Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : August 20, 2023
Accepted : November 9, 2023
Published online : December 31, 2023
doi:10.24659/gsr.10.4_164

Original article

Effect of red wine on AGEs in blood
Shinichi Sugiura 1), Yumeno Iwata 1), Sae Hirano 1), Momoka Nagano 1), Saki Shimada 1),
Mayako Uchida 1), Mika Asano 2), Hirotaka Akita 3)
1) Center for Clinical Pharmacy Education and Research, Faculty of Pharmacy,
Doshisha Women's College of Liberal Arts, Kyoto, Japan
2) MS Dream Inc., Aichi, Japan
3) Department of Dermatology, Fujita Health University Bantane Hospital, Aichi, Japan

Abstract

Purpose: The purpose of this study was to select wines with strong anti-glycation effects based on grape variety, region,and vinification method through basic experiments, and to clarify whether consumption of these wines has an effect on theinhibition of AGEs accumulation in human blood.
Methods: Study subjects were 60 men and women between the ages of 20 and 65 who were able to consume alcohol. The
study design was a prospective crossover open-labeled randomized controlled trial. In the basic study, various wines wereadded to a human serum albumin (HSA)-glucose glycation model and the effect of glycation inhibition was evaluated bymeasuring fluorescent AGEs production. Study participants consumed 125 mL per day of either wine or mineral water, which
has strong anti-glycation effects in basic research and is available for human comparative studies, 6 days per week for 4
continuous weeks. The AGEs accumulation level in the body was measured by an AGEs sensor and the stress level by a stressmeasuring instrument (VM500) before and after ingestion for a total of 4 times. In addition, an email questionnaire regarding
lifestyle influences on AGEs accumulation was administered weekly.
Results: The target wine for intake was a red wine (La Forge Estate Pinot Noir containing 13.5 mL/100 mL of alcohol.
The intake was set at 125 mL with the IC 50 calculated based on the anti-glycation effect of aminoguanidine. There were 48
research collaborators. Nine persons whose response rate to the questionnaire results was less than 50 % and six persons who
were absent from at least one measurement session were excluded. A decrease in AGEs levels was observed in the wine intake
group, and an increase in AGEs levels was observed in the mineral water group, Although the difference was not significant( p = 0.16). A comparison of the Week 2 -5 group (early June to mid-July) and s Week 8 -11 group (late July to early
September) groups showed a strong decreasing trend in AGEs levels before and after wine consumption ( p = 0.06).
Women also showed a trend toward lower AGEs after wine consumption (p = 0.07). Overlapping analysis with the time ofadministration showed a significant decrease in AGEs in women in the Week 8 -11 group who consumed wine (p = 0.02).
Conclusion: Wine consumption was suggested to inhibit the accumulation of AGEs. In particular, the effect of AGEs due
to ultraviolet light was less pronounced in women who used sunscreen on a daily basis, suggesting that the effect of AGEs
accumulation inhibition was achieved in the latter half of the group, when the amount of ultraviolet light reaches its peak.

KEY WORDS: advanced glycation end products (AGEs), red wine
BackgroundIn recent years, "glycation" is thought to be one of
the factors that accelerate aging 1). Glycation is a Maillard
reaction in the body, in which excess carbohydrates ingested
from food and other sources combine with proteins in the
body to eventually produce aging-causing substances called
glycation end products (AGEs) 2). These AGEs are difficult

for the body to break down and are thought to cause various
diseases by affecting skin coloration, wrinkle formation due
to hardening of collagen proteins, and hardening of bloodvessels 3, 4). Foods such as tea 5), vegetables 6), fruits 7) andyogurt 8) have been reported to inhibit this glycation reaction.
Anti-glycation substances, which inhibit the glycation
reaction that occurs in the body, are contained in foods that
we consume in our daily lives, and their efficient intake

Corresponding author: Shinichi Sugiura, PhD
Center for Clinical Pharmacy Education and Research, Faculty of Pharmacy,
Doshisha Women's College of Liberal Arts, Kyoto, Japan.
Koudo, Kyotanabe, Kyoto 610-0395, Japan
TEL & FAX: +81-774-65-8627 e -mail: ssugiura@dwc.doshisha.ac.jp
Co-authors: Iwata Y, yume.hssk.y.y@gmail.com ;Hirano S, saekkonn880000@gmail.com; Nagano M, hutakun023@gmail.com;
Shimada S, org_828@docomo.ne.jp; Uchida M, m-uchida@dwc.doshisha.ac.jp;
Asano M, info@msdream.co.jp; Akita H, hakita@fujita-hu.ac.jp.

_ 16 4 _Glycative Stress Research 2023; 10 (4): 164 -170(c) Society for Glycative Stress ResearchGlycative Stress Research

can be expected to have a preventive effect on aging anddisease. For example, wines differ in grape variety, region,and brewing method, and the characteristics of each brandof wine have been expressed by its unique taste, aroma, andcolor. Furthermore, wine is known to contain antioxidants
and anti-glycation substances such as polyphenols. We
investigated the anti-glycation effects of wine according
to grape variety, region of origin, and brewing method,and identified brands with strong anti-glycation effects
by comparing them in terms of their ability to inhibit the
production of AGEs. In the present study, we wondered
whether wine consumption might be effective in inhibiting
AGEs accumulation in the body, which might lead to theprevention of aging and disease.
The objective of this study was to identify wines withstrong anti-glycation effects through basic experiments andto determine whether consumption of that brand of wine has
an effect on the inhibition of AGEs accumulation in humanblood.

Methods
Basic Research

Commonly available wines were selected ( Table 1 ) andthe anti-glycation effect of the wines was determined. The
anti-glycation effects of the following wines were evaluatedby adding them to a human serum albumin (HSA)-glucose
glycation model 9) and measuring fluorescent AGEs production.
Aminoguanidine (AG) 10, 11), an inhibitor of AGEs productionthat has been reported to prevent or inhibit the progressionof nephropathy, retinopathy, and neuropathy, was used as apositive standard.

Clinical Research
Study design
Prospective crossover open- labeled randomized
controlled trial.
Study subjects
60 men and women between the ages of 20 and 65 who
were able to consume alcohol were included in the study.
Those with alcohol intolerance or an underlying disease
adversely affected by alcohol consumption were excluded.
Study participants who requested a written report were
informed of the results.
Allocation methods
Alcohol-capable men and women between the ages of
20 and 65 years participated in the study. Study participants
were assigned to two groups using random numbers at thetime consent forms were obtained.
Protocols
Wine with a strong inhibitory effect of AGEs production,
selected from the results of basic research, was used as thetest product, and mineral water (Acqua Panna, Tuscany, Italy)
was used as the control product. Participants consumed either
red wine or mineral water, 125 mL per day, 6 days per week
for 4 weeks, followed by a 2-week period of no consumption
to allow the active ingredient to be excreted from the body.
After that, the red wine and mineral water were switched,
and the participants consumed 125 mL each day, 6 days aweek, for 4 weeks. The AGEs accumulation level in the bodywas measured by an AGEs sensor four times before andafter ingestion. Fatigue stress was also measured at the sametime; AGEs were measured using an AGEs sensor (Air Water
Biodesign Inc., Osaka, Japan) was used to measure AGEs,
and VM500 (Fatigue Science Institute Co., Ltd., Yokohama,Japan) was used to measure stress. A summary of the intake

Table 1. Profile of wine used in this research
ID Color

WineryProduct nameVintage

Alcohol% (v/v)①

White

Domaines Paul Mas

Les Tannes en Occitanie Chardonnay 375

2019

13.3

②

Red

Domaines Paul Mas

Les Tannes en Occitanie Cabernet Sauvignon 375

2019

13.5

③

White

Domaines Paul Mas

Les Tannes en Occitanie Sauvignon Blanc

2019

12.1

④

Red

Domaines Paul Mas

Les Tannes en Occitanie Merlot

2019

13.6

⑤

Red

Domaines Paul Mas

Les Tannes en Occitanie Pinot Noir

2019

13.1

⑥

White

Domaines Paul Mas

La Forge Estate Unwooded Chardonnay

2019

13.5

⑦

White

Domaines Paul Mas

La Forge Estate Chardonnay

2019

13.0

⑧

White

Domaines Paul Mas

La Forge Estate Viognier

2019

13.8

⑨

White

Domaines Paul Mas

La Forge Estate Sauvignon Blanc

2018

12.4

⑩

Red

Domaines Paul Mas

La Forge Estate Cabernet Sauvignon

2019

13.8

⑪

Red

Domaines Paul Mas

La Forge Estate Merlot

2019

13.8

⑫

Red

Domaines Paul Mas

La Forge Estate Syrah

2019

13.8

⑬

Red

Domaines Paul Mas

La Forge Estate Pinot Noir

2019

13.5

⑭

Red

Shalauri Wine Cellars

Saperavi

2016

15.0

⑮

Red

Cantina GorettiMontefalco Sagrantino

2015

14.2

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Effect of Red Wine on AGEs in Blood

Table 2. Schedule of clinical studies
11 weeks

10 weeks

9 weeks

8 weeks

7 weeks

6 weeks

5 weeks

4 weeks

Measurement session

3 weeks

2 weeks

1 weekQuestionnaire by email

No drinking(2weeks)

Drinking (4weeks)wine or mineral water

Drinking period

Drinking (4weeks)wine or mineral water

Every Day
(1) Measure( 2) Measure( 3) Measure(4 ) Measure

periods and measurements is shown in Table 2.
Questionnaires were administered via email during
the study period. The questionnaire asked about the qualityof sleep, the presence or absence of mid-onset awakenings,
sleep duration, frequency of breakfast, what to start eating
at meals, presence or absence of defecation, the nature ofstools, whether or not alcoholic beverages other than the
study wine and sun protection were consumed. Constipation
was also defined as having no stool for more than 3 days.
The group was divided into the Week 2 - 5 group (early
June to mid-July) and the Week 8-11 group (late July to midSeptember) by the time of wine consumption. Excluding those
who had nail polish on their fingers and those who answered
less than 50 % of the questionnaire, the analysis was conductedfrom four perspectives: duration of consumption, gender,stool condition, and stress level.

be consumed was a red wine (La Forge Estate Pinot Noircontaining 13. 5 mL /100 mL of alcohol. The intake of red
wine was calculated from the IC 50 of red wine based on theAGEs production inhibitory effect of AG, and was set at 125
mL. The grape variety of La Forge Estate Pinot Noir was
Pinot Noir and the producer was Domaines Paul Mas, a wine
produced by a grape grower in Pécenas near Carcassonne,
Languedoc-Roussillon, France since 1892.

Statistical processin

Difference by intake period

Statistics were obtained using a correspondence
nonparametric test (Wilcoxon signed rank sum test).

Ethical Considerations

This study was conducted after approval (2020 -18) by
the Ethics Committee of Doshisha Women's University.

Results

Basic Research

In basic research, we measured the inhibitory effect ofwine on AGEs production. All red wines measured in thisstudy had a stronger inhibitory effect on AGEs production
than the standard substance aminoguanidine (AG), even at
5-fold dilution ( Fig. 1 ).
In the undiluted solution, the inhibitory effect on AGEs
production was stronger in the following order:
10→13→14→15→12→11→ 2→ 4 → 5→ 3→9 →8→6 → 7→1;
in the 5-fold dilution,
11→15→13→14→10→ 4 →12→ 5→ 2→ 8 → 3 → 9 → 7→1→ 6;
in the 25-fold dilution,
15→ 2→13→14→ 4→10→12→11→ 7 → 3 → 5→1→ 8 → 9 → 6(red wine is indicated by underbar).
Depending on the results of basic research the wine to

Clinical Research

Of the 48 research collaborators, 9 participants with a
response rate of less than 50 % to the questionnaire results
and 6 participants who were absent from at least one
measurement session were eliminated. The status of thestudy participants is shown in the flowchart ( Fig. 2 ).

Comparison of pre- and post-wine intake showed adecrease in AGEs values in the wine intake group andan increase in AGEs in the mineral water group, but thedifference was not significant ( p = 0.16). In a comparison bytreatment period, the first half group (early June to mid-July)and the second half group (late July to early September)showed a strong decreasing trend in AGEs values before andafter wine intake in the first half group compared to those
before and after wine intake in the second half group (p =0.06, Fig. 3). In contrast, there was no difference in AGEs
in the second half group (p = 0.39, Fig. 4 ). AGEs increased
gradually in the 20s, 30s, and 60s, and decreased in the 40s
and 50s (Fig. 5 ).

Differences by gender

Since AGEs generally increase with smoking and sun
exposure, we compared changes in AGEs between men andwomen, assuming that women who use sunscreen on a regularbasis are more likely to have lower AGEs. The results showedthat for men, there was no difference in AGEs levels between
the wine intake and mineral water groups during all intake
periods. On the other hand, women showed a trend toward
lower AGEs after wine intake (p = 0.07). Furthermore, whenanalyzed overlaid with the time of administration, AGEs
were significantly lower in women in the group that consumed
wine from summer to fall (p = 0.02, Fig. 6 ).

_ 16 6 _The inhibition ratio of fluorescence intensity
on fluorescent AGEs formation (%)

Glycative Stress Research

100

**

*
**

**

**

**

**

80

60

40

20

0

AG
① 5 times ② 5 times ③ 5 times ④ 5 times ⑤ 5 times ⑥ 5 times ⑦ 5 times ⑧ 5 times ⑨ 5 times ⑩ 5 times ⑪ 5 times ⑫ 5 times ⑬ 5 times ⑭ 5 times ⑮ 5 times(1mg / mL)
diluteddiluteddiluteddiluteddiluteddiluteddiluteddiluteddiluteddiluteddiluteddiluteddiluteddiluteddilutedFig. 1. Differences in inhibitory effect on fluorescent AGEs formation between wine varieties.

Fifteen variety of wines were used to determine the inhibitory effect of fluorescent AGEs formation. All data were shown as the mean ±SD, n = 3. *p < 0.05, **p < 0.01 vs. AG. AG, aminoguanidine; AGEs, advanced glycation end product; SD, standard deviation.

n = 48(male: 19, Female: 19)

Subjects; Men and women between
the ages of 20 and 65.

Questionnaire
implementation
Less than 50%
response rate

Response rate of
50% or moren = 39(male: 19, Female: 20)

Participation inmeasurement meetings

Not subject

More than 1 absencen = 33(male: 13, Female: 20)

Stool condition

Not subject

No defecation for
more than 3 days

n=5

Defecation

No defecationn = 28Fig. 2. Flowchart of clinical research participants.

_ 167 _

n=6

n=9

Effect of Red Wine on AGEs in Blood

Difference in AGEs
by fluorescence intensity

0.06
0.04
0.02
0

After uptake

Before uptake-0.02†p = 0.06

-0.04
Wine

-0.06

Mineral water

Fig. 3. Difference in AGEs levels before and after intake (early June to mid-July).

All data were shown as the mean ± SD, Wine: n = 16, Mineral water: n = 17. †p < 0.1 vs. mineral water. AGEs,
advanced glycation end product; SD, standard deviation.

Difference in AGEs
by fluorescence intensity

0.06
0.04
0.02

p = 0.390After uptake

Before uptake

-0.02
-0.04
Wine

-0.06

Mineral water

Fig. 4. Difference in AGEs levels before and after intake (late July to mid-September).

All data were shown as the mean ± SD, Wine: n = 17, Mineral water: n = 16. AGEs, advanced glycation end
product; SD, standard deviation.

Changes in AGEs by age group

0.15
0.1
0.05
0
-0.05
-0.1
-0.15
20s
n = 1030s
n = 1140s
n = 10

50s
n=4

60s
n=2

Age group

Fig. 5. Changes in AGEs by age group as a result of wine consumption.

Data includes subjects who responded to less than 50 % of the questionnaires. All data were shown as themean ± SD. AGEs, advanced glycation end products; SD, standard deviation.

_ 16 8 _Glycative Stress Research

0.02

Difference in AGEs
by fluorescence intensity

0.01
0
-0.01

After uptake

Before uptake-0.02*p = 0.02

-0.03
-0.04
Wine

-0.05

Mineral water

Fig. 6. Difference in AGEs levels before and after intake for women (late July to mid-September).

All data were shown as the mean ± SD, Wine: n = 10, Mineral water: n = 10. *p < 0.05 vs. mineral water. AGEs,
advanced glycation end product; SD, standard deviation.

Difference in AGEs
by fluorescence intensity

0.04
0.02
After uptake

Before uptake

0
-0.02
-0.04

*p = 0.05

-0.06
-0.08

Defecation

Not defecation

Fig. 7. Changes in AGEs lowering between constipation and normal stool groups with wine
consumption.

All data were shown as the mean ± SD, Defecation: n = 28, Not defecation: n = 5. *p < 0.05 vs. not defecation.
AGEs, advanced glycation end product; SD, standard deviation.

The effects of constipation

Since AGEs are absorbed from the gastrointestinal tract,
we compared changes in AGEs values between the constipationgroup and the normal stool group for the purpose ofinvestigating the possible effect of AGEs absorption due toconstipation. AGEs levels were significantly higher in theconstipation group than in the normal stool group. Comparisonof the reduction in AGEs with wine consumption showed agreater reduction in AGEs in the normal stool group than in
the constipation group. (p = 0.05, Fig. 7 ).

StressStress was evaluated by dividing the group into twogroups: one with autonomic disturbance and predominantly
activated sympathetic nervous system (stress group) and anormal group, as determined by VM500. In the stress group(n = 10), there was no significant difference in AGEs values
after wine consumption (p = 0.64), while in the normalgroup, AGEs values tended to decrease before and after wine
consumption (p = 0.06). The stress counties with disturbed
autonomic nervous system tended to weaken the inhibitory
effect of wine on AGEs accumulation.

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Effect of Red Wine on AGEs in Blood

Discussion
Depending on the period of consumption, there was atendency for AGEs to decrease in the group that consumed
wine from early June to mid-July, but there was no
predominant difference, whereas there was no change in thegroup that consumed wine from late July to mid-September.
However, when compared by gender, the female group that
consumed wine from late July to early September showeda predominant decrease in AGEs. This is thought to be dueto the fact that from early June to mid-July was the rainyseason with many cloudy days, which reduced the effects ofultraviolet rays, and both men and women showed a tendency
to lower AGEs levels due to wine consumption. In addition,from late July to mid-August, the amount of ultraviolet rays
reached its peak, and the increase in AGEs due to ultraviolet
rays was thought to have had an effect. In a comparison
between men and women, men who did not care about
sunburn and did not have the habit of using a parasol wereless likely to benefit from wine consumption than women,
but among women, the predominant decrease in AGEs in thewine consumption group suggested that the use of sunscreen
on a daily basis affected the effect of wine on suppressing
the increase in AGEs. This suggests that the daily use ofsunscreen may have influenced the effect of wine on AGEs
inhibition.
In comparison between the constipation and nonconstipation groups, the constipation group did not show
any decrease in AGEs due to wine consumption. In general,
AGEs are thought to be absorbed from the intestinal tractby about 10 %, and the increased absorption of AGEs fromthe intestinal tract due to constipation was thought to affectthe inhibition effect of wine on AGEs increase. The results
also suggested that constipation increases the absorption of
AGEs.
It is generally believed that sympathetic nerves areactivated predominantly in high-stress situations and blood
glucose levels rise 12). Since an increase in blood glucose levels
leads to an increase in AGEs, we compared the relationshipbetween stress and the inhibition of AGEs increase by wine.
The results showed that AGEs in the normal group tended todecrease with wine consumption, whereas AGEs in the stressgroup remained unchanged. This indicates that stress inhibits
the wine-induced AGEs lowering effect. In other words, theresults suggest that stress affects aging.

Acknowledgements
This study was funded by a FY2020 Individual Research
Grants in Doshisha Women’s College of Liberal Arts.

Conflict of interest statement
This research was partly supported by Mottox Inc.
(Osaka, Japan). The wine used in this study was also provided
by Mottox, Inc.

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