Healing Through the Restoration of Krebs Cycle Chemistry | Majid Ali MD
HURT HUMAN HABITAT AND ENERGY DEFICIT
—Healing Through the Restoration of Krebs Cycle Chemistry
Human energy deficit states are the consequences of a “hurt” human habitat. The central mechanism of energy deficit is disrupted oxygen homeostasis.
The energy state of an amoeba cannot be dissociated from the energy state of its habitat. A mouse’s energetics are far more complex, however the relationship between the mouse’s cellular energetics and its habitat is the same. And so is the case of humans and their habitat. In this column, I offer some reflections on the relationship between energetics and habitat, and explain my view with a thought experiment.
Human energy deficit is a pandemic now. Regardless of the diagnostic rubric one prefers—chronic fatigue syndrome, fibromyalgia, environmental sensitivity, polymyalgia, post-chemo fatigue, post-traumatic stress syndrome—the story is the same from Lahore to Louisville, Madrid to Moscow, and Honduras to Sydney. Energy deficit, then, can be properly viewed only as a global human habitat problem. Since, adenosine triphosphate (ATP) is the currency of cellular energetics, a study of human energy deficit is essentially a study of the impact of habitat disruption on ATP generation, essentially through Krebs cycle chemistry.1-7 (Information about specific inhibitors of ATPase is included after reference #6.)
(ATP synthase is the enzyme responsible for ATP synthesis. It is also called complex V of the energy-producing electron transfer chain in mitochondria. ATP synthase is observed by electron microscopy as 8nm spheres on the surface of coupling membranes, such as that of the mitochondrion. The synthase has two components: largely extramembranous segment called F1 and intrinsic membrane sector called Fo. There are several well-known inhibitors and/or blockers of the F1 and Fo components of ATP synthase. For example, azide, used as a bacteriostatic agent, is one of the F1 inhibitors. Some others include complex organic molecules, such as aurovertins; the peptide efrapeptin, and tentoxin). Energy transfer inhibitors include oligomycin, venturicidin, and dicyclohexyl carbodiimide (DCCD). These inhibitors bind Fo and block proton transfer and thus inhibit synthesis of ATP. It is noteworthy that F1 is not only involved in ATP generation but also in ATP hydrolysis under certain condition, a revealing example of nature’s preoccupation with complementarity and contrariety at the foundational levels of cellular energetics. I might add here that some ATP synthase inhibitors also block ATP hydrolysis by F1, when it is assembled into a F1 Fo complex.
To examine the link between a habitat and its inhabitants’ impaired Krebs cycle chemistry, I propose the following thought experiment: We put 100 mice in a large cage and add to their drinking water a mixture of inhibitors of ATP synthase mentioned above. In addition, we add to their chow a mixture of compounds which are known to induce uncoupling proteins that further impede mitochondrial electron transfer chain.8-11 A solution of doxycycline (2 mg/mL) and sucrose, for example, is known to induce expression of uncoupling proteins and consequent uncoupling of respiration and oxidative phosphorylation.11 Finally, the cage is not cleaned for the duration of the experiment. With appropriated situated TV cameras, we continuously record the effect of that fundamental rupture of their Krebs cycle biochemistry on their health. We will observe that within days some mice will become tired and listless. Some mice will walk with stiff legs. Some of the rodents will lose fur, others will develop skin infections. Some animals will become ill with diverse inflammatory, infectious, and autoimmune disorders involving the various organ-systems of the mice. With passing days, some mice will show sign of impaired thyroid, adrenal, and pancreatic function. Undoubtedly, the disruptions of mitochondrial function and clogged Krebs cycle chemistry will also adversely effect the pituitary, hypothalamic, and neurotransmitter function of many mice. By varying the compositions of the concoctions used for ATP synthase inhibition and doxycycline-inducible of uncoupling proteins, we can create conditions that set the stage for carcinogenesis. I might point out that this thought experiment is, in reality, a compendium of observations made in various animal models with ATP synthase inhibitors and compounds that uncouple respiration from oxidative phosphorylation.
The point of the above thought experiment: It is not useful to focus on signs and symptoms developed by mice in the cage—or disease that merely represent varying combinations of those symptoms—when what is killing the mice is inhibitors of their cellular energetics in their toxic habitat. I use the word toxic in the larger rubric of habitat. Unique patterns of genetic susceptibilities in individual mice determine the patterns of symptom-complexes, but the underlying problem is the same: toxic habitat. In this model, the mice problems caused by microbial species are secondary.
Now I return to the opening two sentences of this column: Human energy deficit states are caused by hurt human habitat. The central mechanism of energy deficit is disrupted oxygen homeostasis. The true nature of the suffering of people with paralyzing fatigue, persistent tissue pain, and disabling disorders of mood, memory, and mentation cannot be understood, nor ameliorated, except through an understanding of the relationship between the toxicity of the human habitat and disruptions of the Krebs cycle chemistry. This was my message in The Canary and Chronic Fatigue (1994).12 Clinicians do not serve their tired and sick patients well when they focus on a virus in one month and a yeast in the next, on the thyroid deficiency at one time and the adrenal weakness at another, on the leaky bowel in one season and the toxic liver in the next. We now live in a “Lyme-obsessed” era. I ask how did anyone ever managed to stay healthy with the Borrelia borgdorferi in the body during the first half of the last century before the spirochaete was identified? Clearly, then no one called Lyme disease as the “disease of the new century,” nor were people given antibiotics for years to cure Lyme disease. The answer is simple: That was the pre-pesticide, pre-antibiotic, pre-toxic-mind era, and the human habitat had not been viciously violated yet.
Pattern of Impaired Krebs Cycle Biochemistry Indicating a Multi-Level Disruption
In Dysoxygenosis and Oxystatic Therapies, the third volume of The Principles and Practice of Integrative Medicine (2001),13 I discussed at length the disorders of cellular energetics. The crucial point here is that the data strongly suggest the existence of multiple metabolic blocks, most pronounced in the earlier steps of the cycle of the Krebs cycle biochemistry.In the panel A of Figure 1, I summarize the findings in one study of the disruption of Krebs cycle chemistry in 236 patients.14 To support my view of the existence of multiple metabolic blocks in the Krebs cycle, in panel B of the figure I schematically draw an analogy of five water reservoirs (indicated by letters R), each draining into the reservoir below it. If the outflow of those reservoirs is dammed—by, let’s say, beavers — the amount of water held in the reservoir on the top level will increase, and that in the lower reservoirs will diminish to increasing degrees. Note that among the increased 24-hour urinary excretions of the Krebs cycle metabolites(panel A), citric acid accounted for the largest number of cases (196), followed by aconitic acid (26), succinic acid (40), and fumaric acid (1). No increase was seen at the oxaloacetic acid level, indicating maximal impairment of the cycle at steps before the last one.
Figure 1. Data Showing Disruption of the Krebs Cycle Chemistry In 236 Patients Is Shown (Panel A), Indicating the Maximal Impairment of Mitochondria Dysfunction Involving the Early Steps of the Krebs Cycle. In panel B, An Analogy of Five Water Reservoirs (indicated by Letters Rs) Is Drawn to Illustrate the Effects of Multiple Metabolic Defects in the Krebs Cycle (See Text for Explanation).
Acetyl Co A
Oxaloacetic acid (0) Citric acid (196)
Fumaric acid (1) Aconitic acid (26)
The Sun-Soil Model of Restoration of the Krebs Cycle
In Integrative Nutritional Medicine, the fifth volume of The Principles and Practice of Integrative Medicine (2003),15 I presented the Sun-Soil Model of restoration of oxygen homeostasis and the Krebs cycle chemistry. Simply stated, in this model the base trio of the bowel (the entire alimentary tract), blood, and liver ecosystems are represented by the soil-root unit of a rose-bush. The middle trio of the thyroid, adrenals, and pancreas are equivalent to the branches, and the top trio of the hormones, neurotransmitters, and the limbic system constitutes the leaves and flowers. Finally, the sun symbolizes spiritual dynamics of healing. Integrative medicine is not “protocol medicine,” in which patients are prescribed drugs according to predetermined protocols. Each individual with chronic energy deficit state requires an individualized program . In that light, below I present my clinical priorities for the Sun-Soil Model:
The Bowel Ecosystem
The main issues concerning the alimentary tract are:
- oral pathology
- decreased tone of the stomach (usually with reduced acidity, with or without reflux)
- enzyme deficiencies
- diminished bowel tone (with or without prolonged transit time)
- overgrowth of oxyphobic microbial species.16
In the management of those concerns, I liberally prescribe:
- hydrochloric acid and enzyme supplementation;
- antifungal herbs (echinacea, goldenseal, astragalus, burdock root, others) and drugs (Nystatin and others, in biweekly rotation);
- antiparasitic herbs (artemesia, walnut hull, red cloves, and others, even when parasitic tests are negative)
- oral magnesium and potassium
- psyllium and herbal laxatives, if necessary
- high-frequency, low-intensity rebounding (preferably with a trampoline with a safety bar).
In general, I do not use antiviral drugs for viral activation states (which almost always coexist), nor do I advise immediate removal of dental mercury amalgams (I have seen too many serious and persisting clinical setbacks with that).
See our article: Immune Boosting Herbs
The Liver Ecosystem
The main issues concerning the liver are:
- compromised p-450 and other enzymatic detox systems which neutralize endogenous and exogenous toxins
- fatty change in the liver
- biliary and gall bladder dysfunctions.
In the management of those concerns, I liberally prescribe:
- live-protective herbs (milk thistle, dandelion, black radish, and others)
- castor oil liver pack
- lemon juice/maple syrup liver/kidney flushes
See our article: Liver Flush
The Blood Ecosystem
The main issues concerning the blood ecosystem are:
- acidosis and oxidosis
- insufficiency of proteolytic activity in the circulating blood due to excessive clotting
- oxidative coagulopathy (and oxidative lymphopathy)
- vasospasm (due to hyperadrenergic state and oxidative coagulopathy17)
- subclinical vasculitis (with or without the tell-tale vascular skin lesions).
To manage those matters, I liberally prescribe:
- blood cleansers (turmeric powder, ginger, garlic, green tea
- blood alkalizers (cilantro, chlorophyll, chlorella, calcium citrate, and others)
- hydrogen peroxide foot soaks;
- intravenous hydrogen peroxide infusions.
The main issues concerning the thyroid are:
- subclinical hypothyroidism (nearly always present)
- low body temperature
- subclinical iodine deficiency.
To address issues, I prescribe natural thyroid (Armour, Westhyroid, or others) in small doses of 30 mg with small 15 mg increments in nearly all patients who are seven pounds or more in excess of their optimal weight. Needless to say, I closely monitor thyroid function with laboratory tests. In addition, I administer Lugol’s iodine in small doses (5 drops containing 37.5 mg taken in four ounces of water) for periods of four to eight weeks.
See our article: Thyroid Remedies for Cold Hands and Feet
The main issues concerning the adrenal glands are
- subclinical hypofunction of adrenals (as determined by the measurement of 24-hour excretion of adrenal cortical hormones and urinary catecholamine excretion
- Adrenergic hypervigilence caused by chronic anger and resentment associated with chronic energy deficit.
To address issues, I prescribe small doses of hydrocortisone acetate (beginning with 2.5 mg twice daily and increasing it to 15 or 20 mg according to the clinical response of the patient. Other options include DHEA, pregnenolone, androstenedione, schizandra, and Siberian ginseng.
See our article: Creating Conditions for Adrenal Regeneration
The main issues concerning the pancreas are
- inadequate production of pancreatic digestive enzymes, especially of the proteolytic variety
- the insulin dysfunction with roller-coasters which trigger adrenaline and neurotransmitter roller coasters.
To address issues the hypoglycemic/hyperglycemic shifts, I prescribe 2 tablespoons of protein powder breakfast (with 1-2 tablespoons of lecithin and freshly ground small flaxseed each taken with 6 to 12 ounces of vegetable juices.) I also recommend proteolytic enzymes of plant- and animal-derived sources, to be taken between meals.
See our article: Reversing Diabetes By Regenerating Pancreas
The Hormonal and Neurotransmitter Systems
Chronic energy deficit states create difficulties of mood, memory, and mentation by several mechanism, including:
- sadness and depression caused by unrelenting suffering;
- unmasking of pre-existing mood disorders and depression
- accentuation of functional deficits of estrogens, progestins, and androgens (the last-mentioned being especially needed for vaginal dryness and lack of libido)
- sleep disorders.18
To address those concerns, I liberally prescribe methylsufonylmethane (MSM), A-adenosylmethionine (SAMe), St. John’s wort, melatonin, and when necessary, pharmaceutical support for sleep. As for growth hormone, I have found it to be helpful in less than one-third of my patients. The prohibitive cost of this therapy also makes it difficult to use for most patients.
The crucial issue in physical exercise during the recovery process in the chronic energey deficit states is the need for high-frequency,low-intensity exercise which does not add to the problem of rapid build-up of Krebs cycle metabolites in the cells. I recommend incremental exercise with the following three criteria:
- the individual should not experience any negative sensations (muscle soreness, increased fatigue, or mentation difficulties) after 10 minutes of finishing exercise
- the individual should not experience any negative sensations after six hours of finishing exercise
- the individual should not experience any negative sensations after 24 hours of finishing exercise.For detailed specific guidelines, I refer the readers to my book Ghoraa and Limbic Exercise19 on the subject.
The Sun-Soil Model and the Cell Membrane Dynamics
The long-term clinical benefits observed with the applications of the Sun-Soil Model, as described above, can be explained in many ways. Chronic infectious processes are commonly observed in subjects with chronic energy deficit states, and the frequency and intensity of such infections is drastically reduced with the successful use of this model. One can explain such benefits in many ways. Here, I include brief comments about the restoration of cell membrane functionalities with the Sun-Soil Model as one of the primary mechanisms underlying clinical . In 1987, I published Leaky Cell Membrane Disorder,20 a monograph in which I focused on clinical consequences of oxidative cell membrane injury with resulting derangements of ion- gating and ligand-related signalling. The relationship between cell membrane integrity and host defenses against microbial invaders are seldom, if ever, duly considered in clinical medicine. In reality, receptors belonging to the family of pattern recognition receptors (PRRs) play crucial roles in innate immunity.21 The two notable subgroups in this context are the TLRs (Toll-related receptors) and the recently characterized NLRs (NOD-like receptors). The former are essentially transmembrane proteins whose ligand-binding domains point to the extracellular milieu, while the latter (NOD1 and NOD2) are essentially intracellular receptors with transmembrane segments. PRRs (including TLRs and NLRs) are essential for the activation of well known mediators of inflammatory and healing responses, such as NF-êB and mitogen-activated protein kinases (MAKPs).
In closing, chronic energy deficit states are caused by cumulative stresses on the cellular energetic system, including mitochondrial dysfunction, impairment of Krebs cycle chemistry, uncoupling of respiration and oxidative phosphorylation, oxidative coagulopathy, oxidative lymphopathy, and oxidative dysautonomia. These stresses might originally arise from chemical insults, functional nutritional deficits, infectious processes, and chronic anger. However, once established the impairment of Krebs cycle chemistry feeds upon itself, and affects all micro-ecologic cellular and macro-ecologic tissue-organ systems of the body. Thus, the corrective plan of action has to be broad and all-encompassing.
1. Ali M. Spontaneity of Oxidation in Nature and Aging, (monograph). Teaneck, NJ, 1983.
2. Ali M: Darwin, fatigue, and fibromyalgia.J Integrative Medicine 1999;3:5-10.
3. Ali M: Darwin, oxidosis, dysoxygenosis, and integration. J Integrative Medicine 1999;3:11-16.
4. Ali M: Fibromyalgia: an oxidative-dysoxygenative disorder (ODD). J Integrative Medicine 1999; 3:17- 37.
5. Ali Recent advances in integrative allergy care. Current Opinion in Otolaryngology & Head and Neck Surgery 2000;8:260-266.
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7. Harris DA. Bioenergetic at a Glance. 1995. Oxford. Blackwell Science. pages 72-86.
8. Allayee H, Gharalpour A, Lusis AJ. Using mice to dissect genetic factors in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2003;23:1501-1509.
9. Santerre, R. F., Nicolosi, R. J. & Smith, S. C. Respiratory control in preatherosclerotic susceptible and resistant pigeon aortas. Exp. Mol. Pathol. 1974.20:397-406.
10. Dröge, W. Free radicals in the physiological control of cell function. Physiol. Rev. 2002;82:47-95.
11. Bernal-Mizrachi C, Gates AC, Weng, et al. Vascular respiratory uncoupling increases blood pressure and atherosclerosis. Nature. 2005;435:502-506.
12. Ali M: The Canary and Chronic Fatigue (2nd ed). Denville, New Jersey, Life Span Books 1995.
13. Ali M. The Principles and Practice of Integrative Medicine Volume III: Dysoxygenosis and Oxystatic Therapies. New York. Canary 21 Press. 1999. 2nd edition 2005.
14. Ali M. Respiratory-to-Fermentative (RTF) Shift in ATP Production in Chronic Energy Deficit States. Townsend Letter for Doctors and Patients. 2004. August/Sept. issue. 64-65.
15. Ali M. The Principles and Practice of Integrative Medicine Volume V: Integrative Nutritional Medicine: Nutrition Seen Through the Prism of Oxygen Homeostasis. New York. Canary 21 Press. 1999. 2nd edition 2005.
16. Ali M: Oxidative regression to primordial cellular ecology. J Integrative Medicine 1998; 2:4-55.
17. Ali M. Oxidative coagulopathy in environmental illness. Environmental Management and Health. 2000;11:175-191.
18. Ali M: Amenorrhea, oligomenorrhea, and polymenorrhea in CFS and fibromyalgia are caused by oxidative menstrual dysfunction (OMD-I) J Integrative Medicine 1998; 2:101-124.
19. Ali M: The Ghoraa and Limbic Exercise. Denville, New Jersey, Life Span Books 1993.
20. Ali M. Leaky Cell Membrane Disorder (monograph). Teaneck, NJ, 1987.
Meylan E, Tschopp J, Karin M. Intracellular pattern recognition receptors in the host response. Nature. 2006;442:39-44.
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