Third Congress, March 2014 No Disease – Ever! Unlocking The Power of Oxygen Frank Shallenberger, MD, HMD Carson City, NV “The world belongs to the energetic.” Ralph Waldo Emerson Essayist & poet (1803 - 1882) Resources • Bursting With Energy • The Type 2 Diabetes Breakthrough • The Principles and Applications of Ozone Therapy • www.antiagingmedicine.com No Disease-Ever! • Oxygen is the most important nutrient that we take in. But just because we take it in does not mean that we are using it efficiently. • Oxygen Utilization (OU) is the term I coined to refer to how efficiently our body processes oxygen. • The most important factor determining your risk of disease and rate of aging is oxygen utilization. • I have patented and developed a system for measuring oxygen utilization which I have been using for over ten years. No Disease-Ever! • In that time I have not seen one case of cancer or any other disease in a person with optimal oxygen utilization. • Nor have I ever seen any disease develop in a person with optimal oxygen utilization no matter what their age. • This is a fantastic observation, and suggests that anyone who is able to maintain optimum oxygen utilization during their lifetime will be immune to disease across the board. Measuring Oxygen Utilization • FDA approved pulmonary gas analyzer. • Computer driven exercise ergometer. • Computer software to sort and analyze the breath by breath data. • Test takes about 45 minutes. • Completely safe • Athletes – VO2 max Bio-Energy Testing® • A software system uses the data to calculate oxygen utilization based upon how much oxygen is consumed and how much carbon dioxide is produced at rest and during exercise. • Oxygen Utilization is a function of how much oxygen is consumed relative to carbon dioxide produced. • Other measurements: Metabolic Rate, Fat Burning Rate, Resting Fat Metabolism, Heart Function, Lung Function, Functional Strength, Exercise Data, Diet Data. The Cost of Being Sick • Boston Globe: “Retired couples may need $240,000 for health care”. By Mark Jewell. The Associated Press, May 9, 2012 • “Couples who retire this year can expect to spend an average of $240,000 on out-of-pocket medical expenses before they die.” • Life expectancy of 85 for women and 82 for men. • These expenses are above and beyond what Medicare and insurance pays. • And they don’t take into account dental expenses or long term care which could easily add up to thousands more. The Cost of Being Well • • • • • • • • Testing, Supplements, and hormones = $135/month Exercise = $2000 lifetime Food = $0.00 Detoxification = $1000/year Circulation - $200/year $2,820/year per person $56,400 per woman and 47,940 per man Total = $104,340 Can It Really Be Done? • There are an estimated 80,000 people in the United States who are more than 100 years old. • Virtually all of these people have been completely free of disease all their lives. • I have patients in their 80’s who have the oxygen utilization of 35 year olds. Can It Really Be Done? • Because of genetics, not everyone will be able to have optimal oxygen utilization. • But everyone is able to significantly decrease their risk by improving their oxygen utilization. • In an ideal world everyone would have their oxygen utilization measured every 1-2 years. • This lecture will summarize what needs to be done in order to optimize oxygen utilization Mitochondrial Facts • Metabolically active cells contain thousands of mitochondria, which make up ∼40% of the entire cell. There are said to be 10 million billion mitochondria in an adult human (i.e. ∼10% of our body weight). • Mitochondria are not static. According to how you live and the balance of your hormones they are in constant movement within cells, and are constantly changing in size, number and mass. Mitochondrial Facts • Mitochondria divide during mitosis, providing daughter cells with a normal complement of mitochondria. Mitochondria also proliferate during weight training and aerobic exercise. • The number of mitochondria is controlled by T3, which specifically induces mitochondrial division • You get your mitochondria from your mom. Mitochondrial Facts • Genetic forms of obesity including diabetes have defective mitochondrial activity. • This defect leads to a higher ratio of weight gain to food intake. • Experimental evidence indicates that increasing mitochondrial activity in these patients will cure them. Oxygen Utilization Fat Oxygen Lungs Heart Circulation Glucose OU E Free Radicals Hormones, Nutrients, Toxins, Stress Organ Function Elimination Hormones Senses Oxygen Utilization Digestion Repair Thoughts Reproduction What Is Health? • • • • Not the absence of symptoms. Not the absence of disease. Not the absence of abnormal tests. Not the absence of anything – health is the presence of something – Optimum Oxygen Utilization. Every single aspect of healthy living exerts its effects by improving oxygen utilization Decreased oxygen utilization only happens in old folks, right? WRONG! It commonly starts in young, otherwise healthy people. Published in Townsend Letter • 50 Subjects: Randomly selected as they presented to the clinics, 20-40 y/o, asymptomatic, “health conscious”, Carson City, Los Angeles, Grand Junction, and Singapore. • 54% (27) had normal oxygen utilization. • 46% (23) had decreased oxygen utilization. Published in Townsend Letter • 36% (18) had < 90% of predicted oxygen utilization. • 26% (13) had < 80% of predicted oxygen utilization. • 12% (6) had < 60% of predicted oxygen utilization, and fell within the diagnostic category of severe dysfunction. Outline 1. Aging and the diseases of aging are caused primarily by decreased oxygen utilization. 2. Decreased oxygen utilization leads to the excessive free radicals that result in accelerated aging and disease. 3. Decreased oxygen utilization is a unifyng principle. It is caused by many factors. 4. Decreased oxygen utilization exerts its negative effects by decreasing the NAD/NADH ratio. 5. The key to health is to maximize oxygen utilization by eliminating or decreasing the effect of these factors. 1. Aging and the diseases of aging are caused primarily by decreased oxygen utilization Oxygen – The Forgotten Nutrient • The most critical nutrient. • It’s not what you take in, it’s what you utilize. • The difference between you at 20 and you at 70 is your level of oxygen utilization. Aging and Oxygen Utilization Nothing is as consistent and as predictable as the gradual, linear decline in oxygen utilization seen in all aging populations. It starts early! Meta-analysis of the age associated decline in maximal aerobic capacity in men: relation to training status. • Wilson & Tanaka, Am. J. Physiol. Heart Circ. Physiol. Vol. 278: 829-834, 2000 • “Maximal aerobic capacity is an independent risk factor for cardiovascular disease, cognitive dysfunction, and all cause mortality.” • Even highly trained marathon runners show a decrease in oxygen utilization with age. Unlike all of the other parameters of aging, it cannot be trained away. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Trifunovic A, Wredenberg A, et al. Nature. 2004 May 27;429(6990):417-23. • Mice are genetically altered to develop defective oxygen utilization over their lifespan. • Significantly reduced lifespan. • Premature onset of age-related disorders such as lean body mass loss, alopecia, kyphosis, anemia, osteoporosis, reduced fertility, and cardiomegaly. • “These results provide a causative link between decreased oxygen utilization and aging.” Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer. Speakman JR, Talbot DA, et al. Aging Cell. 2004 Jun;3(3):87-95. • Examined a group of mice and measured their resting oxygen utilization. Then they simply noted how long they lived. • All mice were treated the same. The only differences were their natural genetic differences in oxygen utilization. • Mice in the top 25% of oxygen utilization lived 36% longer than mice in the low 25%. Oxygen Utilization and Disease • Varanasi SS, Francis RM, et al. Mitochondrial DNA deletion associated oxidative stress and severe male osteoporosis. Osteoporos Int. 1999;10(2):143-9. • Liang FQ, Godley BF. Oxidative stress-induced mitochondrial DNA damage in human retinal pigment epithelial cells: a possible mechanism for RPE aging and age-related macular degeneration. Exp Eye Res. 2003 Apr;76(4):397-403. Oxygen Utilization and Disease • Patwari P, Lee RT. Thioredoxins, mitochondria, and hypertension. Am J Pathol. 2007 Mar;170(3):805-8. • Eerola E, Pulkki K, et al. Abnormal mitochondria in cultured synovial fibroblasts in rheumatoid and reactive arthritis? Br J Rheumatol. 1988;27 Suppl 2:128-31. Oxygen Utilization and Disease • Modica-Napolitano JS, Kulawiec M, et al. Mitochondria and human cancer. Curr Mol Med. 2007 Feb;7(1):121-31. • Gerbitz KD, Gempel K, Brdiczka D. Mitochondria and diabetes. Genetic, biochemical, and clinical implications of the cellular energy circuit. Diabetes. 1996 Feb;45(2):113-26. Oxygen Utilization and Disease • Biskup S, Moore DJ. Detrimental deletions: mitochondria, aging and Parkinson's disease.Bioessays. 2006 Oct;28(10):963-7. • Moreira PI, Cardoso SM, et al. The key role of mitochondria in Alzheimer's disease. J Alzheimers Dis. 2006 Jul;9(2):101-10. Oxygen Utilization and Disease • Tsutsui H. Oxidative stress in heart failure: the role of mitochondria. Intern Med. 2001 Dec;40(12):1177-82. • Marin-Garcia J, Goldenthal MJ. Heart mitochondria signaling pathways: appraisal of an emerging field. J Mol Med. 2004 Sep;82(9):565-78 2. Decreased oxygen utilization leads to the excessive free radicals that result in accelerated aging and disease. Hypoxia • Generates excessive free radicals. • Deprives cells of vital functions including repair mechanisms, membrane polarization, and enzyme synthesis. This includes the synthesis of anti-oxidant enzymes. • Destroys mitochondria. “Functional Hypoxia” Decreased Oxygen Utilization Is The Metabolic Equivalent of Hypoxia Free Radical Damage is Caused By “Excessive” Radical Activity Secondary to Decreased Oxygen Utilization “Decreased oxygen utilization is toxic to the cell by exacerbating free radical generation in membranes housing electron transfer assemblies.” Antioxidant Adaptation Levine & Kidd • Decreased oxygen utilization accelerates free radical formation, while exhausting antioxidant buffering capacity. Decreased Oxygen Utilization Decreased Free Radical Buffering Increased Free Radical Formation Mitochondrial Decay Aging Degenerative Disease “Oxidative Damage and Mitochondrial Decay in Aging.” Shigenaga MK, Hagen TM, Ames BN Proc. Natl. Acad. Sci. USA Vol. 91, 10771-78, Nov. 1994 • “Oxidants generated by mitochondria appear to be the major source of oxidative lesions that accumulate with age.” • “These lesions cause the age related deficits in mitochondrial function which are associated with the generalized physiological decline known as aging.” • These oxidative lesions are caused by reduced oxygen utilization. Are Free Radicals Bad? “The essential requirement for superoxide radical and nitric oxide formation for physiological functioning and healthy aging” Linnane AW, Kios M, Vitetta L. Mitochondrion, 2007, Vol. 7, Nos. 1-2 “Contrary to the dogma that superoxide anion and hydrogen peroxide formation are highly deleterious to cell function and healthy aging, we suggest this premise is flawed. Superoxide anion and hydrogen peroxide formation are essential to normal cellular function. Superoxide anion and nitric oxide play an intrinsic role in the regulated ordered turnover of proteins, rather than randomly cause protein damage and inactivation. The proposition that metabolic free radical formation is unequivocally deleterious to cell function is rebutted. The concept that a dietary supplement of high concentrations of small-molecule anti-oxidants is a prophylactic/amelioration therapy for the aging process and age associated diseases is questioned as to its clinical validity.” “Oxidative Damage and Mitochondrial MK, Hagen TM, Ames BN Decay in Aging.” Shigenaga Proc. Natl. Acad. Sci. USA Vol. 91, 10771-78, Nov. 1994 • “Oxidants generated by mitochondria appear to be the major source of oxidative lesions that accumulate with age.” • “These lesions cause the age related deficits in mitochondrial function which are associated with the generalized physiological decline known as aging.” • These oxidative lesions are caused by reduced oxygen utilization. “As I see it every day you do one of two things: build health or produce disease in yourself.” Adelle Davis Author and nutritional pioneer 3. Decreased oxygen utilization is caused by: Diet, Hormonal Deficiencies, Nutritional Deficiencies, Smoking, Drugs, Toxins, Decreased Circulation, Decreased Lung Function, Inflammation, Stress, Decreased Fitness Diet • • • • • Carbs!!!! GMO? Low Fiber Processed foods Excessive calories Hormone Deficiencies • • • • Testosterone Estrogen Progesterone Melatonin • • • • Thyroid DHEA Hydrocortisone Growth hormone Diagnosing Hormone Deficiency • Clinical suspicion: age, the signs and symptoms of each hormone deficiency. • Clinical trial. • Laboratory is usually only useful to monitor therapy: establish baselines and prevent excess. Take Home Message Although replacing deficient hormones will make you feel better, that is not the most important reason to replace them. The most important reason why you need to replace your hormones as they become deficient is because through the process of remodeling, hormones will keep your body young and functional. The Reality Of Hormone Replacement. • Next to exercise and diet, replacing deficient hormones is the most effective way to slow down the aging process, and prevent the diseases of aging. It’s dangerous not to take hormones if your body needs them. • Replacing deficient hormones is just as safe as replacing deficient vitamins, minerals, or other molecules that your body depends on. Nutritional Deficiencies • It’s not what you eat, it’s what you absorb and utilize. • Genetic differences • The aging effect • Very few people of all ages don’t require some supplements. Toxins • We make them – acid, intestinal toxins • We live in them – heavy metals • We are prescribed them – drugs • We enjoy them – smoking • Measurement • Detoxification “One of the first duties of the physician is to educate the masses not to take medicine.” Sir William Osler Physician (1849 – 1919) Considered to be the father of modern medicine References • Neustadt J, Pieczenik SR. Medicationinduced mitochondrial damage and disease. Mol Nutr Food Res. 2008 Jul;52(7):780-8. • Drug-Induced Mitochondrial Dysfunction by James A. Dykens and Yvonne Will (Sep 22, 2008) ISBN-10: 0470111313 Drug-Induced Mitochondrial Dysfunction: An Emerging Model for Idiosyncratic Drug Toxicity James A. Dykens Pfizer Drug Safety Research & Development, Sandwich, England Mitochondrial Impairment of Drugs Receiving Black Box Warnings CNS Amphetamines Atomoxetin Droperidol Pergolide Dantrolene Divalproex Felbamate Naltrexone Nefazodone ValproicAcid Alper’s Cholestrol Meds All of them! Antivirals Abacavir Didanosine Emtricitabine Entecavir Emtricitabine Lamivudine Nevirapine Telbivudine Tenofovir Tipranavir Stavudine Zalcitabine Zidovudine Diabetes Anti-depressants & Pioglitazone Anti-Psycholtics Rosiglitazone Too many to list! Metformin Anti-Cancer Flutamide Dacarbazine Gemtuzumab Methotrexate Pentostatin Tamoxifen Daunorubicin Doxorubicin Epirubicin Idarubicin Arsenic Trioxide Cetuximab Denileukin Mitoxantron Anaesthetic Bupivacaine Propofol Antiarhythmic Amiodarone (oral) Disopyramide Dofetilide Ibutilide Hypertension Bosentan Beta-Blocker] Atenolol Antibiotics Isoniazid Ketoconazole Streptozocin Trovafloxacin Tetracycline NSAIDs Celecoxib Diclofenac Diflunisal Etodolac Fenoprofen Ibuprofen Indomethacin Ketoprofen Mefenamic acid Meloxicam Naproxen Nabumetone Oxaprozin Piroxicam Salsalate Sulindac Thioridazine Tolmetin Decreased Circulation • Atherosclerosis • Nitric oxide – vegetables and exercise • Blood pressure • Decreased fitness • Inflammation Decreased Lung Function • Routine measurement in Bio-Energy Testing • The single most predicable event in aging is a decline in lung function. • Asthma, allergies, infections • Interval training • Nebulized remedies Inflammation • • • • • • Dark Field Blood Examination Allergies Adrenal insufficiency Detoxification Chronic infections Anti-inflammatory nutrition Stress • Pain • Thoughts. IE. Belief Systems • Lifestyle. IE. Stimulants, rest/sleep, sugar, alcohol • Drugs/meds • Neurotransmitters • Adrenal exhaustion – Hans Selye: it’s not the stress per se, it’s how your body holds up under the stress. Decreased Fitness • Number 1! How many times have you heard of someone at any age who was in top physical condition and was diagnosed with a degenerative disease? • Can only be determined with oxygen utilization testing. • Interval training • Properly done – 60 minutes per week. “I am still determined to be cheerful and happy, in whatever situation I may be; for I have also learned from experience that the greater part of our happiness or misery depends upon our dispositions, and not upon our circumstances.” Martha Washington The first first lady(1732 - 1802) Decreased Oxygen Utilization Fat Glucose X X Oxygen Lungs Heart Circulation X X T3, Cortisol, DHEA, Nutrients, Toxins X E Free Radicals Take Home Message The most effective way to maximize the effects of ozone therapy is to combine it with other therapies aimed at eliminating the causes of decreased oxygen utilization 4. Decreased oxygen utilization exerts its negative effects by decreasing the NAD/NADH ratio. Decreased OU = Decreased NAD/NADH ratio + Fat Stores T3 Epin Insulin + Glucose NAD - NADH Aminos + Triglyc. Pyruvate PDH (Lipoic, B1) Cortisol A-CoA Carnitine NAD Lungs Circulation Coagulation 2,3 DPG antacids Hyperventilation Cardiolipin (Lipoic/carnitine) ATP + Lactate NAD + NADH Fatty acids Liver NADH CO2 3O2+NADH Free Radicals Krebs Cycle CO2 ADP POOL Ketones B2, B3, B6, B12, Folic, TMG, Mg, Catabolic & Anabolic hormones NAD +2H2O + ATP TFA’s, CoQ10, B12, folic, Heavy metals, “uncouplers” The Optimum NAD/NADH Ratio is 700/1 Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity Lin SJ, Guarente L. and disease Current Opinion in Cell Biology 2003, 15:241–246 • “NAD has emerged as a putative metabolic regulator of transcription, longevity and several age-associated diseases, including diabetes, cancer and neurodegenerative diseases.” • “Calorie restriction (CR) has been shown to decrease the incidence or delay the onset of some of these diseases.” • “Studies in yeast suggest that CR functions by increasing the NAD level and/or the NAD/NADH ratio.” NAD and Cell Signaling • NAD is rate limiting for the reactions involved in cell signaling and the control of many cell processes in the cell nucleus, including DNA repair, apoptosis, and telomere maintenance. • Another function of NAD in cell signaling is as a precursor of cyclic ADP-ribose, which regulates intracellular calcium channels. NAD and Sirtuins • Sir stands for Silent Information Regulator genes. Sir2 is short for Silent mating type Information Regulatior-2. • Sirtuins are hypothesized to play a key role in an organism's response to stresses (such as heat or starvation) and to be responsible for the lifespanextending effects of calorie restriction. • Sirtuins regulate nuclear transcription. These activities of sirtuins are particularly interesting because of their importance in the regulation of aging. • Sirtuins are NAD-dependent. It’s All About The NAD/NADH Ratio • Oxygen does not directly catalyze cellular reactions. It indirectly catalyzes them using NAD. • When NAD catalyzes a reaction, it is converted to NADH. • Oxygen then recycles the NADH back to NAD. • The problem with decreased oxygen utilization is that is results in decreased levels of NAD combined with increased levels of NADH. It’s All About The NAD/NADH Ratio • As the NAD/NADH ratio decreases, all cellular activity slows down. • Less NADH is produced in the Krebs Cycle. • The decrease in NADH further decreases the ratio because there is no NADH for oxygen to react with and form NAD. • The decreasing NAD/NADH ratio spirals downward in a vicious cycle. We call this aging. • NAD/NADH reactions are reversed in order to normalize the ratio. The Cost of Reversing NAD/NADH Reactions • • • • • Increased lactic acidosis – 19 times! Decreased apoptosis leading to cancer. Increased protein catabolism. Increased intra-cellular free radical stress. Increased extracellular free radical stress via PMOR (plasma membrane oxidoreductase) system. • The genesis of all chronic disease! Optimizing Oxygen Utilization is About Optimizing the NAD/NADH Ratio to 700/1 It Happens Locally • Chronic localized pain is caused by localized areas of chronically decreased oxygen utilization. • Vicious cycle starts with trauma or infection. • Edema, inflammation, hyper-coagulation, and endothelial damage lead to a further localized decrease in oxygen utilization. • Decreased oxygen utilization disables the healing mechanisms, and condition becomes chronic resulting in permanent edema, inflammation, hyper-coagulation, endothelial damage, and pain. 5. The key to health is to maximize oxygen utilization by eliminating or decreasing the effect of these factors, and by therapies focussed on oxidizing NADH to NAD. Oxygenations vs. Oxidation • Oxygen is electron stable and hence does not oxidize. It does not directly oxidize NADH. • Oxygenation simply supplies more oxygen to the tissue. • Oxidation therapies: interval intense exercise, ozone, IV hydrogen peroxide. • Ozone is electron deficient. It acts completely different than oxygen in tissue. Ozone therapy (interval intense exercise and IV hydrogen peroxide) is effective for so many diseases including the infirmities of aging because it normalizes the NAD/NADH ratio. Ozone Forms Peroxides • Reacts ionically with • Ozonides are stable double bonds to for days to weeks, produce peroxides easily penetrate cell called ozonides. membranes, and are selectively reactive. • Most ozonides are formed from the short • Once in the cells, chained lipids in cell these ozonides membranes. oxidize NADH to NAD. • Not identified. Ozone Corrects The NAD/NADH Ratio • Ozone therapy, by oxidizing NADH to NAD corrects the ratio and thus improves oxygen utilization by stimulating increasing levels of NADH: Ozonide + NADH = H2O + NAD + O2 • Oxidation therapies are enhanced with the addition of niacin, riboflavin, MethylB12, B6, folic acid (MTHF?), oral NADH. The Stages Of The Aging Process VO2 Max Anaerobic Anaerobic Max OU Anaerobic Glucose Anaerobic Glucose Max ATP Fat Glucose Fat Glucose Fat Healthy Fat Asymptomatic Functional symptoms “Healthy for your age” Fat Mito-Decay & Disease Mitochondrial rate of decay is determined by one thing: oxygen utilization. So the better your oxygen utilization, the longer and better your life will be. • Your starting point is predetermined and fixed. • What is not inevitable is the rate of decay. • Mitochondrial rate of decay is determined by one thing: oxygen utilization, which is the same thing as your NAD/NADH ratio. • So the better your oxygen utilization, the longer and better your life will be. • If you are sick, your NAD/NADH ratio is decreased. This can be reversed. In Summary • Through the process of oxygen utilization, oxygen is converted to water plus energy (NAD and ATP). • Oxygen is also converted to free radicals (superoxide anion, nitric oxide) which are essential to cellular function. • Even when oxygen utilization is optimally efficient some free radical damage to the mitochondria inevitably occurs as a result of this process. So, the longer you are alive, the more damage your mitochondria will have accumulated. In Summary • As oxygen utilization losses efficiency, the rate of free radical damage escalates, and ultimately leads to mitochondrial decay. • Accumulating mitochondrial decay is the central lesion in the aging process and in degenerative disease. It’s why you can’t live forever. • Your risk for premature aging and degenerative disease is determined by your starting point (mitochondrial genetics) and your rate of mitochondrial decay. • Your starting point is predetermined and fixed. What is not inevitable is the rate of decay.