Skip to main content
SpringerLink
Log in
Book cover

Clinical and Preclinical Models for Maximizing Healthspan pp 83–98Cite as

Protocol for the Use of the Ketogenic Diet in Preclinical and Clinical Practice

  • Protocol
  • First Online:

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2138))

Abstract

Many age-related diseases are associated with metabolic abnormalities, and dietary interventions may have some benefit in alleviating symptoms or in delaying disease onset. Here, we review the commonly used best practices involved in applications of the ketogenic diet to facilitate its translation into clinical use. The findings reveal that better education of physicians is essential for applying the optimum diet and monitoring its effects in clinical practice. In addition, investigators should carefully consider potential confounding factors prior to commencing studies involving a ketogenic diet. Most importantly, current studies should improve their reporting on ketone levels as well as on the intake of both macro- and micronutrients. Finally, more detailed studies on the mechanism of action are necessary to help identify potential biomarkers for response prediction and monitoring, and to uncover new drug targets to aid the development of novel treatments.

This is a preview of subscription content, log in via an institution.

Protocol
USD   49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

References

  1. Balasubramanian P, Howell PR, Anderson RM (2017) Aging and caloric restriction research: a biological perspective with translational potential. EBioMedicine 21:37–44

    Article  PubMed  PubMed Central  Google Scholar 

  2. Meidenbauer JJ, Ta N, Seyfried TN (2014) Influence of a ketogenic diet, fish-oil, and calorie restriction on plasma metabolites and lipids in C57BL/6J mice. Nutr Metab (Lond) 11:23. https://doi.org/10.1186/1743-7075-11-23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Roberts MN, Wallace MA, Tomilov AA, Zhou Z, Marcotte GR, Tran D et al (2017) A ketogenic diet extends longevity and healthspan in adult mice. Cell Metab 26(3):539–546.e5. https://doi.org/10.1016/j.cmet.2017.08.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Newman JC, Verdin E (2017) β-Hydroxybutyrate: a signaling metabolite. Annu Rev Nutr 37:51–76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Scheibye-Knudsen M, Mitchell SJ, Fang EF, Iyama T, Ward T, Wang J et al (2014) A high-fat diet and NAD+ activate Sirt1 to rescue premature aging in cockayne syndrome. Cell Metab 20(5):840–855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Weber DD, Aminazdeh-Gohari S, Kofler B (2018) Ketogenic diet in cancer therapy. Aging (Albany NY) 10(2):164–165

    Article  Google Scholar 

  7. Seyfried TN (2014) Ketone strong: emerging evidence for a therapeutic role of ketone bodies in neurological and neurodegenerative diseases. J Lipid Res 55(9):1815–1817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bough KJ, Rho JM (2007) Anticonvulsant mechanisms of the ketogenic diet. Epilepsia 48(1):43–58

    Article  CAS  PubMed  Google Scholar 

  9. Shilpa J, Mohan V (2018) Ketogenic diets: boon or bane? Indian J Med Res 148(3):251–253

    Article  PubMed  PubMed Central  Google Scholar 

  10. Hartman AL, Gasior M, Vining EP, Rogawski MA (2007) The neuropharmacology of the ketogenic diet. Pediatr Neurol 36(5):281–292

    Article  PubMed  PubMed Central  Google Scholar 

  11. Paoli A, Rubini A, Volek JS, Grimaldi KA (2013) Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. Eur J Clin Nutr 67(8):789–796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Seyfried TN, Mukherjee P (2005) Targeting energy metabolism in brain cancer: review and hypothesis. Nutr Metab (Lond) 2:30. https://doi.org/10.1186/1743-7075-2-30

    Article  CAS  Google Scholar 

  13. Stafstrom CE, Rho JM (2012) The ketogenic diet as a treatment paradigm for diverse neurological disorders. Front Pharmacol 3:59. https://doi.org/10.3389/fphar.2012.00059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kossoff EH, Andermann F (2010) Migraine and epilepsy. Semin Pediatr Neurol 17(2):117–122

    Article  PubMed  Google Scholar 

  15. Maggioni F, Margoni M, Zanchin G (2011) Ketogenic diet in migraine treatment: a brief but ancient history. Cephalalgia 31(10):1150–1151

    Article  PubMed  Google Scholar 

  16. PACHECO A, WS EASTERLING, MW PRYER (1965) A pilot study of the ketogenic diet in schizophrenia. Am J Psychiatry 121:1110–1111

    Article  CAS  PubMed  Google Scholar 

  17. Pulsifer MB, Gordon JM, Brandt J, Vining EP, Freeman JM (2001) Effects of ketogenic diet on development and behavior: preliminary report of a prospective study. Dev Med Child Neurol 43(5):301–306

    Article  CAS  PubMed  Google Scholar 

  18. Barañano KW, Hartman AL (2008) The ketogenic diet: uses in epilepsy and other neurologic illnesses. Curr Treat Options Neurol 10(6):410–419

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kraft BD, Westman EC (2009) Schizophrenia, gluten, and low-carbohydrate, ketogenic diets: a case report and review of the literature. Nutr Metab (Lond) 6:10. https://doi.org/10.1186/1743-7075-6-10

    Article  CAS  Google Scholar 

  20. Palmer CM (2017) Ketogenic diet in the treatment of schizoaffective disorder: two case studies. Schizophr Res 189:208–209

    Article  PubMed  Google Scholar 

  21. Taylor MK, Sullivan DK, Mahnken JD, Burns JM, Swerdlo RH (2018) Feasibility and efficacy data from a ketogenic diet intervention in Alzheimer’s disease. Alzheimers Dement 4:28–36

    Google Scholar 

  22. Żarnowska I, Chrapko B, Gwizda G, Nocuń A, Mitosek-Szewczyk K, Gasior M (2018) Therapeutic use of carbohydrate-restricted diets in an autistic child; a case report of clinical and 18FDG PET findings. Metab Brain Dis 33(4):1187–1192

    Article  PubMed  PubMed Central  Google Scholar 

  23. Paoli A, Bosco G, Camporesi EM, Mangar D (2015) Ketosis, ketogenic diet and food intake control: a complex relationship. Front Psychol 6:27. https://doi.org/10.3389/fpsyg.2015.00027

    Article  PubMed  PubMed Central  Google Scholar 

  24. Nyenwe EA, Kitabchi AE (2016) The evolution of diabetic ketoacidosis: an update of its etiology, pathogenesis and management. Metabolism 65(4):507–521

    Article  CAS  PubMed  Google Scholar 

  25. Umpierrez G, Korytkowski M (2016) Diabetic emergencies - ketoacidosis, hyperglycaemic hyperosmolar state and hypoglycaemia. Nat Rev Endocrinol 12(4):222–232

    Article  CAS  PubMed  Google Scholar 

  26. Krebs HA (1966) The regulation of the release of ketone bodies by the liver. Adv Enzym Regul 4:339–354

    Article  CAS  Google Scholar 

  27. Kossoff EH, Zupec-Kania BA, Auvin S, Ballaban-Gil KR, Christina Bergqvist AG, Practice Committee of the Child Neurology et al (2018) Optimal clinical management of children receiving dietary therapies for epilepsy: updated recommendations of the international ketogenic diet study group. Epilepsia Open 3(2):175–192

    Article  PubMed  PubMed Central  Google Scholar 

  28. Matthew Charles Lee Phillips (2019) Ketogenic diet therapies in children and adults with epilepsy. In: Epilepsy – advances in diagnosis and therapy. https://www.intechopen.com/online-first/ketogenic-diet-therapies-in-children-and-adults-with-epilepsy

  29. Roehl K, Sewak SL (2017) Practice paper of the academy of nutrition and dietetics: classic and modified ketogenic diets for treatment of epilepsy. J Acad Nutr Diet 117(8):1279–1292

    Article  PubMed  Google Scholar 

  30. Wibisono C, Rowe N, Beavis E, Kepreotes H, Mackie FE, Lawson JA et al (2015) Ten-year single-center experience of the ketogenic diet: factors influencing efficacy, tolerability, and compliance. J Pediatr 166(4):1030–6.e1. https://doi.org/10.1016/j.jpeds.2014.12.018

    Article  PubMed  Google Scholar 

  31. Wirrell E, Eckert S, Wong-Kisiel L, Payne E, Nickels K (2018) Ketogenic diet therapy in infants: efficacy and tolerability. Pediatr Neurol 82:13–18

    Article  PubMed  Google Scholar 

  32. Wheless JW (2001) The ketogenic diet: an effective medical therapy with side effects. J Child Neurol 16(9):633–635

    Article  CAS  PubMed  Google Scholar 

  33. Kang HC, Chung DE, Kim DW, Kim HD (2004) Early- and late-onset complications of the ketogenic diet for intractable epilepsy. Epilepsia 45(9):1116–1123

    Article  PubMed  Google Scholar 

  34. Phelps JR, Siemers SV, El-Mallakh RS (2013) The ketogenic diet for type II bipolar disorder. Neurocase 19(5):423–426

    Article  PubMed  Google Scholar 

  35. Scott JM, Deuster PA (2017) Ketones and human performance. J Spec Oper Med 17(2):112–116

    PubMed  Google Scholar 

  36. Masood W, Uppaluri KR (2019) Ketogenic diet. StatPearls. StatPearls Publishing LLC, Treasure Island, FL. https://www.ncbi.nlm.nih.gov/books/NBK499830/

    Google Scholar 

  37. Kekwick A, Pawan GL, Chalmers TM (1959) Resistance to ketosis in obese subjects. Lancet 2(7113):1157–1159

    Article  CAS  PubMed  Google Scholar 

  38. Paoli A, Cenci L, Fancelli M, Parmagnani A, Fratter A, Cucchi A et al (2010) Ketogenic diet and phytoextracts comparison of the efficacy of Mediterranean, zone and tisanoreica diet on some health risk factors. Agro Food Industry Hi Tech 21(4):24–29

    Google Scholar 

  39. Cahill GF Jr, Herrera MG, Morgan AP, Soeldner JS, Steinke J, Levy PL et al (1966) Hormone-fuel interrelationships during fasting. J Clin Invest 45(11):1751–1769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Reichard GA Jr, Owen OE, Haff AC, Paul P, Bortz WM (1974) Ketone-body production and oxidation in fasting obese humans. J Clin Invest 53(2):508–515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Owen OE, Morgan AP, Kemp HG, Sullivan JM, Herrera MG, Cahill GFJ (1967) Brain metabolism during fasting. J Clin Invest 46(10):1589–1595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Owen OE, Felig P, Morgan AP, Wahren J, Cahill GF Jr (1969) Liver and kidney metabolism during prolonged starvation. J Clin Invest 48(3):574–583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Cahill GF Jr (2006) Fuel metabolism in starvation. Annu Rev Nutr 26:1–22

    Article  CAS  PubMed  Google Scholar 

  44. Veech RL (2004) The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukot Essent Fatty Acids 70(3):309–319

    Article  CAS  PubMed  Google Scholar 

  45. Güntner AT, Kompalla JF, Landis H, Theodore SJ, Geidl B, Sievi NA et al (2018) Guiding ketogenic diet with breath acetone sensors. Sensors (Basel) 18(11):pii: E3655. https://doi.org/10.3390/s18113655

    Article  CAS  Google Scholar 

  46. Lee RWY, Corley MJ, Pang A, Arakaki G, Abbott L, Nishimoto M et al (2018) A modified ketogenic gluten-free diet with MCT improves behavior in children with autism spectrum disorder. Physiol Behav 188:205–211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Barnard DE, Lewis SM, Teter BB, Thigpen JE (2009) Open- and closed-formula laboratory animal diets and their importance to research. J Am Assoc Lab Anim Sci 48(6):709–713

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Franklin CL, Ericsson AC (2017) Microbiota and reproducibility of rodent models. Lab Anim (NY) 46(4):114–122

    Article  Google Scholar 

  49. Ye F, Li XJ, Jiang WL, Sun HB, Liu J (2015) Efficacy of and patient compliance with a ketogenic diet in adults with intractable epilepsy: a meta-analysis. J Clin Neurol 11(1):26–31

    Article  PubMed  PubMed Central  Google Scholar 

  50. Kraeuter AK, Loxton H, Lima BC, Rudd D, Sarnyai Z (2015) Ketogenic diet reverses behavioral abnormalities in an acute NMDA receptor hypofunction model of schizophrenia. Schizophr Res 169(1–3):491–493

    Article  PubMed  Google Scholar 

  51. Kraeuter AK, van den Buuse M, Sarnyai Z (2019) Ketogenic diet prevents impaired prepulse inhibition of startle in an acute NMDA receptor hypofunction model of schizophrenia. Schizophr Res 206:244–250

    Article  PubMed  Google Scholar 

  52. Peet M (2008) Omega-3 polyunsaturated fatty acids in the treatment of schizophrenia. Isr J Psychiatry Relat Sci 45(1):19–25

    PubMed  Google Scholar 

  53. Alqarni A, Mitchell TW, McGorry PD, Nelson B, Markulev C, Yuen HP et al (2019) Comparison of erythrocyte omega-3 index, fatty acids and molecular phospholipid species in people at ultra-high risk of developing psychosis and healthy people. Schizophr Res 2019:pii: S0920-9964(19)30241-5. https://doi.org/10.1016/j.schres.2019.06.020

    Article  Google Scholar 

  54. Schlögelhofer M, Amminger GP, Schaefer MR, Fusar-Poli P, Smesny S, McGorry P et al (2014) Polyunsaturated fatty acids in emerging psychosis: a safer alternative? Early Interv Psychiatry 8(3):199–208

    Article  PubMed  Google Scholar 

  55. Mitchell ES, Conus N, Kaput J (2014) B vitamin polymorphisms and behavior: evidence of associations with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline. Neurosci Biobehav Rev 47:307–320

    Article  CAS  PubMed  Google Scholar 

  56. Feinman RD, Pogozelski WK, Astrup A, Bernstein RK, Fine EJ, Westman EC et al (2015) Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base. Nutrition 31(1):1–13

    Article  CAS  PubMed  Google Scholar 

  57. Barzegar M, Afghan M, Tarmahi V, Behtari M, Rahimi Khamaneh S, Raeisi S (2019) Ketogenic diet: overview, types, and possible anti-seizure mechanisms. Nutr Neurosci 26:1–10

    Article  Google Scholar 

  58. Van der Auwera I, Wera S, Van Leuven F, Henderson ST (2005) A ketogenic diet reduces amyloid beta 40 and 42 in a mouse model of Alzheimer’s disease. Nutr Metab (Lond) 2:28. https://doi.org/10.1186/1743-7075-2-28

    Article  CAS  Google Scholar 

  59. Ruskin DN, Ross JL, Kawamura M Jr, Ruiz TL, Geiger JD, Masino SA (2011) A ketogenic diet delays weight loss and does not impair working memory or motor function in the R6/2 1J mouse model of Huntington’s disease. Physiol Behav 103(5):501–507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Beckett TL, Studzinski CM, Keller JN, Paul Murphy M, Niedowicz DM (2013) A ketogenic diet improves motor performance but does not affect beta-amyloid levels in a mouse model of Alzheimer’s disease. Brain Res 1505:61–67

    Article  CAS  PubMed  Google Scholar 

  61. Kim DY, Hao J, Liu R, Turner G, Shi FD, Rho JM (2012) Inflammation-mediated memory dysfunction and effects of a ketogenic diet in a murine model of multiple sclerosis. PLoS One 7(5):e35476. https://doi.org/10.1371/journal.pone.0035476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ahn Y, Narous M, Tobias R, Rho JM, Mychasiuk R (2014) The ketogenic diet modifies social and metabolic alterations identified in the prenatal valproic acid model of autism spectrum disorder. Dev Neurosci 36(5):371–380

    Article  CAS  PubMed  Google Scholar 

  63. Choi IY, Piccio L, Childress P, Bollman B, Ghosh A, Brandhorst S et al (2016) A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms. Cell Rep 15(10):2136–2146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Smith J, Rho JM, Teskey GC (2016) Ketogenic diet restores aberrant cortical motor maps and excitation-to-inhibition imbalance in the BTBR mouse model of autism spectrum disorder. Behav Brain Res 304:67–70

    Article  CAS  PubMed  Google Scholar 

  65. Newell C, Bomhof MR, Reimer RA, Hittel DS, Rho JM, Shearer J (2016) Ketogenic diet modifies the gut microbiota in a murine model of autism spectrum disorder. Mol Autism 7(1):37. https://doi.org/10.1186/s13229-016-0099-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Mychasiuk R, Rho JM (2017) Genetic modifications associated with ketogenic diet treatment in the BTBR(T+Tf/J) mouse model of autism spectrum disorder. Autism Res 10(3):456–471

    Article  PubMed  Google Scholar 

  67. Ruskin DN, Murphy MI, Slade SL, Masino SA (2017) Ketogenic diet improves behaviors in a maternal immune activation model of autism spectrum disorder. PLoS One 12(2):e0171643. https://doi.org/10.1371/journal.pone.0171643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cheng B, Yang X, An L, Gao B, Liu X, Liu S (2009) Ketogenic diet protects dopaminergic neurons against 6-OHDA neurotoxicity via up-regulating glutathione in a rat model of Parkinson’s disease. Brain Res 1286:25–31

    Article  CAS  PubMed  Google Scholar 

  69. Murphy P, Likhodii SS, Hatamian M, McIntyre Burnham W (2005) Effect of the ketogenic diet on the activity level of Wistar rats. Pediatr Res 57(3):353–357

    Article  CAS  PubMed  Google Scholar 

  70. Murphy P, Burnham WM (2006) The ketogenic diet causes a reversible decrease in activity level in long-Evans rats. Exp Neurol 201(1):84–89

    Article  CAS  PubMed  Google Scholar 

  71. Sussman D, Germann J, Henkelman M (2015) Gestational ketogenic diet programs brain structure and susceptibility to depression & anxiety in the adult mouse offspring. Brain Behav 5(2):e00300. https://doi.org/10.1002/brb3.300

    Article  PubMed  Google Scholar 

  72. Zhao Z, Lange DJ, Voustianiouk A, MacGrogan D, Ho L, Suh J et al (2006) A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis. BMC Neurosci 7:29. https://doi.org/10.1186/1471-2202-7-29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Verpeut JL, DiCicco-Bloom E, Bello NT (2016) Ketogenic diet exposure during the juvenile period increases social behaviors and forebrain neural activation in adult engrailed 2 null mice. Physiol Behav 161:90–98

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Psychiatric Neuroscience, Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, QLD, Australia

    Ann-Katrin Kraeuter & Zoltán Sarnyai

  2. Discipline of Biomedicine, College of Public Health, Medicine and Veterinary Sciences, James Cook University, Townsville, QLD, Australia

    Ann-Katrin Kraeuter & Zoltán Sarnyai

  3. Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil

    Paul C. Guest

Authors
  1. Ann-Katrin Kraeuter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul C. Guest
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zoltán Sarnyai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zoltán Sarnyai .

Editor information

Editors and Affiliations

  1. Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil

    Paul C. Guest

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Kraeuter, AK., Guest, P.C., Sarnyai, Z. (2020). Protocol for the Use of the Ketogenic Diet in Preclinical and Clinical Practice. In: Guest, P. (eds) Clinical and Preclinical Models for Maximizing Healthspan. Methods in Molecular Biology, vol 2138. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-0471-7_4

Download citation

  • DOI: https://doi.org/10.1007/978-1-0716-0471-7_4

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-0470-0

  • Online ISBN: 978-1-0716-0471-7

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation