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