Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : July 19, 2016
Accepted : August 15, 2016
Published online : September 30, 2016

Review article

Glycative stress and anti-aging: 1. What is glycative stress?
Masayuki Yagi, Yoshikazu Yonei
Antiaging Medical Research Center and Glycative Stress Research Center, Faculty of of Life and Medical Sciences,
Doshisha University, Kyoto, Japan

Abstract

Glycation is a non-enzymatic chemical reaction between amino acid or protein and reducing sugar and it occurs to various
proteins in living organisms. The glycated protein leads to the formation of advanced glycation endproducts (AGEs) throughthe formation of intermediates dominated by carbonyl compounds. Glycative stress is a concept of comprehensively viewing
the stress to living organisms caused by the loads of reducing sugar and aldehyde and its subsequent reactions. Glycativestress in living organisms becomes the factor promoting dysfunction of protein, degeneration of protein (corrected aftertranslation), accumulation of AGEs, impaired TCA cycle, activation of cellular signal, acceleration of tissue damage anddegenerative changes associated with aging. Ultraviolet rays and oxidant stress are positioned as the factors accelerating
glycative stress. Glycative stress is considered a risk factor for aging in anti-aging medicine.

KEY WORDS: Glycative stress, advanced glycation endproduct (AGEs) and risk factor for aging.

Glycation is a non-enzymatic chemical reaction between
amino acid or protein and reducing sugar, discovered by LouisCamille Maillard, a French scientist, and also called Maillard
reaction 1).
Glycation has been attracting attention in the field of foodchemistry because it is a chemical reaction associated withfood coloring, changes of fragrance and flavor during theheating process and decrease in nutrition during storage 2).
The measurement of hemoglobin A1c (HbAlc), a productof glycation reactions in human blood, is clinically applied
as the blood glucose control index in the field of diabetictreatment.
It is known that glycation occurs not only to hemoglobin,
but also to various proteins such as albumin, keratin, globulin
and collagen, and the glycated proteins lead to the formationof advanced glycation endproducts (AGEs) through theformation of various intermediates dominated by calbonylcompounds such as 3-deoxyglucosone (3DG), glyoxsal (GO),methylglyoxsal (MGO), glyceraldehydes and glycolaldehyde.
AGEs show their characteristics such as dark brown color,
fluorescence (excitation wavelength (ex): mainly 370 nm,
fluorescence wavelength (em): 4 40 nm) ( Fig. 1 ) and protein
cross-link formation. The presence of these characteristics
differs by each different material.
AGEs having fluorescence include pentosidine (ex 335nm /em 385 nm) 3), crossline (ex 379 nm /em 463 nm) 4),

pyrropyridine (ex 370 nm /em 455 nm) 5). Non-fluorescent
AGEs includes N ε - (carboxymethyl) lysine (CML) 6),
N -(carboxymethyl) arginine (CMA) 7). Pentosidine andcrossline are crosslinking AGEs.
ε

1. Glycation and AGEs

2. Glycative stress

Glycative stress is a concept of comprehensively viewing
the stress to living organisms caused by the loads of reducing
sugar and aldehyde and its subsequent reaction ( Fig. 2 ) 8).
Glycation in a narrow sense is a reaction system leading
to the formation of AGEs through the formation of Schiffbase, glycated protein and other various intermediates by
non-enzymatic chemical reactions between reducing sugar
and protein. These reactions degenerate tissue proteins andimpair their function.
Meanwhile, beta-oxidation and peroxidation of lipids
within living organisms also produce aldehyde groups andketone groups. Carbonyl groups existing within the moleculesof aldehyde and ketone polarize when electrons are pulled tooxygen atoms with high electronegativity and carbon atoms
become susceptible to nucleophilic attack. Furthermore, whenthese functional groups react against lysine and arginine
compounding protein in an uncontrollable way, the functionof protein is impaired.

Contact Address: Professor Masayuki Yagi. PhD
Glycative Stress Research Center, Faculty of Life and Medical Sciences, Doshisha University
1-3, Tataramiyakodani, Kyotanabe-shi, Kyoto, 610-0394 Japan
Phone/Fax: +81-774-65-6394
E-mail: myagi@mail.doshisha.ac.jp
Co-author: Yonei Y, yyonei@mail.doshisha.ac.jp_ 152 _

Glycative Stress Research 2016; 3 (3): 152- 155(c) Society for Glycative Stress Researchﬂuorescence	  intensity	  Glycative Stress Research

ﬂuorescence	  wavelength	  (nm)	  Fig. 1. Fluorescence spectrum from AGE in glucose-human serum albumin (HSA) model.

HSA (8 mg/mL) + 0.05 mol/L phosphate buffer (pH 7.4) + glucose (0.2 mol/L) solution (solid line), HSA(8 mg/mL) + 0.05 mol/L phosphate buffer (pH 7.4) solution (broken line). Incubated 60℃, 40 hours.
Excitation wavelength at 370 nm.

Figure	  

   Fig. 2. Concept of glycative stress.

Figure	  	    

Excess Glucose, postprandial hyperglycemia; TG, triglyceride; TCA, tricarboxylic acid; AGEs, advanced glycation endproducts: RAGE,receptor for AGE. Quoted and modified from Ref. 8).

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What is glycative stress?
If excessive glucose exists inside the cell, it causes a poor
response of the TCA cycle and fumaric acid increases 9-10).
Fumaric acid reacts with cysteine, an amino acid compounding
protein and forms S-(2-succinyl) cysteine (2SC). This reaction
is called succinylation. Caused by the succinylation of protein,
the function of protein declines or is lost, and this causes
problems in the living organism. The proteins in the livingorganization affected by succinylation include cytoskeletal
protein, heat-shock protein 9) and adiponectin 10).
AGEs accumulated in organisms combine with RAGE
(receptor for AGEs), receptors existing on the surface of cells,
activate cell signal and cause the formation of inflammatory
cytokine 11). RAGE induces cell response from intracellularsignaling and works for disease state formation as thereceptor AGEs 12).
Ligands other than AGEs that connect with RAGE include:‘advanced oxidation protein products (AOPP), that is, oxidative
damaged product, an oxidative stress mediator,’ ‘amyloid beta
protein accumulated in the brain with Alzheimer’s disease,’‘transthyretin accumulated by familial amyloid polyneuropathy,’‘high mobility group B-1 (HMGB-1)/amphoterin, which
relationships with cancer metastasis and inflammation are
pointed out,’ ‘inflammatory mediator S-100 protein’ and‘Mac1 on the surface of white cell’ 3). It is said that CML,
glyceraldehydes and glycolaldehyde modifiers among AGEs
can easily connect with RAGE 13).
Glycative stress promotes dysfunction of protein,degeneration of protein (corrected after translation),
accumulation of AGEs, impaired TCA cycle, activationof cellular signals, acceleration of tissue damage anddegenerative change associated with aging. Ultraviolet rays
and oxidant stress are positioned as the factors accelerating
glycative stress.

3. Glycative stress in anti-aging medicine

Humans intake carbohydrates in food as a major energy
source, so it is impossible to avoid the glycation that occurs
between glucose and protein in their lifetime 14). It is obvious
from the facts that the accumulation of AGEs in the skincollagen of healthy people increases with aging, that theaccumulation of AGEs is larger in diabetic patients than thatof healthy people the same age 15), and that the elasticity ofthe skin of diabetic patients is lower than that of healthypeople 16).
The formation and accumulation of AGEs by glycation
are involved not only in diabetic complaints but also in skinaging 17), the development of Alzheimer’s 18), hypertension 19),
arterial sclerosis 20) and osteoporosis 21). Because the formationof AGEs from collagenous tissues of skin, bone and cartilage
is accompanied by browning and decrease of plasticity, itdraws attention in the fields of beauty and health.
Anti-aging medicine is a preventative medicine aimed
at the improvement of quality of life (QOL), good health andlongevity 22). Human phenotypes of aging include the agingof blood vessels (arterial sclerosis), aging of nerves (dementiaand Alzheimer’s) and aging of bones (osteoporosis). However,the symptoms of these disorders depend on individuals andEvaluating the degree of aging

Aging risk factors

Muscle age

Immunestress
Vascular age

Bone age

Hormone age
Bone age
Muscle age
Vascular age
Neural age
Hormone age

GlycativestressOxidativestress

Lifestylefactors

Psychosomaticstress

Neural age

bone mineral density (Ultrasonography)
muscle mass (PhysionMD)
fingertip accelerated plethysmography (SPD100)
Wisconsin Card Sorting Test
blood test (GH, IGF-I, DHEA-s)

Fig. 3. Aging assessment by Anti-Aging Medical Checkup.

Glycative stress AGEs, insulin resistance
Immune stress DHEA-s, NK cell activity
Oxidative stress urinary OHdG, blood isoprostane
Psychosomatic stress cortisol, DHEA-s
Lifestyle factors exercise, sleep, alcohol consumption, smoking

GH, growth hormone; IGF-I, insulin-like growth factor-I; DHEA-s, dehydroepiandrosterone-sulfate; AGEs, advanced glycation end products;
NK, natural killer; 8-OHdG, 8-hydroxy-deoxyguanosine_ 15 4 _Glycative Stress Research

the risk factors of aging differ by individual.
Therefore, in the anti-aging dock, the degree of aging(functional age) is evaluated as muscle age, vascular age,neural age, hormone age and bone age 23). Furthermore, thefactors involved in the decline in functional age are positioned
as risk factors for aging and evaluated. They are divided into
immune stress, oxidative stress, psychosomatic stress, glycative
stress and lifestyle factor ( Fig. 3 ).
The evaluation results by anti-aging dock aim at focusing
on the items of highest aging degree and those which risk
factor is highest and keep a balance of aging degrees as awhole by rectifying especially remarkable items.
Glycative stress is understood in anti-aging medicine asan aging risk factor, as the influence of the stress caused by
the loads of reducing sugar and aldehyde and its subsequent
reaction grasped as a whole.

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Acknowledgement

This work was partially supported by the JapaneseCouncil for Science, Technology and Innovation, SIP(Project ID 14533567 ), “Technologies for creating nextgeneration agriculture, forestry and fisheries” (fundingagency: Bio-oriented Technology Research Advancement
Institution, NARO

Conflict of interest statement

There are no items deemed to be conflicts of interest in
this research.

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