Presentation on theme: "Modification of the NAD+/NADH ratio to mimic Calorie Restriction An Update for 2014 Alan Cash Terra Biological LLC."— Presentation transcript:
Modification of the NAD+/NADH ratio to mimic Calorie Restriction An Update for 2014 Alan Cash Terra 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 Possible Future 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 Therapeutics Chapter 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 Supplementation increases NAD+/NADH ratio by 900% Krebs, 1968
98% Positive Directional Overlap for genes Changed in common. OAA
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
Applications of Oxaloacetate as a Nutritional Supplement
The Krebs Cycle (Citric Acid Cycle)
OAA effect on Mice 25% increase
Mouse Data: Steve Spindler UC Riverside
Clinical Trial– Diabetic Patients Decrease in Fasting Glucose Levels Average decrease of 24%
Laboratory Research Translates into Commercial Product
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 Fat 29% Reduction in Fat Tissue Mass with OAA Supplementation
Reduced Weight Rebound Due to Lower Gene Expression
After Diet Commercial Product
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
10% increase in Muscle Endurance with OAA AMPK activation as Precursor to Mitochondrial Biosynthesis *
Imagine what a 10% Increase in Endurance Does for competition.
Reduction in Essential Tremor
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 Drugs 2012
21 day tumor growth in nude mice. Ruban, Investigative New Drugs 2012
Temozolomide And Oxaloacetate Rubin, Invest. New Drugs 2012 No tumor cells found In Remaining Mice.
After Review, US FDA Designates Oxaloacetate As an “Orphan Drug” for the Treatment of Gliomas. Designation ( )
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 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
"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, See
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 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
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