Phosphate, Activation, And Aging

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  1. charlie

    charlie The Law & Order Admin

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    Phosphate, activation, and aging

    Recent publications are showing that excess phosphate can increase inflammation, tissue atrophy, calcification of blood vessels, cancer, dementia, and, in general, the processes of aging. This is especially important, because of the increasing use of phosphates as food additives.

    Previously, the complications of chronic kidney disease, with increased serum phosphate, were considered to be specific for that condition, but the discovery of a phosphate-regulating gene named klotho (after one of the Fates in Greek mythology) has caused a lot of rethinking of the biological role of phosphate. In the 19th century, phosphorus was commonly called brain food, and since about 1970, its involvement in cell regulation has become a focus of reductionist thinking. ATP, adenosine triphosphate, is seen as the energy source that drives cell movement as well as the "pumps" that maintain the living state, and as the source of the cyclic AMP that is a general activator of cells, and as the donor of the phosphate group that activates a great number of proteins in the "phosphorylation cascade." When tissues calcified in the process of aging, calcium was blamed (ignoring the existence of calcium phosphate crystals in the tissues), and low calcium diets were recommended. Recently, when calcium supplements haven't produced the intended effects, calcium was blamed, disregarding the other materials present in the supplements, such as citrate, phosphate, orotate, aspartate, and lactate.

    I have a different perspective on the "phosphorylation cascade," and on the other functions of phosphate in cells, based largely on my view of the role of water in cell physiology. In the popular view, a stimulus causes a change of shape in a receptor protein, causing it to become an active enzyme, catalyzing the transfer of a phosphate group from ATP to another protein, causing it to change shape and become activated, and to transfer phosphate groups to other molecules, or to remove phosphates from active enzymes, in chain reactions. This is standard biochemistry, that can be done in a test tube.

    Starting around 1970, when the involvement of phosphorylation in the activation of enzymes in glycogen breakdown was already well known, people began noticing that the glycogen phosphorylase enzyme became active immediately when the muscle cell contracted, and that phosphorylation followed the activation. Phosphorylation was involved in activation of the enzyme, but if something else first activated the enzyme (by changing its shape), the addition of the phosphate group couldn't be considered as causal, in the usual reductionist sense. It was one participant in a complex causal process. I saw this as a possible example of the effect of changing water structure on protein structure and function. This view of water questions the relevance of test tube biochemistry.
    Enzymes are known which suddenly become inactive when the temperature is lowered beyond a certain point. This is because soluble proteins arrange their shape so that their hydrophobic regions, the parts with fat-like side-chains on the amino acids, are inside, with the parts of the chain with water-soluble amino acids arranged to be on the outside, in contact with the water. The "wetness" of water, its activity that tends to exclude the oily parts of the protein molecule, decreases as the temperature decreases, and some proteins are destabilized when the relatively hydrophobic group is no longer repelled by the surrounding cooler water.

    In the living cell, the water is all within a very short distance of a surface of fats or fat-like proteins. In a series of experiments, starting in the 1960s, Walter Drost-Hansen showed that, regardless of the nature of the material, the water near a surface is structurally modified, becoming less dense, more voluminous. This water is more "lipophilic," adapting itself to the presence of fatty material, as if it were colder. This change in the water's properties also affects the solubility of ions, increasing the solubility of potassium, decreasing that of sodium, magnesium, and calcium (Wiggins, 1973).

    When a muscle contracts, its volume momentarily decreases (Abbott and Baskin, 1962). Under extremely high pressure, muscles contract. In both situations, the work-producing process of contraction is associated with a slight reduction in volume. During contraction of a muscle or nerve, heat is given off, causing the temperature to rise. During relaxation, recovering from excitation, heat is absorbed (Curtin and Woledge, 1974; Westphal, et al., 1999; Constable, et al. 1997). In the case of a nerve, following the heating produced by excitation, the temperature of the nerve decreases below the starting temperature (Abbot, et al., 1965). Stretching a muscle causes energy to be absorbed (Constable, et al., 1997). Energy changes such as these, without associated chemical changes, have led some investigators to conclude that muscle tension generation is "entropy driven" (Davis and Rodgers, 1995).

    Kelvin's description (1858) of the physics of water in a soap bubble, "…if a film such as a soap-bubble be enlarged . . . it experiences a cooling effect . . . ," describes the behavior of nerves and muscles, absorbing energy or heat when they are relaxing (or elongating), releasing it when they are excited/contracting.

    Several groups of experimenters over the last 60 years have tried to discover what happens to the missing heat; some have suggested electrical or osmotic storage, and some have demonstrated that stretching generates ATP, arguing for chemical storage. Physical storage in the form of structural changes in the water-protein-lipid system, interacting with chemical changes such as ATP synthesis, have hardly been investigated.

    Early studies of muscle chemistry and contraction found that adding ATP to a viscous solution of proteins extracted from muscle reduced its viscosity, and also that the loss of ATP from muscle caused its hardening, as in rigor mortis; if the pH wasn't too acidic, the dead muscle would contract as the ATP content decreased. Szent-Gyorgyi found that a muscle hardened by rigor mortis became soft again when ATP was added.

    Rigor mortis is an extreme state of fatigue, or energy depletion. Early muscle studies described the phenomenon of "fatigue contracture," in which the muscle, when it reaches the point at which it stops responding to stimulation, is maximally contracted (this has also been called delayed relaxation). Ischemic contracture, in the absence of blood circulation, occurs when the muscle's glycogen is depleted, so that ATP can no longer be produced anaerobically (Kingsley, et al., 1991). The delayed relaxation of hypothyroid muscle is another situation in which it is clear that ATP is required for relaxation. (In the Achilles tendon reflex test, the relaxation rate is visibly slowed in hypothyroidism.) A delayed T wave in the electrocardiogram, and the diastolic contracture of the failing heart show the same process of delayed relaxation. Supplementing the active thyroid hormone, T3, can quickly restore the normal rate of relaxation, and its beneficial effects have been demonstrated in heart failure (Pingitore, et al., 2008; Wang, et al., 2006; Pantos, et al., 2007; Galli, et al., 2008).

    A large part of the magnesium in cells is bound to ATP, and the magnesium-ATP complex is a factor in muscle relaxation. A deficiency of either ATP or magnesium contributes to muscle cramping. When a cell is stimulated, causing ATP to release inorganic phosphate, it also releases magnesium. Above the pH of 6.7, phosphate is doubly ionized, in which state it has the same kind of structural effect on water that magnesium, calcium, and sodium have, causing water molecules to be powerfully attracted to the concentrated electrical charge of the ion. Increasing the free phosphate and magnesium opposes the effect of the surfaces of fats and proteins on the water structure, and tends to decrease the solubility of potassium in the water, and to increase the water's "lipophobic" tendency to minimize its contacts with fats and the fat-like surface of proteins, causing the proteins to rearrange themselves.

    These observations relating to the interactions of water, solutes and proteins in muscles and nerves provide a coherent context for understanding contraction and conduction, which is lacking in the familiar descriptions based on membranes, pumps, and cross-bridges, but I think they also provide a uniquely useful context for understanding the possible dangers of an excess of free phosphate in the body.

    A few people (M. Thomson, J. Gunawardena, A.K. Manrai) are showing that principles of mass-action help to simplify understanding the networks of phosphorylation and dephosphorylation that are involved in cell control. But independently from the phosphorylation of proteins, the presence of phosphate ion in cell water modifies the cell's ion selectivity, shifting the balance toward increased uptake of sodium and calcium, decreasing potassium, tending to depolarize and "activate" the cell.
    About 99% of the publications discussing the mechanism of muscle contraction fail to mention the presence of water, and there's a similar neglect of water in discussions of the energy producing processes in the mitochondrion. The failure of mitochondrial energy production leads to lipid peroxidation, activation of inflammatory processes, and can cause disintegration of the energy producing structure. Increased phosphate decreases mitochondrial energy production (Duan and Karmazyn, 1989), causes lipid peroxidation (Kowaltowski, et al., 1996), and activates inflammation, increasing the processes of tissue atrophy, fibrosis, and cancer.

    For about twenty years it has been clear that the metabolic problems that cause calcium to be lost from bones cause calcium to increase in the soft tissues, such as blood vessels. The role of phosphate in forming calcium phosphate crystals had until recently been assumed to be passive, but some specific "mechanistic" effects have been identified. For example, increased phosphate increases the inflammatory cytokine, osteopontin (Fatherazi, et al., 2009), which in bone is known to activate the process of decalcification, and in arteries is involved in calcification processes (Tousoulis, et al., 2012). In the kidneys, phosphate promotes calcification (Bois and Selye, 1956), and osteopontin, by its activation of inflammatory T-cells, is involved in the development of glomerulonephritis, as well as in inflammatory skin reactions (Yu, et al., 1998). High dietary phosphate increases serum osteopontin, as well as serum phosphate and parathyroid hormone, and increases the formation of tumors in skin (Camalier, et al., 2010). Besides the activation of cells and cell systems, phosphate (like other ions with a high ratio of charge to size, including citrate) can activate viruses (Yamanaka, et al., 1995; Gouvea, et al., 2006). Aromatase, the enzyme that synthesizes estrogen, is an enzyme that's sensitive to the concentration of phosphate (Bellino and Holben, 1989).

    More generally, increased dietary phosphate increases the activity of an important regulatory enzyme, protein kinase B, which promotes organ growth. A high phosphate diet increases the growth of liver (Xu, et al., 2008) and lung (Jin, et al., 2007), and promotes the growth of lung cancer (Jin, et al., 2009). An extreme reduction of phosphate in the diet wouldn't be appropriate, however, because a phosphate deficiency stimulates cells to increase the phosphate transporter, increasing the cellular uptake of phosphate, with an effect similar to the dietary excess of phosphate, i.e., promotion of lung cancer (Xu, et al., 2010). The optimum dietary amount of phosphate, and its balance with other minerals, hasn't been determined.

    While increased phosphate slows mitochondrial energy production, decreasing its intracellular concentration increases the respiratory rate and the efficiency of ATP formation. A "deficiency" of polyunsaturated fatty acids has this effect (Nogueira, et al., 2001), but so does the consumption of fructose (Green, et al., 1993; Lu, et al., 1994).

    In a 1938 experiment (Brown, et al.) that intended to show the essentiality of unsaturated fats, a man, William Brown, lived for six months on a 2500 calorie diet consisting of sucrose syrup, a gallon of milk (some of it in the form of cottage cheese), and the juice of half an orange, besides some vitamins and minerals. The experimenters remarked about the surprising disappearance of the normal fatigue after a day's work, as well as the normalization of his high blood pressure and high cholesterol, and the permanent disappearance of his frequent life-long migraine headaches. His respiratory quotient increased (producing more carbon dioxide), as well as his rate of resting metabolism. I think the most interesting part of the experiment was that his blood phosphate decreased. In two measurements during the experimental diet, his fasting plasma inorganic phosphorus was 3.43 and 2.64 mg. per 100 ml. of plasma, and six month after he had returned to a normal diet the number was 4.2 mg/100 ml. Both the deficiency of the "essential" unsaturated fatty acids, and the high sucrose intake probably contributed to lowering the phosphate.
    In 2000, researchers who were convinced that fructose is harmful to the health, reasoned that its harmful effects would be exacerbated by consuming it in combination with a diet deficient in magnesium. Eleven men consumed, for six months, test diets with high fructose corn syrup or starch, along with some fairly normal U.S. foods, and with either extremely low magnesium content, or with slightly deficient magnesium content. The authors' conclusion was clearly stated in the title of their article, that the combination adversely affects the mineral balance of the body.
    However, looking at their results in the context of these other studies of the effects of fructose on phosphate, I don't think their conclusion is correct. Even on the extremely low magnesium intake, both their magnesium and calcium balances were positive, meaning that on average their bodies accumulated a little magnesium and calcium, even though men aged 22 to 40 presumably weren't growing very much. To steadily accumulate both calcium and magnesium, with the calcium retention much larger than the magnesium, the minerals were probably mostly being incorporated into their bones. Their phosphate balance, however, was slightly negative on the "high fructose" diet. If the sugar was having the same effect that it had on William Brown in 1938 (and in animal experiments), some of the phosphate loss was accounted for by the reduced amount in blood and other body fluids, but to continue through the months of the experiment, some of it must have represented a change in the composition of the bones. When there is more carbon dioxide in the body fluids, calcium carbonate can be deposited in the bones (Messier, et al., 1979). Increased carbon dioxide could account for a prolonged negative phosphate balance, by taking its place in the bones in combination with calcium and magnesium.

    Another important effect of carbon dioxide is in the regulation of both calcium and phosphate, by increasing the absorption and retention of calcium (Canzanello, et al., 1995), and by increasing the excretion of phosphate. Increased carbon dioxide (as dissolved gas) and bicarbonate (as sodium bicarbonate) both increase the excretion of phosphate in the urine, even in the absence of the parathyroid hormone. Below the normal level of serum bicarbonate, reabsorption of phosphate by the kidneys is greatly increased (Jehle, et al., 1999). Acetazolamide increases the body's retention of carbon dioxide, and increases the amount of phosphate excreted in the urine.
    Much of the calcium dissolved in the blood is in the form of a complex of calcium and bicarbonate, with a single positive charge (Hughes, et al., 1984). Failure to consider this complexed form of calcium leads to errors in measuring the amount of calcium in the blood, and in interpreting its physiological effects, including its intracellular behavior. Hyperventilation can cause cramping of skeletal muscles, constriction of blood vessels, and excitation of platelets and other cells; the removal of carbon dioxide from the blood lowers the carbonic acid, changing the state and function of calcium. Hyperventilation increases phosphate and parathyroid hormone, and decreases calcium (Krapf, et al., 1992).

    Since estrogen tends to cause hyperventilation, lowering carbon dioxide, its role in phosphate metabolism should be investigated more thoroughly. Work by Han, et al. (2002) and Xu, et al. (2003) showed that estrogen increases phosphate reabsorption by the kidney, but estrogen also increases cortisol, which decreases reabsorption, so the role of estrogen in the whole system has to be be considered.

    This calcium solubilizing effect of bicarbonate, combined with its phosphaturic effect, probably accounts for the relaxing effect of carbon dioxide on the blood vessels and bronchial smooth muscles, and for the prevention of vascular calcification by the thyroid hormones (Sato, et al., 2005, Tatar, 2009, Kim, et al., 2012). Distensibility of the blood vessels and heart, increased by carbon dioxide, is decreased in hypothyroidism, heart failure, and by phosphate.

    While fructose lowers intracellular phosphate, it also lowers the amount that the intestine absorbs from food (Kirchner, et al.,2008), and the Milne-Nielsen study suggests that it increases phosphate loss through the kidneys. The "anti-aging" protein, klotho, increases the ability of the kidneys to excrete phosphate (Dërmaku-Sopjani, et al., 2011), and like fructose, it supports energy production and maintains thermogenesis (Mori, et al., 2000).

    Lowering the amount of phosphate in the blood allows the parathyroid hormone to decrease. While the parathyroid hormone also prevents phosphate reabsorption by the kidneys, it causes mast cells to release serotonin (and serotonin increases the kidneys' reabsorption of phosphate), and possibly has other pro-inflammatory effects. For example, deleting the PTH gene compensates for the harmful (accelerated calcification and osteoporosis) effects of deleting the klotho gene, apparently by preventing the increase of osteopontin (Yuan, et al., 2012).

    Niacinamide is another nutrient that lowers serum phosphate (Cheng, et al., 2008), by inhibiting intestinal absorption (Katai, et al., 1989), and also by reducing its reabsorption by the kidneys (Campbell, et al., 1989). Niacinamide's reduction of free fatty acids by inhibiting lipolysis, protecting the use of glucose for energy, might be involved in its effect on phosphate (by analogy with the phosphate lowering action of a deficiency of polyunsaturated fatty acids). Aspirin is another antilipolytic substance (de Zentella, et al., 2002) which stimulates energy production from sugar and lowers phosphate, possibly combined with improved magnesium retention (Yamada and Morohashi, 1986).

    A diet that provides enough calcium to limit activity of the parathyroid glands, and that is low in phosphate and polyunsaturated fats, with sugar rather than starch as the main carbohydrate, possibly supplemented by niacinamide and aspirin, should help to avoid some of the degenerative processes associated with high phosphate: fatigue, heart failure, movement discoordination, hypogonadism, infertility, vascular calcification, emphysema, cancer, osteoporosis, and atrophy of skin, skeletal muscle, intestine, thymus, and spleen (Ohnishi and Razzaque, 2010; Shiraki-Iida, et al., 2000; Kuro-o, et al., 1997; Osuka and Razzaque, 2012). The foods naturally highest in phosphate, relative to calcium, are cereals, legumes, meats, and fish. Many prepared foods contain added phosphate. Foods with a higher, safer ratio of calcium to phosphate are leaves, such as kale, turnip greens, and beet greens, and many fruits, milk, and cheese. Coffee, besides being a good source of magnesium, is probably helpful for lowering phosphate, by its antagonism to adenosine (Coulson, et al., 1991).

    Although increased phosphate generally causes vascular calcification (increasing rigidity, with increased systolic blood pressure), when a high level of dietary phosphate comes from milk and cheese, it is epidemiologically associated with reduced blood pressure (Takeda, et al., 2012).
    Phosphate toxicity offers some interesting insights into stress and aging, helping to explain the protective effects of carbon dioxide, thyroid hormone, sugar, niacinamide, and calcium. It also suggests that other natural substances used as food additives should be investigated more thoroughly. Excessive citric acid, for example, might activate dormant cancer cells (Havard, et al., 2011), and has been associated with malignancy (Blüml, et al., 2011). Nutritional research has hardly begun to investigate the optimal ratios of minerals, fats, amino acids, and other things in foods, and how they interact with the natural toxicants, antinutrients, and hormone disrupters in many organisms used for food.

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    "These studies demonstrate for the first time that estrogen stimulates intestinal sodium-dependent phosphate absorption in female rats. This stimulation is associated with increased NaPi-IIb mRNA and protein expression."
    Nihon Yakurigaku Zasshi. 1986 Nov;88(5):395-401. [Effect of sodium salicylate on renal handling of calcium, phosphate and magnesium]. [Article in Japanese] Yamada S, Morohashi T. "On the other hand, we observed increased urinary excretion of Pi and decreased Mg excretion, which resulted from the changes in tubular
    reabsorption of Pi and Mg, respectively."
    J Biol Chem. 1995 Dec 15;270(50):30168-72. Stimulation of the herpes simplex virus type I protease by antichaeotrophic salts. Yamanaka G, DiIanni CL, O'Boyle DR 2nd, Stevens J, Weinheimer SP, Deckman IC, Matusick-Kumar L, Colonno RJ.
    Proc Assoc Am Physicians. 1998 Jan-Feb;110(1):50-64. A functional role for osteopontin in experimental crescentic glomerulonephritis in the rat. Yu XQ, Nikolic-Paterson DJ, Mu W, Giachelli CM, Atkins RC, Johnson RJ, Lan HY.
    PLoS Genet. 2012;8(5):e1002726. Deletion of PTH rescues skeletal abnormalities and high osteopontin levels in Klotho-/- mice. Yuan Q, Sato T, Densmore M, Saito H, Schüler C, Erben RG, Lanske B.
    J Pharm Pharmacol. 2002 Apr;54(4):577-82. Non-steroidal anti-inflammatory drugs inhibit epinephrine- and cAMP-mediated lipolysis in isolated rat adipocytes. de Zentella PM, Vázquez-Meza H, Piña-Zentella G, Pimentel L, Piña E.
     
  2. Amazoniac

    Amazoniac Member

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  3. Amazoniac

    Amazoniac Member

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    - Phosphate Additives in Food—a Health Risk

    "It used to be thought that the only health risk posed by phosphate lay in the promotion of calcification in blood vessels and bodily organs. Recently, however, important discoveries have been made about the hormonal regulation of phosphate metabolism. It is now known that the serum phosphate concentration is controlled by two newly discovered factors called fibroblast growth factor 23 (FGF23) and klotho; that phosphate causes lasting damage to the cardiovascular system, either by a direct mechanism or by way of these hormonal factors; and that phosphate accelerates aging processes in animal models (e2, e3)."

    "Phosphate induces vascular calcification both in vitro and in vivo (16, e6). What occurs is not merely the passive precipitation of calcium × phosphate, but rather an active cellular process in which smooth-muscle cells in blood vessels are reprogrammed to become osteoblast-like cells (“osteogenic transdifferentiation”) (16). This process, originally identified in cell culture and in animal experiments, has since been demonstrated in human arteries as well (17, e7). Moreover, it has recently been shown that increased phosphate intake leads to a marked impairment of endothelial-cell function in the vascular system, both in experimental animals and in man (18). Phosphate-induced vascular changes may be the link connecting elevated serum phosphate concentrations to premature aging and death."

    "In particular, phosphate added to animal fodder accelerates age-related organ complications such as muscle and skin atrophy, the progression of chronic renal failure, and cardiovascular calcifications (e2). Phosphate added to human food probably has similar effects in man. Inexpensive food containing additives (processed food), and fast food in particular, are extraordinarily rich in phosphate additives. Such foods are consumed in greater amounts by the poor. In the USA, hyperphosphatemia has been found to be twice as common among persons of low income than among persons of high income."

    "Phosphate occurs naturally in the form of organic esters in many kinds of food, including meat, potatoes, bread, and other farinaceous products; the consumption of such foods cannot be restricted without incurring the risk of lowering protein intake. Naturally occurring phosphate in food is organically bound, and only 40% to 60% of it is absorbed in the gastrointestinal tract (e1)."

    "On the other hand, an avoidable risk to health that has not attracted sufficient attention to date arises from the increased use of phosphate as a food additive and preservative. This “free” (not organically bound) phosphate is very effectively absorbed in the gastrointestinal tract. Typical foods with large amounts of added phosphate are processed meat, ham, sausages, canned fish, baked goods, cola drinks, and other soft drinks. Dietary counseling is all the more difficult because the phosphate content in food—and, in particular, the added phospate content—is not marked on the package."

    "Cola drinks and flavored soft drinks often contain large quantities of phosphoric acid (E 338) as an acidifying agent. Such agents are given to lower the pH of food and thereby inhibit the growth of yeast, fungi, and bacteria." "In particular, the phosphate that is added to cola drinks interrupts a glycation reaction, which, if unhindered, would produce so-called advanced glycation end products (AGE) and color the beverage pitch-black. Thus, cola drinks owe their brown color to phosphate."​

    - Understanding Sources of Dietary Phosphorus in the Treatment of Patients with Chronic Kidney Disease

    "Serum P levels can rise slightly with a high-P diet, especially immediately after a P-rich meal (3). High serum P concentrations inhibit the renal 1-α-hydroxylation of vitamin D, leading to a reduction in serum calcium (22). Elevated serum P may also suppress serum calcium by causing a saturated serum calcium-P product to precipitate in tissues. These factors can promote increased release of PTH (23). Frequent or sustained elevations of PTH levels can have adverse effects on bone mineral content and architecture, although the significance of such borderline or temporary hyperparathyroidism without kidney dysfunction is unclear (24). A controlled trial of young women found no adverse effects of a P-rich diet of up to 3000 mg/d on bone-related hormones and biochemical markers of bone reabsorption as long as dietary calcium intakes were maintained at almost 2000 mg/d (25)."

    "There is a strong and positive correlation between dietary protein and P intake, which is responsible for the frequent association of high protein intake in the diet with excessive ingestion of P and the development of hyperphosphatemia in people with CKD (27)."

    "Inorganic P, such as P additives, are not protein bound; they are salts that more readily disassociate and are absorbed in the intestinal tract (50). Indeed, it is believed that >90% of inorganic P may be absorbed in the intestinal tract, as opposed to only 40 to 60% of the organic P present in natural foods (51,52). The major public health implication from these considerations is that the P burden from inorganic P–containing food additives is disproportionately high relative to organic P. In the early 1990s, P additives contributed approximately 500 mg/d P to the American diet, whereas today P additives may contribute as much as 1000 mg/d P to the average American diet (37,51,53,54)."

    "Two food items are of special relevance to patients with CKD: Soft drinks and cheese. Substantial amounts of phosphoric acid are usually present in most colas and many other beverages but not in root beer, for instance (Table 3) (53). Many but not all clear-colored soft drinks or teas are low in P (Table 3) (46); however, most of these drinks contain little to no protein or other organic compounds, and the P is almost exclusively from additives. Being in liquid form, the inorganic P in these drinks are perhaps even more readily absorbable. The high additive-based P burden is a dietary challenge in almost all nations throughout the world. Table 4 illustrates variations in P content across diverse types of cheese in German-speaking regions of Europe. The quantity of P in a 50-g portion of cheese varies from <100 mg in Brie cheese to almost half a gram in processed soft cheese, which contains a significant amount of P salt (45,46)."​

    - Phosphorus Additives in Food and their Effect in Dialysis Patients

    "In 2005, a low-phosphorus (116 mg phosphorus per 8 fl oz) 2% milk was introduced commercially (22), and hopefully more of these low-phosphorus foods will be available in the near future. Another important issue to consider is that addition of phosphorus goes hand in hand with addition of sodium because most of the phosphate is added as a sodium salt and sodium chloride is frequently added independently as a food preservative or for taste or appearance improvement."​


    It's possible to take the commitment too far:

    - Phosphate—a poison for humans? :ss

    "There are the following 2 mechanisms of intestinal phosphate absorption: a passive paracellular pathway through tight junctions and an active transport pathway through the sodium-dependent phosphate cotransporter Npt2b.[15] Active transport of phosphate is regulated by calcitriol (1,25-dihydroxyvitamin D), which induces the expression of Npt2b on the apical membrane of intestinal epithelial cells.[16] Low-phosphate diets also upregulate Npt2b expression independent of calcitriol,[17] although the detailed mechanism of this regulation remains unclear."

    "In addition to these intrinsic factors, the type of the diet also has a considerable impact on intestinal phosphate absorption. The modern diet often contains high levels of phosphate in the form of preservatives and additive salts that are readily absorbed by the intestine and can contribute to an individual’s phosphate burden.[13,14] In contrast, phosphate in plants is primarily in the form of phytic acid and is generally not bioavailable to humans because humans do not have the digestive enzyme phytase that degrades phytic acid.[18]"​

    - Antacid-induced Osteomalacia

    "Hypophosphataemia is a well-known side effect of antacids which are used in renal failure to bind phosphate in the gut and lower serum phosphate. In adults, sporadic hypophosphataemic osteomalacia is associated with oncogenic and non-tumoural phosphate diabetes or with acquired Fanconi's tubulopathies."

    "Lotz et al. induced an experimental syndrome of phosphate depletion in normal subjects and in patients with parathyroid dysfunction (5). By administering AI(OH)3 and Mg(OH)2, they provoked peculiar symptoms and biological changes like: skeletal pain, muscular weakness, hypophosphataemia, hypophosphaturia, and hypercalciuria. In normal volunteers, a decrease in the 24-hour urinary phosphate excretion to undetectable levels was observed from the 6th day of phosphate depletion, whereas the 24-hour urinary calcium excretion rose 5 - fold and intestinal calcium absorption increased after 73 days up to 75 % as compared to 45% in the control period (5)."

    "Hypophosphataemia is a potent stimulus to the renal 25-hydroxyvitamin-D-1-alpha-hydroxylase enzyme, even more than parathyroid hormone and hypocalcaemia (23,24). It is appropriate to find an increased level of 1,25-dihydroxyvitamin D as in our case (14,15,19,20). Increased intestinal absorption of calcium (5,8) as well as hypercalciuria has also been observed in adult patients abusing antacids. Hypercalciuria is not only the net result of the increased intestinal calcium absorption but may also partly be induced by the increased bone resorption mediated by the elevation of 1,25-dihydroxyvitamin D (15,20,24). Nevertheless, in growing children, hypocalciuria has instead been reported (21)."

    "In every case, healing is rapidly achieved after cessation of antacid intake with or without phosphorus supplementation. Serum and urinary phosphate, calcium excretion all return within the normal range in two to five days. Skeletal pain and weakness disappear after one to eight weeks. Serum alkaline phosphatase activity may remain elevated for more than 6 months, as obselwed in our patient."

    "It is a little surprising that so few cases of antacid-induced osteomalacia have been reported despite the large use of these compounds. It is possible that some other conditions are needed to permit the development of full-blown osteomalacia. For example, a prolonged antacid treatment of at least 18 months has, been described in all reported cases. Some patients suffered from psychiatric behaviour and self-administered high quantities of antacids. In none of the reported eases, had any patient suffered from an intestinal malabsorption syndrome but low b-carotene levels have been reported in a few patients (9-14, our case). Moreover, a low phosphorus diet superimposed upon antacid therapy may favour the occurrence of osteomalacia (14)."

    "It is possible that a great number of "forme fruste" hypophosphataemic osteomalacia remain unrecognized in elderly patients treated with antacids. Skeletal pain and proximal weakness are quite common symptoms in elderly patients that may be misinterpreted as rheumatic or neurologic complaints. Twenty-four-hour urinary phosphate excretion measurement may be useful in those patients since values over 300 mg/day should rule out the diagnosis of phosphate depletion (5)."​

    - Osteomalacia

    "The fact that phosphate depletion per se can cause osteomalacia is best illustrated by the few patients who have developed osteomalacia following prolonged administration of phosphate binding antacids (Lotz et al, 1968). Later studies have shown that this osteomalacia is not due to excessive aluminium deposition from absorption of the antacids [] (Carmichael et al, 1984). As the hypophosphataemia stimulates renal 1a-hydroxylase activity, patients with osteomalacia due to phosphate depletion characteristically have elevated plasma levels of 1,25(OH)2D, which leads to hypercalciuria. Treatment is by withdrawal of phosphate-binding agents, but bone healing may be aided by the addition of phosphate supplements and vitamin D."

    "It is also possible to induce hypophosphataemia by inadequate phosphate administration during parenteral nutrition (Klein and Chesney, 1986). This was a cause of rickets in premature infants, although aluminium intoxication may be a more important cause of osteomalacia in such adults receiving parenteral feeding."​
     
  4. GorillaHead

    GorillaHead Member

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    So whats the overall best suggestion to avoid this?
     
  5. commas

    commas Member

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    use dairy as primary source of protein to have a good calcium intake to balance the phosphate, avoid whole grains, avoid antacids, eat/drink fruit, drink coffee if you can handle it, take vitamin D, use sodium bicarb (although you should be careful with this and probsbly better to use in OJ instead of plain water)
     
  6. cinderella

    cinderella Member

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    @charlie it is great to post this, specially since there is a rise of posts on the #raypeat and #raypeatinspired Instagram accounts where 'fans' share photos of foods loaded with meat, following the keto/primal fashion. Newcomers might get confused about Ray Peat's message in this way.
     
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