This article is the first part of Chapter 2 of The Declaration of the Age of Physical Medicine (Yoon Jong-won). It is an academic exposition presenting the author's hypothesis of physical medicine, and the body text, figures, and citations follow the original manuscript.
In the previous chapter we saw why one never gets better even after a lifetime of medication. The blood pressure drug lowers the number but does not restore the vessel itself, the cholesterol drug lowers the cholesterol but does not stop the damage to the vessel wall, and the diabetes drug supplements the insulin signal but does not restore the very place where that signal is to operate. It became clear there that it is not the drug that is wrong, but the very road on which the drug travels that is narrowing.
Then what exactly is that road, and what is flowing after what, and how, within our body? To answer this question, in this chapter we take one step inside our body. Within the human body there is flow everywhere. The blood flowing inside a vessel moves on top of a difference of pressure, the oxygen entering the blood from the alveoli moves along a difference of concentration, and the signal of a nerve cell is an electrical pulse created by the difference of potential across the inside and outside of the cell membrane. The system in which these three differences interlock with one another and operate is the human body itself. In physics this difference is called a gradient.
That gradient is life becomes clearest in one simple comparison. The chemistry of a corpse and the chemistry of a living person are almost the same. The same molecules, the same proteins, the same DNA, the same enzymes are contained in almost the same amounts. But one is alive, and the other is dead. What is it that divides the two states?
By chemistry it is difficult to distinguish the two states. Looking only at the kinds and amounts of molecules, the difference between a corpse and a living person is slight. What divides the two states is not the molecules, but whether the gradients those molecules create are being maintained, and whether flow is occurring on top of those gradients. In the body of a living person, a gradient of concentration is maintained inside and outside the cell so that oxygen flows, a gradient of pressure is maintained between the arteries and the veins so that blood flows, and a gradient of potential is maintained across the inside and outside of the nerve-cell membrane so that the signal flows. In a corpse the same molecules are contained in almost the same amounts, but all those gradients have vanished. Since the gradients have vanished, flow does not occur either.
Life is not a stationary structure. Life is the very state in which gradients are being maintained and flow is ceaselessly occurring on top of those gradients. And so the underlying reality of aging and chronic disease is also, before any abnormality of molecular signals, a physical event in which flow is blocked and the pathway narrows. This is the reason this book bears the name physical medicine. This chapter draws the map of that gradient within the human body, and unravels in turn how that terrain collapses and how that collapse becomes the start of aging and chronic disease.
There is one more place to note. It is the fact that the great giants of science who rewrote the history of humanity laid the foundation of this big picture of flow and gradient, one era at a time. 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 toward disorder, and Darwin revealed the providence of life that the one who survives in a harsh environment is the one that adapts. But on top of that great framework, the place of how the micro-dimensional gradient collapses within one person's body and how it surfaces as aging and chronic disease long remained a blank that was never filled. The spine proposition of this book, namely that the root cause of aging and chronic disease is microcalcification and that this microcalcification is the decisive place where the gradient collapses within the human body, is the last piece that fills that blank. This chapter unravels, on top of the map of gradient within the human body, exactly into what place that last piece is fitted.
Life Is a System in Which Flow Is Maintained
The 19th-century French physiologist Bernard was the first to organize this insight in the language of medicine. He noted that the human body maintains its internal environment constant while ceaselessly exchanging matter and energy with the external environment. Even when the external temperature changes, the body temperature is maintained near 36.5 degrees; even when the external food varies, the blood sugar stays within a narrow range; and even when the external oxygen concentration changes slightly, the oxygen partial pressure of arterial blood is maintained constant. He saw this constant internal environment as the very condition of life's freedom. It was the idea that the ability to keep one's own internal consistency without being swayed by the outside is the very essence of being alive.
In the early 20th century, the American physiologist Cannon formalized this concept under the name homeostasis. His book published in 1932 expressed the human body as the "wisdom of the body" and unraveled the operating principle of homeostasis. The core of homeostasis is not stillness. It is balance through ceaseless motion. When oxygen enters, carbon dioxide must leave; when nutrition enters, waste products must leave; and when a signal is sent, the signal must be retrieved. If the flow in one direction does not exactly balance the flow in the other direction, homeostasis collapses.
Expressing this in the language of physics makes it clearer. There are two kinds of equilibrium. Static equilibrium and dynamic equilibrium. Static equilibrium is a state in which two weights press with the same weight from both sides so that it does not move. Dynamic equilibrium is a state in which water enters on one side and the same amount leaves on the other side, so that the water level is maintained constant.
Static equilibrium is the equilibrium of death. Dynamic equilibrium is the equilibrium of life.
Life stands on top of dynamic equilibrium. Oxygen enters the lungs each moment and is carried to the cells each moment, and at the same time carbon dioxide leaves the cells for the lungs and is discharged through breathing. Nutrition is absorbed from the intestine at each meal and carried to the cells each moment, and at the same time waste products leave the cells for the kidneys and are discharged as urine. While the two directions of flow exactly balance, we do not separately feel that we are alive. It is because the flow is so natural that it is not seen. But if one side stops even for a moment, for instance if the oxygen supply is cut off for just 4 minutes, we lose consciousness.
Life is the very flow that is newly created each moment. If a corpse is a collection of stationary molecules, life is the pattern in which the same molecules are ceaselessly flowing. To be alive is to flow ceaselessly.
This insight gives medicine one important conclusion. It is that the underlying reality of aging and chronic disease lies not in the amount of the molecule itself, but in the manner in which the molecule flows. Even if the same amount of oxygen is in the lungs, if it does not flow to the cells the cells starve; and even if the same amount of insulin is secreted, if it does not flow to the target cells the blood sugar does not drop. To understand aging and chronic disease precisely, one must raise the view by one stage, from the amount of the molecule to the flow of the molecule.
How does flow occur? Physics gives one clear answer. For flow to occur, three things are needed. Energy, a gradient, and a medium. Energy creates the gradient, the gradient creates the flow, and the flow occurs through the medium. River water flows along the gradient of height created by gravity, with the medium of water, and electricity flows along the gradient of potential difference, with the medium of electrons. The blood of the human body follows the same law. The pressure energy that the heart creates makes a gradient of pressure between the arteries and the veins, and along that gradient the medium of blood flows. Water, electricity, and blood appear on the surface to be different events, but in their essence there are the same three terms.
Recalling a city's water and sewage systems makes the flow of the human body clearer. A city is alive on top of two kinds of pathway systems. One is the water supply through which clean water enters, and the other is the sewer through which used water leaves. The two pathways do not operate separately. Only when they operate simultaneously within the same city can the city be alive. If even one pathway is blocked, the city begins to be paralyzed. It is the same for the human body. The artery is the incoming water supply and the vein is the outgoing sewer, and the smallest place where those two systems meet is the microvasculature. While the incoming flow and the outgoing flow occur simultaneously in the microvasculature, the human body is alive, and when those two directions weaken simultaneously, the human body begins to be paralyzed.
Flow and you live, block and you die. This is the simplest proposition that runs through this entire book. And this proposition is not an abstract philosophy, but a physical fact operating each moment within the human body.
Three Gradients: Pressure, Concentration, Potential
The gradients operating in the human body are diverse, but they can be bundled into three representative types. The pressure gradient, the concentration gradient, and the potential gradient. These three each drive different systems while, at the same time, interlocking with one another to maintain the flow of the whole body.
The pressure gradient is the engine of blood circulation. When the heart pumps up about 5 liters of blood per minute, the left-ventricular systolic pressure reaches about 120 mmHg, and passing through the aorta, the arterioles, the capillaries, and the venules, the pressure gradually drops so that by the time it reaches the right atrium it approaches 0 mmHg. This pressure difference is the physical driving force that pushes the blood in one direction. The moment the pressure gradient vanishes, that is, the moment the heart stops, the blood stagnates and the tissue loses its oxygen supply. That the heart beats about 100,000 times a day, pumping up more than 7,000 liters of blood a day, is the work of ceaselessly regenerating this pressure gradient.
The concentration gradient operates at the levels of respiration, the kidney, and the cell, respectively. The oxygen partial pressure of the alveoli is about 100 mmHg, and the oxygen partial pressure of the venous blood entering the pulmonary capillaries is about 40 mmHg. This difference of 60 mmHg is the driving force that diffuses oxygen from the alveoli into the blood, and in the tissue a concentration gradient in the opposite direction delivers oxygen from the blood to the cells. In the kidney, the difference of hydrostatic pressure and colloid osmotic pressure on the two sides of the glomerulus filters the plasma and creates about 180 liters of primary urine a day for an adult. And at the cellular level, the concentration differences existing inside and outside the cell execute the signals of life. One of the most important of these is the gradient of calcium ions, which we will address in detail later.
The potential gradient drives the electrical systems of the nervous system and the heart. In the resting state, the nerve-cell membrane maintains a negative potential in which the inside of the cell is about 70 millivolts lower than the outside, which is called the resting potential. When a stimulus enters, the sodium channels open and the inside of the cell momentarily switches to a positive potential of up to +30 millivolts, and this change propagates rapidly along the axon, creating an action potential. The sodium-potassium pump is the device that ceaselessly regenerates this potential gradient, moving 3 sodium ions out and 2 potassium ions in per molecule of ATP it consumes. When this pump stops operating, the cell's electrical signal vanishes within a few minutes. The beating of the heart also occurs on top of the same potential-gradient mechanism, and the electrocardiogram is a record measuring the changes of this electrical gradient from outside the body.
These three gradients do not operate independently of one another. Blood must move by the pressure gradient for the oxygen concentration gradient to be maintained, ATP must be supplied to the cells through the concentration gradient for the sodium-potassium pump to operate and the potential gradient to be maintained, and the potential gradient must be normal for the heart to beat and create the pressure gradient again. The three gradients maintain the life of the human body on top of a single triangular structure that supports one another. When one axis within this structure weakens, the other two axes waver together, and when this chain crosses a certain critical point, disease manifests clinically.
Calcium: A Ten-Thousand-Fold Gradient Executes Life
Among the numerous concentration gradients existing in the human body, the physically most extreme is the gradient of calcium ions. The calcium concentration outside the cell is at the level of about 1 millimolar, and the free calcium concentration inside the cell is at the level of about 100 nanomolar. Unifying the units, a difference of about ten-thousand-fold is being maintained across the inside and outside of the cell membrane. In the early 21st century, a comprehensive review published by Clapham in the journal Cell is regarded as the representative document that most systematically organized the scale and meaning of this gradient. A review published around the same time by Berridge and others in the journal Nature Reviews Molecular Cell Biology describes how this gradient evolved into a universal grammar of signal transduction.
The reason this ten-thousand-fold gradient can be physically maintained is that the cell ceaselessly consumes energy to pump calcium ions out of the cell. The calcium pumps of the cell membrane and the exchange transporters existing in the cell membrane and the endoplasmic reticulum perform this work. When ATP production stops, the pumps stop, and the gradient gradually vanishes. That is, the very fact that this gradient is "being maintained" is evidence of being alive. A cell in which the gradient has vanished is by definition a dead cell. The most precise cell-level example of the statement examined earlier, that dynamic equilibrium is the equilibrium of life, is precisely this calcium gradient.
Why is this ten-thousand-fold gradient important? It is because this gradient is the medium that physically executes almost every important function of the cell. The first division of a fertilized egg is initiated by the enormous calcium wave that occurs after the sperm enters the egg. Muscle contraction occurs at the moment the calcium concentration inside the muscle fiber surges about 100-fold. The release of neurotransmitters at a nerve terminal occurs at the moment the action potential reaches the terminal and opens the calcium channels, and the entering calcium fuses the vesicles with the cell membrane. Hormone secretion, the activation of immune cells, and ultimately even the execution of apoptosis are all carried out through changes in calcium concentration.
If DNA is the blueprint of life, calcium is the executing code that carries out that blueprint into physical reality. Other ions such as sodium, potassium, and magnesium are also essential to the activity of life, but the only ion that maintains an extreme gradient reaching ten-thousand-fold is calcium. The cell-level events that occur when this gradient collapses (calcium overload, mitochondrial collapse, apoptosis) are also the cell-level common pathway of aging and chronic disease to be addressed in the following chapters.
The Microvasculature: A Bidirectional Exchange System
For flow to occur, there must be a pathway through which the flow can travel. The most decisive pathway in the human body is the blood vessel. But the large vessels we commonly recall (the aorta, the veins, the arteries) are in fact only part of the pathway. The place where the real flow occurs is the microvasculature, far thinner than those.
The aorta is a thick pathway reaching about 2 to 3 centimeters in diameter. The blood that leaves the heart moves rapidly along this thick pathway. But for oxygen or nutrition to reach the cell, it must branch out from this large pathway into gradually thinner pathways. The artery branches into arterioles, and the arteriole branches again into terminal arterioles, finally arriving at the microvascular network.
The microvascular network is not made of one kind of vessel. Five kinds of components make up one system. The first component is the arteriole. It is a thin tube 30 to 50 micrometers in diameter, and it has a thick smooth-muscle layer, so it regulates the resistance of flow. The second component is the metarteriole. At 10 to 20 micrometers in diameter, it has smooth muscle partially remaining, so it determines the amount of flow entering the capillary. The third component is the capillary. At 5 to 10 micrometers in diameter, it is the thinnest pathway, made of only a single layer of endothelial cells, and it is where the main body of bidirectional exchange occurs. The fourth component is the venule. At 10 to 50 micrometers in diameter, it is the starting point of the immune response, where white blood cells pass through the vessel wall into the tissue. The fifth component is the lymphatic capillary. It is a one-way pathway that sends the fluid, large molecules, and immune cells that were not retrieved in the space between the capillary and the cell back into the lymphatic system.
[Figure 1] The Five Components of the Microvasculature
| Component | Diameter | Feature | Role |
|---|---|---|---|
| Arteriole | 30-50 μm | Thick smooth-muscle layer | Regulation of flow resistance |
| Metarteriole | 10-20 μm (varies by tissue) | Partial smooth muscle | Determines amount of capillary flow |
| Capillary | 5-10 μm | Single layer of endothelial cells | The main body of bidirectional exchange |
| Venule | 10-50 μm | White blood cells can pass through | White-blood-cell outflow, inflammatory response |
| Lymphatic capillary | 10-50 μm | One-way start | Retrieval of large molecules, immune cells |
This capillary network reaches everywhere in the human body. The total number of cells in the human body is estimated at about 37 trillion, and for all these cells to be supplied with oxygen and nutrition, capillaries must extend right up next to the cells. If the length of the entire microvasculature is connected, it is estimated to reach roughly one hundred thousand kilometers. It is a length that could wrap around the Earth more than twice. This vast web extends up close to every cell, so that most cells, because of the oxygen diffusion limit, are placed within roughly 100 to 200 micrometers of the nearest capillary, the tissue being made that way. It is because, if they were farther than that, it would be difficult for oxygen to reach the cell through diffusion.
In the early 20th century, the Danish physiologist Krogh precisely measured the distribution and number of capillaries within skeletal muscle. He showed that hundreds of capillaries are distributed within a one-millimeter-square cross section. The same research presented a model for calculating the distance and pressure by which oxygen diffuses from the capillary to the cell. For this research he received the Nobel Prize in Physiology or Medicine in 1920. A century later, the capillary model he presented is still used as the starting point of microcirculation physiology.
The most decisive of the five components is the capillary. The capillary is not a simple pathway. It is an exchange system in which the incoming flow and the outgoing flow occur simultaneously. The capillary wall is made of a single layer of endothelial cells, so it is very thin. Through this thin wall, oxygen, glucose, amino acids, hormones, immune cells, and drugs leave on one side and diffuse into the space between the tissue, and through the same wall, carbon dioxide, lactate, uric acid, waste products, and inflammatory substances enter from the other side and are retrieved back into the bloodstream.
[Figure 2] Supply and Discharge by Microvascular Component
| Component | Supply (to tissue) | Discharge (from tissue) |
|---|---|---|
| Arteriole | Pressure regulation, blood-flow distribution | |
| Metarteriole | Determines capillary entry amount | |
| Capillary | Oxygen, glucose, amino acids, hormones, immune cells, drugs | Carbon dioxide, lactate, uric acid, waste products, inflammatory substances |
| Venule | White-blood-cell outflow during inflammation | Retrieval stage after capillary exchange |
| Lymphatic capillary | Retrieval of large proteins, lipids, immune cells, residual fluid |
The five components are not separate stages. Pressure is created in the arteriole, the capillary entry amount is regulated in the metarteriole, bidirectional exchange occurs in the capillary, and retrieval follows in the venule and the lymphatic capillary. All of this is one continuous flow system operating simultaneously. When one stage weakens, the whole system wavers at the same time. This very simultaneity is also the physical basis for microvascular blockade occurring in both directions simultaneously in one organ.
At the end of the 19th century, the British physiologist Starling formalized the physical law governing this bidirectional exchange. This principle, named after him, showed that the difference between the pressure inside the capillary and the pressure of the space between the tissue determines the direction of fluid flow. At one end of the capillary the pressure is high, so fluid leaves the capillary for the tissue, and at the other end the pressure is low, so fluid is retrieved from the tissue into the capillary. The two directions of flow occur simultaneously within one capillary.
This principle has become more precise over a century. A review published by Levick and Michel in the journal Cardiovascular Research organized the point that a polysaccharide protective layer on the inside of the capillary wall regulates fluid exchange more delicately. It means the capillary is not simply a membrane through which fluid passes, but a delicate system that actively regulates flow. A model study published around the same time by Pries and Secomb in the journal Microcirculation showed that the capillary network adaptively changes its structure according to the oxygen demand of the tissue. The microvasculature is a living system, a system that ceaselessly regulates its own structure.
Here the most powerful physical answer to why the microvasculature becomes the most decisive site of aging and chronic disease appears. Poiseuille's law examined earlier showed that the amount of fluid flowing through a tube is proportional to the fourth power of the tube's radius. If the radius is halved, the flow rate drops to one-sixteenth. The place where this fourth-power sensitivity operates most dramatically is precisely the microvasculature. In a capillary with a radius of 5 micrometers, even if that radius decreases by just 1 micrometer the flow rate decreases by about 59 percent, if it decreases by 2 micrometers by about 87 percent, and if it decreases by 3 micrometers by about 97 percent. This micrometer-level change, which is not captured by angiography or ordinary ultrasound, decisively governs the actual oxygen supply of the tissue.
[Figure 3] Change in Flow Rate with Decrease in Capillary Radius
| Radius decrease | Remaining radius | Flow rate decrease | Clinical meaning |
|---|---|---|---|
| 0 μm | 5 μm | 0% | Normal (baseline) |
| 1 μm | 4 μm | about 59% | Retinal, peripheral-nerve hypoxia begins during exercise |
| 2 μm | 3 μm | about 87% | Critical hypoxia of kidney, brain even at rest |
| 3 μm | 2 μm | about 97% | Multiple chronic-disease manifestation, survival mode fixed |
| 4 μm | 1 μm | about 99.8% | Virtual occlusion, irreversible tissue damage |
This passage touches on a familiar weakness of modern medicine. The imaging diagnosis commonly used in the clinic captures well the narrowing of relatively thick vessels such as the aorta, the coronary arteries, and the cerebral vessels. But the very site where most of the human body's chronic diseases (diabetic retinopathy, diabetic nephropathy, peripheral neuropathy, neurodegenerative diseases such as Alzheimer's) begin and progress is the microvasculature, which is not captured well by imaging. Even if the large vessels still look fine, the microvasculature may already be extensively damaged, and in many aging-related chronic diseases microvascular damage is observed as an important common pathway that determines their progression.
Looking at how the pathway of flow is made, the meaning of flow being blocked becomes clear. When flow weakens in any one of the five components, the whole microcirculation wavers. But the most decisive event occurs at the capillary level. When the capillary wall thickens, or the inside of the capillary narrows, or the capillary itself disappears, bidirectional exchange drops simultaneously. Oxygen cannot go to the cell, and waste products cannot leave the cell. The two directions of flow are cut off simultaneously. This is the physical underlying reality of the blockade that occurs at the microvascular level, and the exact location where the microvascular microcalcification dual blockade addressed as the central proposition in this book operates.