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<h1>Lactate vs. CO2 in wounds, sickness, and aging; the other approach to cancer</h1>
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<p class="nav"><span class="nav-left">Listed under <a href="/ray-peat.html">Ray Peat</a>.</span><span class="nav-right"><a href="/theme.html">Theme</a></span></p>
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<p>From the <a href="https://raypeat.com/articles/articles/lactate.shtml" target="_blank">original article</a> in 2009. Author: <a href="https://raypeat.com/" target="_blank">Ray Peat</a>.</p>
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<h2>Glossary</h2>
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<p><strong>Aerobic
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glycolysis,</strong> the conversion of glucose to lactic acid even in the
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presence of oxygen. The presence of oxygen normally restrains glycolysis
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so that glucose is converted to carbon dioxide instead of lactic acid.
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</p>
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<p><strong>Anaerobic
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glycolysis,</strong> the increased conversion of glucose to lactic acid when
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the supply of oxygen isn't sufficient, which is a normal event during
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intense muscle action. </p>
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<p><strong>"Warburg
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Effect"</strong> refers to Otto Warburg's observation that cancer cells
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produce lactic acid even in the presence of adequate oxygen. Cancer
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cells don't "live on glucose," since they are highly adapted
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to survive on protein and fats. </p>
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<p><strong>Pasteur
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Effect,</strong> the normal response of cells to restrain glycolysis in the
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presence of adequate oxygen. </p>
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<p><strong>Crabtree
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Effect,</strong> observed originally in yeast, refers to the inhibition of
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respiration in the presence of glucose. This occurs in cancers (e.g.,
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Miralpeix, et al., 1990) and in rapidly proliferating normal cells (e.g.,
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Guppy, et al., 1993). </p>
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<p><strong>"Cancer
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metabolism"</strong> or stress metabolism typically involves an excess
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of the adaptive hormones, resulting from an imbalance of the demands
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made on the organism and the resources available to the organism. Excessive
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stimulation depletes glucose and produces lactic acid, and causes cortisol
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to increase, causing a shift to the consumption of fat and protein rather
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than glucose. Increased cortisol activates the Randle effect (the inhibition
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of glucose oxidation by free fatty acids), accelerates the breakdown
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of protein into amino acids, and activates the enzyme fatty acid synthase,
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which produces fatty acids from amino acids and pyruvate, to be oxidized
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in a "futile cycle," producing heat, and increasing the liberation
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of ammonia from the amino acids. Ammonia suppresses respiratory, and
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stimulates glycolytic, activity. </p>
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<p>The
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presence of lactic acid in our tissues is very meaningful, but it is
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normally treated as only an indicator, rather than as a cause, of biological
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problems. Its presence in rosacea, arthritis, heart disease, diabetes,
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neurological diseases and cancer has been recognized, and recently it
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is being recognized that suppressing it can be curative, after fifty
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years of denial. </p>
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<p>The
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influence of politics on science is so profound that neither historians
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nor scientists often care to consider it honestly and in depth.</p>
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<p>From the 19th century until the second quarter of the 20th century, cancer
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was investigated mainly as a metabolic problem. This work, understanding
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the basic chemistry of metabolism, was culminating in the 1920s in the
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work of Otto Warburg and Albert Szent-Gyorgyi on respiration. Warburg
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demonstrated as early as 1920 that a respiratory defect, causing aerobic
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glycolysis, i.e., the production of lactic acid even in the presence
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of oxygen, was an essential feature of cancer. (The formation of lactic
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acid is normal and adaptive when the supply of oxygen isn't adequate
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to meet energy demands, for example when running.)</p>
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<p>Many
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people recognized that this was likely to be the key to the "cancer
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problem." But in the US, several factors came together to block
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this line of investigation.</p>
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<p>The
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world wars contributed to the isolation of German scientists, and Warburg,
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of the famous Jewish banking family, continued his work in Germany with
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the support of the government, despite his open opposition to Nazism.
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In the years after the war, nothing positive could be said in the US
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about his work on cancer.</p>
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<p>The
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metabolic interpretation of disease that had been making progress for
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several decades was suddenly submerged when government research financing
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began concentrating on genetic and viral interpretations of disease.</p>
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<p>If
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an apparently non-infectious disease couldn't be explained on the basis
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of an inherited tendency---insanity, epilepsy, diabetes, toxemia of
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pregnancy, and cancer, for example---then genetic changes occurring
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in the individual, as a result of chance or a virus, were invoked. Nutrition
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and other conditions of life were until fairly recently said to have
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no influence on health if the person consumed sufficient calories and
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a minimum amount of the essential vitamins, minerals, and protein. The
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cult of genetic determinism was so powerful that it wasn't affected
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by the facts.</p>
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<p>In
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1932, a pediatrician, Alexis Hartmann (with M. Senn) in St. Louis, injected
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intravenously a solution of sodium lactate into patients with metabolic
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acidosis, and several of them survived---despite the fact that some
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of them were already suffering from an excess of lactate. The subsequent
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widespread use of lactate solutions in hospitals has contributed to
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the general denial of its toxicity.</p>
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<p>Hartmann
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and Senn used racemic lactate, that is, a mixture of D-lactate and L-lactate.
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Our own tissues produce mostly L-lactate, but they can produce small
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amounts of D-lactate; larger amounts are produced by diabetics. Intestinal
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bacteria can produce large amounts of it, and it has many toxic effects.
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Methylglyoxal can be formed from either form of lactate, and it is an
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important factor in the glycation of proteins. It can also be formed
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from MDA, a product of lipid peroxidation. Protein glycation is an important
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factor in diabetes and aging, but glucose, rather than lactate and polyunsaturated
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fats, is commonly said to be the cause.</p>
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<p>About
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50 years ago, lactate was known to induce the formation of new blood
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vessels, and for a much longer time it has been known to cause vasodilation
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and edema. In 1968, it was shown to stimulate collagen synthesis.</p>
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<p>Normally,
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collagen synthesis and neovascularization are caused by lack of oxygen,
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but lactate can cause them to occur even in the presence of oxygen.
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Maintenance of a normal extracellular matrix is essential for normal
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functioning and cellular differentiation. Abnormally stimulated collagen
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synthesis probably accelerates tumor growth (Rajkumar, et al., 2006). </p>
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<p>Nervous
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and hormonal factors can cause lactate to accumulate, even without prior
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damage to the mitochondria (e.g., B. Levy, et al., 2003). Psychological,
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as well as physical, stress and overactivation of glutamate receptors
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can cause harmful accumulation of lactate in the brain (Uehara, et al.,
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2005). Rather than just being "associated with" tissue damage,
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lactate directly contributes to the damage, for example in the brain,
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causing nerve cell loss by increasing the release of excitotoxic glutamate
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(Xiang, et al, 2004). When a panic reaction is produced by sodium lactate,
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the reduction of protective neurosteroids appears to contribute to the
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excitatory state (Eser, et al. 2006); this would make the brain more
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susceptible to damage.</p>
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<p>
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Lactate increases blood viscosity, mimics stress, causes inflammation,
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and contributes to shock. Lactated Ringer's solution contributes to
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the tissue damage caused by shock, when it's used to resuscitate shock
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victims (Deree, et al., 2007, 2008): it contributes to the inflammatory
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processes associated with shock, unlike the use of hypertonic saline
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and other solutions. Lactate contributes to diabetes, inhibiting the
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ability to oxidize glucose. It promotes endothelial cell migration and
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leakiness, with increased vascular permeability factor (VPF or vascular
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endothelial growth factor, VEGF) (Nagy, et al. 1985): this can lead
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to breakdown of the "blood-brain barrier." </p>
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<p>In
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the brain, lactate can cause nerve damage, increasing intracellular
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fat accumulation, chromatin clumping, and mitochondrial swelling (Norenberg,
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et al., 1987).</p>
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<p>The
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lactate in peritoneal dialysis solution impairs differentiation and
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maturation of (immune, monocyte derived) dendritic cells; according
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to the authors of the study, "These findings have important implications
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for the initiation of immune responses under high lactate conditions,
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such as those occurring within tumor tissues or after macrophage activation<strong>" </strong>
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(Puig-Kröger, et al., 2003).<strong> </strong></p>
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<p>Lactate
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also causes macrophages and synovial fibroblasts to release PGE2, which
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can contribute to inflammation and bone resorption (Dawes and Rushton,
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1994). This is the prostaglandin known to activate the formation of
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estrogen (Haffty, et al., 2008).</p>
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<p>Hartmann's
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lactated solution has been widely used in hospitals for resuscitation
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and for patients after heart surgery and other stressful procedures,
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but until recently only a few people have objected to its use, and most
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of the objection has been to the use of racemic lactate, rather than
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to lactate itself. In recent years several studies have compared hypertonic
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saline (lacking the minerals considered essential since Sydney Ringer
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formulated his solution around 1885), and have found it in some cases
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superior to the "balanced" lactate solution. Even hypertonic
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glucose, without minerals, has produced good results in some studies.</p>
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<p>A
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solution containing a large amount of lactate has been used for peritoneal
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dialysis when there is kidney failure, but several studies have compared
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solutions using bicarbonate instead of lactate, and found that they
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don't cause the severe damage that always happened with the traditional
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solution.</p>
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<p>While
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Warburg was investigating the roles of glycolysis and respiration in
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cancer,<strong> </strong>a physician with a background in chemistry, W.F. Koch,
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in Detroit, was showing that the ability to use oxygen made the difference
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between health and sickness, and that the cancer metabolism could be
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corrected by restoring the efficient use of oxygen. He argued that a
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respiratory defect was responsible for immunodeficiency, allergy, and
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defective function of muscles, nerves, and secretory cells, as well
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as cancer. Koch's idea of cancer's metabolic cause and its curability
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directly challenged the doctrine of the genetic irreversibility of cancer
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that was central to governmental and commercial medical commitments.</p>
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<p>Albert
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Szent-Gyorgyi respected Koch's work, and spent years investigating the
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involvement of the lactate metabolites, methylgyoxal and glyoxal, in
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cell physiology, but since the government's campaign against Koch was
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still active when Szent-Gyorgyi came to the U.S., he worked out many
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of the implications of Koch's work relating to cellular oxidation without
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mentioning his name.</p>
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<p>Lactate
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formation from glucose is increased when anything interferes with respiratory
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energy production, but lactate, through a variety of mechanisms, can
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itself suppress cellular respiration. (This has been called the Crabtree
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effect.) Lactate can also inhibit its own formation, slowing glycolysis.
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In the healthy cell, the mitochondrion keeps glycolysis working by consuming
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pyruvate and electrons (or "hydrogens") from NADH, keeping
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the cell highly oxidized, with a ratio of NAD+/NADH of about 200. When
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the mitochondrion's ability to consume pyruvate and NADH is limited,
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the pyruvate itself accepts the hydrogen from NADH, forming lactic acid
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and NAD+ in the process. As long as lactate leaves the cell as fast
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as it forms, glycolysis will provide ATP to allow the cell to survive.
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Oxygen and pyruvate are normally "electron sinks," regenerating
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the NAD+ needed to produce energy from glucose.</p>
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<p>But
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if too much lactate is present, slowing glycolytic production of ATP,
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the cell with defective respiration will die unless an alternative electron
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sink is available. The synthesis of fatty acids is such a sink, if electrons
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(hydrogens) can be transferred from NADH to NADP+, forming NADPH, which
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is the reducing substance required for turning carbohydrates and pyruvate
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and amino acids into fats. </p>
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<p>This
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transfer can be activated by the transhydrogenase enzymes in the mitochondria,
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and also by interactions of some dehydrogenase enzymes.</p>
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<p>The
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enzyme, fatty acid synthase (FAS), normally active in the liver and
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fat cells and in the estrogen-stimulated uterus, is highly active in
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cancers, and its activity is an inverse indicator of prognosis.
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Inhibiting it can cause cancer cells to die, so the pharmaceutical industry
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is looking for drugs that can safely inhibit it. This enzyme is closely
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associated with the rate of cell proliferation, and its activity is
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increased by both cortisol and estrogen.</p>
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<p>The
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first biochemical event when a cell responds to estrogen is the synthesis
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of fat. Estrogen can activate transhydrogenases, and early studies of
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estrogen's biological effects provided considerable evidence that its
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actions were the result of the steroid molecule's direct participation
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in hydrogen transfers, oxidations and reductions. E.V. Jensen's claim
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that estrogen acts only through a "receptor protein" which
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activated gene transcription was based on his experimental evidence
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indicating that estrogen doesn't participate in oxidation and reduction
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processes in the uterus, but subsequently his claim has turned out to
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be false.</p>
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<p>Glycolysis
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is very inefficient for producing usable energy compared to the respiratory
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metabolism of the mitochondria, and when lactate is carried to the liver,
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its conversion to glucose adds to the energy drain on the organism. </p>
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<p>The
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hypoglycemia and related events resulting from accelerated glycolysis
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provide a stimulus for increased activity of the adaptive hormones,
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including cortisol. Cortisol helps to maintain blood sugar by increasing
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the conversion of protein to amino acids, and mobilizing free fatty
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acids from fat stores. The free fatty acids inhibit the use of glucose,
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so the stress metabolism relies largely on the consumption of amino
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acids. This increases the formation of ammonia, yet the combination
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of glycolysis and fat oxidation provides less carbon dioxide, which
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is needed for the conversion of ammonia to urea. Ammonia stimulates
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the formation of lactate, while carbon dioxide inhibits it.</p>
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<p>Starving
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an animal with a tumor increases the stress hormones, providing free
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fatty acids and amino acids, and accelerates the tumor's growth (Sauer
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and Dauchy, 1987); it's impossible to "starve a tumor," by
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the methods often used. Preventing the excessive breakdown of protein
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and reducing the release of fatty acids from fat cells would probably
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cause many cancer cells to die, despite the availability of glucose,
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because of lactate's toxic effects, combined with the energy deficit
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caused by the respiratory defect that causes their aerobic glycolysis.
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Recently, the intrinsically high rate of cell death in tumors has been
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recognized. The tumor is maintained and enlarged by the recruitment
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of "stem cells." These cells normally would repair or regenerate
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the tissue, but under the existing metabolic conditions, they fail to
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differentiate properly.</p>
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<p>The
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extracellular matrix in the tumor is abnormal, as well as the metabolites
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and signal substances being produced there, and the new cells fail to
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receive the instructions needed to restore the normal functions to the
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damaged tissue. These abnormal conditions can cause abnormal differentiation,
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and this cellular state is likely to involve chemical modification of
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proteins, including remodeling of the chromosomes through acetylation
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of the histones (Alam, et al., 2008; Suuronen, et al., 2006). The protein-protective
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effects of carbon dioxide are replaced by the protein-damaging effects
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of lactate and its metabolites.</p>
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<p>The
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ability of lactic acid to displace carbon dioxide is probably involved
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in its effects on the blood clotting system. It contributes to disseminated
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intravascular coagulation and consumption coagulopathy, and increases
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the tendency of red cells to aggregate, forming "blood sludge,"
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and makes red cells more rigid, increasing the viscosity of blood and
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impairing circulation in the small vessels. (Schmid-Schönbein, 1981;
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Kobayashi, et al., 2001; Martin, et al., 2002; Yamazaki, et al., 2006.)</p>
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<p>The
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features of the stress metabolism include increases of stress hormones,
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lactate, ammonia, free fatty acids, and fat synthesis, and a decrease
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in carbon dioxide. Factors that lower the stress hormones, increase
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carbon dioxide, and help to lower the circulating free fatty acids,
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lactate, and ammonia, include vitamin B1 (to increase CO2 and reduce
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lactate), niacinamide (to reduce free fatty acids), sugar (to reduce
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cortisol, adrenaline, and free fatty acids), salt (to lower adrenaline),
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thyroid hormone (to increase CO2). Vitamins D, K, B6 and biotin are
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also closely involved with carbon dioxide metabolism. Biotin deficiency
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can cause aerobic glycolysis with increased fat synthesis (Marshall,
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et al., 1976). </p>
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<p>A
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protein deficiency, possibly by increasing cortisol, is likely to contribute
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to increased FAS and fat synthesis (Bannister, et al., 1983), but the
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dietary protein shouldn't provide an excess of tryptophan, because of
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tryptophan's role as serotonin precursor--serotonin increases inflammation
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and glycolysis (Koren-Schwartzer, et al., 1994). </p>
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<p>Incidental
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stresses, such as strenuous exercise combined with fasting (e.g., running
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or working before eating breakfast) not only directly trigger the production
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of lactate and ammonia, they also are likely to increase the absorption
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of bacterial endotoxin from the intestine. Endotoxin is a ubiquitous
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and chronic stressor. It increases lactate and nitric oxide, poisoning
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mitochondrial respiration, precipitating the secretion of the adaptive
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stress hormones, which don't always fully repair the cellular damage.</p>
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<p>Aspirin
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protects cells in many ways, interrupting excitotoxic processes by blocking
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nitric oxide and prostaglandins, and consequently it inhibits cell proliferation,
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and in some cases inhibits glycolysis, but the fact that it can inhibit
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FAS (Beynen, et al., 1982) is very important in understanding its role
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in cancer.</p>
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<p>There
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are several specific signals produced by lactate that can promote growth
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and other features of cancer, and it happens that aspirin antagonizes
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those: HIF, NF-kappaB, the kinase cascades, cyclin D1, and heme oxygenase. </p>
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<p>Lactate
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and inflammation promote each other in a vicious cycle (Kawauchi, et
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al., 2008).</p>
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<p>The
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toxic mechanism of bacterial endotoxin (lipopolysaccharide) involves
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inappropriate stimulation (Wang and White, 1999) of cells, followed
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by inflammation and mitochondrial inhibition. The stimulation seems
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to be a direct "biophysical" action on cells, causing them
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to take up water (Minutoli, et al., 2008), which is especially interesting,
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since estrogen's immediate excitatory effect causes cells to take up
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water.</p>
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<p>Hypoosmolarity
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itself is excitatory and anabolic. It stimulates lipolysis and fat oxidation
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(Keller, et al. 2003), and osmotic swelling stimulates glycolysis and
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inhibits mitochondrial respiration (Levko, et al., 2000). Endotoxin
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causes hyponatremia (Tyler, et al., 1994), and a hypertonic salt solution
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is protective, lactate solutions are harmful. Other stresses and inflammations
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also cause hyponatremia.</p>
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<p>One
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of the effects of endotoxin that leads to prolonged cellular excitation
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is its inhibition of the glucuronidation system (Bánhegyi, et al.,
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1995), since this inhibition allows excitatory estrogen to accumulate.</p>
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<p>In
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women and rats, antibiotics were found to cause blood levels of estrogen
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and cortisol to decrease, while progesterone increased. This effect
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apparently resulted from the liver's increased ability to inactivate
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estrogen and to maintain blood sugar when the endotoxin stress was decreased.</p>
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<p>Now
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that hog farmers' use of antibiotics to stimulate growth has been discouraged,
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they have sought vegetables that have a natural antibiotic effect, reducing
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the formation and absorption of the intestinal toxins. The human diet
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can be similarly adjusted, to minimize the production and absorption
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of the bacterial toxins. </p>
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<p>In
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2007, two Canadian researchers announced that they were investigating
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the drug dichloroacetate, which blocks glycolysis, stopping the production
|
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of lactic acid, as a cancer treatment, with success. The drug (dichloroacetate)
|
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has toxic side effects, but it is useful in several other conditions
|
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involving over-production of lactic acid. Other drugs that inhibit glycolysis
|
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have also shown anticancer effects in animals, but are in themselves
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very toxic. On the theoretical level, it would be better to inhibit
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only aerobic glycolysis, rather than inhibiting enzymes that are essential
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for all glycolysis.</p>
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<p>Since
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endotoxemia can produce aerobic glycolysis in an otherwise healthy person
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(Bundgaard, et al., 2003), a minimally "Warburgian" approach--i.e,,
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a merely reasonable approach--would involve minimizing the absorption
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of endotoxin. Inhibiting bacterial growth, while optimizing intestinal
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resistance, would have no harmful side effects. Preventing excessive
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sympathetic nervous activity and maintaining the intestine's energy
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production can be achieved by optimizing hormones and nutrition. Something
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as simple as a grated carrot with salt and vinegar can produce major
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changes in bowel health, reducing endotoxin absorption, and restoring
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constructive hormonal functions.</p>
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<p>Medical
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tradition and inertia make it unlikely that the connection between cancer
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and bowel toxins will be recognized by the mainstream of medicine and
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|
governemt. In another article I will describe some of the recent history
|
|
relating to this issue. </p>
|
|
<p>It's
|
|
nice that some cancer researchers are now remembering Warburg, but unfortunately
|
|
they are usually just fitting the fact of cancer's aerobic glycolysis
|
|
into the genetic mutant cell paradigm, thinking of the respiratory defect
|
|
as just another opportunity for killing the evil deviant cancer cell,
|
|
rather than looking for the causes of the respiratory defect. Warburg,
|
|
Koch, and Szent-Gyorgyi had a comprehensive view of biology, in which
|
|
the aerobic production of lactate, resulting from a respiratory defect,
|
|
itself was functonally related to the nature of cancer. </p>
|
|
<p>A
|
|
focus on correcting the respiratory defect would be relevant for all
|
|
of the diseases and conditions (including heart disease, diabetes, dementia)
|
|
involving inflammation and inappropriate excitation, not just for cancer.
|
|
</p>
|
|
<h2>References</h2>
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in lactate content, reflecting stimulation of glycolysis. The enzyme's
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the Warburg hypothesis and provide metabolic markers of cancer prognosis.</strong>
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Cell Biol. 2008 May;10(5):611-8. <strong>p53 regulates glucose metabolism
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through an IKK-NF-kappaB pathway and inhibits cell transformation.</strong>
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Kawauchi K, Araki K, Tobiume K, Tanaka N. "Cancer cells use aerobic
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glycolysis preferentially for energy provision and this metabolic change
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is important for tumour growth. Here, we have found <strong>a link between
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|
the tumour suppressor p53, the transcription factor NF-kappaB and glycolysis." </strong>
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"Taken together, <strong>these data indicate that p53 restricts activation
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|
of the IKK-NF-kappaB pathway through suppression of glycolysis.</strong>
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These results suggest that a positive-feedback loop exists, whereby
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|
glycolysis drives IKK-NF-kappaB activation, and that hyperactivation
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of this loop by loss of p53 is important in oncogene-induced cell transformation."</p>
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</p>
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</small>
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