Tired of being tired?
  by James South MA

According to Dr. Michael Schmidt in his book Tired of Being Tired, chronic fatigue, tiredness and low energy plague millions of people in the Western world. Indeed, fatigue, chronic tiredness and low energy are the most common reasons which lead people to seek medical care. Dr. Schmidt notes that a 1987 survey found that 24% of adults who visit primary care health clinics "always feel tired". (1)

Constant fatigue and low energy are not restricted to those who suffer the relatively uncommon "Chronic Fatigue Syndrome," nor are they direct indicators of any specific disease.  Dr. Schmidt lists a host of factors or conditions associated with chronic fatigue and low vitality: vitamin/mineral insufficiency; food allergy/intolerance; blood sugar disorders; hidden infections; depression; thyroid problems; physical inactivity; poor sleep/insomnia; cancer, heart or lung disease; antibiotic/prescription drug overuse; stress; chemical toxicity... and more! (1)

Yet more people suffering chronic low energy receive thorough medical exams which rule out these conditions and more, and then are told by their physicians that there is nothing medically wrong with them, with the barely (if at all) hidden implication that perhaps "It's all in your head", or that they're just neurotic hypochondriacs.

Fortunately for the "energetically-challenged," scientific research has uncovered a cluster of issues relating to nutrition, cellular energy metabolism, and free radical/antioxidant biochemistry, which offers both explanation and remedy for the modern epidemic of the "low energy blues."

ENERGY: E=ATP

Energy is needed at all levels of our being - from the microscopic to the macroscopic.  At the cellular level, energy is used to make new proteins, to bring nutrients into a cell and expel cellular wastes, to repair damaged DNA, to synthesize neurotransmitters, etc.  At the organ level, the heart uses energy to pump blood, the kidneys use energy to filter wastes while recycling precious nutrients, the brain uses energy to conduct electrical nerve impulses, the lungs use energy to take in oxygen and expel carbon dioxide and so on.  At the level of the whole person, we use energy to walk, run, talk, chop wood, lift objects, work a computer keyboard, ad infinitum. The energy source for all these levels is the same - it is the bio-energy molecule ATP (adenosine triphosphate) the "universal energy currency of the cell." As Mathews and van Holde point out, "The processes of photosynthesis and metabolism of foodstuffs are used mainly to produce ATP.  It is probably no exaggeration to call ATP the single most important substance in bio-chemistry." (2,p.83)  ATP is the energy of life.  Where there is no ATP, there is no life. Where ATP is low, energy is low. It's that simple.

FROM FOOD TO ENERGY

ATP does not come ready-made in the food we eat.  Rather, the trillions of cells which make up the human body must each generate their own ATP from the glucose, fatty acids and amino acids derived from digestion of the carbohydrates, fats and proteins provided by the food we eat. After digestion/absorption by the stomach/small intestine and processing by the liver, molecules of glucose, fatty acids and amino acids are transported through the bloodstream to the trillions of ever-hungry cells waiting to convert these nutrient molecules into the ATP the cells/organs need to power their every activity.

Cells primarily "burn" glucose and fatty acids to make ATP, but amino acids - especially alanine and the branch-chained amino acids - may also be used as fuel during intense exercise, hard physical labor, starvation, or even during periods of low blood sugar between meals.

Once inside the cell, these fuel molecules are processed through three interlocking ATP-energy production cycles. The first cycle is the glycolytic cycle. This nine-step cycle "burns" only glucose, and is driven by enzymes that exist in the cytoplasm of the cell - the gel-like watery fluid between the cell's outer membrane and the nucleus. If the glucose is metabolized in the absence of oxygen (anaerobic glycolysis), then one molecule of glucose generates two molecules of ATP-bioenergy, as well as two molecules of lactic acid - a "waste product" that may cause the "muscle burn" and skin redness associated with intense exercise.

If glucose is "burned" with oxygen (aerobic glycolysis), then one molecule of glucose yields two ATP's, but two "bonus products" are also made that serve as further ATP-producing fuels in the next two ATP-generation cycles: the Kreb's or citric acid cycle and the electron transport chain.

The first "bonus product" is two molecules of NADH - the reduced (energy rich) coenzyme form of vitamin B3, which will make six ATP's when successfully processed through the electron transport chain. The other "aerobic bonus" is pyruvic acid, which can then be converted by the multi-enzyme pyruvate dehydrogenase complex into acetyl coenzyme A, the starting fuel for the Krebs'/citric acid cycle, which in turn feeds the electron transport chain with more NADH , altogether, if every step of the complex, interlocking ATP "tri-cycle" works perfectly (it doesn't always happen), in the presence of adequate oxygen, then one molecule of glucose starting through aerobic glycolysis can ultimately generate 38 ATP molecules. Thus anaerobic glycolysis is only about 5% as energy efficient (2/38) as the combined aerobic glycolysis/citric acid cycle/ETC energy metabolism "tri-cycle."

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MITOCHONDRIA: WHERE THE (ATP) ACTION IS

Mitochondria are tiny, sausage-shaped organelles that exist inside virtually all cells, except for red blood cells. Their number may range from 50-2500 per cell, and they may account for 20% of the cell volume in high-energy cells (brain, heart, liver).

It is inside the mitochondria that both the Kreb's/citric acid cycle and electron transport chain occur. Fatty acids are metabolized inside the matrix, or innermost part of the mitochondria, producing acetyl coenzyme A to feed the Kreb's cycle. The Kreb's cycle enzymes are also found in the matrix. The electron transport chain is a chain of five enzyme complexes embedded in the inner mitochondrial membrane, where NADH and FADH2 (the energy-rich coenzyme form of vitamin B2, produced in the Kreb's cycle) are processed to generate ATP.

Each NADH can yield 3 ATPs, with each FADH2 yielding 2 ATPs]

A phenomenon unique to the mitochondria is the existence of mitochondrial DNA (mtDNA), located inside the matrix. MtDNA encodes for 13 of the proteins that make up the five electron transport chain enzyme complexes, while the DNA of the cell nucleus encodes for about 60 of the proteins that make up the electron transport chain.(3).

Research of the past decade has shown that mtDNA is one of the "Achilles' heels" of ATP energy generation (3,4,5,6) - more on that later.

ACTIVE ENZYMES: THE MITOCHONDRIAL SPARK PLUGS

In order for food-derived fuels to be broken down step-by-step through the glycolytic cycle and mitochondrial citric acid cycle/electron transport chain to yield ATP, they must be processed by enzymes.  Enzymes are catalysts that facilitate and radically speed up these steparise breakdowns. Enzymes are analogous to spark plugs in a gasoline engine. If the fuel were pumped into a gas engine without working spark plugs, no combustion and hence no energy release would occur.  Similarly, if the multiple enzymes involved in the three interlocking ATP cycles are working poorly, ATP will be underproduced or not produced at all. A functional enzyme is called a "holoenzyme". It is composed of two parts - the "apoenzyme" and the "coenzyme". The apoenzyme is a specific protein, with a unique shape and composition that enables it to process a specific biochemical in a specific way. For example, the succinate dehydrogenase apoenzyme, when activated by its appropriate coenzyme, helps convert succinic acid in the Krebs' cycle into the next phase of the cycle - fumaric acid, and simultaneously produces FADH2 as a fuel for the electron transport chain.  With few exceptions, enzymes are ultraspecialists - they act on only one or a few substances, in only one or a few ways.

The coenzyme is the "activator" of the apoenzyme. Without its proper coenzyme, even the most perfectly formed apoenzyme will be inert, and will not do its catalyst job.  And it turns out that coenzymes are always made of the active form of vitamins, or of vitamin-like substances, such as lipoic acid or coenzyme Q10.  A coenzyme form of a vitamin is always more complex than its basic form, the form which we get from food or supplements.  For example, the basic form of vitamin B1 is thiamin, while the coenzyme form is thiamin pyrophosphate (TPP).  The basic form of vitamin B3 is niacin or niacinamide, while the coenzyme form is nicotinamide adenine dinucleotide (NADH).  Coenzymes often have a mineral partner that serves as a "co-activator" of the apoenzyme. For many of the enzymes of the glycolytic cycle and Krebs' cycles, the mineral co-activator is magnesium. (7,p.159)  Once ATP is formed, it is normally complexed with magnesium. (2,p.84)

The vitamins used as coenzymes in the three interlocking ATP cycles are vitamin B1 (thiamin), B2 (riboflavin), B3 (niacin/amide), B5 (pantothenic acid), biotin, and the B vitamin-like substance lipoic acid, as well as Coenzyme Q10. Other vitamins, such as B6 (pyridoxine), B12 (cobalamin) and folic acid are used to transform various amino acids into forms that allow them to be "burned" in the glycolytic and Kreb's cycles (8,pp. 423-427, 463-478)]. 

VITAMIN-COENZYMES: THE LINK BETWEEN FOOD & ENERGY

When a person suffers a severe enough nutritional deficiency of a specific nutrient for a long enough period of time, a classic nutritional deficiency disease will usually result. In east Asia earlier in this century, the vitamin B1-deficiency disease "beriberi" was widespread due to the reliance on polished white rice, low in B1, as the chief foodstuff. In the American South in the late 1800's-early 1900's, the B3 deficiency disease "pellagra" was common due to the low-B3 corn-based diet, with 10,000 people dying from pellagra every year.  During long sailing voyages in the period 1500-1780, often as much as 1/3 to 1/2 of a ship's crew would sicken or perish from scurvy, the vitamin C deficiency disease, due to the lack of C-containing fresh fruits and vegetables in the shipboard diet.

Thanks in part to the government-mandated fortification of basic foodstuffs such as flour and cereals with small amounts of vitamins B1, B2 and B3, and with C added to other foods such as fruit juices, the classic nutritional deficiency diseases are a mostly historical curiosity in the Western world. Western governments, often with the aid of scientific Food and Nutrition Boards, have set RDAs (Recommended Dietary Allowance) for most of the major vitamin and mineral nutrients, and have even required food packaging to provide detailed information on the nutrient levels of various foods, to aid choosing a nutrient-adequate diet. Given the widespread availability of cheap food in the Western world, so that even poor people can easily obtain calorie-adequate diets, it is usually assumed that a dietary/cellular deficiency of key energy-promoting nutrients (such as the B vitamins and magnesium) is rarely, if ever, a cause of inadequate cellular ATP production. Yet an examination of various lines of evidence, both conceptual and scientific, will show that such assumption is dubious at best. To put it simply, the evidence of near-universal absence of classic nutritional deficiency diseases does not equal evidence for a near-universal optimum level (both dietary and cellular) of energy-enhancing nutrients.

The first problem to be considered is the RDAs.  Numerous dietary studies in recent years have shown that most Americans fail to consume the US RDA for various nutrients.  For example, Kant and Block reported in 1990 that "71% of males and 90% of females consumed less than 1980 RDA of vitamin B-6" (9) With regard to the B vitamin folic acid, Subar et al stated in 1989 that "Based on the Recommended Dietary Allowance of 400 mcg/d, our results suggest that folate intake in the United States is low...." (10)

Ironically, the very fact that Americans consume less than the (1980) RDAs has led the Food and Nutrition Board, which sets the RDAs, to lower them in the 1989 RDA revisions, and again in the recent late 1990s RDA revisions.  Thus the 1989 folate RDA was halved to 200mcg/day, a level more in line with the actual average US consumption of folate (10). The 1989 vitamin E RDA was halved from 30 IU to 15 IU, with typical US intakes being 10-15 IU (7-10 mg). (11,p.33)  Yet even the conservative, establishment researcher A.T. Diplock had argued in 1987 in the prestigious journal Free Radical Biology & Medicine that "It appears likely that the present [1980] RDA will prove too low and the evidence suggests that an increase of between three and five-fold [i.e. to 90-150 IU] would be expected to be beneficial...." (12)  The general lowering of (already modest) RDAs in the last two US RDA revisions has been based in part on the question-begging "logic" that since Americans are a basically healthy people, and since they routinely fail to consume the earlier higher RDAs of most nutrients, therefore the new lower RDAs are more appropriate. In a land where over $1 trillion (1/7 of the total national income) is spent annually on "health" - i.e. disease-care; where cancer is one of the leading causes of death of children; where half the adult population is medically obese; where tens of millions suffer diabetes, asthma, allergies, arthritis, ulcers/heartburn, chronic insomnia, depression, alcoholism, drug addiction, vision disorders, etc., to assume that Americans are healthy just because they don't suffer classic nutritional deficiency diseases is rather Alice-in-Wonderland "logic," indeed.

However, there is a deeper conceptual and scientific falseness to the RDAs beyond their recent specious downward revisions. Part of the problem stems from the conceptual framework of the RDAs as such. The 1980 Recommended Dietary Allowances states that "RDA are recommendations for healthy populations. Special needs for nutrients arising from such problems as premature birth, inherited metabolic disorders, infections, chronic diseases and the use of medications require special dietary and therapeutic measures. These conditions are not covered by the RDAs.... The requirement for a nutrient is the minimum intake that will maintain normal function and health.... For certain nutrients, the requirements may be assessed as the amount that will just prevent failure of a specific function or the development of specific deficiency signs - an amount that may differ greatly from that required to maintain maximum [i.e. optimum] body stores," [author's note]. (13, pp.1-3)

With regard to the first statement, since the majority of Western peoples (especially Americans) suffer either chronic diseases such as diabetes, arthritis, asthma, allergies, depression etc or routinely take both over-the-counter and prescription medications, such as aspirin/ibuprofen/acetaminophen, allergy medications, Zantac, Maalox, laxatives, Prozac, heart drugs, cholesterol-lowering statin drugs etc. Then by the National Research Council's own statement the RDAs are irrelevant to their required (for optimum health) nutrient intake.  The second two RDA statements focus on minimum nutrient intake, and on just [i.e. barely] avoiding specific physiologic function failure and/or specific nutritional deficiency symptoms. This makes it clear that the RDAs were never formulated as a guide to maintaining robust, vibrant, high energy, optimal health, but are merely intended to keep a person "healthy" enough to (barely) avoid classical nutritional deficiency diseases like scurvy and pellagra, or to avoid their heart or brain or liver failing today or tomorrow - but who knows about next week or next month?

In 1964 Myron Brin published a classic analysis of the five stages of the development of a vitamin or nutrient deficiency. He illustrated this scheme with reference to vitamin B1. In the first, or preliminary stage, inadequate thiamin availability due to faulty diet, malabsorption or abnormal metabolism leads to a greatly reduced urinary thiamin loss. In the second, or biochemical stage, the activity of a blood cell enzyme - transketolase - for which thiamin is the coenzyme, is significantly reduced; adding thiamine to a blood sample from the developing-deficiency person increases their transketolase activity.  In the third, or physiologic stage, various general symptoms develop, such as lessened appetite, insomnia, increased irritability, and malaise develop. In the fourth, or clinical stage, a constellation of symptoms classically specific to thiamine deficiency disease (beriberi) develops - e.g. intermittent claudication, polyneuritis, bradycardia, peripheral edema, cardiac enlargement and ophthalmoplegia. In the fifth, or anatomical stage, histopathological changes due to cellular structural damage are seen, such as cardiac hypertrophy, degeneration of the granular layer of the cerebellum, and swelling of the microglia. (14)

Although Brin's five-stage deficiency scheme is exemplified with regard to thiamin, it is in principle applicable to any nutrient, as Brin himself notes. Brin's scheme is especially illuminating with regard to the RDAs, since the "just preventing failure of specific functions" or "just preventing specific deficiency signs" criteria of nutrient requirement, which underlies the RDA concept, are only evidenced in the fourth (clinical) and fifth (anatomical) stages of developing nutrient deficiency disease. The first three stages, although they are objectively, empirically measurable and observable phases of a developing nutrient deficiency, do not involve either "specific deficiency signs" or "failure of a specific nutrient-related function."  Furthermore, it should be noted that "malaise," which developed in the third (physiologic) stage of B1 (and which is common to many illnesses and nutrient deficiency diseases), is a general bodily weakness - i.e. a felt experience of low energy and vitality.  This is hardly surprising, given the key roles of coenzyme B1 in the glycolytic and Kreb's cycles and a demonstrable failure of an apoenzyme - transketolase - to be fully saturated with - i.e. activated by - B1, is measurable in the early second (biochemical) stage.

What follows from this is quite simple. The RDA level of nutrients may keep most people out of the severe illness-leading-to-death fourth and fifth nutrient deficiency stages, but RDA nutrient levels cannot be presumed to be adequate to keep one out of the first three stages of "subclinical" deficiency disease, let alone in a more optimal, vibrant, energized state of health.

Drawing upon and extending Brin's work, Dr. Karl Folkers, M.D., Ph.D., the "godfather" of CoQ10 research, developed a methodology to determine a more realistic RDA for vitamin B6, pyridoxine (the official RDA is 2mg), and published his research in 1993. (15)  Folkers noted that 16 years of ongoing biochemical and clinical research had strongly confirmed the existence of a B6 deficiency in carpal tunnel syndrome, and had also shown B6 to be a specific and successful prophylactic and therapy for carpal tunnel syndrome.  Folkers had also discovered an easily measurable enzyme - EGOT (erythrocyte glutamine oxaloacetic transaminase) - whose specific activity (SA) could be correlated both with carpal tunnel syndrome remission and with varying B6-intake levels. Folkers discovered that a maximally B6-saturated EGOT apoenzyme specific activity level is approximately 0.7.  Folkers tested 17 patients who had no overt symptoms of carpal tunnel syndrome (which Folkers and others believe to be a specific B6-deficiency sign) and determined their EGOT SA levels before and after dosages of 2, 25 and 50mg of B6. The initial mean level of EGOT SA was 0.35 +/- 0.06.  After 12 weeks dosage of 2mg B6 (the typical period established for response to B6), the EGOT SA increased to only 0.45 +/- 0.07.  With a dose of 25mg B6, EGOT SA rose to 0.64+/-0.08, but 6 of 13 subjects at that dose had a SA of only 0.5-0.6.  At a dose of 50mg B6 for 7 subjects, every one showed an EGOT SA very close to 0.7, the "ideal" level.  Folkers' research established that even for "well" patients a more realistic B6 RDA is 25-50mg (12-25 times the US RDA), while carpal tunnel syndrome patients may require 100mg or more to achieve the "ideal" EGOT SA and to achieve complete and ongoing symptom remission. (15).

Based upon the previous reasoning, as well as my own clinical experience working with hundreds of fatigue/low energy clients over the past 25 years, as well as the published clinical experience of colleagues such as Robert Crayhon (11) and Dr. Robert Atkins (16), my first and basic recommendation for a "super-energy" regime is the following: 25-150mg of the "basic Bs" - B1, B2, B3, B5, B6; 300-10,000mcg biotin; 100-1,000mcg B12; 400-2,000mcg folic acid. Magnesium, ideally as malate, succinate, aspartate, glycinate, or chloride; 400-800mg daily. Bs to be taken in divided dose with breakfast and lunch; magnesium 100-200mg with each of three meals and at bedtime (magnesium is anti-stress/relaxing, as well as energizing).  Reduce magnesium dose if diarrhea should develop.

THE "METAVITAMIN" METABOLIC ENERGY ENHANCERS

In his 1981 article "Toward a Bio-Energy Supplement," (17) M.F. McCarty provides a persuasive rationale for including what he terms "metavitamins," and which I call "metabolic enhancers," in a comprehensive energy supplement.  The key "metavitamins" are alpha-lipoic acid, carnitine/acetyl l-carnitine, and coenzyme Q10.

All four of these substances are life-critical cellular vitamin-like nutrients, even though they are not, strictly speaking, vitamins.  A vitamin is generally considered to be an organic substance that an organism requires for its normal health and metabolism, in relatively small amounts, and which it cannot make itself, but must get preformed from diet (or supplements).  Yet three classic vitamins - A, D, B3 - can be made within the human body (from beta-carotene, cholesterol and tryptophan, respectively), and are still considered vitamins.  Carnitine, lipoic acid and CoQ10 are all normal dietary constituents, and are absolutely essential for life, yet they are (somewhat arbitrarily) not considered vitamins, since they can be made within the body.

Lipoic acid is an essential part of the enzyme complex that feeds pyruvic acid from the glycolytic cycle into the Kreb's cycle enzyme. (18)  No lipoic acid = no ATP from the Kreb's cycle or electron transport chain; not enough cellular lipoic acid = not enough cellular ATP. Lipoic acid has been in medical use in Germany for decades, both to treat liver diseases and to treat diabetic neuropathy. (17,18,19)  Dr. Lester Packer, a lipoic acid "enthusiast" recommends 50mg twice daily. (19)  I have found 50-100mg twice daily with meals to be an excellent energy aid - I have used it for the past 13 years as a key part of my own energy regimen.

Coenzyme Q10 (CoQ10) is an absolutely energy-critical cellular nutrient. When one molecule of glucose is aerobically metabolized through the glycolytic and Kreb's cycles, only 4 ATPs are directly produced by these cycles. Their main contribution is to send NADH (reduced coenzyme B3) and FADH2 (reduced coenzyme B2) to the electron transport chain, where 5 enzyme complexes use these substances to generate the other 34 ATPs that can arise from "combusting" one molecule of glucose. Complex I (NADH dehydrogenase) uses NADH to pass electrons on to CoQ10.  Complex II (succinate dehydrogenase) uses Kreb's cycle-generated FADH2 to pass electrons on to CoQ10. CoQ10 then passes these electrons to Complex III (cytochrome b).  From there cytochrome c passes the electrons on to Complex IV (cytochrome oxidase), where they combine with oxygen and hydrogen ions to make water.  This electron transport chain enzyme complex activity in turn operates Complex V - ATP synthase, which produces the actual ATP that powers everything we do. (20, pp.66-73)  CoQ10 is obviously the "linch-pin" of the electron transport chain, uniting 3 of the 5 enzyme complexes that ultimately make most of our ATP.

Like many other substances produced by the body, levels of CoQ10 decline with age.  Although CoQ10 is found in food such as salmon, liver and other organ meats, it is nearly impossible to get enough CoQ10 from diet alone, especially in our later years.... Dr. Karl Folkers was the first to suggest that the age-related decline in CoQ10 was a contributing factor to... Cancer, heart disease and Alzheimer's disease.... Since CoQ10 is involved in the production of ATP, it made sense that a decline in the production of this antioxidant would disrupt the body's energy-producing system.... In fact, heart muscle biopsies in patients with various heart diseases showed a CoQ10 deficiency in 50 to 75 percent of all cases". (19, pp.94-96)

Idebenone is a synthetic derivative of CoQ10.  Various studies have shown that Idebenone may function even better as an antioxidant and electron transport chain agent than CoQ10. Thus Latini et al report that "A stimulation of respiratory and phosphorylating activity [i.e. ATP production] has been observed in mitochondria prepared from rats treated with Idebenone.... Our experiments suggest that Idebenone, by increasing brain adenosine levels and nucleotide phosphorylation [i.e. ATP production], may be beneficial in ischemic [low oxygen] disorders". (21)  Wieland et al note that "idebenone, a synthetic CoQ10 derivative, is known to have greater antioxidative capacity than CoQ10, which is not restricted to the reduced form of the molecule [only reduced - i.e. non-oxidized - CoQ10 is an effective antioxidant]. In our experiments, idebenone was far more effective than CoQ10 in preventing oxygen radical-mediated damage to microsome lipids and proteins.... It is noteworthy that after oral administration idebenone can preserve the electron transfer activity in the terminal respiratory chain [ETC] of mitochondria, thus stimulating ATP formation.  debenone is non-toxic to humans and has been used successfully in the therapy of patients suffering from a variety of neurological disorders". (22)  "Idebenone significantly suppressed by about 10% the non-respiratory oxygen consumption [i.e. oxygen which generates toxic free radicals rather than ATP]..., which [is] closely associated with non-enzymatic [free radical] reactions such as lipid peroxidation, membrane lysis and swelling of mitochondria.  Thus, idebenone may contribute to stimulate the net ATP formation by the well-coupling of electron and energy transfer, and by the reduction of [toxic] non-respiratory oxygen consumption in cerebral metabolism." (23) Thus a combination of CoQ10 (50-100mg) and Idebenone (45-90mg), taken with fat-containing meals, may provide effective enhancement to the electron transport chain production of ATP.

Carnitine is a B vitamin-like substance the body makes from the aminos lysine and methionine, with the help of vitamins B3, B6 and C. (24) Carnitine is generally found in the same animal foods that are rich in CoQ10.  Carnitine is the only substance that will serve to transport fats (fatty acids) into the mitochondrial matrix, where they can be converted to acetyl coenzyme A and "plugged in" to the Kreb's cycle to produce ATP. Without a carnitine "escort," the fatty acids cannot pass through the inner mitochondrial membrane. (24)  Carnitine also functions to couple pyruvic acid from the glycolytic cycle to the Kreb's cycle, especially in conditions of maximal physical exertion, thus enhancing ATP production when it is most in demand. (25)

Carnitine expert Brian Leibovitz in a 1993 review article wrote that "...studies of endurance athletes have revealed that subjects given 2g of carnitine (twice daily) had higher levels of electron transport system [ETC] components. Specifically, carnitine supplements increased the activities of NADH, cytochrome c reductase, succinate cytochrome c reductase, and cytochrome oxidase.... Carnitine supplements are also important in maintaining optimal health. Available evidence strongly suggests that one cannot achieve optimal health without taking carnitine supplements" (24).

Acetyl l-carnitine is carnitine's "alter ego."  Carnitine and Acetyl l-carnitine can interconvert to each other under some circumstances. (25)  In their excellent review "Oxidative damage and mitochondrial decay in aging" Shigenaga, Hagen and Ames state that "A rapidly growing body of evidence suggests that the apparent age-related deficits in mitochondrial function can be slowed or reversed by Acetyl l-carnitine, a normal component of the inner mitochondrial membrane that serves as a precursor from acetyl-CoA as well as the neurotransmitter acetylcholine.... Acetyl l-carnitine has been shown to reverse the age-related decrease in the levels of mitochondrial membrane phospholipid cardiolipin and the activity of the phosphate carrier in rat heart mitochondria.... Acetyl l-carnitine's function in the aging brain is supported by its ability to create a shift in ATP production from [anaerobic] glycolytic pathways to mitochondria.... It is plausible that Acetyl l-carnitine can increase the metabolic efficiency [of ATP production] of compromised sub-population of mitochondria and cause a redistribution of the metabolic workload, resulting in increased cellular efficiency...." (3)

The various performance studies cited by Leibovitz typically use 2-4 grams per day of carnitine. (24)  Robert Crayhon in his book The Carnitine Miracle recommends 1-4 grams daily.  He writes that "Acetyl l-carnitine in particular appears to be important in maximizing carbohydrate metabolism.... Older adults benefit greatly from carnitine during exercise.  Carnitine levels decline with age.... For these and many other reasons, carnitine is a must supplement for those over forty who want to maximize their energy and exercise endurance" (11,pp.70-71)

For those who wish to gain both the energy enhancing and mitochondrial rejuvenation effects of carnitine/Acetyl l-carnitine, a regimen of 1 gram carnitine plus 500mg Acetyl l-carnitine twice daily will probably be a reasonable dose.

NADH: THE ENERGIZING COENZYME

As discussed earlier, NADH is the key molecule used in the electron transport chain to generate ATP.  Both the aerobic glycolytic and Kreb's cycle generate NADH that the electron transport chain then "converts" to ATP through its five enzyme assemblies.  It is almost literally true to say that, given a healthy glycolytic system and mitochondrial citric acid cycle/electron transport chain, NADH=ATP.  It is then a major breakthrough in energy supplementation that has occurred in the 1990's. The first stabilized, absorbable NADH supplement was developed by George Birkmayer, M.D., Ph.D., in 1993.  Birkmayer has used his oral NADH successfully in a published open-label trial as medication in 205 patients suffering from depression (of which fatigue is a common symptom). (26)  Birkmayer has also successfully used a daily 5mg NADH dose in both an open-label trial with 470 Parkinson patients, as well as with 60 Parkinson patients at a German clinic in a double blind trial. (26)  In a 1995 study conducted with competitive-level cyclists and long-distance runners using 5mg NADH daily, a significant range of performance improvements was found, including increased oxygen capacity, decreased reaction time, and greater mental activity and alertness. (26)  In a recent study performed with a European soccer team, players were given 5mg NADH for one month.  Blood levels of L-dopa and noradrenaline were increased, and vigilance, alertness, concentration, and stress capacity improved. (26)  Birkmayer points out that "A deficiency of NADH will result in an energy deficit at the cellular level, the symptom of which is fatigue.... The more NADH a cell has available, the more [ATP] energy it can produce.  Unfortunately, the level of NADH in our body declines with aging and so do the NADH-dependent enzymes, in particular those for energy production". (26)  A daily dose of 5-10mg NADH, taken upon arising on an empty stomach, should be a key part of any serious energy-enhancement program.

ATP: THE ULTIMATE ENERGY SUPPLEMENT?

In his 1981 bio-energy supplement article, McCarty points out that various nucleosides (adenosine, inosine) and nucleotides (ATP, inosine monophosphate) have been used clinically in Europe for decades. Adenosine and ATP have been the preferred German nucleoside/tides. They have been used to reduce angina pain and lower/eliminate nitoglycerin requirements in angina heart patients, and to improve psychological status in cerebral atherosclerosis patients. (17)  "Although all tissues require [adenosine] nucleotides for an energy source (ATP)..., not all tissues have an optimal capacity for de novo nucleotide production. Indeed it appears that many tissues have an absolute or partial dependence on an external source.  If they are to function optimally.... most cell membranes possess transport mechanisms enabling the transfer of nucleosides (the non-phosphorylated form of nucleotides) from the extracellular space [i.e. blood] to the cytosol, where these nucleosides can then be phosphorylated to nucleotides [e.g. AMP, ADP, ATP] by special kinases.... Hepatocyte [liver cell] ATP levels can indeed be substantially raised by adenosine." (17)  McCarty notes that nucleotides such as ATP are quickly converted into nucleosides by blood phosphatase enzymes, when given by injection or sublingually. Nucleosides are digested when swallowed.  But since cells can absorb blood-carried adenosine and convert it to AMP and ADP, the precursors of ATP and sublingual ATP supplements promise a "short-cut" way to quickly raise cellular ATP levels. Indeed, when AMP and ADP levels build up inside cells, this serves as a signal to activate mitochondrial ATP production via the electron transport chain, using the ADP as substrate for ATP. (2,pp.83-85)  That is why the 1975 paper by Lund et al was able to report a 3-fold increase in ATP and adenosine nucleotides in liver cells (in vitro) 60 minutes after adding 0.5mM of adenosine. (27)

In the various German studies McCarty reported on, modest doses of adenosine (12mg intramuscularly 3 times weekly, plus 2-3mg sublingually per day) brought significant clinical benefit. Thus taking one - three 10mg sublingual ATP tabs daily may prove an effective way to boost cellular ATP levels, especially when combined with previously discussed energy-enhancing measures.

FREE RADICALS: MITOCHONDRIA'S WORST NIGHTMARE

So far this article has focused on "offensive" ways to boost ATP energy levels.  However, it pays to "play defense" as well, due to the unique susceptibility of mitochondria to free radical damage.

"Oxidants [free radicals] are produced continuously at a high rate as a by-product of aerobic metabolism. These oxidants include superoxide..., H2O2 [hydrogen peroxide], and hydroxyl radicals... (the same oxidants produced by radiation) and possibly singlet oxygen.... They damage cellular macromolecules, including DNA, protein and lipid.... Mitochondria constitute the greatest source of oxidants.... Cross-links of inner mitochondrial membrane proteins by oxidants, or reactive aldehydes generated from lipid peroxidation, may also result in increased [superoxide] and hydrogen peroxide production, thus further increasing the damage that can lead to mitochondrial dysfunction....

Studies in mammalian cell culture show that oxidative stress can adversely affect the activity of key mitochondrial enzymes and subsequently lead to a decline in ATP production.... Oxidant-induced damage to inner mitochondrial membrane proteins can lead to increased leakage of [superoxide] and hydrogen peroxide that may cause [mitochondrial] DNA mutations," (3)

It thus turns out that by increasing mitochondrial ATP production, we are increasing our risk of mitochondrial oxidative/free radical damage, since "a small percentage of electrons leak away from the main stream of the mitochondrial respiratory chain [electron transport chain],..." (28)  And superoxide begat hydrogen peroxide and hydrogen peroxide begat hydroxyl radicals, and hydroxyl radicals begat mitochondrial mayhem!

Thus it is essential to any serious energy-enhancement program to provide a suitable range of antioxidants to quench the electron transport chain-produced free radicals before they can spread and do serious damage to mitochondrial DNA, proteins and lipids - the very substances which make up our mitochondria.

It is important not to rely on just one or two "pet favorite" antioxidants, such as vitamin C or vitamin E, for several reasons.  Some antioxidants (e.g. vitamin C) work best in the watery portions of cells and tissues, while others (e.g. vitamin E) work best in the lipid-rich membranes of cells, mitochondria, ribsomes, etc.  Also, different antioxidants quench different free radicals - vitamin E (tocopherol) quenches singlet oxygen and polyunsaturated fatty acid radicals, while vitamin C (ascorbate) neutralizes hydroxyl and superoxide radicals. (29, p.48)

Another important aspect of antioxidants is their ability to regenerate each other.  When tocopherol quenches a free radical, it itself becomes a (weak) radical - the tocopheryl quinone radical.  But fortunately ascorbate can regenerate tocopheryl radical back to tocopherol for reuse.  But the ascorbate becomes oxidized into dehydroascorbic acid (DHA).

Fortunately along comes glutathione to reconvert DHA back to C; but now glutathione is oxidized.  Lipoic acid, in its reduced from DHLA, can then regenerate oxidized glutathione. (18)   And NADH can regenerate oxidized lipoic acid. (18)

CONCLUSIONS

Lester Packer, one of the world's foremost free radical/antioxidant researchers, has discovered a network of 5 chief antioxidants which mutually reinforce and regenerate each other.  They are lipoic acid, vitamin E, vitamin C, CoQ10, and glutathione. (19)  Birkmayer notes that NADH is the most powerful antioxidant of all, in addition to being the chief fuel for ATP production. (26)

Thus three of the chief ATP-enhancers - CoQ10, lipoic acid, and NADH - are also three of the key mitochondria-protecting antioxidants.  And as noted earlier, Idebenone is an even more effective CoQ10-like antioxidant than CoQ10 itself.  Packer has also reported that lipoic acid supplements can boost cellular GSH levels "an astounding 30%" (19, p.35).

Thus, by adding 100-400 IU vitamin E as mixed tocopherols or d-alpha tocopheryl succinate (taken with a fat-containing meal) and 250-500mg vitamin C (ascorbic acid or magnesium ascorbate) three or four times daily to the previously described ATP-enhancement regimen, one has safely "covered all the bases" in preventing the very mitochondrial damage that might otherwise ensue from successfully increasing ATP-production through energy-enhancement supplements.

The energy-supplement program described in this article is intended for "reasonably healthy" people.  Those suffering any serious illness, especially liver, kidney, or intestinal disease, may need to modify and/or use it under medical supervision.

THE ENERGY PROGRAM AT A GLANCE

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