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Файл:Age endocrinology. Study aid for students of medical universities
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adults found that frequent sleep was associated with excessive daytime sleepiness
(EDS), depression, pain, and nocturia.
Epidemiological studies have shown that up to 20 % of older adults have
reported EDS. EDS usually coexists with a variety of adverse health conditions,
including cognitive impairment, cardiovascular events, and an increased risk of
mortality. Of course, EDS is not part of normal aging and can be a signal or symptom
of certain diseases. An epidemiological study found a linear decrease in the
prevalence of EDS with age from 30 to 75 years. In addition, the prevalence of EDS
declined at a faster rate after age 75. Daytime naps can be a practice to reduce
daytime sleepiness, however some older people may experience daytime sleepiness
but do not fall asleep during the day.
Sleep quality
Researchers might expect older adults to complain more about their sleep than
younger and middle-aged individuals due to the fact that objectively measured sleep
parameters decline with age. However, this may not be the case, as there can be
significant differences between objective and self-reported sleep perceptions, and
comorbidities play an important role in this. For example, although a number of
epidemiological studies have shown that up to 50 % of older adults self-report poor
sleep, a large proportion of these complaints are associated with poor health and
disease burden. Evidence shows that older people are less likely to report poor sleep
than younger people, especially after controlling for comorbidities and health
conditions. Vitiello M. V. et al. (2004) objectively studied sleep in 150 healthy older
adults who reported no sleep problems and found that a significant proportion (33 %
of women and 16 % of men) had objectively measured sleep disturbances. Healthy
seniors may tend to perceive good quality sleep. In addition, individuals in older age
groups expect their sleep to become less sound as they age, and they may accept
some noticeable sleep changes as part of normal aging.
As described above, many characteristics of sleep change during adulthood.
For example, nighttime sleep duration, sleep efficiency, non-REM sleep, and selfreported bad sleep decrease with age; while the number of awakenings, the frequency
of WASO and the frequency of daytime sleep increases. However, most of these
changes stabilize around the age of 60, and then in older age groups, most sleep
variables remain largely unchanged.
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11.2. AGE-RELATED CHANGES IN CIRCADIAN RHYTHMS
The circadian system regulates a number of human physiological functions,
including body temperature, heart rate, blood pressure, release of certain hormones,
bone remodeling, sleep-wake rhythm, and activity-rest patterns. It is well shown in
the literature that circadian rhythms become less stable with aging, which is
characterized by a decrease in their amplitude and ability to adapt to a phase shift
(changes in the phases of circadian rhythms). The suprachiasmatic nucleus (SCN) is
the central endogenous circadian stimulator that regulates the 24-hour circadian
rhythm. Violation of the latter with age may be associated with a progressive decline
in SCN function.
Leading the phases of the circadian rhythm
The timing and structure of sleep is mainly regulated by the circadian system
and the homeostatic regulation of sleep. Older people usually experience a shift to
earlier hours of sleep. They tend to be sleepy in the early evening hours and wake up
early in the morning, earlier than they would like. This earlier sleep time in the
elderly may be related to the age-advance of the circadian rhythm phases. This phase
advance is observed not only in the sleep-wake cycle, but also in the rhythm of body
temperature, as well as in the secretion of melatonin and cortisol, which in older
people occur about an hour ahead of those in young and middle age. However, Duffy
J. F. et al. (2002) found that phase advances in sleep time were greater than at other
times, suggesting that this sleep homeostasis may be related to early bedtime in the
elderly.
Decreased amplitude of circadian rhythms
Aging is associated with a decrease in the amplitude of a number of circadian
rhythms in older people, including body temperature, melatonin and cortisol
secretion, activity, and sleep. The age-related decrease in circadian amplitude may be
associated with sleep disturbance in the elderly. It is known that, compared with
young people, the elderly are more likely to wake up closer to the time when the body
temperature has reached a minimum. This discovery showed that the biological clock
(such as body temperature) in older people can also regulate their wake time, which
can lead to even earlier awakenings. In addition, a decrease in the amplitude of
daytime activity can lead to daytime naps, which also reduces the amplitude of the
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rhythm of sleep and wakefulness. The age-related decrease in the amplitude of
melatonin secretion also plays a role in sleep disorders in the elderly.
Adaptation to Circadian Rhythm Phase Shifts
Older adults face great difficulty in adapting to phase shifts such as shift work
and jet lag. Monk T. H. et al. (2000) found that older adults take longer to adjust to
phase shifts, and they report a longer period of sleep disturbance and daytime
dysfunction. Age-related loss of rhythmic function within the SCN may partly
explain this deterioration.
Changes in sleep homeostasis
So what makes us fall asleep at night and wake up in the morning? Sleep and
wake patterns are regulated by two interrelated systems: one is called sleep-wake
homeostasis and is regulated by internal signals from the body, and the second is the
circadian (daily) rhythm and is regulated by external signals, primarily daylight.
Homeostasis of sleep and wakefulness, despite the complicated name, is an intuitive
process: the longer we are awake, the more we want to sleep, and the longer we sleep,
the sooner we wake up. Scientists call this “sleep pressure” because it increases
during wakefulness and decreases as soon as you fall asleep. Sleep homeostasis is
disrupted with age. The age-related decline in TST and sleep efficiency may be partly
due to the decline in sleep homeostatic pressure with aging. In addition, reduced
homeostatic sleep pressure contributes to an increase in the number of nocturnal
awakenings and a decrease in daytime sleepiness. For example, Klerman E. b. et al.
(2004) showed that older people had 2.7 times more nocturnal awakenings than
younger people in most circadian phases.
11.3. HORMONES, AGING,
EPIGENETIC FACTORS AND SLEEP
Age-related changes in neuroendocrine function during normal aging are
associated with modifications in sleep quality and sleep architecture. Most studies in
this area group older people into one age group compared to young or middle-aged
people, and there are limited data characterizing age-related hormonal changes within
the oldest age group.
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A growth hormone
STH secretion and slow wave sleep influence each other. Growth hormone
secretion primarily pulsates during nocturnal sleep (regardless of whether the sleep is
productive, delayed, or fragmented) about 1 hour after sleep onset and decreases on
brief awakenings. On the other hand, inhibition of growth hormone releasing
hormone (GHRH) suppresses growth hormone secretion, promotes corticotropinreleasing hormone production, and reduces SWS. In addition, there is an age-related
decrease in the secretion of growth hormone. Growth hormone secretion peaks during
adolescence, declines rapidly exponentially between young age and middle age, and
then slowly declines between middle and old age. This phenomenon is similar to the
observed age-related decrease in SWS. The decline in nocturnal GH secretion with
aging may have a direct or indirect effect on SWS and contributes to the decline in
SWS with aging.
Cortisol
Secretion has a distinct circadian pattern that peaks shortly after morning
awakening, gradually declines throughout the day and reaches its minimum late in the
evening, and then rises to a morning peak. Sleep, especially SWS, inhibits cortisol
secretion. An increase in cortisol secretion during sleep can lead to awakening. The
circadian rhythm of cortisol changes with aging, which is manifested in a decrease in
the amplitude of its secretion, an increased nighttime level. Elevated nocturnal
cortisol levels may contribute to reduced SWS and frequent nighttime awakenings in
the elderly.
Prolactin
There is no clear evidence that prolactin secretion affects sleep. However, sleep
affects the secretion of prolactin. Sleep is associated with increased secretion of
prolactin, whether it is during the day or at night. In addition, decreased SWS or
fragmented sleep may be associated with decreased prolactin levels during nighttime
sleep. Studies show an increase in prolactin secretion during SWS or by increasing
SWS, as well as a decrease in prolactin secretion with prolonged wakefulness during
the sleep period. Prolactin secretion during sleep may decrease with age due to lighter
and more fragmented sleep in the elderly. It is known that nocturnal prolactin in
healthy older people was significantly lower than in younger people.
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Thyroid-stimulating hormone
TTH has a circadian pattern of secretion that maintains a stable low level
during the daytime, begins to rise in the late afternoon, peaks at the onset of sleep,
and then gradually decreases during the night and returns to its daytime level after
waking up in the morning. Studies have shown that SWS was associated with
decreased nocturnal TSH secretion, and awakenings were associated with increased
nocturnal TSH secretion. The circadian rhythm of TTH secretion is maintained
during aging. However, studies show that the total 24-hour secretion of thyroid
hormones in the elderly is reduced, and TTH levels are slightly elevated.
Melatonin
The 24-hour plasma melatonin profile is primarily regulated by the alternation
of light and dark, as well as the sleep-wake cycle. Melatonin usually remains stable at
low levels during the daytime, begins to increase gradually in the evening (2 hours
before normal sleep) and remains elevated in the middle of the sleep period, and then
gradually falls to daytime levels in the morning (at 8 00–9 00). The onset of evening
sleepiness correlates with an increase in melatonin secretion in the evening. Total
melatonin secretion decreases with aging, but daytime melatonin (which is already at
a low basal level) may remain unchanged. The increase in nocturnal melatonin levels
in the elderly is significantly reduced compared to the young. Evidence suggests that
the age-related decline in melatonin secretion contributes to increased sleep
disturbance in the elderly.
Sex hormones
Changes in the secretion of gonadotropic and sex steroids with aging are
associated with sleep disorders in the elderly. In men, testosterone levels gradually
decrease with age after the age of 30. Older men are also characterized by low daily
testosterone levels, which is associated with increased fragmentation of sleep in the
elderly. In women, plasma concentrations of estradiol decrease and folliclestimulating hormone levels increase significantly during menopause and
postmenopause. These changes in sex hormones are associated with complaints of
difficulty falling asleep. In addition, a decrease in endogenous estrogen and
progesterone levels may have a negative effect on the upper respiratory tract, hence
increasing the incidence of postmenopausal sleep disturbances.
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11.4. RISK FACTORS FOR SLEEP DISORDERS IN THE ELDERLY
As mentioned above, most sleep parameters in healthy people decrease with
age up to 60 years, then, basically, remain unchanged. In addition, older adults are
less likely to complain of sleep problems and tend to accept some sleep changes as
normal with aging. But in a large percentage of cases, people of older age groups
have polymorbid somatic pathology, mental illness, accompanied by sleep disorders,
changes in social activity, lifestyle. Indeed, up to 50–60 % of older people report poor
sleep quality. Thus, the sleep problems reported by the elderly tend to be
multifactorial and not necessarily related to age alone.
Somatic and mental polymorbidity
About 67 % of older people have multiple comorbidities. Osteoarthritis,
cardiovascular pathology, diseases of the respiratory system, gastrointestinal tract,
diabetes mellitus are the most common. Approximately 90 % of people aged 65 and
over are taking medication to treat chronic conditions. More than a third of them are
usually prescribed more than five drugs. Discomfort and emotional stress associated
with health conditions contribute to an increase in nocturnal awakenings and EDS in
the elderly. In addition, chronic diseases are positively associated with the prevalence
of sleep disorders, including insomnia, sleep apnea, and restless leg syndrome. It
should be noted that not only do sleep disorders cause polymorbidity in the elderly,
but sleep disorders can also have a negative impact on comorbidities and related
symptoms. A number of studies have shown that polypharmacy in the elderly can
lead to EDS, exacerbate primary sleep disturbances, and be a cause of comorbid
insomnia.
Depression and anxiety, common psychiatric problems in the elderly, usually
lead to insomnia. Thus, epidemiological studies have shown that more than 50 % of
the elderly with depression suffer from insomnia. In addition, longitudinal studies
suggest that insomnia may increase the risk of depression in older adults. There was
also a positive relationship between depression and EDS, as well as the presence and
severity of obstructive sleep apnea.
Primary sleep disorders
Several primary sleep disorders, common in the elderly, contribute to poor
sleep. Sleep disorders include insomnia, sleep apnea, periodic limb movements
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during sleep, restless leg syndrome, and REM sleep disorder. It has been noted that
the prevalence of primary sleep disorders is significantly higher in the elderly
compared to the young. Somatic and psychological age-related diseases contribute to
an increase in the prevalence of insomnia symptoms (approximately 50 %) in the
elderly. Interestingly, the prevalence of insomnia in healthy older adults is similar to
that in young adults. An increase in the frequency of sleep disturbances in the elderly
may also be associated with an age-related decrease in the function of the pharyngeal
muscles and an increase in the number of comorbidities. Primary sleep disturbance
contributes to poor sleep in terms of difficulty falling asleep, increased number of
nocturnal awakenings, HR and complaints of inability to sleep.
Social, environmental factors and lifestyle
Many social factors and lifestyle changes in the elderly contribute to sleep
problems. Older retirees tend to be more sedentary, have more flexible sleep
schedules (which may be irregular), have more opportunities to sleep during the day,
and be more involved in social life than before. These factors affect both sleep
homeostasis and its circadian regulation, thereby contributing to sleep disturbances.
In addition, the loss of loved ones can lead to emotional stress and loneliness, which
are also known to contribute to sleep disturbance. In addition, many older people,
especially those with polymorbidity, lose independence in daily life and may move to
a new place of residence, in particular long-term care facilities. This move can be a
major life event and create a range of physical and psychological stressors that will
increase sleep problems. Finally, other environmental factors such as temperature,
noise, and light exposure are also associated with sleep quality in older people.
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12. VITAMIN D HYPOVITAMINOSIS
Hypovitaminosis D is widespread among the elderly and senile and has been
proposed as one of the causative mechanisms for the development of sarcopenia and
dementia. However, diagnostic criteria for determining vitamin D levels as low vary
among scientific societies and countries. Most scientists and clinicians consider
vitamin D levels above 75 nmol/L to be adequate. In the Russian Federation, severe
vitamin D deficiency is considered to be at levels less than 10 ng/ml (less than
25 nmol/l), vitamin D deficiency — 10-20 ng/ml (25-50 nmol/l), vitamin D
deficiency — 20-30 ng/ml (50-75 nmol/l), adequate levels of vitamin D — 30 ng/ml
or more (75 nmol/l or more).
Vitamin D metabolism is regulated by the skin, liver, and kidneys. Sunlight
plays an important role in this process as 80-90 % of vitamin D3 production in the
skin is caused by ultraviolet radiation (UVB), while food (fatty fish, eggs, fortified
milk and plant foods) only 10-20 % of vitamin D 3 from its daily requirement. UVB
converts 7-dehydrocholesterol to previtamin D, which is then converted to
cholecalciferol (or vitamin D3). Cholecalciferol subsequently binds to vitamin D
binding globulin and this complex is transported to the liver, where it is hydroxylated
to 25-hydroxyvitamin D3 (or 25 (OH) vitamin D), the major circulating form. 25(OH)
vitamin D undergoes final hydroxylation in the proximal tubule of the kidney to form
1,25 dihydroxyvitamin D3 or calcitriol, the biologically active form. Calcitriol
interacts with vitamin D receptors (VDRs) in cell nuclei with subsequent activation
of calcium channels.
Vitamin D synthesis is dependent on a number of factors such as sunlight
exposure, sunscreen use, skin pigmentation, kidney and liver function. In elderly and
senile people, hypovitaminosis D is due to a decrease in the ability of the skin to
synthesize cholecalciferol from its precursor 7-dehydrocholesterol and low
expression of VDR, which plays a mutually aggravating role. In this regard, the status
of vitamin D in this population and the possibility of its influence on the development
of age-related diseases are relevant for research. This review of the literature is
devoted to the analysis of the relationship between hypovitaminosis D and the
development of sarcopenia and cognitive impairment in older age groups.
12.1. VITAMIN D AND MUSCLE TISSUE
VDRs are expressed in human muscle fibers, especially in the early stages of
their development, and decrease with maturation. Vitamin D has been shown in vitro
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to play an important role in muscle tissue development, as myoblasts can differentiate
into myocytes due to the VDR signal. In addition to genomic effects, vitamin D has
non-genomic effects that play a direct role in muscle contraction due to its
involvement in the regulation of membrane calcium channels. Thus, vitamin D,
depending on its level, increases the influx of calcium into the cytoplasm of muscle
cells within a few minutes by activating two kinases, namely c-Src and PI3K.
Activation of PI3K leads to increased levels of inositol triphosphate (IP3) and
diacyLHlycerol (DAG). IP3 induces expulsion of calcium from the sarcoplasm, while
DAG in the cytosol, along with calcium, is a key component of protein kinase C
(PKC) activation. PKC interacts with calcium channels located on the cell membrane,
resulting in a greater influx of calcium into the cytosol. Calcium binds to the
troponin-tropomyosin complex, which causes muscle contraction.
The effect of vitamin D on muscle tissue was confirmed by experimental
models of mice knocked out by VDR. Thus, in VDR null mice, muscle mass is
reduced, and the fibers have a smaller diameter compared to wild-type littermates.
In addition, muscle tissue development is impaired in VDR null mice. These
mice express transcription factors characteristic of early muscle fiber development,
such as myf5, E2A, and myogenin, for a longer period, suggesting that VDR is a key
factor in proper muscle cell growth and maturation. In addition, the effect of vitamin
D on muscle development is independent of its effect on blood calcium levels, as has
been demonstrated in VDR null mice with normal blood calcium levels.
In addition to participating in the development of muscle tissue, vitamin D
plays a role in the control of muscle atrophy. Thus, vitamin D is involved in the
degradation of muscle protein through the control of the ATP-ubiquitin-dependent
system. In rats, a significant increase in protein ubiquitination was demonstrated in
vitamin D deficiency.
In humans, the role of vitamin D in the normal functioning of muscle tissue is
supported by a number of studies. Patients with VDR mutations or severe vitamin D
deficiency have been shown to have generalized muscle atrophy and muscle wasting
that occurs even before changes in bone metabolism. A number of authors have
found that vitamin D deficiency is closely associated with reduced muscle mass and
function at older ages, suggesting a role for hypovitaminosis D in the development of
sarcopenia. A study of more than 4,000 older adults found that patients with vitamin
D levels lower than <30 nmol/L were more likely to have impaired muscle function,
with reduced physical performance and muscle strength, but no increased risk of
falls. Houston D.K. et al. (2007) in Invecchiare study in Chianti (InCHIANTI) in
966 participants (mean age 75 years) showed a significant relationship between
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vitamin D levels, muscle strength (determined using dynamometry) and physical
activity (assessed using the timed test). up and go, balance tests). Individuals with
serum vitamin D levels below 25 nmol/L had lower physical activity scores than
those with levels above 25 nmol/L. Muscle strength as measured by dynamometry
was also significantly higher in patients with vitamin D levels above 50 nmol/L than
in patients below this threshold.
The Progetto Veneto Anziani (Pro.VA) study of 2694 elderly patients
(1597 women and 1097 men, mean age 74 years, 40 % of women and 20 % of men
had serum vitamin D levels below 50 nmol/l) showed that lower vitamin D levels
have been associated with lower walking speed and muscle strength regardless of
gender.
It has been proven that increased muscle atrophy associated with vitamin D
deficiency is characterized by a decrease in exercise tolerance, impaired muscle
tissue morphology, which manifests itself in low cross-sectional area of muscle fibers
and impaired contraction of fast fibers.
Due to the fact that VDR expression is increased after muscle injury, it has
been suggested that vitamin D may play a role in muscle tissue regeneration, which is
especially important in patients with sarcopenia.
Thus, the above data convincingly proves the important role of vitamin D in
the normal functioning of muscle tissue.
However, the role of vitamin D supplements in restoring muscle mass and
function remains to be proven. Meta-analysis and systematic reviews of the literature
have found only modest, often non-statistically significant, improvements in muscle
strength with vitamin D supplementation, along with calcium supplementation and
exercise.
Analysis of randomized, placebo-controlled clinical trials has shown
significant heterogeneity in patients, baseline vitamin D levels, doses of vitamin D
supplements, and methods used to measure muscle strength and mass, making it
difficult to compare studies. Although the aging population itself is a very
heterogeneous group, a more accurate selection of individuals for the study will
reveal the role of vitamin D supplementation in the prevention and treatment of
sarcopenia in the elderly and senile.
Moreover, a number of studies have suggested that intermittent large bolus
cholecalciferol (150,000 IU every 3 months) not only fails to prevent falls but, on the
contrary, increases their risk and is ineffective in improving mineral bone density and
its metabolism. These facts can be explained by the fact that the people included in
these studies were without hypovitaminosis D and received treatment at doses
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