Nervous mechanisms of aging and cognitive decline

Over the past century, advances in the treatment of diseases of young and middle age have contributed to a significant increase in people's life expectancy. One of the main health problems faced by the aging generation is the decline of cognitive function, mainly caused by Alzheimer's disease, diagnosed in more than 50% of U.S. residents over the age of 85. As the average life expectancy of a person increases, this frightening figure can only grow, which indicates the existence of an urgent need to study the mechanisms of deterioration of cognitive abilities of aging people. The main risk factor for the development of Alzheimer's disease and senile dementia is age as such, therefore, the mechanisms underlying these processes must be considered in the context of the molecular biology of the aging process.

Fortunately, over the past 15 years, scientists have made considerable progress in studying the molecular mechanisms of aging. The most significant achievement is the identification using methods of functional genetic analysis of signaling mechanisms that are the main regulators of aging and life expectancy. These mechanisms have been preserved in the course of evolution in a wide range of organisms, including yeast, nematodes, fruit flies and mammals. The study of these model systems indicates that the rate of aging is not strictly constant, but changes under the influence of various factors (Table 1). The results of recent studies have shown that disruption of the fundamental mechanisms of aging can be one of the causes of the development of neurodegenerative diseases.

Table 1. Signaling mechanisms affecting the aging of model organisms and the mammalian brain.

Two important technical achievements have provided a person with new opportunities to study the biological aspects of brain aging. The appearance of microchips made possible a global analysis of gene expression in human cells and model organisms, resulting in the identification of signaling mechanisms preserved during evolution. At the same time, the improvement of functional visualization methods has provided specialists with an unprecedented opportunity to study the functioning of the cognitive mechanisms of the brain of elderly people. To get a more complete picture of the aging processes of the human brain and the body as a whole, scientists will have to solve the difficult task of integrating these two levels of analysis.

The growing understanding of the basic molecular mechanisms of brain aging and the role of the brain in the aging processes of the whole organism is gradually bringing us closer to the emergence of methods for the treatment and prevention of age-related cognitive impairment and Alzheimer's disease.

The trajectory of brain agingHuman aging is accompanied by structural and neurophysiological changes in the brain and a decrease in cognitive functions of varying degrees.

Functional imaging techniques have provided an unprecedented opportunity to observe the nervous activity of the brain and its changes in the aging process (Fig. 1).

Figure 1. Disorders of the functional activity of the brain in the aging processFunctional visualization of brain activation processes during the task demonstrates changes in the activation profile of the aging brain.

but,
above:The image shows simultaneous activation of the medial zone of the prefrontal cortex, the cortex of the posterior cingulate gyrus and the lateral part of the parietal cortex in young people and a decrease in the severity of this joint activation in the aging brain;

below:
The hypothetical interaction of these areas of the cortex may ensure the coordination of their work in young people, while a decrease in the severity of these interactions may be the cause of the observed disturbances in the activity of the aging brain.
b:
The images obtained using positron emission tomography show that young people performing a memorization task have an activation of the right hemisphere of the brain. In elderly people who show poor results when performing this test, the activation of the right hemisphere zone also occurs, whereas in elderly people who do well with the test, sections of both hemispheres are activated. Apparently, in this case, the involvement of additional zones is observed, compensating for the age-related extinction of the functions of the brain regions that ensure the formation of memories. These observations indicate that the process of normal aging is characterized by serious violations of the biological mechanisms that control the work of the brain.

Perhaps one of the reasons for the appearance of these disorders is damage to the myelinated fibers connecting neurons of various parts of the cerebral cortex. Despite the minimal loss of cortical layer neurons during normal brain aging, the conductivity and integrity of brain structures are disrupted due to changes in the physiology of synapses. In addition, the study of gene expression in the brain cells of aging mice, rats, monkeys and humans revealed significant changes in the expression of genes encoding synaptic mediators. In the prefrontal cortex of humans and rhesus monkeys, with age, there is a pronounced suppression of the activity of many genes whose protein products inhibit the transmission of nerve impulses mediated by gamma-aminobutyric acid (gamma-aminobutyric acid, GABA), which may disrupt the balance between inhibitory and excitatory nerve impulses. This may increase neural activity in the prefrontal cortex of aging individuals. Initially, this mechanism plays a compensatory role, but over time it causes a person's predisposition to excitotoxicity and the development of neurodegenerative changes.

Excitotoxicity (English to excite – to excite, activate) is a pathological process leading to damage and death of nerve cells under the influence of neurotransmitters capable of hyperactivating synaptic receptors sensitive to glutamate. At the same time, the excessive intake of calcium ions into the cell activates a number of enzymes that destroy cytosolic structures and leads to the launch of cell apoptosis.

It is very important to find out whether there is a clear line between these functional changes that develop in almost every aging individual and the pathological processes underlying neurodegenerative diseases such as Alzheimer's disease. The data obtained by functional magnetic resonance imaging indicate that normal and pathological aging of the brain is characterized by various changes in the activity of the hippocampus and certain regions of the cerebral cortex. With normal aging, there is a decrease in the metabolic activity of the base of the hippocampus and the dentate gyrus, whereas an early indicator of Alzheimer's disease is a decrease in the activity of the entorhinal region of the cerebral cortex. At the tissue level, the distinctive signs of the development of Alzheimer's disease are the death of neurons starting in the entorhinal cortex and hippocampus, as well as a decrease in the volume of the temporal lobes. However, other signs of Alzheimer's disease (such as loss of synapses, amyloid plaques and neurofibrillary cords) are often detected in healthy elderly people who do not suffer from cognitive impairment. To clarify the relationship between Alzheimer's disease and normal aging of the brain, only the study of the mechanistic foundations of the aging process on model organisms can.

Mechanisms of brain aging preserved in the course of evolutionGenome-wide analysis of changes in the expression of genes of nematodes Caenorhabditis elegans, as well as the brains of Drosophila flies (Drosophila melanogaster), mice, rats, chimpanzees and humans revealed several functional categories of genes preserved during evolution, the expression of which changes as the body ages (Table 2). The results of most studies of this class indicate an age-related decrease in activity mitochondria.

In addition, the most pronounced decrease in the expression of genes involved in mitochondrial energy metabolism is observed in people suffering from cognitive impairment and Alzheimer's disease. Another universal characteristic of aging is an increase in the expression of genes involved in the formation of stress reactions. Perhaps the brain uses the mechanisms of stress resistance preserved during evolution to protect against pathological changes that cause degeneration of neurons.

Table 2. Models of changes in gene expression in aging brain cells preserved during evolution

Some categories of genes, including those involved in the formation of stress reactions and ensuring the functioning of mitochondria, demonstrate the profiles of age-related changes in gene expression preserved during evolution. At the same time, the expression of other genes, including those that ensure the functioning of inhibitory intermediate neurons, changes only in aging mammals. In the brains of aging mice, the expression of some mitochondrial genes increases, and the rest decreases.

Despite the proven evolutionary preservation of a number of aging mechanisms and gene expression profiles, a recent direct comparison of changes in gene expression occurring as the brain ages in mice, rhesus monkeys and humans revealed significant evolutionary differences in changes in the expression of more than 150 genes. The expression of a significant part of the genes that control the aging process (mainly ensuring the functioning of neurons) increases in the brains of aging mice, but decreases in the brains of older people. According to the results of counting neurons in the cortex of the aging human brain using biochemical and stereological methods, these variations in gene expression profiles have no relation to the nature and rate of neuronal death. (Stereology is the analysis of three–dimensional objects based on their images, usually of a smaller dimension – flat, one-dimensional, point).

In any case, when working with animal models, it is necessary to take into account the specific features of changes in gene expression, since they can be determining factors in the development of neurodegenerative diseases.

Mitochondrial disordersThe results of the analysis of gene expression indicate that the reduced expression of mitochondrial genes is a well-preserved sign of aging of organisms in the course of evolution.

Apparently, the efficiency of the functioning of mitochondria has a pronounced effect on the aging process of all tested organisms and, depending on the conditions, can both positively and negatively affect their life expectancy.

It is logical to assume that a decrease in the efficiency of the functioning of mitochondria negatively affects the health of the body and reduces its life expectancy. Indeed, the results of a number of experiments on invertebrates and mammals testify to the validity of this statement. Various methods of stimulating mitochondrial functions, on the contrary, contribute to an increase in life expectancy. The mechanisms that prolong the life of model organisms have not been studied much, however, according to the most convincing hypothesis, increasing the efficiency of the electron transport chain reduces the synthesis and release of reactive oxygen species (ROS) that damage cell components and, thus, accelerate the aging process.

Mitochondrial dysfunction has a particularly pronounced effect on the brain and muscle tissue. Mutations of mitochondrial DNA cause hereditary human encephalomyopathies characterized by various disorders of the brain and muscles, the severity and age of manifestation of which depends on the number of pathologically altered mitochondria in the cell. There is every reason to assert that the normal extinction of mitochondrial functions can contribute to an age-related decrease in the efficiency of neurons and myocytes. In the human brain, the extinction of mitochondrial functions can have the most pronounced effect on populations of neurons with large bioenergetic needs, such as large pyramidal neurons that die in Alzheimer's disease. Thus, a decrease in the functionality of mitochondria can contribute to brain aging and increase the likelihood of age-related pathologies.

Paradoxically, under certain conditions, a decrease in mitochondrial functions increases life expectancy. For the first time, this phenomenon was discovered on nematodes with a mutation of the clk-1 gene, the protein product of which is involved in the synthesis of ubiquitin, which plays an important role in mitochondrial respiration. Such mutants are characterized by a reduced rate of mitochondrial respiration, manifested by a slowdown in their development, a decrease in activity and an increase in life expectancy. Screening conducted using the RNA interference method showed that a decrease in the activity of many genes that ensure the efficient operation of the electron transport chain can increase life expectancy. This effect is characterized by pronounced dose dependence. A moderate decrease in the efficiency of the electron transfer circuit increases the lifespan, while a strong decrease reduces it. Recently obtained data suggest that such an increase in life expectancy may be the result of triggering a nuclear transcriptional reaction to mitochondrial defects, called a retrograde reaction. Triggering this reaction leads to activation of genes that provide resistance to oxidative stress and detoxification of xenobiotics.

Selective suppression of the expression of electron transport chain components in neurons increases the lifespan of adult fruit flies. Mutant mice heterozygous for the Coq7 gene (the mouse orthologue of the clk-1 gene) are distinguished by longevity, which indicates a high probability of spreading this pattern to mammals as well. Moreover, transgenic mice characterized by reduced activity of the cytochrome-C oxidase complex (a component of the electron transport chain) also have a long lifespan and increased resistance of brain neurons to excitotoxicity. The underlying mechanisms of this phenomenon are unclear, but one possible explanation is that with a moderate increase in the concentration of ROS, they act as signaling molecules that trigger the mechanisms of cell survival and, accordingly, contribute to an increase in life expectancy.

The described phenomenon indicates the possibility that initially the decrease in the expression of mitochondrial genes observed in the cells of the aging brain may be part of an active compensatory mechanism for increasing resistance to stress. Such a compensatory reaction can be effective against short-term stress. However, chronic stress associated with aging can further suppress mitochondrial activity and trigger a vicious cycle of neurodegeneration (Fig. 2)

Figure 2. Mechanisms of regulation of aging of the brain and the body as a whole, preserved in the course of evolutionAbbreviations:

CR (caloric restriction) – calorie restriction of the diet
TOR –TOR-mediated signaling mechanism
ROS (reactive oxygen species) – ROS, reactive oxygen species
Ub – ubiquitin
IIS (insulin/IGF-1 signaling pathway) is a signaling mechanism mediated by insulin/insulin–like growth factor-1

Oxidative stress and epigenetic changesThere is a lot of evidence in favor of the fact that the accumulation of oxidative damage is the central mechanism of age-associated extinction of body functions preserved during evolution.

The study of changes in the expression of genes associated with aging of nematodes and fruit flies, as well as the brains of mice, rats, chimpanzees and humans demonstrated a marked increase in the expression of genes responsible for the formation of a reaction to oxidative stress. The use of dietary antioxidants can prevent the development of age-related changes in gene expression in mouse brain cells, and also helps to reduce the degree of deterioration of cognitive function and prevents oxidative damage to rat brain cells.

In the aging human brain, oxidative damage to specific promoters leads to the blocking of a number of genes. There is an assumption that non-regenerating postmitotic cells, such as neurons, react to uncorrected DNA damage not by entering apoptosis, but by triggering epigenetic mechanisms to suppress the activity of the damaged region of the genome.

The results of a recent study have demonstrated the important role of changes in epigenetic status in controlling the expression of genes that ensure plasticity of brain synapses and memory. The authors used a mouse model in which artificially induced expression of the p25 gene encoding the cyclin-dependent kinase-5 (CDK5) regulator caused neuron degeneration. Temporary expression of this gene caused neurodegeneration to a certain degree, loss of some synapses in the hippocampus and memory impairment. Exposure to certain external stimuli, as well as the introduction of a pharmacological form of a histone deacetylase inhibitor, increased the plasticity of synapses and contributed to the restoration of memories. These data indicate the important role of epigenetic changes in the mechanisms of memory loss associated with neurodegenerative processes. In addition, they point to the existence of differences between the mechanisms of loss of the ability to memorize and the mechanisms of loss of the ability to extract information stored in memory. Considering that the aging of the human brain is accompanied by memory disorders and a decrease in synapse activity, but not the loss of a significant number of neurons, it is possible that the loss of the ability to recall lies at the heart of age-related memory disorders. If this is the case, then there is hope that pharmacological interventions that alter the epigenetic status can eventually be used to improve the symptoms of cognitive decline associated with aging and neurodegenerative diseases.

Autophagy and protein metabolismStudies using model organisms have shown that autophagy (degradation of spent cell components in lysosomes with subsequent use of the obtained fragments as a building material) is a critical regulator of the aging process.

Activation of autophagy turned out to be a necessary condition for increasing the lifespan of nematodes under conditions of suppression of the activity of the signaling mechanism mediated by insulin-like growth factor-1 (IGF-1) and a low-calorie diet. Activation of autophagy in the neurons of fruit flies is sufficient to increase the lifespan of these insects, whereas suppression of autophagy causes neurodegeneration and premature death of fruit flies. The suppression of autophagy in mouse neurons has a similar effect. In transgenic fruit flies and mice whose cells are not capable of autophagy, neurodegeneration is accompanied by the accumulation of aggregates of ubiquitinated proteins, which resembles the symptoms observed in the brains of people with Huntington's and Alzheimer's diseases. The expression of the BECN1 gene, as well as a number of other key genes regulating the autophagy mechanism, decreases in neurons of the aging human brain, which may increase their susceptibility to the toxic effects of protein aggregates.

The signaling mechanism mediated by TOR kinase is a central regulator of protein homeostasis, acting by suppressing autophagy and mRNA translation. Reducing the activity of this mechanism prolongs the life of yeast, nematodes and fruit flies. Moreover, the TOR inhibitor rapamycin prolongs the life of mice even in cases when its administration is started at late stages of life. Rapamycin, by activating autophagy, suppresses the formation of pathological protein aggregates and slows down the progression of neurodegenerative diseases in model organisms. Thus, modulating the TOR-mediated signaling mechanism is a potential approach to the treatment of neurodegenerative diseases.

Accumulation of aggregates of ubiquitinated proteins can accompany normal aging of the human brain and usually reaches pathological levels in neurodegenerative diseases such as Alzheimer's disease and taupathies. The study of a mouse model with chronically reduced activity of proteasomes in brain cells revealed increased concentrations of several proteins in the brains of such animals, the expression of some of which is impaired in the brain cells of patients with Alzheimer's disease. Moreover, spatial memory disorders were observed in such mice, which confirms the potential role of proteasome disorders in the deterioration of cognitive functions associated with Alzheimer's disease. Aggregates of ubiquitinated proteins are practically not found in other aging tissues, which may explain the unusual longevity of postmitotic neurons that maintain a metabolically active status throughout a person's life.

Signaling mechanism mediated by insulin and insulin-like growth factor-1

A decrease in the activity of the insulin- and IGF-1-mediated metabolic pathway is a mechanism preserved in the course of evolution that increases the lifespan of nematodes, fruit flies and mammals. Polymorphisms of genes encoding two components of this mechanism (IGF-1 receptor and FOXO3 transcription factor) are associated with human longevity and healthy aging. It should also be noted that in order to prolong the life of some model organisms, it is enough to selectively reduce the activity of this mechanism in the cells of the nervous system.

In mammals, insulin and IGF-1 have a neurotrophic effect and prevent apoptotic death of neurons. They also improve the ability of humans and a number of animal models to learn and memorize. At the same time, suppression of the insulin- and IGF-1-mediated signaling mechanism in neurons is sufficient to increase the lifespan of mice. This indicates the duality of the effects exerted by these two factors. Indeed, inhibition of the considered signaling mechanism in nematode cells under certain conditions suppresses the accumulation of beta-amyloid plaques and cell death. And knockout of IGF-1 receptor genes or Irs2 insulin receptor substrate reduces the severity of cognitive impairment and neurodegeneration, and also prevents premature death of mice with Alzheimer's disease model. Patients with Alzheimer's disease are characterized by reduced expression of components of the insulin-mediated and IGF-1 signaling mechanism, but it is unclear whether this is a manifestation of an active neuroprotective reaction or a secondary manifestation of the neurodegeneration process.

Low-calorie diet and sirtuinsA low–calorie diet is a balanced reduction in the nutritional value of the diet, which does not lead to depletion of the body, is the only intervention known to man that consistently causes an increase in the life expectancy of many species, including primates (demonstrated on rhesus macaques).

A low-calorie diet has a beneficial effect on the functioning of the brain and reduces the risk of developing age-related pathologies. It prevents age-related changes in the expression of many genes in the brain of mice, reduces the severity of age-related brain atrophy in rhesus monkeys and has a pronounced positive effect on age-related learning and memorization disorders in rodents and humans. A three-month low-calorie diet was enough to improve the verbal memory of healthy elderly people by about 20%. There is evidence that a low-calorie diet forms resistance to Alzheimer's disease. This is supported by the fact that it reduces the accumulation of beta-amyloid and improves the learning and memory of mice with a simulated disease.

The molecular basis of the positive effects of a low-calorie diet has only recently begun to become clear. The yeast gene encoding NAD+-dependent deacetylase SIR2 was recognized as one of the first to be involved in the body's response to a low-calorie diet. A similar role of homologues of this gene (sirtuins) was demonstrated a little later in studies with fruit flies and mammals. However, the nature of the influence of sirtuins depends on many factors. For example, in mouse models of neurodegenerative diseases, increased SIRT1 activity prevents degeneration of damaged axons and age-related degeneration of brain cells. However, the fact that transgenic mice with short lifespans that do not have a functional Sirt1 gene are characterized by low levels of oxidative stress and more efficient functioning of neuroprotective mechanisms in the aging brain indicates the ability of SIRT1 to have a certain negative effect on the state of the brain. Given this inconsistency of the effects caused by sirtuins, future studies should be devoted to a detailed study of the mechanisms of action of sirtuins and their therapeutic potential in the treatment of neurodegenerative diseases.

The potential role of the brain in the regulation of agingRecently, there is more and more evidence that the brain is the central regulator of aging, coordinating the physiological changes of all body tissues.

A number of mutations that disrupt the work of sensitive neurons increase the lifespan of nematodes. Moreover, the removal of certain neurons can prolong the life of not only nematodes, but also fruit flies. An illustrative example of the central regulatory function of the nervous system is the ability of a pair of specific C.elegans neurons (ASI neurons) to change the lifespan of nematodes in a low-calorie diet. ASI neurons control the energy exchange of C.elegans, which makes them a kind of analogue of the mammalian hypothalamus.

The hypothalamus is a region of the brain that regulates metabolism and energy consumption, as well as coordinates the physiological processes occurring in the body through hormonal signals. Suppression of the action of hormones of the hypothalamic-pituitary axis increases the lifespan of mice. Moreover, overexpression of the uncoupling protein of mitochondria UCP2 in specific cells of the hypothalamus of rodents is sufficient to increase their lifespan. These data indicate the important role of hypothalamic hormones in controlling the aging process of the body.

The mechanisms triggered by hormones produced by the hypothalamus may play a role in the age-related deterioration of cognitive function. One of the components of the mechanism used by the hypothalamus to coordinate stress reactions is the regulation of the synthesis of glucocorticoid hormones in the adrenal glands. Glucocorticoids directly affect another region of the brain – the hippocampus, which in response, according to the principle of negative feedback, suppresses hypothalamic stimulation of the release of glucocorticoids (Fig. 3). However, excessive synthesis of glucocorticoids caused by chronic or acute stress can disrupt the functioning of hippocampal neurons and increase the likelihood of neurodegeneration. Moreover, primary neurodegeneration of the hippocampus in patients with Alzheimer's disease can disrupt the coordination of physiological processes in the body carried out by the hippocampus and hypothalamus. Perhaps there are other, unknown to date, hormonal mechanisms that ensure the integration of the functioning of the brain and the physiology of the body as a whole (Fig. 3 shows the dotted line.)

Figure 3. The potential role of the brain in the regulation of agingThe prospects

The main risk factor for neurodegeneration and cognitive decline is brain aging.

The mechanisms that have been preserved in the course of evolution that control the aging of the body, described above, influence the development of pathological changes in the brain and the process of deterioration of cognitive function in animal models of Alzheimer's disease and other neurodegenerative diseases. However, it is possible to study the role of these mechanisms in normal (age-related) and pathological deterioration of cognitive functions only by conducting targeted clinical interventions.

Recent data suggest that the relationship between certain regions of the brain deteriorates with age. The reason for this may be changes in gene expression that affect the functioning of synapses, as well as the integrity and myelination of axons. To date, it is not clear to what extent such a functional disruption of interactions between brain regions impairs the functioning of physiological feedback loops controlled by the brain. Such a loss of the integrity of relationships can contribute to the development of age-related physiological changes and ensure a person's predisposition to age-associated pathological changes in the brain. The study of the described hypothetical mechanisms in the future can bring scientists a lot of valuable information.

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Nature: Nicholas A. Bishop, Tao Lu & Bruce A. Yankner, Neural mechanisms of aging and cognitive decline.

14.05.2010