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Ketone bodies and dementia
brain and stress
Nerve cells in the hippocampus of the brain are vulnerable to stress and are the first to degenerate under strong stress. This is why older people often develop dementia rapidly after traumatic events. Compounds that protect hippocampal neurons from oxidative stress have been extensively explored, as they are particularly vulnerable to reactive oxygen species.
brain and drugs
The following three conditions are necessary for the development of drugs targeting dementia.
1. to protect nerve cells.
2. transfer to the brain in sufficient quantity
3. No side effects.
From the current level of science, condition 1 can be easily cleared. But 2 is a problem. It is said that most compounds have near zero penetration into the brain, and there is a clear physiological basis for this. This is because there are great challenges in getting drugs from outside the body into the brain. Even if it does pass, it is very small (a few percent at most). No matter what kind of excellent drug is developed, there remains the problem of how to send the drug to the brain at an effective concentration.
However, ketone bodies are synthesized in the liver and can freely cross the blood-brain barrier. Therefore, it is far preferable to convert your body to the ketone body system and extend your healthy lifespan on your own. If the necessary amount of several mM (read as "millimol": unit of concentration) in the body can be easily achieved by restricting carbohydrates, it is better for (prevention of) dementia. increase.
Ketone bodies and synapses
Ketone bodies are not only energy substrates for nerve cells, but they also protect the nerves, promote synaptic regeneration in the brain, and maintain overall brain function. The action of ketone bodies is most effective at the "synapse" between nerve cells.
Synapses play a similar role to semiconductors in computers. Just as the performance of semiconductors determines the performance of computers, the performance of synapses determines the performance of the brain. Ketone bodies can act directly on this synapse. When there is a certain level of electrical signal at the synapse, the electrical signal is transmitted across the synapse to the next nerve cell. The difference from semiconductors is that nerve cells are electrically insulated from each other. The transmission of information during this time is mediated by chemical substances called neurotransmitters, not by electrical energy. Because this substance is interposed, it is necessary to convert energy from electrical energy to chemical energy and from chemical energy to electrical energy.
A large amount of energy is required for this energy conversion, and mitochondria are accumulated in synapses to cover that large amount of energy. Since mitochondria are the energy production factories of all cells, their concentration also means that there is a particularly high demand for energy in that location. Therefore, when nerve cells run out of energy, the synaptic function is the first to greatly decline. Synaptic transmission is not possible due to lack of energy. This is what is happening in neurons in the early stages of dementia.
In the early stages of dementia, there are many neurons that are unable to perform synaptic transmission due to lack of energy, so ketone bodies are very useful for such neurons. If we can increase ketone bodies, we may be able to eliminate the energy shortage in nerve cells and alleviate the symptoms of dementia.
Again, the great thing about ketone bodies is that they act directly on mitochondria, which are massively accumulated at synapses, to become energy substrates. In other words, it may be possible to solve the deterioration of synaptic function at once.
Ketone bodies freely pass through the blood-brain barrier, pass through the cell membrane of nerve cells, reach the mitochondria of nerve cells, and become energy substrates. For the prevention of dementia,
It seems that the liver should be in a state where it can synthesize ketone bodies in the body.
Happiness substance serotonin and memory substance glutamate
There are two neurotransmitters that play important roles in the brain. Serotonin and glutamate.
Serotonin is called a “happiness substance” and is a neurotransmitter that is absolutely necessary for people to live life with a sense of happiness. If you don't have enough serotonin, you won't feel happy no matter what you do, and you tend to be negative about things. In other words, the possibility of becoming “depressed” increases. On the other hand, glutamate is called a "memory substance" and is a neurotransmitter that is absolutely necessary for remembering both the past and the present. If glutamate doesn't work properly, you can't remember what happened just a few seconds ago, or you'll go out and forget where you were and where you were going. Eventually you forget who you are. In other words, "dementia" ...
Older Japanese now fear "dementia," while many younger Japanese suffer from "depression." These two brain diseases have something in common at the synaptic level. In other words, synaptic transmission fails due to lack of energy. It is said that neuronal cell death does not occur in the early stages of both depression and dementia. At the synapse, the energy produced by the mitochondria is in short supply. Since ketone bodies act directly on these mitochondria as energy substrates, it is thought that these two early pathological conditions can be greatly improved.
In other words, if ketone bodies are continuously increased, the actions of serotonin and glutamic acid can continue to function normally, and it may be possible to greatly extend the healthy lifespan of the brain.
Action on nerve cells
I have seen that ketone bodies have the ability to solve the energy shortage of neuronal synapses at once, but why is that?
This is because ketone bodies are better energy substrates than glucose. Compared to glucose, it has an overwhelmingly high energy efficiency, so to speak, it is a "super fuel".
Glucose first enters the cytoplasm but is not completely oxidized, whereas ketone bodies enter the mitochondria directly and are completely oxidized. Therefore, the energy efficiency of ketone bodies is overwhelmingly high.
In an experiment, when you add ketone bodies to nerve cells and observe the action of beta-hydroxybutyric acid, a compound of ketone bodies, on nerve cells, you will be amazed at the dramatic effects.
Ketone bodies at 1 mM almost completely inhibited neuronal cell death caused by reactive oxygen species. This concentration of 1 mM is also a concentration that can be reached with daily carbohydrate restriction.
“Restricting carbohydrates and increasing ketone bodies to 1 mM or more may prevent dementia.”
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Finally, I will introduce the thesis.
This is this year's (2020) paper on ketone bodies.
Experiments show that A beta (the causative substance of dementia) decreases when ketone bodies are applied to nerve cells.
β-Hydroxybutyrate Ameliorates Aβ-Induced Downregulation of TrkA Expression by Inhibiting HDAC1/3 in SH-SY5Y Cells.
2020 Jan-Dec;35:1533317519883496. doi: 10.1177/1533317519883496. Epub 2019 Oct 24.PMID: 31648544 Free article.
Tyrosine kinase receptor A (TrkA) plays an important role in the protection of cholinergic neurons in Alzheimer's disease (AD). This study was designed to investigate whether β-hydroxybutyrate (BHB), an endogenous histone deacetylase (HDAC) inhibitor, …
The following paper is a famous paper that ketone bodies suppress HDAC and protect against oxidative stress.
Suppression of Oxidative Stress by β-Hydroxybutyrate, an Endogenous Histone Deacetylase Inhibitor.
Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, Grueter CA, Lim H, Saunders LR, Stevens RD, Newgard CB, Farese RV Jr, de Cabo R, Ulrich S, Akassoglou K, Verdin E .
Science. 2013 Jan 11;339:211-214.
In this study, we report that the ketone body β-hydroxybutyrate (βOHB) is an endogenous inhibitor of class I histone deacetylases (HDACs). Administering βOHB to mice or increasing endogenous βOHB by fasting or calorie restriction resulted in a global increase in histone acetylation in renal tissue. In addition, HDAC inhibition by βOHB increased the transcription of genes encoding oxidative stress resistance (FOXO3A, MT2, etc.). Addition of βOHB to HEK293 cells increased histone acetylation of the Foxo3a and Mt2 promoters, both of which gene expression was activated by selective deletion of HDAC1 and HDAC2. βOHB-treated mice showed resistance to oxidative stress (protein carbonylation by paraquat, etc.) along with increased FOXO3A and MT2 activity.
[Conclusion]
βOHB is an endogenous HDAC inhibitor, and when its concentration is increased by mM due to fasting or caloric restriction, it induces epigenetic changes (increase in histone acetylation) in tissues, resulting in the expression of oxidative stress resistance genes (Foxo3a, etc.). It has been clarified that increasing the oxidative stress resistance of living organisms is brought about. It has long been known that ketone body production by a low-carbohydrate diet confers resistance to neuronal oxidative stress damage (neuroprotective effect). The results of this study suggest that the effects of ketogenic diets and caloric restriction may be mediated by βOHB's HDAC-inhibiting effect.