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Файл:Age endocrinology. Study aid for students of medical universities
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differences in opinion regarding the interpretation of these results, they certainly raise
the question of whether STH concentration in a healthy, i.e. non-genetically mutated
human to play any role in the control of aging and longevity. This question was
definitively answered by the demonstration that mice lacking growth hormone or its
receptors have a significant increase in lifespan and multiple symptoms of delayed
aging.
The first reports of aging and lifespan of hypopituitary pygmy mice lacking
somatotrophs appeared in the 1970s, but the findings were inconsistent with regard to
their lifespan, ranging from a shortened, normal lifespan to a significant increase.
It is interesting to study other mutant mice Ames dwarf (Prop1df) and Snell
dwarf (Pit1dw), with the absence due to mutation of the Pit 1 and Prop-1 proteins
necessary for the differentiation of hormone-specific cell types in the anterior
pituitary gland. Both types of homozygous mutant mice lacked cells producing STH,
prolactin, and thyroid-stimulating hormone, resulting in a deficiency of these three
hormones. In this regard, Ames and Snell mice had similar phenotypes: dwarfs
characterized by female sterility, reduced levels of insulin, IGF-1, glucose, and
thyroid hormones. Both of these strains of mice showed an increase in lifespan of
more than 40 %.
The hypothesis that the increase in lifespan in these mutants is due to the
absence of STH signaling was subsequently supported by the demonstration that mice
with STH resistance due to growth hormone receptor deletion and mice with isolated
somatotropin deficiency are also pre-LH survivors. Thus, Ghr -/- mice that have a
defect in the STH receptor gene are also known as Laron mice, which is similar to
human Laron syndrome. Mice homozygous for this deletion are born of normal size
but reach less than 50 % of their adult wild-type weight. Ghr -/- mice have higher
than normal levels of STH but very low levels of IGF-1, approximately 20 % of those
of control mice. In addition, their fasting glucose concentration and insulin levels
decrease throughout life, age-related changes in cognitive function and the
musculoskeletal system, the risks of developing cancer are delayed and / or reduced.
Although Ghr -/- mice have normal insulin sensitivity, they are obese, which is
mainly due to increased accumulation of subcutaneous adipose tissue. An analysis of
the survival curves of Ghr -/- mice showed that their mortality rate is the most
significant indicator of aging, and in these mutants it is lower than in mice without
mutations. The average lifespan of female and male Ghr -/- mice was 21 % and 40 %,
respectively, longer than wild-type control mice. In contrast to wild-type control and
Ames dwarf mice, calorie restriction did not increase lifespan in Ghr -/- mice,
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supporting the hypothesis that the STH/IGF-1 axis and caloric restriction may have
similar mechanisms for extending lifespan.
However, it is an interesting fact that not all mice with reduced STH or IGF-1
levels show an increase in lifespan. Mice that have elevated growth hormone
antagonist (GHA) levels provide such an example. GHA mice express a molecule
that competes with endogenous STH for growth hormone receptor binding and results
in a marked reduction in STH-induced intracellular signaling, and as a result, these
mice are dwarfed and have reduced levels of IGF-1 and STH. Contrary to the
previously discussed mutations with reduced STH STH/IGF-1 signaling, GHA mice
do not show an increase in lifespan compared to controls. This mutation is an
interesting exception to the previously mentioned ones. That is, GHA mice are dwarf,
have low STH and concomitant decrease in IGF-1, but do not show an increase in
lifespan. However, there are several key phenotypic differences other than lifespan
between GHA and Ghr -/- mice. Thus, the decrease in the level of IGF-1 in GHA
mice is less pronounced compared to Ghr -/- by 20–25 % and 80 %, respectively.
Other striking differences between Ghr -/- and GHA mice are weight gain and the
degree of insulin sensitivity. Thus, GHA transgenic mice, which are dwarfed in the
early months, eventually gain weight that approaches that of the control group, are
insulin resistant, while Ghr -/- remain dwarfed and with high insulin sensitivity even
in old mice.
In humans, resistance or insensitivity to STH, also known as Laron's syndrome,
is caused by homozygous mutations in the growth hormone receptor or STH -induced
intracellular signaling molecules. Laron and colleagues have been studying a cohort
of 60 patients since 1958. The growth of patients ranged from 108 cm to 142 cm,
they suffered from obesity from early childhood, some patients had a violation of the
metabolism of glycemic metabolism.
Life expectancy data are not available for this cohort due to the fact that many
patients were treated with recombinant IGF-1 and most patients are still alive.
In adults, the etiology of STH deficiency can be different, but most often
develops as a result of tumors of the anterior pituitary gland or as a result of their
treatment, or is a consequence of a traumatic brain injury. Numerous studies have
provided evidence that growth hormone deficiency in adults is associated with
obesity, decreased muscle mass and bone mineral density, as well as a deterioration
in overall well-being and quality of life. Symptoms of STH deficiency in adults
resemble the changes in body composition, cognitive and sexual function that usually
accompany aging. This similarity, together with evidence that growth hormone levels
gradually decrease during adulthood, has led to interest in the use of growth hormone
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to reduce or eliminate the unwanted effects of aging. However, subsequent studies
have shown side effects of recombinant STH therapy.
Following the reported increase in lifespan in Ames dwarf mice, many
researchers have focused their efforts on identifying the mechanisms responsible for
the slower aging of these and other STH-associated mutations. Since oxidative stress
and mitochondrial generation of reactive oxygen species (ROS) and the associated
oxidative damage to various cellular components have long been established as an
important and possibly key mechanism of aging, a large amount of work has been
directed to the study of this system in Ames pygmy mice and others. to LH-living
mutant mice. Work by the Brown-Borg laboratory provided evidence that Ames
dwarf mice produce less ROS, have higher activity of antioxidant enzymes such as
catalase, copper-zinc and manganese superoxide dismutases in the kidney, liver,
heart, and hypothalamus, and are less prone to lipid protein oxidation. and, very
importantly, nuclear and mitochondrial DNA. The biological significance of good
antioxidant defense in these animals was confirmed by subsequent studies, which
showed that Ames dwarf mice have greater resistance to paraquat, a toxic compound
that causes severe oxidative stress in the lungs and other organs. The decrease in ROS
production can be seen as evidence of an increase in the efficiency of mitochondrial
function. More recent studies have described organ-specific differences between
Ames dwarf and normal mice in the expression and activity of various components of
the mitochondrial electron transport chain, as well as in the expression and activation
of PGC1α, a key regulator of mitochondrial biogenesis. Improvements in
mitochondrial function in mice with STH-associated mutations provide a likely
explanation for differences in the animal's energy metabolism as detected by indirect
calorimetry and may be related to improved thermogenesis.
The association of longevity with stress tolerance has been established in
worms, fruit flies, and mice. Cellular stress can be induced by various extracellular or
intracellular stimuli such as heat, hypoxia, radiation, glucose deprivation, and
accumulation of reactive oxygen species. To avoid damage to organelles and DNA,
as well as protein aggregation, a cell can respond to stress by activating survival
mechanisms such as autophagy or by inducing apoptosis. Various stress stimuli
inhibit mTOR, a subunit of intracellular multimolecular signaling complexes, the
“target of rapamycin”, promoting cell growth, metabolism, and survival in conditions
of nutrient excess. Prolonged activation of mTOR can cause cellular stress through
the accumulation of unfolded proteins and ROS, as well as stem cell depletion.
Inhibition of mTOR by rapamycin, calorie restriction, or reduced STH/IGF-1
signaling stimulates autophagy and is thought to result in improved response to
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cellular stress and increased longevity in invertebrates. The ability to withstand
various environmental stressors is also associated with slower or delayed aging in
mammals. Evidence for enhanced stress tolerance in long-lived pygmy mice is not
limited to survival after receiving a sublethal or lethal dose of paraquat. Dermal
fibroblasts isolated from Ames dwarfs and other long-lived STH-linked mutants are
more resistant in cell culture to various cytotoxic agents, glucose deprivation, and
inducers of oxidative damage compared to fibroblasts obtained from genetically
normal animals. Patients with Laron syndrome (Ecuadorian cohort) also show
decreased stress-induced signaling. This finding was investigated by comparing the
results of incubation of human epithelial cells with sera from these patients or with
sera from their healthy relatives. Patient sera caused an increase in SOD2 expression
and a decrease in mTOR mRNA levels. Following H2O2 treatment, cells treated with
patient serum showed less DNA breakage.
STH-deficient mice and STH-resistant populations are characterized by
hypoinsulinemia with reduced or “normally low” glucose levels and no insulin
resistance. Studies on the interactive effects of longevity genes and calorie restriction
have found a strong link between insulin sensitivity and life expectancy. In GHR -/mice, changes in gene expression associated with insulin signaling and insulin
receptor activation are organ-specific. Although insulin sensitivity is not uniformly
associated with lifespan in different mutant and transgenic mice, Selman C. consider
that high insulin sensitivity in STH-associated mutants is an important mechanism for
slower and healthier aging. It should be emphasized that increased sensitivity of
tissues to insulin has also been associated with human longevity, a particularly
striking example is the study of people from long-lived families. In addition, a
modest decrease in insulin levels and a marked improvement in tissue sensitivity to
insulin, together with a decrease in systolic blood pressure, represent a physiological
situation in direct contrast to the metabolic syndrome, a condition associated with an
increased risk of age-related chronic diseases and a decrease in life expectancy. The
opposite effect is realized with a high tissue sensitivity to insulin, as well as with a
reduced secretory ability of pancreatic β-cells in hypopituitary dwarfs and GHR -/mice, which may be directly related to the absence of STH signals and the known
effects of somatotropin on target tissues of insulin and development of pancreatic
islets.
Increased adiponectin levels, decreased blood levels of pro-inflammatory
cytokines, and mTOR resistance; especially mTORC1, represent important
mechanisms for improving insulin signaling in STH-deficient and STH -resistant
mice. Interestingly, each of these mechanisms is involved in the control of healthy
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aging and longevity through mechanisms not directly related to insulin sensitivity.
Thus, adiponectin has anti-inflammatory and anti-atherogenic effects, while it has
been proven that even mild chronic inflammation is a key mechanism of aging and a
key risk factor for many age-related diseases. The target of rapamycin or homologous
signaling is an important regulator of aging in organisms ranging from yeast and
worms to insects and mammals. Treatment with rapamycin suppresses mTOR
activity and prolongs lifespan in mice, reducing cancer risk, but insulin sensitivity
decreases rather than improves, at least initially. In GHR -/- mice and Ames dwarf
mice, healthy aging and increased longevity are promoted by increased levels of
adiponectin and high insulin sensitivity, low levels of IL-6, mTOR signaling, and
hypothalamic inflammation that is characteristic of weight loss phenotypes, calorie
restriction. Surprisingly, in STH -linked mutants, these characteristics coexist with
obesity. This paradox has been explored in studies involving the surgical removal of
intra-abdominal (visceral) fat deposits. The results showed that, compared with
normal animals, the visceral adipose tissue of the mutants produces less TNFα and
IL-6 and more adiponectin and thus promotes insulin sensitivity rather than insulin
resistance.
Of particular note is the effect of congenital STH deficiency on inflammation
and the immune system. Although the actions of STH are often described as antiinflammatory, STH-deficient and STH-resistant mice are characterized by reduced
expression of pro-inflammatory cytokines in adipose tissue, the hypothalamus, and
other brain regions, decreased NLRP3-inflammation activation, reduced
hypothalamic astrogliosis, and elevated adiponectin levels. This shift from a pro-to anti-inflammatory profile is likely to promote healthy aging and longer lifespans for
these mutants. The causal role of “inflammation” in the development of diseases and
reduced life expectancy is well understood, and studies in the laboratory of D. Cai,
whose scientists provided convincing evidence that inflammation of the
hypothalamus contributes to the aging of mice.
In Ames and Snell dwarf mice, a number of immune system parameters are
suppressed, resembling normal animals on a hypocaloric diet. This likely represents a
shift in the distribution of energy from food towards other energy-intensive processes
and, in particular, thermogenesis. These animals show normal antibody production in
response to exposure to infectious agents and a delay in immunosenescence, the
aging of immune cells.
Elevated levels of STH and IGF-1 in mammals have been shown to be
associated with the development of breast and colon cancer. Thus, in STH -transgenic
mice, oncological diseases are more common. In addition, in people with acromegaly,
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a number of researchers have noted an increase in the incidence of colon cancer,
although an overall increase in the incidence of tumors in these patients has not been
confirmed. Ames, Snell Ghr -/- mice, characterized by low levels of somatotropin
and/or IGF-1, have been shown to have a lower incidence of cancer. The human
studies are consistent with the results of biological experiments in mice: tumors are
practically absent in patients with Laron's syndrome.
Inhibition of mTOR by rapamycin, or caloric restriction, increases tumor
resistance and increases lifespan across species.
There is strong evidence that adult height is an STH- and IGF-1-dependent trait
that is negatively associated with the lifespan of domestic dogs, a species in which an
astonishing range of over 100-fold difference in body size is observed in selection. A
similar relationship between body size and lifespan has also been noted in laboratory
rats, domestic cats, and horses. The relationship of height to longevity in humans is
less clear and is often described as controversial. However, there are many examples
of short people living longer than taller people in the same population. The results of
a study on the longevity of Japanese American men showed significantly longer life
expectancy in shorter ones. Importantly, this has been associated with insulin levels,
insulin resistance, which have previously been shown to be associated with familial
longevity, and heterogeneity of FOXO3, a gene with a well- documented association
with longevity in various human populations. In addition, human longevity is
associated with circulating levels of IGF-1 and with polymorphisms in the gene
encoding IGF-1 receptors.
Other mechanisms thought to link reduced somatotropin levels to slow aging
include regulation of energy metabolism to increase fatty acid oxidation and
mitochondrial efficiency, increased levels of humanin, a mitochondrial product that
regulates cellular responses to stress, and increased stem cell populations., reduced
mutation rates, which means improved genome maintenance and significant changes
in gene expression profiles, including micro-RNA expression.
Thus, the studies reviewed above provide clear evidence that in laboratory
mice, reduced STH or growth hormone resistance contributes to stress resilience,
healthy aging, and a significant increase in lifespan. But, nevertheless, these data are
contradictory, since it is clearly proven that it is the decrease in the level of STH with
age that somehow contributes to aging and shortening of life expectancy.
Many of the physiological actions of growth hormone are mediated by IGF-1,
which also plays a key role in negative feedback control of STH expression.
Circulating levels of IGF-1 regulate the degree of somatotropin secretion and activity.
Not surprisingly, the age-related decrease in growth hormone secretion is associated
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with a general parallel, albeit less pronounced, decrease in plasma IGF-1 levels.
Assessing the functional and pathological consequences of the concomitant decrease
in STH and IGF-1 levels is complicated by the fact that while some actions of growth
hormone are mediated by IGF-1, some are not. Moreover, the effects of STH and
IGF-1 on the same process or target tissue can be different, and in some cases even
opposite. For example, growth hormone is lipolytic while IGF-1 is not, STH
promotes insulin resistance, while IGF-1 reduces it and mimics the various effects of
insulin.
The difficulty in interpreting the effects of STH in terms of resulting changes
in IGF-1 levels is due to differences in the regulation of IGF-1 expression in different
organs. Although IGF-1 expression in the liver, the main source of circulating IGF-1,
is clearly STH-dependent, IGF-1 expression in other tissues is not. In mice with
deletion of STH receptors in all tissues, IGF-1 expression in the liver is significantly
reduced, moderately reduced in the kidneys, and unchanged in the heart and brain. As
a result, in both STH -deficient and STH -resistant mutants, a significant suppression
of plasma levels of IGF-1 coexists with maintenance of normal or increased
expression of IGF-1 in different areas of the brain. Analysis of local tissue-specific
expression and activity of IGF-1 is important to decipher the phenotypic
consequences of altered STH signaling, including its effect on lifespan. Animal
studies with a deletion of PAPP-A, a protease that cleaves IGF-1 binding proteins,
have provided important evidence for the role of local (tissue) availability of
biologically active IGF-1 in the control of aging and longevity.
Similar to the age-related decrease in somatotropin levels, the decrease in IGF1 levels is thought to cause or contribute to the functional deficits that develop with
aging. Animal and cell culture studies have provided very strong evidence for the
neuroprotective and cardioprotective effects of IGF-1. Moreover, epidemiological
studies show that high levels of IGF-1 increase the risk of cancer development and
progression, but reduce the risk of cognitive dysfunction, dementia, and
cardiovascular disease.
However, research in this area is also not without controversy. The results of
tissue-specific deletion of IGF-1 receptors in the heart and central nervous system
have been reported to prevent rather than accelerate various age-related changes.
Decrease in insulin/IGF-1 signaling (IIS) or homologous signaling pathways delays
aging and extends lifespan in organisms ranging from yeast to mice, likely by
downregulating mTOR activity and reducing inhibitory cytoplasmic sequestration of
FOXO family transcription factors. Evidence for a “biphasic” (U-shaped) relationship
between IGF-1 levels and lifespan, with both high and low IGF-1 levels increasing
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mortality from age-related diseases in mice, may explain some of the seemingly
conflicting results.
Thus, the understanding of the role of the somatotropic axis — STH/IGF-1 in
the control of aging in mammals is still far from complete, and the interpretation of
many studies remains controversial.
Future studies are likely to determine whether a slight or temporary decrease in
the activity of the somatotropic axis by dietary or pharmacological means can have a
beneficial effect on life expectancy and the risk of age-related diseases in humans.
Given the pleiotropic effects of the STH and IGF-1 axis, it is also likely that selective
manipulation of only a few, or perhaps a single target of the growth axis, may be
more effective than reducing growth hormone secretion or resistance for longevity.
Current and future clinical studies will undoubtedly determine whether recombinant
STH therapy can help people suffering from sarcopenia or other manifestations of the
“frailty” syndrome, and determine the indications for such treatment.
However, at the moment the following facts remain indisputable:
1. Somatotropin is a powerful metabolic hormone with pleiotropic effects,
which is positioned as a “fountain of youth”.
2. There is a clear age-related decline in both STH and IGF-1, referred to as
somatopause.
3. Recombinant human growth hormone and IGF-1 are approved therapeutic
agents for patients with growth hormone deficiency or primary IGF-1 deficiency,
respectively; such therapy may not be applicable in the endocrinologically healthy
elderly.
4. In laboratory mice, STH deficiency or resistance to it is associated with a
delayed onset of aging and a reduction in age-related morbidity and a significant
increase in lifespan.
Further research is needed to explore the impact of the STH/IGF-1 axis on
lifespan and association with age-related diseases in humans and to look for possible
impacts on it.
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5. HYPOTHALAMUS-PITUITARY-ADRENAL AXIS.
CHANGES IN ADRENAL HORMONE SECRETION DURING AGING
It is assumed that aging is associated with a loss of balance between the two
main processes, damage and restoration towards the predominance of the first, which
leads to a change in the function of organs and systems.
Cortisol secretion undergoes modification with age. Unlike most hormones,
which decline with aging, mean cortisol concentrations increase, tend to have
irregular, low-amplitude spikes, and the circadian profile becomes flattened, with
elevated evening and nighttime levels and a lower early morning peak. In addition,
with aging, the negative feedback of the HPA axis in response to cortisol secretion is
disturbed due to a decrease in its sensitivity, which may be associated with several
factors, such as impaired vascular trophism and a decrease in the number of
glucocorticoid receptors in the brain, changes in cortisol clearance in cerebrospinal
fluid.
Elevated cortisol levels and reduced sensitivity of the HPA axis have been
associated with low cognitive status, dementia, degenerative and vascular diseases,
depression, and anxiety, according to several authors. In addition, higher
concentrations of free cortisol in the urine are positively correlated with Alzheimer's
disease, and in saliva with a high risk of death, the development of diabetes mellitus
and hypertension. In addition, aging in various tissues such as the central nervous
system, skeletal muscle, bones, and skin increases the activity of 11-β-hydroxysteroid
dehydrogenase type 1, which converts cortisone to active cortisol, which leads to an
increase in local production of cortisol.
Dehydroepiandrosterone (DHEA) and its sulphate ester (DHEAS), produced
and secreted by the zona reticularis of the adrenal cortex in response to ACTH
stimulation, is significantly reduced during aging by about 1–2 % per year, which
represents one of the largest endocrine changes found during human aging, with a
final decrease in old age by 5-10 times compared to the young, which leads to
“adropause”. By age 70–80, DHEAS levels are about 30% of peak levels in women
and 20 % in men compared to people under 40 years of age. In peripheral tissues,
DHEA/DHEAS are converted to androgens and estrogens, playing a significant role,
especially in older men when less than 50 % of androgens are produced in the
testicles.
The secretion of DHEA/DHEAS is very important in the development of
frailty. Higher levels of the hormone are associated with better overall health,
psychological status and functional ability, muscle strength, bone density, anti-
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inflammatory effects, reduced risk of death from cardiovascular disease, and
increased life expectancy in men. Cross-sectional studies have found a relationship
between DHEA-S levels and diseases such as Alzheimer's disease, type 2 diabetes,
and depression. Lower DHEAS levels are associated with cognitive impairment, as
well as higher cardiovascular mortality and the risk of cardiovascular events in
people over 50 years of age.
A decrease in DHEAS levels with a simultaneous increase in plasma cortisol
characterizes the dissociation of the cortical secretory response, which can be caused
by selective depletion of zona reticularis cells, leading to impaired androgen
secretion. In particular, the cells of the zona reticularis seem to be sensitive to agerelated changes in blood vessels, a decrease in vascularization, which leads to their
damage. Thus, the release of DHEA in response to exogenous administration of
ACTH markedly decreases with age.
The ratio of glucocorticoid concentration to DHEA gradually increases with
age. Cortisol has a neurotoxic effect, causes degenerative changes in neurons, their
apoptosis due to their high sensitivity to metabolic and vascular changes. On the
other hand, DHEA has a neuroprotective effect, protecting neurons from structural
damage and functional impairment. Therefore, the observed increase in the
cortisol/DHEA ratio during aging leads to an increase in neurotoxicity and probably
contributes to the onset of age-related neurodegenerative diseases.
It has been proven that in men and women, the secretion of aldosterone by the
adrenal cortex decreases with age. In addition, plasma renin activity is reduced.
Despite a limited number of studies and small sample sizes in most of them, the
general observation is that a decrease in aldosterone secretion and plasma renin
activity in the elderly can have a significant impact on the diagnosis of hypertension
and the choice of drugs for its treatment.
Basal epinephrine secretion decreases with age: hormone production in the
medulla is 40 % lower in older healthy men compared to younger ones. Plasma
concentrations of adrenaline and noradrenaline decrease or do not change
significantly with age with lower secretion of these hormones, mainly due to a
decrease in the clearance of these hormones. In addition, acute stress-stimulated
adrenaline (as a percentage of baseline) is reduced by 33–44 % in older adults
compared to younger controls. The exact mechanisms responsible for the decrease in
adrenaline release from the adrenal medulla observed with aging are not known. To
some extent, they may be associated with an age-related decrease in the activity of
preganglionic nerve fibers, or, possibly, depletion of cells that synthesize
catecholamines.
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