Oxaloacetate Supplementation

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

2. Discussion Outline • 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. Part I Review of Mechanism of Action

4. Published Information • 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” • 2010Anti-Aging Therapeutics Chapter 6 “Modification of NAD+/NADH”

5. Calorie Restriction 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. Mechanisms of Calorie Restriction-- NAD+/NADH • NAD+/NADH h in calorie restriction, Lifespan h Lin 2003, Easlon 2008, Edwards 2013, Lee 2012, Braidy 2011 • NAD+ Salvage h human cell lifespan h Van der Veer 2007 • NAD+ precursors h lifespan h Belenky 2007 • AMPK h Lifespan h NAD+/NADH h AMPK h Greer 2007, Rafaeloff-Phail 2004 • Mitochondrial NAD+ h Cell survival h Yang 2007

7. Mechanisms of Calorie Restriction-- NAD+/NADH • NAD+/NADH i Sarcopenia h Pugh, 2013 • NAD+/NADH h mitochondrial density and Energy h Chuang 2013 • NAD+ i mitochondrial OXPHOS i Gomes 2013 • NAD+/NADH h breast cancer metastasis i Santidrian 2013

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

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

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

12. OAA & Gene Response

13. Part Two Applications of Oxaloacetate as a Nutritional Supplement

14. Oxaloacetic Acid (OAA)A Human Metabolite h The Krebs Cycle (Citric Acid Cycle)

15. OAA & Lifespan

16. OAA & Lifespan OAA effect on Mice 25% increase

17. OAA Effect on Mice Mouse Data: Steve Spindler UC Riverside

18. OAA & Lifespan

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

20. OAA & Glucose Support

21. Anti-Aging/Glucose Support Laboratory Research Translates into Commercial Product www.benaGene.com

22. OAA & Glucose Support • 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

23. OAA & Glucose Support

24. OAA & Glucose Support • 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. OAA & Fat Production 20-30% Decrease in Genes that Create & Store Fat 29% Reduction in Fat Tissue Mass with OAA Supplementation

26. OAA & Fat Production Reduced Weight Rebound Due to Lower Gene Expression

27. Weight Maintenance After Diet Commercial Product

28. OAA & Tissue Protection • 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. OAA & Endurance • 10% increase in Muscle Endurance with OAA • AMPK activation as Precursor to Mitochondrial Biosynthesis *

30. National Metal AthletesFind More Endurance Imagine what a 10% Increase in Endurance Does for competition.

31. Reduction in Essential Tremor www.TremorStop.com

32. Part 3 Clinical Trial Updates for Oxaloacetate as a Potential Drug for Disease Treatment

33. OAA Future Applications(Not as a Dietary Supplement) • 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. OAA & Cancer • 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 & Cancer OAA Reduces Glioblastoma Tumor Growth by 50% Rubin, Inv. New Drugs 2012

36. Combining Oxaloacetate with Chemotherapy Improves Treatment 21 day tumor growth in nude mice. Ruban, Investigative New Drugs 2012

37. Oxaloacetate with Chemotherapy Greatly Improves Survival (237%) Temozolomide And Oxaloacetate No tumor cells found In Remaining Mice. Rubin, Invest. New Drugs 2012

38. FDA Designates Oxaloacetate as a new “Orphan Drug” After Review, US FDA Designates Oxaloacetate As an “Orphan Drug” for the Treatment of Gliomas. Designation (12-3704)

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

40. Gliaxal Improves Malignant Glial Tumor Treatment in Clinical Cases Case studies indicate that Gliaxal, either alone or in combination with other therapies, stopped tumor growth in 88% of the patients (N = 17)

41. GliaxalCase Studies Results

42. Making A Difference • "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. Clinical Trial To Begin • 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. Oxaloacetate & Parkinson’s Substantial Improvement in Quality of Life Patient QOL Impact Score Improved From 79 to 8

45. Parkinson’s Pre-Clinical

46. Oxaloacetate QOL Survey • 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 http://clinicaltrials.gov/ct2/show/NCT01741701

47. Oxaloacetate & Parkinson'sPre-clinical Case Studies

48. Oxaloacetate & Alzheimer’s Increases in serum APP alpha (Pistel, 2012)

49. Oxaloacetate & Alzheimer’sDecreases in a-Beta (1-40) (Pistel, 2012)

50. Oxaloacetate & Alzheimer'sDecreases in A-Beta (1-42) (Pistel, 2012)