oxaloacetate supplementation
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Oxaloacetate Supplementation. Modification of the NAD+/NADH ratio to mimic Calorie Restriction An Update for 2014. Alan Cash Terra Biological LLC. Discussion Outline. Part 1 – Review of Mechanism of Action: Using Oxaloacetate to increase the NAD+/NADH Ratio - PowerPoint PPT PresentationTRANSCRIPT
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
