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

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

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No Disease – Ever!Unlocking The Power of Oxygen

Frank Shallenberger, MD, HMDCarson City, NV

Third Congress, March 2014

“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.

EOxygenLungsHeart

Circulation

Fat Glucose

Hormones, Nutrients, Toxins, Stress

Oxygen Utilization

FreeRadicals

OU

Digestion Thoughts

Organ Function

Hormones Repair

Reproduction

EliminationSenses

OxygenUtilization

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.

• 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.

Published in Townsend Letter

Outline1. 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 UtilizationNothing 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.

• 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.”

Trifunovic A, Wredenberg A, et al.Nature. 2004 May 27;429(6990):417-23.

Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer.

• 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%.

Speakman JR, Talbot DA, et al.Aging Cell. 2004 Jun;3(3):87-95.

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.

Decreased Oxygen UtilizationIs The

Metabolic Equivalentof

Hypoxia

“Functional Hypoxia”

Free Radical Damage is Caused By “Excessive” Radical Activity Secondary to

Decreased Oxygen Utilization

• Decreased oxygen utilization accelerates free radical formation, while exhausting anti- oxidant buffering capacity.

“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

Decreased Free

RadicalBuffering

Increased Free

Radical Formation

MitochondrialDecay

Aging DegenerativeDisease

“Oxidative Damage and Mitochondrial Decay in Aging.”

• “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.

Shigenaga MK, Hagen TM, Ames BN Proc. Natl. Acad. Sci. USA Vol. 91, 10771-78, Nov. 1994

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 Decay in Aging.”

• “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.

Shigenaga MK, Hagen TM, Ames BN Proc. Natl. Acad. Sci. USA Vol. 91, 10771-78, Nov. 1994

“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. 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: 0470111313

Drug-Induced Mitochondrial Dysfunction: An Emerging Model for Idiosyncratic Drug Toxicity

James A. Dykens Pfizer Drug Safety Research & Development,

Sandwich, England

Antivirals Abacavir Didanosine Emtricitabine Entecavir Emtricitabine Lamivudine Nevirapine Telbivudine Tenofovir Tipranavir Stavudine Zalcitabine Zidovudine

DiabetesPioglitazoneRosiglitazoneMetformin

Anti-Cancer Flutamide Dacarbazine Gemtuzumab Methotrexate Pentostatin TamoxifenDaunorubicin Doxorubicin Epirubicin Idarubicin Arsenic Trioxide Cetuximab Denileukin Mitoxantron

Anaesthetic BupivacainePropofol Antiarhythmic Amiodarone (oral)DisopyramideDofetilideIbutilide

HypertensionBosentanBeta-Blocker]Atenolol

AntibioticsIsoniazid Ketoconazole Streptozocin TrovafloxacinTetracycline

NSAIDsCelecoxibDiclofenacDiflunisalEtodolac FenoprofenIbuprofenIndomethacin Ketoprofen Mefenamic acid Meloxicam Naproxen Nabumetone Oxaprozin Piroxicam Salsalate Sulindac Thioridazine Tolmetin

CNSAmphetaminesAtomoxetinDroperidolPergolideDantrolene DivalproexFelbamate Naltrexone Nefazodone ValproicAcid Alper’s

Cholestrol MedsAll of them!

Anti-depressants & Anti-PsycholticsToo many to list!

Mitochondrial Impairment of Drugs Receiving Black Box Warnings

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)

EOxygen

LungsHeart

Circulation

Fat Glucose

T3, Cortisol, DHEA, Nutrients, Toxins

Decreased Oxygen Utilization

FreeRadicalsX

XX

XX

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

Glucose LiverFatStores

Fattyacids

Pyruvate + Lactate

CO2

NAD

Carnitine

PDH (Lipoic, B1)NAD

KrebsCycle

B2, B3, B6, B12,Folic, TMG, Mg,

Catabolic & Anabolic hormonesCO2

3O2+NADH +2H2O +

ATP

ATP

Insulin+ +

TFA’s, CoQ10, B12, folic,Heavy metals, “uncouplers”

A-CoA

Aminos

Triglyc.

-

Cortisol++

Ketones

T3Epin

NAD

NADH

ADPPOOL

NAD

NADH

NADH

LungsCirculation

Coagulation2,3 DPGantacids

Hypervent-ilation

Cardiolipin(Lipoic/carnitine)

FreeRadicals

The Optimum

NAD/NADH Ratio is

700/1

Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease

• “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.”

Lin SJ, Guarente L. Current Opinion in Cell Biology 2003, 15:241–246

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 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.

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 Utilizationis

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

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.

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.

VO2Max

Glucose

Glucose

Glucos

e

Anaerobic Anaerobic

Anaerobic

Healthy Mito-Decay&

Disease

The Stages Of The Aging Process

Fat

FatFatFat

Glucose

Anaerobic

MaxOU

AsymptomaticFunctional symptoms

“Healthy for your age”

MaxATPFat

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.