The integrity of the cerebral vascular system is one of the decisive factors for the preservation of human cognitive functions in adulthood and aging. There is strong evidence that cerebrovascular function decreases with aging. Many authors have shown an age-dependent deterioration in blood flow due to atherosclerosis and loss of innervation of the basal surface of the arteries of the brain.
Local blood flow in the cerebral cortex decreases already at the age of 40-50 years compared with its level in 20-22 years . When examining healthy people aged 20 to 59 years, M. Devous et al. Found an age-dependent decrease in blood flow (slope of the curve of blood flow versus age: –0.33 ml . Min . 100 g / year). A similar dynamics of the blood supply to the brain during aging is also observed in living animals .
The main changes in the BBB transport function during aging are associated with a restructuring of the connective tissue and smooth muscles of the large vascular walls, thickening of the vascular basement membrane, thinning of the endothelium, increased pericytic glia and loss of endothelial mitochondria. These changes, in general, entail deep violations in microvessels, the inclusion of foreign substances in the basement membrane, and changes in the specific proteins and lipids that form it. With aging, focal and transient gaps in the BBB develop. Thus, neuronal populations in a specific region of the brain become vulnerable. In old and senile age, the action of proteolytic enzymes on the basement membrane is also enhanced, which increases the permeability of the BBB with an increase in the transcellular transport activity of endothelial cells .
At the same time, for a number of substances, the BBB permeability decreases with aging. A decrease in the transport of hexose and butyrate, choline and triiodothyronine was found. The transport of most neutral and basic amino acids is stable during aging. However, methionine transport assessed by PET in humans decreases with age, starting at 5 years old . The potential mechanism of age-dependent changes is associated with an increase in the number of arteriovenous anastomoses, which deprives some parts of the brain of sufficient nutrition. Changes in microvessels are also caused by the restructuring of the protein composition and the accumulation of lipid peroxidation products together with a change in the viscosity of the membrane of isolated microvessels. The concentration of monoamine and purine metabolites and metabolic products of norepinephrine depends on the intensity of energy metabolism; the latter have a strong effect on the permeability of G EB . With aging, the neurotransmitter regulation of LMK also changes. The mediator activity, especially of beta-adrenergic neurotransmitters, is significantly reduced in cerebral microvessels during aging . Many neurotransmitters pass poorly through the endothelial membrane and accumulate inside the endothelium of the capillaries of the brain. The capillary walls normally contain DOPA decarboxylase and monoamine oxidase, which cleave neurotransmitters that act on blood vessels . With aging, this mechanism is disrupted. The deterioration of the BBB functions seriously affecting the brain activity: in particular, when such violations increases regularly slow rhythm EE D .
Along with the vascular system, the circulatory system of cerebrospinal fluid (CSF) is also aging. In this case, the choroid plexus is calcified, CSF turnover decreases. The arachnoid membrane thickens, and as a result, CSF is contaminated with various metabolites .
BBB permeability can be affected by substances in the blood, as well as blood acidity. With aging, the blood pH decreases (L. Frassetto, A. Sebastian, 1996) , which leads to a change in the flow of certain substances from the blood to the brain and CSF. It was shown that when rats were given drugs that lower blood pH, the intake of labeled sodium in the choroid plexus and CSF decreased. Acid salts were administered intraperitoneally to rats with removed kidneys and the rate of labeled sodium in various parts of the brain and in the CSF was determined. Severe acidosis (arterial blood pH 7.2) caused by injection of hydrochloric acid reduced the rate of sodium intake in both CSF and brain tissue by about 25%, while mild acidosis (pH 7.3) from NH injection 4 Cl reduced sodium intake in the brain by 18%, and in CSF by 10%.
So, although, in general, with aging, the transport of a number of substances to the brain decreases somewhat due to an increase in vascular resistance caused by atherosclerosis, the appearance of arteriovenous anastomoses and a change in the BBB permeability, the main substances freely reach the cells of nerve tissue.
The average level of oxygen metabolism significantly decreases with aging. With age, this indicator decreases significantly in the cerebral hemispheres, and more so in the left hemisphere. A particularly noticeable decrease in O 2 metabolism is observed in the region of the left caudate nucleus. The pattern is so characteristic that in some cases the rate of absorption of O 2 is used to determine the biological age.
A large number of works devoted to the age-related dynamics of brain energy metabolism are associated with the study of glucose metabolism. According to S. H , glucose is central to cerebral metabolism. It contributes to the synthesis of ATP and neurotransmitters: acetylcholine, glutamate, aspartate, GABA and glycine. Glucose metabolism in neurons is controlled by insulin and cortisol antagonist through gain and insulin desensitization RECEP tori .
Normal aging of the mammalian brain is associated with a number of genetic metabolic changes, which probably include primary hereditary variations of neuronal insulin receptors, desensitization of neuronal insulin receptors during the circulation of the stress hormone cortisol, and subsequent receptor dysfunction due to changes in membrane structure and function. The consequences of even mild impaired glucose metabolism and energy production are associated with changes in homeostasis that are characteristic of the aging process. Due to shifts in glucose metabolism and energy production, deviations in the binding and release of acetylcholine, Ca ++ exchange , etc. occur . Additional formation of free radicals and structural rearrangements of the membranes are considered as primary changes during aging. Stress in the elderly and senile age causes more severe and prolonged disorders of homeostasis, affecting the membranes .
According to most authors, cerebral glucose metabolism decreases with age in humans and animals . Total glucose consumption decreased by about 6% for every 10 le m . Only a few studies did not find changes in glucose uptake by the brain when calculated per unit volume of nerve tissue, taking into account non-severe cerebral atrophy, which usually occurs during normal aging .
Glucose hypometabolism can be observed in humans and animals even at normal levels of cerebral blood flow (D. Dastur et al., 1963). It was shown that in rats after 3 months, glucose consumption in many parts of the brain decreases, although blood flow remains normal until 12 months . Violation of the conjugation of blood flow and glucose metabolism during aging compared with adulthood is due to the use of other substances, in particular ketone bodies , as an energy substrate, in addition to glucose . Such a change in energy metabolism is accompanied by a decrease in cerebral pH .
With aging, glucose consumption varies in different parts of the brain in a different way. The most characteristic glucose hypometabolism in the frontal regions was found that with normal aging, a relative decrease in energy metabolism in the frontal regions is covariantly associated with an increase in metabolism in the parieto-occipital associative regions, basal ganglia, midbrain and cerebellum. A similar profile correlated with age. According to Dunn fired , glucose hypometabolism observed except the frontal areas and in other parts of the associative – temporal, temporo-parietal areas, and in the anterior cingulate gyrus and the anterior thalamus.
It was also found that during aging in conditions of calm wakefulness, the correlation between the level of glucose consumption in the frontal and parietal parts of the brain decreases in both men and women .
With aging, changes occur in the oxygen and glycolytic pathways of glucose metabolism in humans and animals. The activity of many enzymes of the glycolytic glucose metabolism is reduced (G. Ulfert et al., 1982). The content in the brain of rats of the end product of glycolysis – lactate decreases at the age of 24 and 30 months and corresponds to 91 and 87% of the level at a young age (G. Ulfert et al., 1982). Pyruvate content is reduced by 15% in the brain of rats at the age of 24 months compared with 12-month-old animals.
Due to mitochondrial changes, disturbances in the oxygen pathway of glucose metabolism occur, and these deviations are more significant than in glycolysis. With aging, changes occur in the mitochondrial genome (C. Lee , which leads to impaired mitochondrial functional activity, decreased tissue respiration, and oxidative phosphorylation.
The content of macroergic compounds – ATP and creatine phosphate compounds – gradually decreases with age. Thus, the level of ATP in the brain of rats was lower at the age of 12 months compared to the 6-month-old age 1.1 times, at 30 months the decrease was 6% from the level of 12 months. The level of creatine phosphate decreased in rats aged 24 and 30 months to 93 and 90%, respectively, of its content in 12 months .
In humans, creatinine and creatine in CSF as indicators energy brain metabolism (these substances are formed from the collapse of high-energy creatine phosphate compounds), also has a positive correlation with ages m .
With aging, the pH level in neurons decreases. Such an effect was revealed in studies of hippocampal sections in mice, and the extracellular pH did not change with age (E. Roberts, T. Sick, 1996). In the future, this pattern was confirmed in the study by NMR spectroscopy of intracellular pH in the occipital regions in healthy people between the ages of 23 and 69 years, were in a state of quiet Waking Ania . The authors also found that in people older than 40 years, immediately after photostimulation, the pH decreases, at a younger age this is not observed. The development of internal neuronal acidosis during aging can disrupt the processes of tissue respiration and oxidative phosphorylation in mitochondria and contribute to the enhancement of free radical oxidation .
T. Funahashi et al. (1994) showed that older gerbils are more susceptible to damage due to ischemia / reperfusion (PIR) than younger ones. Using the in vivo PIR method, it was shown that in the cortex the intracellular pH decreases to 6.35 with ischemia, and then increases with reperfusion, but in older animals it is significantly slower than in young ones. Macroergic phosphates of the brain decrease with ischemia and are restored by reperfusion in young animals after 20 minutes, and in older animals after 50 minutes. In vitro, it was shown that in homogenates of both young and old brain, the level of peroxidation increased when the pH decreased from 7.4 up to 6.4. It was found that at low pH endogenous Fe can catalyze to a greater extent damage caused by oxidative stress than at normal pH. Since the brain pH and the level of macroergic phosphates remain lower for a longer time in old gerbils during PIR, it can be assumed that brain mitochondria in old animals to a lesser extent than in young animals can withstand oxidative stress caused by PIR.
Thus, with aging, cerebral energy metabolism changes at all levels: cerebral blood flow decreases, BBB functions are impaired, conjugation between cerebral blood flow and glucose metabolism decreases due to the use of ketone bodies as an energy substrate, glucose metabolism is detected. Due to mitochondrial changes, tissue respiration and oxidative phosphorylation are reduced. Reduced, although to a lesser extent, glycolysis. In the nervous tissue, the content of macroergic compounds is reduced. The intracellular pH in the brain decreases. Although these changes during normal aging are relatively small, they increase the sensitivity of the brain to oxidative stress and other damaging factors.