Continuing from the previous part, we examine what happens when the flow stops, and the blank spaces of essential hypertension and diabetes. The cited references follow the original manuscript.
What Happens When the Flow Stops
What happens when the flow is blocked? Medicine knows two scenarios well. Ischemia and congestion.
Ischemia is a state in which the supply is blocked. The most typical is a state in which the artery is blocked so that oxygen and nutrition cannot reach the cell. Myocardial infarction is a state in which the heart's artery is blocked so that the myocardial cells do not receive oxygen, and cerebral infarction is a state in which the brain's artery is blocked so that the brain cells do not receive oxygen. Medical imaging catches such blockage of large arteries relatively well. The standard treatment of the emergency room is also concentrated on reopening the blocked artery.
Congestion is a state in which the discharge is blocked. It is a state in which the vein is blocked so that waste products cannot leave the tissue. When a leg vein is blocked the leg swells, when a hepatic vein is blocked ascites fills, and when venous pressure rises in heart failure water fills the lungs. Congestion is not as dramatic as ischemia, but when it progresses chronically it slowly destroys the tissue.
Ischemia and congestion at the level of large vessels are a domain medicine handles well. Precise treatments such as thrombolytics, stent procedures, and vascular bypass surgery have developed. But when the same thing happens at the microvascular level, the story is different. Ischemia and congestion at the microvascular unit are not caught well by imaging tests, and they cannot be reopened by emergency treatment either. Yet their effect slowly accumulates within the body of the same person.
When one microvessel is partially blocked, the cells of the narrow area that capillary is in charge of receive less oxygen and nutrition and, at the same time, discharge less waste. The damage of one area looks small. But when partial blockade at the microvascular level occurs dispersed throughout one whole organ, the organ function slowly drops. When this happens in the kidney, the glomerular filtration rate drops a little each year. When it happens in the heart, the chest begins to feel tight during exercise. When it happens in the brain, concentration and memory gradually drop.
The cell makes a decision between two modes when the flow is partially cut off. Recovery mode and survival mode. The cell in recovery mode repairs damage, divides, and maintains normal function. The cell in survival mode postpones repair, stops dividing, and holds on while maintaining only minimal function. If the supply of oxygen and nutrition is sufficient, the cell chooses recovery mode. If the supply is insufficient, it switches to survival mode.
In the latter half of the 20th century, the American molecular biologist Semenza revealed at the molecular level how the cell senses oxygen concentration. When oxygen becomes deficient, one protein inside the cell is activated and simultaneously regulates hundreds of genes. This protein is called hypoxia-inducible factor. The same research showed that when this protein is activated, the cell slows its division, reduces its metabolism, and sends signals for the formation of new vessels. It is the cell changing its own priorities in order to survive. This discovery brought the Nobel Prize in Physiology or Medicine in the 21st century to three scientists who revealed the oxygen-sensing mechanism.
A review published by Carreau and others in the Journal of Cellular and Molecular Medicine showed that the normal oxygen partial pressure of human tissue is far lower than we commonly think. In the alveoli the oxygen partial pressure reaches 100 mmHg, but the deeper one goes into the tissue, the more rapidly that value drops, so that in some tissues the oxygen partial pressure is maintained below 20 mmHg even in the normal state. It means that even a slight weakening of flow at the microvascular level can immediately drive the tissue into a critical hypoxic state.
The cell in survival mode gives up many things in order to survive. If the flow is restored again, the cell can return to recovery mode. But if the partial cutoff of flow persists chronically, survival mode becomes the norm. Recovery becomes progressively more difficult, and in the end the cell ages, or dies, or escapes control and begins abnormal proliferation. The underlying reality of aging and chronic disease is made precisely within this chronic survival mode.
At this point, whether the cutoff of flow occurs in only one direction or in both directions is decisive. If only the supply is blocked, the cell starves but holds on somehow. If only the discharge is blocked, the cell is poisoned but holds on weakly. But when the two directions are blocked simultaneously, the cell gives up recovery mode and switches to chronic survival mode. This is where the reason lies that aging and chronic disease begin in earnest when both directions are cut off simultaneously at the microvascular level.
Then what is the physical event that simultaneously cuts off bidirectional flow in the microvasculature? The most powerful answer to this question is calcification. Calcium and phosphate are slowly deposited on the wall of the microvasculature in the form of hydroxyapatite, and this deposition strips the vessel wall of its elasticity and narrows the inner diameter, in the end sharply reducing the effective blood flow of the tissue through the fourth-power sensitivity. This process progresses quietly over several years to several decades, and the moment it crosses the critical point, it surfaces as a "sudden" clinical event.
Vascular calcification has long been understood simply as a passive aging phenomenon in which the vessel "hardens" as it grows old. But from the early 21st century this view changed fundamentally. A review paper published by Demer and Tintut in the journal Circulation in 2008 comprehensively established that vascular calcification is not a passive deposition but an active, cell-mediated process similar to bone formation. Under certain conditions, vascular smooth muscle cells convert to a phenotype resembling osteoblasts, generate a mineralizing matrix on their own, and deposit hydroxyapatite, the same component as bone, into the vessel wall. In other words, the vessel does not "harden"; it "manufactures" the calcification itself.
A review published by Shanahan and others in the journal Circulation Research in 2011 organized the molecular-level regulatory mechanism of this active calcification process. The hypercalcemia and hyperphosphatemia frequently observed in patients with chronic kidney disease activate the osteogenesis-related genes of vascular smooth muscle cells, and these cells secrete small vesicles that induce the nucleation of minerals. In the normal state, inhibitory proteins such as matrix Gla protein, fetuin-A, and osteopontin prevent calcification, but when the functional balance among them collapses, calcification proceeds as a self-promoting process.
The traditional classification by which medicine describes this calcification is based on anatomical location. Intimal calcification, occurring in the vessel's intimal layer, proceeds together with atherosclerosis, with cholesterol, macrophages, and the inflammatory response at its center. This is the main mechanism of coronary plaque rupture and myocardial infarction. Medial calcification, occurring in the vessel's medial layer, proceeds together with aging, diabetes, and chronic kidney disease, and becomes the direct cause of vessel wall stiffening and systolic hypertension.
[Figure 4] Comparison of Intimal Calcification and Medial Calcification
| Category | Intimal calcification | Medial calcification |
|---|---|---|
| Site of occurrence | Vessel intimal layer | Vessel medial layer |
| Accompanying condition | Atherosclerosis | Aging, diabetes, chronic kidney disease |
| Core mechanism | Cholesterol, macrophages, inflammation | Osteogenic phenotype conversion of smooth muscle cells |
| Clinical result | Plaque rupture, acute myocardial infarction | Vessel wall stiffening, systolic hypertension |
| Speed of progression | Relatively fast, localized | Chronic, systemic |
The two calcifications differ in anatomical location, associated diseases, and clinical implications, but physically they perform one common function. They reduce the effective inner diameter of the vessel, strip away its elasticity, and paralyze the system that regulates flow rate and pulse pressure. In other words, the calcification that has occurred in the microvasculature cuts off bidirectional flow simultaneously. The oxygen supply drops, and the waste discharge drops. And when this cutoff accumulates chronically, the cells of that area lose recovery mode forever.
This is the answer to exactly where the 30-year limit of drug treatment examined earlier comes from. The drug is not at fault. It is the road the drug travels that is narrowing. Even if the same amount of insulin is secreted, if the microvasculature is hardened it does not reach the target cell; even if the same amount of antibiotic is administered, if the microvasculature is narrowed it does not reach the site of infection; and even if the same amount of anticancer drug enters, if the microvascular network has collapsed it does not reach the tumor cell. Chemical medicine succeeded in precisely handling the shape and reaction of molecules. But the next stage, in which that molecule is carried on the flow to the target, belongs to the physics layer on top of the chemistry layer. When the flow of that physics layer is alive, all the drugs of chemical medicine exert their original effect. When the flow begins to weaken, the effect of the same drug progressively drops.
We have now seen the exact place where microvascular bidirectional blockade occurs, and that its physical underlying reality is vessel wall calcification. Then what difference does this perspective make in the clinic? If we reread, in the same place, the two chronic diseases that modern medicine carries the largest number of patients for while never explaining their root cause, an unexpected integration begins to be seen.
Essential Hypertension and Diabetes: The Blank Space Medicine Left
Modern medicine still leaves the root causes of the two most common chronic diseases unexplained without a complete account. They are essential hypertension and diabetes.
According to the clinical reference resource of the U.S. National Library of Medicine, about 90 to 95 percent of hypertension patients worldwide are classified as having essential or primary hypertension, for which no specific single cause can be identified. Cases like secondary hypertension, in which a specific underlying disease is found, account for only 5 to 10 percent, and the vast majority of the rest remain of unknown cause. That more than 90 percent of the chronic disease for which medicine carries the largest number of patients is bundled under the name essential, that is, "the cause is not known," is a fact worth taking to heart once.
Diabetes is similar. Insulin resistance and pancreatic beta-cell dysfunction, known as the pathological mechanism of type 2 diabetes, merely describe the phenomenon; there is no single-cause explanation for why these two progress slowly in certain people. Factors such as genetic predisposition, obesity, lack of exercise, and diet have been identified as risk factors, but there is no integrated explanation of through what final common pathway these factors produce diabetes. And the real problem of diabetes lies not in high blood sugar itself but in the complications by which high blood sugar damages the microvasculature over decades and destroys the retina, kidney, and nerves, yet the mechanism of this microvascular damage is likewise not fully explained.
These two blank spaces are connected into one pathway in the gradient perspective of this book. An important axis of essential hypertension can be reinterpreted as the accumulation of increased microvascular resistance and vessel stiffening. We confirmed earlier that even a slight decrease in radius at the microvascular stage drops the flow rate by a large margin. To maintain the same tissue perfusion, the heart must push blood at a higher pressure, and the state in which this compensation has become chronic can be observed as the blood pressure reading.
From this perspective, the word essential can be reinterpreted not as a simple unknown cause but as a name pointing to a state in which the physical condition at the microvascular level has already advanced. The reason specialty medicine could not find the cause of essential hypertension is that medicine saw only the large mains of the city's water and sewage system and did not see the micro-pathways of the alleyways.
Diabetes is likewise similar. Insulin resistance is a state in which signal transduction is not properly executed at the cellular level, and for this signal transduction to be executed, both the calcium gradient and microvascular blood flow must be normal. For insulin to reach the target cell, the microvasculature must be alive, and for the insulin signal to be carried out inside the cell, the calcium gradient across the inside and outside of the cell must operate normally.
When chronic microvascular damage and disturbance of calcium metabolism accumulate over the long term, the very execution of the insulin signal is physically weakened, and this is observed as insulin resistance. That the complications of diabetes are largely microvascular diseases is, from this perspective, no coincidence. The progression and complications of diabetes are deeply entangled with microvascular damage, and blood sugar is one axis of the most visible marker showing that progression on the surface.
Contrasting this interpretation with the latest synthesis in aging research reveals an interesting coincidence. A comprehensive review published by López-Otín and others in the journal Cell in 2023 organized the twelve hallmarks of aging. They are genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis.
Although these twelve are each described independently, most of them are downstream results that are commonly accelerated under the condition of microvascular bidirectional blockade and calcium gradient collapse. Mitochondrial dysfunction originates in the microvascular cutoff of the oxygen and nutrition supply, chronic inflammation originates in the microvascular cutoff of waste discharge, and cellular senescence originates in the chronicity of bidirectional cutoff. Gradient collapse is the upstream cause, and the twelve hallmarks of aging are its downstream manifestations. This perspective is one of the core threads of the following chapters.
Seeing this far, it begins to be seen that the chronic diseases for which modern medicine carries the largest number of patients (essential hypertension, type 2 diabetes, chronic kidney disease, neurodegenerative disease, and aging itself) share the same physical site under different names. That shared site is precisely the microvasculature, the event occurring at that site is the simultaneous blockade of bidirectional flow, and the physical medium of that blockade is the deposition of calcium and phosphorus.
[Figure 5] A Self-Check of Everyday Micro-Stagnation
| Your flow: a self-check of everyday micro-stagnation. Please check whether two or more of the following items apply to you. 1. Your hands and feet are colder than before (especially the toes). 2. Your recovery time after exercise is getting longer. 3. Small wounds do not heal well (especially wounds on the feet). 4. Drowsiness after meals has worsened. 5. You often wake up around 3 a.m. If two or more items apply to you, there is a strong possibility that our body's micro-flow is already partially weakened. The test results of the large vessels may come back normal. But the flow at the microvascular level is still slowly progressing in a domain that ordinary medical imaging does not see. The following chapters address how that progression begins and how it accelerates. |
|---|
The Blank the Giants Left, and the Last Piece
At the end of this chapter, let us step back and organize the big picture again. There were great giants who rewrote the history of humanity. Newton built the physical framework by which all things move, thermodynamics proved the absolute directionality of nature that a system whose flow has stopped collapses, and Darwin revealed the providence of life that the one who survives in a harsh environment is the one that adapts. On top of that, specialty medicine has raised, one stage at a time, the precision of diagnosis and treatment through diagnostic-name classification and molecular targets. We stand on top of the enormous framework of these giants.
But on top of that framework, one picture converging on the underlying reality of the human body's aging and chronic disease long remained a blank that was never filled. The last piece that fills that blank is the DIAH-7M integration theory that this book calls out. It is the integrated pathway in which the four signals of deficiency, inflammation, acidosis, and hypoxia are chronically pulled so that calcium is released from bone, that calcium settles on the microvascular wall and creates microcalcification dual blockade, and that dual blockade splits into seven clinical patterns and surfaces as the more than 200 aging and chronic diseases of specialty medicine. The DIAH trigger is the starting point, microcalcification dual blockade is the underlying reality, and 7M is the surface. This integrated pathway, to be formalized in the middle part of this book, is the last piece that fills, at the level of the human body, the blank the giants left.
[Figure 6] The Blank the Giants Left, and the Last Piece the DIAH-7M Integration Theory Filled
| Master and specialty | Universal law of the universe and life | The blank before the human body's aging and chronic disease | The last piece "The Age of Physical Medicine" filled |
|---|---|---|---|
| Newton (physics, mechanics) | The laws of force and motion. The physical framework by which all things move | The movement of the vast universe was founded, but the physical blockade of the microvasculature within the human body had not reached the seat of founding | Elucidation of dual blockade: it is established that the event in which microcalcification of the microvascular wall simultaneously blockades the pathway and the signal is the underlying reality of aging and chronic disease |
| Thermodynamics (entropy) | A system whose flow has stopped collapses toward disorder | The universal principle that a system collapses when the flow stops was founded, but the seat of at what place and by what medium the ecosystem within the human body collapses had not been filled | Elucidation of gradient collapse: the process by which the gradient that sustained life collapses as the oxygen supply and waste discharge are cut off is established within the human body |
| Darwin (theory of evolution) | The one who survives in a harsh environment is the one that adapts | The evolution of species over millions of years was founded, but the seat of the adaptation event occurring within one person's body had not been directly established | Elucidation of the underlying reality of cancer: it is established that cancer is an event made at the end of the adaptation the cell chose in order to survive in the environment of a collapsed gradient |
| Specialty medicine (molecular target) | The classification of diagnostic names and the refinement of molecular targets | At the place where disease was finely divided into roughly 17,000 to 55,000 diagnostic classifications, one picture converging on the underlying reality of aging and chronic disease had not been filled | The DIAH-7M integration theory: it binds the more than 200 aging and chronic diseases into one underlying reality and establishes the integrated pathway leading from the DIAH trigger, through microcalcification dual blockade, to 7M |
We have reread the human body as a map of gradient. We confirmed that the three gradients of pressure, concentration, and potential drive the flows of blood and oxygen and signal, and that among them the ten-thousand-fold calcium gradient across the inside and outside of the cell physically executes almost every function of life. The site where these gradients are actually maintained or collapse is, for the most part, the microvasculature, and the fourth-power sensitivity of the microvasculature showed how a micrometer-level change creates a clinical difference. The calcification occurring on the microvascular wall is the form in which that gradient collapse becomes physically fixed, and we examined that the one layer of the human body that the medicine of the chemistry layer has not seen is precisely this layer of flow and gradient. And we confirmed that this perspective can fill the two greatest blank spaces of medicine, essential hypertension and diabetes, with a single physical pathway.
But is this appearance we saw within our body a thing that exists only in our body? If the river and the star and the ecosystem all operate on top of the same law, the picture of essential hypertension and diabetes seen within the microvasculature becomes not a simple medical event but a manifestation of a cosmic universal law. In the next chapter, we step back one pace and place our body again within the cosmic seat of that law. Earlier we examined the three gradients within the human body. The fact that blood flows by the pressure gradient, oxygen moves by the concentration gradient, and the nerve signal is transmitted by the potential gradient. These three gradients are not a special event that operates only in the human body. All of nature moves on top of the same three gradients. Let us deeply examine the fact that the reason the river flows, the reason the star shines, and the reason the ecosystem circulates are on top of one and the same law as the law of flow seen within the human body.
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