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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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Presentation on theme: "Modification of the NAD+/NADH ratio to mimic Calorie Restriction An Update for 2014 Alan Cash Terra Biological LLC."— Presentation transcript:

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

2  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 Possible Future applications  Part 4- Patient Profiles that may benefit

3 Review of Mechanism of Action

4  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 Therapeutics Chapter 6 “Modification of NAD+/NADH”

5 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.

6  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

7  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

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

9 Oxaloacetate Supplementation increases NAD+/NADH ratio by 900% Krebs, 1968

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11 98% Positive Directional Overlap for genes Changed in common. OAA

12 Gene SymbolGene Title Affy- matrix Gene Number Change in Gene Expression Calorie Restricted to Control Change in Gene Expression benaGene to ControlGene function Foxa1forkhead289130% Increase40% Increase regulation of transcription, DNA-dependent // inferred from electronic annotation Foxa3forkhead % Increase70% 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 Foxq1forkhead % Increase 210% Increase regulation of transcription, DNA-dependent // inferred from electronic annotation Foxq1forkhead % Increase 220% Increase regulation of transcription, DNA-dependent // inferred from electronic annotation

13 Applications of Oxaloacetate as a Nutritional Supplement

14  The Krebs Cycle (Citric Acid Cycle)

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16 OAA effect on Mice 25% increase

17 Mouse Data: Steve Spindler UC Riverside

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19 Clinical Trial– Diabetic Patients Decrease in Fasting Glucose Levels Average decrease of 24%

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21 Laboratory Research Translates into Commercial Product

22  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

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24  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.

25 20-30% Decrease in Genes that Create & Store Fat 29% Reduction in Fat Tissue Mass with OAA Supplementation

26 Reduced Weight Rebound Due to Lower Gene Expression

27 After Diet Commercial Product

28  OAA protects mitochondrial DNA in the brain Yamamoto 2003  retinal pigmented epithelium (RPE), damaged in age-related macular degeneration (AMD) are protected by zinc and OAA Wood 2003  pancreatic islet cells and neurons are protected by OAA  Chang 2003, Berry 2006  OAA is a powerful anti-oxidant  Desagher 1997, O’Donnell-Tormey 1987

29  10% increase in Muscle Endurance with OAA  AMPK activation as Precursor to Mitochondrial Biosynthesis *

30 Imagine what a 10% Increase in Endurance Does for competition.

31 Reduction in Essential Tremor

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

33  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.

34  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

35 OAA Reduces Glioblastoma Tumor Growth by 50% Rubin, Inv. New Drugs 2012

36 21 day tumor growth in nude mice. Ruban, Investigative New Drugs 2012

37 Temozolomide And Oxaloacetate Rubin, Invest. New Drugs 2012 No tumor cells found In Remaining Mice.

38 After Review, US FDA Designates Oxaloacetate As an “Orphan Drug” for the Treatment of Gliomas. Designation ( )

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

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

41 Age Sex Diagnosis Prior Treatments Concurrent Treatments Gliaxal Duration Best Response 63 M Anaplastic Oligodendroglioma Surgery, Radiation and Chemotherapy Avastin 3 months Progressive 52 MLow-Grade Oligodendroglioma Surgery None 8 months No Growth 44F 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 62M Glioblastoma Surgery, radiation and Chemotherapy Temodar 4 monthsNo Growth 69 F Glioblastoma Surgery, radiation and Chemotherapy None 2 months No Growth 36M Low-Grade Oligodendroglioma Surgery, Radiation and Chemotherapy Temodar 2 months No Growth 24 M Anaplastic Astrocytoma SurgeryKetogenic 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 MLow-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

42  "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

43  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

44 Substantial Improvement in Quality of Life Patient QOL Impact Score Improved From 79 to 8

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46  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, See

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48 (Pistel, 2012)

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51 * *

52 Alzheimer Model Mice show memory improvements 50% Increase in Short-Term Memory (Pistel, 2013)

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

54 Patient Profiles that may receive benefit from oxaloacetate

55  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

56  As an Experimental Drug Clinical Trial  Parkinson’s Disease  Glioblastoma  Alzheimer’s Disease  2-hydroxyglutaric aciduria  Mitochondrial disease  Diabetes  Necessary for Clinical Trial  IRB Approval  Data sent to ClinicalTrials.gov  Patient Approval Form  30-day FDA notification prior to the trial

57 Alan Cash Terra Biological LLC San Diego, CA Web:


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