CN112089709A - New application of vitamin K2 in preparation of medicines for delaying brain aging - Google Patents

Abstract

The invention relates to the field of medicine, and particularly discloses a new application of vitamin K2 in preparation of a medicine for delaying brain aging.

Description

New application of vitamin K2 in preparation of medicines for delaying brain aging

The invention relates to the technical field of medicine, in particular to a new application of vitamin K2 in preparing a medicament for delaying brain aging.

Background of the inventionbrain aging (aging of brain) is the process of brain growth and development into aging, and includes a series of slow changes of physiology, morphology and function, including neuronal degeneration and apoptosis (death) and brain atrophy, and decline of memory and thinking ability, which belong to normal inevitable life activities.

At present, the biological and molecular mechanisms of brain aging are not clarified, only brain aging can be considered as a natural process of life, can not be changed, and a medicine without specificity can be definitely used for resisting or delaying brain aging (the resisting or delaying brain aging can also be considered as a treatment means for the brain aging in a medical sense), and generally, only a medicine for promoting the blood circulation of the brain and nourishing nerves is adopted, and the effect is not clear.

The invention aims to disclose the application of vitamin K2 in the preparation of a novel medicament which can be used for delaying (i.e. treating) brain aging.

The applicant finds that the vitamin K2 has a definite effect of delaying brain aging, so the invention relates to the application of the vitamin K2 in the preparation of a novel medicament for delaying (i.e. treating) brain aging.

The invention also relates to a medicament for delaying brain aging, comprising vitamin K2, (K2, which appears separately in the present document, is vitamin K2), and a pharmaceutically acceptable carrier or diluent, which is diluted with soybean oil or/and glycerol, or with water, as an example, since K2 is fat-soluble.

Vitamin K includes naturally occurring K1, K2 and synthetic K3, K4, K5, K7. Among them, K1 is widely existed in various green plants, and human body can take in abundant K1 through green vegetables. But K2 has biological activity, so that the intestinal bacteria of human bodies can synthesize K2, and the human bodies can also convert part of ingested K1 into K2 in the liver.

Vitamin K2 is a fat-soluble vitamin, and includes a series of terpene side chain compounds containing 2-methyl-1, 4-naphthoquinone core and a number of isoprene structural units different from each other at C3, and is classified into K2(10), K2(20), K2(35), K2(40), etc. according to the number of carbon elements in the terpene side chain. The molecular formula is C16H16O2(C5H8) n.

The roles of K2 in humans have been found to mainly include: 1. promoting the formation of prothrombin, accelerating the coagulation and maintaining the normal coagulation time, so the composition can be used for accelerating the coagulation. 2. The primary osteocalcin secreted by the auxiliary osteoblast is carboxylated to become active osteocalcin, so that calcium ions in blood are promoted to generate bone calcium, and the bone density is increased, so that the composition can be used for treating and preventing osteoporosis. 3. K2 has been found to be useful against tumors, but the mechanism is not well defined.

The applicant finds that the K2 calcitonin can be used for delaying brain aging, has a remarkable effect, and can be used for preparing related medicines. The biological mechanism of the effect is analyzed and related to the induction and promotion effect of the blood calcium on the brain aging: the long-term high blood calcium level of the old can generate chronic toxicity to the brain cells of central nerves, especially cholinergic nerve cells, to cause cell necrosis, thereby causing brain atrophy and brain function reduction, namely brain aging. Vitamin K2 can promote calcium ion in blood to transfer to bone calcium, reduce blood calcium level, and reduce calcium ion concentration in brain cells, thereby delaying brain aging process.

The applicant has also analyzed the mechanism of brain aging, the cause of osteoporosis and hypercalcemia in the elderly, and some misunderstanding of this phenomenon from the current medical point of view, see the data attached later in this application, which may not be directly relevant to this application, but which is helpful to understand the therapeutic mechanism of this application.

It should be noted that the brain cells belong to highly differentiated non-dividing cells, the brain cells reduced by degeneration and death are not generally regenerated, and the process of brain aging is irreversible, so that K2 cannot cure and recover damaged brain cells, but rather impedes and delays the damage process, i.e., the process and the development speed of brain aging. Of course, impedance and retardation of brain aging may also be regarded as a therapeutic means for brain aging in a medical sense, as long as such impedance and retardation have an effect, i.e., can be regarded as having a therapeutic effect on brain aging. Moreover, K2 promotes the transfer of calcium from blood to bone calcium, reduces the higher calcium ion concentration inside and outside the brain cell membrane, improves the nerve activity of brain cells, especially cholinergic nerves, and thus can play a role in rapidly improving memory and thinking activity, which all have positive medical significance.

Description of the drawings figure 1 is a schematic diagram of the projection structure of the cholinergic nerve and associated nerve nuclei of the brainstem network. FIG. 2 is a schematic diagram of the projection of the cholinergic nerves and associated nuclei of the limbic system compartment and basal forebrain. FIG. 3 is a schematic diagram of the human blood calcium regulation mechanism. FIG. 4 is a schematic diagram of the induction and progression of brain aging.

The use and practice of the invention is described below.

Firstly, a medicine containing K2 is prepared by adopting vitamin K2. The invention relates to a new application of vitamin K2, and a medicine prepared from the vitamin K2 is used for delaying and treating brain aging. The acquisition of K2, the preparation of injection or capsule can directly adopt or refer to the technology of K2 related medicine for treating osteoporosis.

The medicament of the invention comprises vitamin K2, and a pharmaceutically acceptable carrier or diluent, wherein the carrier or diluent is soybean oil or/and glycerol or is diluted by water because K2 is fat-soluble.

Obtaining materials: vitamin K2 has previously been used to accelerate blood coagulation or to treat osteoporosis and is well established and commercially available. For example, Flavobacterium or other suitable bacteria are used for fermentation culture in a culture medium, and then organic solvent extraction is used for obtaining the product.

The administration mode is as follows: the medicine can be in the form of capsules or injections and is administered orally or by injection. Preferably orally in capsules. Since K2 is fat soluble, it can be made into capsule with soybean oil and glycerol, and is convenient for oral administration. An exemplary 50mg size capsule is made from about 25mg soybean oil, 25mg glycerin, and 100 μ g vitamin K2, with 100 μ g vitamin K2 as the active ingredient.

The dosage of the medicine is as follows: the dosage of K2 in delaying brain aging can be basically similar to that in treating senile osteoporosis, for example, the dosage of K2 contained in the medicine is as follows: is administered in one or two times per day at a dose of 100-300 μ g (microgram). As a preventive and health care, the lower dosage can be reduced to about half of the aforementioned dosage: 50-100 mug (microgram) per day, administered in one or two doses. One suitable common amount: 100 μ g (μ g) each time, once a day. Or as determined by a physician, depending on the circumstances. (obviously, K2 is used in adult amounts for treating or preventing brain aging, so children's amounts are generally not considered).

Generally, even if K2 is used in a slight excess amount, no obvious toxic and side effects exist, and the problems of nausea, jaundice, rash, inflammation and the like sometimes occur in very few people, so the administration is stopped and doctors are consulted.

Secondly, the application and the effect of the medicine prepared by K2 in delaying the brain aging.

Because brain aging is not organic lesion or functional abnormality but only slow decline of brain function, and the effect of K2 on brain aging is not capable of reversing the aging, but delaying the brain aging process and improving brain function, the verification of the curative effect cannot adopt ex vivo brain cells to carry out experiments, cannot find direct physicochemical indexes in human bodies, and can only adopt subjective brain function evaluation.

Experimental arrangement: 20 healthy old people aged 75 plus or minus 2 years and 10 healthy old people aged 75 years and 2 healthy old people aged 75 years and 10 healthy old people aged male and female, respectively, have no other diseases which can obviously affect brain functions, and are divided into two groups, namely an experimental group and a control group, wherein 10 healthy old people aged 75 years and 10 healthy old people aged 2 years are aged 10 healthy old people aged 75 years. Vitamin K2 and placebo were administered separately, wherein the experimental group used 50mg size capsules consisting of soybean oil, glycerol and K2, containing 100 μ g of K2, orally one tablet per day. The control group was a 50mg size capsule made of only soybean oil and glycerin, and was orally administered one capsule per day. The two groups are administered for 1 month, and are administered for 1 month at an interval of one month, with a total period of 1 year. Through comprehensive evaluation of the memory, thinking ability, mental state, operation ability and daily activity ability of the family members, the score is obviously changed into-2, the score is slightly changed into-1, the score is not changed into 0, the score is slightly improved into +1, and the score is obviously improved into + 2.

The results are shown in the following table.

Table 1: evaluation table of effect of calcitonin for delaying brain aging. (unit: human).

Since brain aging is slow and the 1 year period is short, the number of "unchanged" people in both experiments is a large proportion. But the two show more significant difference compared with other terms: the number of "significantly worse", "somewhat worse" individuals in the control group was significantly greater than in the experimental group, while the number of individuals in the experimental group who did not "significantly worse", "unchanged" or "somewhat improved" were also significantly greater than in the control group. The experiment group has obvious impedance effect on the brain aging and can delay the process of the brain aging.

The applicant has also called for attention to the effects on brain aging of abnormal phenomena in the elderly, in which blood calcium levels are generally high. (see accompanying data below for details).

Accompanied by data. The pathogenesis of brain aging and senile dementia and the wrong way of calcium supplement for the elderly. The following is the research and analysis data of the applicant on brain aging and senile dementia, which may not be directly related to the technical scheme of the invention, but is helpful for understanding the application principle of the invention. The applicant also hopes to disclose these data by way of patent application, so that medical personnel can study more technologies for delaying brain aging and treating senile dementia, and pay more attention to the negative effects of the current popular theory and practice for calcium supplement of the elderly.

Brain aging (aging of brain) is a phenomenon that the brain grows and develops into an aging stage, and a series of slow changes of physiology, morphology and function occur, including degeneration, failure and death of brain cells, brain atrophy caused by the degeneration, failure and death of brain cells, reduction of cognitive, memory and thinking abilities, partial memory loss and the like. Brain aging is a process of normal vital activities, and basically occurs in every person, but the time and the process of occurrence are different.

1. The current theory of brain aging. There is no known theory on the mechanism of brain aging, and many scholars put forward different theories from different perspectives, and the following are more important.

The theory of free radicals: also known as the theory of oxidative damage. It is believed that free radicals produced by the metabolic processes of cells damage brain cells, causing cell degeneration and death, leading to brain aging. There are other similar theories of cell damage accumulation.

The theory of DNA association: including the theory of DNA damage, the theory of mitochondrial DNA mutation, the theory of telomeres, and the like. It is believed that damage, mutation or alteration of intracellular DNA induces brain aging.

The theory of immunity and endocrinology: changes in the immune and endocrine systems of the body are thought to lead to brain aging.

The theory of the gene is as follows: brain aging is thought to occur naturally, under the control of presenile genes.

The common mechanistic theory is as follows: aging is considered to be a process in which the above-mentioned factors act together, affect each other, gradually accumulate, and change from quantitative to qualitative.

It is to be noted that these theories are basically the theories of life aging, and can be said to be mechanisms of aging of other organs and tissues of the human body, and there is no specific mechanism for brain aging. However, in humans, the brain is specialized, and brain cells are highly differentiated cells and do not divide and reproduce since birth, so that it seems that the DNA damage theory, the mitochondrial DNA mutation theory and the telomere theory are not suitable for explaining brain aging. In addition, the brain has a blood brain barrier, and many substances in the systemic circulation even including partial immune substances and hormones secreted by the human body can not enter the brain through hematology and encephalology, so the biochemical environment of brain cells is relatively stable and is not easily influenced by environmental factors. In the genetics, what is the induction factor, because brain aging occurs at a certain age, which indicates that even with a gene that affects brain aging, it needs to be expressed under the induction of a certain factor? How does the gene affecting aging, in turn, express? Nor is it currently elucidated. Although it is easy to understand the increase of free radicals leading to cell damage and death in the theory of free radicals, it is also proved by a lot of experiments, however, the free radicals are used as the intermediate products of biological metabolism, which are generated as an intermediate result in the process of brain aging, so that the free radicals can exist in the process of brain aging, but cannot be the initial cause of brain aging. For the common mechanistic theory, although it is easy to understand that biological aging is an irreversible process caused by the interaction and interaction of various factors, it always has an induction, initiation, and subsequent change process? Then, what is the most important causative factor? How is the process of change induced? Nor is it currently elucidated.

2. The applicant analyzes the induction and influence of substance concentration in blood plasma, especially calcium ion concentration, on brain aging according to the working mechanism of the brain, especially according to the working process of the cholinergic nerve of the brain in carrying out synaptic transmission action and the control mechanism of the cholinergic nerve on brain function.

2.1 aging of the body not the aging of cells of an organ or a part, but a substantially simultaneous aging process involving organs, tissues and cells of various parts of the body, can cause various cells to enter a certain process almost in unison, more probably two factors: it is natural and essential that the gene itself determines the cell's division, reproduction and activity, and thus its aging and death. Secondly, the cells are affected by the change of certain physicochemical environment, which is mainly the change of the concentration of various extracellular substances for the cells, which affects the activity of the cells and may cause the cells to enter the aging process. Of these two factors, the former (genetic factor) is an internal factor, the latter (physicochemical factor) is an external factor, and more likely, the former is a cause, and the latter has an inducing and promoting effect on cell aging. However, it is known that brain cells are differentiated cells and generally do not undergo division and propagation, so that changes in the physicochemical environment outside the brain cells may have a greater influence on the induction and progression of brain aging.

The basic form of life existence is cells, which is also the fundamental difference between life and non-life substances. The cell membrane separates the substance world inside and outside the cell, and forms the difference of various substance concentrations, especially various ion concentrations through a semipermeable membrane, and various substances, especially various ions, perform the movement of flowing in and out through various channels inside and outside the cell membrane due to the concentration difference, which is the most basic action of life and is the essence of life activity. Therefore, the change of the concentration of substances inside and outside the cell membrane, especially the change of the concentration of various ions, can directly affect the movement of ions inside and outside the cell membrane, thereby affecting the physiological activities and functions of cells and triggering the growth, activity, aging and even death of the cells. Among them, the influence of the change in the concentration of calcium ions on the cell activity has been widely recognized and experimentally confirmed.

The brain is mainly composed of nerve cells, and the nerve cells perform actions such as signal transmission, integration, triggering and the like through the flow of various ions and substances (including neurotransmitters and neuromodulators) inside and outside the cells besides the influence of the ion concentration on the cell activities of the nerve cells, so that various brain functions are realized. Therefore, various concentrations of substances, including ion concentrations, are particularly important for the proper functioning of brain cells. The ions directly involved in nerve activity, most notably potassium ion K +, sodium ion Na +, and calcium ion Ca2+, and various ion channels that control their activity. The potassium channel and the sodium channel are mainly used for signal transmission and integration of postsynaptic membranes, and under the action of neurotransmitters, the sodium channel and the potassium channel are opened or closed to cause the flow of sodium ions and potassium ions, so that the change of membrane potential is triggered, and whether neurons can integrate and trigger action potential or not is determined, namely, the relationship between 'yes' and 'no' is determined. The calcium ion channel can coexist in a pre-synaptic and post-synaptic membrane, wherein the pre-synaptic membrane is a voltage-gated calcium channel which is commonly present in neurons of various neurotransmitter types and controls synaptic transmission by controlling the release of various neurotransmitters; while postsynaptic membrane calcium channels are primarily ligand-gated channels, the most prominent of which are cholinergic receptor-gated channels of the cholinergic (ACh) nerve. In cholinergic nerves, both the presynaptic membrane's voltage-gated calcium channels are relied upon to control calcium influx to release cholinergic neurotransmitters, while the postsynaptic membrane's cholinergic ligands open and are primarily calcium channels, producing membrane excitatory potentials by calcium influx. Therefore, if it is stated that the change of the calcium ion concentration affects the activity of brain cells, the most significant is the cholinergic nerve whose presynaptic and postsynaptic membranes depend on the calcium ion channel to work.

Here we also strongly note that, according to the existing clinical data, in the brain of brain aging, especially senile dementia (AD), a particular pathological condition of brain aging, it is the cholinergic nerve that is most damaged and most seriously damaged first. Therefore, it is necessary to analyze the action of cholinergic nerve on brain work and the influence of the change of extracellular calcium ion concentration on cholinergic nerve work to reveal the influence of the change of calcium ion concentration on brain aging and senile dementia.

2.2 the role cholinergic nerves play in brain working mechanisms. The applicant analyzed the different roles of the neurons of different neurotransmitters in the information processing of the central nervous system of the brain in the specification of the previously filed chinese patent application 2015101775882, "multichannel neurostimulation device and its applications": the brain mainly adopts amino acid energy nerves to form a main channel for information processing, adopts cholinergic nerves to generate exciting pulses to excite and control the nerve activity of the information processing channel in a time sequence mode, adopts single (group) aminergic nerves and neuropeptide nerves to carry out various modulations on the nerve activity of the information processing channel, and therefore joint processing of information is achieved together.

In the postsynaptic membrane, the ligand-gated channel of cholinergic neurotransmitter ACh reacts very fast without the pre-existing depolarization of the cell membrane, and under the conditions of resting potential and hyperpolarization, once the ligand is combined with a receptor, the gated channel can be directly caused to be opened, calcium ions flow in rapidly to cause strong membrane excitation, and most of the channels can directly cause the outbreak of action potential. Furthermore, the axonal release of ACh from cholinergic neurons is rapid and transient, and after release, ACh, in addition to binding to receptors, also diffuses out of the synaptic cleft and is rapidly degraded by cholinesterase, i.e., ACh in the synaptic cleft can be rapidly cleared after release. Therefore, the action potential pulse of cholinergic nerve has the characteristics of rapid and strong synaptic transmission action and rapid recovery, and can often make the projected neurons of the postsynaptic membrane generate strong membrane excitation and trigger action potential.

This characteristic of cholinergic neurons makes them suitable for motor output of peripheral nerves, nerve-muscle junctions, cardiac muscle, smooth muscle, etc., while in the central nerve of the brain, cholinergic nerves are mainly concentrated in two major sites: the first is brainstem network. The cholinergic nerve nuclei in the inner area and the outer area of the brain stem network structure and the thalamus, the hypothalamus, the superior thalamus and the like form a synchronous pulse oscillation loop respectively, and the work of the thinking nervous system, the motor nervous system, the visceral nervous system and the endocrine nervous system of the brain is controlled in a mode of excitation pulse and time sequence control, and related signal projection is shown as a figure 1. Most typically, the synchronous pulse oscillation loop of the thinking system is formed by the back and forth projection of the 'midbrain reticular structure (brain stem reticular structure inner side region) → thalamus plateaus kernel → thalamus reticular core → mesencephalon reticular structure', the synchronous pulse oscillation loop emits lateral branches to cortical neurons on nodes of the thalamus plateaus kernel, and the thinking activity of the thinking system, particularly the maintenance and switching of the 'attention' direction of the thinking system, are controlled by the excitation pulse. The second is the medial septal and oblique zonal nuclei present in the limbic compartment, and the Meynert basal nuclei of the basal forebrain (basal forebrain complex). The associated signal projection is as in figure 2. The projections and actions of this part of the cholinergic nuclei include: projecting upward cortex, particularly sensory cortex and motor cortex (including a tattoo), and cooperatively exciting integrated processing of sensory information and motor information, particularly cooperatively generating synaptic plasticity to form cognitive memory and motor action memory (namely, programmed memory); projecting towards the cingulate gyrus and the hippocampus structure, and carrying out cooperative excitation on the integrated treatment of intermediate information (namely declarative information) of a thinking system, particularly synaptotactic plasticity is generated cooperatively to form long-term memory, namely hippocampal memory; and performing bidirectional mutual projection with the amygdala and the hypothalamus to perform mutual modulation on the work of each other and cooperatively form emotional memory.

Therefore, the cholinergic nerve is mainly used as a synchronous excitation pulse in the central nerve of the brain, and plays an important role in exciting and controlling the nerve activity of an information processing channel, similar to the clock signal and time sequence control function of an electronic computer. If there is a problem with cholinergic nerves, such stimulation and timing control will be problematic, and the activities of other neurons will be impossible or chaotic, and the brain functions such as cognition, memory, thinking, and emotion will be severely affected.

2.3 cholinergic nerve activity is affected and impaired by calcium ion concentration.

2.3.1 synaptic transmission of cholinergic nerves includes:

firstly, a synaptic front film: action potential transmission to axon terminal → depolarization of presynaptic membrane → opening of calcium ion channel of presynaptic membrane → influx of extracellular calcium ion → release of vesicle of transmitter ACh → entry of ACh into synaptic cleft;

the method comprises the following steps: ACh binds to receptors in the posterior membrane → receptor activation opens ion channels → influx of positive ions, especially calcium ions → production of membrane potential excitation, which triggers the action potential of the posterior membrane neurons when the excitation potential reaches a threshold.

During this synaptic transmission action, the requirement for calcium ions: before action, namely in a resting state, the calcium ion concentration in cells is low enough, so that ACh cannot be released in advance, and therefore, the transmitter vesicle has enough ACh storage to ensure high sensitivity to action; during action, the extracellular calcium ion concentration is high enough to ensure sufficient calcium ion influx and produce a strong enough physiological activity for synaptic transmission. Under normal resting conditions, the extracellular calcium ion concentration is about 2mmol/L, while the intracellular cytosolic calcium ion concentration is 0.1-0.2. mu. mol/L, which are maintained at a very high concentration difference of about 10000 times, so that the transmission action can be stronger and quicker when the pulse signal of the axon comes, i.e. the synaptic transmission action is better completed.

Cells maintain this concentration difference in a two-dimensional balance: under a resting state, high-concentration calcium ions outside the membrane continuously enter the cells through diffusion due to concentration pressure, and the calcium ions entering the cells also cause a small amount of release of a calcium reservoir in the cells; in a resting state, the mechanism of calcium ion efflux in cells mainly comprises: free calcium ions are continuously transported to the outside of cells by means of a plasma membrane calcium ion pump, namely, calcium ion-ATPase, and when the concentration of the calcium ions in the cells is increased, the calcium ions can be combined with calmodulin to activate the calcium ion pump so as to accelerate the discharge of the calcium ions, and in addition, the calcium ions are absorbed and fixed in an intracellular calcium reservoir through the calcium ion pump and exist in the form of inorganic calcium (calcium oxide, calcium phosphate) or organic calcium (protein calcium), so that the concentration difference is jointly maintained. In the balance of calcium inside and outside a cell body in a resting state, calcium ions enter the cell body because of ion concentration difference, and the action of energy consumption is inevitable, and the discharge of the calcium ions is the transportation of inverse concentration, so the energy consumption is needed.

When the action potential comes and synapse transmission action occurs, calcium ions mainly enter by opening a calcium ion channel in a large amount and trigger large amount of release of calcium ions in an intracellular calcium reservoir, so that the concentration of the calcium ions in the cell is rapidly increased and the transmission action is triggered, and after the transmission action is finished, the calcium ions are discharged by mainly depending on a sodium ion-calcium ion exchanger and are fixed in the intracellular calcium reservoir again.

2.3.2 and when the concentration of calcium ions around the brain tissue, i.e. outside the brain cells, changes, the effect on the activity of the brain cells is:

the method has the advantages that when the concentration of extracellular calcium ions is insufficient, calcium ions are insufficiently flown when a calcium channel is opened, so that the release of neurotransmitters of a presynaptic membrane is insufficient, the membrane excitation of a posterior membrane is insufficient, and the efficiency of synaptic transmission is directly insufficient or even fails.

And secondly, on the contrary, when the concentration of the extracellular calcium ions is too high, the activity of cells can be seriously influenced, and the hypercalcemia is also caused. Hypocalcemia and hypercalcemia have many studies related thereto, and the mechanism and symptoms thereof are omitted here.

And when the concentration of extracellular calcium ions is temporarily higher, the release of the pre-synaptic membrane neurotransmitter is favorably improved, or the membrane excitation potential of the posterior membrane is improved, so that the synaptic transmission efficiency is enhanced, and certain positive influence is exerted on synaptic plasticity.

Fourthly, when the concentration of the extracellular calcium ions is higher for a long time, although the level of the extracellular calcium ions is not reached, the symptom of the hypercalcemia can not appear yet, because of the high concentration for a long time, more calcium ions can enter the cells through diffusion in a resting state and exceed the calcium discharge capacity in the cells, the calcium balance is broken to increase the intracellular calcium ions (although the concentration is still far lower than the extracellular concentration) until a new calcium balance is formed, and the intracellular calcium ion concentration is higher under the new balance. Furthermore, the increase in extracellular calcium concentration also allows more calcium ions to enter the cells each time the calcium channel is opened, which also results in excessive free calcium ions in the cells. The damage of the excessive intracellular free calcium ions to cells has been proved by research. The damage mainly comprises: more free radicals are generated, cell structures are damaged, and amyloid (A beta) precipitates are generated to form nerve Senile Plaques (SP); activation of more calpain kinases, leading to tau hyperphosphorylation; the ACh transmitter in the transmitter vesicle is abnormally released in a resting state, so that the reserve amount of ACh of the presynaptic membrane is reduced; some of these released ACh mediators are lost by enzymatic breakdown, and some bind to the ligand of the postsynaptic membrane, causing the ligand-gated channel to be opened abnormally and prematurely, resulting in desensitization of some channels.

2.3.3 summarizing, the long-term high calcium ion concentration around brain tissue can cause excessive intracellular free calcium ions, thereby causing two major damages to cranial nerves: one is structural and physicochemical damage to the nerve cells themselves, which can accumulate and ultimately lead to brain cell death. Secondly, abnormal physicochemical reaction is generated in advance, so that the transmitter reserve of the presynaptic membrane is reduced, partial ligands of the postsynaptic membrane are combined in advance and are desensitized, the synaptic transmission efficiency is reduced and even fails, and the pulse sending action of the neuron is weakened and even ineffective. The damage should be extensive in a variety of cells, but as both the anterior and posterior membranes of cholinergic nerves rely primarily on calcium ion channels to function, cholinergic nerves become more sensitive to the damage, the damage occurs earlier and the damage is more severe. From the above analysis of "the role of the 2.2 cholinergic nerve in the brain working mechanism", we know that the cholinergic nerve is mainly used as a synchronous excitation pulse in the central nerve of the brain to play an important role in excitation and control, similar to the clock signal and timing control of an electronic computer. If the cholinergic nerve is in a problem, the stimulation and the time sequence control are in a problem, the activities of other neurons cannot be carried out or are disordered, and the brain functions such as cognition, memory, thinking, emotion and the like are affected, so that the other neurons are disabled and disused, so that the neurons are degraded and even die, and various manifestations of brain aging are further aggravated.

Then, do the extracellular calcium ion concentration in brain cells increase for a long time in the elderly? This is true in the case of the elderly, who have long-term abnormal high levels of calcium due to problems with bone degeneration and the regulation mechanism of calcium in the blood, and which, despite the blood-brain barrier, have long-term high levels of calcium ions surrounding brain tissue, as will be analyzed below.

2.4 blood calcium, regulation of blood calcium and abnormal blood calcium of the elderly.

2.4.1 calcium in humans, regulation of blood calcium. The calcium in human body mainly exists in the form of bone calcium and blood calcium, wherein the bone calcium accounts for most of the calcium and is equivalent to a calcium storage warehouse, and the blood calcium has little amount but has great influence on the physiological activities of the human body. The normal blood calcium concentration defined in the current medicine is 2.25-2.58 mmol/L, and the lower or higher range is easy to cause hypocalcemia and hypercalcemia, and more serious symptoms appear. In order to maintain the blood calcium level stable, the human body has a set of blood calcium regulation mechanism, which is the current medical knowledge, and the regulation mechanism and the pathway are shown in fig. 3. In brief, the following: when the blood calcium level is too low, the parathyroid gland increases the secretion of parathyroid hormone (PTH), on one hand, promotes renal tubules and small intestines to enhance the calcium uptake and absorption, on the other hand, stimulates the osteoclast activity of bones, so that more bone calcium is decomposed and released into blood, and the blood calcium level is rapidly increased; when the blood calcium level is too high, the thyroxine secretes a little, and the thyroid C cells increase the secretion of Calcitonin (CT), so that on one hand, the absorption of calcium by renal tubules and small intestines is reduced, on the other hand, the osteoclast activity of bones is inhibited, the osteoblast activity is relatively promoted, the blood calcium is combined and fixed into the bones to form bone calcium, and the blood calcium level is reduced; the body maintains the blood calcium level stable through the secretion balance of parathyroid hormone PTH and calcitonin CT. In this regulatory mechanism, the interconversion of bone calcium and blood calcium is more rapid and important since bone calcium has a greater reserve, while the uptake and absorption of calcium by the renal tubules and small intestine is less effective.

2.4.2 clinical data show that the blood calcium level of human body is characterized by high in both heads and low in the middle of young and middle of young children and old people. For children, since the whole body is in a vigorous growth phase, bones are growing and renewing rapidly, osteoblasts and osteoclasts are active and bone formation is greater than that of osteoclasts, it is understandable to maintain a high blood calcium level, which is equivalent to maintaining a transit warehouse with sufficient calcium material to meet the needs of bone growth. Moreover, during this vigorous growth process, the body of the child is also very powerful in scavenging free radicals and other toxins, so that higher blood calcium levels do not cause any damage to the body of the child. By the middle-aged and young years, the skeleton is no longer growing but is renewed, the activities of osteoblasts and osteoclasts are in equilibrium, and the blood calcium level is reduced, which is also normal and reasonable. The bone of the elderly only degenerates but does not grow, the demand of the body of the elderly for calcium is not much, however, after the age of 50 (climacteric), the blood calcium level of the human body is abnormally and generally increased and reaches the highest level of life in the age of 70, and at the same time, the bone calcium content of the human body is reduced year by year, so the total calcium content in the human body is also reduced year by year, and osteoporosis is easy to occur, which is obviously abnormal.

For such abnormal phenomena, the currently popular view is that: the old people have poor calcium absorption function, so that the blood is lack of calcium, and therefore, the old people absorb bone calcium and release the bone calcium into the blood calcium through a blood calcium regulation mechanism, so that the blood calcium is higher and the osteoporosis is caused. The applicant believes that this view is erroneous. (see point 5 later, namely '5. analysis of errors of the existing calcium supplement theory and practice for the old'). The applicant analyzed that: osteoporosis in the elderly is not induced by insufficient calcium absorption and low blood calcium, but is most often caused by changes in hormone secretion in the elderly. First, sex hormone secretion changes, which affect the balance of secretion of parathyroid hormone PTH and calcitonin CT, PTH is increased relative to CT secretion, resulting in decreased osteogenic activity and increased osteoclastic activity, more osteocalcium is released into the blood calcium due to osteoclastic activity, resulting in bone degeneration, i.e., osteoporosis, and also in elevated blood calcium. Secondly, in the process of osteogenesis, vitamin K2 is needed to assist the carboxylation of osteocalcin to promote the calcium ion in blood to generate bone calcium, the gastrointestinal flora of the elderly is changed, the capacity of synthesizing and converting K2 is reduced, K2 is insufficient, the osteogenesis activity is influenced to cause bone degeneration, and osteoporosis and blood calcium increase are also caused. In addition, the aged may have reduced stimulation intensity and weakened strength to bones and muscles due to reduced limb activities, especially high-intensity activities, and may also cause bone degeneration, promoting the progress of the change. Therefore, the change and activity of hormone secretion are reduced, which leads to the contradiction of osteoporosis and high blood calcium in the elderly. Of course, this is only to cause the elderly to have hypercalcemia in the normal range, or just slightly out of the normal range, and is mostly insufficient for morbid hypercalcemia, so that this phenomenon is not of much concern.

2.4.3 in conclusion, the higher blood calcium of the elderly is a common abnormal phenomenon. Although the brain has a blood brain barrier, the blood brain barrier does not prevent calcium ions, but dynamically regulates the calcium ions under a balance mechanism (the activity of cranial nerves depends on the calcium ions), and when the blood calcium level is high for a long time, the calcium ion level outside brain cells is also high, and further the calcium ion level inside the brain cells is high until a new balance is formed. Therefore, when the blood calcium level of the old is high for a long time, the calcium ion level in brain cells is high, so that the brain cells are damaged chronically, namely, the brain aging is induced.

The applicant analyzed: for the elderly, even if the phenomenon of high blood calcium is not generated, the concentration of intracellular calcium ions is likely to be high, because in calcium balance, the inflow of extracellular calcium ions is generated due to the extremely high concentration difference between the inside and the outside of the membrane, and is a natural diffusion action without energy consumption, the efflux of intracellular calcium ions is a reverse concentration transport, and needs to depend on an ion pump and consume energy, and because the metabolism of the elderly is reduced, the cell activity is reduced, and the energy supply is reduced, the extracellular calcium discharge capacity of the elderly is reduced, so that the intracellular calcium ion balance is deviated, the intracellular calcium ion concentration is increased in a resting state, and chronic cell damage, namely brain aging is caused. (this can be confirmed by experiment).

2.5 other causative factors of brain aging. Brain aging, like aging of other organ tissues, is more of a systemic, variable process that can be induced by a variety of factors and carried out by interacting with each other through a variety of actions. In addition to the induction of higher calcium ion levels mentioned above, brain aging may also be induced by several other factors.

2.5.1 brain use for a short period of time. The long-term poor neural activity, especially the long-term poor memory activity, can cause the synaptic connection between neurons established by means of memory to be weakened or even partially fail, which can cause the capability of thinking or forming new memory to be reduced, thereby further causing the neural activity to be reduced, and the connection of the whole neural network gradually becomes sparse due to sequential circulation, which belongs to a change of using one to waste and another to retreat. In addition, when the neural network is in tension thinking or forms memory, the cholinergic nerve needs to emit a high-rhythm excitation pulse, and the long-term lack of thinking or memory activity indicates that the cholinergic nerve is in low-rhythm emission for a long time, namely the cholinergic nerve is in a low-function state for a long time, so that the cell metabolism is too low, and the damage is caused to the cells. This is also the reason why people with a short brain life are prone to brain aging. Therefore, proper use of the brain, especially for memory activity, is of interest in preventing brain aging.

2.5.2 prolonged overuse of the brain, stress, anxiety, or depression. Conversely, prolonged excessive brain use, mental stress or anxiety can be detrimental, in which cholinergic nerves sustain prolonged high-rhythmic stimulation pulses (EEG signals show high-rhythmic EEG) that cause the calcium channels to open more frequently and more calcium to enter the cells, (especially when the calcium concentration is high) and if there is insufficient time for the calcium-ATPase to transport the calcium out of the cells, the intracellular free calcium will be excessive and the neurotransmitter reserve will be insufficient, causing cell damage and functional decline, inducing brain aging (i.e., the "2.3 cholinergic nerve activity affected and damaged by the calcium concentration" section). This is also the reason why brain aging is likely to occur in people who have prolonged excessive use of the brain and anxiety and depression due to mental stress. Therefore, in order to prevent brain aging, it is necessary to have enough time for the brain to rest after high-intensity thinking or memory activity, or high-rhythm neural activity such as mental stress and excessive anxiety, and especially to perform enough slow wave sleep (i.e. deep sleep in which the neural activity is in a very low rhythm state of 0.5 to 3 hz), which is obviously one of the biological positive meanings of sleep, especially slow wave sleep.

2.5.4 influence of the Gene. The age of brain aging and the progression rate of brain aging vary from person to person, and therefore, certain genetic influences are also involved. This may include affecting the expression of genes involved in A.beta.protein precipitation and in the hyperphosphorylation of the au protein, and may also affect differences in the calcium influx and calcium efflux capacity of the plasma membrane of brain cells, and so forth. But it is clear that the genes only affect the brain aging process and not the initial causative factors.

2.5.3 Induction of other drugs or substances. Clinical studies have shown that certain drugs or substances (e.g., aluminum) induce early onset of brain aging and even Alzheimer's disease. Applicants believe that these drugs or substances may act indirectly through a variety of triggering mechanisms. For example, by affecting calcium balance, resulting in an increase in calcium ion concentration, or by affecting neurotransmitter or mediator release or absorption, to affect neuronal activity and function, and the like. But can directly induce brain aging, should be a substance change directly involved in brain nerve activity, including sodium ion, potassium ion, calcium ion and various neurotransmitters, especially ACh. One of the direct inducers is the change in the concentration of calcium ions.

Generally, aging of the body is a systemic mechanism (aging common mechanism) with multiple aspects of combined action, and normal physiological activities of the body depend on the balance of various substances (including endocrine, hormone, nutritional factors, various ions and the like) to maintain, once a certain cause appears, a certain balance is broken, all aspects are affected with each other, so that more balances are broken, and the aging process is promoted together. From the perspective of biological evolution and from the nonlinear process of body aging, reproductive aging seems to be the root cause of body aging, which causes the rapid decrease of sex hormone secretion in a short time, and further causes the change of other various hormone secretion, and causes more balance to be broken, thereby causing the changes of the activities and functions of other organs to enter the aging process together. The brain cells can not divide and reproduce, and the physical and chemical environment of the brain is relatively stable, so the brain aging is more induced by other aging of the body outside the brain. There may be many ways to influence and transmit the aging of the body to the aging of the brain, and one of the obvious ways is: the balance of parathyroid hormone and calcitonin secreted by a blood calcium regulation mechanism is broken, the secretion of PTH is increased relative to CT, so that the activity of osteoblasts is weakened, the activity of osteoclasts is increased, more bone calcium is released into the blood calcium, the blood calcium is increased, the long-term elevation of the blood calcium is caused, the calcium balance inside and outside cells is broken due to the increase of calcium ion diffusion and inflow, the free calcium inside the brain cells is also increased for a long time, (meanwhile, the calcium discharge capacity is reduced due to the reduction of the activity of a cell ion pump, the change is promoted), the nerve activity of the brain cells is influenced, the cell damage is caused, and finally, the brain aging is caused.

2.6 initiation and progression of brain aging. FIG. 4 is a schematic illustration of applicants' described brain aging induction and progression. The induction of brain aging, which is a more factor, is described here as three induction factors, namely, low long-term nerve activity, high blood calcium level and long-term nerve overactivity, which directly cause two direct changes, namely reduction of cholinergic nerve function and increase of intracellular free calcium; intermediate changes in intermediate processes that in turn lead to increased free radicals, precipitation of a β protein, hyperphosphorylation of tau protein, increased ACh consumption, decreased synthesis, etc.; then causing the change of neural structure forms such as synapse degeneration or disappearance, nerve cell degeneration and death (apoptosis), neural network connection reduction, brain atrophy and the like; and finally, the brain function is reduced, such as the reduction of cognitive memory thinking ability, memory loss, the reduction of motor and activity ability, and the like. Once the brain aging is started, various changes of the middle process of the brain aging often have the effect of mutual promotion, and the process of the brain aging is further promoted. Such as: the increase of intracellular free calcium can lead to the increase of free radicals, the increase of free radicals can lead to the increase of A beta protein precipitation, and the increase of A beta protein precipitation can lead to the excessive internal flow of calcium ions, thereby further increasing the intracellular free calcium.

3. A method for delaying brain aging is provided. According to factors that directly induce brain aging: if the blood calcium concentration is high for a long time, the brain is used less for a long time, the brain is excessively used for a long time, or mental stress or anxiety is generated, the following method for delaying the brain aging may be used.

3.1 appropriate use of brain. For people with little brain use, "multi-purpose brain" is widely recommended. However, the applicant wanted to point out that: "brain use" includes thinking and memory, which are different in brain nerve activity, and memory activity requires more involvement of cholinergic nerve and stimulation pulse of high rhythm, and it is preferable to perform appropriate learning and memory activities for preventing brain aging according to the mechanism of brain aging and the action of cholinergic nerve. For general thinking, the effect may not be obvious.

3.2 take care of the rest after the high rhythmic neural activity. For people who are frequently nervous, nervous and anxious, the brain needs to have enough rest time to be in a low-rhythm activity state, so that calcium-ATPase can transport out intracellular calcium ions and reduce intracellular free calcium. The best method for performing low-rhythmic neural activity is slow wave sleep, i.e., deep sleep, (including dreams, which are high-rhythmic neural activity), or closed-eye tranquilization in a calm state, or low-intensity simple exercise such as gymnastics, and the like.

3.3 the process of aging of the organism is delayed. Theoretically, since brain aging is induced and affected by aging of the body outside the brain, if the aging process of the body can be delayed, it can be naturally delayed. If the reproductive aging is the root cause of the aging of the body, the aging of the body can be delayed to a certain extent in the reproductive aging generation stage, namely, the sex hormone is supplemented properly in the menopause, so that the brain aging is also delayed from the root cause. However, since the sex hormones comprehensively affect various physiological activities of the body, the use of the sex hormones needs to be carefully performed.

3.4 correct for elevated blood calcium levels. According to the induction mechanism of calcium ions to brain aging, if the concentration of free calcium in brain cells can be reduced, the damage to the brain cells can be reduced and the function of cholinergic nerves can be restored, thereby delaying the brain aging. The applicant analyzed: the damage caused by higher free calcium to brain cells is accumulated for a long time and also needs a longer time to recover slowly. If a calcium channel blocker (calcium antagonist) or a calcium binding protein (including calmodulin) is used to reduce the intracellular calcium ion concentration, it can only act for a short time, and if the extracellular calcium ion concentration (blood calcium concentration) is still high at the source, the calcium ion will continuously enter the cell by diffusion, so the action is temporary, and cannot change the trend, and the treatment effect is limited. On the other hand, if a calcium chelating agent is used to lower the blood calcium level, the drug stimulates the blood calcium regulation mechanism when lowering the blood calcium, causing the bone calcium to be released rapidly by the osteoclasts to migrate into the blood calcium, so that it is difficult to maintain a low blood calcium level for a long time, causing its therapeutic effect to be insignificant, and also causing or aggravating senile osteoporosis. The calcitonin promotes the transfer and solidification of blood calcium to bone calcium, can maintain a lower blood calcium level for a long time, and reduces the calcium ion concentration outside brain cells from the source, so that the calcium ion concentration in the brain cells and the damage caused by the calcium ion concentration are gradually reduced, thereby having more remarkable effect, improving the bone calcium density while reducing the blood calcium, and preventing senile osteoporosis. Of course, calcitonin, a hormone, although used clinically for the treatment of osteoporosis, has long-term side effects to be observed. In addition, vitamin K2 can assist in carboxylation of osteocalcin secreted by osteoblasts to become active osteocalcin, promote calcium ions in blood to generate bone calcium, and increase bone density, so that the blood calcium level can be reduced, and theoretically, the vitamin K2 should also have certain effects.

4. Senile dementia. Senile dementia, namely Alzheimer Disease (AD), is a special pathological brain aging, the brain presents progressive degenerative changes, and compared with the common brain aging, the senile dementia can cause more serious phenomena of nerve cell apoptosis, brain atrophy, serious deterioration of memory and thinking in a shorter time and rapidly aggravate to cause cognitive and thinking disorders until the dementia.

The cause of AD may be similar to brain aging, but the aging process is accelerated greatly due to the induction of a specific event or the more serious cell damage and functional decline caused by the induction of AD due to the difference in genes or constitutions of patients. Such as: for physical reasons, when calcium intake is sufficient, it can result in higher plasma calcium ion concentrations. Such as: due to the structure and the shape of the calcium channel of the nerve cell, when the calcium ion concentration outside the cell membrane is higher, the calcium ion inflow is increased, so that the calcium ion concentration inside the cell in a resting state is higher. For another example: due to its gene, (presenilin PS gene expression), when intracellular calcium ion concentration is high, the phenomenon of free radical increase or generation of a β protein precipitation or tau protein hyperphosphorylation is more serious, resulting in more serious brain cell damage and apoptosis. And so on. Particularly, when the brain is induced by a special event, such as serious high blood calcium caused by fracture, nervous dysfunction caused by psychosis such as depression and the like, the aging process of the brain is greatly accelerated compared with that of the common brain, and the pathological brain aging is generated.

AD also appears to be irreversible, given that its progression is damage and death of brain cells. Most of the existing medicines only can relieve symptoms, for example, in case of serious damage to cholinergic nerve, acetylcholine releasing agent or cholinesterase inhibitor is adopted to promote cholinergic nerve activity and improve relative brain function. According to the mechanism of brain aging, the long-term high concentration of calcium ions in plasma is an important inducing factor, so that the adoption of calcitonin CT or vitamin K2 to promote the transfer of calcium from blood to bone, correct the high concentration of calcium in blood and reduce the concentration of calcium ions in cells can reduce the damage to brain cells, resist the aging process and improve the brain function. In addition, studies report that certain polysaccharide is used for regulating gastrointestinal bacterial flora to achieve the effect of treating AD, and supposing that the treatment effect is true, the applicant analyzes that the mechanism of the polysaccharide is that the gastrointestinal bacterial flora promotes the generation of vitamin K2 or/and promotes the conversion of K1 to K2, so that the level of K2 in a body is increased, and then the transfer of calcium from blood to bone is promoted, so that the level of the calcium from blood is reduced, so that the therapeutic effect is achieved.

5. The current theory and the method for calcium supplement of the old people are wrong. The old people generally have high blood calcium, but osteoporosis also occurs, and the current medical view is that the old people need to supplement calcium because the calcium is poorly absorbed and the bone calcium is transferred to the blood calcium due to the calcium deficiency in blood. Applicants analyzed this view and the mistakes of their calcium supplementation practices.

5.1 clinical data show that the blood calcium level of human body is characterized by high in both heads and low in the middle of young and middle of children and old people. For children, since the whole body is in a vigorous growth phase, bones are growing and renewing rapidly, osteoblasts and osteoclasts are active and bone formation is greater than that of osteoclasts, it is understandable to maintain a high blood calcium level, which is equivalent to maintaining a transit warehouse with sufficient calcium material to meet the needs of bone growth. Moreover, during this vigorous growth process, the body of the child is also very powerful in scavenging free radicals and other toxins, so that higher blood calcium levels do not cause any damage to the body of the child. By the middle-aged and young years, the skeleton is no longer growing but is renewed, the activities of osteoblasts and osteoclasts are in equilibrium, and the blood calcium level is reduced, which is also normal and reasonable. The old people only degenerate and do not grow, and bone turnover is slowed down, so that the body of the old people has little demand for calcium, and the blood calcium is supposed to be maintained at a low level. However, after the age of 50 years (climacteric period), the blood calcium level of human body is abnormally and generally increased and reaches the highest level of life in the age of 70 years, and at the same time, the bone calcium content of human body is reduced year by year, so that the total calcium content in the body is also reduced year by year, and the osteoporosis is easy to appear.

For this abnormal phenomenon, a popular medical view is now: in order to maintain sufficient blood calcium, the body absorbs bone calcium and releases the bone calcium into the blood calcium through a blood calcium regulation mechanism, so that the blood calcium is higher and thus osteoporosis is caused. According to the view point, the high blood calcium of the old cannot indicate that the old is not lack of calcium, and just indicates that the old is lack of calcium in vivo, so the blood calcium regulation mechanism can release bone calcium into the blood calcium, so the calcium should be supplemented, and the calcium is supplemented in a large dose, and the vitamin D is supplemented to enhance the calcium absorption. Such theories are replete with various medical articles and magazines, as well as various medical and health lectures. It is the theory that many researchers are habitually thinking that the old people are calcium-deficient, and disregarding the fact that the blood calcium of the old people is high for a long time, and do not pay attention to the chronic neurotoxicity of the high blood calcium of the old people and the induction effect thereof on brain aging and even partial senile dementia.

5.2 the applicant believes that there are conceptual permutations and logical errors in this theory: the concept replacement, namely 'bone calcium deficiency' (osteoporosis) and 'blood calcium deficiency' (blood calcium deficiency), is two completely different concepts, and the elderly have bone calcium deficiency rather than blood calcium deficiency. Calcium deficiency in the blood may lead to bone calcium deficiency, which may occur only when there is a severe deficiency in calcium intake, and should then be manifested as a significant hypocalcemia. Bone calcium deficiency is not entirely equal to blood calcium deficiency, but more so because skeletal osteoblasts have diminished activity and osteoclasts have increased activity, or because of problems with the regulation of blood calcium. Secondly, if the body releases bone calcium into the blood calcium through the blood calcium regulation mechanism because of the lack of the blood calcium, the regulation process of the blood calcium regulation mechanism should be stopped when the blood calcium concentration rises to a normal level, and particularly when the blood calcium is too high, the blood calcium should be fixed into the bone calcium through the regulation mechanism and the normal blood calcium level is recovered, so that the situation that the blood calcium concentration is too high and the osteoporosis continues to progress and the bone calcium continues to be released into the blood calcium can not occur for a long time. What is the case, according to clinical data, there is no period in which the trend of calcium in blood is lower from the middle-aged to the elderly, and how to explain calcium deficiency in the elderly?

Therefore, the applicant believes that osteoporosis in the elderly is not induced by insufficient calcium absorption and intake and low blood calcium, but is mainly caused by changes in hormone secretion in the elderly. Firstly, the change of the secretion of climacteric sex hormone (which belongs to reproductive aging, and the applicant believes that the reproductive aging is the root cause of the aging of the whole body), further influences the balance of the secretion of parathyroid hormone PTH and calcitonin CT, the increase of PTH relative to CT causes the weakening of osteoblast activity and the increase of osteoclast activity, more osteocalcium is released into the blood calcium due to the activity of osteoclast, and the bone degeneration, namely osteoporosis is caused, and the blood calcium is also increased. Secondly, in the process of osteogenesis, vitamin K2 is needed to assist the carboxylation of osteocalcin to promote the calcium ion in blood to generate bone calcium, the gastrointestinal flora of the elderly is changed, the capacity of synthesizing and converting K2 is reduced, K2 is insufficient, the osteogenesis activity is influenced to cause bone degeneration, and osteoporosis and blood calcium increase are also caused. In addition, the aged may have reduced stimulation intensity and weakened strength to bones and muscles due to reduced limb movement, especially high-intensity movement, and may also cause bone degeneration, which accelerates the progression of the change. The applicant speculates that: when the muscle moves, the activity of the muscle cells may cause changes in the surrounding physicochemical environment, such as changes in the concentration of a substance or ion, which may be transmitted to bone tissue, affecting changes in the activity of osteoblasts and osteoclasts, thereby affecting the phenomenon of bone formation or osteoclasts, and thus, the reduction of activity in the elderly may also lead to and promote bone degeneration. Therefore, the changes and activities of hormone secretion are reduced, which leads to the contradiction that the senile people have osteoporosis and high blood calcium. Of course, this only leads to the appearance of hypercalcemia in the normal range of the elderly, or only slightly outside the normal range, which is mostly insufficient for morbid hypercalcemia, and this phenomenon and its induction of brain aging and even senile dementia have not been of interest for a long time.

Therefore, if bone calcium is to be increased by ingestion, preferably before menopause, some effect may be obtained. Once the human body enters the climacteric period and enters the bone degeneration stage, the calcium supplement only raises the blood calcium, and the blood calcium supplement is difficult to be fixed in the bone calcium. In particular, if elderly osteoporosis patients have high blood calcium levels and attempt to treat osteoporosis by calcium supplementation, it is clearly incorrect, although this may be somewhat antagonistic to the metastatic release of bone calcium to blood calcium by increasing blood calcium levels, but with little effect (indeed current elderly people do have limited effectiveness in treating osteoporosis by calcium supplementation, so some "experts" consider it to be calcium supplementation at higher doses) and may induce a process that accelerates brain aging, even, based on similar cell damage mechanisms, too high blood calcium may cause damage to other visceral cells, which is not easily noticed, but is a slow process due to brain aging and other cell damage.

5.3 the applicant believes that the phenomena of osteoporosis and hypercalcemia in the elderly are similar to the phenomena of progressive wasting of the body and elevation of blood sugar caused by diabetes: without the disclosure of diabetes, we would misunderstand that body wasting is nutrient malabsorption and take nutrition-increasing measures, and with the correct knowledge of diabetes we would know that nutrition-increasing is wrong in this case, and body wasting is not nutrient malabsorption but a problem with the blood glucose regulation mechanism, and correct measures are taken to intervene in the blood glucose regulation mechanism. Similarly, osteoporosis (which corresponds to bone wasting) in many elderly people, not insufficient absorption and uptake of calcium, but problems with bone degeneration and the regulation mechanism of blood calcium, in which case calcium supplementation by increased intake is wrong, but should intervene against bone degeneration and the regulation mechanism of blood calcium. The method comprises the following steps: the muscle and bone stimulation device has the advantages that an organism can exercise with certain strength, so that stimulation to muscles and bones is strengthened, activity of osteoblasts is promoted, and bone degeneration is prevented or slowed down; secondly, the sex hormone is properly supplemented in the menopause, the bone degeneration is fundamentally delayed, but the supplementation of the sex hormone can comprehensively influence various physiological functions of the body and needs to be carefully carried out; and thirdly, secretion of parathyroid hormone is inhibited, or calcitonin is supplemented, direct intervention is carried out on a blood calcium regulation mechanism, and the calcitonin can inhibit osteoclast activity and promote osteoblast activity, so that calcium transfer in plasma is consolidated into bones, and the bone calcium density is enhanced. In fact, calcitonin has been used clinically to treat osteoporosis with good results. Of course, calcitonin is a hormone, and its long-term side effects remain to be further observed. In addition, vitamin K2 can assist the carboxylation of primary osteocalcin secreted by osteoblasts to become active osteocalcin, promote calcium ions in blood to generate bone calcium, increase bone density, and can be used for treating and preventing osteoporosis.

6. Interestingly, the applicant noticed that the effects of changes in blood glucose and calcium levels on the body are very similar: too high or too low blood glucose (even for short periods) can have a severe impact on the life activities of the body, causing severe symptoms or even coma, while a bit higher blood glucose for a short period of time does not cause any significant damage to the body, but chronic damage to various organs and tissues (i.e., diabetes) can be unconsciously caused by a long-term higher blood glucose level. Similarly, too high or too low blood calcium (even for a short period of time) can have a severe effect on the life activities of the body and can cause severe symptoms of cardiac, respiratory and neural activity, while a short period of time with a little higher blood calcium does not cause any significant damage to the body, but a long period of time with higher blood calcium can unknowingly cause chronic damage to the cranial nerves (which applicants speculate may include other organs and tissues), induce brain aging, and even some people may have senile dementia.

Thus, the applicant also believes that: we would seem to evaluate the long-term hazard to the body of blood calcium levels in the normally high or upper-critical state in the current medically defined range of blood calcium (2.25-2.58 mmol/L). In addition, the applicant also proposed: given that blood glucose and blood calcium have similar regulatory mechanisms and changes in their levels have similar effects on body health, we seem to be concerned about whether they also have similar regulatory mechanisms for other substances and ion concentrations in plasma? And what effect on the health of the body? The pathological manifestations of these substances or ions at concentrations above or below the normal range may already be understood, but their chronic effects on health in the lower or higher state of the normal range over a long period of time are worth further investigation. (applicants, in another previously filed patent application 2017100454879, disclose that excessive iron ion levels in plasma may be responsible for a subset of the mechanisms that lead to Parkinson's disease).

Claims (6)

1. The new use of vitamin K2 in the manufacture of a medicament for the delay of aging (i.e. treatment) of the brain.

2. A medicament for the delay (i.e. treatment) of brain ageing which comprises vitamin K2 together with a pharmaceutically acceptable carrier or diluent. Such as: soybean oil, or/and glycerol.

3. The new use of K2 in the manufacture of a medicament according to claim 1, or a medicament according to claim 2, wherein: the vitamin K2 is a general name of a series of terpene side chain compounds containing 2-methyl-1, 4-naphthoquinone parent nucleus and a plurality of isoprene structural units with different numbers at the C3 position.

4. The new use of K2 in the manufacture of a medicament according to claim 1, or a medicament according to claim 2, wherein: the drug produces therapeutic effects by modulating the reduction of blood calcium concentration.

5. The new use of K2 in the manufacture of a medicament according to claim 1, or a medicament according to claim 2, wherein: the medicine can promote the transfer of blood calcium to bone calcium, reduce the level of blood calcium, and reduce the concentration of calcium ions in brain cells, thereby delaying the process of brain aging.

6. The new use of K2 in the manufacture of a medicament according to claim 1, or a medicament according to claim 2, wherein: the medicine is in the form of injection or capsule and is administrated in an injection or oral way.

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