1. No Disease – Ever! Unlocking The Power of Oxygen
Third Congress, March 2014
No Disease – Ever! Unlocking The Power of Oxygen
Frank Shallenberger, MD, HMD
Carson City, NV

2. “The world belongs to the energetic
“The world belongs to the energetic.” Ralph Waldo Emerson Essayist & poet ( )

3. Resources Bursting With Energy The Type 2 Diabetes Breakthrough
The Principles and Applications of Ozone Therapy

4. 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.

5. 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. 

6. 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

7. 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.

11. 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.

12. 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

13. 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.

14. 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

16. 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.

17. 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.

18. 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.

19. E Oxygen Utilization Fat Glucose Oxygen OU Free Radicals Lungs Heart
Circulation OU
Oxygen
Free
Radicals
Hormones, Nutrients, Toxins, Stress

20. Oxygen Utilization Organ Function Elimination Senses Hormones Repair
Digestion
Thoughts
Reproduction

21. 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.

22. Every single aspect of healthy living exerts its effects by improving oxygen utilization

23. Decreased oxygen utilization only happens in old folks, right. WRONG
Decreased oxygen utilization only happens in old folks, right? WRONG! It commonly starts in young, otherwise healthy people.

24. Published in Townsend Letter
50 Subjects: Randomly selected as they presented to the clinics, 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.

25. 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.

26. Outline
Aging and the diseases of aging are caused primarily by decreased oxygen utilization.
Decreased oxygen utilization leads to the excessive free radicals that result in accelerated aging and disease.
Decreased oxygen utilization is a unifyng principle. It is caused by many factors.
Decreased oxygen utilization exerts its negative effects by decreasing the NAD/NADH ratio.
The key to health is to maximize oxygen utilization by eliminating or decreasing the effect of these factors.

27. 1. Aging and the diseases of aging are caused primarily by decreased oxygen utilization

28. 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.

29. 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!

30. 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: , 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.

31. Premature ageing in mice expressing defective mitochondrial DNA polymerase.
Trifunovic A, Wredenberg A, et al.
Nature May 27;429(6990):
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.”

32. Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer.
Speakman JR, Talbot DA, et al.
Aging Cell 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%.

33. 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 Apr;76(4):

34. Oxygen Utilization and Disease
Patwari P, Lee RT. Thioredoxins, mitochondria, and hypertension. Am J Pathol 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:

35. Oxygen Utilization and Disease
Modica-Napolitano JS, Kulawiec M, et al. Mitochondria and human cancer. Curr Mol Med Feb;7(1):  
Gerbitz KD, Gempel K, Brdiczka D. Mitochondria and diabetes. Genetic, biochemical, and clinical implications of the cellular energy circuit. Diabetes Feb;45(2):

36. Oxygen Utilization and Disease
Biskup S, Moore DJ. Detrimental deletions: mitochondria, aging and Parkinson's disease.Bioessays Oct;28(10):963-7.
 Moreira PI, Cardoso SM, et al. The key role of mitochondria in Alzheimer's disease. J Alzheimers Dis Jul;9(2):

37. Oxygen Utilization and Disease
Tsutsui H. Oxidative stress in heart failure: the role of mitochondria. Intern Med Dec;40(12):
 Marin-Garcia J, Goldenthal MJ. Heart mitochondria signaling pathways: appraisal of an emerging field. J Mol Med Sep;82(9):565-78

38. 2. Decreased oxygen utilization leads to the excessive free radicals that result in accelerated aging and disease.

39. 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.

40. Decreased Oxygen Utilization Is The Metabolic Equivalent of Hypoxia
“Functional Hypoxia”
Decreased Oxygen Utilization Is The Metabolic Equivalent of Hypoxia

41. 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 anti-
oxidant buffering capacity.

42. Decreased Free Radical Increased Free Radical
Oxygen
Utilization
Decreased Free Radical
Buffering
Increased Free Radical
Formation
Mitochondrial
Decay
Degenerative
Disease
Aging

43. “Oxidative Damage and Mitochondrial Decay in Aging.”
Shigenaga MK, Hagen TM, Ames BN Proc. Natl. Acad. Sci. USA
Vol. 91, , 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.

44. Are Free Radicals Bad?

45. “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

46. “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.”

47. “Oxidative Damage and Mitochondrial Decay in Aging.”
Shigenaga MK, Hagen TM, Ames BN Proc. Natl. Acad. Sci. USA
Vol. 91, , 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.

48. “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

49. 3. Decreased oxygen utilization is caused by: Diet, Hormonal Deficiencies, Nutritional Deficiencies, Smoking, Drugs, Toxins, Decreased Circulation, Decreased Lung Function, Inflammation, Stress, Decreased Fitness

50. Diet
Carbs!!!!
GMO?
Low Fiber
Processed foods
Excessive calories

51. Hormone Deficiencies Testosterone Estrogen Progesterone Melatonin
Thyroid
DHEA
Hydrocortisone
Growth hormone

52. 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.

53. 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.

54. 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.

55. 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.

56. Toxins We make them – acid, intestinal toxins
We live in them – heavy metals
We are prescribed them – drugs
We enjoy them – smoking
Measurement
Detoxification

57. “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

58. References
Neustadt J, Pieczenik SR. Medication-induced 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: 

59. Pfizer Drug Safety Research & Development,
Drug-Induced Mitochondrial Dysfunction: An Emerging Model for Idiosyncratic Drug Toxicity
James A. Dykens
Pfizer Drug Safety Research & Development,
Sandwich, England

60. 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!
Anti-depressants & Anti-Psycholtics
Too many to list!
Antivirals
Abacavir
Didanosine
Emtricitabine
Entecavir
Lamivudine
Nevirapine
Telbivudine
Tenofovir
Tipranavir
Stavudine
Zalcitabine
Zidovudine
Diabetes
Pioglitazone
Rosiglitazone
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

61. Decreased Circulation
Atherosclerosis
Nitric oxide – vegetables and exercise
Blood pressure
Decreased fitness
Inflammation

62. 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

63. Inflammation Dark Field Blood Examination Allergies
Adrenal insufficiency
Detoxification
Chronic infections
Anti-inflammatory nutrition

64. 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.

65. 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.

66. “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( )

67. Decreased Oxygen Utilization
Fat
Glucose X X E
Lungs
Heart
Circulation X X
Oxygen
Free
Radicals X
T3, Cortisol, DHEA, Nutrients, Toxins

68. 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

69. 4. Decreased oxygen utilization exerts its negative effects by decreasing the NAD/NADH ratio.
Decreased OU = Decreased NAD/NADH ratio

70. Heavy metals, “uncouplers”+ +
Insulin
Glucose
Fat
Stores
Liver
NAD -
NADH
Aminos T3
Epin
Pyruvate
ATP
+ Lactate + +
NAD
PDH (Lipoic, B1)
CO2
ADP
POOL
Triglyc.
Cortisol
NADH
A-CoA
Ketones
Carnitine
Fatty
acids
NADH
B2, B3, B6, B12,
Folic, TMG, Mg,
Catabolic &
Anabolic hormones
NAD
Krebs
Cycle
CO2
Lungs
Circulation
Coagulation
2,3 DPG
antacids
Hypervent-
ilation
ATP
3O2+NADH H2O +
NAD
Free
Radicals
Cardiolipin
(Lipoic/carnitine)
TFA’s, CoQ10, B12, folic,
Heavy metals, “uncouplers”

71. The Optimum NAD/NADH Ratio is 700/1

72. Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease
Lin SJ, Guarente L.
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.”

73. 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.

74. NAD and Sirtuins Sirtuins are NAD-dependent.
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 lifespan-extending 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.

75. 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.

76. 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.

77. 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!

78. Optimizing Oxygen Utilization is About Optimizing the NAD/NADH Ratio to 700/1

79. 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.

80. 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.

81. 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.

82. 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.

83. Ozone Forms Peroxides
Reacts ionically with double bonds to produce peroxides called ozonides.
Most ozonides are formed from the short chained lipids in cell membranes.
Not identified.
Ozonides are stable for days to weeks, easily penetrate cell membranes, and are selectively reactive.
Once in the cells, these ozonides oxidize NADH to NAD.

85. 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.

86. The Stages Of The Aging Process
VO2
Max
Anaerobic
Anaerobic
Max OU
Glucose
Anaerobic
Anaerobic
Glucose
Max
ATP
Fat
Fat
Glucose
Glucose
Fat
Fat
Fat
Asymptomatic
Functional symptoms
“Healthy for your age”
Mito-Decay
&
Disease
Healthy

87. 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.

88. 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.

89. 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.