Continuing from the previous part, this article examines the whereabouts of the leaked calcium and the dual blockade. The cited references follow the original manuscript.
[Figure 5] The Three Variables of Calcification Acceleration and Their Connection to the DIAH Triggers
| Variable | Core event | Related clinical condition | DIAH trigger connection |
|---|---|---|---|
| ① Supersaturation | Rise in calcium and phosphorus concentration | Chronic renal failure, high-phosphate environment | D (deficiency → parathyroid hormone hyperactivity) |
| ② Bone-forming cell conversion | Identity conversion of vessel-wall cells | Inflammation, oxidation, high blood sugar, aging products | I (chronic inflammation), A (acidification) |
| ③ Decrease of inhibiting factors | Weakening of Matrix GLA, Fetuin-A, pyrophosphate | Aging, vitamin K deficiency, chronic renal failure | D (nutritional deficiency), H (hypoxia) |
What must be noted is the fact that all three of these variables are directly connected to the DIAH triggers seen in the previous chapter. Deficiency shakes the balance of calcium and phosphorus, inflammation and acidification turn on the identity conversion of the vessel-wall cells, and chronic deficiency and hypoxia weaken the inhibiting factors. Inside the body of a person whose DIAH triggers are pulled, the three variables of calcification acceleration are also activated together. The same person's everyday life is, while starting the leakage of calcium, at the same time rapidly making the place where that calcium will settle.
The Microscopic Change Comes Before Imaging
The clinical course of aging and chronic disease has one characteristic time order. The symptoms the patient first complains of (fatigue, numbness of the hands and feet, blurred vision, minute decline of motor ability, cognitive dulling) show no abnormality on imaging. The doctor performs the standard examination and receives a normal result. The doctor reassures the patient that there is nothing seriously wrong. But the patient's symptoms do not disappear. After time has passed, when large vessel calcification is caught on macroscopic imaging, only then is a diagnosis made and treatment begun.
There is a patient's remark commonly heard in the clinic. "They say the checkup result is normal, but my body is not like it used to be." This one sentence is not a mere complaint. It is the accurate molecular-level expression of the fact that, at a dimension standard imaging cannot catch, but a dimension where the patient's everyday life is clearly changing, microvascular microcalcification is accumulating. This period is not a period of laziness. It is not a problem of the patient's will or lifestyle habits. It is a progression phase in which microcalcification is accumulating at a dimension that ordinary imaging cannot see. The patient's complaint is accurate. It is only that medicine's diagnostic tools have not yet reached that dimension.
Why does this time order occur? The answer lies again in Poiseuille's law. The fact that the flow rate is proportional to the fourth power of the pathway radius. What this fourth power means is that even if the pathway narrows only a little, the flow decreases by a large margin. When the radius decreases by half, the flow rate drops to one-sixteenth. Even if it decreases only to 90 percent, the flow rate drops to a level of about 65 percent.
In the microvasculature, even a small deposition makes an enormous effect. In the large vessels, the same amount of deposition gives almost no effect. So the small microcalcification of the microvasculature is already meaningfully reducing the flow, while the same volume of deposition in the large vessels still appears to have no effect. Damage progresses from the microscopic to the macroscopic, but diagnosis follows in reverse, from the macroscopic to the microscopic. The symptom comes first, and the imaging is caught later.
The Framingham Heart Study, which tracked several thousand residents of a town in the state of Massachusetts in the United States for decades, made this fact clear at the population scale. The analysis of that study, published by Mitchell and others in the American cardiovascular journal Circulation, showed that the stiffening of the arteries (the increase of stiffness occurring in both the microvasculature and the large vessels) is a powerful independent predictor of cardiovascular events even after all the standard risk factors have been adjusted for. That is, even if all the standard items such as cholesterol, blood pressure, diabetes, and smoking are normalized, arterial stiffening itself meaningfully predicts the future occurrence of myocardial infarction, stroke, and heart failure. The population data confirmed the fact that the stiffening that is not caught by standard diagnosis but progresses in the underlying reality is the true starting point of the clinical event.
This time order is the reason aging and chronic disease become difficult. When the patient's symptoms first begin, they are not visible on imaging. By the time they begin to be visible on imaging, it is the point when an event that has already accumulated for years to decades in the microvasculature has reached the macroscopic dimension. The fact that the standard diagnostic point is far behind on the time axis of the underlying reality. This is the clinical structure that makes aging and chronic disease irreversible.
But the same fact gives one hope. The event made in the underlying reality of the microvasculature is progressing from far earlier than macroscopic imaging. That period is, before the macroscopic event has hardened, a period in which recovery is possible. If we can handle aging and chronic disease not by the time of diagnosis but by the time of the underlying reality, we come to have the possibility of intervening before the event hardens irreversibly.
Defining the Root Cause: The Common Underlying Reality of Aging and Chronic Disease
Earlier we saw that the leaked calcium settles on the microvascular wall and makes microcalcification. We saw that this microcalcification operates together at the same spot in the pathway dimension and the signal dimension and forms the dual blockade. We saw that the dual blockade is an irreversible event that cuts off recovery mode and converts to survival mode. And we saw that this event begins in the microvasculature and accumulates over the time of the underlying reality, invisible to standard imaging.
Now it can be organized into one proposition. Whatever starting point it begins from (genetic mutation, chronic infection, environmental exposure, natural aging), the progression-phase underlying reality of aging and chronic disease converges into one place. It is the microvascular calcification by the dual blockade. This one sentence is the core claim of this whole book. Atherosclerosis, renal failure, diabetic complications, osteoporosis, dementia, cancer, and aging, which specialty medicine has seen separately, are all the same one underlying reality manifested only at a different place.
Genetic mutation deforms cellular metabolism and makes chronic inflammation and oxidative stress. Chronic infection directly accumulates inflammation. Environmental toxicity makes deficiency and hypoxia, and natural aging gradually pulls all the triggers. All these starting points arrive at the same conclusion. They pull the triggers of deficiency, inflammation, acidosis, and hypoxia, start the leakage of calcium, and accumulate calcification on the microvascular wall. The common underlying reality is made not at the starting point but in the process of progression.
Every cell of the human body is in direct contact with the microvasculature. No cell can live without the microvasculature. When microcalcification deposits on that microvascular wall, supply is blocked in one direction. Oxygen cannot reach, glucose cannot reach. Amino acids, hormones, immune cells, and drugs cannot reach the cell either. The cell begins to starve. And most decisively, oxygen becomes deficient.
In the other direction of the same microvascular wall, discharge is blocked. The carbon dioxide the cell has made cannot go out. Metabolic waste, lactate, uric acid, toxins, and excess inflammatory substances begin to pile up around the cell. The cell is submerged in its own waste. But one more important fact is that when discharge is blocked, oxygen shortage also deepens. When carbon dioxide accumulates, the acidity inside the cell rises, and acidification lowers the efficiency of the oxygen-transport protein. Supply and discharge are both events of one dimension. It is material transport through the microvascular pathway, that is, pathway blockade (DLT). This makes chronic hypoxia.
But the underlying reality of aging and chronic disease is not completed by pathway blockade alone. When the same calcium causes fluctuation in the blood and disturbs the calcium second-messenger signal inside the cell, the cell cannot accurately interpret the external signal and loses the precision of its functional operation. This is signal blockade (CAM). At the spot where pathway blockade (DLT) and signal blockade (CAM) operate together, the compensation pathway itself disappears and the irreversible event begins. This is the dual blockade.
The first to clearly show how a cell whose supply is blocked and whose oxygen has become deficient reacts was about a century ago. A series of studies published by the German biochemist Warburg in the 1920s showed that in an oxygen-deficient environment, the cell abandons normal respiratory metabolism and converts to fermentative metabolism. He made clear that the same conversion is a core characteristic of cancer cells, and for his contribution to the whole of his research on respiratory metabolism, he received the Nobel Prize in Physiology or Medicine in 1931. A follow-up paper he published in the American general-science journal Science in 1956 organized the same conclusion in an even clearer expression. It is that the starting point of the cancer cell is a chronic hypoxic environment.
Over the century since, molecular biology has precisely unraveled this process. A review published by Semenza of Johns Hopkins University in the United States in the American life-science journal Cell organized that one core signaling factor activated in a hypoxic environment had been discovered. When that signal turns on, oncogenes are activated, the cell's metabolism is deformed, and the cell's identity changes. For this discovery the Nobel Prize in Physiology or Medicine was awarded in 2019.
A cell in which a chronic hypoxic environment has been made by microvascular dual blockade: when that cell converts to fermentative metabolism, loses its identity, and enters the road of infinite proliferation, that is cancer. The starting points of cancer are various. Cancer that begins with genetic mutation, cancer that begins with carcinogenic-virus infection, cancer that begins with the accumulation of natural mutations following aging: the starting points differ. But when the tumor begins to grow, inside it the microvasculature is abnormally formed, and the chronic hypoxia that is the core characteristic of the tumor microenvironment is made. The spot where the tumor cell converts to fermentative metabolism is exactly the same as the spot of the microvascular dual blockade. Whatever the starting point, in the underlying reality of the progression phase the same event occurs.
When a cell is exposed to hypoxia for a longer time and fails at carcinogenic adaptation, a different result comes out. It is cell death. The nerve cells of the brain have a higher oxygen dependence than any cell of the human body. The brain, which is only about 2 percent of the human body's weight, uses about 20 percent of the oxygen consumption. When the microvascular dual blockade occurs in the brain's microvasculature, the nerve cells begin to die before any other cell.
A comprehensive review published by Iadecola of the Cornell University Medical College in the United States in the American neurology journal Neuron organized that the damage of the neurovascular unit (the functional unit that the brain's nerve cells make by combining with the microvasculature) is the common upstream of almost all neurodegenerative diseases including Alzheimer's, Parkinson's, multiple sclerosis, and vascular dementia. It is that the neurodegenerative diseases that specialty medicine has diagnosed separately were manifestations of a microvascular event, differing only in place.
When hypoxia becomes chronic for a longer time, yet another result comes out. As a protective reaction the cell secretes collagen and the tissue hardens. The hardening of atherosclerosis, the fibrosis of cirrhosis, the renal sclerosis of renal failure, and pulmonary fibrosis are all the same chronic hypoxic reaction appearing as a result that differs only in place. At the same time, inside the cell, mitochondrial function declines, reactive oxygen species accumulate, and DNA damage piles up.
A comprehensive aging-medicine review published by the López-Otín et al. multinational research group of the University of Oviedo in Spain in the American life-science journal Cell organized the molecular-dimension indicators of aging into twelve. Genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem-cell exhaustion, altered intercellular communication, chronic inflammation, microbiome changes, disabled macroautophagy. The fact that review made clear is that these twelve indicators do not occur separately but accumulate on one common foundation. That common foundation is the chronic decline of microvascular flow. Aging is not simply the result of time itself. It is the accumulated result of the microvascular dual blockade.
The same one event, the dual blockade of the microcalcification made by the calcium leaked in the microvasculature, makes different clinical results depending on at which place it occurs. In the microvasculature of the heart, myocardial infarction; in the cerebral vessels, cerebral infarction; in the brain's neurovascular unit, Alzheimer's and Parkinson's; in the kidney, chronic renal failure; in the liver, cirrhosis; in the pancreas and muscle, diabetic complications; in the cellular adaptation event, cancer; in the whole body, accelerated aging. All are manifestations of one event, differing only in place.
[Figure 6] The Clinical Results the Microvascular Dual Blockade Makes: Manifestation by Place
| Place (organ, tissue, cellular dimension) | Clinical result | Core event |
|---|---|---|
| Cardiac microvasculature | Myocardial infarction, coronary artery disease | Myocardial hypoxia, necrosis |
| Cerebral vessels | Cerebral infarction, stroke, vascular dementia | Brain-tissue hypoxia, necrosis |
| Brain neurovascular unit | Alzheimer's, Parkinson's, multiple sclerosis | Nerve-cell death |
| Renal microvasculature | Chronic renal failure, diabetic nephropathy | Glomerular hardening, filtration failure |
| Hepatic microvasculature | Cirrhosis, non-alcoholic fatty liver | Hepatocyte fibrosis |
| Pancreatic and muscle microvasculature | Diabetic complications, insulin resistance | Metabolic signal blockade |
| Cellular adaptation (chronic hypoxia) | Cancer | Fermentative-metabolism conversion, proliferation |
| Systemic chronic hypoxia | Accelerated aging, chronic inflammation | Accumulation of the twelve indicators |
This definition integrates the view of medicine into one event. That specialty medicine has handled atherosclerosis, dementia, cancer, renal failure, and aging each with a different mechanism is by no means having seen wrongly. It is only that, with the view of the specialty, the one underlying reality above them was not visible. Though the starting points are various, the progression-phase underlying reality converges into one place. Microvascular calcification by the dual blockade. From this definition we come to meet the seven damage patterns of the following chapter. It is the story of the branching in which the same molecular event splits into seven clinical forms.
[Figure 7] Microvascular Dual Blockade Self-Check
| Your Microvasculature, a Dual-Blockade Self-Check. Check whether any of the following items apply to you. 1. You were told the standard examination is normal, but in everyday life you feel minute abnormalities such as fatigue, numbness of the hands and feet, blurred vision, and cognitive dulling. 2. You have, in your family history, two or more of atherosclerosis, high blood pressure, diabetes, renal failure, and osteoporosis. 3. On the deficiency-inflammation-acidosis-hypoxia (DIAH) self-check, two or more items applied to you. 4. You have one of the conditions that shake the balance of calcium and phosphorus: chronic renal failure, a high-phosphate environment, chronic deficiency. 5. After your 50s, your recovery speed has noticeably slowed and minor ailments do not easily go away. If two or more items apply, there is a strong likelihood that the dual blockade is in progress in your microvasculature. It means that the time of the underlying reality, not caught on standard imaging, is already progressing. Seeing the time of the underlying reality is different from waiting for the time of diagnosis. |
|---|
If the dual blockade of the microvasculature is the underlying reality of aging and chronic disease, how is that underlying reality manifested into the various forms of aging and chronic disease that we see? The vessel hardens and is blocked and becomes myocardial infarction; the same event, when it occurs at a different place, becomes cerebral infarction; at yet another place it becomes renal failure; and at yet another place it becomes Alzheimer's. Through what branching the same underlying-reality event splits into seven clinical patterns, and how the collapse that is the final stage of DTDMC surfaces, is the story of the following chapter. We call these seven clinical patterns the 7M.
References
[1] Demer, L. L., & Tintut, Y. (2008). Vascular calcification: Pathobiology of a multifaceted disease. Circulation, 117(22), 2938-2948.
[2] Lanzer, P., Boehm, M., Sorribas, V., Thiriet, M., Janzen, J., Zeller, T., St Hilaire, C., & Shanahan, C. (2014). Medial vascular calcification revisited: Review and perspectives. European Heart Journal, 35(23), 1515-1525.
[3] Poiseuille, J. L. M. (1846). Recherches expérimentales sur le mouvement des liquides dans les tubes de très petits diamètres. Mémoires de l'Académie Royale des Sciences, 9, 433-544.
[4] Sutera, S. P., & Skalak, R. (1993). The history of Poiseuille's law. Annual Review of Fluid Mechanics, 25, 1-20.
[5] Onsager, L. (1931). Reciprocal Relations in Irreversible Processes. I. Physical Review, 37(4), 405-426.
[6] Hofbauer, L. C., Brueck, C. C., Shanahan, C. M., Schoppet, M., & Dobnig, H. (2007). Vascular calcification and osteoporosis: from clinical observation towards molecular understanding. Osteoporosis International, 18(3), 251-259.
[7] Speer, M. Y., Yang, H. Y., Brabb, T., Leaf, E., Look, A., Lin, W. L., Frutkin, A., Dichek, D., & Giachelli, C. M. (2009). Smooth muscle cells give rise to osteochondrogenic precursors and chondrocytes in calcifying arteries. Circulation Research, 104(6), 733-741.
[8] Reynolds, J. L., Joannides, A. J., Skepper, J. N., McNair, R., Schurgers, L. J., Proudfoot, D., Jahnen-Dechent, W., Weissberg, P. L., & Shanahan, C. M. (2004). Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: A potential mechanism for accelerated vascular calcification in ESRD. Journal of the American Society of Nephrology, 15(11), 2857-2867.
[9] Schurgers, L. J., Cranenburg, E. C., & Vermeer, C. (2008). Matrix Gla-protein: The calcification inhibitor in need of vitamin K. Thrombosis and Haemostasis, 100(4), 593-603.
[10] Thompson, B., & Towler, D. A. (2012). Arterial calcification and bone physiology: Role of the bone-vascular axis. Nature Reviews Endocrinology, 8(9), 529-543.
[11] Mitchell, G. F., Hwang, S. J., Vasan, R. S., Larson, M. G., Pencina, M. J., Hamburg, N. M., Vita, J. A., Levy, D., & Benjamin, E. J. (2010). Arterial stiffness and cardiovascular events: The Framingham Heart Study. Circulation, 121(4), 505-511.
[12] Tintut, Y., Honda, H. M., & Demer, L. L. (2021). Biomolecules orchestrating cardiovascular calcification. Biomolecules, 11(10), 1482.
[13] Abedin, M., Tintut, Y., & Demer, L. L. (2004). Vascular calcification: Mechanisms and clinical ramifications. Arteriosclerosis, Thrombosis, and Vascular Biology, 24(7), 1161-1170.
[14] Warburg, O. (1956). On the origin of cancer cells. Science, 123(3191), 309-314.
[15] Semenza, G. L. (2012). Hypoxia-inducible factors in physiology and medicine. Cell, 148(3), 399-408.
[16] Iadecola, C. (2017). The neurovascular unit coming of age: A journey through neurovascular coupling in health and disease. Neuron, 96(1), 17-42.
[17] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2023). Hallmarks of aging: An expanding universe. Cell, 186(2), 243-278.