Ketone-based metabolic therapy: Is increased nad+ a primary mechanism?

Frontiers in Molecular Neuroscience

Volumn 10, Issue , 2017, Pages

  Elamin, Marwa ^a   Ruskin, David N ^b   Masino, Susan A ^b   Sacchetti, Paola ^a  

^a UNIVERSITY OF HARTFORD   (United States)

^b TRINITY COLLEGE   (United States)

Author keywords

Alzheimer s disease; Epilepsy; Hippocampus; Ketone bodies; Longevity; Metabolism; Neurodegeneration; Nicotinamide adenine dinucleotide

Indexed keywords

KETONE BODY; NICOTINAMIDE ADENINE DINUCLEOTIDE; SIRTUIN 1; SOMATOMEDIN C; TUMOR NECROSIS FACTOR;

ALZHEIMER DISEASE; APOPTOSIS; ARTICLE; BODY WEIGHT LOSS; BRAIN CORTEX; CELL PROLIFERATION; DEMENTIA; GENE EXPRESSION; HIPPOCAMPUS; HUMAN; KETOGENESIS; KETOGENIC DIET; METABOLIC REGULATION; MITOCHONDRIAL BIOGENESIS; NERVOUS SYSTEM INFLAMMATION; NONHUMAN; OXIDATIVE STRESS;

EID: 85041288122     PISSN: 16625099     EISSN: None     Source Type: Journal    
DOI: 10.3389/fnmol.2017.00377     Document Type: Article

References (110)

1. Achanta, L. B., and Rae, C. D. (2017). β-Hydroxybutyrate in the brain: one molecule, multiple mechanisms. Neurochem. Res. 42, 35–49. doi: 10.1007/s11064-016-2099-2
2. Ahn, Y., Narous, M., Tobias, R., Rho, J. M., and 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, 371–380. doi: 10.1159/000362645
3. + metabolism in health and disease. Trends Biochem. Sci. 32, 12–19. doi: 10.1016/j.tibs.2006.11.006
4. Boison, D. (2017). New insights into the mechanisms of the ketogenic diet. Curr. Opin. Neurol. 30, 187–192. doi: 10.1097/wco.0000000000000432
5. Bough, K. J., and Rho, J. M. (2007). Anticonvulsant mechanisms of the ketogenic diet. Epilepsia 48, 43–58. doi: 10.1111/j.1528-1167.2007.00915.x
6. Bough, K. J., Wetherington, J., Hassel, B., Pare, J. F., Gawryluk, J. W., Greene, J. G., et al. (2006). Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Ann. Neurol. 60, 223–235. doi: 10.1002/ana. 20899
7. Braak, H., and Braak, E. (1998). Evolution of neuronal changes in the course of Alzheimer’s disease. J. Neural Transm. Suppl. 53, 127–140. doi: 10.1007/978-3-7091-6467-9_11
8. Branco, A. F., Ferreira, A., Simões, R. F., Magalhães-Novais, S., Zehowski, C., Cope, E., et al. (2016). Ketogenic diets: from cancer to mitochondrial diseases and beyond. Eur. J. Clin. Invest. 46, 285–298. doi: 10.1111/eci.12591
9. Brownlow, M. L., Benner, L., D’Agostino, D., Gordon, M. N., and Morgan, D. (2013). Ketogenic diet improves motor performance but not cognition in two mouse models of Alzheimer’s pathology. PLoS One 8:e75713. doi: 10.1371/journal.pone.0075713
10. Brownlow, M. L., Jung, S. H., Moore, R. J., Bechmann, N., and Jankord, R. (2017). Nutritional ketosis affects metabolism and behavior in sprague-dawley rats in both control and chronic stress environments. Front. Mol. Neurosci. 10:129. doi: 10.3389/fnmol.2017.00129
11. Caraballo, R., Vaccarezza, M., Cersósimo, R., Rios, V., Soraru, A., Arroyo, H., et al. (2011). Long-term follow-up of the ketogenic diet for refractory epilepsy: multicenter Argentinean experience in 216 pediatric patients. Seizure 20, 640–645. doi: 10.1016/j.seizure.2011.06.009
12. Castro, K., Baronio, D., Perry, I. S., Riesgo, R. D. S., and Gottfried, C. (2017). The effect of ketogenic diet in an animal model of autism induced by prenatal exposure to valproic acid. Nutr. Neurosci. 20, 343–350. doi: 10.1080/1028415x. 2015.1133029
13. Chen, D., Bruno, J., Easlon, E., Lin, S. J., Cheng, H. L., Alt, F. W., et al. (2008). Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev. 22, 1753–1757. doi: 10.1101/gad.1650608
14. Cheng, C. M., Kelley, B., Wang, J., Strauss, D., Eagles, D. A., and Bondy, C. A. (2003). A ketogenic diet increases brain insulin-like growth factor receptor and glucose transporter gene expression. Endocrinology 144, 2676–2682. doi: 10.1210/en.2002-0057
15. Cotter, D. G., Schugar, R. C., and Crawford, P. A. (2013). Ketone body metabolism and cardiovascular disease. Am. J. Physiol. Heart Circ. Physiol. 304, H1060–H1076. doi: 10.1152/ajpheart.00646.2012
16. Cullingford, T. E., Eagles, D. A., and Sato, H. (2002). The ketogenic diet upregulates expression of the gene encoding the key ketogenic enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in rat brain. Epilepsy Res. 49, 99–107. doi: 10.1016/s0920-1211(02)00011-6
17. Cunnane, S. C., Courchesne-Loyer, A., St-Pierre, V., Vandenberghe, C., Pierotti, T., Fortier, M., et al. (2016). Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer’s disease. Ann. N Y Acad. Sci. 1367, 12–20. doi: 10.1111/nyas.12999
18. Dai, Y., Zhao, Y., Tomi, M., Shin, B.-C., Thamotharan, S., Mazarati, A., et al. (2017). Sex-Specific life course changes in the neuro-metabolic phenotype of Glut3 null heterozygous mice: ketogenic diet ameliorates electroencephalographic seizures and improves sociability. Endocrinology 158, 936–949. doi: 10.1210/en.2016-1816
19. Douris, N., Melman, T., Pecherer, J. M., Pissios, P., Flier, J. S., Cantley, L. C., et al. (2015). Adaptive changes in amino acid metabolism permit normal longevity in mice consuming a low-carbohydrate ketogenic diet. Biochim. Biophys. Acta 1852, 2056–2065. doi: 10.1016/j.bbadis.2015.07.009
20. Dukes, L. D., McIntyre, M. S., Mertz, R. J., Philipson, L. H., Roe, M. W., Spencer, B., et al. (1994). Dependence on NADH produced during glycolysis for β-cell glucose signaling. J. Biol. Chem. 269, 10979–10982.
21. Dupuis, N., Curatolo, N., Benoist, J.-F., and Auvin, S. (2015). Ketogenic diet exhibits anti-inflammatory properties. Epilepsia 56, e95–e98. doi: 10.1111/epi. 13038
22. Edmond, J. (1992). Energy metabolism in developing brain cells. Can. J. Physiol. Pharmacol. 70, S118–S129. doi: 10.1007/978-1-4684-1209-3_17
23. Evangeliou, A., Vlachonikolis, I., Mihailidou, H., Spilioti, M., Skarpalezou, A., Makaronas, N., et al. (2003). Application of a ketogenic diet in children with autistic behavior: pilot study. J. Child Neurol. 18, 113–118. doi: 10.1177/08830738030180020501
24. Feng, Z.-C., Roberts, E. L., Sick, T. J., and Rosenthal, M. (1988). Depth profile of local oxygen tension and blood flow in rat cerebral cortex, white matter and hippocampus. Brain Res. 445, 280–288. doi: 10.1016/0006-8993(88) 91190-0
25. Forsythe, C. E., Phinney, S. D., Feinman, R. D., Volk, B. M., Freidenreich, D., Quann, E., et al. (2010). Limited effect of dietary saturated fat on plasma saturated fat in the context of a low carbohydrate diet. Lipids 45, 947–962. doi: 10.1007/s11745-010-3467-3
26. Forsythe, C. E., Phinney, S. D., Fernandez, M. L., Quann, E. E., Wood, R. J., Bibus, D. M., et al. (2008). Comparison of low fat and low carbohydrate diets on circulating fatty acid composition and markers of inflammation. Lipids 43, 65–77. doi: 10.1007/s11745-007-3132-7
27. Freeman, J. M., and Vining, E. P. G. (1999). Seizures decrease rapidly after fasting: preliminary studies of the ketogenic diet. Arch. Pediatr. Adolesc. Med. 153, 946–949. doi: 10.1001/archpedi.153.9.946
28. García-Escudero, V., Martín-Maestro, P., Perry, G., and Avila, J. (2013). Deconstructing mitochondrial dysfunction in Alzheimer disease. Oxid. Med. Cell. Longev. 2013:162152. doi: 10.1155/2013/162152
29. Gomez-Arbelaez, D., Bellido, D., Castro, A. I., Ordoñez-Mayan, L., Carreira, J., Galban, C., et al. (2017). Body composition changes after very low-calorie-ketogenic diet in obesity evaluated by three standardized methods. J. Clin. Endocrinol. Metab. 102, 488–498. doi: 10.1210/jc.2016-2385
30. Heinemann, U., Beck, H., Dreier, J. P., Ficker, E., Stabel, J., and Zhang, C. L. (1992). The dentate gyrus as a regulated gate for the propagation of epileptiform activity. Epilepsy Res. Suppl. 7, 273–280.
31. Hori, A., Tandon, P., Holmes, G. L., and Stafstrom, C. E. (1997). Ketogenic diet: effects on expression of kindled seizures and behavior in adult rats. Epilepsia 38, 750–758. doi: 10.1111/j.1528-1157.1997.tb01461.x
32. Hui, L., Chen, X., Bhatt, D., Geiger, N. H., Rosenberger, T. A., Haughey, N. J., et al. (2012). Ketone bodies protection against HIV-1 Tat-induced neurotoxicity. J. Neurochem. 122, 382–391. doi: 10.1111/j.1471-4159.2012.07764.x
33. Hu, Z. G., Wang, H. D., Jin, W., and Yin, H. X. (2009). Ketogenic diet reduces cytochrome c release and cellular apoptosis following traumatic brain injury in juvenile rats. Ann. Clin. Lab. Sci. 39, 76–83. Available online at: http://www.annclinlabsci.org/content/39/1/76.full
34. Hussain, T. A., Mathew, T. C., Dashti, A. A., Asfar, S., Al-Zaid, N., and Dashti, H. M. (2012). Effect of low-calorie versus low-carbohydrate ketogenic diet in type 2 diabetes. Nutrition 28, 1016–1021. doi: 10.1016/j.nut.2012. 01.016
35. Janke, R., Dodson, A. E., and Rine, J. (2015). Metabolism and epigenetics. Annu. Rev. Cell Dev. Biol. 31, 473–496. doi: 10.1146/annurev-cellbio-100814-125544
36. Jenkins, D. J. A., Wong, J. M. W., Kendall, C. W. C., Esfahani, A., Ng, V. W. Y., Leong, T. C. K., et al. (2009). The effect of a plant-based low-carbohydrate (‘‘Eco-Atkins’’) diet on body weight and blood lipid concentrations in hyperlipidemic subjects. Arch. Intern. Med. 169, 1046–1054. doi: 10.1001/archinternmed.2009.115
37. Jeong, E. A., Jeon, B. T., Shin, H. J., Kim, N., Lee, D. H., Kim, H. J., et al. (2011). Ketogenic diet-induced peroxisome proliferator-activated receptor-γ activation decreases neuroinflammation in the mouse hippocampus after kainic acid-induced seizures. Exp. Neurol. 232, 195–202. doi: 10.1016/j. expneurol.2011.09.001
38. Kashiwaya, Y., Bergman, C., Lee, J.-H., Wan, R., King, M. T., Mughal, M. R., et al. (2013). A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer’s disease. Neurobiol. Aging 34, 1530–1539. doi: 10.1016/j.neurobiolaging.2012. 11.023
39. Kashiwaya, Y., Takeshima, T., Mori, N., Nakashima, K., Clarke, K., and Veech, R. L. (2000). D-β-hydroxybutyrate protects neurons in models of Alzheimer’s and Parkinson’s disease. Proc. Natl. Acad. Sci. U S A 97, 5440–5444. doi: 10.1073/pnas.97.10.5440
40. Khodadadi, S., Sobhani, N., Mirshekar, S., Ghiasvand, R., Pourmasoumi, M., Miraghajani, M., et al. (2017). Tumor cells growth and survival time with the ketogenic diet in animal models: a systematic review. Int. J. Prev. Med. 8:35. doi: 10.4103/2008-7802.207035
41. Kim, D. Y., Hao, J., Liu, R., Turner, G., Shi, F.-D., and Rho, J. M. (2012). Inflammation-mediated memory dysfunction and effects of a ketogenic diet in a murine model of multiple sclerosis. PLoS One 7:e35476. doi: 10.1371/journal. pone.0035476
42. Klement, R. J., Champ, C. E., Otto, C., and Kämmerer, U. (2016). Anti-tumor effects of ketogenic diets in mice: a meta-analysis. PLoS One 11:e0155050. doi: 10.1371/journal.pone.0155050
43. Kobow, K., Kaspi, A., Harikrishnan, K. N., Kiese, K., Ziemann, M., Khurana, I., et al. (2013). Deep sequencing reveals increased DNA methylation in chronic rat epilepsy. Acta Neuropathol. 126, 741–756. doi: 10.1007/s00401-013-1168-8
44. Koustova, E., Rhee, P., Hancock, T., Chen, H., Inocencio, R., Jaskille, A., et al. (2003). Ketone and pyruvate Ringer’s solutions decrease pulmonary apoptosis in a rat model of severe hemorrhagic shock and resuscitation. Surgery 134, 267–274. doi: 10.1067/msy.2003.245
45. Krikorian, R., Shidler, M. D., Dangelo, K., Couch, S. C., Benoit, S. C., and Clegg, D. J. (2012). Dietary ketosis enhances memory in mild cognitive impairment. Neurobiol. Aging 33, 425.e19–425.e27. doi: 10.1016/j. neurobiolaging.2010.10.006
46. Kussmaul, L., and Hirst, J. (2006). The mechanism of superoxide production by NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria. Proc. Natl. Acad. Sci. U S A 103, 7607–7612. doi: 10.1073/pnas. 0510977103
47. Landry, J., Sutton, A., Tafrov, S. T., Heller, R. C., Stebbins, J., Pillus, L., et al. (2000). The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proc. Natl. Acad. Sci. U S A 97, 5807–5811. doi: 10.1073/pnas. 110148297
48. Lin, S. H., Vincent, A., Shaw, T., Maynard, K. I., and Maiese, K. (2000). Prevention of nitric oxide-induced neuronal injury through the modulation of independent pathways of programmed cell death. J. Cereb. Blood Flow Metab. 20, 1380–1391. doi: 10.1097/00004647-200009000-00013
49. Liu, X., Lee, Y. J., Liou, L.-C., Ren, Q., Zhang, Z., Wang, S., et al. (2011). Alpha-synuclein functions in the nucleus to protect against hydroxyurea-induced replication stress in yeast. Hum. Mol. Genet. 20, 3401–3414. doi: 10.1093/hmg/ddr246
50. 2,’’ in Molecular Cell Biology, (4th Edn), New York, NY: W.H. Freeman.
51. Lusardi, T. A., Akula, K. K., Coffman, S. Q., Ruskin, D. N., Masino, S. A., and Boison, D. (2015). Ketogenic diet prevents epileptogenesis and disease progression in adult mice and rats. Neuropharmacology 99, 500–509. doi: 10.1016/j.neuropharm.2015.08.007
52. Lussier, D. M., Woolf, E. C., Johnson, J. L., Brooks, K. S., Blattman, J. N., and Scheck, A. C. (2016). Enhanced immunity in a mouse model of malignant glioma is mediated by a therapeutic ketogenic diet. BMC Cancer 16:310. doi: 10.1186/s12885-016-2337-7
53. Maalouf, M., Sullivan, P. G., Davis, L., Kim, D. Y., and Rho, J. M. (2007). Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation. Neuroscience 145, 256–264. doi: 10.1016/j.neuroscience.2006.11.065
54. Martinez, C. C., Pyzik, P. L., and Kossoff, E. H. (2007). Discontinuing the ketogenic diet in seizure-free children: recurrence and risk factors. Epilepsia 48, 187–190. doi: 10.1111/j.1528-1167.2006.00911.x
55. Masino, S. A. (2017). Ketogenic Diet and Metabolic Therapies: Expanded Roles in Health and Disease. New York, NY: Oxford University Press.
56. Masino, S. A., and Geiger, J. D. (2008). Are purines mediators of the anticonvulsant/neuroprotective effects of ketogenic diets? Trends Neurosci. 31, 273–278. doi: 10.1016/j.tins.2008.02.009
57. 1 receptors. J. Clin. Invest. 121, 2679–2683. doi: 10.1172/JCI57813
58. Masino, S. A., Svedova, J., Kawamura, M. Jr., DiMario, F. D. Jr., and Eigsti, I.-M. (2011b). ‘‘Adenosine and autism—recent research and a new perspective,’’ in Autism—A Neurodevelopmental Journey from Genes to Behaviour, ed. V. Eapen (Rijeka: InTech), 103–122.
59. Masino, S. A., and Rho, J. M. (2012). ‘‘Mechanism of ketogenic diet action,’’ in Jasper’s Basic Mechanisms of the Epilepsies, eds J. L. Noebels, M. Avoli, M. A. Rogawski, R. W. Oslen, and A. V. Delgado-Escueta, (4th Edn.) (Bethesda, MD: National Center for Biotechnology Information), 1003–1018.
60. McKenzie, A. L., Hallberg, S. J., Creighton, B. C., Volk, B. M., Link, T. M., Abner, M. K., et al. (2017). A novel intervention including individualized nutritional recommendations reduces hemoglobin a1c level, medication use, and weight in type 2 diabetes. JMIR Diabetes 2:e5. doi: 10.2196/diabetes.6981
61. Mosconi, L., Mistur, R., Switalski, R., Tsui, W. H., Glodzik, L., Li, Y., et al. (2009). FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer’s disease. Eur. J. Nucl. Med. Mol. Imaging 36, 811–822. doi: 10.1007/s00259-008-1039-z
62. Muller-Schwarze, A. B., Tandon, P., Liu, Z., Yang, Y., Holmes, G. L., and Stafstrom, C. E. (1999). Ketogenic diet reduces spontaneous seizures and mossy fiber sprouting in the kainic acid model. Neuroreport 10, 1517–1522. doi: 10.1097/00001756-199905140-00023
63. Nabbout, R., Mazzuca, M., Hubert, P., Peudennier, S., Allaire, C., Flurin, V., et al. (2010). Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES). Epilepsia 51, 2033–2037. doi: 10.1111/j.1528-1167.2010. 02703.x
64. Nandivada, P., Fell, G. L., Pan, A. H., Nose, V., Ling, P.-R., Bistrian, B. R., et al. (2016). Eucaloric ketogenic diet reduces hypoglycemia and inflammation in mice with endotoxemia. Lipids 51, 703–714. doi: 10.1007/s11745-016-4156-7
65. Naoi, M., Maruyama, W., Shamoto-Nagai, M., Yi, H., Akao, Y., and Tanaka, M. (2005). Oxidative stress in mitochondria: decision to survival and death of neurons in neurodegenerative disorders. Mol. Neurobiol. 31, 81–93. doi: 10.1385/mn:31:1-3:081
66. Neal, E. G., Chaffe, H., Schwartz, R. H., Lawson, M. S., Edwards, N., Fitzsimmons, G., et al. (2008). The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol. 7, 500–506. doi: 10.1016/s1474-4422(08)70092-9
67. Newman, J. C., Covarrubias, A. J., Zhao, M., Yu, X., Gut, P., Ng, C.-P., et al. (2017). Ketogenic diet reduces midlife mortality and improves memory in aging mice. Cell Metab. 26, 547.e8–557.e8. doi: 10.1016/j.cmet.2017.08.004
68. Newport, M. T., Vanitallie, T. B., Kashiwaya, Y., King, M. T., and Veech, R. L. (2015). A new way to produce hyperketonemia: use of ketone ester in a case of Alzheimer’s disease. Alzheimers Dement. 11, 99–103. doi: 10.1016/j.jalz.2014. 01.006
69. Noh, H. S., Hah, Y.-S., Nilufar, R., Han, J., Bong, J.-H., Kang, S. S., et al. (2006). Acetoacetate protects neuronal cells from oxidative glutamate toxicity. J. Neurosci. Res. 83, 702–709. doi: 10.1002/jnr.20736
70. Paoli, A. (2014). Ketogenic diet for obesity: friend or foe? Int. J. Environ. Res. Public Health 11, 2092–2107. doi: 10.3390/ijerph110202092
71. Partsalaki, I., Karvela, A., and Spiliotis, B. E. (2012). Metabolic impact of a ketogenic diet compared to a hypocaloric diet in obese children and adolescents. J. Pediatr. Endocrinol. Metab. 25, 697–704. doi: 10.1515/jpem-2012-0131
72. Patel, A., Pyzik, P. L., Turner, Z., Rubenstein, J. E., and Kossoff, E. H. (2010). Long-term outcomes of children treated with the ketogenic diet in the past. Epilepsia 51, 1277–1282. doi: 10.1111/j.1528-1167.2009.02488.x
73. Pathak, D., Berthet, A., and Nakamura, K. (2013). Energy failure: does it contribute to neurodegeneration? Ann. Neurol. 74, 506–516. doi: 10.1002/ana.24014
74. Pawlosky, R. J., Kemper, M. F., Kashiwaya, Y., King, M. T., Mattson, M. P., and Veech, R. L. (2017). Effects of a dietary ketone ester on hippocampal glycolytic and tricarboxylic acid cycle intermediates and amino acids in a 3xTgAD mouse model of Alzheimer’s disease. J. Neurochem. 141, 195–207. doi: 10.1111/jnc. 13958
75. Pulford, D. S. (1927). Ketogenic diets for epileptics. Cal. West. Med. 27, 50–56.
76. Reger, M. A., Henderson, S. T., Hale, C., Cholerton, B., Baker, L. D., Watson, G. S., et al. (2004). Effects of β-hydroxybutyrate on cognition in memory-impaired adults. Neurobiol. Aging 25, 311–314. doi: 10.1016/s0197-4580(03) 00087-3
77. Roberts, M. N., Wallace, M. A., Tomilov, A. A., Zhou, Z., Marcotte, G. R., Tran, D., et al. (2017). A ketogenic diet extends longevity and healthspan in adult mice. Cell Metab. 26, 539.e5–546.e5. doi: 10.1016/j.cmet.2017.08.005
78. Ruskin, D. N., Fortin, J. A., Bisnauth, S. N., and Masino, S. A. (2017a). Ketogenic diets improve behaviors associated with autism spectrum disorder in a sex-specific manner in the EL mouse. Physiol. Behav. 168, 138–145. doi: 10.1016/j.physbeh.2016.10.023
79. Ruskin, D. N., Murphy, M. I., Slade, S. L., and Masino, S. A. (2017b). Ketogenic diet improves behaviors in a maternal immune activation model of autism spectrum disorder. PLoS One 12:e0171643. doi: 10.1371/journal.pone. 0171643
80. Ruskin, D. N., Kawamura, M., and Masino, S. A. (2009). Reduced pain and inflammation in juvenile and adult rats fed a ketogenic diet. PLoS One 4:e8349. doi: 10.1371/journal.pone.0008349
81. Ruskin, D. N., Suter, T. A. C. S., Ross, J. L., and Masino, S. A. (2013a). Ketogenic diets and thermal pain: dissociation of hypoalgesia, elevated ketones, and lowered glucose in rats. J. Pain 14, 467–474. doi: 10.1016/j.jpain.2012.12.015
82. Ruskin, D. N., Svedova, J., Cote, J. L., Sandau, U., Rho, J. M., Kawamura, M., et al. (2013b). Ketogenic diet improves core symptoms of autism in BTBR mice. PLoS One 8:e65021. doi: 10.1371/journal.pone.0065021
83. + activate sirt1 to rescue premature aging in cockayne syndrome. Cell Metab. 20, 840–855. doi: 10.1016/j.cmet. 2014.10.005
84. Schmidt, M., Pfetzer, N., Schwab, M., Strauss, I., and Kämmerer, U. (2011). Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer: a pilot trial. Nutr. Metab. (Lond) 8:54. doi: 10.1186/1743-7075-8-54
85. Schwartzkroin, P. A. (1999). Mechanisms underlying the anti-epileptic efficacy of the ketogenic diet. Epilepsy Res. 37, 171–180. doi: 10.1016/s0920-1211(99)00069-8
86. Seyfried, T. N., and Mukherjee, P. (2005). Targeting energy metabolism in brain cancer: review and hypothesis. Nutr. Metab. 2:30. doi: 10.1186/1743-7075-2-30
87. Shimazu, T., Hirschey, M. D., Newman, J., He, W., Shirakawa, K., Le Moan, N., et al. (2013). Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211–214. doi: 10.1126/science.1227166
88. Spilioti, M., Evangeliou, A. E., Tramma, D., Theodoridou, Z., Metaxas, S., Michailidi, E., et al. (2013). Evidence for treatable inborn errors of metabolism in a cohort of 187 Greek patients with autism spectrum disorder (ASD). Front. Hum. Neurosci. 7:858. doi: 10.3389/fnhum.2013.00858
89. Streijger, F., Plunet, W. T., Lee, J. H. T., Liu, J., Lam, C. K., Park, S., et al. (2013). Ketogenic diet improves forelimb motor function after spinal cord injury in rodents. PLoS One 8:e78765. doi: 10.1371/journal.pone.0078765
90. Sullivan, P. G., Rippy, N. A., Dorenbos, K., Concepcion, R. C., Agarwal, A. K., and Rho, J. M. (2004). The ketogenic diet increases mitochondrial uncoupling protein levels and activity. Ann. Neurol. 55, 576–580. doi: 10.1002/ana. 20062
91. Tay, J., Luscombe-Marsh, N. D., Thompson, C. H., Noakes, M., Buckley, J. D., Wittert, G. A., et al. (2015). Comparison of low- and high-carbohydrate diets for type 2 diabetes management: a randomized trial. Am. J. Clin. Nutr. 102, 780–790. doi: 10.3945/ajcn.115.112581
92. + channels by oxidized and reduced pyridine nucleotide coenzymes. Am. J. Physiol. Cell Physiol. 288, C366–C376. doi: 10.1152/ajpcell.00354.2004
93. van der Veer, E., Ho, C., O’Neil, C., Barbosa, N., Scott, R., Cregan, S. P., et al. (2007). Extension of human cell lifespan by nicotinamide phosphoribosyltransferase. J. Biol. Chem. 282, 10841–10845. doi: 10.1074/jbc. c700018200
94. Vanitallie, T. B., Nonas, C., Di Rocco, A., Boyar, K., Hyams, K., and Heymsfield, S. B. (2005). Treatment of Parkinson disease with diet-induced hyperketonemia: a feasibility study. Neurology 64, 728–730. doi: 10.1212/01. WNL.0000152046.11390.45
95. Verpeut, J. L., DiCicco-Bloom, E., and Bello, N. T. (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. doi: 10.1016/j.physbeh.2016.04.001
96. Volek, J. S., Fernandez, M. L., Feinman, R. D., and Phinney, S. D. (2008). Dietary carbohydrate restriction induces a unique metabolic state positively affecting atherogenic dyslipidemia, fatty acid partitioning, and metabolic syndrome. Prog. Lipid Res. 47, 307–318. doi: 10.1016/j.plipres.2008.02.003
97. Volek, J. S., Phinney, S. D., Forsythe, C. E., Quann, E. E., Wood, R. J., Puglisi, M. J., et al. (2009). Carbohydrate restriction has a more favorable impact on the metabolic syndrome than a low fat diet. Lipids 44, 297–309. doi: 10.1007/s11745-008-3274-2
98. Westman, E. C., Yancy, W. S. Jr., Mavropoulos, J. C., Marquart, M., and McDuffie, J. R. (2008). The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus. Nutr. Metab. 5:36. doi: 10.1186/1743-7075-5-36
99. + and NADH content. J. Neurosci. Res. 89, 1956–1964. doi: 10.1002/jnr.22638
100. Yancy, W. S. Jr., Foy, M., Chalecki, A. M., Vernon, M. C., Westman, E. C., and Westman, E. C. (2005). A low-carbohydrate, ketogenic diet to treat type 2 diabetes. Nutr. Metab. 2:34. doi: 10.1186/1743-7075-2-34
101. Yang, X., and Cheng, B. (2010). Neuroprotective and anti-inflammatory activities of ketogenic diet on MPTP-induced neurotoxicity. J. Mol. Neurosci. 42, 145–153. doi: 10.1007/s12031-010-9336-y
102. + metabolism: bioenergetics, signaling and manipulation for therapy. Biochim. Biophys. Acta 1864, 1787–1800. doi: 10.1016/j.bbapap.2016.06.014
103. Yeung, F., Hoberg, J. E., Ramsey, C. S., Keller, M. D., Jones, D. R., Frye, R. A., et al. (2004). Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 23, 2369–2380. doi: 10.1038/sj.emboj.7600244
104. Zhang, J., Cao, Q., Li, S., Lu, X., Zhao, Y., Guan, J.-S., et al. (2013). 3-Hydroxybutyrate methyl ester as a potential drug against Alzheimer’s disease via mitochondria protection mechanism. Biomaterials 34, 7552–7562. doi: 10.1016/j.biomaterials.2013.06.043
105. + repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352, 1436–1443. doi: 10.1126/science.aaf2693
106. Zhao, Z., Lange, D. J., 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. doi: 10.1186/1471-2202-7-29
107. Zhu, J., and Chu, C. T. (2010). Mitochondrial dysfunction in Parkinson’s disease. J. Alzheimers Dis. 20, S325–S334. doi: 10.3233/JAD-2010-100363
108. Zhu, X., Liu, Q., Wang, M., Liang, M., Yang, X., Xu, X., et al. (2011). Activation of Sirt1 by resveratrol inhibits TNF-α induced inflammation in Fibroblasts. PLoS One 6:e27081. doi: 10.1371/journal.pone.0027081
109. 3 -Hydroxybutyrate administration prevents myocardial damage after coronary occlusion in rat hearts. Am. J. Physiol. Heart Circ. Physiol. 283, H1968–H1974. doi: 10.1152/ajpheart.00250.2002
110. Zuccoli, G., Marcello, N., Pisanello, A., Servadei, F., Vaccaro, S., Mukherjee, P., et al. (2010). Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: case report. Nutr. Metab. 7:33. doi: 10.1186/1743-7075-7-33