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Lead Article
Early AGEing and metabolic diseases: is perinatal exposure to
glycotoxins programming for adult-life metabolic syndrome?
Fl
avio A. Francisco*, Lucas P.J. Saavedra*, Marcos D.F. Junior ,C
atia Barra, Paulo Matafome,
Paulo C.F. Mathias, and Rodrigo M. Gomes
Perinatal early nutritional disorders are critical for the developmental origins of
health and disease. Glycotoxins, or advanced glycation end-products, and their pre-
cursors such as the methylglyoxal, which are formed endogenously and commonly
found in processed foods and infant formulas, may be associated with acute and
long-term metabolic disorders. Besides general aspects of glycotoxins, such as their
endogenous production, exogenous sources, and their role in the development of
metabolic syndrome, we discuss in this review the sources of perinatal exposure to
glycotoxins and their involvement in metabolic programming mechanisms. The
role of perinatal glycotoxin exposure in the onset of insulin resistance, central ner-
vous system development, cardiovascular diseases, and early aging also are dis-
cussed, as are possible interventions that may prevent or reduce such effects.
INTRODUCTION
The developmental origins of health and disease con-
cept focuses on the potential associations between a
suboptimal fetal and/or postnatal environment and
several pathologies in the offspring, such as the meta-
bolic syndrome. Several animal models have been de-
veloped to explore the pathophysiology and
mechanisms of developmental programming of the
metabolic syndrome. Features of cardiometabolic dis-
eases have been found in the offspring of diabetic
rodents, as well as in the offspring of rodents fed a
high-fat diet or fructose-enriched diet.
1–5
High sugar
intake is associated with harmful effects, such as car-
diovascular diseases, obesity, insulin resistance, and
diabetes. In this way, hyperglycemia is related to in-
creased levels of advanced glycation end-products
(AGEs), and these glycotoxins are closely associated
with the development and progression of diabetes and
its complications.
6–11
AGEs also are involved in the
deterioration of metabolic homeostasis in obesity,
namely the development of insulin resistance–associ-
ated pathologies such as cardio- and cerebrovascular
diseases, nonalcoholic steatohepatitis, and central ner-
vous system disorders, including dementia, in adult
and pediatric patients.
12–26
Vascular aging due to
AGEs exposure, or vascular AGEing, is related to oxi-
dative stress due to increased generation of reactive
species of oxygen and nitrogen,
27–30
endothelial dys-
function,
31–33
and changes in the extracellular matrix
32
and in inflammatory factors.
34
Infant formulas are
used worldwide as a substitute for breast milk; previ-
ous studies have reported high AGE content in breast
milk.
35–38
Thus, infants’ exposure to these nutritional
Affiliation: F.A. Francisco, L.P.J. Saavedra, and P.C.F. Mathias are with the Department of Biotechnology, Genetics, and Cellular Biology,
State University of Maringa, Maringa, PR, Brazil. M.D.F. Junior and R.M. Gomes are with the Department of Physiological Sciences, Federal
University of Goi
as, Goi^
ania, GO, Brazil. C. Barra and P. Matafome are with the Institute of Physiology and Coimbra Institute of Clinical and
Biomedical Research, Faculty of Medicine, and the Center for Innovative Biotechnology and Biomedicine, University of Coimbra; and the
Clinical Academic Center of Coimbra, Coimbra, Portugal.
*These authors contributed equally.
Correspondence: R.M. Gomes, Department of Physiological Sciences, Biological Sciences Institute 2, room 101, Federal University of Goi
as,
Esperanc¸a Ave s/n, 74690-900 Goi^
ania, GO, Brazil. Email: Gomesrm@ufg.br.
Key words: advanced glycation end products (AGEs), glycotoxins, metabolic programming, metabolic syndrome, methylglyoxal.
V
CThe Author(s) 2020. Published by Oxford University Press on behalf of the International Life Sciences Institute.
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doi: 10.1093/nutrit/nuaa074
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contaminants early in life may contribute to the develop-
ment of cardiometabolic disorders at adulthood.
37,39,40
In this review, we provide an overview of the cur-
rent knowledge about the contribution of perinatal
glycotoxin exposure to metabolic programming and
the development of metabolic syndrome–related pa-
thologies. Evidence of increased glycotoxin exposure
of the fetus or newborn, due to maternal or infant di-
etary AGE consumption, in addition to infant for-
mula feeding, on developmental programming of
metabolic syndrome are discussed, as are interven-
tions to prevent the consequences of perinatal expo-
sure to AGEs. Figure 1 provides an overview of main
sources and potential mechanisms of the develop-
ment of cardiometabolic disease development during
adult life, due to the exposure to glycotoxins during
perinatal life.
CLINICAL EVIDENCE OF PERINATAL PROGRAMMING
FOR ADULT-LIFE METABOLIC SYNDROME
Pregnancy is a critical period for the health of both the
fetus and the mother and is very sensitive to environ-
mental disturbances. Several studies established a rela-
tionship between disturbances in the pregnancy and
diseases in offspring throughout life.
41–50
The magni-
tude of such effects depends on the stage of gestation in
which the fetus was exposed and the nature of the ag-
gressive agent.
44
It is well established that tobacco, alco-
hol, distress, nutritional unbalances, and other
metabolic disruptors affect the proper development of
the fetus during intrauterine life.
46,48,50–52
One of the
most common gestational disorders is gestational diabe-
tes mellitus (GDM), which is associated with pregesta-
tional overweight and has been implicated in adverse
perinatal outcomes such as increased weight gain dur-
ing the gestational period and high sugar consump-
tion.
45,53,54
Fetal development is very susceptible to
diabetes, given that this condition can promote severe
changes in tissues and organs, with cardiovascular and
neural tube defects being the most frequent malforma-
tions.
43,46
Mothers with pregestational diabetes mellitus
(PGDM) and a poorly controlled hyperglycemia during
the first trimester have a 5% to 10% higher risk of hav-
ing newborns with a major birth defect and a 15% to
20% higher risk of spontaneous abortion.
55
On the
other hand, GDM is associated more with pregnancy
complications, such as macrosomia, and pre- and peri-
natal mortality, than with congenital anomalies.
46
The
offspring of mothers with PGDM have increased adi-
posity and overweight resulting from transplacental
passage of maternal glucose and induction of fetal
hyperinsulinemia.
46
Pregnant women with GDM have
an increased risk of delivering large-for-gestational-age
(LGA) newborns, who have an higher risk of being
obese at childhood.
43,56
Diet composition before and during pregnancy
may influence the metabolic profile of both the
mother and the newborn, and may affect the new-
born’s size at birth.
57,58
Nutritional changes may lead
to impairment of fetal growth and intrauterine
growth restriction, as well as fetal adiposity, insulin
resistance, and pancreatic b-cell dysfunction.
59
In a
case-control study, Amezcua-Prieto et al
58
suggest the
increased consumption during pregnancy of industrial
bakery products, pastries, and products containing re-
fined sugar is associated with a higher risk of having
a small-for-gestational-age (SGA) newborn. In con-
trast, higher consumption of whole-grain cereal and
bread is related to a lower risk of delivering an SGA
infant.
58
According to another cohort study, the daily
consumption of artificially sweetened beverages dur-
ing pregnancy induces a 2-fold higher risk of having
a child with overweight at the child’s first year.
60
Ornoy et al
46
showed that the offspring of mothers
with GDM have a high frequency of overweight, as
do babies who are breastfed by mothers with diabe-
tes. Palatianou et al
61
found an increased association
of the LGA condition with nondiabetic obesity com-
pared with type 2 diabetes. On the other hand, LGA
infants from mothers with diabetes (either GDM or
PGDM) are above the 90th percentile in height and
weight and have increased weight gain in the first 4
months of life.
46,62
A meta-analysis performed by
Schellong et al
63
revealed a predisposition to adult-
hood overweight in LGA newborns but not in SGA
newborns. However, both the LGA and SGA condi-
tions have a similar risk for development of adult-
hood diabetes, with the risk that following a U-
shaped and not a linear relationship.
64
Children who
are SGA born to mothers with PGDM and associated
nephropathy are more susceptible to prematurity, re-
duced growth at age 3 years and body weight and
height below the 50th percentile when compared with
children of mothers with PGDM without complica-
tions. As well, SGA individuals who gained a sub-
stantial amount of weight in early childhood
exhibited higher risk of developing hypertension and
diabetes and also higher coronary heart disease mor-
tality in adulthood compared with their age-matched
counterparts.
59
Thus, maternal obesity and type 2 diabetes affect
birth weight, and both the SGA and LGA conditions
are associated with increased risk of metabolic impair-
ment and related complications in the adult life.
Moreover, the presence of diabetic complications in the
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mother is apparently related to an increased risk to the
newborn.
Metabolic effects of glycotoxins on metabolic
syndrome
One of the main glycotoxins is methylglyoxal (MG),
which may change cell behavior through modification
of biomolecules, such as proteins and DNA, and conse-
quent formation of AGEs.
18
Modification of arginine
residues by MG leads to the formation of Nd-(5-hydro-
5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) and
argpyrimidine from the imidazolones family, whereas
lysine modification leads to the formation of methyl-
glyoxal lysine dimer and (carboxyethyl)lysine.
65–69
Modification of amino acid residues by MG affects in-
tracellular (i.e., transcription factors and cytoplasmic
proteins, including the proteasome and stress-response
pathways), circulating (ie, hemoglobin, albumin, or lip-
oproteins), and extracellular matrix proteins, changing
cell behavior and activating inflammatory and death
pathways.
18,70–77
Indeed, MG modifies proteasome sub-
units and protein quality-control pathways (namely,
Hsc70, Hsp90, and Hsp27), causing endoplasmic reticu-
lum stress and impaired degradation of misfolded pro-
teins, in turn leading to a vicious circle of progressive
accumulation of misfolded proteins and impaired acti-
vation of detoxification systems.
78–81
Besides directly
modifying protein structure through modification of
amino acid residues, MG also increases oxidative stress,
namely, the formation of superoxide anion,
82–85
hydro-
gen peroxide, and peroxynitrite
82,83,86
in different types
of cells, including endothelial cells,
87
rat kidney mesan-
gial cells,
88
rat hepatocytes,
86,89
blood cells,
83,90
osteo-
blasts,
90
and in rat and mouse neurons.
91–94
MG also
induces the depletion of antioxidant defenses, predis-
posing cells for oxidative damage.
82,88,95–99
Given that
MG detoxification systems, namely the glyoxalase sys-
tem, are glutathione dependent, such mechanisms lead
to a self-perpetuating circle of reactive oxygen species
and AGEs formation and mitochondrial dysfunction.
97
Extracellular AGEs may change cell behavior
through activation of membrane receptors, such as
RAGE, which recognizes 2 major types of ligands: imi-
dazolones (MG-derived) and Ne-(carboxymethyl)lysine
(CML) adducts.
100
Upon activation, RAGE triggers in-
tracellular signaling pathways such as NF-jB, involved
in activation of inflammatory and proliferation or stress
signals, as well as generation of oxidative stress.
75,101–106
Inhibition of RAGE or expression of soluble RAGE iso-
forms with the ability to scavenge AGEs prevented vas-
cular disease in several animal models.
101,107,108
Thus,
MG-induced changes in cell behavior involve several
mechanisms, namely the modification of biomolecules,
accumulation of misfolded proteins, activation of mem-
brane receptors, generation of oxidative stress, changes
in transcription factors, and activation of inflammatory
or stress pathways.
MG has been implicated in the development of dia-
betes complications such as retinopathy, nephropathy,
and peripheral neuropathy, given that its levels are in-
creased in patients with diabetes patients, and insulin-
independent cells like endothelial cells, podocytes, and
neurons are more susceptible to hyperglycemia-driven
MG formation.
18
Several studies have addressed the in-
volvement of MG in the mechanisms governing the de-
velopment of such pathologies, namely endothelial cell
senescence and angiogenesis impairment,
70,77,109,110
podocyte effacement and death,
111,112
glomerular fibro-
sis,
76,101,105,113
apoptosis of retinal pericytes and retinal
pigmented cells,
114–117
and changes in the nociception
and pain stimuli (hyperalgesia).
118,119
Moreover, MG is
involved in the pathophysiology of cardio- and cerebro-
vascular diseases. MG causes structural changes in the
blood-brain barrier
120,121
and is involved in other neu-
rodegenerative disorders, such as increased neurotoxic-
ity,
122,123
b-amyloid protein neurotoxic effects,
124,125
and loss of dopaminergic neurons.
126–128
In the cardio-
vascular system, MG impairs calcium handling between
sarcoplasmic reticulum and cytoplasm of cardiomyo-
cytes
129
and also affects survival and apoptotic pathways
during ischemia,
130,131
and angiogenic deficits.
132
Features of endothelial dysfunction, hypertension, and
atherosclerosis have also been reported, such as oxida-
tive stress and stiffness of the aorta, impaired elasticity,
acetylcholine-dependent relaxation, nitric oxide bio-
availability,
33,133–136
activation of the renin-angiotensin
system,
137,138
increased glycoxidation of low-density li-
poprotein particles
139,140
and increased risk of throm-
bosis and atherosclerosis through platelet
hyperaggregation and RAGE activation.
141,142
Besides being implicated in the development of dia-
betic complications or associated diseases, MG also con-
tributes to the process of loss of metabolic homeostasis
itself, namely in the development of b-cell dysfunction
and insulin resistance. MG transiently activates insulin
secretion due to b-cell depolarization,
143
but it hampers
b-cell survival and long-term insulin synthesis and se-
cretion.
144
In insulin signaling, MG causes a redox-
independent inhibition of the insulin-receptor pathway
and GLUT4 translocation in muscle cells and 3T3 adi-
pocytes.
9,145,146
In vivo, MG caused insulin resistance in
several animal models,
144,145,147
but only when supra-
physiological doses were used.
18
Other studies did not
show MG-induced insulin resistance, which was only
observed in obese animal models.
25,148,149
Several stud-
ies have also shown AGE-induced overexpression of in-
flammatory mediators in the liver,
26,150,151
but again,
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hepatic insulin resistance was only observed in obese
animals.
26
Such results suggest that glycation may have
an impact in obesity-associated insulin resistance, possi-
bly through increased depletion of antioxidant and de-
toxifying mechanisms, but has a less dramatic effect in
lean models. In humans, elevated MG and AGE levels
have been reported in patients with diabetes and in met-
abolically unhealthy, obese patients, but no correlation
was found between AGE levels and impaired glucose
homeostasis.
152,153
Nevertheless, AGE-restricted diets
improve insulin sensitivity in normal and overweight
individuals, as well as patients with metabolic syndrome
and type 2 diabetes.
154–157
Reports have shown the im-
pact of oral AGE restriction in the improvement of in-
sulin resistance, even in patients with metabolic
syndrome, which may reduce the risk of progression
from metabolically unhealthy and obese and having
metabolic syndrome to type 2 diabetes.
In summary, MG and MG-derived AGEs are in-
volved in several pathologies associated with metabolic
syndrome and diabetes, but their progressive accumula-
tion in biological systems may be also associated with
impaired lipid handling and increased susceptibility to
oxidative damage, which may contribute to the develop-
ment of insulin resistance in adipose tissue and liver in
obesity and predispose to the metabolically unhealthy,
obese phenotype. Together with increased b-cell dam-
age, such mechanisms are likely to contribute to the
progressive deterioration of metabolic homeostasis and
development of prediabetes and type 2 diabetes.
Importantly, the impact of early glycotoxin exposure
since the perinatal period is unknown, although recent
evidence suggests such exposure may increase the risk
of metabolic dysregulation and development of
diabetes-like complications in adult life.
Sources of perinatal glycotoxins exposure
In utero exposure to AGEs during embryonic
development. Similar to the other types of diabetes,
GDM-related hyperglycemia increases serum levels of
MG and AGEs, such as CML.
158,159
Increased serum
AGE levels are associated with insulin resistance, oxida-
tive stress, cardiovascular diseases, and diabetes comor-
bidities in normal individuals and pregnant
women.
33,160–164
In addition to hyperglycemia, mater-
nal AGEs may also derive from dietary absorption,
given that industrialized foods are rich in AGEs
54
and
given their possible transfer to the embryo through the
placenta.
35
Accordingly, Konishi et al
165
reported the
impairment of implantation and placental growth and
function by the accumulation of AGEs through RAGE
activation, oxidative stress, low human chorionic go-
nadotropin levels, and apoptosis in human first-
trimester trophoblasts. Similarly, Hao et al
166
and
Haucke et al
167
reported the adverse effects of GDM
through raised AGEs levels during embryonic develop-
ment, which promote RAGE activation, inflammation,
and AGE accumulation in the embryo. This environ-
mental stress may collaborate to cause embryo resorp-
tion, fetus malformation, or preterm birth.
168
On the
other hand, knockout of soluble RAGE in pregnant dia-
betic rats prevents embryonic dysmorphogenesis,
169
and the administration of the soluble form of RAGE
during pregnancy reduces NF-jB activity in rat fetal
tissues.
170
Elevated sugar-sweetened soft beverages and re-
fined carbohydrates consumption during pregnancy
arestronglycorrelatedwithhighserumAGElevels,
offspring congenital heart defects, SGA newborns, and
increased risk of offspring overweight.
58,60,170,171
These data reinforce the role of AGE exposure on the
diabetic embryopathy and its implications for proper
fetus development, which are widely related to devel-
opmental origins of diseases at later stages of life.
However, data regarding the mechanisms involved in
AGEs passage through the placenta are not currently
available, to our knowledge, and studies are necessary
in this field.
Glycotoxin exposure during lactation period through
breast milk and infant formula. The lactation period is
essential to the proper development and maturation of
different organs and systems of the newborn, because
breast milk is to supply this nutritional demand. Given
the abundance of evidence regarding the importance of
breastfeeding in infant health, the World Health
Organization recommends exclusive breastfeeding until
6 months of life and complementary until age 2 years.
172
Breastfeeding prevents diseases such as diabetes, multi-
ple sclerosis, and celiac disease.
173
More than just a
source of calories, breast milk is an important source of
bioactive molecules such as antibodies, oligosacchar-
ides, and hormones, which exert beneficial effects for
the healthy development of newborns.
173,174
Insulin
may be found in breast milk and plays an important
role in the process of gut maturation, decreasing perme-
ability to macromolecules.
175
The milk composition depends on the maternal
metabolic status and there is evidence that breast milk
may also be a source of glycotoxins during lactation.
Human studies have shown that the neonatal intake of
breast milk from mothers with diabetes was related to
overweight and glucose intolerance.
176
Mericq et al
35
found a correlation between blood AGE levels of lactat-
ing mothers and their infants, raising the question of
whether maternal diet during lactation influences infant
glycoxidative stress. Even in other diseases, such as
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beriberi, when an accumulation of glucose metabolites
such as MG occurs, there is an increased concentration
of these substances in breast milk.
177
Infants whose
mothers smoked during pregnancy and/or lactation
have increased accumulation of AGEs in their skin, in-
dicating that the transmission of glycotoxins from
mother to child may also occur through breast milk.
37
Altered composition of breast milk from obese dams,
caused by high-sugar consumption, programs rat off-
spring to develop obesity due to the impairment of mel-
anocortin system.
178
Other studies have demonstrated that the levels
and effects of breast-milk AGEs may also originate in
maternal diet. Cows fed a diet high in AGEs had in-
creased glycated compounds in their milk, such as MG-
H1.
179
On the other hand, a diet low in AGEs during
pregnancy and the neonatal period prevented the devel-
opment of type 1 diabetes in the offspring of NOD
mice.
38
In this regard, it was previously demonstrated
that oral administration of MG to lactating rats in-
creased the content of the glycation intermediary fruc-
tosamine in their milk, which was related to the
development of a diabetic phenotype in the offspring
during adult life.
180
Such observations are in line with
evidence that AGE levels in the blood could be derived
from the diet and not just produced endogenously. In
fact, a strong correlation between intake of AGEs and
AGE levels in the plasma has been demonstrated.
181,182
Similarly, evidence from human studies have shown
that dietary restriction of AGEs decreases their concen-
tration in plasma and their renal excretion.
155,183–185
In
animals fed a
14
C-labelled, AGE-rich diet, as in humans,
10% of dietary AGEs are absorbed.
183,186
Indeed, the
glycation compound pirralyne, as well as major AGEs
such as CML, (carboxyethyl)lysine, and MG-H1, are
absorbed in the form of dipeptides via PEPT1 trans-
porter in intestinal cells.
187,188
Another source of glycotoxins during the perinatal
period are infant formulas, which commonly contain
high levels of AGEs, reaching almost a 35-fold higher
concentration of CML than breast milk of healthy
mothers.
39,189
AGEs are formed in heat-treated foods,
as a product from Maillard reaction, or nonenzymatic
browning. In fact, traditional methods of cooking that
use high temperature (100C–250C), such as frying,
baking, and grilling, contribute to a higher grade of
AGE formation, because foods rich in reducing sugars
and proteins are more prone to the formation of these
compounds.
190–192
For instance, grilled beef has 5 times
higher AGE levels (5963 kU/100 g) than boiled beef
(1124 kU/100 g).
193
Also, infant formulas are rich in
sugars and proteins, and their industrial production
includes heat treatment. Hence, it was demonstrated
that hydrolysate infant formulas, rich in whey, have
higher concentrations of CML because whey proteins
are subjected to great heat treatment during
manufacturing of infant formula.
194
A positive correlation between formula-derived
AGEs, increased AGE circulating levels, and their uri-
nary excretion was found in newborns, indicating its
absorption.
189,195
In an animal model of intrauterine
growth restriction, animals fed a high-AGE formula
during suckling had CML accumulation in renal tubu-
lar cells that was associated with increased protein oxi-
dation and expression of pro-inflammatory and
apoptotic factors.
36
Similarly, intrauterine growth re-
stricted piglets fed a high-AGE formula during suckling
have increased liver oxidative stress at adulthood, due
to impaired antioxidant activity.
196
Some authors sug-
gest high consumption of glycation compounds through
infant formulas during early life may predispose to the
development of oxidative stress and diseases later in
life, such as diabetes.
35,197
It was observed that increased
maternal AGE levels were correlated with the infant
AGE levels, which may precondition the young to high
oxidative stress, inflammation, and insulin resistance.
35
A more recent investigation observed decreased insulin
sensitivity in infants fed AGE-rich formula compared
with those fed only breast milk, although the specific
AGE contribution to decreased insulin sensitivity was
not clear, because no differences were observed in
infants fed a low-AGE formula.
198
In this context, it was shown that glycation of
dairy protein by MG or glyoxal may decrease the pro-
tein digestibility by proteases, mainly due to cross-
linked AGEs.
199
On the other hand, noncross-linked
AGEs,suchasCML,(carboxyethyl)lysine,andMG-H1
are more prone to be absorbed by intestinal epithelial
cells.
200
High-molecular-weight AGEs are harder to di-
gest and absorb, so they are more able to advance in
the intestinal tract and interact with the colonic micro-
biota.
200,201
In fact, dietary AGEs may influence the
microbiota composition. In rats, dietary AGEs reduced
the diversity of microbiota, decreasing short-chain
fatty acid–producing bacteria and damaging the co-
lonic epithelial barrier.
202
Human studies also report
the interaction between dietary AGEs and changes in
gut microbiota composition, highlighting the impor-
tance of this interaction to human health.
203,204
However, little is known about the mechanisms of
AGE absorption in the neonatal gut. The newborn gut
is not totally mature, and the epithelial gut barrier of
newborns is still permeable to the passage of macro-
molecules, such as hormones, carbohydrates, and pep-
tides.
175,205
Thus, the newborn gut may be more
complacent to the passage of glycotoxins, making the
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rat pup more susceptible to the absorption and accu-
mulation of AGEs and their precursors. Newborn rats
are more susceptible to the toxic effects of orally deliv-
ered MG, because the lethal dose is almost 4 times
lower than that for an adult male rat (531 mg/kg vs
1990 mg/kg).
206
In short, exposure to increased AGE
levels by infant formulas or via breast milk are detri-
mental to health and proper development of the infant.
In general, the mechanisms of AGE absorption, diges-
tion, and interaction with the microbiota are not well
understood, and less is known about these mecha-
nisms in infancy; thus, more studies are necessary to
clarify them.
EFFECTS OF PERINATAL AGE EXPOSURE ON
PROGRAMMING OF METABOLIC SYNDROME,
CARDIOVASCULAR DISEASES AND EARLY AGING
Although several studies have reported high perinatal
exposure to AGEs during embryonic development and
lactation, little is known about their effects in metabolic
programming and in increasing the risk of development
of noncommunicable diseases in adulthood. Moreover,
the consumption of AGEs through milk or infant for-
mulas disturbs metabolic homeostasis in newborns and
is associated with pancreatic dysfunction and cardiovas-
cular and central nervous system diseases. Exposure of
lactating rats to high dietary levels of sucrose or high-
fructose corn syrup was observed to lead to increased
free fatty acid levels, adiposity, and liver fat in the off-
spring at weaning.
207
Accordingly, Csongov
aetal
208
have shown increased predisposition for weight gain
and insulin resistance in the progeny of females fed an
AGE-rich diet during pregnancy, and Francisco et al
180
have shown a similar impact of increased maternal ex-
posure to MG during lactation leading to an impaired
lipid profile and adiposity in the offspring. The authors
also reported decreased b-cell function in the off-
spring.
180
Accordingly, using type 1 diabetic NOD
mice, 2 different studies have shown the impact of peri-
natal AGE exposure on b-cell function. Peppa et al
38
have shown that low-glycotoxin fetal and neonatal envi-
ronments, through maternal AGE dietary restriction,
decreased T-cell inflammatory activity in the pancreas,
resulting in lower glycemia and increased survival.
Accordingly, Borg et al
209
have shown deteriorated b-
cell function in the progeny of NOD females exposed to
increased dietary AGE levels during pregnancy and
lactation.
The impact of perinatal AGEs exposure to other
pathologies is less studied, although a few studies have
implicated perinatal AGEing in the development of car-
diovascular diseases and central nervous system
disorders. Vascular diseases in adult life are associated
with increased glycoxidative stress, and increased pre-
natal AGE exposure also resulted in early cardiac
changes. Embryos of diabetic female rats accumulated
higher levels of CML, which was associated with lower
vascular endothelial growth factor levels.
210
As well,
AGE levels were increased in the heart of newborns of
streptozotocin-induced diabetic dams and were associ-
ated with increased oxidative stress and inflammatory
markers.
168
Recent reports have suggested impairment of the
AGE-RAGE axis in preterm birth. Chiavaroli et al
211
have shown decreased levels of soluble RAGE and en-
dogenous secretory RAGE in overweight prepubertal
children who were LGA or SGA, and these were corre-
lated with insulin resistance. In the central nervous sys-
tem, increased hippocampal RAGE expression was
observed in the offspring of streptozotocin-induced dia-
betic female rats, which was associated with increased
excitability and behavioral changes.
212
Increased glyca-
tion during gestational diabetes has been implicated in
impaired neural development, namely, in the decrease
of cortical neural precursor cells.
213
Authors have
shown that glyoxalase pathway disruption during em-
bryonic development leads to premature neurogenesis,
depletion of cortical neural precursor cells, and behav-
ioral changes, which were found in the offspring of dia-
betic murine mothers.
213
Thus, high AGE levels in mothers can predispose
their progeny to impaired metabolic homeostasis, and
recent data suggest defining cutoff values for maternal
glycated albumin levels during pregnancy to prevent
neonatal complications.
214,215
INTERVENTIONS TO PREVENT PERINATAL AGE
EXPOSURE AND METABOLIC PROGRAMMING
As previously described, exposure to glycotoxins during
perinatal life may occur in utero, because AGEs can
cross the placental barrier and impair fetal develop-
ment, activating the RAGE axis and increasing oxida-
tive stress, which may underlie the embryopathy related
to GDM. Furthermore, the exposure during lactation
may occur via breast milk, because maternal circulating
AGE levels may influence AGE concentration in the
milk. It is well established that uncontrolled glycemia in
GDM increases MG and AGE circulating levels, to
which the embryo is exposed. Thus, the first approach
to prevent MG and AGE exposure should be a proper
glycemic control. Metformin was suggested as an effi-
cient and safe drug for GDM treatment.
216
Besides im-
proving insulin sensitivity and decreasing hepatic
gluconeogenesis, metformin may directly react with
and scavenge MG, preventing the formation of MG-
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derived AGEs such as MG-H1.
217,218
During lactation,
the same interventions may be administered to treat
maternal diabetes, thus preventing the transmission of
glycotoxins from mother to the infant through breast
milk.
As previously described, the diet is one of the main
sources of external glycotoxins. Because maternal AGEs
may be transmitted to the infant via placenta or breast
milk, the consumption of ultraprocessed or high-
temperature cooked food should be discouraged or con-
trolled, because they present high levels of AGEs. The
intake of fresh foods should be encouraged, such as in
natura vegetables and fruits as part of balanced diet.
Attention should be taken in the cooking process,
avoiding high temperature methods such as frying and
grilling, opting for low-temperature methods such as
boiling.
AGEs are largely found in infant formulas, contrib-
uting to increase the pool of AGEs in the infant. As rec-
ommended by the World Health Organization,
breastfeeding must be exclusive during the first
6 months of life.
172
In this sense, infant formula must be
implemented only when breast milk was not available,
thus avoiding unnecessary use. As mentioned, the in-
dustrial process to obtain whey protein leads to a higher
degree of AGE formation; therefore, the addition of
whey protein should be avoided. The use of milk from
different animals, such as goat, should be encouraged,
because their amino acidic profile is more similar to the
human milk, making the addition of whey protein un-
necessary, thus reducing the amount of AGEs in the fi-
nal product.
194
Thus, some interventions may be taken to prevent
AGE exposure during perinatal life, including proper
glycemic control in mothers with diabetes and the
adoption of a balanced diet low in ultraprocessed food.
Quitting smoking may also be an important interven-
tion, because smoking during lactation may increase
AGE levels in breast milk.
37
Infant formulas should be
prescribed with caution, and industry should be en-
couraged to develop infant formulas with low AGE
levels.
CONCLUSION
More studies are needed to understand the mechanisms
underlying the effects of perinatal, neonatal, and in-
fancy exposure to glycotoxins to prevent the metabolic
programming of diseases due to the embryo and infant
exposure to AGEs. In clinical practice, the advice to
Figure 1 Main sources and potential mechanisms by which exposure to glycotoxins during perinatal life (eg, gestation, lactation)
may potentially program cardiometabolic disease development during adult life. Abbreviations: AGE, advanced glycation end product;
MG, methylglyoxal.
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pregnant and lactating women about the importance of
the diet and glycemic control is essential. To study the
long-term effects of intrauterine and postnatal exposure
to glycotoxins in humans, a long follow-up of the off-
spring and mother is required, given that studies about
this issue are currently scarce.
Acknowledgments
Author contributions. F.A.F., P.M., and R.M.G. outlined
and drafted the manuscript. All the authors contributed
to the writing of the manuscript. P.M., P.C.F.M., and
R.M.G. supervised the work. All the authors revised and
approved the manuscript for publication.
Funding. Financial support was received from the fol-
lowing Brazilian funding agencies: Conselho Nacional
de Desenvolvimento Cient
ıfico e Tecnol
ogico and
Coordenac¸~
ao de Aperfeic¸oamento Pessoal de N
ıvel
Superior. None of the funding agencies were involved
with the conception, design, performance, or approval
of this study.
Declaration of interest. None.
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