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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

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oxaloacetate supplementation

Oxaloacetate Supplementation

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

An Update for 2014

Alan Cash

Terra Biological LLC

discussion outline
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
part i
Part I

Review of

Mechanism of Action

published information
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”

calorie restriction
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.
mechanisms of calorie restriction nad nadh
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

mechanisms of calorie restriction nad nadh1
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

mechanisms of calorie restriction nad nadh2
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
proven biochemistry
Proven Biochemistry

Oxaloacetate Supplementation

increases

NAD+/NADH

ratio by 900%

Krebs, 1968

oaa gene response
OAA & Gene Response

98% Positive Directional

Overlap for genes

Changed in common.

OAA

part two
Part Two

Applications of Oxaloacetate as a Nutritional Supplement

oxaloacetic acid oaa a human metabolite
Oxaloacetic Acid (OAA)A Human Metabolite

h

The Krebs Cycle

(Citric Acid Cycle)

oaa lifespan1
OAA & Lifespan

OAA effect on Mice

25% increase

oaa effect on mice
OAA Effect on Mice

Mouse Data:

Steve Spindler

UC Riverside

oaa glucose support
OAA & Glucose Support

Clinical Trial– Diabetic Patients

Decrease in Fasting Glucose Levels

Average decrease of 24%

anti aging glucose support
Anti-Aging/Glucose Support

Laboratory Research

Translates into

Commercial Product

www.benaGene.com

oaa glucose support2
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
oaa glucose support4
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.
oaa fat production
OAA & Fat Production

20-30% Decrease in Genes that Create & Store Fat

29% Reduction in Fat Tissue Mass with OAA Supplementation

oaa fat production1
OAA & Fat Production

Reduced Weight Rebound Due to Lower Gene Expression

weight maintenance
Weight Maintenance

After Diet

Commercial Product

oaa tissue protection
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
oaa endurance
OAA & Endurance
  • 10% increase in Muscle Endurance with OAA
  • AMPK activation as Precursor to Mitochondrial Biosynthesis

*

national metal athletes find more endurance
National Metal AthletesFind More Endurance

Imagine what a 10%

Increase in Endurance

Does for competition.

part 3
Part 3

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

oaa future applications not as a dietary supplement
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.
oaa cancer
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
oaa cancer1
OAA & Cancer

OAA Reduces Glioblastoma Tumor Growth by 50%

Rubin, Inv. New Drugs

2012

combining oxaloacetate with chemotherapy improves treatment
Combining Oxaloacetate with Chemotherapy Improves Treatment

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

oxaloacetate with chemotherapy greatly improves survival 237
Oxaloacetate with Chemotherapy Greatly Improves Survival (237%)

Temozolomide

And

Oxaloacetate

No tumor cells found

In Remaining Mice.

Rubin, Invest. New Drugs 2012

fda designates oxaloacetate as a new orphan drug
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)

medical food for glial tumors
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
gliaxal improves malignant glial tumor treatment in clinical cases
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)

making a difference
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

clinical trial to begin
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
oxaloacetate parkinson s
Oxaloacetate & Parkinson’s

Substantial Improvement in Quality of Life

Patient QOL Impact Score Improved From 79 to 8

oxaloacetate qol survey
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

oaa alzheimer s
OAA & Alzheimer’s

Alzheimer Model Mice show memory improvements

50% Increase in Short-Term Memory

(Pistel, 2013)

clinical trial in alzheimer s starts
Clinical Trial in Alzheimer’sStarts
  • A Clinical Phase 1 trial is beginning with oxaloacetate supplementation and Alzheimer’s disease at the University of Kansas.
part four
Part Four

Patient Profiles that may receive benefit from oxaloacetate

patient profiles
Patient Profiles
  • 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
patient profiles1
Patient Profiles
  • 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
for more information
For More Information

Alan Cash

Terra Biological LLC

San Diego, CA 92130

858-947-5722

acash@benaGene.org

Web:

www.benaGene.com

www.Gliaxal.com