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This theory of transcendental importance, is directly related to the three previously mentioned theories of ageing.
The ageing process is manifested by bone loss involving the entire skeleton. Between ages 40 and 80, women lose 28% of humeral bone mass by cortical thinning. Age related bone loss appears to be an unavoidable consequence of sustained calcium deficiency. Calcium deficiency does not occur in fish living in sea water where calcium is abundant. Terrestrial environment, where calcium is much less abundant, leaves their hosts under a constant menace of calcium deficiency.
Living systems have developed special hormonal mechanisms to maintain constant levels of blood calcium. Whenever serum calcium levels are lower than normal, hormonal parathyroid mechanisms induce bone resorption while calcium is extracted from bones and transferred to the circulatory fluids to adjust the low levels of blood calcium. It is a main physiological requisite for maintaining constant blood calcium levels. In normal human blood, total plasma calcium is 2.50 mmol/L. The adult human body contains approximately 1100 grams of calcium. Ninety-nine percent of the calcium is in the skeleton.
Chronic and sustained calcium deficiency induces a continual active shift of calcium from bones to blood (bone resorption), in order to maintain constant blood levels of calcium. When the period of growth ceases, bones can not reabsorb calcium as easily as when it was extracted from bones. There is an accumulation of calcium in the blood which is rapidly eliminated by the kidneys A fraction of this excess incidentally penetrates cells of different organelles and tissues.
If the calcium content of a cell increases, its efficiency decreases. High intracellular calcium is regarded as cell calcification which is the final common pathway for cell ageing and death.
Optimum cell function occurs when calcium ions in the surrounding fluids of the cell are maintained several fold higher than the intracellular calcium concentration. There is a 5.000 fold excess of calcium in the external-cellular fluids as compared to the inside of the cell. The importance of this imbalance of concentrations is the energy gradient that results from it. The following example helps to clarify this biophysical phenomena:
- HYDROELECTRICITY, THE MAIN SOURCE OF THE WORLD'S USABLE ENERGY IS ORIGINATED THROUGH A WATER GRADIENT. WATER FLOWS IN A GRADIENT BETWEEN TWO LEVELS.
- ELECTRICAL ENERGY IS GENERATED IN THIS PROCESS
In living cells, energy is produced through similar gradients systems. A calcium gradient is formed when the high external concentrations of calcium ions flows inside the cell in which the calcium ion concentration is low. When this flow of calcium ions, cross the membrane of the cell, energy is produced.
Calcium ions are positively charged. Any difference in concentrations between two locations of ions separated by a membrane, will produce a chemical and an electrical imbalance or gradient.
The energy produced through influx of calcium ions across a cell's membrane is vital for the efficiency of cell functions. Part of the energy is stored in the form of ATP (Adenosine triphosphate). Cells with sufficient energy perform successfully. With low energy, various cell functions are impaired.
When the period of bone growth stops the following sequence of events occurs:
- a.-The demand for calcium from cells to bones ceases.
- b.-Calcium increases inside the cell.
- c.-The calcium gradient is less pronounced.
- d.- Less energy is produced by the cell.
- (In the analogy with electric energy, this could be equivalent to a decrease in the height between the two levels of water. Consequently the generation of electrical energy decreases)
The power of the calcium gradient depends on the ability to maintain a low calcium concentration inside the cell.
There is a sustained bone loss accompanying the process of ageing. Physiologically, this means that bones are continuously loosing calcium, part of which is directly transferred to the inside of a wide variety of cells and tissues. High intracellular calcium reduces the power of the calcium gradient, therefore, the energy produced by the cell decreases. The cell works with difficulties, there is an increase in metabolic errors, due to lack of repair energy. The cell ages and approaches death.
This theory presents a crucial influence of calcium on ageing, but its arguments fall in a closed circle concerning the effects of calcium.
- High intake of calcium enhances bone formation decreasing the appearance of bone fractures in elderly people.
- It will also increase intracellular, calcium concentrations IN all cells in the body. High intracellular calcium, as pointed out above, leads to a decrease in the production of cell energy, cell senescence and death.
The influence of calcium on cell senescence presented in this theory of ageing, if integrated with my hypothesis on ageing, results in the following arguments which represents new developments in the theory of calcium on ageing.
- The efficiency of the calcium gradient depends on the ability of the cell to maintain a low intracellular concentration of calcium ions. For accomplishing this task, the cell must continuously eject calcium ions out of the cell. This process requires energy. Cell energy calculations based on the first and second laws of thermodynamics indicate that the energy produced through the flux of ions which occurs when cell membrane calcium-channels open, is not enough to expel all the calcium ions that flowed inside the cell. This because part of the energy produced is partially used for the physiological necessities of the cell. Therefore to maintain the calcium gradient at its active levels, additional energy is required. The energy to expel the calcium ions might come from mitochondrial oxygen or from driving forces due to calcium absorption in bone formation.
1.- Energy provided by oxygen.
The production of energy through oxygen is mainly due to transfer and movement of electrons while the energy produced through the calcium gradient is due to a mechanical movements of ions. (ions = electrically charged atoms). Energy produced due to movement of ions, is stored in the form of ATP and could be released in small increments, in accordance with physiological requirements In other words, calcium gradient allows the energy produced to be gradually released.
For maintaining a cell in its optimal conditions, the cell must have enough energy to expel its calcium ions. The cell must fight not to become calcified as cell calcification means its senility and death. To expel the calcium ions the cell needs the energy that comes from oxygen.
Increase in oxygen consumption by the cell, produces damaging free radicals which are the direct inducers of cell senescence. When oxygen is introduced into the cell to generate energy, the cell is introducing a molecular element that induces damaging oxidation-reactions and free radicals.
So far we have seen that calcium and oxygen have on the one hand, anti-ageing properties, and on the other, senescence inducing characteristics as follows: (Table 3, Page 44)
- I.- ANTI-AGEING PROPERTIES
- a) High Calcium intake avoids bone loss.
- b) High oxygen intake provides the energy required to maintain a low intracellular calcium.
- II.- INDUCERS OF SENESCENCE:
- a) High calcium intake induces cell calcification
- senescence and death.
- b) High oxygen intake increases free radical
- damage, shortening life span.
2.- Energy provided through the driving force of bone formation
To understand the bio-physical laws governing this important process I will briefly explain the relation between entropy, life and ageing.
In accordance with principles of the second law of thermodynamics, if there is a difference between the calcium concentrations inside and outside the cell, there is a condition of order or low entropy. As these differences in calcium concentration decrease, the strength of the gradient decreases. As the gradient disappears the disorder of the ions increases, a process which is known as increase in entropy. The existence of life is favored by low entropy conditions, while approach to death is characterized by increases in entropy. Living organisms are not a system in a state of equilibrium. They contain various concentrations, and electrical potential gradients. When the organism ages, the strength of these gradients decreases, and entropy increases. When the organism dies, these gradients and the non equilibrium systems disappear, entropy rises further.
In accordance with the second law of thermodynamics, ageing and death are processes characterized by an increase in entropy.
The following conclusion arises:
- The process of human ageing is related to the states of entropy occurring within the organism. By maintaining low entropy conditions (strong gradients) in the cell's calcium system, sufficient energy is generated, senescence is delayed.
The main idea I wish to introduce now in my hypothesis of human ageing is that:
- A low entropy condition is maintained, naturally, while the organism is in the process of growth. As soon as growth ceases, entropy increases.
In other words, the calcium gradient is strong, with low intracellular calcium concentrations, during the process of bone growth. The growth of bones requires a constant input of calcium into bone tissues. The calcium required for the growth of bones is provided from the calcium in blood, which in turn it comes from the calcium reserves located in cells.
During growth there is a permanent demand for calcium from the intracellular reserves. Calcium is taken out of the cell and directed to bone formation. As long as bones are growing, calcium is shifted from cells to bones, intracellular calcium is maintained at low levels.
In the analogy with the water gradient, the force in bones to pump calcium out of the cell could be compared to the force of gravity which constantly pushes the water down.
The extracellular blood calcium is 5000 fold higher than the intracellular. This strong calcium gradient is a highly ordered condition of low entropy that is preserved during the developmental periods of infancy and adolescence. In these periods of life there is a low entropy condition in the calcium systems, calcium gradients are characterized by their strength. Whenever there is a flow of calcium inside the cell, there is a large amount of energy produced.
During growth, energy from oxygen is not essential to expel the calcium ions. Because of the high demand of calcium from bones, there is a constant draining of calcium ions dragged out of the cell and shifted to the bones.
This constant bone demand of calcium ions in periods of body growth is a powerful pump dragging calcium ions from intracellular sites and maintaining a low intracellular concentration and a strong gradient. This strong gradient is a low entropy condition. The majority of calcium ions are orderly and situated extracellularly
The energy produced by the calcium gradient in periods of growth like infancy or adolescence could be observed when looking at the large amounts of moving energy of infants and adolescents compared with adults.
At the end of the adolescence period, the demand of calcium from intercellular reserves for bone formation concludes. Bone epiphyses close at the age of about 18 years old. From then onwards in adult life, for maintaining low intracellular calcium, energy must be provided from oxygen. The automatic cell outflow of calcium due to bone formation ceases. The "pump" that shifted calcium out of the cell to form bones, ceases at the time body growth ends.
In accordance with previous argumentation presented here, senescence starts when growth stops. At this crucial period of life the low entropy system generated during the period of bone growth, is interrupted. From now on in life, entropy of the calcium system increases in accordance with the principles of the second law of thermodynamics. The gradients lose their strength, intracellular calcium increases, until cell death.
The laws of physics and thermodynamics see life as a non equilibrium system which contains several gradients of ion, temperature, and electrical potentials. With the initiation of the process of ageing the power of these gradients deteriorates. When the organisms die these gradients disappears. The calcium ion gradient is of main importance. Cardiac contractility is due to rhythmical increased availability of intracellular calcium in myocardial gradients. Muscular contraction is universally dependent on electrochemical calcium gradients across the inner mitochondrial membrane. For maintaining these gradients actively, calcium ions must be continuously moving from intracellular to extracellular areas.
- Bone formation is the main traction force to move calcium ions out of the cell and create gradients, just as the force of gravity is the main attractive force to make water fall in a hydro electric power plant.
When the period of growth stops, bone formation ceases. The traction force to create calcium gradients disappears. The cell has to rely on mitochondrial oxygen-energy to maintain the gradients.
The calcium ion electrochemical gradient is the driving force for many chemical reaction to occur spontaneously. When this occurs energy in the form of heat is produced or released
Life follows the laws of matter and the universe. Electrons protons and neutrons are the building blocks of the universe as of living systems. Matter tends to expand, to occupy the maximum space, in other words, to increase its entropy. Life works against this tendency. Matter tends to become ordered in a minimum space, a process which represents a decrease in entropy.
The fight between life and death is the struggle to maintain a situation of low entropy when matter and the universe tend to increase its entropy.
The process of growth, because it favors the creation of gradients, represents the main force against increase in entropy and death.
A gradient is an ordered situation in which a number of ions are positioned at a different side of a membrane. Ions as elements of the universe have the tendency to expand, to disrupt this order, and increase the entropy of the system. Therefore ions, cross the membrane to expand or increase the disorder or entropy of the system. The process of growth act against this tendency to increase the entropy because it drags calcium ions out of the cell creating an ordered situation in which calcium ions will become extracellularly located.
The process of growth is the main force working against increases in entropy.
Increase in entropy is the driving force leading towards death.
When ageing is considered in relation to the principles of entropy, the role of atmospheric oxygen is crucial, because it is a direct factor determining the end of the period of growth. We have seen that the period of growth in living systems is extended in conditions of low oxygen pressure. We have also seen that high atmospheric oxygen pressures cause’s oxidation damage to oxygen sensitive dopaminergic areas of the brain, reducing the synthesis of dopamine which in turn reduces the synthesis of growth hormone. The extent of damage oxygen causes to neurons involved in the production of growth hormone, starts at birth, and reaches a threshold at about 18 years of age. At this age enough neurons have been damaged to cause alterations in hormone secretions that signals ephyphyseal closure, and cessation of growth.
In conditions of high atmospheric oxygen pressure, the period of growth will cease earlier. The opposite will occur in conditions of low atmospheric oxygen pressure, where the period of growth will be delayed accordingly. By extending the period of growth, the period of physiological low entropy will be lengthened, and the arrival of senescence, delayed.
I have now introduced into my hypothesis of ageing a biophysical explanation of senescence by integration of principles from the retarded growth theory of ageing proposed in the beginning of the century and the calcium theory of ageing. The hypothesis presented in this dissertation intends to demonstrate that atmospheric oxygen, is indirectly proportional to body growth, and directly proportional to entropy states. In other words:
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