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Файл:Age endocrinology. Study aid for students of medical universities
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In the past few years, even dual and triple receptor agonists have been
developed, with remarkable results in animal models. Indeed, the dual GLP-1
agonist/glucose-dependent insulinotropic peptide (GIP) DA5-CH increased working
memory and pre-LH-term spatial memory in an AD APP/PS1 transgenic mouse
model (9 months of age). It also resulted in a decrease in amyloid plaques in the
hippocampus and phosphorylated tau. The deficiency of pre-LH-term potentiation of
the late phase of the hippocampus was reversed, and growth factor kinases p-PI3K
and p-AKT were elevated. Excessive p-GSKβ activation in the hippocampus was
reduced. Encouraging results were also observed with the dual GLP-1/GIP receptor
agonist DA-JC4, which reduced levels of phosphorylated tau in the rat cerebral cortex
and hippocampus, prevented spatial learning dysfunction, reduced the chronic
inflammation response in the brain, reduced apoptosis, and reactivated transmission
pathways. insulin signals in an STZ-induced rat model of AD. Recently, a triple
receptor agonist activating GLP-1, GIP, and glucagon receptors that improved
memory showed an anti-apoptotic effect, protection against synaptic loss, reduced
total Aβ, neuroinflammation, and oxidative stress in the cerebral cortex and
hippocampus.
Despite a large body of data on the neuroprotective effects of GLP-1RA in
animal models of AD, human studies are still scarce. In a randomized, double-blind,
placebo-controlled study in patients with AD who received liraglutide for 6 months,
compared with placebo, no effect on Aβ deposition was observed. In a later 26-week,
randomized, double-blind, placebo-controlled study, statistical power was insufficient
to conclude on Aβ accumulation and cognitive function scores in AD patients treated
with liraglutide compared with placebo.
10.9. DRUG CORRECTION OF NEURODEGENERATIVE CHANGES
IN THE BRAIN, TAKING INTO ACCOUNT PATHOGENESIS
Because T2DM shares several pathogenic characteristics with
neurodegenerative disorders, as discussed previously, it has been suggested that some
of the drugs used in T2DM therapy may have potential benefit in the treatment of
AD: a brief characterization of the drugs is provided below:
1. Metformin
✓ Repairs mitochondria, attenuates the effects of AGE by activating AMPK in
neurons
✓ Activates insulin signaling and reduces tau phosphorylation in neuronal cell
lines
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✓ Induces protein phosphatase 2A and reduces tau phosphorylation in Tau
transgenic mouse neurons
✓ Attenuates Cognitive Impairment in Leptin-Resistant Obese Mice
✓ Increases production of amyloid beta protein in human cell models (negative
effect)
✓ Reduces the risk of cognitive decline in diabetic patients
✓ Improves Cognitive Function in Depressed Patients
✓ Increases the risk of cognitive impairment in studies done on patients with
AD (negative effect)
2. Sulfonylureas
✓ Glimepiride protects neurons from beta-amyloid-induced synaptic
degeneration in vitro
✓ Gliclazide has an antioxidant effect on the brain in diabetic rats
✓ Glibenclamide reduces depression and anxiety in AD rats
✓ In combination with metformin, reduce the risk of dementia in patients with
diabetes
3. Glitazones
✓ Neuroprotective effects in AD associated with inhibition of inflammation
and Aβ deposition
✓ Pioglitazone Interferes with Decreased Glial Activation in AD Mice
✓ Pioglitazone Enhances Akt Signaling and Tau Hyperphosphorylation in AD
Mice
✓ Combined with leptin, pioglitazone reduces brain amyloid levels in mice
with AD
✓ Pioglitazone improves cognition and regional cerebral blood flow in patients
with T2DM
✓ Pioglitazone may provide cognitive improvement in early and mild-to-
moderate AD in humans
4. Glucagon-like peptide 1 agonists
✓ Reduce oxidative stress and apoptosis of brain cells; improves synaptic
plasticity in AD mice
✓ Influence cellular mechanisms of neuronal defense and mitochondrial
function
✓ AD mice
✓ Prevent the decline in brain glucose metabolism in patients with AD
5. DPP 4 inhibitors
✓ Decreased tau phosphorylation, amyloid load, and cognitive impairment
with improved memory
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✓ Improved incretin levels, reduced Aβ deposition, tau phosphorylation, GSK-
3β and ROS activation
✓ Improving Glucose Control and Preventing Cognitive Decline in Elderly
T2DM Patients
6. Insulin
✓ Attenuates cognitive impairment and improves memory in adults with AD
✓ In vitro inhibits apoptosis; in vivo regulates tau phosphorylation, Aβ
metabolism and clearance
✓ Improves memory, mood, cerebral glucose metabolism; preserves brain
volume in AD patients
Metformin
Metformin is a biguanide that reduces insulin-mediated hepatic glucose
production, improves insulin sensitivity, and is a first-line therapy for T2DM. It
rapidly crosses the blood-brain barrier, distributes to brain regions, and, through
activation of the AMPK pathway, appears to have a neuroprotective effect on human
neural stem cells by restoring mitochondrial function and attenuating the effects of
advanced glycation end products.
Data on the effect of metformin on neurodegenerative disorders are
contradictory. In vitro studies have reported the ability of metformin to reduce tau
phosphorylation in neuronal cell lines. In vivo studies have shown that in leptinresistant obese mice, metformin attenuated cognitive impairment and AD -like
pathology. In contrast, a cell culture study showed that metformin increased Aβ
production.
Observational studies in individuals with T2DM taking metformin show a
reduction in the manifestations of mild cognitive impairment (MCI) and dementia
compared with placebo. Long-term treatment with metformin appears to reduce the
risk of cognitive decline in diabetic patients and to reduce depression and improve
cognitive function by altering glucose metabolism in depressed patients. A pilot
clinical study in patients with MCI over 12 months showed that metformin improved
cognitive function in people without diabetes compared to placebo.
A clinical study examining the effects of various T2DM treatments on
cognition found that diabetic patients who used metformin alone had better cognition
in verbal learning, working memory, and executive function compared to participants
in other forms of diabetes care.
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On the other hand, an increased risk of cognitive impairment and the
development of AD has been demonstrated with the use of metformin in a study
conducted on patients with AD. This phenomenon was partly due to metformininduced vitamin B 12 deficiency. However, a cognitive function analysis performed
8–10 years after metformin therapy in the Diabetes Prevention Program Outcomes
Study (DPPOS) did not show any adverse effects from long-term use of metformin.
Randomized clinical trials currently planned will evaluate whether metformin
can prevent cognitive decline or improve cognitive function in humans.
Sulfonylureas
Sulfonylureas are hypoglycemic drugs that stimulate the release of insulin by
blocking ATP -RESPONSIVE potassium channels in pancreatic beta cells. In vitro,
glimepiride protects neurons from amyloid-beta-induced synaptic degeneration. In
rats with streptozotocin-induced diabetes, gliclazide had an antioxidant effect on the
brain. In addition, glibenclamide reduces depression and anxiety in AD rats.
An 8-year clinical prospective study in patients with T2DM showed that the
combination of sulfonylurea and metformin reduced the risk of developing dementia,
however, another case-control study showed that long-term use of sulfonylurea drugs
did not affect the risk of developing dementia.
Further research is needed to confirm a potential therapeutic role for this class
of drugs.
Thiazolidinediones (glitazones)
The thiazolidinediones (TZDs) (pioglitazone and rosiglitazone) are potent and
selective stimulants of peroxisome proliferator-activated nuclear gamma receptors
(PPAR gamma), which improve insulin sensitivity in muscle, adipose, and liver
tissues; reduce systemic insulin resistance. TZDs may play a role in improving
neuronal function and memory formation. These drugs have shown neuroprotective
effects in AD by inhibiting inflammatory gene expression and altering Aβ formation
and deposition.
Pioglitazone is able to penetrate into the brain, inhibits glial activation and
reduces the clinical manifestations of AD.
AD mice, pioglitazone administered for 4 months enhances Akt signaling,
improves spatial learning, and reduces tau hyperphosphorylation. In addition, the use
in combination with leptin reduces memory deficits and amyloid levels in the brain.
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A pilot study of patients with T2DM who received pioglitazone for 6 months
showed an improvement in cognitive function and regional cerebral blood flow in the
parietal lobe. However, an 18-month study in non-diabetic AD patients evaluating the
safety of pioglitazone showed no effect on cognition.
A meta-analysis of the effect of PPAR-gamma agonists in patients with AD has
shown that pioglitazone alone can provide clinical improvement in the early stages of
mild to moderate AD.
A phase 3 clinical trial of the efficacy of pioglitazone in patients with mild
cognitive impairment using an algorithm to evaluate genetic biomarkers for
preclinical diagnosis such as APOE status and genotypes is ongoing. (Clinical trial
ID: NCT01931566). The data will be available in 2021.
Glucagon-like peptide-1 (GLP-1) receptor agonists
Another class of hypoglycemic drugs are GLP-1 receptor agonists. GLP-1 is an
incretin peptide secreted by the intestine that enhances glucose-dependent insulin
secretion and inhibits glucagon secretion. GLP-1 also has trophic properties such as
stimulating β-cell neogenesis, growth and differentiation, inhibiting β-cell apoptosis,
and increasing cell survival.
GLP-1 and most analogues cross the blood-brain barrier and the GLP-1
receptor is expressed in many regions of the brain such as the frontal lobe,
hypothalamus, thalamus, hippocampus, cerebellum and substantia nigra. GLP-1 plays
a neuroprotective role: in the AD mouse brain, apparently by reducing apoptosis,
protecting neurons from oxidative stress, and protecting synapses from the harmful
effects of Aβ-induced reduced synaptic plasticity in the hippocampus. Native GLP-1
has a short half-life because it is readily degraded by dipeptidyl peptidase-4 (DPP-4).
Several more stable than native GLP-1 analogues have been developed. These
include exenatide, liraglutide, and lixisenatide, which cross the blood-brain barrier
and, regardless of their effect on glucose control, affect cellular pathways of neuronal
defense, mitochondrial function, apoptosis, and oxidative stress. Because of their
neuroprotective effects, GLP-1 analogues have been explored as potential drugs for
the treatment of AD and other neurodegenerative disorders. In studies in a mouse
model of AD, GLP-1 analogs reduced tau neuronal hyperphosphorylation, prevented
synaptic loss, improved motor function, improved synaptic plasticity, attenuated
memory and learning deficits, and decreased Aβ in the brain. The neuroprotective
effects of liraglutide appear to be mediated through the PI3K-Akt signaling pathway,
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while the effects of lixisenatide have been attributed to induced Akt and MEK
signaling pathways.
A pilot clinical study showed that 6-month treatment of AD patients with
liraglutide prevents a decrease in brain glucose metabolism, which reduces the risk of
disease progression. Other studies evaluating the efficacy of GLP-1 analogs in
patients with AD are ongoing.
Of course, GLP-1 analogs have the advantage of not affecting blood sugar
levels in non-diabetic people and therefore may represent a potential safe treatment
for AD or other neurodegenerative conditions also in non-T2DM patients.
Dipeptidyl peptidase-4 (DPP-4) inhibitors
DPP-4 are hypoglycemic drugs that, by inhibiting DPP-4, the proteolytic
enzyme responsible for the degradation of GLP-1, prolong its plasma half-life by
stabilizing its level and causing a functional enhancement of its hypoglycemic effect.
DPP-4 inhibitors have shown neuroprotective effects that may be partially mediated
by the effects of GLP-1 in the brain.
In animal models of AD, treatment with DPP-4 inhibitors (saxagliptin,
vildagliptin, sitagliptin) reduces tau phosphorylation, amyloid load, and inflammatory
markers, and reverses cognitive deficits with improved memory.
In human neuronal cells, linagliptin reduces Aβ deposition, tau
hyperphosphorylation, prevents GSK3β activation, and attenuates intracellular ROS
production by stimulating 5'AMP-activated protein kinase (AMPK)-Sirt1 signaling.
All these effects contribute to the improvement of cognitive functions.
In elderly patients with T2DM and mild cognitive impairment, treatment with a
DPP-4 inhibitor improves glucose control and prevents cognitive decline. Also, in a
prospective clinical study evaluating 6-month treatment with sitagliptin in elderly
patients with T2DM, improvements in cognitive function were reported.
Insulin
Insulin has several effects on the brain with respect to cognition, learning,
memory, and synaptic plasticity, possibly involving the brain's complex insulin/IR
signaling pathway. Insulin administration slows cognitive decline and improves
memory in adults with AD. However, systemic insulin administration is characterized
by low penetration into the brain and an increased risk of hypoglycemia. For these
reasons, several clinical trials have examined intranasal insulin administration. After
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intranasal administration, insulin, bypassing the blood-brain barrier, reaches
biologically significant concentrations in the brain. In vitro, insulin inhibits neuronal
apoptosis through activation of protein kinase B and in vivo regulates tau
phosphorylation, Aβ precursor protein metabolism, and Aβ clearance.
Intranasal insulin administration improves memory and mood in healthy adults,
as well as in patients with mild cognitive impairment and late onset AD, who
improve cerebral glucose metabolism and preserve brain volume. The therapeutic
effect of insulin on the central nervous system is dose dependent and is modulated by
the APOE genotype, a strong genetic predictor of AD.
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11. SLEEP AND AGING:
AGE-RELATED, ENDOCRINE AND EPIGENETIC ASPECTS
There is no doubt that sleep changes with age. Aging is associated with a
decrease in the ability to maintain sleep (the number and duration of awakenings
increase, the duration of night and deep (slow phase) sleep decreases. Here we will
discuss in detail age-related changes in sleep duration, its initiation, efficiency,
maintenance, quality, sleep stages, behavior during nap time/s. An important aspect
of this discussion is the differentiation between changes in sleep that occur from
childhood to age 60 (or 65) and changes that occur later with age. M. M. et al. (2004)
conducted an in-depth analysis of changes in sleep from childhood to old age, using
the results of a meta-analysis of 65 polysomnography or actigraphy studies that
included 3 577 healthy people aged 5 to 102 years. The results are discussed below.
11.1. SLEEP DURATION
In the current literature, there is evidence that, in general, total sleep time
(TST) decreases with age (from children to the elderly). However, no further agerelated decrease in TST was observed when older age groups were analyzed.
Campbell S. S. et al. in 2007 conducted a study involving 50 healthy adults aged 19
to 81 years, to assess spontaneous sleep over a 24-day period in young people,
middle-aged and old people. Compared with young people, middle-aged and elderly
people had significantly shorter nighttime sleep durations: 10.5 hours, 9.1 hours, and
8.1 hours, respectively. Data obtained from the SIESTA database on 160 healthy
adults (without complaints of sleep) aged 20 to 90 showed that TST decreased by
about 8 minutes per decade in men and 10 minutes per decade in women. Similar
data are reflected in three meta-analyses: age is linearly associated with TST
reduction, with a decrease of approximately 10-12 minutes per decade in the adult
population. This association was stronger when young people were compared with
middle-aged and older people, but disappeared at age 60 and over. These data
indicate that TST plateaus after age 60. In addition, the association was stronger in
women than in men.
The beginning of sleep
Current evidence does not support the notion that the ability to initiate sleep
significantly decreases with age, but suggests that both sleep latency and the ability to
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fall asleep again after nocturnal awakenings increase somewhat after age 60. For
example, the results of two meta-analyses show that sleep latency increases with age.
However, the magnitude of the changes is very modest. In these studies, sleep latency
remains constant from childhood to adolescence. A significant age-related increase in
sleep latency was found only when comparing young and old people. Mathematical
modeling using data from seven studies (involving 258 patients aged 17 to 91)
showed that sleep latency increased between the late teens and twenties, remained
constant from age 30 to about 50, and then steadily increases. However, no
information was provided on the magnitude of the changes. In addition, despite the
fact that healthy older people were more likely than younger people to wake up more
often, older people retained the ability to restore sleep and fell asleep as quickly as
younger people.
Sleep efficiency
Sleep efficiency remains largely unchanged from childhood to adolescence and
declines significantly into adulthood. Unlike all other sleep parameters, which remain
stable after age 60, sleep efficiency continues to decline very slowly with age.
Sleep maintenance
Aging from birth to old age is associated with a decrease in the ability to
maintain sleep, which is manifested by an increase in the number of awakenings
(awakening index) and a greater duration of wakefulness before sleep (WASO), but
also tends to plateau after 60 years. In Ohayon's meta-analysis M. M. et al. (2004)
noted that the age-related changes in WASO reached the largest values among all
sleep parameters: a steady increase in WASO by 10 minutes per decade from 30 to 60
years. WASO remained unchanged after 60 years.
Stages of sleep
In general, deep sleep (non-REM sleep) in adults decreases with age. During
nocturnal sleep, the proportion of stage 1 and stage 2 rapid eye movement (REM)
sleep increases with age, while the proportion of non-REM sleep and REM sleep
decreases with age. These changes were not significant among healthy older people
over the age of 60. In addition, the association between age and reduced REM latency
was minimal. A linear decrease in the proportion of REM with a small rate of 0.6 %
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per decade from 19 to 75 years is known, with a further slight increase in the
proportion of REM from 75 to 85 years.
In addition, there were gender differences in age-related changes in sleep
stages. Meta-analysis by Ohayon M. M. et al. (2004) showed that the age-related
effect on the percentage of stage 1 sleep was stronger in women, and they also had a
lower percentage of stage 2 sleep and a greater percentage of SWS than age-matched
men. The SIESTA study demonstrated that women had no change in SWS with age,
in contrast to men who had a 1.7% decrease in SWS per decade. In addition, women
experienced a lower rate of increase in stage 1 sleep, a higher rate of increase in stage
2 sleep, and a higher rate of REM decline compared to men. These results suggest
that men may be more prone to age-related decline in SWS than women.
Daytime sleep and daytime sleepiness
Daytime sleep for many people throughout life is a daily routine. The results of
epidemiological studies show that daytime sleep is more common in older people
than in younger people. A number of studies have found that older people sleep more
during the day than younger and middle-aged people. Beh H. C. demonstrated the
fact that in older age groups, the frequency of daytime sleep increases with age. A
study of 7 664 people aged 20–99 from a nationally representative sample of Japan
found that a higher proportion of older people (27.4 %) sleep more frequently
(≥4 days per week) than younger people (11.9 %) and middle-aged persons (14.4 %).
However, there is no clear evidence that sleep duration differs between individuals of
different age groups. Campbell S. S. et al. in 2007 showed that sleep duration did not
differ between young, middle-aged and older people, but the number of daytime naps
increased with age. Yoon I. Y. et al. (2003) found that young and old sleep at
different times. So, older people are more likely to sleep in the early evening hours,
and young people — during the day.
People prefer to take a nap during the day for many reasons, such as to
compensate for the loss of nighttime sleep, to restore energy and reduce daytime
sleepiness, or simply to relax. Cultural background also has a significant impact on
nap habits. For example, daytime naps are a common practice for people from China,
the Mediterranean, and several Latin American countries. Older people may sleep
more during the day due to the lifestyle changes that come with aging. For example,
the elderly may spend less time on work, physical and social activities, so they have
more opportunities to sleep during the day than young and middle-aged people. In
addition, Foley D. J. et al. (2007) in a nationally representative survey of US older
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