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Файл:Age endocrinology. Study aid for students of medical universities
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Postmenopause is characterized by a predominant accumulation of adipose
tissue in the abdomen with an increase in the ratio of visceral and subcutaneous fat.
In fact, estrogen is able to regulate regional lipid accumulation mainly through
interaction with the estrogen receptor α (ERα), which is found in subcutaneous rather
than visceral adipocytes to a greater extent. ERα play a crucial role in the activity of
adipocytes, as well as in the sexual dimorphism of the distribution of adipose tissue.
The interaction of E2 with ERα appears to promote a gynoid (gluteofemoral)
distribution thought to be associated with a healthy metabolic profile. In contrast, the
accumulation of visceral fat associated with menopause leads to chronic
inflammation, which in turn contributes to the development of metabolic diseases
such as T2DM and cardiovascular disease.
During inflammation, there is an increase in the production of ROS, which
further aggravates the inflammation process. Inflammatory cytokines such as IL-6
stimulate the generation of reactive phagocytic cell species (macrophages and
neutrophils). In turn, OxS enhances the release of pro-inflammatory mediators from
immunocompetent cells, thereby causing a toxic vicious cycle and leading to agerelated diseases.
9.3. STUDIES SHOWING THE ROLE OF OXIDATIVE STRESS
IN THE PATHOGENESIS OF POSTMENOPAUSAL OSTEOPOROSIS
In vitro and animal studies
Animal studies support the detrimental effects of OxS on bone tissue. It has
been shown that the growth of intracellular ROS is the result of oophorectomy in
animals. In addition, an increase in ROS in bone tissue leads to stimulation of
osteoclastogenesis in two ways: firstly, by increasing the sensitivity of osteoclast
precursors to RANKL, and secondly, by inducing additional osteoclastogenic
cytokines (IL-1, IL-6 and IL-7). Moreover, induction of superoxide production
increases both in vivo and in vitro the number and activity of osteoclasts.
Accumulating evidence suggests that OxS can also influence the osteoblast cell
cycle. Studies have shown that ROS reduces the lifespan of these cells in OvX and
aged mice. Overall, endogenous and dietary antioxidants appear to slow bone loss in
a number of animal studies. Accordingly, transgenic mice lacking cytoplasmic SOD
were found to have low bone mass. A number of studies have shown that various
forms of vitamin E prevented the decline in trabecular index and bone volume in
OvX rats. Deng L. et al. (2014) found that in the group of mice supplemented with
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gamma-trienol, there was no decrease in bone mass caused by oophorectomy. Other
preclinical studies also show that commonly consumed fruits, rich in antioxidants,
have a pronounced effect on bone tissue, stimulating bone formation and preventing
resorption.
Clinical researches
A negative and positive relationship was found between peripheral markers of
oxidative damage and antioxidant status, respectively, and bone mineral density
(BMD) in the femoral neck, entire thigh, or lumbar spine. So, a number of authors
have found that higher serum concentrations of OxS markers correlated with an
increased rate of bone resorption, OxS markers correlated with the RANKL/OPG
ratio in postmenopausal women with osteopenia. In addition, OxS scores are
predictors of femoral fracture.
Among the antioxidants thought to be associated with osteoporosis, UA
showed the most compelling results. A retrospective study including 615 Japanese
women found a positive correlation between UA and BMD levels in the lumbar
spine. An Australian study of 356 peri- and postmenopausal women confirmed the
protective role of UA in bone metabolism and its association with BMD. It is known
that higher serum UA levels have been associated with higher bone mass, lower bone
turnover, and a lower incidence of vertebral body fractures. In vitro experiments have
shown that UA inhibits osteoclastogenesis and reduces the production of ROS.
However, numerous studies have failed to find a significant increase in OxS in
osteoporotic women compared to healthy postmenopausal women. In our opinion,
negative results do not exclude the role of OxS in the development of
postmenopausal osteoporosis due to the fact that:
• Since postmenopausal osteoporosis is multifactorial, ROS can reasonably be
considered only one of many components of its complex and multifaceted
pathogenesis.
• Currently, there is no “gold standard” for quantifying redox imbalance, and
the sensitivity and specificity of the studied OxS markers remains unknown.
• Most of the studies have a similar design, and, therefore, they take a “static”
snapshot of the analyzed group at a certain point in time, which does not allow
studying the dynamics of processes.
Thus, further research into the relationship between OxS and postmenopausal
osteoporosis is needed.
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9.4. ANTI-OSTEOPOROTIC THERAPY AIMED AT OXIDATIVE STRESS
The question arises: could OxS-targeted therapy have an impact on the
prevention and treatment of postmenopausal osteoporosis?
Currently, there are various effective drugs for the treatment of
postmenopausal osteoporosis and the prevention of its complications.
Menopausal hormone therapy (MHT) is known to normalize bone metabolism and
preserve BMD, thereby significantly reducing the likelihood of fractures. Despite
initial concerns about the safety of such therapy, a 10-year randomized trial
completed in 2008 found significantly lower rates of mortality, heart failure, and
myocardial infarction without any apparent increase in cancer risk in women younger
than 60 years of age receiving MHT in early postmenopause. These data are
consistent with the results of studies in OvX rats treated with estrogen replacement
therapy (ERT). Lopez- Grueso R. et al. (2014) showed that ERT can prevent redox
imbalance and counteract typical post-surgical dysmetabolic disorders only if therapy
is started early after oophorectomy. Based on these results, the authors argue that
ERT can activate antioxidant enzymes and therefore promote longevity.
Unfortunately, to our knowledge, there are no clinical studies to support this
hypothesis in humans.
Along with pharmacological interventions, reducing the risk of osteoporosis
can be achieved through lifestyle changes, including exercise, adequate calcium and
protein intake, and elimination of risk factors such as physical inactivity, smoking,
and alcohol abuse. According to generally accepted recommendations, sufficient
intake of calcium and vitamin D is mandatory to achieve maximum bone mass and
prevent further bone loss in postmenopausal women. Diet can also be a source of
some antioxidants, which can have a positive effect on bone metabolism, bone mass,
and reduce the risk of fractures.
The antiresorptive effect of vitamin E found in animal studies has prompted a
number of scientists to conduct major clinical trials. In a study of
951 postmenopausal women who smoked, high vitamin E intake was associated with
a significantly lower risk of hip fracture. Accordingly, in a large epidemiological
study (n = 61,433 perimenopausal women), vitamin E supplementation resulted in a
reduction in the incidence of fractures of any location. In contrast, in contrast to the
above results, a longitudinal study by MacDonald H.M. et al. (2004) noted a direct
relationship between increased vitamin E intake and greater loss of BMD at the
femoral neck. Finally Wolf R.L. et al. (2004) failed to show any significant
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association between daily vitamin E intake (and serum levels) and femoral and
vertebral BMD in 11,068 elderly women.
In addition to vitamin E, many scientists have evaluated the effect of other
antioxidants on bone tissue. A large population-based case-control study showed that
intake of β-carotene and selenium, but not vitamin C, was associated with a reduction
in the incidence of hip fractures. Daily intake of lycopene, one of the isomers of β-
carotene that is abundant in tomato fruits, may suppress bone resorption, as
evidenced by an inverse relationship between lycopene intake and serum levels of
resorption markers. Unfortunately, the encouraging preclinical results obtained with
flavonoids, resveratrol and pectin have not been replicated in humans. On the
contrary, clinical studies of the last two decades have shown a positive effect of
vegetable and fruit consumption on bone tissue.
It is now generally accepted that no antioxidant alone is able to resist OxS only
in combination with other antioxidants. A typical example in this area is αtocopherol. After reacting with ROS, it itself becomes a free radical that can be
neutralized by a finely orchestrated synergistic action of a network of endogenous
antioxidants, including glutathione, reduced glutathione, and vitamin C. Thus, further
clinical studies are needed to develop combinations of antioxidants and their
regimens for OxS therapy research.
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10. CARBOHYDRATE METABOLISM: CHANGE WITH AGE
Carbohydrate metabolism is maintained by a balance between the intake, use
and production of glucose and is under the strict hormonal control of insulin and
contrainsular hormones and changes with increasing chronological age. Fasting
plasma glucose levels rise by about 0.055 mmol/L every decade from the fourth
decade onwards, and glucose levels gradually increase 2 hours after an oral glucose
tolerance test. However, there is no data to support changes in the amount of glucose
consumed with age.
Insulin is secreted in a pulsatile pattern consisting of two stereotypical pulses:
high-frequency pulses with a pulse interval of about 6 minutes and ultradian pulses
with a pulse interval of about 90 minutes. Pulsatile secretion accounts for at least
70 % of secreted insulin. Total and pulsatile insulin secretion is altered in T2DM.
However, even in healthy elderly people, dysfunction and deficiency of β-cells,
impaired insulin secretion were found with a characteristic decrease in both the
amplitude and the number of high-frequency impulses, as well as the frequency of
ultradian impulses, both during basal and stimulated secretion. It has been proven that
in the elderly, insulin clearance in the liver increases. In addition, insulin resistance
increases with age. This may be due to a change in body composition (increase in fat
mass, especially visceral mass and decrease in muscle mass), which, in turn, depends
on calorie intake, reduced physical activity, medication and polymorbidity. However,
although exercise improves insulin action and slows the development of diabetes,
there is no evidence that exercise reverses age-related changes in β-cells. With
increasing age, taking into account genetic, environmental factors, the risk of
developing T2DM INCREASES, reaching a plateau or even decreasing after 85
years. Timely diagnosis of carbohydrate metabolism disorders is necessary, followed
by the formation of a plan for diagnostic and treatment measures, which will reduce
the percentage of complications and improve the quality of life.
10.1. INSULIN AND GLUCAGON-LIKE PEPTIDE-1:
AGE-RELATED CHANGES, ROLE IN THE DEVELOPMENT
OF NEURODEGENERATIVE DISEASES
The relevance of neurodegenerative diseases throughout the world stimulates
research into the etiology and pathogenesis of these nosologies. Currently, a number
of researchers have reported on the relationship between metabolic disorders and
degenerative changes in the brain. From this perspective, the gut/brain axis and
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impaired insulin secretion appear to be the main actors in the development of
neurodegenerative diseases. Indeed, insulin acts as a neurotrophic factor, and its
receptor is widely distributed in cognitively significant areas of the brain, such as the
hippocampus and the dopaminergic system.
Previously it was believed that the brain is insensitive to insulin and unaffected
by its influence organ, because. the hormone cannot pass through the blood-brain
barrier. The possibility of local insulin synthesis in any part of the brain was also
denied. However, in 1967, R. Margolis and N. Altshuler proved that the level of
insulin rises in the cerebrospinal fluid of dogs when it is administered intravenously.
In this connection, a version appeared that the hormone can still cross the blood-brain
barrier through a highly specialized transport system.
Ten years later, Ya. Khavrankova and colleagues discovered insulin itself and
its receptors in different parts of the rat brain.
It is now known that the insulin transport system in different areas of the brain
varies significantly, which leads to differentiation of insulin permeability for different
populations of neurons, as a result of which the hypothalamus, medulla oblongata,
and pons have a higher concentration of insulin, while the occipital lobe and thalamus
have a relatively low one. The insulin transport system changes significantly in
conditions of starvation, overeating, obesity and aging, in patients with T2DM and
AD. In addition, there is a second version of the appearance of insulin in the brain —
the synthesis of the hormone directly in the brain. These representations are based on
the detection of mRNA for insulin in the hypothalamus, hippocampus and neuron
cultures.
However, it is now widely accepted that insulin plays an important role in
neuronal viability and brain function. In fact, insulin action is necessary for neuronal
synaptic plasticity and promotes learning and memory. It has also been shown that
insulin promotes the formation of a neural network, the activation of neuronal stem
cells, the growth, repair and neuroprotection of neurons, the regulation of energy
metabolism, and the protection of cells from oxidative stress. Therefore, changes in
insulin metabolism and signaling in the central nervous system may contribute to the
development of a number of brain diseases.
Over the past 20 years, many studies have shown an association between
neurodegenerative disorders such as AD and impaired insulin signaling in the central
nervous system, suggesting that reduced insulin action and insulin resistance may
play an important role in the pathogenesis of these diseases.
In recent years, special attention has been paid to studying the role of
glucagon-like peptide-1 (GLP-1), a hormone synthesized in the intestine, which is
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one of the main components of the gut / brain axis, and at the same time protects
pancreatic beta cells from apoptosis and stimulates secretion. insulin.
Glucagon-like peptide-1 is an endogenous peptide hormone produced by
intestinal L-cells in response to food intake. First, the peptide precursor of GLP-1 is
formed (1–37). The GLP-1 precursor protein (1–37) is then converted by proteolytic
cleavage and amidation into two active forms of GLP-1 with the same biological
activity, namely GLP-1 (7–37) and amidated GLP-1 (7–36). GLP-1 is degraded by
dipeptidyl peptidase IV (DPP IV), a serine aminopeptidase expressed in various
organs such as the liver, pancreas, intestine, and brain. GLP-1 stimulates insulin
secretion from pancreatic beta cells under conditions of hyperglycemia and reduces
glucagon secretion from alpha cells, restoring insulin sensitivity, leading to
normoglycemia.
Signal transduction of glucagon-like peptide-1 is mediated by the GLP-1
receptor (GLP-1R), a G protein-coupled receptor leading to cyclic adenosine
monophosphate (cAMP)-DEPENDENT protein kinase A (PKA) activation and
cAMP-regulated guanine nucleotide exchange factor (Epac). Activation of Epac and
PKA synergistically enhances insulin release from beta-pancreatic cells through
phosphorylation of the SNARE-associated Snapin protein and activation of voltagegated L-type calcium channels.
Of note, GPL-1R can drive signal transduction even by activating the
PI3K/AKT axis, as seen in the apoptosis-protective action of GLP-1 via regulation of
CREB and protein survival factors such as Bcl-2 and Bcl-XL via actions of βarrestin-1 and phosphorylation of ERK1/2. In addition, activation of the PI3K/AKT
axis can induce the inhibition of specific caspases and NF-κB, resulting in inhibition
of the release of pro-inflammatory cytokines.
GLP-1 exerts its influence on various organs and tissues, such as the
cardiovascular and central nervous systems, lungs, kidneys, etc. The key role of
GLP-1 in the prevention of cardiovascular disorders has been proven, which makes
GLP-1 and its analogues huge resource in the treatment of these diseases. GLP-1 is
also involved in the reduction of oxidative stress, in the regulation of autophagy, and
in the anti-inflammatory protection of the central nervous system.
10.2. INSULIN AND THE INSULIN SIGNALING SYSTEM IN THE BRAIN
Insulin and IGF-1 regulate a number of biological processes through the
binding and activation of two closely related tyrosine kinase receptors, the insulin
receptor (IR) and the IGF-1 receptor (IGF-1R). Several studies have shown that IR
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and IGF-1R, as well as their common downstream pathways, are abundant in the
brain, and more importantly, these pathways function as regulators of neurogenesis,
brain function and energy balance, and systemic homeostasis. The highest
concentration of IR is found in the hypothalamus, hippocampus, olfactory bulb,
cerebellum, amygdala, and cerebral cortex, which indicates the multifunctionality of
insulin.
Insulin is a peptide hormone consisting of two chains and 51 amino acid
residues that cannot pass passively through the blood-brain barrier, but is
nevertheless found in the cerebrospinal fluid. The origin of “brain” insulin is
controversial. One hypothesis is that plasma insulin is able to cross the blood-brain
barrier via a saturable transport process, possibly via the 1R-vascular endothelium.
Supporting this hypothesis is the evidence that cerebrospinal fluid insulin levels are
lower (about 25 %) than those circulating in the blood, and its concentrations increase
after meals or with peripheral insulin infusion. Another possibility is evidence that
there are areas of the brain, such as the hypothalamus, that lack an effective barrier to
access insulin to the central nervous system. The third hypothesis suggests that
insulin is synthesized in areas of the brain, but this assumption requires further
research.
After reaching the central nervous system, insulin binds to IR, which belongs
to the tyrosine kinase receptor family. Interestingly, the IR subunits found in the brain
have a different structure from the peripheral ones, and the main difference is the
lower molecular weight of the brain IR subunits, probably due to different
glycosylation. Moreover, the brain preferentially expresses the A (–exon 11) IR
isoform, which has a higher affinity for IGF-2, in contrast to peripheral tissues, which
preferentially express the B (+exon 11) isoform.
It is assumed that insulin has neuroprotective properties and has a neurotrophic
effect on the neurons of the central nervous system. Moreover, it may positively
influence cognitive functions including emotions, attention, executive functioning,
learning and memory.
After insulin binds to IR, receptor autophosphorylation occurs and activated IR
phosphorylates the IR substrate protein cascade (Pic. 5). Among IR substrates (IRS)
mRNA IRS-2 in the brain is the most abundant compared to IRS-1; IRS-4, which are
mainly expressed in embryonic development, are also found in the adult mouse brain,
especially in the hypothalamus. At the whole body level, IRS-1 appears to be critical
for growth, and IRS-1-null mice result in increased brain-body ratios. On the other
hand, disruption of the IRS-2 gene reduces neuronal proliferation during development
by 50 %, and as a consequence, IRS-2 null mice exhibit a reduced brain surface to
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body surface ratio. Furthermore, during aging, neurofibrillary tangles containing
phosphorylated tau accumulated in the hippocampus of IRS-2 knockout mice,
suggesting that IRS-2 signaling is neuroprotective. Despite this, IRS-2-null mice are
long-lived, consistent with the role of central insulin/IGF signaling in the control of
mammalian lifespan. IRS-4 may synergistically interact with IRS-2 in the
hypothalamus to control food intake, energy expenditure, and glucose metabolism.
Pic. 5. Insulin signaling pathway5
After binding of insulin to the insulin receptor (IR), autophosphorylation
occurs, which is necessary for its activation. The activated insulin receptor then
phosphorylates the IRS proteins. IRSs activate PI3K, which catalyzes the addition of
a phosphate group to the membrane lipid PIP2, thereby converting it to PIP3. PTEN
can convert PIP3 back to PIP2. Membrane-bound PIP3 recruits and activates PDK-1,
which phosphorylates and activates Akt and atypical PKCs. Akt mediates most of the
metabolic effects of insulin and brain synaptic plasticity, neuronal homeostasis, and
memory.
5
https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click
%20on%20image%20to%20zoom&p=PMC3&id=6275025_ijms-19-03306-g001.jpg
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Abbreviations: IRS (Insulin Receptor Substrate), PI3K (phosphatidylinositol-3kinase), PIP2 (phosphatidylinositol-4,5-bisphosphate), PIP3 (phosphatidylinositol3,4,5-triphosphate), PTEN (phosphatase and tensin homologue),
Specific inactivation of IR in the brain (i.e., neuron-specific IR knockouts —
NIRKO mice) has shown that the lack of IR in the brain determines altered metabolic
phenotypes, including obesity, insulin resistance, plays an important role in the
regulation of energy metabolism. Moreover, insulin resistance in the brain exists as a
phenomenon independent of peripheral insulin resistance and carbohydrate
metabolism. This means that reduced insulin sensitivity in the brain has different
consequences than in peripheral tissues. Recently published data showed that
peripheral insulin and glucose tolerance was comparable in aged wild-type and
APP/PS1 (model AD) mice, while levels of serine phosphorylated IRS-1 were
elevated in the brains of APP/PS1 mice. This provides some support for the
suggestion that central insulin resistance may exist independently from peripheral
insulin resistance and is associated with degenerative processes in AD.
One of the major downstream pathways of IRS proteins is the PI3K/Akt
cascade. This in turn targets multiple downstream pathways including mTORC1,
glycogen synthase kinase 3β (GSK-3β), and the FoxO family of transcription factors
(Figure 5). Many of these pathways have been shown to play a key role in the normal
functioning of the brain.
10.3. T2DM AND NEURODEGENERATIVE PROCESSES:
THE ROLE OF DISORDERS IN THE INSULIN SIGNALING SYSTEM
OF THE BRAIN, INSULIN RESISTANCE AND HYPERINSULINEMIA
T2DM is an age-related chronic disease with an increasing prevalence. There
are currently more than four hundred million people worldwide with diabetes, and
this number is expected to increase dramatically over the next thirty years. T2DM,
characterized by insulin resistance and chronic inflammation, causes accelerated
aging and leads to premature morbidity and mortality. The effect OF T2DM on the
brain is now well known: the disease is a major risk factor for cognitive decline and
dementia. In fact, T2DM increases the long-term risk of developing dementia by
almost 2-fold, and one in ten cases of dementia in the world's population may be
associated with the consequences of T2DM. The relationship in the prevalence of
these chronic diseases is due to the fact that diabetes and dementia share several
features that lead to brain damage, the most important of which are impaired insulin
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