
- The most frequent skin lesion that correlated with elevatedSA F ( p < 0.05) was acanthosis nigricans, especially inpatients diagnosed with MS.
- The skin plays a major role in the metabolism and removalof reactive oxygen species (ROS), and MS is a factor inexcess ROS and decreased antioxidant activity. This finding
is consistent with previous reports 12).
- The accumulation of AGEs in the skin is more indicative ofclinical age-related changes (seborrhea, actinic keratosis,
telangiectasia, and deep wrinkles).
Aging is a complex, multifactorial process in which
genetic, endogenous, and environmental factors play asignificant role. Since the skin is the largest organ of thehuman body and is the boundary between the organism andthe environment, it affects not only the appearance of youth
but also various physiological functions. Aging skin exhibits
impairments in skin permeability, angiogenesis, lipid andsweat production, immune function, and vitamin D synthesis,
as well as the development of precancerous lesions andcarcinogenesis 13). The effect of glycoconjugates on aging skinis governed by the simple act of covalently cross-linking two
collagen fibers, making the two not easily repairable.
In humans, with aging, the skin becomes drier andthinner, and photoaged spots become more prominent. Thesephenomena are influenced by epigenetic and genetic factors.
There are two types of skin aging: endogenous (personal andgenetic) and exogenous (environmental caused by ultraviolet
radiation, radiation, exogenous substances, pollutant). Oneof these causes is premature aging due to accumulation of
AGEs 14), which cause biological changes involving activationof molecular synthesis (extracellular matrix, cytokines,
and enzymatic activation of matrix degradation, i.e.,
metalloproteinases). The formation of AGEs is accelerated
by ultraviolet (UV) exposure, oxygen, reactive oxygen
species (ROS), transition metals with redox activity, andintermediate aldehydes. RAGE, receptor for AGEs, activates
various molecular pathways in vivo and are involved ininflammation, immune response, cell proliferation, and gene
expression. When AGEs are exposed to UVA radiation,
ROS, i.e. superoxide anion, hydrogen peroxide, and hydroxyl
radicals, are produced. These ROS stimulate nicotinamide
adenine dinucleotide phosphate oxidase (NOX) to induce theproduction of superoxide anion and reduce the antioxidant
defense system of cells 15).

The main features of MS are central obesity, glucose
intolerance, dyslipidemia, and arterial hypertension. It isestimated that about 1/3 of the population is affected bythis disease 16). A variety of dermatological diseases havebeen associated with MS and/or its related conditions. MS
also accelerates aging, at least in part, by causing damage
to cardiovascular, renal, and other tissues, leading topathological premature aging. In MS patients, there is chronic
latent inflammation due to oxidative stress throughout thebody, including the skin. This is a condition in which the net
amount of reactive ROS exceeds the antioxidant capacity.
Pro-inflammatory cytokines are released and a defensive
inflammatory response in the skin ensues.
Excess ROS cause lipid peroxidation and oxidative
damage to proteins and DNA. ROS affect the biosynthesisof collagen and increase inflammation. Specifically, thefollowing reactions occur;- Activation of MMPs.
- Activation of the aryl hydrocarbon receptor (AhR).
- Activation of transition metals by ROS and redox, which
promotes the formation of AGEs 17).
The fat accumulation in MS associated with progressive
insulin resistance triggers a cascade of hormonal changes,
including effects on growth hormone. Hormones are selfregulating and synergistic. As a result, exacerbation ofandrogen-dependent skin diseases such as acne and malepattern baldness can be expected. Concurrently, inflammatory
markers, i.e., TNF-α, IL-17, IL-23, and oxidative stress may
be involved in many autoimmune and inflammatory skindiseases 18). Therefore, it is likely that impaired skin physiology
may predispose to MS and vice versa 19).
In 2012, Nagel et al. investigated the relationship between
the parameters of MS and skin cancer 20). The results showed
a positive relationship between malignant melanoma (MM)and elevated blood pressure in women. Furthermore, menwith malignant melanoma tended to have a higher BMI.
Women with squamous cell carcinoma / non-melanoma skincancer tended to have increased FPG and TG. Also, thedevelopment of xanthomas and tendon xanthomas (although
clearly not a proliferative tumor-like disease) is a very typicalmanifestation of congenital hyperlipoproteinemia 20).

MS and glycative stress
In recent years, the prevalence of glycative stressinduced diseases such as T2DM has been increasing, and it
is easy to understand the relationship between T2DM andincreased AGEs because of the marked increase in blood
glucose concentration, but it should be noted that MS anddyslipidemia also are triggers for increased glycative stress.
Sato K et al. reported that HFD -high-fat diettreatment
suppressed GAPDH activity in rat liver, resulting in an
increase in glyceraldehyde (GA) and methylglyoxal (MGO) 21).
GA is a highly reactive aldehyde that carbonylates surrounding
substances and produces MGO. GA and MGO carbonylate
and glycate proteins to produce AGEs. This is an important
finding indicating that glycative stress is involved in HFD-

_ 19 8 _Glycative Stress Research

induced fatty liver. This is an important finding indicatingthat glycative stress is involved in HFD-induced fatty
liver. AGEs increase the expression of CRP in hepatocytes
and induce an inflammatory response 22). AGEs promote
the progression from simple fatty liver to non-alcoholicsteatohepatitis (NASH) 23).
The mechanism by which HFD inhibits GAPDH is
unknown. It has been shown that under conditions of highglycative stress, such as hyperglycemia, TCA cycling isimpaired and fumaric acid increases, resulting in the formationof 2SC-GAPDH by succinylation of cysteine residue(-SH) of GAPDH, and thus GAPDH activity is decreased.
We speculate that HFD may induce TCA cycle damage bya similar mechanism. MGO is conjugated to glutathione(GSH) and then metabolized to lactate by glyoxalase I & II.
In the present data, GSH was also decreased in the MS group,suggesting that the activity of glyoxalase to degrade MGO
may be decreased.
MDA is an oxidative stress product produced by the
non-enzymatic oxidation of polyunsaturated fatty acids by
ROS. In the present study, MDA was higher in the MS group,
indicating that oxidative stress is stronger in MS. In addition,
MDA tends to react with the sulfhydryl group of cysteine 24).
HFD ingestion produces more MDA than MGO in the liver 25),
which reacts with cysteine, reducing the amount of freecysteine. Since cysteine deficiency triggers a decrease inaldehyde trapping actions, the reaction of MGO and MDA
with the cysteine residues (-SH) of SOD-1 and GPx-1 isenhanced, reducing enzyme activity without decreasingprotein levels.

Conclusion
The skin plays a major role in the metabolism andremoval of ROS, whereas MS is a risk factor for increased
ROS and decreased antioxidant capacity. Accumulation of
AGEs in the skin is associated with inflammatory processes
in the body (increased CRP, oxidative stress parameters) andclinically manifests aging-related lesions (seborrheic keratosis,
telangiectasia, skin wrinkles). SAF has been shown to havesignificance in relation to skin aesthetics, functionality, andhealth status.

Conflict of interest declaration
None to be noted.

Acknowledgements
An outline of this study was presented at the Anti-Aging
Medicine World Conference (AMWC) 2017, May 5-8, 2017,
Monte- Carlo, Monaco.

Glycative stress and age-related changes in the skinMore specifically, oxidative stress and inflammation areassociated with MS, and consequently, ROS damage to DNA
and mitochondrial function and hormonal dysregulation(including insulin resistance) are associated with the aging
process. Glycation of collagen in the skin is thought to berelated to both MS parameters and aging. AGEs form crosslinks with collagen fiber bundles, inhibiting their mobility
and reducing skin elasticity 26). This phenomenon is more
intense in diabetics and accelerates skin aging. Intrinsic
factors such as the Maillard reaction and oxidative stressaffect gene expression in fibroblasts, lowering levels of
MMP inhibitors and increasing production of MMPs which
degrade collagen 19).
It also causes changes in skin tissue. Previously, ourresearch group looked into the tissue changes in the skinstructure of MS patients and found a high incidence ofclinical hyperpigmentation and telangiectasia. Furthermore,dermal elasticity, thickening of the spinous layer andbasement membrane, spinousness, and mild Τ lymphocytic
infiltration around capillaries were observed. The
accumulation of Bcl-2, an anti-apoptotic protein, in theepidermis was more pronounced in MS patients, indicatingthat MS patients also induce various degenerative changes inskin tissue 27).

_ 19 9 _Glycation and Metabolic Syndrome in the Skin Premature Aging

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