This piece is from the middle section of Chapter 9 of Stones in the Body: More Frightening Than Cancer (Yoon Jong-won). It is a narrative containing the author's academic hypothesis, and the body, figures, and citations follow the manuscript as written.
Stage 2, 1M Obstruction & Rupture: it blocks or bursts
When 4M Hardening progresses further, 1M Obstruction & Rupture occurs. When calcium protrudes into the vascular lumen, the inner diameter narrows, and in the end it becomes blocked. When a coronary artery is blocked it is myocardial infarction, and when a cerebral artery is blocked it is cerebral infarction.
A vessel that has hardened and lost its elasticity cannot adapt to changes in pressure. When blood pressure rises sharply, the weakened area bursts. When a cerebral vessel bursts it is cerebral hemorrhage, and when the aorta bursts it is aortic rupture.
Summary: Progression from 4M to 1M. Stage 1, 4M Hardening: the vessel wall hardens → loss of elasticity, hypertension. Stage 2, 1M Obstruction & Rupture: the lumen is blocked or ruptured → myocardial infarction, cerebral infarction, cerebral hemorrhage
The "blocking and bursting" phenomenon explained in the 1M section is in fact something that occurs after 4M Hardening has preceded it. The vessel first hardens (4M), and then it becomes blocked or bursts (1M).
Hypertension: the result of a hardened vessel
"The systolic pressure is high but the diastolic pressure is low." This is the typical pattern of hypertension in the elderly. A blood pressure like 160 systolic and 70 diastolic. This is a sign that the vessel has hardened.
In hypertension of a young person, the systolic and diastolic pressures rise together (for example, 150/100). This is because the vessel is still flexible. In hypertension of an elderly person, only the systolic pressure is high while the diastolic pressure is normal or low (for example, 170/70). This is because the vessel has hardened and has no elasticity.
When vascular hardening becomes severe, it becomes difficult to control even with blood pressure medication. The medication tries to relax the vessel, but a vessel that has hardened does not relax. The experience of "the blood pressure does not come down even when I take the medication" comes from here.
5. Valve Hardening: Heart Valve Disease
The heart valves are also a target of 4M Hardening.
Calcific Valve Disease: the valve hardens like stone
The heart has four valves. As these valves open and close, they make the blood flow in only one direction. The valves are originally thin and flexible, so they open and close by fluttering lightly.
When calcium is deposited in large amounts on a valve, the valve becomes thick and stiff. A valve that has hardened does not open properly (stenosis). Or it does not close properly (regurgitation).
The most common one is aortic valve calcification. The aortic valve is at the outlet through which blood leaves the left ventricle for the aorta. When this valve hardens, the left ventricle must contract more strongly in order to push out the blood. A burden is placed on the heart, and in the end it leads to heart failure.
Aortic valve calcification is found in about 25% of the elderly aged 75 and over. When symptoms appear (chest pain, fainting, difficulty breathing) the prognosis is very poor. If the valve is not replaced, the mortality rate within 2-3 years exceeds about 50%. It is repeatedly emphasized in many clinical studies and guidelines that aortic valve calcification and stenosis become common in old age, and that once symptoms appear the prognosis worsens sharply.
From 2M Dysfunction to 4M Hardening
Valve disease also progresses from 2M to 4M. In the early stage the valve is in a 2M Dysfunction state in which it becomes stiff. When listened to with a stethoscope a "murmur" is heard, but the heart function is still maintained.
As time passes it becomes a 4M Hardening state in which the valve hardens completely. At this stage it cannot be resolved with medication. Surgery to replace the valve is required.
6. Joint Hardening: the joint hardens
4M Hardening operates in the joints as well. The end of 2M Dysfunction is 4M Hardening.
Late-Stage Osteoarthritis: the joint hardens
In the early stage of osteoarthritis the joint is in a stiff 2M Dysfunction state. It is stiff in the morning but loosens with movement.
In the late stage of osteoarthritis it becomes a 4M Hardening state in which the joint hardens completely. The cartilage wears away completely, bone directly touches bone, and bone spurs (bone spur) and calcium are deposited around the joint. The range of motion of the joint is extremely limited.
At this stage it does not recover with exercise or medication. Artificial joint surgery (removing the hardened joint and replacing it with an artificial joint) is the only method.
Ankylosing Spondylitis: the spine hardens like bamboo
Ankylosing spondylitis is an autoimmune disease in which severe inflammation occurs in the spinal joints and, secondarily, calcification and ossification progress. It has a strong association with the HLA-B27 gene.
In the early stage the lower back is in a stiff 2M Dysfunction state, but as it progresses the entire spine becomes a 4M Hardening state. In this process it proceeds in the order inflammation → fibrosis → ossification, and finally the vertebrae are connected by newly formed bone (syndesmophyte) and harden into one.
In severe ankylosing spondylitis, a finding called "bamboo spine (bamboo spine)" is seen on X-ray. Bending or twisting the lower back becomes entirely impossible.
[Ankylosing Spondylitis and DIAH-7M]
The main cause of ankylosing spondylitis is the autoimmune reaction. However, chronic inflammation (I) promotes ossification, and abnormal calcium metabolism may contribute to this process. From the DIAH-7M perspective it can be understood as the pathway "inflammation → calcification/ossification," and this is not the sole cause of the disease.
Late-Stage Adhesive Capsulitis (Frozen Shoulder)
Frozen shoulder can also begin at 2M and progress to 4M Hardening. In the early stage the shoulder is in a stiff 2M Dysfunction state. In the late stage the joint capsule hardens completely, becoming a 4M Hardening state in which the arm can barely be moved.
This is the reason it has been given the nickname "frozen shoulder (frozen shoulder)." The main cause of frozen shoulder is inflammation and fibrosis of the joint capsule, and diabetes, thyroid disease, and trauma are risk factors.
7. Hardening of the Skin and Organs: Scleroderma
4M Hardening can appear not only in the blood vessels and joints but also in the skin and the internal organs.
Scleroderma: the skin hardens
Scleroderma (scleroderma) is an autoimmune disease in which collagen is excessively deposited in the skin and internal organ tissue, so that the tissue hardens. The exact cause is not known, but immune system abnormalities, vascular damage, genetic predisposition, and environmental factors act in a compound manner.
When the skin hardens it is hard to make facial expressions, hard to bend the fingers, and the skin is pulled taut. When the internal organs harden, the esophagus hardens so that it is hard to swallow food, the lungs harden (pulmonary fibrosis) so that it is hard to breathe, and the heart hardens so that heart failure comes.
In some scleroderma patients, lumps of calcium form beneath the skin. This is called "calcinosis (calcinosis)." This is one of the complications of scleroderma, and chronic inflammation and tissue damage promote the calcium deposition.
[Scleroderma and DIAH-7M]
The main cause of scleroderma is the autoimmune reaction, and abnormal calcium metabolism is not the direct cause. However, in that chronic inflammation (I) contributes to tissue fibrosis and calcium deposition, and in that "the phenomenon of tissue hardening," the final result of 4M Hardening, appears, it connects to the DIAH-7M framework.
Pulmonary Fibrosis: the lungs harden
A normal lung is soft and elastic like a sponge. When you breathe in it expands, and when you breathe out it shrinks.
In pulmonary fibrosis, collagen is excessively deposited in the lung tissue, so that the lung hardens stiffly. A lung that has hardened does not expand. You cannot breathe in deeply. Oxygen is not delivered to the blood.
The causes of pulmonary fibrosis are varied. There are idiopathic (cause unknown), autoimmune disease, occupational exposure (asbestos, dust), medication, radiation, and others. Idiopathic pulmonary fibrosis (IPF) is a case in which the cause cannot be known, and the prognosis is poor.
A pulmonary fibrosis patient becomes more and more short of breath, comes to need an oxygen supply, and in the end may die of respiratory failure. Some antifibrotic drugs can slow the progression, and in severe cases a lung transplant is required.
8. Summary of the 4M Hardening Mechanism
4M Hardening is the phenomenon in which calcium is deposited in large amounts in soft tissue so that the tissue itself hardens stiffly.
The 4M Hardening mechanism formula: DIAH operating for a long period → cumulative calcium efflux → immune cell activation (IL-1β, IL-6, TNF-α) → I (inflammation) vicious cycle → mass calcium deposition → cell phenotype conversion (osteoblastic transformation) → ossification/hardening of the tissue
The most frightening point of 4M Hardening is its irreversibility. At the 2M Dysfunction stage, if you intervene it can improve. But once it crosses over into the 4M Hardening stage, it is hard to turn back with medication or exercise. A vessel that has hardened does not become soft again. A joint that has hardened must be replaced with an artificial joint. A lung that has hardened needs a transplant.
That is why it is important to intervene at the 2M Dysfunction stage. The time when you feel "it is stiff" is the last chance. After it has hardened completely it is too late.
[The Analogy and the Actual Mechanism]
The expression "calcium accumulates and hardens" explains the core process, but various factors act together in actual tissue hardening, such as fibrosis (collagen deposition), cell degeneration, and inflammatory reaction. Especially in scleroderma, pulmonary fibrosis, and others, the autoimmune reaction is the main cause, and calcification is in many cases a secondary phenomenon.
[Interaction with Other Risk Factors]
The diseases related to 4M Hardening interact, in addition to DIAH, with the following factors: vascular hardening (hypertension, diabetes, dyslipidemia, smoking, chronic kidney disease), autoimmune diseases (ankylosing spondylitis-HLA-B27, scleroderma), environmental exposure (occupational dust, asbestos-pulmonary fibrosis), metabolic factors (abnormal phosphate metabolism-chronic kidney disease). The DIAH-calcium pathway acts together with these factors and contributes to tissue hardening.
5M Overflow & Burst (it overflows and bursts)
1. "A lump grows," "the mind grows more and more clouded": the 5M Overflow & Burst that we know
"They say a lump has formed in the uterus." "They say the prostate has enlarged." "They say a tumor was found."
And one more thing.
"These days I keep forgetting." "They say Mother is in the early stage of dementia." "Grandfather can't recognize people."
If I told you that abnormal calcium metabolism is involved in these two things ("a lump growing" and "memory disappearing"), would you believe it?
From 1M to 4M, "calcium deposition" was the core. Calcium accumulates and blocks (1M), grows dull (2M), is coated and blocked (3M), and hardens (4M). Calcium is something that "accumulates" in the tissue.
5M Overflow & Burst is different. The core of 5M is "abnormal intracellular calcium signaling." It is not that calcium accumulates in the tissue, but that the regulation of calcium concentration inside the cell collapses.
Overflow & Burst (氾破) means "it overflows and bursts." 氾 means "water overflows," and 破 means "it bursts." When intracellular calcium regulation collapses, some cells proliferate excessively (tumor), and some cells are damaged and die (neurodegeneration). When it overflows, it bursts. This is the essence of 5M Overflow & Burst.
2. The Definition of 5M Overflow & Burst: intracellular calcium homeostasis collapses
5M Overflow & Burst is the phenomenon in which intracellular calcium homeostasis collapses, so that a cell overproliferates or is damaged and dies.
Let us compare a cell to a small factory. A normal factory receives an appropriate amount of raw material (calcium) and produces an appropriate amount. But what happens if the raw material regulation system suddenly breaks down and raw material pours in?
The First Scenario: it runs excessively
If the factory can handle it, it runs excessively. Production explodes. The factory itself expands. This is cell overproliferation. Uterine fibroids, prostatic enlargement, and tumors are this case.
The Second Scenario: it stops from overload
If the factory cannot handle it, the machinery overheats and is damaged. The factory stops. This is cell damage and death. When brain nerve cells are damaged it becomes a neurodegenerative disease.
The same cause (abnormal intracellular calcium regulation) creates a different result (overproliferation or death). It differs according to the type and state of the cell. Cells with the ability to divide overproliferate, and cells that do not divide (brain nerve cells) are damaged.
[The Analogy and the Actual Mechanism]
The expression "calcium pours into the cell" is an analogy to aid understanding. In reality a complex process is involved in which intracellular calcium homeostasis (calcium homeostasis) collapses. Regulatory abnormalities of several systems, such as calcium channels, calcium pumps, and intracellular calcium stores (endoplasmic reticulum, mitochondria), act in a compound manner.
3. From DIAH to Abnormal Intracellular Calcium: why calcium regulation collapses
Let us follow the process by which intracellular calcium homeostasis collapses from the beginning.
Stage 1: The DIAH Trigger Operates
If there is D (Deficiency), calcium is drawn out of the bone and blood calcium rises. If there is I (Inflammation), calcium is consumed in the inflammatory reaction and is replenished from the bone. If there is A (Acidosis), bone calcium is mobilized in order to neutralize the acid. If there is H (Hypoxia), the cell's energy production decreases.
Stage 2: Abnormality in the Cell's Calcium Regulation System
A normal cell keeps the intracellular calcium concentration low through several systems. It is at a level of about one ten-thousandth of the calcium concentration outside the cell. This enormous concentration difference is the basis of calcium signaling.
The calcium regulation system includes calcium pumps (which use ATP), calcium channels, and intracellular stores (endoplasmic reticulum, mitochondria). In the H (Hypoxia) state, as energy production falls, the regulation of the calcium pumps and channels wavers and intracellular calcium homeostasis collapses, and as a result the whole body bears a 'calcium regulation burden,' and this burden may in the long term also affect the bone and blood calcium balance. In the I (Inflammation) state, inflammatory cytokines can excessively activate the calcium channels.
Stage 3: The Intracellular Calcium Concentration Rises
In a state where the calcium regulation system is damaged, if the blood calcium concentration also rises, the intracellular calcium concentration becomes prone to rising. Normally the regulation system would maintain balance, but when the system is damaged, intracellular calcium accumulates.
Stage 4: Two Results
When the intracellular calcium concentration rises abnormally high, two results can appear.
In cells with the ability to divide (uterine muscle cells, prostate cells, and others), calcium can activate the proliferation signaling pathway. Cell division is promoted, and overproliferation can occur.
In cells that do not divide (brain nerve cells), excessive calcium can cause mitochondrial dysfunction, increased generation of reactive oxygen species, and activation of the cell death pathway.
[Interaction with Other Risk Factors]
Tumors or neurodegeneration do not occur from abnormal intracellular calcium alone. Genetic factors, hormonal changes, environmental factors, and aging act in a compound manner. The DIAH-calcium pathway is understood as interacting with these factors and contributing to the occurrence of disease.
4. Cell Overproliferation: Uterine Fibroids, Prostatic Enlargement, Thyroid Nodules
The first result of 5M Overflow & Burst is cell overproliferation. When an abnormality in calcium signaling arises in cells with the ability to divide, proliferation can be promoted.
Uterine Fibroids: the uterine muscle enlarges
Uterine fibroids are a very common benign tumor found in about 70% of women of childbearing age. It is the uterine muscle cells overproliferating and enlarging like a lump.
The cause of uterine fibroids has not been completely elucidated, but hormones such as estrogen and progesterone play a major role. Genetic factors, growth factors, and abnormal cell signaling are also involved. Calcium signaling plays a role in the cell proliferation pathway and may contribute to the occurrence of uterine fibroids.
A small fibroid has no symptoms. But when it enlarges the menstrual volume increases, menstrual cramps become severe, and a feeling of pressure is felt in the pelvis.
Benign Prostatic Hyperplasia: the prostate enlarges
A man's prostate tends to enlarge as he ages. Prostatic enlargement is found in about 50% of men in their 60s and about 90% of men in their 80s.
The main cause of prostatic enlargement is the influence of male hormones (testosterone, DHT). Aging, hormonal imbalance, and growth factors act in a compound manner. An abnormality in the calcium signaling of the prostate cells can contribute to proliferation, but hormonal factors play a more important role.
When the enlarged prostate presses on the urethra, urine does not come out well, and one gets up often at night to urinate.
Hyperthyroidism and Thyroid Nodules
The most common cause of hyperthyroidism is Graves' disease (an autoimmune disease). Autoantibodies excessively stimulate the thyroid so that hormones are oversecreted. The heart beats fast, one sweats a lot, and body weight drops.
Thyroid nodules are mostly benign, and iodine deficiency, genetic factors, and radiation exposure are causes. An abnormality in intracellular calcium signaling can contribute to thyroid cell proliferation, but it is not the main cause.
[The DIAH-7M Perspective]
In these benign tumors, an abnormality in calcium signaling can play some role, but hormones (estrogen, testosterone, thyroid-stimulating hormone, and others) are the more important cause. In the DIAH-7M framework it can be understood that chronic inflammation (I) creates an environment for cell proliferation, and that an abnormality in calcium signaling contributes to the proliferation pathway.
5. Nerve Cell Damage: Alzheimer's Disease and Neurodegeneration
The second result of 5M Overflow & Burst is cell damage and death. When an abnormality in calcium regulation arises in cells that do not divide, the cell is damaged.
Brain Nerve Cells Do Not Divide
Most cells of our body divide. Skin cells, blood cells, and intestinal cells are continuously made anew. But brain nerve cells are different. The brain nerve cells of an adult hardly divide at all. Since they are not made anew, once they die they are hard to replace.
When an abnormality in calcium signaling arises in dividing cells, it can lead to overproliferation. But what about when an abnormality in calcium regulation arises in brain nerve cells that do not divide? Since it cannot be resolved by division, it leads to cell damage.
"The Calcium Hypothesis of Alzheimer's Disease"
Alzheimer's disease has long been explained by "the accumulation of amyloid beta (Aβ)." It is that protein debris piles up in the brain so that nerve cells die.
But the amyloid hypothesis alone makes it hard to fully explain Alzheimer's disease. The "Calcium Hypothesis of Alzheimer's Disease (Calcium Hypothesis of AD)" proposes that an abnormality in intracellular calcium homeostasis plays an important role in neurodegeneration.
According to research published in Nature Communications, in an Alzheimer's disease model, calcium was excessively accumulated in the mitochondria of the nerve cells. Mitochondrial calcium overload can lead to increased generation of reactive oxygen species, decreased energy production, and activation of the cell death pathway.
Aging and Calcium Regulation
An aged nerve cell has decreased efficiency of ATP (energy) production. When ATP is insufficient, the calcium pumps cannot operate properly. Also, an aged cell has decreased calcium buffering capacity as well.
A young brain cell adapts well to changes in calcium concentration. An aged brain cell has decreased calcium regulation ability and becomes vulnerable to damage.
Calcium Excitotoxicity (Calcium Excitotoxicity)
When calcium pushes excessively into a brain cell, the cell becomes excessively excited (excitation). It is like overrevving an engine. Because of this the mitochondria are overloaded and generate reactive oxygen species in large amounts, and in the end the cell self-destructs. This is medically called 'excitotoxicity by calcium (calcium excitotoxicity).' It is being researched that this mechanism is involved in Alzheimer's disease, Parkinson's disease, nerve damage after stroke, and others.
[Multifactorial Nature]
Alzheimer's disease is a very complex disease. Amyloid accumulation, tau protein abnormality, neuroinflammation, vascular factors, genetic factors (APOE4 and others), and lifestyle factors act in a compound manner. The calcium hypothesis is one of these various hypotheses, and it is hard to conclude that calcium abnormality is the sole cause. That said, whether abnormal calcium homeostasis contributes to the neurodegeneration process is a field being actively researched.
5M Overflow & Burst → 6M Disconnection
In Alzheimer's disease, 5M and 6M can operate in succession.
5M Overflow & Burst: abnormal intracellular calcium regulation → the beginning of nerve cell damage. 6M Disconnection: death of the damaged nerve cells → neural connections are severed → decline in cognitive function. 6. Malignant Tumors: Cancer and Calcium Signaling
A benign tumor only enlarges and does not spread elsewhere. A malignant tumor (cancer) proliferates infinitely and metastasizes elsewhere.
The Relationship Between Cancer and Calcium Signaling
The characteristic of a cancer cell is "proliferation that does not stop." A normal cell stops after dividing appropriately. A cancer cell does not stop.
In cancer cells, abnormalities in the calcium signaling system are commonly found. Changes in the expression of calcium channels, abnormal calcium pump function, and continuous activation of the calcium signaling pathway are reported. According to a review published in Nature Reviews Cancer, abnormal calcium signaling is involved in the proliferation, survival, and metastasis of cancer cells.
[The Multifactorial Causes of Cancer]
Cancer is a very complex disease. Gene mutations (tumor suppressor genes, oncogenes), environmental factors (carcinogens, radiation), viral infection, chronic inflammation, hormones, and lifestyle act in a compound manner. An abnormality in calcium signaling can contribute to the occurrence and progression of cancer, but it is not the sole cause.
5M Overflow & Burst + 6M Disconnection
In the DIAH-7M framework, cancer can be understood as "5M + 6M."
5M Overflow & Burst: the cancer cells overproliferate. 6M Disconnection: the overproliferated cancer cells invade and destroy normal tissue
Cancer causes harm in two directions. One is that it itself enlarges (5M), and the other is that it kills the surrounding normal tissue (6M).
7. Enlargement and Expansion: Cardiac Hypertrophy, Obesity
5M Overflow & Burst can be involved not only in tumors but also in the enlargement of organs and changes in tissue.
Cardiac Hypertrophy: the heart enlarges
When hypertension is long-standing, the heart enlarges. In the hypertensive state the heart must overcome a higher pressure and push out the blood. This mechanical load is the main cause of the hypertrophy of the cardiac muscle cells.
In the process of cardiac muscle cell hypertrophy, calcium signaling plays an important role. The calcium-calcineurin pathway and others mediate the hypertrophic response. However, the main cause of cardiac hypertrophy is the pressure load (hypertension), and calcium signaling plays the role of mediating this process.
At first the pump function is maintained by a compensatory action. But when the hypertrophy becomes severe, the heart hardens (4M Hardening), and in the end the pump function declines (heart failure).
Obesity and Calcium
The main cause of obesity is an imbalance between energy intake and expenditure. Overeating, lack of exercise, genetic factors, hormonal abnormality, and the gut microbiome act in a compound manner.
In some studies a relationship between calcium intake and weight management has been reported, but this field is still under debate. There is research that calcium signaling within fat cells can affect fat metabolism, but the main cause of obesity is energy imbalance.
8. Summary of the 5M Overflow & Burst Mechanism
5M Overflow & Burst is the phenomenon in which intracellular calcium homeostasis collapses, so that a cell overproliferates or is damaged and dies.
The 5M Overflow & Burst mechanism formula: DIAH → calcium efflux → change in blood calcium + damage to the cell's calcium regulation system → abnormal intracellular calcium homeostasis → overproliferation (benign/malignant tumor) or damage/death (neurodegeneration, excitotoxicity)
5M Overflow & Burst is distinguished from 1M through 4M. In 1M through 4M, "calcium deposition" is the core. Calcium accumulates in the tissue and causes problems. In 5M, "abnormal intracellular calcium signaling" is the core. Inside the cell the calcium regulation collapses and causes problems.
It is the same calcium, but depending on where and how the problem arises, it creates a different result: if it accumulates in the tissue → it blocks (1M), grows dull (2M), is blocked (3M), hardens (4M). If the intracellular regulation collapses → it overproliferates or is damaged (5M)
[The Analogy and the Actual Mechanism]
The expression "calcium pours into the cell" used in this chapter is an analogy to aid understanding. In reality a regulatory abnormality of complex systems is involved, such as calcium channels, calcium pumps, intracellular stores, and calcium-binding proteins.