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Modification of the NAD+/NADH ratio to mimic Calorie Restriction An Update for 2014 Alan Cash Terra Biological LLC

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Modification of the NAD+/NADH ratio to mimic Calorie Restriction

An Update for 2014

Alan CashTerra Biological LLC

Part 1 – Review of Mechanism of Action:Using Oxaloacetate to increase the NAD+/NADH Ratio

Part 2 - Current Applications of Oxaloacetate as a Nutritional Supplement– Specific Information to support your practice

Part 3- Clinical Trial Update for PossibleFuture applications

Part 4- Patient Profiles that may benefit

Review of Mechanism of Action

2009 Aging CELL“Oxaloacetate Supplementation Increases

Lifespan in C. elegans through an AMPK/ FOXO-dependent pathway”

2009 Open Longevity Science“Oxaloacetic Acid Supplementation Mimics

Calorie Restriction”

2010 Anti-Aging TherapeuticsChapter 6 “Modification of NAD+/NADH”

Benefits: Increases in average and maximal lifespan—

up to a 40% increase is seen in mammals. Decreases in cancer incidence—up to a 55%

decrease. Decreases in neurodegenerative diseases

such as Alzheimer’s and Parkinson’s disease. Complete protection against type II

diabetes. Reduction in cardiovascular risk and, in

particular, atherosclerosis. Reduction in inflammatory diseases, such as

auto-immune type diseases.

NAD+/NADH in calorie restriction, Lifespan Lin 2003, Easlon 2008, Edwards 2013, Lee 2012,

Braidy 2011 NAD+ Salvage human cell lifespan

Van der Veer 2007 NAD+ precursors lifespan

Belenky 2007 AMPK Lifespan

NAD+/NADH AMPK Greer 2007, Rafaeloff-Phail 2004

Mitochondrial NAD+ Cell survival Yang 2007

NAD+/NADH Sarcopenia Pugh, 2013

NAD+/NADH mitochondrial density and Energy Chuang 2013

NAD+ mitochondrial OXPHOS Gomes 2013

NAD+/NADH breast cancer metastasis Santidrian 2013

How to increase the NAD+/NADH Ratio?Calorie Restriction (via glucose starvation)Prolonged Exercise (via Gluconeogenesis)Supplementation with oxaloacetic acid

Oxaloacetate Malate

NADH NAD+

Malate Dehydrogenase

NAD+/NADH Ratio

Delta G = -29.7

Oxaloacetate Supplementationincreases NAD+/NADH ratio by 900%

Krebs, 1968

Malate

OxaloacetateNADH

NAD+

Inner Mitochondrial Membrane

Malate Dehydrogenase

Cytosol Mitochondria

DG -29.7

Oxaloacetate

Malate

NADH

NAD+

Malate Dehydrogenase

DG -29.7

AscorbicAcid

AMPKActivation

Oxaloacetate

DAF-16Transcription

Factor

Life Extension

Cell Membrane

?

?

98% Positive Directional Overlap for genes Changed in common.

OAA

Gene Symbol Gene Title

Affy-matrix Gene

Number

Change in Gene

Expression Calorie

Restricted to Control

Change in Gene

Expression benaGene to

Control Gene function

Foxa1 forkhead 2891 30% Increase 40% Increase

regulation of transcription, DNA-dependent // inferred from electronic annotation

Foxa3 forkhead 13370 100% Increase 70% Increase

cell glucose homeostasis // inferred from mutant phenotype // regulation of transcription, DNA-dependent // inferred from mutant phenotype /// cellular response to starvation // inferred from mutant phenotype

Foxq1 forkhead 6994 110% Increase210%

Increase

regulation of transcription, DNA-dependent // inferred from electronic annotation

Foxq1 forkhead 30006 190% Increase220%

Increase

regulation of transcription, DNA-dependent // inferred from electronic annotation

Applications of Oxaloacetate as a Nutritional Supplement

The Krebs Cycle(Citric Acid Cycle)

OAA effect on Mice

25% increase

Mouse Data:Steve SpindlerUC Riverside

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Clinical Trial– Diabetic PatientsDecrease in Fasting Glucose Levels

Average decrease of 24%

Laboratory ResearchTranslates into Commercial Productwww.benaGene.com

73 year-old European Woman Currently on Anti-Diabetic medicines

Diaprel MR/ (80 mg)- 2 per day – Extended release Gliclazide (80 mg), a once per day diabetic drug

Merckformin (1,000 mg)- 1 per day- (Metformin, Glucophage) – used for Type 2 diabetes

Avandamet- 1 per day- a combination of metformin and rosiglitazone used for diabetes

Fasting glucose levels dropped 23%. Glucose levels after a meal dropped

34.5%, indicating a major improvement in glucose management and glucose tolerance.

Metformin use reduced by 50% during the study.

Results are statistically significant.

20-30% Decrease in Genes that Create & Store Fat29% Reduction in Fat Tissue Mass with OAA Supplementation

Reduced Weight Rebound Due to Lower Gene Expression

After DietCommercial Product

OAA protects mitochondrial DNA in the brainYamamoto 2003

retinal pigmented epithelium (RPE), damaged in age-related macular degeneration (AMD) are protected by zinc and OAAWood 2003

pancreatic islet cells and neurons are protected by OAAChang 2003, Berry 2006

OAA is a powerful anti-oxidantDesagher 1997, O’Donnell-Tormey 1987

10% increase in Muscle Endurance with OAA

AMPK activation as Precursor to Mitochondrial Biosynthesis

*

Imagine what a 10%Increase in EnduranceDoes for competition.

Reduction in Essential Tremor www.TremorStop.com

Clinical Trial Updates for Oxaloacetate as a Potential Drug for Disease Treatment

Potential Support for: Cancer Alzheimer’s Parkinson’s Stroke Epilepsy Diabetes

Animal Data looks good, but still early in the research effort.

These statements have not been evaluated by the FDA. Oxaloacetate is not intended to diagnose, treat, cure or prevent any disease.

Calorie Restriction deceases cancer risk Currently one of the most effective broad-based

methods to reduce cancer risk High NAD+/NADH ratio decreases cancer

Metastasis Santidrian 2013

Oxaloacetic Acid Supplementation prevents Human Lung Cancer cells from reproducing In vitro results Does not affect normal cells Prevents replication of cancer cells by increasing

intercellular debris, but does not kill the cells. Cancer cells did not reproduce after OAA solution

removed for six weeks. Farah 2007

OAA Reduces Glioblastoma Tumor Growth by 50%

Rubin, Inv. New Drugs2012

21 day tumor growth in nude mice. Ruban, Investigative New Drugs 2012

TemozolomideAndOxaloacetate

Rubin, Invest. New Drugs 2012

No tumor cells foundIn Remaining Mice.

After Review, US FDADesignates OxaloacetateAs an “Orphan Drug” for theTreatment of Gliomas.Designation (12-3704)

Medical Foods are a unique category- Allow immediate implementation-Food Additives or GRAS only-Used under Physician Supervision-Must have a Scientific Basis

Case studies indicate that Gliaxal, either alone or in combination with other therapies, stopped tumor growth in 88% of the patients (N = 17)

 Age  Sex  Diagnosis Prior Treatments

Concurrent Treatments

 Gliaxal Duration

 Best Response

 63  M  Anaplastic Oligodendroglioma  Surgery, Radiation and Chemotherapy

 Avastin  3 months  Progressive

 52  M Low-Grade Oligodendroglioma   Surgery  None  8 months  No Growth

 44 F   Anaplastic Astrocytoma  Surgery, Radiation and Chemotherapy

 None  7 months  No Growth

 44  M  Glioblastoma  Surgery, Radiation and Chemotherapy

 Temodar  6 months  No Growth

 44  M  Glioblastoma  Surgery, Radiation and Chemotherapy

 Everolimus, XL184  5 months  Tumor Reduction

 62  M  Glioblastoma  Surgery, Radiation and Chemotherapy

 None  4 months  Progressive

 34  F  Anaplastic Astrocytoma  Surgery, Radiation and Chemotherapy

 Everolimus, XL184  4 months  Tumor Reduction

 26  M  Low-grade Oligodendroglioma  Surgery  None  4 months  No Growth

 62 M   Glioblastoma  Surgery, radiation and Chemotherapy

Temodar   4 months No Growth 

 69  F  Glioblastoma  Surgery, radiation and Chemotherapy

 None  2 months  No Growth

 36 M   Low-Grade Oligodendroglioma   Surgery, Radiation and Chemotherapy

 Temodar  2 months  No Growth

 24  M  Anaplastic Astrocytoma  Surgery Ketogenic Diet  9 months   Tumor Reduction

 44  M  Glioblastoma  Surgery, Radiation and Chemotherapy

 Temodar  2 months  No Growth

 50   M  Glioblastoma  Surgery, Radiation and Chemotherapy

 Nilotinib  1 month  No Growth

 51  M Low-Grade Oligodendroglioma   Surgery, Radiation and Chemotherapy

 Temodar  1 months  No Growth

 51  M  Low-Grade Oligodendroglioma  Surgery  None  1 month  No Growth

 10  F  Anaplastic Astrocytoma  Surgery  Radiation, Temodar

 1 month  No Growth

"My son has an astrocytoma.  With a ketogenic diet and significant nutritional support including Gliaxal Medical Food, the last two MRI's have showed no change and some small amount of shrinkage.  The Oncologist says it is very slow growing tumor and is not gung-ho on any aggressive action.  He said to keep up what we are doing and follow-up MRI in 4 months.  It's been tough trying to keep a 24-year old healthy kid on the program, but he is doing pretty well.  We plan to continue with Gliaxal.  We have used 2 to 10 capsules three times per day with no side effects.  THANK YOU.”

                 Dr. Loren Stockton

Starting a Phase 1 clinical trial in Pediatric Brain Cancer this summer at Rady Children’s Hospital, San Diego

Continuing case studies at UCSD and George Washington University

Substantial Improvement in Quality of Life

Patient QOL Impact Score Improved From

79 to 8

Effective in 54% of patients surveyed (N=13)

In the Effective Group, the average improvement in Quality of Life score was 63%(P < 0.05)

Range of improvement varied between 20% and 90%

Currently in Phase II Clinical Trial, Seehttp://clinicaltrials.gov/ct2/show/NCT01741701

(Pistel, 2012)

(Pistel, 2012)

(Pistel, 2012)

**

(Pistel, 2012)

Alzheimer Model Mice show memory improvements

50% Increase in Short-Term Memory

(Pistel, 2013)

A Clinical Phase 1 trial is beginning with oxaloacetate supplementation and Alzheimer’s disease at the University of Kansas.

Patient Profiles that may receive benefit from oxaloacetate

As a Nutritional Supplement Anti-Aging – General Population Helps to maintain proper glucose function Improves Mitochondrial Function and Density Weight Maintenance

Reduces the “Rebound Effect” After Dieting Increases Endurance & Fights Fatigue

Elderly Patients Fatigued Patients Athletes

Mood swings within PMS Constipation Reduction Glutamate Reduction

As an Experimental Drug Clinical TrialParkinson’s DiseaseGlioblastomaAlzheimer’s Disease2-hydroxyglutaric aciduriaMitochondrial diseaseDiabetes

Necessary for Clinical Trial IRB ApprovalData sent to ClinicalTrials.govPatient Approval Form30-day FDA notification prior to the trial

Alan CashTerra Biological LLCSan Diego, CA [email protected]

Web:www.benaGene.com

www.Gliaxal.com