Continuing from the previous part, we look at how calcium is executed at each stage of the cycle of life, and how it works in reverse during the period of decline.
Movement and Response
Consider skeletal muscle contraction. DNA designs skeletal muscle. It arranges actin and myosin filaments, positions troponin and tropomyosin, and installs the sarcoplasmic reticulum. To use the metaphor of a robotic arm, the motor and gears and joints are all assembled. But without an operating command, the robotic arm does not move. When the brain issues the command to move, calcium operates the robotic arm. The signal is transmitted through the motor nerve, acetylcholine is released at the neuromuscular junction, the muscle cell membrane depolarizes, and calcium released from the sarcoplasmic reticulum binds to troponin C, whereupon the actin-myosin interaction occurs and the muscle contracts. Every movement of walking, running, grasping, and throwing is executed this way. DNA designed the muscle, but what makes the muscle move is calcium. This is the execution code.
Consider speaking. DNA designs the vocal system. It makes the vocal cords, positions the muscles of the tongue, and programs the muscles of the lips and jaw and soft palate. To use the metaphor of a musical instrument, the strings and the resonating body and the keys are all ready. But if no one plays it, no music comes out. When we speak, calcium plays the instrument. A language command goes out from Broca's area, calcium flows into the vocal cord muscles and the vocal cords vibrate, calcium flows into the tongue muscles and the tongue moves, and calcium flows into the lip muscles and the lips change shape. Speaking a single word requires dozens of muscles to coordinate with precise timing. DNA designed the vocal system, but what makes us speak is calcium. This is the execution code.
Protection and Defense
Consider the immune response. DNA designs the immune system. It makes T cells, B cells, macrophages, and mast cells, and programs the system that synthesizes antibodies. To use the metaphor of an army, the soldiers are trained and the weapons are stockpiled. But without the order to sortie, the army does not move. When a pathogen invades, calcium issues the order to sortie. When a T cell recognizes an antigen, the intracellular calcium concentration rises, the calcineurin pathway is activated, and the T cell is activated. When a mast cell recognizes an allergen, calcium flows in and histamine granules are released. DNA designed the immune system, but what executes the immune response is calcium. This is the execution code.
Consider wound healing. DNA designs the coagulation system and the tissue regeneration system. To use the metaphor of a fire brigade, the fire trucks and firefighters and equipment are on standby. But without the order to respond, the fire is not put out. When a blood vessel is damaged, calcium issues the order to respond. When platelets contact the collagen exposed at the injury site, intracellular calcium rises, the platelets are activated, change shape, and aggregate with one another. At several stages of the coagulation cascade, calcium plays an essential role as coagulation factor IV. DNA designed the hemostatic system, but what stops the bleeding is calcium. This is the execution code.
Consider coughing and sneezing. DNA designs the cough reflex and the sneeze reflex. To use the metaphor of an emergency ejection device, the sensor and the firing system are ready. But if no one presses the firing button, the foreign matter is not ejected. When foreign matter enters the airway, calcium presses the firing button. When the irritant receptors are activated, the reflex signal is transmitted to the brainstem, a command goes out from the brainstem to the respiratory muscles, calcium flows into the muscles and an explosive contraction occurs, and air and foreign matter are ejected at a speed of tens to over a hundred kilometers per hour. DNA designed the defensive ejection reflex, but what executes that reflex is calcium. This is the execution code.
Consider blinking. DNA designs the eyelid system. To use the metaphor of a car wiper, the wiper blade and motor are installed. But if the wiper is not operated, the windshield is not wiped clean. At every moment, calcium operates the wiper. When calcium flows into the orbicularis oculi muscle the eyelid closes, and when calcium leaves the eyelid opens. Ten thousand to twenty thousand times a day, this process is repeated and the cornea is kept moist. DNA designed the blinking system, but what makes the eye blink is calcium. This is the execution code.
Consider the pupillary reflex. DNA designs the iris. To use the metaphor of a camera aperture, the aperture blades and the drive mechanism are installed. But if the aperture is not adjusted, the exposure is not right. When the light grows brighter, calcium closes the aperture. A parasympathetic signal is transmitted to the pupillary sphincter, a neurotransmitter is released, calcium flows into the muscle, and when the muscle contracts the pupil grows smaller. DNA designed the pupillary reflex, but what adjusts the size of the pupil is calcium. This is the execution code.
Consider tear secretion. DNA designs the lacrimal gland. To use the metaphor of a sprinkler, the water tank and the pipes and the nozzles are installed. But if the water is not sprayed, the lawn dries out. When the eyes grow dry or emotion wells up, calcium operates the sprinkler. When an autonomic nerve signal reaches the lacrimal gland, calcium flows into the cells, and tears are secreted. DNA designed the tear secretion system, but what makes tears flow is calcium. This is the execution code.
Consider sweating. DNA designs the sweat glands. To use the metaphor of a radiator, the coolant circulation system is installed. But if the coolant is not circulated, the engine overheats. When body temperature rises, calcium runs the radiator. When a sympathetic nerve signal reaches the sweat gland, calcium flows into the cells, and sweat is secreted. DNA designed the sweat secretion system, but what makes sweat flow is calcium. This is the execution code.
Consider goosebumps. DNA designs the arrector pili muscles. To use the metaphor of a hedgehog's quills, it is the system that raises the quills when a threat is felt. When we are cold or afraid or moved, calcium raises the quills. A sympathetic nerve signal is transmitted to the arrector pili muscle, calcium flows into the muscle and it contracts, and the hair stands on end. DNA designed the piloerection response, but what makes the goosebumps rise is calcium. This is the execution code.
Consider airway cleaning. DNA designs the cilia of the airway epithelium. To use the metaphor of a broom, the cleaning tool is ready. But if the broom is not moved, the dust is not swept away. At every moment, calcium moves the broom. According to the changes in intracellular calcium in the ciliated cells, and in particular the pattern of calcium oscillations, the ciliary beat frequency is regulated. As the cilia beat rhythmically, they push mucus and dust and pathogens up toward the pharynx. DNA designed the airway cleaning system, but what conducts the tempo of the cleaning is calcium. This is the execution code.
| Function | What DNA designed | What calcium executes | Metaphor |
|---|---|---|---|
| Immunity | T cells, B cells, mast cells | T cell activation, histamine release | Army sortie |
| Hemostasis | Platelets, coagulation factors | Platelet activation, coagulation cascade | Fire brigade response |
| Cough/sneeze | Cough reflex circuit | Explosive muscle contraction | Emergency ejection |
| Blinking | Orbicularis oculi, blink reflex | Opening and closing of the eyelid | Wiper |
| Pupillary reflex | Iris muscles | Pupil constriction/dilation | Camera aperture |
| Tears | Lacrimal gland | Tear secretion | Sprinkler |
| Sweat | Sweat glands | Sweat secretion | Radiator |
| Goosebumps | Arrector pili muscles | Hair standing on end | Hedgehog quills |
| Airway cleaning | Cilia, mucous cells | Ciliary beating | Sweeping with a broom |
Higher Functions
Consider learning and memory. DNA designs the synaptic plasticity system. To use the metaphor of a computer storage device, the hard disk and the storage circuits are installed. But without a write command, the data is not stored. When we learn something new, calcium issues the write command. When the NMDA receptor is activated, calcium flows in, and calcium activates a series of signal transduction pathways so that the synapse is strengthened. This is long-term potentiation, LTP. Conversely, a calcium signal of a particular pattern weakens the synapse. This is long-term depression, LTD. DNA designed the learning system, but what writes and erases memory is calcium. This is the execution code.
Consider emotion. DNA designs the emotion system. It positions the neurons that synthesize dopamine, serotonin, oxytocin, and endorphins, and builds the emotion-processing circuits in the brain. To use the metaphor of an orchestra, the instruments are positioned and the score is ready. But if the conductor does not raise the baton, the music does not begin. Joy, sadness, anger, fear, love. In every emotion, calcium raises the baton. When a reward is anticipated, calcium flows into the dopamine neurons, dopamine is released, and pleasure is felt. DNA designed the emotion system, but what makes us feel emotion is calcium. This is the execution code.
Consider the stress response. DNA designs the stress response system. To use the metaphor of an emergency alarm system, the sensor and the siren and the emergency lights are installed. But if the alarm is not sounded, one cannot prepare for the danger. When a threat is detected, calcium sounds the emergency alarm. When a sympathetic nerve signal reaches the adrenal medulla, calcium flows into the chromaffin cells, and adrenaline is secreted into the blood. The heart beats fast, blood pressure rises, blood flow rushes to the muscles, and the pupils dilate, preparing to fight or flee. DNA designed the stress response, but what executes that response is calcium. This is the execution code.
Consider sleep. DNA designs the sleep regulation system. To use the metaphor of a lighting timer, the timer and the lighting circuit are installed. But if the timer does not work, the light does not turn off on time. When night comes, the sympathetic input changes, the melatonin synthesis program of the pineal gland is switched on, and one of the signals that executes and coordinates that program inside the cell is calcium. Melatonin is secreted into the blood and drowsiness comes. DNA designed the sleep regulation system, but what makes us fall asleep is calcium. This is the execution code.
Consider yawning. DNA designs the yawn reflex. To use the metaphor of a ventilation fan, the fan and the motor are installed. But if the fan is not turned, the air does not circulate. When we are sleepy or bored or the state of arousal shifts, calcium turns the ventilation fan. Yawning is a reflex behavior that appears among the various signals that switch the state of the brain, and calcium takes charge of executing the muscle contraction and the neurotransmission. When the yawn reflex begins, calcium flows into the jaw muscles and the mouth opens wide, and calcium flows into the diaphragm and a deep inhalation occurs. DNA designed the yawn reflex, but what makes us yawn is calcium. This is the execution code.
Consider the gene switch. DNA designs the gene expression regulation system. To use the metaphor of a library, the books are classified and shelved. But if a book is not taken out, the information is not used. When the environment changes, calcium takes out the book. When cytosolic calcium rises, transcription factors are activated through calcineurin or the calcium/calmodulin-dependent pathway, and the expression of particular genes is switched on or off. If DNA has written down the rule "in this situation, make this protein," calcium is the approval stamp that decides whether to execute that rule right now or not. DNA designed the rules of gene expression, but what decides whether to execute those rules is calcium. This is the execution code.
Consider cell membrane stability. DNA designs the cell membrane. To use the metaphor of a building's electrical system, the wiring and the circuit breakers and the grounding are installed. But if the electricity is not supplied stably, the building does not work properly. The calcium outside the cell regulates the stability and excitability of the cell membrane. When calcium binds to the surface of the cell membrane, the activation threshold of the sodium channels is stabilized. When blood calcium falls, the cell membrane becomes unstable and the nerves and muscles become excessively excitable. This is why tetany appears in hypocalcemia. Calcium is at once the execution button that moves life splendidly and the safety device that keeps life from being shaken. This is the execution code.
| Function | What DNA designed | What calcium executes | Metaphor |
|---|---|---|---|
| Learning/memory | NMDA/AMPA receptors, plasticity machinery | Induction of LTP/LTD | Writing to a storage device |
| Emotion | Dopamine/serotonin/oxytocin neurons | Neurotransmitter release | Conducting an orchestra |
| Stress | Adrenal medulla, adrenaline synthesis system | Adrenaline secretion | Emergency alarm |
| Sleep | Pineal gland, melatonin synthesis system | Coordination of melatonin secretion | Lighting timer |
| Gene regulation | Transcription factors, promoters/enhancers | Activation of transcription factors | Taking a book out of the library |
| Cell membrane stability | Cell membrane, ion channels | Stabilization of the excitability threshold | Electrical circuit breaker |
Reproductive Functions
Consider the sexual response. DNA designs the sexual response system. To use the metaphor of a hydraulic system, the pump and the valves and the cylinders are installed. But if the system is not run, it does not work. When sexual stimulation is given, calcium runs the system. Calcium is regulated in the vascular smooth muscle so that the blood vessels relax and blood flow rushes in, and at the climax calcium flows into the muscles and rhythmic contractions occur. DNA designed the sexual response, but what executes that response is calcium. This is the execution code.
Consider sperm motility and uterine contraction and milk secretion. DNA designs all of these systems. To use the metaphor of a marathon runner, the muscles and the cardiopulmonary system are trained. But without a starting signal, the running does not begin. At each stage of reproduction, calcium sends the starting signal. When sperm swim toward the egg, calcium regulates the movement of the flagellum. At childbirth, calcium flows into the uterine smooth muscle and labor pains occur. During lactation, calcium flows into the myoepithelial cells of the mammary gland and milk is secreted. DNA designed the reproductive system, but what executes reproduction is calcium. This is the execution code.
| Function | What DNA designed | What calcium executes | Metaphor |
|---|---|---|---|
| Sexual response | Vascular smooth muscle, sensory nerves | Vascular relaxation, muscle contraction | Hydraulic system |
| Sperm motility | Flagellar structure | Regulation of flagellar beating | Marathon start |
| Uterine contraction | Uterine smooth muscle | Induction of labor pains | Starting signal |
| Milk secretion | Mammary gland, myoepithelial cells | Ejection reflex | Delivery execution |
In the stage of flourishing, calcium has no time to rest. Every time the heart beats, every time we breathe, every time we think, every time we feel emotion, every time we move, every time we respond to a threat, calcium presses the execution button. DNA designed life, but without calcium the blueprint stays on paper. Billions of heartbeats, hundreds of millions of breaths, hundreds of billions of signal transmissions across 100 trillion synapses. All of this is made possible by the execution of calcium. The key to flourishing is calcium.
4. The Stage of Decline: The Same Code Working in Reverse
When reproduction ends, the period of decline comes. In this period the same execution code begins to work in reverse. When menopause comes, as if a switch has been flipped, calcium metabolism is reversed. On one side, calcium absorption decreases. Gastric acid secretion declines so that calcium salts do not dissolve well, the skin's ability to synthesize vitamin D decreases, the kidney's ability to activate vitamin D falls, and the expression of the intestinal calcium transport proteins decreases as well. On the other side, calcium efflux from the bones increases. When estrogen decreases, osteoclast activity increases and the bone dissolves rapidly, calcitonin secretion also decreases so that the inhibition of bone resorption weakens, and parathyroid hormone levels rise so that more calcium is mobilized from the bone. I call this a double lock. The door coming in is closed, and the door going out is opened. These are changes that occur in different organs, by different mechanisms, at different times. And yet they all head toward the same result. This may be the outcome of what the evolutionary biologist George Williams called antagonistic pleiotropy. The calcium-mobilizing ability that was advantageous for reproductive success in youth weakens the bones after reproduction. Evolution chose the reproduction of youth even at the cost of sacrificing the health of old age. DNA designed decline. More precisely, decline is the late effect of the genes that were selected for reproductive success in youth. And what executes this designed decline is also calcium. Only the direction has been reversed. The key to decline is also calcium.
5. The Stage of Death: The Last Execution Button
When decline continues, one enters the stage of death. And in this final stage too, calcium works as the execution code. At the cellular level, death usually occurs in the form of apoptosis. A cell whose DNA is severely damaged, or that has been infected by a virus, or that is at risk of turning cancerous, must quietly remove itself. To use the metaphor of a demolition specialist company, it is the system that safely dismantles an aged building. But if the demolition button is not pressed, the demolition does not begin. When the damage grows large, calcium presses the demolition button. The calcium imbalance tilts in the direction of breaking down the mitochondria, and at that point the apoptotic cascade is executed in earnest. Calcium is released from the endoplasmic reticulum, this calcium flows into the mitochondria, and when the calcium inside the mitochondria becomes excessive, the mitochondrial permeability transition pore opens, cytochrome c is released, the caspase cascade begins, and the cell is systematically broken down. In DNA the command "damaged cells, die" is encoded. All the proteins involved in apoptosis are designed by DNA. But what finally executes that command is calcium. The key to death is also calcium.
6. The Stage of Return: The Completion of the Cycle
Even after death, the journey of calcium continues. This is the stage of return. When a body is cremated, what remains is mainly the mineral of the bone, calcium phosphate. When the remains are scattered on a mountain or in the sea, calcium returns to the environment. When a body is buried, over time the bone breaks down and seeps into the soil. To use the metaphor of the water cycle, it is like the water that evaporates from the sea becoming clouds, falling as rain, flowing down rivers, and returning once more to the sea. The calcium we hold is a guest that stays for only a moment within the immense cycle of the whole earth. It is the cycle in which the shells of sea creatures pile up on the seafloor and become limestone, the limestone uplifted by crustal movement weathers and is released into the soil, plants absorb this through their roots and hold calcium in their leaves and stems and fruit, and animals eat that and fill their bones. Someday the calcium of our bones too will return to soil and water, and become the skeleton of another life. DNA disappears with the individual, but calcium cycles. The key to return is also calcium. The cycle is completed.
| Stage | What DNA designed | What calcium executes | Metaphor |
|---|---|---|---|
| Birth | Egg activation system, cortical granules | Initiating life with a calcium wave | Raising the curtain of a performance |
| Growth | Growth plate, osteoblasts, cell cycle | Bone formation, timing of cell division | Construction at a building site |
| Flourishing | Every physiological system of the whole body | Trillions of executions: beating, breathing, thinking... | Trillions of execution buttons |
| Decline | Calcium absorption/efflux regulation system | Double lock: absorption down, efflux up | Working in reverse |
| Death | Apoptotic machinery | Executing death through calcium overload | Demolition button |
| Return | Mineral structure (bone) | Return to the environment, cycle | The water cycle |
DNA designs, and calcium executes. At birth a calcium wave awakens life, in growth calcium builds the bones, in flourishing calcium presses the execution button trillions of times, in decline the same calcium code works in reverse, in death calcium presses the last button, and in return calcium becomes the material of the next life. Without DNA there is no blueprint. Without calcium the blueprint stays on paper. To use the metaphor of a computer, DNA is the program stored on the hard disk. However elaborate the program, if the execution button is not pressed, nothing appears on the screen.
Calcium is that execution button. And this button is pressed trillions of times at every moment. Every time the heart beats, every time we breathe, every time we think, every time we blink. DNA designs life, and calcium executes life. This is the way that 3.8 billion years of evolution chose.
The Exit That Evolution Designed: Antagonistic Pleiotropy
Let us think again about what happens in the body of a woman after menopause. Estrogen decreases. Calcium drains out of the bones. Bone density falls. The spine collapses and the hip joint weakens. The risk of fracture rises. From the traditional medical point of view, this is a breakdown. Just as a machine wears out with long use, the body too grows weak when it lives long. Aging is the result of wear. But another point of view is possible. It is the evolutionary-biological point of view.
Evolution works in the direction of maximizing reproductive success. Natural selection favors the individual that leaves more genes to the next generation. During the reproductive period, the individual has value to the genes. But what happens when reproduction ends? The genes have already been passed to the next generation. To put it in the extreme, it may be advantageous to later generations for an individual whose reproduction has ended to exit quickly. From this point of view, aging may not be a breakdown but a designed exit.
The evolutionary biologist George Williams called this antagonistic pleiotropy in a paper published in 1957. In English it is antagonistic pleiotropy. When a single gene has several effects it is called pleiotropy, and when those effects act in opposite directions it is called antagonistic pleiotropy. If there is a gene that has an effect advantageous in youth but harmful in old age, what does natural selection do? Because reproduction happens mainly in youth, the advantage in youth matters more than the harm in old age. Therefore natural selection comes to favor such a gene. Let us apply this to calcium metabolism. In youth, the ability to mobilize calcium rapidly from the bones is important. This is because the fetal bones must be built during pregnancy, and calcium must be supplied through breast milk during lactation.
Evolution selected genes with an outstanding version of this ability. The problem is after reproduction has ended. That calcium-mobilizing ability that helped us in our youth does not stop but keeps working. Now there is no fetus to give calcium to, and no calcium to send through breast milk, and yet the system still mobilizes calcium from the bones. That ability that helped us in our youth now gnaws away at our bones. Aging and osteoporosis are not a simple breakdown but the price that evolution paid for reproductive success in youth. Evolution chose the reproduction of youth even at the cost of sacrificing the health of old age. This is the evolutionary reason why we grow old and hurt because of calcium.