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djledda-web/raypeat-articles/processed/phosphate-activation-aging....

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  1. <html>

  2.     <head><title></title></head>

  3.     <body>

  4.         <h1></h1>

  5. 

  6.         <p></p>

  7.         <blockquote>

  8.             <h2>

  9.                 <strong><span style="color: #222222"><span style="font-family: georgia, times, serif"><span

  10.                                 style="font-size: large"

  11.                             ><span style="font-style: normal">Phosphate, activation, and aging</span></span></span

  12.                         ></span></strong>

  13.             </h2>

  14.         </blockquote>

  15.         <blockquote></blockquote>

  16.         <blockquote>

  17.             <span style="color: #222222"><span style="font-family: georgia, times, serif"><span

  18.                         style="font-size: medium"

  19.                     >Recent publications are showing that excess phosphate can increase inflammation, tissue atrophy,

  20.                         calcification of blood vessels, cancer, dementia, and, in general, the processes of aging. This

  21.                         is especially important, because of the increasing use of phosphates as food additives.</span

  22.                     ></span></span>

  23.         </blockquote>

  24.         <blockquote></blockquote>

  25.         <blockquote>

  26.             <span style="color: #222222"><span style="font-family: georgia, times, serif"><span

  27.                         style="font-size: medium"

  28.                     ><span style="font-style: normal"><span style="font-weight: normal"

  29.                             >Previously, the complications of chronic kidney disease, with increased serum phosphate,

  30.                                 were considered to be specific for that condition, but the discovery of a

  31.                                 phosphate-regulating gene named klotho (after one of the Fates in Greek mythology) has

  32.                                 caused a lot of rethinking of the biological role of phosphate. In the 19th century,

  33.                                 phosphorus was commonly called brain food, and since about 1970, its involvement in cell

  34.                                 regulation has become a focus of reductionist thinking. ATP, adenosine triphosphate, is

  35.                                 seen as the energy source that drives cell movement as well as the "pumps" that maintain

  36.                                 the living state, and as the source of the cyclic AMP that is a general activator of

  37.                                 cells, and as the donor of the phosphate group that activates a great number of proteins

  38.                                 in the "phosphorylation cascade." When tissues calcified in the process of aging,

  39.                                 calcium was blamed (ignoring the existence of calcium phosphate crystals in the

  40.                                 tissues), and low calcium diets were recommended. Recently, when calcium supplements

  41.                                 haven't produced the intended effects, calcium was blamed, disregarding the other

  42.                                 materials present in the supplements, such as citrate, phosphate, orotate, aspartate,

  43.                                 and lactate.</span></span></span></span></span>

  44.         </blockquote>

  45.         <blockquote></blockquote>

  46.         <blockquote>

  47.             <span style="color: #222222"><span style="font-family: georgia, times, serif"><span

  48.                         style="font-size: medium"

  49.                     >I have a different perspective on the "phosphorylation cascade," and on the other functions of

  50.                         phosphate in cells, based largely on my view of the role of water in cell physiology. In the

  51.                         popular view, a stimulus causes a change of shape in a receptor protein, causing it to become an

  52.                         active enzyme, catalyzing the transfer of a phosphate group from ATP to another protein, causing

  53.                         it to change shape and become activated, and to transfer phosphate groups to other molecules, or

  54.                         to remove phosphates from active enzymes, in chain reactions. This is standard biochemistry,

  55.                         that can be done in a test tube.</span></span></span>

  56.         </blockquote>

  57.         <blockquote>

  58.             <span style="color: #222222"><span style="font-family: georgia, times, serif"><span

  59.                         style="font-size: medium"

  60.                     >Starting around 1970, when the involvement of phosphorylation in the activation of enzymes in

  61.                         glycogen breakdown was already well known, people began noticing that the glycogen phosphorylase

  62.                         enzyme became active immediately when the muscle cell contracted, and that phosphorylation

  63.                         followed the activation. Phosphorylation was involved in activation of the enzyme, but if

  64.                         something else first activated the enzyme (by changing its shape), the addition of the phosphate

  65.                         group couldn't be considered as causal, in the usual reductionist sense. It was one participant

  66.                         in a complex causal process. I saw this as a possible example of the effect of changing water

  67.                         structure on protein structure and function. This view of water questions the relevance of test

  68.                         tube biochemistry.</span></span></span>

  69.         </blockquote>

  70.         <blockquote></blockquote>

  71.         <blockquote>

  72.             <span style="color: #222222"><span style="font-family: georgia, times, serif"><span

  73.                         style="font-size: medium"

  74.                     >Enzymes are known which suddenly become inactive when the temperature is lowered beyond a certain

  75.                         point. This is because soluble proteins arrange their shape so that their hydrophobic regions,

  76.                         the parts with fat-like side-chains on the amino acids, are inside, with the parts of the chain

  77.                         with water-soluble amino acids arranged to be on the outside, in contact with the water. The

  78.                         "wetness" of water, its activity that tends to exclude the oily parts of the protein molecule,

  79.                         decreases as the temperature decreases, and some proteins are destabilized when the relatively

  80.                         hydrophobic group is no longer repelled by the surrounding cooler water.&nbsp;</span></span

  81.                 ></span>

  82.         </blockquote>

  83.         <blockquote></blockquote>

  84.         <blockquote>

  85.             <span style="color: #222222"><span style="font-family: georgia, times, serif"><span

  86.                         style="font-size: medium"

  87.                     ><span style="font-style: normal"><span style="font-weight: normal"

  88.                             >In the living cell, the water is all within a very short distance of a surface of fats or

  89.                                 fat-like proteins. In a series of experiments, starting in the 1960s, Walter

  90.                                 Drost-Hansen showed that, regardless of the nature of the material, the water near a

  91.                                 surface is structurally modified, becoming less dense, more voluminous. This water is

  92.                                 more "lipophilic," adapting itself to the presence of fatty material, as if it were

  93.                                 colder. This change in the water's properties also affects the solubility of ions,

  94.                                 increasing the solubility of potassium, decreasing that of sodium, magnesium, and

  95.                                 calcium (Wiggins, 1973).</span></span></span></span></span>

  96.         </blockquote>

  97.         <blockquote></blockquote>

  98.         <blockquote>

  99.             <span style="color: #222222">&nbsp;<span style="font-family: georgia, times, serif"><span

  100.                         style="font-size: medium"

  101.                     ><span style="font-style: normal"><span style="font-weight: normal"

  102.                             >When a muscle contracts, its volume momentarily decreases (Abbott and Baskin, 1962). Under

  103.                                 extremely high pressure, muscles contract. In both situations, the work-producing

  104.                                 process of contraction is associated with a slight reduction in volume. During

  105.                                 contraction of a muscle or nerve, heat is given off, causing the temperature to rise.

  106.                                 During relaxation, recovering from excitation, heat is absorbed (Curtin and Woledge,

  107.                                 1974; Westphal, et al., 1999; Constable, et al. 1997). In the case of a nerve, following

  108.                                 the heating produced by excitation, the temperature of the nerve decreases below the

  109.                                 starting temperature (Abbot, et al., 1965). Stretching a muscle causes energy to be

  110.                                 absorbed (Constable, et al., 1997). Energy changes such as these, without associated

  111.                                 chemical changes, have led some investigators to conclude that muscle tension generation

  112.                                 is "entropy driven" (Davis and Rodgers, 1995).&nbsp;</span></span></span></span></span>

  113.         </blockquote>

  114.         <blockquote></blockquote>

  115.         <blockquote>

  116.             <span style="color: #222222">&nbsp;<span style="font-family: georgia, times, serif"><span

  117.                         style="font-size: medium"

  118.                     ><span style="font-style: normal"><span style="font-weight: normal"

  119.                             >Kelvin's description (1858) of the physics of water in a soap bubble, "…if a film such as a

  120.                                 soap-bubble be enlarged . . . it experiences a cooling effect . . . ," describes the

  121.                                 behavior of nerves and muscles, absorbing energy or heat when they are relaxing (or

  122.                                 elongating), releasing it when they are excited/contracting.&nbsp;</span></span></span

  123.                     ></span></span>

  124.         </blockquote>

  125.         <blockquote></blockquote>

  126.         <blockquote>

  127.             <span style="color: #222222"><span style="font-family: georgia, times, serif"><span

  128.                         style="font-size: medium"

  129.                     ><span style="font-style: normal"><span style="font-weight: normal"

  130.                             >Several groups of experimenters over the last 60 years have tried to discover what happens

  131.                                 to the missing heat; some have suggested electrical or osmotic storage, and some have

  132.                                 demonstrated that stretching generates ATP, arguing for chemical storage. Physical

  133.                                 storage in the form of structural changes in the water-protein-lipid system, interacting

  134.                                 with chemical changes such as ATP synthesis, have hardly been investigated.</span></span

  135.                         ></span></span></span>

  136.         </blockquote>

  137.         <blockquote>

  138.             <span style="color: #222222"><span style="font-family: georgia, times, serif"><span

  139.                         style="font-size: medium"

  140.                     ><span style="font-style: normal"><span style="font-weight: normal"

  141.                             >Early studies of muscle chemistry and contraction found that adding ATP to a viscous

  142.                                 solution of proteins extracted from muscle reduced its viscosity, and also that the loss

  143.                                 of ATP from muscle caused its hardening, as in rigor mortis; if the pH wasn't too

  144.                                 acidic, the dead muscle would contract as the ATP content decreased. Szent-Gyorgyi found

  145.                                 that a muscle hardened by rigor mortis became soft again when ATP was added.&nbsp;</span

  146.                             ></span></span></span></span>

  147.         </blockquote>

  148.         <blockquote></blockquote>

  149.         <blockquote>

  150.             <span style="color: #222222">&nbsp;<span style="font-family: georgia, times, serif"><span

  151.                         style="font-size: medium"

  152.                     ><span style="font-style: normal"><span style="font-weight: normal"

  153.                             >Rigor mortis is an extreme state of fatigue, or energy depletion. Early muscle studies

  154.                                 described the phenomenon of "fatigue contracture," in which the muscle, when it reaches

  155.                                 the point at which it stops responding to stimulation, is maximally contracted (this has

  156.                                 also been called delayed relaxation). Ischemic contracture, in the absence of blood

  157.                                 circulation, occurs when the muscle's glycogen is depleted, so that ATP can no longer be

  158.                                 produced anaerobically (Kingsley, et al., 1991). The delayed relaxation of hypothyroid

  159.                                 muscle is another situation in which it is clear that ATP is required for relaxation.

  160.                                 (In the Achilles tendon reflex test, the relaxation rate is visibly slowed in

  161.                                 hypothyroidism.) A delayed T wave in the electrocardiogram, and the diastolic

  162.                                 contracture of the failing heart show the same process of delayed relaxation.

  163.                                 Supplementing the active thyroid hormone, T3, can quickly restore the normal rate of

  164.                                 relaxation, and its beneficial effects have been demonstrated in heart failure

  165.                                 (Pingitore, et al., 2008; Wang, et al., 2006; Pantos, et al., 2007; Galli, et al.,

  166.                                 2008).</span></span></span></span></span>

  167.         </blockquote>

  168.         <blockquote></blockquote>

  169.         <blockquote>

  170.             <span style="color: #222222">&nbsp;<span style="font-family: georgia, times, serif"><span

  171.                         style="font-size: medium"

  172.                     ><span style="font-style: normal"><span style="font-weight: normal"

  173.                             >A large part of the magnesium in cells is bound to ATP, and the magnesium-ATP complex is a

  174.                                 factor in muscle relaxation. A deficiency of either ATP or magnesium contributes to

  175.                                 muscle cramping. When a cell is stimulated, causing ATP to release inorganic phosphate,

  176.                                 it also releases magnesium. Above the pH of 6.7, phosphate is doubly ionized, in which

  177.                                 state it has the same kind of structural effect on water that magnesium, calcium, and

  178.                                 sodium have, causing water molecules to be powerfully attracted to the concentrated

  179.                                 electrical charge of the ion. Increasing the free phosphate and magnesium opposes the

  180.                                 effect of the surfaces of fats and proteins on the water structure, and tends to

  181.                                 decrease the solubility of potassium in the water, and to increase the water's

  182.                                 "lipophobic" tendency to minimize its contacts with fats and the fat-like surface of

  183.                                 proteins, causing the proteins to rearrange themselves.&nbsp;</span></span></span></span

  184.                 ></span>

  185.         </blockquote>

  186.         <blockquote></blockquote>

  187.         <blockquote>

  188.             <span style="color: #222222">&nbsp;<span style="font-family: georgia, times, serif"><span

  189.                         style="font-size: medium"

  190.                     ><span style="font-style: normal"><span style="font-weight: normal"

  191.                             >These observations relating to the interactions of water, solutes and proteins in muscles

  192.                                 and nerves provide a coherent context for understanding contraction and conduction,

  193.                                 which is lacking in the familiar descriptions based on membranes, pumps, and

  194.                                 cross-bridges, but I think they also provide a uniquely useful context for understanding

  195.                                 the possible dangers of an excess of free phosphate in the body.</span></span></span

  196.                     ></span></span>

  197.         </blockquote>

  198.         <blockquote></blockquote>

  199.         <blockquote>

  200.             <span style="color: #222222">&nbsp;<span style="font-family: georgia, times, serif"><span

  201.                         style="font-size: medium"

  202.                     ><span style="font-style: normal"><span style="font-weight: normal"

  203.                             >A few people (M. Thomson, J. Gunawardena, A.K. Manrai) are showing that principles of

  204.                                 mass-action help to simplify understanding the networks of phosphorylation and

  205.                                 dephosphorylation that are involved in cell control. But independently from the

  206.                                 phosphorylation of proteins, the presence of phosphate ion in cell water modifies the

  207.                                 cell's ion selectivity, shifting the balance toward increased uptake of sodium and

  208.                                 calcium, decreasing potassium, tending to depolarize and "activate" the cell.</span

  209.                             ></span></span></span></span>

  210.         </blockquote>

  211.         <blockquote></blockquote>

  212.         <blockquote>

  213.             <span style="color: #222222">&nbsp;<span style="font-family: georgia, times, serif"><span

  214.                         style="font-size: medium"

  215.                     ><span style="font-style: normal"><span style="font-weight: normal"

  216.                             >About 99% of the publications discussing the mechanism of muscle contraction fail to

  217.                                 mention the presence of water, and there's a similar neglect of water in discussions of

  218.                                 the energy producing processes in the mitochondrion. The failure of mitochondrial energy

  219.                                 production leads to lipid peroxidation, activation of inflammatory processes, and can

  220.                                 cause disintegration of the energy producing structure. Increased phosphate decreases

  221.                                 mitochondrial energy production (Duan and Karmazyn, 1989), causes lipid peroxidation

  222.                                 (Kowaltowski, et al., 1996), and activates inflammation, increasing the processes of

  223.                                 tissue atrophy, fibrosis, and cancer.</span></span></span></span></span>

  224.         </blockquote>

  225.         <blockquote></blockquote>

  226.         <blockquote>

  227.             <span style="color: #222222">&nbsp;<span style="font-family: georgia, times, serif"><span

  228.                         style="font-size: medium"

  229.                     ><span style="font-style: normal"><span style="font-weight: normal"

  230.                             >For about twenty years it has been clear that the metabolic problems that cause calcium to

  231.                                 be lost from bones cause calcium to increase in the soft tissues, such as blood vessels.

  232.                                 The role of phosphate in forming calcium phosphate crystals had until recently been

  233.                                 assumed to be passive, but some specific "mechanistic" effects have been identified. For

  234.                                 example, increased phosphate increases the inflammatory cytokine, osteopontin

  235.                                 (Fatherazi, et al., 2009), which in bone is known to activate the process of

  236.                                 decalcification, and in arteries is involved in calcification processes (Tousoulis, et

  237.                                 al., 2012). In the kidneys, phosphate promotes calcification (Bois and Selye, 1956), and

  238.                                 osteopontin, by its activation of inflammatory T-cells, is involved in the development

  239.                                 of glomerulonephritis, as well as in inflammatory skin reactions (Yu, et al., 1998).

  240.                                 High dietary phosphate increases serum osteopontin, as well as serum phosphate and

  241.                                 parathyroid hormone, and increases the formation of tumors in skin (Camalier, et al.,

  242.                                 2010).&nbsp; Besides the activation of cells and cell systems, phosphate (like other

  243.                                 ions with a high ratio of charge to size, including citrate) can activate viruses

  244.                                 (Yamanaka, et al., 1995; Gouvea, et al., 2006). Aromatase, the enzyme that synthesizes

  245.                                 estrogen, is an enzyme that's sensitive to the concentration of phosphate (Bellino and

  246.                                 Holben, 1989).</span></span></span></span></span>

  247.         </blockquote>

  248.         <blockquote></blockquote>

  249.         <blockquote>

  250.             <span style="color: #222222">&nbsp;<span style="font-family: georgia, times, serif"><span

  251.                         style="font-size: medium"

  252.                     ><span style="font-style: normal"><span style="font-weight: normal"

  253.                             >More generally, increased dietary phosphate increases the activity of an important

  254.                                 regulatory enzyme, protein kinase B, which promotes organ growth. A high phosphate diet

  255.                                 increases the growth of liver (Xu, et al., 2008) and lung (Jin, et al., 2007), and

  256.                                 promotes the growth of lung cancer (Jin, et al., 2009). An extreme reduction of

  257.                                 phosphate in the diet wouldn't be appropriate, however, because a phosphate deficiency

  258.                                 stimulates cells to increase the phosphate transporter, increasing the cellular uptake

  259.                                 of phosphate, with an effect similar to the dietary excess of phosphate, i.e., promotion

  260.                                 of lung cancer (Xu, et al., 2010). The optimum dietary amount of phosphate, and its

  261.                                 balance with other minerals, hasn't been determined.</span></span></span></span></span>

  262.         </blockquote>

  263.         <blockquote></blockquote>

  264.         <blockquote>

  265.             <span style="color: #222222">&nbsp;<span style="font-family: georgia, times, serif"><span

  266.                         style="font-size: medium"

  267.                     ><span style="font-style: normal"><span style="font-weight: normal"

  268.                             >While increased phosphate slows mitochondrial energy production, decreasing its

  269.                                 intracellular concentration increases the respiratory rate and the efficiency of ATP

  270.                                 formation. A "deficiency" of polyunsaturated fatty acids has this effect (Nogueira, et

  271.                                 al., 2001), but so does the consumption of fructose (Green, et al., 1993; Lu, et al.,

  272.                                 1994).</span></span></span></span></span>

  273.         </blockquote>

  274.         <blockquote>

  275.             <span style="color: #222222"><span style="font-family: georgia, times, serif"><span

  276.                         style="font-size: medium"

  277.                     >In a 1938 experiment (Brown, et al.) that intended to show the essentiality of unsaturated fats, a

  278.                         man, William Brown, lived for six months on a 2500 calorie diet consisting of sucrose syrup, a

  279.                         gallon of milk (some of it in the form of cottage cheese), and the juice of half an orange,

  280.                         besides some vitamins and minerals. The experimenters remarked about the surprising

  281.                         disappearance of the normal fatigue after a day's work, as well as the normalization of his high

  282.                         blood pressure and high cholesterol, and the permanent disappearance of his frequent life-long

  283.                         migraine headaches. His respiratory quotient increased (producing more carbon dioxide), as well

  284.                         as his rate of resting metabolism. I think the most interesting part of the experiment was that

  285.                         his blood phosphate decreased. In two measurements during the experimental diet, his fasting

  286.                         plasma inorganic phosphorus was 3.43 and 2.64 mg. per 100 ml. of plasma, and six month after he

  287.                         had returned to a normal diet the number was 4.2 mg/100 ml. Both the deficiency of the

  288.                         "essential" unsaturated fatty acids, and the high sucrose intake probably contributed to

  289.                         lowering the phosphate.</span></span></span>

  290.         </blockquote>

  291.         <blockquote></blockquote>

  292.         <blockquote>

  293.             <span style="color: #222222">&nbsp;<span style="font-family: georgia, times, serif"><span

  294.                         style="font-size: medium"

  295.                     ><span style="font-style: normal"><span style="font-weight: normal"

  296.                             >In 2000, researchers who were convinced that fructose is harmful to the health, reasoned

  297.                                 that its harmful effects would be exacerbated by consuming it in combination with a diet

  298.                                 deficient in magnesium. Eleven men consumed, for six months, test diets with high

  299.                                 fructose corn syrup or starch, along with some fairly normal U.S. foods, and with either

  300.                                 extremely low magnesium content, or with slightly deficient magnesium content. The

  301.                                 authors' conclusion was clearly stated in the title of their article, that the

  302.                                 combination adversely affects the mineral balance of the body.&nbsp;</span></span></span

  303.                     ></span></span>

  304.         </blockquote>

  305.         <blockquote></blockquote>

  306.         <blockquote>

  307.             <span style="color: #222222">&nbsp;<span style="font-family: georgia, times, serif"><span

  308.                         style="font-size: medium"

  309.                     ><span style="font-style: normal"><span style="font-weight: normal"

  310.                             >However, looking at their results in the context of these other studies of the effects of

  311.                                 fructose on phosphate, I don't think their conclusion is correct. Even on the extremely

  312.                                 low magnesium intake, both their magnesium and calcium balances were positive, meaning

  313.                                 that on average their bodies accumulated a little magnesium and calcium, even though men

  314.                                 aged 22 to 40 presumably weren't growing very much. To steadily accumulate both calcium

  315.                                 and magnesium, with the calcium retention much larger than the magnesium, the minerals

  316.                                 were probably mostly being incorporated into their bones. Their phosphate balance,

  317.                                 however, was slightly negative on the "high fructose" diet. If the sugar was having the

  318.                                 same effect that it had on William Brown in 1938 (and in animal experiments), some of

  319.                                 the phosphate loss was accounted for by the reduced amount in blood and other body

  320.                                 fluids, but to continue through the months of the experiment, some of it must have

  321.                                 represented a change in the composition of the bones. When there is more carbon dioxide

  322.                                 in the body fluids, calcium carbonate can be deposited in the bones (Messier, et al.,

  323.                                 1979). Increased carbon dioxide could account for a prolonged negative phosphate

  324.                                 balance, by taking its place in the bones in combination with calcium and

  325.                                 magnesium.&nbsp;</span></span></span></span></span>

  326.         </blockquote>

  327.         <blockquote></blockquote>

  328.         <blockquote>

  329.             <span style="color: #222222">&nbsp;<span style="font-family: georgia, times, serif"><span

  330.                         style="font-size: medium"

  331.                     ><span style="font-style: normal"><span style="font-weight: normal"

  332.                             >Another important effect of carbon dioxide is in the regulation of both calcium and

  333.                                 phosphate, by increasing the absorption and retention of calcium (Canzanello, et al.,

  334.                                 1995), and by increasing the excretion of phosphate. Increased carbon dioxide (as

  335.                                 dissolved gas) and bicarbonate (as sodium bicarbonate) both increase the excretion of

  336.                                 phosphate in the urine, even in the absence of the parathyroid hormone. Below the normal

  337.                                 level of serum bicarbonate, reabsorption of phosphate by the kidneys is greatly

  338.                                 increased (Jehle, et al., 1999). Acetazolamide increases the body's retention of carbon

  339.                                 dioxide, and increases the amount of phosphate excreted in the urine.&nbsp;</span></span

  340.                         ></span></span></span>

  341.         </blockquote>

  342.         <blockquote></blockquote>

  343.         <blockquote>

  344.             <span style="color: #222222"><span style="font-family: georgia, times, serif"><span

  345.                         style="font-size: medium"

  346.                     >Much of the calcium dissolved in the blood is in the form of a complex of calcium and bicarbonate,

  347.                         with a single positive charge (Hughes, et al., 1984). Failure to consider this complexed form of

  348.                         calcium leads to errors in measuring the amount of calcium in the blood, and in interpreting its

  349.                         physiological effects, including its intracellular behavior. Hyperventilation can cause cramping

  350.                         of skeletal muscles, constriction of blood vessels, and excitation of platelets and other cells;

  351.                         the removal of carbon dioxide from the blood lowers the carbonic acid, changing the state and

  352.                         function of calcium. Hyperventilation increases phosphate and parathyroid hormone, and decreases

  353.                         calcium (Krapf, et al., 1992).</span></span></span>

  354.         </blockquote>

  355.         <blockquote></blockquote>

  356.         <blockquote>

  357.             <span style="color: #222222"><span style="font-family: georgia, times, serif"><span

  358.                         style="font-size: medium"

  359.                     >Since estrogen tends to cause hyperventilation, lowering carbon dioxide, its role in phosphate

  360.                         metabolism should be investigated more thoroughly. Work by Han, et al. (2002) and Xu, et al.

  361.                         (2003) showed that estrogen increases phosphate reabsorption by the kidney, but estrogen also

  362.                         increases cortisol, which decreases reabsorption, so the role of estrogen in the whole system

  363.                         has to be be considered.&nbsp;</span></span></span>

  364.         </blockquote>

  365.         <blockquote></blockquote>

  366.         <blockquote>

  367.             <span style="color: #222222">&nbsp;<span style="font-family: georgia, times, serif"><span

  368.                         style="font-size: medium"

  369.                     ><span style="font-style: normal"><span style="font-weight: normal"

  370.                             >This calcium solubilizing effect of bicarbonate, combined with its phosphaturic effect,

  371.                                 probably accounts for the relaxing effect of carbon dioxide on the blood vessels and

  372.                                 bronchial smooth muscles, and for the prevention of vascular calcification by the

  373.                                 thyroid hormones (Sato, et al., 2005, Tatar, 2009, Kim, et al., 2012). Distensibility of

  374.                                 the blood vessels and heart, increased by carbon dioxide, is decreased in

  375.                                 hypothyroidism, heart failure, and by phosphate.&nbsp;</span></span></span></span></span

  376.             >

  377.         </blockquote>

  378.         <blockquote></blockquote>

  379.         <blockquote>

  380.             <span style="color: #222222">&nbsp;<span style="font-family: georgia, times, serif"><span

  381.                         style="font-size: medium"

  382.                     ><span style="font-style: normal"><span style="font-weight: normal"

  383.                             >While fructose lowers intracellular phosphate, it also lowers the amount that the intestine

  384.                                 absorbs from food (Kirchner, et al.,2008), and the Milne-Nielsen study suggests that it

  385.                                 increases phosphate loss through the kidneys. The "anti-aging" protein, klotho,

  386.                                 increases the ability of the kidneys to excrete phosphate (Dërmaku-Sopjani, et al.,

  387.                                 2011), and like fructose, it supports energy production and maintains thermogenesis

  388.                                 (Mori, et al., 2000).&nbsp;</span></span></span></span></span>

  389.         </blockquote>

  390.         <blockquote></blockquote>

  391.         <blockquote>

  392.             <span style="color: #222222">&nbsp;<span style="font-family: georgia, times, serif"><span

  393.                         style="font-size: medium"

  394.                     ><span style="font-style: normal"><span style="font-weight: normal"

  395.                             >Lowering the amount of phosphate in the blood allows the parathyroid hormone to decrease.

  396.                                 While the parathyroid hormone also prevents phosphate reabsorption by the kidneys, it

  397.                                 causes mast cells to release serotonin (and serotonin increases the kidneys'

  398.                                 reabsorption of phosphate), and possibly has other pro-inflammatory effects.&nbsp; For

  399.                                 example, deleting the PTH gene compensates for the harmful (accelerated calcification

  400.                                 and osteoporosis) effects of deleting the klotho gene, apparently by preventing the

  401.                                 increase of osteopontin (Yuan, et al., 2012).</span></span></span></span></span>

  402.         </blockquote>

  403.         <blockquote></blockquote>

  404.         <blockquote>

  405.             <span style="color: #222222">&nbsp;<span style="font-family: georgia, times, serif"><span

  406.                         style="font-size: medium"

  407.                     ><span style="font-style: normal"><span style="font-weight: normal"

  408.                             >Niacinamide is another nutrient that lowers serum phosphate (Cheng, et al., 2008), by

  409.                                 inhibiting intestinal absorption (Katai, et al., 1989), and also by reducing its

  410.                                 reabsorption by the kidneys (Campbell, et al., 1989). Niacinamide's reduction of free

  411.                                 fatty acids by inhibiting lipolysis, protecting the use of glucose for energy, might be

  412.                                 involved in its effect on phosphate (by analogy with the phosphate lowering action of a

  413.                                 deficiency of polyunsaturated fatty acids). Aspirin is another antilipolytic substance

  414.                                 (de Zentella, et al., 2002) which stimulates energy production from sugar and lowers

  415.                                 phosphate, possibly combined with improved magnesium retention (Yamada and Morohashi,

  416.                                 1986).</span></span></span></span></span>

  417.         </blockquote>

  418.         <blockquote></blockquote>

  419.         <blockquote>

  420.             <span style="color: #222222">&nbsp;<span style="font-family: georgia, times, serif"><span

  421.                         style="font-size: medium"

  422.                     ><span style="font-style: normal"><span style="font-weight: normal"

  423.                             >A diet that provides enough calcium to limit activity of the parathyroid glands, and that

  424.                                 is low in phosphate and polyunsaturated fats, with sugar rather than starch as the main

  425.                                 carbohydrate, possibly supplemented by niacinamide and aspirin, should help to avoid

  426.                                 some of the degenerative processes associated with high phosphate: fatigue, heart

  427.                                 failure, movement discoordination, hypogonadism, infertility, vascular calcification,

  428.                                 emphysema, cancer, osteoporosis, and atrophy of skin, skeletal muscle, intestine,

  429.                                 thymus, and spleen (Ohnishi and Razzaque, 2010; Shiraki-Iida, et al., 2000; Kuro-o, et

  430.                                 al., 1997; Osuka and Razzaque, 2012). The foods naturally highest in phosphate, relative

  431.                                 to calcium, are cereals, legumes, meats, and fish. Many prepared foods contain added

  432.                                 phosphate. Foods with a higher, safer ratio of calcium to phosphate are leaves, such as

  433.                                 kale, turnip greens, and beet greens, and many fruits, milk, and cheese. Coffee, besides

  434.                                 being a good source of magnesium, is probably helpful for lowering phosphate, by its

  435.                                 antagonism to adenosine (Coulson, et al., 1991).</span></span></span></span></span>

  436.         </blockquote>

  437.         <blockquote></blockquote>

  438.         <blockquote>

  439.             <span style="color: #222222"><span style="font-family: georgia, times, serif"><span

  440.                         style="font-size: medium"

  441.                     >Although increased phosphate generally causes vascular calcification (increasing rigidity, with

  442.                         increased systolic blood pressure), when a high level of dietary phosphate comes from milk and

  443.                         cheese, it is epidemiologically associated with reduced blood pressure (Takeda, et al.,

  444.                         2012).</span></span></span>

  445.         </blockquote>

  446.         <blockquote></blockquote>

  447.         <blockquote>

  448.             <span style="color: #222222">&nbsp;<span style="font-family: georgia, times, serif"><span

  449.                         style="font-size: medium"

  450.                     ><span style="font-style: normal"><span style="font-weight: normal"

  451.                             >Phosphate toxicity offers some interesting insights into stress and aging, helping to

  452.                                 explain the protective effects of carbon dioxide, thyroid hormone, sugar, niacinamide,

  453.                                 and calcium. It also suggests that other natural substances used as food additives

  454.                                 should be investigated more thoroughly. Excessive citric acid, for example, might

  455.                                 activate dormant cancer cells (Havard, et al., 2011), and has been associated with

  456.                                 malignancy (Blüml, et al., 2011). Nutritional research has hardly begun to investigate

  457.                                 the optimal ratios of minerals, fats, amino acids, and other things in foods, and how

  458.                                 they interact with the natural toxicants, antinutrients, and hormone disrupters in many

  459.                                 organisms used for food.</span></span></span></span></span>

  460.         </blockquote>

  461.         <blockquote></blockquote>

  462.         <blockquote>

  463.             <span style="color: #222222">&nbsp;<span style="font-family: georgia, times, serif"><span

  464.                         style="font-size: medium"

  465.                     ><span style="font-style: normal"><span style="font-weight: normal"><h3>REFERENCES</h3></span></span

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  761.                         style="font-size: medium"

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  765.                         suggested that during prolonged exposure to low levels of CO2 (up to 1% CO2), calcium metabolism

  766.                         is controlled by the uptake and release of CO2 in the bones."</span></span></span>

  767.         </blockquote>

  768.         <blockquote></blockquote>

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  771.                         style="font-size: medium"

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  774.                         Masuzaki H, Ogawa Y, Sugawara A, Nabeshima Y, Nakao K. "Uncoupling protein-1 gene expression of

  775.                         BAT and body temperature in klotho mice are lower than those in wild-type mice, suggesting that

  776.                         klotho mice have less energy expenditure than wild-type mice." "All these changes of parameters

  777.                         for energy homeostasis in klotho mice are very similar to those reported under food-restricted

  778.                         conditions.</span></span></span>

  779.         </blockquote>

  780.         <blockquote></blockquote>

  781.         <blockquote>

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  788.         <blockquote></blockquote>

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  807.                         Razzaque MS.</span></span></span>

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  831.                 ></span>

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  842.             <span style="color: #222222">&nbsp;<span style="font-family: georgia, times, serif"><span

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  848.                                 H, Ok E.</span></span></span></span></span>

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  854.                     >Int J Cardiol. 2012 May 26. Serum osteoprotegerin and osteopontin levels are associated with

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  858.                         have recently emerged as&nbsp;</span></span></span>

  859.         </blockquote>

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  861.             <span style="color: #222222"><span style="font-family: georgia, times, serif"><span

  862.                         style="font-size: medium"

  863.                     >key factors in both vascular remodeling and development of atherosclerosis." "These preliminary

  864.                         results suggest that OPG and OPN levels are significantly correlated with vascular function

  865.                         contributing to the pathogenesis of atherosclerosis in CAD."&nbsp;</span></span></span>

  866.         </blockquote>

  867.         <blockquote></blockquote>

  868.         <blockquote>

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  873.                         IDC,&nbsp; Langeberg LK, Sheng M, Scott JD.</span></span></span>

  874.         </blockquote>

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  880.                         biological model. Wiggins PM.</span></span></span>

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  883.         <blockquote>

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  885.                         style="font-size: medium"

  886.                     >Am J Physiol Gastrointest Liver Physiol. 2008 Oct;295(4):G654-63. High dietary inorganic phosphate

  887.                         enhances cap-dependent protein translation, cell-cycle progression, and angiogenesis in the

  888.                         livers of young mice. Xu CX, Jin H, Lim HT, Kim JE, Shin JY, Lee ES, Chung YS, Lee YS, Beck G

  889.                         Jr, Lee KH, Cho MH.</span></span></span>

  890.         </blockquote>

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  892.         <blockquote>

  893.             <span style="color: #222222"><span style="font-family: georgia, times, serif"><span

  894.                         style="font-size: medium"

  895.                     >Nutr Cancer. 2010;62(4):525-32. Low dietary inorganic phosphate stimulates lung tumorigenesis

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  897.                         YC, Chae CH, An GH, Lee KH, Cho MH.</span></span></span>

  898.         </blockquote>

  899.         <blockquote></blockquote>

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  902.                         style="font-size: medium"

  903.                     >Am J Physiol Gastrointest Liver Physiol. 2003 Dec;285(6):G1317-24. Regulation of intestinal

  904.                         NaPi-IIb cotransporter gene expression by estrogen. Xu H, Uno JK, Inouye M, Xu L, Drees JB,

  905.                         Collins JF, Ghishan FK.</span></span></span>

  906.         </blockquote>

  907.         <blockquote>

  908.             <span style="color: #222222"><span style="font-family: georgia, times, serif"><span

  909.                         style="font-size: medium"

  910.                     >"These studies demonstrate for the first time that estrogen stimulates intestinal sodium-dependent

  911.                         phosphate absorption in female rats. This stimulation is associated with increased NaPi-IIb mRNA

  912.                         and protein expression."</span></span></span>

  913.         </blockquote>

  914.         <blockquote></blockquote>

  915.         <blockquote>

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  917.                         style="font-size: medium"

  918.                     >Nihon Yakurigaku Zasshi. 1986 Nov;88(5):395-401. [Effect of sodium salicylate on renal handling of

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  920.                         other hand, we observed increased urinary excretion of Pi and decreased Mg excretion, which

  921.                         resulted from the changes in tubular</span></span></span>

  922.         </blockquote>

  923.         <blockquote>

  924.             <span style="color: #222222"><span style="font-family: georgia, times, serif"><span

  925.                         style="font-size: medium"

  926.                     >reabsorption of Pi and Mg, respectively."</span></span></span>

  927.         </blockquote>

  928.         <blockquote></blockquote>

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  943.         </blockquote>

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  947.                         style="font-size: medium"

  948.                     >PLoS Genet. 2012;8(5):e1002726. Deletion of PTH rescues skeletal abnormalities and high osteopontin

  949.                         levels in Klotho-/- mice. Yuan Q, Sato T, Densmore M, Saito H, Schüler C, Erben RG, Lanske

  950.                         B.</span></span></span>

  951.         </blockquote>

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  959.         </blockquote>

  960.         <p></p>

  961. 

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