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Файл:Comprehensive geriatric assessment from theory to practice. Study aid
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person's biological age. Telomeres are made up of repetitive DNA
sequences linked by specific nucleoproteins that protect the ends of
chromosomes. Telomeres shorten with each cell division, causing cell
aging as the length decreases beyond a critical length. The found
relationship between age-related shortening of telomeres and coronary
heart disease makes it possible to predict mortality from all causes and
from cardiovascular diseases.
Hannum G. et al. (2013) and Horvath S. (2013) described 2 widely
used predictors of age — DNA methylation (DNAmAges, also called
epigenetic clocks) based on 71 and 353 CpGs, respectively. DNAmAge
appears to be a good predictor of all-cause mortality and, to a lesser extent,
cardiovascular disease.
During aging, somatic cells accumulate mutations in DNA, which
leads to the appearance of mutant clones and mosaicism. Expression of
hematopoietic cells associated with somatic mutation (clonal
hematopoiesis) is usually associated with cancer, however, a number of
researchers have demonstrated its association with an increased risk of
developing cardiovascular diseases, which makes it possible to identify
clonal hematopoiesis as a possible new biomarker of vascular aging.
Another characteristic of aging is low-level chronic inflammation,
which can be assessed by measuring levels of pro-inflammatory molecules
such as elevated C-reactive protein and interleukin 6. Inflammation, a risk
factor for many chronic diseases, including cardiovascular disease, is due
in part to increased intestinal permeability and altered composition of the
microbiota. Gut dysbiosis can also become an estimate of biological age,
as it is associated with longevity and various diseases.
Aging affects the level of proteins, metabolites and other
biomolecules. Thus, higher rates of morbidity and mortality are associated
with levels of insulin-like growth factor-1, growth hormone and lowdensity lipoprotein.
Vascular functional and structural biomarkers of aging.
Structural changes that occur in arteries with age include
fragmentation of elastin, accumulation of collagen, and loss of smooth
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muscle cells, leading to decreased vascular flexibility and increased
vascular stiffness. The most common method for determining arterial
stiffness is pulse wave velocity, the speed at which an elevated pressure
wave travels along the arterial tree. Spreading from the aorta to the
capillaries, the pulse wave attenuates. In clinical practice, the pulse wave
velocity of the carotid and femoral arteries is studied, the method for
determining the cardio-ankle vascular index (CAVI) is used. Pulse wave
velocity correlates with chronological age, and a high pulse wave velocity
increases the risk of cardiovascular disease and all-cause mortality.
Arterial stiffness usually precedes and contributes to hypertension, but
hypertension can also exacerbate arterial stiffness, indicating a positive
feedback loop. Blood pressure also increases with age and is associated
with CV events and mortality.
A characteristic feature of vascular aging is atherosclerosis, which is
characterized by the accumulation of lipid plaques in the intima, which can
lead to acute myocardial infarction or stroke. Endothelial dysfunction, a
major factor in atherogenesis, can be measured using ultrasound
(definition of flow-mediated dilation). Flow-mediated dilation declines
with aging and is an independent predictor of cardiovascular
complications. Ultrasonography of the intima-media complex is often used
as a marker of subclinical atherosclerosis. The carotid intima-media
complex increases with age and is associated with both the prevalence and
incidence of CVD and mortality. However, an increase in the intima-media
complex may also reflect non-atherosclerotic processes. More advanced
stages of atherosclerosis can be assessed by determining the presence of
plaques, their number, thickness, area and volume, which outperforms the
carotid intima-media complex as a predictor of future events associated
with cardiovascular disease.
Vascular aging is also characterized by the deposition of calcium
phosphate crystals in both the arterial intima (usually associated with
atherosclerosis) and the media of the arteries (called Mönckeberg's calcific
sclerosis). Both types of calcification often develop in parallel and are not
always easily distinguished by imaging techniques. Computed tomography
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is the “gold standard” for quantifying cardiac angiography (multispiral
computed tomography of the heart, called virtual coronary angiography).
Although virtual coronary angiography may be affected by the presence of
medial calcification, it is commonly used as a surrogate marker for the
degree of atherosclerosis. Virtual coronary angiography parameters
correlate with chronological age and are a powerful predictor of
cardiovascular disease and all-cause mortality.
At the same time, estimation of biological age based on one of the
previously mentioned biomarkers often does not reflect the complexity of
the aging process and may give suboptimal indicators. Complex
biomarkers may consist of combinations of several biomarkers. For
example, prediction of cardiovascular disease development is improved by
integrating the carotid intima-media complex with aortic pulse wave
velocity into the vascular aging index. Similarly, the Frailty Index 34,
which consists of 34 indicators of health and function of various organs
and systems, outperforms DNAmAge in predicting the risk of death. Many
other estimates of biological age have been developed by combining
physical, physiological and biochemical parameters, for example, the
Klemer-Dubal biological age index is based on 10 biomarkers. However,
since a number of predictors of biological age are complex and expensive
to perform, they often become impractical and inaccessible to the public.
Factors affecting the biological aging of the vascular system.
Gender and hereditary factors.
Life expectancy for women is higher than for men, and the vast
majority of centenarians are women. In addition, the risk of coronary heart
disease is higher in men, especially those under the age of 50. Women
were found to have longer telomeres, younger DNA, and lower rates of
virtual coronary angiography than men of the same age. This fact can be
partly explained by the angioprotective effect of estrogens. There is also a
possible adverse effect of testosterone on aging, as eunuchs have been
reported to live longer than normal males of the same socioeconomic
status. However, the impact of testosterone on cardiovascular health
remains controversial.
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Life expectancy is also significantly influenced by hereditary factors,
mainly genetic and epigenetic. For example, a family history of
cardiovascular disease increases the future risk of developing them from
40 % to 75 %, depending on the degree of relationship. Moreover, many
genetic variants are associated with exceptionally long lifespans, and the
offspring of centenarians show signs of a low epigenetic age of blood
cells. There are also ethnic differences in biological age, morbidity and
mortality from cardiovascular diseases. However, a meta-analysis of twin
studies found that genetics account for only 20 % to 30 % of lifespan
variation, indicating that aging and longevity are heavily modulated by
other factors such as environment and lifestyle.
Environment and lifestyle.
The influence of the environment on vascular aging begins before
birth through intrauterine (developmental) programming. Parental lifestyle
during pregnancy can adversely affect the long-term health of offspring.
Pathological anatomical studies have revealed atherosclerotic lesions in the
arteries of fetuses and newborns of smoking or hypercholesterolemic
mothers, possibly reflecting epigenetic changes. After birth, the rate of
biological aging can be influenced by a wide range of environmental and
lifestyle factors. Physical inactivity is a major risk factor for mortality, and
even a small amount of daily exercise reduces cardiovascular disease and
all-cause mortality.
Another key modulator of vascular function and CVD risk is a
healthy diet including unprocessed plant foods, moderate consumption of
lean meats and fish, the Mediterranean diet, and the hypertension
prevention diet. Refined sugar, processed meats, hydrogenated vegetable
oils, and high amounts of salt are key components of Western-style diets
that contribute to the development of atherosclerosis and hypertension. In
addition to the types of food consumed, the amount of food consumed
plays a crucial role in aging, and overeating increases the risk of obesity,
cardiovascular disease and death. Remarkably, the exceptional longevity
of the Japanese living on the island of Okinawa is due in part to a
moderate and steady decline in calorie intake.
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Smoking, drugs and alcohol abuse are clearly associated with
accelerated vascular aging and reduced life expectancy. However,
moderate alcohol consumption is associated with a lower incidence of
coronary heart disease and has some cardiometabolic benefits. Other
factors influencing aging and life expectancy are air quality, water quality,
sleep duration and quality, psychological factors, and socioeconomic
status.
Diseases and vascular age.
Numerous hereditary and acquired conditions and diseases can
accelerate vascular aging and lead to early death. For example, obesity is a
risk factor for insulin resistance, type 2 diabetes, and is associated with
reduced life expectancy, due in part to increased mortality from
cardiovascular disease. Obesity and adipose tissue distribution affect many
markers of vascular age, including arterial stiffness, carotid intima-media
complex, and markers of inflammation. In addition, type 2 diabetes
mellitus is a common cause of kidney damage, which is characterized by
extensive vascular calcification and increased cardiovascular mortality.
Autoimmune diseases such as systemic lupus erythematosus and
rheumatoid arthritis contribute to atherosclerosis, supporting the concept
of a central role for inflammation in aging and associated vascular disease.
In addition, premature vascular aging is common in people infected with
the human immunodeficiency virus, due in part to the side effects of
antiretroviral drugs.
Early vascular aging is a sign of many genetic diseases. Familial
dyslipidaemias, such as familial hypercholesterolemia, are a group of
genetic pathologies that alter lipid metabolism and require
pharmacological treatment to prevent early atherosclerosis. Generalized
arterial calcification in infants and pseudoxanthoma elastica are hereditary
syndromes associated with impaired extracellular pyrophosphate
metabolism and arterial calcification. Generalized arterial calcification in
infants begins in utero and causes severe calcific stenosis, hypertension,
heart failure, and death within the first 6 months of life. Elastic
pseudoxanthoma has a milder course and signs of cardiovascular disease.
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Progeria in children (Hutchinson-Gilford syndrome) is caused by
mutations in the LMNA gene and is characterized by age-related vascular
changes such as atherosclerosis, arterial stiffness, and calcification. These
defects lead to death in the second decade of life, usually from myocardial
infarction or stroke. Patients with Werner's syndrome carrying mutations
in the WRN gene develop age-related diseases, including type 2 diabetes,
atherosclerosis, myocardial infarction, and cancer, and die in middle age.
Strategies for slowing down vascular aging.
Studies of factors and diseases that accelerate and slow biological
aging have revealed many mechanisms that control this process. In
addition to the obvious smoking cessation measures, as well as excessive
alcohol consumption, a number of other interventions can reduce both
global and vascular biological aging. One of the most notable interventions
is physical activity, especially aerobic exercise, which has been associated
with reduced incidence of age-related diseases, reduced vascular and
molecular biological age and CVD risk factors, and increased life
expectancy in humans.
Calorie restriction and fasting are the best proven strategies for life
extension. Even without increasing physical activity, reducing energy
intake in obese individuals improves endothelial function and reduces
arterial stiffness and blood pressure, due in part to weight loss and adipose
tissue mass. Similarly, a 2-year follow-up in the CALERIE
(Comprehensive Assessment of the Long-term Effects of Calorie
Reduction) trial showed a reduction in the risk of cardiovascular disease,
inflammation, and biological age in non-obese individuals. However,
chronic calorie restriction can lead to loss of muscle mass, bone density,
and its long-term effects on non-obese people remain unknown.
Changes in dietary composition can also have a strong modulating
effect on aging and vascular disease. For example, the Mediterranean diet
and the hypertension prevention diet prevent weight gain and are
associated with a lower risk of adverse clinical events. In addition, a high
intake of vegetables and fruits is associated with improved endothelial
function, decreased arterial stiffness and blood pressure. The structure and
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function of the arteries can be improved and the risk of cardiovascular
disease reduced by consuming cocoa, tea, coffee, dairy products, fish, nuts,
seeds, whole grains, legumes and olive oil. In addition, dietary sodium
restriction reduces blood pressure and arterial stiffness.
At the same time, despite the undeniable positive impact of
behavioral strategies on life expectancy, long-term adherence to these
habits is usually low. Thus, the use of pharmacological drugs to prevent
accelerated aging is a more reliable alternative. The key signaling cascades
regulated by caloric restriction are the mechanical target of rapamycin
(mTOR), adenosine monophosphate-activated protein kinase (AMPK), and
the sirtuin pathways (Sirtuins or Silent Information Regulator 2 proteins,
SIR2) are a family of evolutionarily conserved NAD-dependent proteins,
possessing deacetylase or adenosine diphosphate-ribosyltransferase
activity.Evolutionarily preserved mediators of longevity). Aging
deregulates these pathways, and their pharmacological correction increases
lifespan in various species, including mammals.
Rapamycin, an mTOR inhibitor that also activates AMPK, is
commonly used as an immunosuppressant in organ transplant recipients
and as an antiproliferative agent in the treatment of certain cancers.
Compared to other immunosuppressive agents, rapamycin reduces arterial
stiffness, blood pressure, and carotid intima-media complex in kidney
transplant recipients, suggesting its vasculoprotective properties. In
addition, rapamycin and its analogs exhibit anti-atherosclerotic properties
in preclinical models and are used to prevent in-stent restenosis and
cardiac allograft vasculopathy. However, the use of rapamycin for
angioprotection in aging is limited by adverse side effects including
hyperglycemia, hyperlipidemia, and insulin resistance. Ongoing research is
testing rapamycin analogs for a safer alternative, and some positive effects
have been reported, including immunostimulation and reduced rates of
infectious disease in the elderly.
Metformin is the most prescribed type 2 diabetes drug and has few
side effects. In addition to improving insulin sensitivity, metformin targets
a number of age-related mechanisms, including AMPK activation and
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mTOR inhibition. Metformin reduces indicators of vascular age, including
arterial stiffness, endothelial dysfunction and virtual coronary angiography
of the heart, reduces the risk of cardiovascular disease and mortality.
Resveratrol is a polyphenol naturally present in red wine, grapes, and
other berries. It activates sirtuin-1 and AMPK and inhibits the mTOR
pathway. Resveratrol has shown vasculoprotective effects in preclinical
models, and clinical trials have demonstrated modest reductions in systolic
blood pressure in hypertensive patients and glycemia in patients with type
2 diabetes. However, some undesirable side effects have been reported,
such as a possible reduction in the benefits of exercise in the elderly.
Nicotinamide adenine dinucleotide precursors, such as nicotinamide
riboside and nicotinamide mononucleotide, are another group of sirtuin
activators proven to slow vascular aging in mice. Preliminary studies in
humans have suggested their potential use in reducing arterial stiffness and
blood pressure.
Interventions targeting the inflammation process are emerging as a
potential therapy against vascular aging. Blockade of tumor necrosis
factor-α reduces arterial stiffness and carotid intima-media complex in
patients with rheumatoid arthritis, and inhibition of interleukin-1β reduces
the risk of recurrent cardiovascular disease in patients with myocardial
infarction and elevated levels of C-reactive protein. However, the use of
anti-inflammatory therapy in patients with severe pathology is limited by
the increased risk of fatal infections.
Because gut dysbiosis promotes inflammation, prebiotics and
probiotics may provide additional benefits. In addition, a number of drugs
widely prescribed for the treatment of chronic age-related vascular disease,
such as aspirin, statins, and antihypertensive drugs, can also be considered
anti-aging drugs. However, these compounds are not currently
administered to healthy people.
Thus, age-related vascular damage depends not only on hereditary
factors, but also on lifestyle, environment and comorbidities. In this
regard, the assessment of the risk of developing vascular diseases in order
to develop recommendations for their early prevention should be based not
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on chronological, but on biological age. Currently, many biomarkers of
biological age have been described. However, more research is needed to
test and refine existing biomarkers of aging and to identify more accurate,
simple, and reliable indicators.
Various current anti-aging strategies that promote healthy aging and
delay the onset of age-related vascular disease have low adherence other
than pharmacological interventions. At the same time, pharmacological
approaches to delay aging in healthy people are controversial due to their
long-term side effects, sometimes exceeding the benefits. However, it is
clear that anti-aging interventions should be aimed at extending health, not
just extending life expectancy. Strategies to promote healthy aging will not
only benefit the individual, but will also reduce the medical, economic and
social burdens on governments associated with the progressive aging of
the world's population.
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2. GERONTOLOGY AND GERIATRICS IN THE SAMARA REGION:
PAST, PRESENT AND FUTURE
The increase in the average duration of human life is the most
remarkable result of scientific, technological and social progress. The most
important demographic phenomenon at the turn of the XX–XXI centuries.
was a global increase in life expectancy and, as a result, an adequate
increase in the proportion of older people in the general population of the
population of countries around the world. So, in 1950, people 60 years and
older accounted for 8 % of the world population, in 2000 — already 10 %,
and in 2050, according to UN forecasts, their share will reach 21 %. In
Russia, the share of people over 60 as of January 1, 2016 was 20.3 %, by
2025 it is expected to increase to 23.9 %, by 2050 to 28.8 %. Samara
region repeats the all-Russian trends: people over 60 years old make up
22.5 % of the entire population of residents. According to the United
Nations Demographics Division experts classification, the demographic
structure of the Samara region can be characterized as the old population
(the third level, in which people over 65 make up more than 7 % of the
total population), and it is assessed as “stable”. Thus, the demographic
situation today leaves no doubt that caring for people of older age groups
is a requirement of the time and a huge medical and social problem.
Research in the field of gerontology in our country is currently a
continuation of research conducted in the USSR. The Academy of
Sciences of the USSR, the Academy of Medical Sciences of the USSR,
branch research institutes, universities, and medical schools took an active
part in the work on the study of aging.
“In order to answer the question of whether it is possible to influence
old age in a favorable sense, it is necessary to study it from various points
of view,” wrote the father of gerontology I.I. Mechnikov in his book
“Etudes of Optimism”.
Samara State Medical University (SamSMU) has been a platform for
the study of geriatric aspects of medicine for many years. Professor Tikhon
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