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Metabolic Therapies:
Implications and Practical Application Dominic P. D’Agostino, PhD
Assistant Professor
Molecular Pharmacology and Physiology
Hyperbaric Biomedical Research Lab
University of South Florida Morsani College of Medicine
Metabolic Therapy Research
CNS Oxygen Toxicity (seizures)
Neurodegenerative diseases
Metabolic diseases
Cancer
CNS Oxygen Toxicity
Seizures
• Results from breathing oxygen at >2.5 ATA O2
Diving Hyperbaric O2 Therapy
Why do these seizures occur and
how can we prevent them?
Atomic Force Microscopy (AFM)
Fluorescence Microscopy
Laser Scanning Confocal Microscopy
Electrophysiology
Radio Telemetry (EEG)
Adapted to hyperbaric chambers
Methods to Study CNS-OT
Mitochondria O2
ROS
Strategies to prevent
CNS O2 toxicity?
• Dive within Exposure Limits
• Antioxidants
• Antiepileptic Drugs (AEDs)
Starvation
Delay in Seizure
(> 250%)
Bitterman, et al. Brain Res.
761, 146-50, 1997
36 hr
24 hr
How Does Starvation
Change Brain Metabolism?
Modified Diagram from: Oliver E. Owen. “Ketone Bodies as a Fuel for the Brain during
Starvation, ”Biochemistry And Molecular Biology Education Vol. 33, No. 4, 2005:246–251
Ketone Bodies Fuel the Brain
During Starvation
Ketones
-OHB
Glucose
Diagram from: Chapter 26 - Alternative Fuel Utilization by Brain, George F. Cahill, Jr. &
Thomas T. Aoki from Cerebral Metabolism and Neural Function (1980)
20IU of Insulin was administered
Subjects survived without brain damage or
coma
All 3 were asymptomatic
Ketones preserved brain
metabolism during severe
hypoglycemia
severe hypoglycemia!! (1-2 mmol/l)
Owen OE, Morgan AP, Kemp HG, Sullivan JM, Herrera MG, Cahill
GF Jr. Brain metabolism during fasting. J. Clin.Invest., 1967.
Ketosis Provides Resilience Against Hypoglycemia
Ketone
Bodies Energy substrates from fatty acid oxidation
Ketosis Blood levels >0.5 mmol/L.
Nutritional
Ketosis Dietary strategy to elevate blood ketones
Keto-
acidosis Pathologically high ketones (>10 mmol/L)
Keto-
Adaptation
Physiological shift towards using fat and
ketones for fuel
Exogenous
Ketones
Synthetic or naturally derived substances to
artificially produce “instant ketosis”
Glucose
Insulin
Diet
Body Fat
Ketones (energy!)
Difficult to sustain…
↓ Glucose ↑ BHB
↑ Acetone
(Metron)
↑ AcAc
Rapid and Sustained Ketosis (15 minutes to >2-8 hrs)
D’Agostino, D.P., et.al . AJP Regulatory, Integrative and
Comparative Physiology, 2013 May 15;304(10):R829-36.
Kesl SL, et al. Methods of sustaining dietary
ketosis in Sprague-Dawley rats. FASEB Journal
(2014) vol. 28 no. 1 Supplement 643.5
50-100 mL dose
575 %
Seizure
Resistance
Therapeutic Ketosis (KD) Ketone
Ester
D’Agostino, D.P., et.al . AJP Regulatory, Integrative and
Comparative Physiology, 2013 May 15;304(10):R829-36.
Adapted from: Kristopher Bough and Jong Rho. Anticonvulsant
Mechanism of the Ketogenic Diet. Epilepsia, 48 (1): 43-58, 2007.
Elevated Ketones Lowered Glucose
Ketogenic Diet, Ketone Esters
βHB
AcAc
Acetone
GABA/Glutamate
Ratio
2-3x Higher
TCA Cycle
Intermediates
2-5x Higher
Adenosine
Carnosine
Anserine
Glucose
Insulin
ROS
Oxidative
Stress
Neurological Disorders are Associated with
Impaired Brain Energy Metabolism
(FDG-PET Scan)
NORMAL BRAIN ALZHEIMER’S BRAIN
GLUT-3
Healthy Cells have Metabolic Flexibility
Glucose Normal Diet
(High Carb)
Ketones Ketogenic Diet
(High Fat)
Cancer Lacks Metabolic Flexibility
Ketones (Ketogenic Diet)
Cancer Glucose Normal Diet
(High Carb)
Cancer has very high rates of glucose metabolism
Cancer Imaging
(FDG-PET Scan)
Otto H. Warburg
Nobel Prize (1931) Medicine
First to describe Cancer
as a Metabolic Disease
• High glycemic diets increase risk of cancer
• Hyperglycemia = poor prognosis
• Blood glucose correlated to tumor growth
• Ketogenic diet: 4:1 fat (75-85% fat) ▫ Lowers glucose, Induces ketosis
▫ Suppresses insulin
▫ Reduces growth factors
Seyfried et al. British Journal of
Cancer (2003) 89, 1375 – 1382
High Glucose and Low Oxygen
Drive the Warburg Effect Gnagnarella, et al; 2008
Average PO2
30-60 mmHg 2-30 mmHg
**Causes chemo/radioresistance
Healthy Brain Cells Brain Cancer Cells
High Pressure Oxygen Damages Cancer Cells
Neuroscience; 31;159(3):1011-22, 2009
Effect of Ketones on Cancer Cells
Even in the presence of high glucose!
Poff et al. International Journal of Cancer: 2014 Oct. 1;135(7):1711-20.
NO Ketones Ketones (5 mM)
Ketones Increase
Cancer Cell Death
Ketones Reduce
Cancer Cell
Proliferation of
Summary (pancreatic cancer model)
1. Ketones (BHB and AcAc) inhibit cancer growth
2. Ketones increase cancer cell death (apoptosis)
3. Suppressed oncogenic growth signals (e.g. c-Myc)
4. KD reduced tumor growth and prevents cachexia
Can Nutritional Ketosis and
HBOT Prolong Survival from
Metastatic Cancer?
Metabolic Stress
Glucose
Insulin Oxygen
Ketones
Dr. Angela Poff
The VM-M3 Model of
Metastatic Cancer Developed by Dr. Thomas Seyfried, Boston College
1. Similar to human metastatic cancer
2. Tumor cells glow (firefly gene)
3. Immunocompetent
Shelton, et. Al, 2009
IJC, Volume 126
Liver Metastasis
Methods: Treatment Groups
• Standard Diet
• Ketogenic Diet (KD)
• Ketone Ester (10%, KE)
• Hyperbaric Oxygen (HBOT):
▫ 2.5 ATA, 90 min, 3/week
Ketosis and HBOT dramatically slows
metastatic cancer and extends survival
Survival Time Survival Time
21 Days Post Tumor Cell Transplant
How can we Implement
Metabolic Therapy?
Practical Guidelines
* Patients should be monitored by their own physician, while working closely with the Registered Dietitian
• http://www.charliefoundation.org/ • www.ketogenic-diet-resource.com • www.dietarytherapies.com
“Standard Diet” vs. “Ketogenic Diet”
Ketogenic Diets differ from the Standard Diet in
macronutrient distribution.
Carbohydrate intake decreases to <10% of kcals.
Ketogenic diet is NOT a HIGH PROTEIN diet
Challenges To Initiation and Compliance
Liver cancer and/or elevated liver enzymes
Kidney stones and/or renal disease
Pancreatitis
Fat malabsorption issues
Gallbladder obstruction or removal
Medications
Lack of support
High cholesterol
Food selection
Weight loss
Metabolic management of cancer following changes
in plasma glucose & ketones
Metabolic Management of Cancer
Ketones
Glucose
Seyfried et al. Carcinogenesis. 2014, Mar;35(3):515-27
Zuccoli G, at al.:Case Report. Nutrition and Metabolism (Lond). 2010 Apr 22;7:33.
CASE REPORT: UNPUBLISHED
• 10 y/o male
• 2009 – Ependymoma diagnosis
• 7 neurosurgeries
• 2X radiotherapy courses
• Resistant to treatment
02/2014 – started HBOT (100 sessions) with carbohydrate restriction
Rt Parietal Lesion 100 HBOT sessions
+ Diet Therapy
Midline Lesions
Case Report: Unpublished
(5 Months)
Clinical Trials (Pilot Studies)
“Ketogenic Diet and Cancer “
Sept 1, 2014: 13 Results
Summary: Potential Therapeutic Implications
• Nutritional ketosis mimics the metabolic state of fasting
and decreases potential for seizures
• Non-toxic, cost-effective, readily implementable
• Possibly effective against aggressive, late-stage cancers
• KD and HBOT have potential synergy with standard care
• Neuroprotective against chemotherapy and radiation
Future Directions
• Determine best method to achieve the “metabolic zone”
• Determine dose for HBOT (2.5 ATA O2; 90 min; 3x/week))
• Evaluate in other cancer models (brain, breast, ovarian)
• Explore nontoxic metabolic drugs (e.g. Metformin)
• Test a phytonutrient cocktail (e.g. green tea, turmeric, etc)
• Clinical Trails
Questions?
the USF TAMPA TEAM
Al Bino
Dr. Raffaele Pilla
(alumnus)
Carol Landon
Shannon Kesl
Jacob
Sherwood
Dr. Chris Rogers
Dr. Rami Grossman
(alumnus)
Dr. Angela Poff Nate Ward Geoff
Ciarlone Dr. Heather Held
Teryn
Gerhed
(fall 2014)
Dr. Csilla Ari
Dr. Dominic
D’Agostino
Dr. J.B. Dean
Dr. Helen McNally
Purdue University
Resources
www.ketogenic-diet-resource.com
www.dietarytherapies.com
http://www.charliefoundation.org/
http://www.rsg1foundation.com/
http://www.nutritionchoices.ie/
www.ketonutrition.org
Questions?
References Poff A, Ari C, Seyfried TN, D’Agostino, DP. The Ketogenic Diet and Hyperbaric Oxygen Therapy
act Synergistically to Prolong Survival in Mice with Systemic Metastatic Cancer. PLoS ONE,
2013; 8 (6): e65522 DOI: 10.1371/journal.pone.0065522
Seyfried TN, Poff A, D’Agostino, DP. Cancer as a Metabolic Disease: Implications for Novel
Therapeutics. Carcinogenesis. 2014, Mar;35(3):515-27. doi: a10.1093/carcin/bgt480..
Poff A, Ari C, Seyfried TN, D’Agostino, DP. Ketone Supplementation Decreases Tumor Cell
Viability and Prolongs Survival of Mice with Metastatic Cancer. International Journal of Cancer:
IJC-13-2481, 2013.
Seyfried TN, Marsh J, Mukherjee P, Zuccoli G, D’Agostino DP. Metabolic Therapy: A New
Paradigm for Managing Malignant Brain Cancer. Cancer Letters, 2014 Jul 25. pii: S0304-
3835(14)00352-8. doi: 10.1016/j.canlet.2014.07.015.
D'Agostino DP, Olson JE, Dean JB. Acute hyperoxia increases lipid peroxidation and induces
plasma membrane blebbing in human U87 glioblastoma cells. Neuroscience; Mar
31;159(3):1011-22, 2009.
Seyfried TN, Marsh J, Mukherjee P, Zuccoli G, D’Agostino DP. Could Metabolic Therapy Become
a Viable Alternative to the Standard of Care for Managing Glioblastoma? Oncology &
Hematology Review, 2014;10(1):13–20
Elevated rates of glycolysis and fermentation, excessive lactate production
– up to 200 X rate of normal cells
• Drives anabolic processes
• Acidifies microenvironment
• Most consistent cancer phenotype,
present in most, if not all, cancers
Anaerobic
Fermentation
~2 ATP
per glucose
Aerobic
Respiration
~38 ATP
per glucose Mitochondrion
+O2 +O2
Cancer Metabolism & The Warburg Effect
Healthy
Cell
Cancer
Cell
Tumor hypoxia promotes cancer
progression and the Warburg Effect
Regulation of cancer cell metabolism by hypoxia-inducible factor 1; Semenza, G.
HIF-1 implicated in every aspect of
cancer progression
Reported Positive Effects of
Nutritional Ketosis • Weight loss (Atkins diet)
• Alzheimer’s disease Nutr Metabolism 2009 Aug 10;6:31
• Parkinson’s disease Curr Treat Options Neurol. 2008 Nov;10(6):410-9.
• Lou Gehrig’s disease (ALS) BMC Neurosci. 2006 Apr 3;7:29
• Traumatic brain injury J Neurotrauma. 2011 Sep;28(9):1813-25
• Cancer Nutr Metabolism . 2007 Feb 21;4:5.
• Seizures J Child Neurol. 2009 Aug;24(8):979–88
How can we exploit the neuroprotective
and metabolic effect of ketones?
Case Report (published) Stage IV Glioblastoma
The Metabolic Zone
Zuccoli G, at al.: Case Report. Nutrition and Metabolism (Lond). 2010 Apr 22;7:33.
Human Studies?
• The Warburg Effect is a
universal feature of
cancers and serves as
the basis for one of the
most important
diagnostic tools in
cancer treatment
• Radioactively-labeled
glucose quickly taken up
by cancer cells
Metastatic Melanoma
FDG-Glucose PET Scan
Oxygen Rebreather
100% O2 No Bubbles = Quiet