Summary of our current and ongoing work on ketogenic diets for performance and resilience

1. Ketogenic Dieting
Emerging Evidence of Fat
and Ketones as Fuel
Dominic D’Agostino, PhD
University of South Florida, Tampa, USA
College of Medicine

2. We Thank our Sponsors!
They Make Research Possible!
ALS
Foundation

3. Research Overview
1. Cellular and molecular mechanisms of CNS
oxygen toxicity (seizures)
2. Development and testing metabolic strategies
 Seizures
 Cancer
 Neurodegenerative Disease
 Performance, Strength, Body Composition

4.  Atomic Force Microscopy (AFM)
 Fluorescence Microscopy
 Laser Scanning Confocal Microscopy
 Electrophysiology
 Radio Telemetry (EEG, EMG, ECG)
 Behavioral and Exercise Performance
 Adapted to hyperbaric/hypobaric
chambers
Mitochondria
EEG
EEG
EMG, diaphragm
ECG,
HR
telemetry
module
sensing
module
Methods
Cellular, Molecular and Metabolic

5. Neuroprotection in Extreme Environments
(CNS oxygen toxicity seizures)
 Antioxidants
 Drugs (AEDs. Etc.)
 Pre-conditioning
 Starvation ketosis
Special-Ops Diving

6. Modifiied 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
How does fasting change brain metabolism?
-OHB
Glucose
Following 1 week fast
Glucose (2.9 mM) < Ketones (4.5 mM)
Metabolic
Zone

7. “Prolonged Therapeutic Fasting in this
patient (457lbs) had NO ill-effects”

8. Ketones
(energy!)
Glucose
Insulin
Dietary Fat
Body Fat
Difficult to sustain…

9. Ketones
(energy!)
D’Agostino, D.P., et.al . AJP Regulatory, Integrative and Comparative Physiology,
2013 May 15;304(10):R829-36.

10. Does Ketone Supplementation
Provide Performance
Enhancement and Resilience?

11. Single Dose
575 %
Seizure
Resistance
Ketone Ester
Ongoing Testing in Other Seizure Models
Cognitive Performance
Physical Performance
Special Ops Diving
Evidence the Ketones Enhance Brain Metabolism
• Ketone Esters Prevents CNS-OT Seizures
D’Agostino, D.P., et.al . AJP Regulatory, Integrative and
Comparative Physiology, 2013 May 15;304(10):R829-36.
Butanediol

12. 225
230
235
240
245
250
255
260
265
0-5min 5-10min 10-15min 15-20min 20-25min 25-30min
Ketones Placebo
Power(watts)
* *
**
*
* P < 0.02
* * P < 0.002
Ketone Esters Improve
Muscle Power Output
(Oxford University and NIH)
Power output in rowers

13. Peter Attia, MD
Effect of Exogenous Ketones
on Metabolic Efficiency

14. 2,800
2,900
3,000
3,100
3,200
3,300
3,400
3,500
VO2
VO2
(BHB)
Effect of Acute Ketosis (BHB salts) on Oxygen Consumption
Fixed Power Output (180 Watts)
Segment Test 1 Test 2 (BHB) Difference
Last 5 min 3,298 mL/min 3,032 mL/min -8.8%
Last 10 min 3,255 mL/min 3,023 mL/min -7.7%
Last 15 min 3,210 mL/min 3,012 mL/min -6.6%
Full 20 min 3,065 mL/min 2,890 mL/min -6.0%
Ketones : 0.6 mM
Ketones : 2.0 mM (BHB salts)
Test set #1: mild nutritional ketosis
0.6 mM 2.0 mM
Test set #2: 15.6 gm Exogenous BHB ketone salt
20 min

15. Multiple Mechanisms Working In Synergy!
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
10-20x Higher
BHB
AcAc
Acetone
2-3x Higher
Krebs Cycle
Intermediates
2-5x Higher
Adenosine
Carnosine
Anserine
Glucose
Insulin
ROS
Oxidative
Stress
Science (2013)
Jan 11;339(6116):211-4
Inflammation
(NLRP3 Inflammasone)
Nature Medicine (2015)
Jan 11;339(6116):211-4

16. What are the Effects of
Nutritional Ketosis on Muscle
Strength, Performance and
Body Composition?

17. Ketones decrease leucine
oxidation and promotes protein
synthesis in humans
Nutritional ketosis preserves lean
body mass and strength under
conditions of reduced calorie intake
and intense training

18. Retention of Lean Body Mass with Ketogenic Diet +
Branched-Chain Amino Acid Supplementation in a
Mouse Model of Metastatic Cancer
Standard
Diet
Ketogenic
Diet
3 Weeks Post Tumor
Cell Transplant
(Bioluminescent Tumor Imaging)
Ketogenic
Diet
+
BCAAs
Nate Ward et. al. FASEB Journal (2014)
vol. 28 no. 1 Supplement 824.2
Sponsored by:
>50% Increase in Survival Time

19. Ketogenic Diet
High-Carb
Ketogenic Diet produces retention of LBM
and significant reductions in bodyfat

20. The Effects of Ketogenic Dieting (8 Wks) on Body
Composition, Strength, Power, and
Hormonal Profiles in Resistance Training Males
(Under review: Nutrition & Metabolism)
1. Increase in Strength, Power and Hypertrophy of Ketogenic
Diet group was similar to Western Diet group.
2. Improved body composition (power to weight ratio)
3. Blood Biomarkers stayed in normal (excluding ketones)
• Elevated testosterone in KD group compared to WD control
Summary

21. Wilson, Lowery, Volek, D’Agostino et al 2014
Blood Ketones

22. Ketogenic Diet Vs. Cyclic Keto Diet (calorie restricted)
(Blood Ketones)
7 0 %
F A T
5 % C H O
2 5 % P R O
7 0 %
F A T
5 % C H O
2 5 % P R O
7 0 %
F A T
5 % C H O
2 5 % P R O
7 0 %
F A T
5 % C H O
2 5 % P R O
7 0 %
F A T
5 % C H O
2 5 % P R O
2 5 %
F A T
5 0 %
C H O
2 5 %
P R O
2 5 %
F A T
5 0 %
C H O
2 5 %
P R O
Weekdays Weekends

23. -3 kg -3 kg
Body Composition
KD vs. CKD
• 16 Trained Individuals
• KD or CKD for 6 weeks
(2 weeks adaptation)
• Resistance Training 3x/wk
Wilson, Lowery, Volek, D’Agostino et al 2014

24. Wilson, Lowery, Volek, D’Agostino et al 2014
Max Strength Strength Endurance
Strength
KD vs. CKD

25. • Ketones function as alternative fuels.
• Nutritional ketosis produces fat loss and protein sparing effect.
• Ketone supplementation circumvents need for carb restriction to
sustain ketosis.
• Sustained Ketogenic Dieting is superior to Cyclic Keto Dieting
 Would performance muscle sparing effects be greater at higher
plasma levels of ketones (e.g. 2-4)?
 Are there deleterious effects from using exogenous ketones?
 Would the protein sparing, appetite suppression and enhanced
energy production make exogenous ketones ideal for
bodybuilding?
Summry, Insights and Questions
Questions?

26. Jacob M. Wilson
Ryan P. Lowery
Jacob Ormes
Matthew Sharp
Kevin Shields
Michael Roberts
Eduardo O. De Souza
Jacob Rauch
Jeremy Silva
Jordan M. Joy
Jeff S Volek
Thank you for all of your support !!

27. 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

28. Future Neuroprotective Applications
• Alzheimer’s disease Nutr Metabolism 2009 Aug 10;6:31
• Brain injury J Neurotrauma. 2011 Sep;28(9):1813-25
• 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
• Brain cancer Nutr Metabolism . 2007 Feb 21;4:5.
• Metabolic Disorders Brain Dev. 2011 Nov;33(10):856-65.
• Friedreich's ataxia
• Multiple Acyl-CoA Dehydrogenase Deficiency (MADD)
• Pyruvate Dehydrogenase (PDH) deficiency
• Glucose Transporter Deficiency Syndrome (GLUT1DS)

29. Nutritional Ketosis for “Terminal Epilepsy” and
Bodybuilding

30. Case Study
unpublished Dr. Fred Hatfield (aka Dr. Squat)
Confirmed by 2 additional oncologists

31. Ketones
Water soluble high energy substrates from fatty acid oxidation
Ketosis A metabolic state with blood levels >0.5 mmol/L.
Nutritional
Ketosis
Carbohydrate restriction-induced ketosis
Keto-
acidosis
Runaway ketogenesis (>10 mmol/L). Occurs in Type 1 Diabetics
Keto-
Adaptation
Metabolic shift from glucose-based metabolism to fatty acid and ketone
metabolism (takes several weeks of sustained ketosis)

32. 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
Keto-adapted subjects were asymptomatic
severe hypoglycemia!! (1-2 mmol/l)
Ketones are Neuroprotective as an Alternative Fuel
Modified from Holt & Hanley, 2007
Pathological
Hypoglycemia