Diet, Exercise and Medicine

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Mitochondria and mortality

Ray Peat PhD

Diet, exercise, and medicine, damaging or repairing

respiratory metabolism

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MAIN IDEAS AND CONTEXTS

+ Lactic acid and carbon dioxide have opposing effects. Intense

exercise damages cells in ways that cumulatively impair

metabolism. There is clear evidence that glycolysis, producing

lactic acid from glucose, has toxic effects, suppressing

respiration and killing cells. Within five minutes, exercise

lowers the activity of enzymes that oxidize glucose. Diabetes,

Alzheimer's disease, and general aging involve increased lactic

acid production and accumulated metabolic (mitochondrial)

damage.

+ The products of glycolysis, lactic acid and pyruvic acid,

suppress oxidation of glucose.

+ Adaptation to hypoxia or increased carbon dioxide limits the

formation of lactic acid. Muscles are 50% more efficient in

the adapted state; glucose, which forms more carbon dioxide

than fat does when oxidized, is metabolized more efficiently

than fats, requiring less oxygen. Lactic acidosis, by

suppressing oxidation of glucose, increases oxidation of fats,

further suppressing glucose oxidation.

+ Estrogen is harmful to mitochondria, progesterone is

beneficial.

+ Progesterone's brain-protective and restorative effects involve

mitochondrial actions.

+ Thyroid hormone, palmitic acid, and light activate a crucial

respiratory enzyme, suppressing the formation of lactic acid.

Palmitic acid occurs in coconut oil, and is formed naturally in

animal tissues. Unsaturated oils have the opposite effect.

+ Heart failure, shock, and other problems involving excess

lactic acid can be treated " successfully " by poisoning

glycolysis with dichloroacetic acid, reducing the production

of lactic acid, increasing the oxidation of glucose, and

increasing cellular ATP concentration. Thyroid, vitamin B1,

biotin, etc., do the same.

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Since reading Warburg's publications in the late 1960s and early

70s, and doing my own research on tissue respiration, I have been

convinced that Warbug was on the right track in seeing

mitochondrial respiration as the controlling influence in cell

differentiation, and in seeing cancer as a reversion to a primitive

form of life based on a " respiratory defect. " Harry Rubin's

studies of cells in culture have expanded Warburg's picture of the

process of cancerization, showing that genetic changes occur only

after the cells have been transformed into cancer.

It is now well recognized that defective mitochondrial respiration

is a central factor in diseases of muscles, brain, liver, kidneys,

and other organs. The common view has been that the mitochondrial

defects are produced by genetic defects, that are either inherited

or acquired, and are irreversible.

Mitochondria depend on some genes in the nuclear chromosomes, but

they also contain some genes, and mutations in these specific

mitochondrial genes have been associated with various diseases, and

with aging. Although these aren't the genes that the cancer

establishment has focussed on as " the cause " of cancer, for people

interested in the achievements of Warburg and Rubin, it is

important to know whether mutations in these mitochondrial genes

are the cause of respiratory defects, or whether a respiratory

defect causes the mutations. Recent research seems to show that

physiological problems precede and cause the mutations.

Warburg believed that mitochondria supported specialized cell

functions by concentrating themselves in the places where energy is

needed. This idea has some interesting implications. For example,

when the amount of thyroid hormone is increased, or when the

organism adapts to a high altitude, the number of mitochondria

increases. But in energy deficient states such as diabetes, they

don't. How are these crucial organelles called into existence by

the hormone that increases respiration and energy, and also by the

hypoxic conditions of high altitudes? In both of these conditions,

the availability of oxygen is limiting the ability to produce

energy. In both conditions, carbon dioxide concentration in tissue

is higher, in one case, because thyroid stimulates its production,

in the other, because the Haldane effect limits its loss from the

lungs.

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SOME DEFINITIONS

Glycolysis: The conversion of glucose to lactic acid, providing

some usable energy, but many times less than oxidation provides.

Lactic acid, produced by splitting glucose to pyruvic acid followed

by its reduction, is associated with calcium uptake and nitric

oxide production, depletes energy, contributing to cell death.

Crabtree effect: Inhibition of cellular respiration by an excess

of glucose; excess of glucose promotes calcium uptake by cells.

Pasteur effect: Inhibition of glycolysis (fermen-tation) by oxygen.

Randle effect: The inhibition of the oxidation of glucose by an

excess of fatty acids. This lowers metabolic efficiency. Estrogen

promotes this effect.

Lactated Ringer's solution: A salt solution that has been used to

increase blood volume in treating shock; the lactate was apparently

chosen as a buffer in place of bicarbonate as a matter of

convenience rather than physiology. This solution is toxic, partly

because it contains the form of lactate produced by bacteria, but

our own lactate, at higher concentrations, produces the same sorts

of toxic effect, damaging mitochondria. Estrogenic phytotoxins

damage mitochondria, kill brain cells; tofu is associated with

dementia.

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Could carbon dioxide, a major product of mitochondria, help to call

mitochondria into existence? My answer to this is " yes, " and it

will help to briefly explain how I see mitochondria. Although I

have no hesitancy in accepting that organelles can be exchanged

between species, and that it is conceivable that mitochondria might

have been derived from symbiotic bacteria, I am reluctant to

believe that something happens just because it could happen. For

example, Francis Crick proposed that life on earth originated when

genes arrived here on space dust from some other world. That's a

theoretical possibility, but what's the point? It just avoids

explaining how the highly organized material came into existence

somewhere else, and it probably seriously interfered with the

consideration of the ways life could arise here. Similarly, some

people like to think that mitochondria and chloroplasts were

originally bacteria, that came into symbiosis with another kind of

living material, consisting of nucleus and cytoplasm. Like Crick's

" space germs, " it can be argued that it's possible, but the problem

is that this explanation can stop people from thinking freshly

about the nature of the various organelles, and how they came to

exist. (How did cells originate? How did mitochondria originate?

" Germs. " )

Since I have a view of how cells came to exist, under conditions

that exist on earth, I should consider whether that view doesn't

also reasonably account for their various components. Sidney Fox's

proteinoid microspheres provide a good model for the spontaneous

formation of primitive cells; variations of that idea can account

for the formation of organelles (such as mitochondria and nuclei

within cells, and chromosomes within nuclei). The value of this

idea, of a self-stimulating process in mitochondrial generation, is

that it suggests many ways to test the idea experimentally, and it

suggests explanations for developmental and pathological processes

that otherwise would have no coherent explanation.

Proteinoid microspheres and coacervates form by acquiring molecules

from solution, condensing them into a separate phase, with its own

physical properties. At every phase boundary, there are numerous

physical forces, especially electronic properties, that make each

kind of interface different from other kinds. Small changes of pH,

temperature, of salts and other solutes can alter the interfacial

forces, causing particles to dissolve, or grow, or fragment, or to

move. In the way that carbon dioxide alters the shapes and

electrical affinities of hemoglobin and other proteins, I propose

that it increases the stability of the mitochondrial coacervate,

causing it to " recruit " additional proteins from its external

environment, as well as from its own synthetic machinery, to

enlarge both its structure and its functions.

In the relative absence of carbon dioxide, or excess of alternative

solutes and adsorbents, such as lactic acid, the stability of the

mitochondrial phase would be decreased, and the mitochondria would

be degraded in both structure and function. As the back side of

the idea that carbon dioxide stabilizes and activates mitochondria,

the idea that lactic acid is involved in the degrading of

mitochondria can also be tested experimentally, and it is already

supported by a considerable amount of circumstantial evidence.

This combination of sensitivity to the environment, with a kind of

positive feedback or inertia either upward or downward, corresponds

to what we actually see in mitochondrial physiology and pathology.

The Crabtree effect, which is the suppression of respiration by

glycolysis, is often described as the simple opposite of the

Pasteur effect, in which respiration limits glycolysis to the rate

that allows its product to be consumed oxidatively. But the

Pasteur effect is a normal sort of control system; when the Pasteur

effect fails, as in cancer, there is glycolysis which is relatively

independent of respiration, causing sugar to be consumed

inefficiently. Embryonic tissues sometimes behave in this manner,

leading to the suggestion that glycolysis is closely related to

growth. Unlike the logical Pasteur effect, the Crabtree effect

tends to lower cellular energy and adaptability. Looking at many

situations in which increasing the glucose supply increases lactic

acid production and suppresses respiration, leading to maladaptive

decrease in cellular energy, I have begun thinking of lactic acid

as a toxin. The use of Ringer's lactate solution in medicine has

led many people to assume that lactate must be beneficial, or they

wouldn't put it in the salt solution that is often used in

emergiencies; however, I think its use here, as a buffer, is simply

a convenience, because of the instability of some bicarbonate

solutions.

On the organismic level, it is clear that lactic acid is " the

essence of hyperventilation, " and that it produces edema and

malfunction on a grand scale: The panic reaction, shock lung,

vascular leakiness, brain swelling, and finally multiple organ

failure, all can be traced to an excess of lactic acid, and the

related features of hyperventilated physiology. Otto Warburg

apparently thought of lactate as simply a sign of the respiratory

defect that characterizes cancer. V.S. Shapot at least hinted at

its possible role in turning on the catabolic reactions leading to

cancer cachexia (wasting). I think a good case can be made for

lactate as the cause of the respiratory defect in cancer, just as

it is usually the immediate cause of the respiratory derangement of

hyperventilation on the organismic level.

The Crabtree effect is usually thought of as just something that

happens in tumors, and some tissues that are very active

glycolytically, and some bacteria, when they are given large

amounts of glucose. But when we consider lactate, which is

produced by normal tissues when they are deprived of oxygen or are

disturbed by a stress reaction, the Crabtree effect becomes a very

general thing. The " respiratory defect " that we can see on the

organismic level during hyperventilation, is very similar to the

" systemic Crabtree effect " that happens during stress, in which

respiration is shut down while glycolysis is activated. Since

oxidative metabolism is many times more efficient for producing

energy than glycolysis is, it is maladaptive to shut it down during

stress.

Since the presence of lactate is so commonly considered to be a

normal and adaptive response to stress, the shut-down of

respiration in the presence of lactate is generally considered to

be caused by something else, with lactate being seen as an effect

rather than a cause. Nitric oxide and calcium excess have been

identified as the main endogenous antirespiratory factors in

stress, though free unsaturated fatty acids are clearly involved,

too. However, glycolysis, and the products of glycolysis, lactate

and pyruvate, have been found to have a causal role in the

suppression of respiration; it is both a cause and a consequence of

the respiratory shutdown, though nitric oxide, calcium, and fatty

acids are closely involved.

Since lactic acid is produced by the breakdown of glucose, a high

level of lactate in the blood means that a large amount of sugar is

being consumed; in response, the body mobilizes free fatty acids as

an additional source of energy. An increase of free fatty acids

suppresses the oxidation of glucose. (This is called the Randle

effect, glucose-fatty acid cycle, substrate-competition cycle,

etc.) Women, with higher estrogen and growth hormone, usually have

more free fatty acids than men, and during exercise oxidize a

higher proportion of fatty acids than men do. This fatty acid

exposure " decreases glucose tolerance, " and undoubtedly explains

women's higher incidence of diabetes. While most fatty acids

inhibit the oxidation of glucose without immediately inhibiting

glycolysis, palmitic acid is unusual, in its inhibition of

glycolysis and lactate production without inhibitng oxidation.

I assume that this largely has to do with its important function

in cardiolipin and cytochrome oxidase.

Exercise, like aging, obesity, and diabetes, increases the levels

of circulating free fatty acids and lactate. But ordinary activity

of an integral sort, activates the systems in an organized way,

increasing carbon dioxide and circulation and efficiency.

Different types of exercise have been identified as destructive or

reparative to the mitochondria; " concentric " muscular work is said

to be restorative to the mitochondria. As I understand it, this

means contraction with a load, and relaxation without a load. The

heart's contraction follows this principle, and this could explain

the observation that heart mitochondria don't change in the course

of ordinary aging.

When a person has an accident, or surgery, and goes into shock, the

degree of lactic acidema is recognized as an indicator of the

severity of the problem. Lactated Ringer's solution has been

commonly used to treat these people, to restore their blood

pressure. But when prompt treatment with lactated Ringer's

solution has been compared with no early treatment at all, the

patients who are not " rescuscitated " do better than those who got

the early treatment. And when Ringer's lactate has been compared

with various other solutions, synthetic starch solutions, synthetic

hemoglobin polymer solution, or simply a concentrated solution of

sodium chloride, those who received the lactate solution did least

well. For example, of 8 animals treated with another solution, 8

survived, while among 8 treated with Ringer's lactate, 6 died.

Mitochondrial metabolism is now being seen as the basic problem in

aging and several degenerative diseases. The tendency has been to

see random genetic deterioration as the driving force behind

mitochondrial aging. Genetic repair in mitochondria was assumed

not to occur. However, recently two kinds of genetic repair have

been demonstrated. One in which the DNA strand is repaired, and

another, in which sound mitochondria are " recruited " to replace the

defective, mutated, " old " mitochondria. In ordinary nuclear

chromosomal genes, DNA repair is well known. The other kind of

repair, in which unmutated cells replace the genetically damaged

cells, has been commonly observed in the skin of the face: During

intense sun exposure, mutant cells accumulate; but after a period

in which the skin hasn't been exposed to the damaging radiation,

the skin is made up of healthy " young " cells. In the way that the

skin can be seen to recover from genetic damage, that had been

considered to be permanent and cumulative, simply by avoiding the

damaging factor, mitochondrial aging is coming to be seen as both

avoidable and repairable.

The stressful conditions that physiologically harm mitochondria are

now being seen as the probable cause for the mitochondrial genetic

defects that accumulate with aging. Stressful exercise, which has

been known to cause breakage of the nuclear chromosomes, is now

seen to damage mitochondrial genes, too. Providing energy, while

reducing stress, seems to be all it takes to reverse the

accumulated mitochondrial genetic damage. Fewer mitochondrial

problems will be considered to be inherited, as we develop an

integral view of the ways in which mitochondrial physiology is

disrupted. Palmitic acid, which is a major component of the

cardiolipin which regulates the main respiratory enzyme, becomes

displaced by polyunsaturated fats as aging progresses. Copper

tends to be lost from this same enzyme system, and the state of the

water is altered as the energetic processes change.

While the flow of carbon dioxide moves from the mitochondrion to

the cytoplasm and beyond, tending to remove calcium from the

mitochondrion and cell, the flow of lactate and other organic ions

into the mitochondrion can produce calcium accumulation in the

mitochondrion, during conditions in which carbon dioxide synthesis,

and consequently urea synthesis, are depressed, and other synthetic

processes are changed.

Glycolysis produces both pyruvate and lactate, and excessive

pyruvate produces almost the same inhibitory effect as lactate;

since the Crabtree effect involves nitric oxide and fatty acids as

well as calcium, I think it is reasonable to look for the simplest

sort of explanation, instead of trying to experimentally trace all

the possible interactions of these substances; a simple physical

competition between the products of glycolysis and carbon dioxide,

for the binding sites, such as lysine, that would amount to a phase

change in the mitochondrion. Glucose, and apparently glycolysis,

are required for the production of nitric oxide, as for the

accumulation of calcium, at least in some types of cell, and these

coordinated changes, which lower energy production, could be

produced by a reduction in carbon dioxide, in a physical change

even more basic than the energy level represented by ATP. The use

of Krebs cycle substances in the synthesis of amino acids, and

other products, would decrease the formation of CO2, creating a

situation in which the system would have two possible states, one,

the glycolytic stress state, and the other, the carbon dioxide

producing energy-efficient state.

Besides the frequently discussed interactions of excessively

accumulated iron with the unsaturated fatty acids, producing lipid

peroxides and other toxins, the accumulated calcium very probably

forms some insoluble soaps with the free fatty acids which are

released even from intracellular fats during stress. The growth of

new mitochondria probably occasionally leaves behind such useless

materials, combining soaps, iron, and porphyrins remaining from

damaged respiratory enzymes.

When the background of carbon dioxide is high, circulation and

oxygenation tend to prevent the anaerobic glycolysis that produces

toxic lactic acid, so that a given level of activity will be

harmful or helpful, depending on the level of carbon dioxide being

produced at rest. Preventively, avoiding foods containing lactic

acid, such as yogurt and sauerkraut, would be helpful, since

bacterial lactic acid is much more toxic than the type that we form

under stress. Avoiding the stress-promoting antithyroid

unsaturated oils is extremely important. Their role in diabetes,

cancer, and other age-related and degenerative diseases (and I

think this includes the estrogen-promoted autoimmune diseases) is

well established. Avoiding phytoestrogens and other things that

increase estrogen exposure, such as protein deficiency, is

important, because estrogen causes increased levels of free fatty

acids, increases the tendency to metabolize them at the expense of

glucose metabolism, increases the tissue content of unsaturated

fatty acids, and inhibits thyroid functions. Light promotes

glucose oxidation, and is known to activate the key respiratory

enzyme. Winter sickness (including lethargy and weight gain), and

night stress, have to be included within the idea of the

" respiratory defect, " shifting to the antirespiratory production of

lactic acid, and damaging the mitochondria.

Therapeutically, even powerful toxins that block the glycolytic

enzymes can improve functions in a variety of organic disturbances

" associated with " (caused by) excessive production of lactic acid.

Unfortunately, the toxin that has become standard treatment for

lactic acidosis -- dichloroacetic acid -- is a carcinogen, and

eventually produces liver damage and acidosis. But several

nontoxic therapies can do the same things: Palmitate (formed from

sugar under the influence of thyroid hormone, and found in coconut

oil), vitamin B1, biotin, lipoic acid, carbon dioxide, thyroid,

naloxone, acetazolamide, for example. Progesterone, by blocking

estrogen's disruptive effects on the mitochondria, ranks along with

thyroid and a diet free of polyunsaturate fats, for importance in

mitochondrial maintenance.

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