This article is the first part of Chapter 5 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.
Let us recall the moment a person reaches death. Whether they suddenly collapse from a heart attack, lie in the intensive care unit from sepsis, cannot stop bleeding from a major accident, or are in hospice from a long cancer. On the death certificate, different disease names are written. But within that person's body, during the last few minutes, what on earth is happening?
The answer medicine has tracked is shocking. Whatever the diagnostic name one dies of, in the body at the last moment the same four events occur simultaneously. Oxygen becomes deficient, the body fluid tilts toward acidic, the nutrition supply is cut off, and the tissue collapses and inflammation signals explode. There are more than a thousand causes-of-death diagnoses, but the last molecular event is one.
Let us recall again that abbreviation called out at the end of the previous chapter. Binding the English initials of these four events, we call it DIAH. Deficiency (D), Inflammation (I), Acidosis (A), Hypoxia (H). And the place where these four gather together we call the four gateways. They are the four gates through which every death of the human body passes.
That a trigger is pulled means the human body has sensed a crisis. And there is one emergency medicine the human body always takes out to respond to a crisis. It is dissolving and drawing calcium out of the bone. Calcium is the medium mobilized first in every emergency situation of the human body, and its storehouse is the bone. More than 99 percent of the calcium is stored in the bone, and when a crisis strikes, that storehouse opens first.
Unraveling how calcium is mobilized in each of the four triggers reveals the human body's intricate emergency system. In deficiency, to maintain the blood calcium concentration, parathyroid hormone is secreted and draws calcium from the bone. In inflammation, calcium is mobilized as the activation signal of immune cells. In acidosis, to neutralize the acid, the carbonate and phosphate buffer systems of the bone are mobilized, and in that process calcium comes out together. In hypoxia, as the hypoxia-adaptation signal and the vasodilation signal turn on, calcium enters once more as a mediator. Four crises, four emergency prescriptions, but the medium is all one. It is calcium.
Here a shocking second fact is revealed. That the DIAH four gateways open wide all at once is the last moment of death, but those four triggers are, even while one is alive, in the midst of everyday life, weakly but ceaselessly, being pulled and released. Within the ordinary day of a person who cuts sleep short with overtime and fills their meals with instant food, small deficiency and small inflammation and small acidosis and small hypoxia progress simultaneously. And with each of those small crises, the human body draws a little calcium out of the bone every day. That event that explodes at the last moment of death is being pulled a little every day while one is alive. That is the way our everyday life builds aging and chronic disease a little every day.
What happens when that small pulling accumulates? The answer is aging and chronic disease. Atherosclerosis, diabetes, Alzheimer's, osteoporosis, chronic renal failure, and various tumors. The manifestations of aging and chronic disease that we have diagnosed separately in specialty medicine are all the surfacing, at different places, of the event in which the DIAH trigger is chronically pulled and calcium repeatedly leaves the bone. Chronic disease is, in the end, the road of slowly dying. If the four gateways opening wide all at once is death, chronic disease is the event in which the same four signals, the triggers, are pulled a little every day.
This event is, before any abnormality of molecular signals, a physical event. It is the physical cutoff of flow, in which oxygen cannot reach, nutrition cannot enter, and acidic substances cannot leave. And the medium of that emergency prescription is the physical entity calcium. This is the reason this book bears the name physical medicine. Then one question remains. Where does the calcium that leaves the bone every day like that go? That answer is the subject of the next chapter.
This chapter unravels the identity of those four triggers one by one. It examines in turn what sub-signals each trigger is composed of, how it is pulled in everyday life, and how it causes the conversion of calcium. When we clearly understand deficiency, inflammation, acidosis, and hypoxia, the starting point of aging and chronic disease begins to be seen. And the fact that we are pulling the trigger a little every day also begins to be seen together.
D: Deficiency
The first trigger is deficiency. When the human body is not sufficiently supplied with the core resources needed for the operation of the microvasculature, an emergency signal is activated.
Deficiency does not simply mean eating less food. Even if calories are being taken in sufficiently, the micronutrients essential to the operation of the microvasculature can be lacking. The greatest paradox of modern dietary life is that caloric excess and micronutrient deficiency progress simultaneously.
Deficiency is divided into five kinds.
[Figure 1] D: The Five Kinds of Deficiency
| Code | Kind of deficiency | Main cause | Effect on the human body |
|---|---|---|---|
| D-PH | Physical-stimulus deficiency | Sedentary living, lack of exercise, microgravity | Bone-formation stimulus ↓ |
| D-NT | Nutritional deficiency | Processed food, micronutrient deficiency | Shortage of bone and microvascular resources |
| D-LF | Sleep and sunlight deficiency | Lack of sleep, indoor living | Collapse of hormonal rhythm |
| D-MD | Drug-induced deficiency | Steroids, some gastric-acid suppressants | Direct suppression of bone formation |
| D-HR | Hormonal deficiency | Menopause, testosterone decline | Weakened maintenance of bone calcium |
First, physical-stimulus deficiency. The bones of our body maintain their strength and density when a certain physical stimulus is applied. The actions of walking, running, lifting, and holding act as pressure applied to the bone, stimulating the activity of the cells that make bone. When sedentary living lengthens and physical activity decreases, this stimulus vanishes, and the bone begins to lose the reason to maintain its own strength. The fact that the bone density of astronauts who have been to space drops sharply within a short time clearly shows the decisive role of physical stimulus. The most direct and most frequently omitted item among deficiencies is precisely this physical stimulus.
This fact is revealed most dramatically in spaceflight data. According to data published by Lang and others in the Journal of Bone and Mineral Research, the spinal and hip bone density of astronauts who performed long-duration spaceflight missions decreased meaningfully each month. A follow-up study published by Gabel and others in the British Journal of Sports Medicine showed that after flight the strength and density of the shinbone decreased by about 2.9 to 3.9 percent, and that the longer the flight period, the more the loss accelerated. Data that the lumbar spine and hip bone density and muscle mass of astronauts who flew 4 to 14 months on the Mir space station in the 1990s decreased by a large margin was organized by LeBlanc and others in the Journal of Musculoskeletal and Neuronal Interactions. When gravity, the simplest physical stimulus, vanishes, the bone rapidly loses its own mineral.
Second, nutritional deficiency. Insufficient intake of calcium itself, magnesium deficiency, protein deficiency, and the shortage of various micronutrients including vitamin D are included here. Modern dietary life has the paradox in which caloric excess and micronutrient deficiency progress simultaneously. A diet centered on processed food supplies sufficient calories, but it cannot sufficiently supply the micronutrients needed for bone metabolism and microvascular operation.
Third, sleep and sunlight deficiency. When sleep time decreases or sleep is frequently interrupted, the human body's hormone-secretion rhythm wavers. In particular, the hormones that make bone are most actively secreted during deep sleep. Without sufficient sunlight exposure, the synthesis of sunlight-dependent hormones including vitamin D drops. The everyday life of the modern person, who spends long hours only indoors and whose sleep is disturbed, becomes the soil of sleep and sunlight deficiency.
Fourth, drug-induced deficiency. The long-term use of some drugs has a direct effect on bone and calcium metabolism. Steroid-class drugs directly suppress the activity of the cells that make bone, some gastric-acid suppressants interfere with calcium absorption, and some diuretics increase calcium excretion. A drug taken every day for a chronic disease can, as a result, have a long-term side effect that makes calcium leave the bone.
Fifth, hormonal deficiency. The decline of estrogen in women after menopause and the decline of testosterone in elderly men are representative. These hormones play a decisive role in maintaining the calcium of the bone. The clinical phenomenon in which the speed of osteoporosis progression accelerates in women after menopause clearly shows the fact that hormonal deficiency is a powerful trigger of bone calcium leakage.
The five deficiencies do not operate separately. A person who is lacking in one is likely to be lacking in the others as well. It is because the same dietary life creates several deficiencies simultaneously. And all five deficiencies act in the same direction. They shake the human body's calcium homeostasis, stimulate parathyroid hormone, and accelerate the conversion of calcium from medium to enemy.
How these five deficiencies lead to calcium withdrawal from the bone is clearly organized at the molecular level. According to a document in StatPearls, the U.S. national medical standard database, the moment the blood calcium drops even minutely, parathyroid hormone is secreted within seconds, stimulates the osteoclasts, and immediately releases calcium from the bone. It is the fastest emergency-withdrawal system the human body has. Going one step further, a review published by Wein and Kronenberg in the journal Cold Spring Harbor Perspectives in Medicine showed at the molecular level that in a deficiency situation, parathyroid hormone directly promotes the micro-remodeling around the osteocytes and rapidly releases the mineral storehouse of the bone. These facts, discovered separately in specialty medicine, converge exactly under the one higher condition of deficiency.
I: Inflammation
The second trigger is inflammation. But it is not the inflammation we commonly recall, that is, the acute inflammation in which a trauma site swells red. It is chronic low-grade inflammation. It is a state in which the body ceaselessly sends inflammation signals at a weak intensity.
Aging biology has organized this chronic low-grade inflammation under the name inflammaging. It is the concept that aging itself is the accumulation of chronic low-grade inflammation. A comprehensive summary published by Franceschi and Campisi in the Journals of Gerontology Series A formalized that inflammaging is a major risk factor for the morbidity and mortality of the elderly, and a comprehensive review published by Franceschi and others in the journal Nature Reviews Endocrinology organized how inflammaging contributes to the pathophysiology of aging-related diseases through the connection of gut microbes and metabolic inflammation. Chronic inflammation is the common soil of all aging and chronic disease, and one of the most powerful driving forces of microvascular blockade.
Chronic inflammation is made by seven pathways.
[Figure 2] I: The Seven Kinds of Inflammation
| Code | Kind of inflammation | Main cause | Effect on the human body |
|---|---|---|---|
| I1 | Autoimmunity | Immune malfunction | Attack on one's own tissue |
| I2 | Chronic infection | Latent virus, periodontitis | Continuous immune stimulation |
| I3 | Dietary inflammation | Processed food, high sugar, trans fat | Increase of cytokines |
| I4 | Environmental inflammation | Fine dust, heavy metals, environmental hormones | Continuous immune activation |
| I5 | Stress inflammation | Chronic stress, collapse of cortisol pattern | Weakened immune regulation |
| I6 | Sleep inflammation | Lack of sleep, sleep fragmentation | Inflammatory cytokines ↑ |
| I7 | Microbiome inflammation | Gut microbe imbalance, antibiotics | Gut mucosal permeability ↑ |
First, autoimmunity. It is a state in which the immune system wrongly recognizes its own tissue as an external intruder and attacks it. Rheumatoid arthritis, lupus, and Hashimoto's thyroiditis are representative, but even in a state where such a diagnosis has not been made, there are many cases in which a weak autoimmune reaction against one's own tissue progresses ceaselessly.
Second, chronic infection. Chronic periodontitis, latent viruses, chronic sinusitis, and chronic Helicobacter infection of the gastrointestinal tract ceaselessly stimulate the immune system. A slight infection that the patient does not recognize persists for decades and creates the soil of chronic inflammation.
Third, dietary inflammation. It is the inflammation that processed food, a high-sugar diet, trans fat, and highly refined grains create. The Western-style diet ceaselessly stimulates the human body's immune system and increases the secretion of cytokines. The fact that the effect of a single meal remains in the immune state for hours to days has been widely reported.
Fourth, environmental inflammation. It is the inflammation that fine dust, heavy metals, pesticides, environmental hormones, and synthetic chemicals create. The modern person living in the city ceaselessly receives environmental stimuli through the respiratory tract and the skin and the gastrointestinal tract, and the immune system responds to it and maintains a chronically activated state. That fine-dust exposure is connected to cardiovascular disease is a widely confirmed clinical fact.
Fifth, stress inflammation. Chronic stress collapses the cortisol-secretion pattern and shakes the immune-regulation system. Cortisol is originally a hormone that suppresses inflammation, but when the secretion pattern is chronically shaken, it operates rather in the direction of stoking inflammation. The molecular pathway by which mental stress is converted into physical inflammation is well organized.
Sixth, sleep inflammation. When sleep time decreases or sleep is frequently interrupted, the balance of the immune system collapses and inflammatory cytokines increase. The effect of sleep on immunity operates not merely at the dimension of rest, but at the core dimension of immune-cell regeneration and antibody production.
Seventh, microbiome inflammation. When the balance of gut microbes is disturbed, the permeability of the gut mucosa increases, and molecules that should originally be inside the gut leak into the bloodstream. The immune system ceaselessly reacts to these leaked-in molecules and causes chronic inflammation. Antibiotic overuse, dietary-fiber deficiency, and a processed-food diet are the major factors that shake the microbiome balance.
The seven inflammations operate on the same soil. When one is activated the others are likely to be activated too, and all of them maintain the immune system in a chronically activated state. Chronic inflammation damages the microvascular wall and creates the nucleation sites where calcium can settle. If deficiency started the emergency withdrawal, inflammation makes the place where the withdrawn calcium settles.
How this chronic inflammation dissolves bone becomes clear from the integrated discovery of immunology and bone metabolism. According to a comprehensive review published in the journal Immune Network, chronic inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-17) induce the expression of a signaling molecule called RANKL and directly promote the differentiation of osteoclasts and bone resorption. Also, a study published by Kitaura and others in the Journal of Clinical Investigation showed, stage by stage, that TNF-α stimulates the expression of M-CSF in stromal cells, and M-CSF induces the expression of the RANK receptor in osteoclast precursors, mediating inflammatory bone lysis. The bone loss that occurs simultaneously in autoimmune patients and chronic-infection patients has been handled separately in specialty medicine, but its molecular pathway is one.
A: Acidosis
The third trigger is acidosis. It means a state in which the human body's acid-base balance has tilted toward the acidic side.
The acid-base balance of the blood is maintained in a very narrow range. The pH of normal blood stays between 7.35 and 7.45. If it leaves this narrow range, enzymes do not operate, proteins denature, and cells cannot live. The human body maintains this narrow range at any cost.
One of those costs is the bone. When the human body suffers from an acid burden, it releases the calcium and alkaline minerals stored in the bone to neutralize the acid. It is because the bone is the human body's largest acid-base buffer system. A chronic acid burden means chronic calcium withdrawal. Here lies the reason acidosis becomes a powerful trigger of the calcium medium-enemy conversion.
Acidosis is divided into four kinds.
[Figure 3] A: The Four Kinds of Acidosis
| Code | Kind of acidosis | Main cause | Effect on the human body |
|---|---|---|---|
| A1 | Dietary acidity | Meat, processed food, fructose, refined grains | Acid-base burden ↑ |
| A2 | Metabolic acidity | Lack of exercise, weakened micro-flow | Accumulation of lactate, uric acid |
| A3 | Weakened kidney acid-base | Renal failure, aging | Acid excretion ↓ |
| A4 | Weakened lung acid-base | Chronic lung disease, shallow breathing | Carbon dioxide excretion ↓ |
First, dietary acidity. A diet rich in meat, processed food, refined grains, and fructose creates an acid burden as a metabolic result. Conversely, vegetables and fruits create an alkaline burden and restore the human body's buffering capacity. It has been widely reported in analyses that the diet of pre-agricultural humanity was alkaline-dominant, but the diet after industrialization has been reversed to acid-dominant.
Second, metabolic acidity. When lack of exercise and weakened micro-flow accumulate, the metabolic waste products lactate and uric acid accumulate in the tissue. Acidic waste that should normally be rapidly removed through flow leaves slowly due to microvascular weakening. A vicious cycle is created in which microvascular weakening itself further accelerates acidosis.
Third, weakened kidney acid-base regulation. The kidney is the core organ that excretes the human body's acid into the urine. When kidney function weakens, acid excretion decreases, and here lies the reason chronic metabolic acidosis appears in chronic renal failure patients. Even if kidney function is within the normal range, the kidney's acid-excretion capacity gradually drops with aging.
Fourth, weakened lung acid-base regulation. The lung regulates the acid-base balance by excreting carbon dioxide. When chronic lung disease, a shallow breathing pattern, lack of exercise, and the decrease of lung capacity with aging accumulate, the lung's acid-regulation capacity weakens. It is a small difference, but it accumulates with time and becomes the soil of chronic acidosis.
The four acidoses all act in one direction. They accumulate an acid burden in the human body and make calcium be withdrawn from the bone as an emergency to buffer that burden. If deficiency is the signal of the emergency withdrawal and inflammation makes the place to settle, acidosis determines the amount and frequency of the emergency withdrawal.
The molecular mechanism of this cost was organized in a review published by Krieger and others in the journal Current Opinion in Nephrology and Hypertension. That research showed that when metabolic acidosis occurs, the bone is mobilized as the human body's immediate pH buffer, and the acidic environment promotes the expression of PGE2 and RANKL and activates the osteoclasts. Also, a comprehensive review published by Krieger and Bushinsky in the journal Kidney International organized that in the short term acidosis causes physicochemical calcium release, and in the long term it causes cell-mediated active bone resorption. Acidosis and bone loss are not two separate events, but two faces of the same molecular circuit over the passage of time.
H: Hypoxia
The fourth trigger is hypoxia. It means a state in which the cell does not receive enough oxygen.
The fact that hypoxia does not stop at merely a state of oxygen shortage is clear at the molecular level. When the cell senses hypoxia, a protein called hypoxia-inducible factor is activated and simultaneously regulates hundreds of genes. The hypoxia signal makes the cell slow its division, reduce its metabolism, and attempt the formation of new vessels. Short-term hypoxia is a protective reaction by which the cell endures a crisis. But chronically persisting hypoxia changes from protection into damage.
Hypoxia occurs in three dimensions.