Intermittent Fasting and Caloric Restriction: Neuroplasticity and Neurodegeneration

  • Andrea Rodrigues Vasconcelos
  • Ana Maria Marques Orellana
  • Amanda Galvão Paixão
  • Cristoforo Scavone
  • Elisa Mitiko KawamotoEmail author
Living reference work entry


The central nervous system plays a key and important role in regulating dietary energy consumption. Studies in the literature have shown that high calorie intake is deleterious to the physiological function of neurons. On the other hand, low-calorie intake has demonstrated to be beneficial, protecting neurons against harmful effects that could lead to the development of neurodegeneration. This chapter aimed to review the main aspects of dietary energy restriction protocols, such as intermittent fasting and calorie restriction, in relation to neuronal plasticity, cognition, and neurodegeneration.


Dietary energy restriction Caloric restriction Intermittent fasting Cognition Cognitive function Memory Neurogenesis Neuroplasticity Brain Hormesis Hippocampus Neurodegeneration Alzheimer’s disease Parkinson’s disease 

List of Abbreviations

Amyloid-β peptide


Alzheimer’s disease


A disintegrin and metalloproteinase 10


Amyloid precursor protein


Brain-derived neurotrophic factor




Central nervous system


Caloric restriction


Cyclic AMP response element-binding protein


Dopamine active transporter


Dietary energy restriction


Dentate gyrus


Forkhead box O


Glial cell line-derived neurotrophic factor


Glucose-regulated protein 78


Glucose transporter 3


Heme oxygenase 1


Heat-shock protein 70


Intermittent fasting






Morris water maze


Nuclear factor κB


N-Methyl-D-aspartate receptor


Parkinson’s disease


Peroxisome proliferator-activated receptor gamma coactivator 1-α


Peroxisome proliferator-activated receptors


Reactive oxygen species




Substantia nigra


Superoxide dismutase 2


Tropomyosin receptor kinase B


Vesicular monoamine transporter


Ventral tegmental area


World Health Organization


  1. Abrous DN, Koehl M, Le Moal M (2005) Adult neurogenesis: from precursors to network and physiology. Physiol Rev 85:523–569CrossRefPubMedGoogle Scholar
  2. Al-Shafei AI (2014) Ramadan fasting ameliorates arterial pulse pressure and lipid profile, and alleviates oxidative stress in hypertensive patients. Blood Press 23:160–167CrossRefPubMedGoogle Scholar
  3. Attwell D, Iadecola C (2002) The neural basis of functional brain imaging signals. Trends Neurosci 25:621–625CrossRefPubMedGoogle Scholar
  4. Bahammam A (2003) Sleep pattern, daytime sleepiness, and eating habits during the month of Ramadan. Sleep Hypnosis 5:165–174Google Scholar
  5. Bahammam AS, Alaseem AM, Alzakri AA et al (2013a) The effects of Ramadan fasting on sleep patterns and daytime sleepiness: an objective assessment. J Res Med Sci 18:127–131PubMedPubMedCentralGoogle Scholar
  6. Bahammam AS, Nashwan S, Hammad O et al (2013b) Objective assessment of drowsiness and reaction time during intermittent Ramadan fasting in young men: a case-crossover study. Behav Brain Funct 9:32CrossRefPubMedPubMedCentralGoogle Scholar
  7. Camandola S, Mattson MP (2017) Brain metabolism in health, aging, and neurodegeneration. EMBO J 36:1474–1492CrossRefPubMedGoogle Scholar
  8. Clarke DD, Sokoloff L (1999) Circulation and energy metabolism of the brain. In: Siegel GJ, Agranof BW, Albers RW, Fisher SK, Uhler MD (eds) Basic Neurochemistry. Lippincott-Raven, PhiladelphiaGoogle Scholar
  9. Colman RJ, Anderson RM, Johnson SC et al (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325:201–204CrossRefPubMedPubMedCentralGoogle Scholar
  10. Devoto A, Lucidi F, Violani C et al (1999) Effects of different sleep reductions on daytime sleepiness. Sleep 22:336–343CrossRefPubMedGoogle Scholar
  11. Dong W, Wang R, Ma LN et al (2015) Autophagy involving age-related cognitive behavior and hippocampus injury is modulated by different caloric intake in mice. Int J Clin Exp Med 8:11843–11853PubMedPubMedCentralGoogle Scholar
  12. Drapeau E, Mayo W, Aurousseau C et al (2003) Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis. Proc Natl Acad Sci U S A 100:14385–14390CrossRefPubMedPubMedCentralGoogle Scholar
  13. Duan W, Mattson MP (1999) Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson’s disease. J Neurosci Res 57:195–206CrossRefPubMedGoogle Scholar
  14. Eckles-Smith K, Clayton D, Bickford P et al (2000) Caloric restriction prevents age-related deficits in LTP and in NMDA receptor expression. Brain Res Mol Brain Res 78:154–162CrossRefPubMedGoogle Scholar
  15. Farooq A, Herrera CP, Almudahka F et al (2015) A prospective study of the physiological and neurobehavioral effects of Ramadan fasting in preteen and teenage boys. J Acad Nutr Diet 115:889–897CrossRefPubMedGoogle Scholar
  16. Ferreira FR, VBMG S, Lopes EJ et al (2006) Effect of feed restriction on learning, memory and stress of rodents. Biosci J 22:91–97Google Scholar
  17. Fontan-Lozano A, Saez-Cassanelli JL, Inda MC et al (2007) Caloric restriction increases learning consolidation and facilitates synaptic plasticity through mechanisms dependent on NR2B subunits of the NMDA receptor. J Neurosci 27:10185–10195CrossRefPubMedGoogle Scholar
  18. Gillette-Guyonnet S, Vellas B (2008) Caloric restriction and brain function. Curr Opin Clin Nutr Metab Care 11:686–692CrossRefPubMedGoogle Scholar
  19. Goldhamer A, Lisle D, Parpia B et al (2001) Medically supervised water-only fasting in the treatment of hypertension. J Manip Physiol Ther 24:335–339CrossRefGoogle Scholar
  20. Graff J, Kahn M, Samiei A et al (2013) A dietary regimen of caloric restriction or pharmacological activation of SIRT1 to delay the onset of neurodegeneration. J Neurosci 33:8951–8960CrossRefPubMedPubMedCentralGoogle Scholar
  21. Green MW, Rogers PJ, Elliman NA et al (1994) Impairment of cognitive performance associated with dieting and high levels of dietary restraint. Physiol Behav 55:447–452CrossRefPubMedGoogle Scholar
  22. Green MW, Elliman NA, Rogers PJ (1995) Lack of effect of short-term fasting on cognitive function. J Psychiatr Res 29:245–253CrossRefPubMedGoogle Scholar
  23. Halagappa VK, Guo Z, Pearson M et al (2007) Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the triple-transgenic mouse model of Alzheimer’s disease. Neurobiol Dis 26:212–220CrossRefPubMedGoogle Scholar
  24. Hartman AL, Rubenstein JE, Kossoff EH (2013) Intermittent fasting: a “new” historical strategy for controlling seizures? Epilepsy Res 104:275–279CrossRefPubMedGoogle Scholar
  25. Harvie MN, Pegington M, Mattson MP et al (2011) The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomized trial in young overweight women. Int J Obes 35:714–727CrossRefGoogle Scholar
  26. Harvie M, Wright C, Pegington M et al (2013) The effect of intermittent energy and carbohydrate restriction v. daily energy restriction on weight loss and metabolic disease risk markers in overweight women. Br J Nutr 110:1534–1547CrossRefPubMedGoogle Scholar
  27. Horne BD, Muhlestein JB, Anderson JL (2015) Health effects of intermittent fasting: hormesis or harm? A systematic review. Am J Clin Nutr 102:464–470CrossRefPubMedGoogle Scholar
  28. Jeon BT, Heo RW, Jeong EA et al (2016) Effects of caloric restriction on O-GlcNAcylation, Ca(2+) signaling, and learning impairment in the hippocampus of ob/ob mice. Neurobiol Aging 44:127–137CrossRefPubMedGoogle Scholar
  29. Johnson JB, Summer W, Cutler RG et al (2007) Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma. Free Radic Biol Med 42:665–674CrossRefPubMedGoogle Scholar
  30. Kaptan Z, Akgun-Dar K, Kapucu A et al (2015) Long term consequences on spatial learning-memory of low-calorie diet during adolescence in female rats; hippocampal and prefrontal cortex BDNF level, expression of NeuN and cell proliferation in dentate gyrus. Brain Res 1618:194–204CrossRefPubMedGoogle Scholar
  31. Kennedy C, Sakurada O, Shinohara M et al (1978) Local cerebral glucose utilization in the normal conscious macaque monkey. Ann Neurol 4:293–301CrossRefPubMedGoogle Scholar
  32. Kishi T, Hirooka Y, Nagayama T et al (2015) Calorie restriction improves cognitive decline via up-regulation of brain-derived neurotrophic factor: tropomyosin-related kinase B in hippocampus of obesity-induced hypertensive rats. Int Heart J 56:110–115CrossRefPubMedGoogle Scholar
  33. Kjeldsen-Kragh J, Haugen M, Borchgrevink CF et al (1991) Controlled trial of fasting and one-year vegetarian diet in rheumatoid arthritis. Lancet 338:899–902CrossRefPubMedGoogle Scholar
  34. Kuhla A, Lange S, Holzmann C et al (2013) Lifelong caloric restriction increases working memory in mice. PLoS One 8:e68778CrossRefPubMedPubMedCentralGoogle Scholar
  35. Lee J, Duan W, Long JM et al (2000) Dietary restriction increases the number of newly generated neural cells, and induces BDNF expression, in the dentate gyrus of rats. J Mol Neurosci 15:99–108CrossRefPubMedGoogle Scholar
  36. Lee J, Duan W, Mattson MP (2002a) Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem 82:1367–1375CrossRefPubMedGoogle Scholar
  37. Lee J, Seroogy KB, Mattson MP (2002b) Dietary restriction enhances neurotrophin expression and neurogenesis in the hippocampus of adult mice. J Neurochem 80:539–547CrossRefPubMedGoogle Scholar
  38. Leybaert L, De Bock M, Van Moorhem M et al (2007) Neurobarrier coupling in the brain: adjusting glucose entry with demand. J Neurosci Res 85:3213–3220CrossRefPubMedGoogle Scholar
  39. Lipsky RH, Marini AM (2007) Brain-derived neurotrophic factor in neuronal survival and behavior-related plasticity. Ann N Y Acad Sci 1122:130–143CrossRefPubMedGoogle Scholar
  40. Longo VD, Mattson MP (2014) Fasting: molecular mechanisms and clinical applications. Cell Metab 19:181–192CrossRefPubMedPubMedCentralGoogle Scholar
  41. Ma L, Zhao Z, Wang R et al (2014) Caloric restriction can improve learning ability in C57/BL mice via regulation of the insulin-PI3K/Akt signaling pathway. Neurol Sci 35:1381–1386CrossRefPubMedGoogle Scholar
  42. Marosi K, Mattson MP (2014) BDNF mediates adaptive brain and body responses to energetic challenges. Trends Endocrinol Metab 25:89–98CrossRefPubMedGoogle Scholar
  43. Martinet LE, Sheynikhovich D, Benchenane K et al (2011) Spatial learning and action planning in a prefrontal cortical network model. PLoS Comput Biol 7:e1002045CrossRefPubMedPubMedCentralGoogle Scholar
  44. Maswood N, Young J, Tilmont E et al (2004) Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson’s disease. Proc Natl Acad Sci U S A 101:18171–18176CrossRefPubMedPubMedCentralGoogle Scholar
  45. Mattson MP (2002) Brain evolution and lifespan regulation: conservation of signal transduction pathways that regulate energy metabolism. Mech Ageing Dev 123:947–953CrossRefPubMedGoogle Scholar
  46. Mattson MP (2008a) Dietary factors, hormesis and health. Ageing Res Rev 7:43–48CrossRefPubMedGoogle Scholar
  47. Mattson MP (2008b) Hormesis defined. Ageing Res Rev 7:1–7CrossRefPubMedGoogle Scholar
  48. Mattson MP (2010) The impact of dietary energy intake on cognitive aging. Front Aging Neurosci 2:5PubMedPubMedCentralGoogle Scholar
  49. Mattson MP, Duan W, Guo Z (2003) Meal size and frequency affect neuronal plasticity and vulnerability to disease: cellular and molecular mechanisms. J Neurochem 84:417–431CrossRefPubMedGoogle Scholar
  50. Means LW, Higgins JL, Fernandez TJ (1993) Mid-life onset of dietary restriction extends life and prolongs cognitive functioning. Physiol Behav 54:503–508CrossRefPubMedGoogle Scholar
  51. Michalsen A, Schlegel F, Rodenbeck A et al (2003) Effects of short-term modified fasting on sleep patterns and daytime vigilance in non-obese subjects: results of a pilot study. Ann Nutr Metab 47:194–200CrossRefPubMedGoogle Scholar
  52. Morand-Ferron J, Cole EF, Quinn JL (2016) Studying the evolutionary ecology of cognition in the wild: a review of practical and conceptual challenges. Biol Rev Camb Philos Soc 91:367–389CrossRefPubMedGoogle Scholar
  53. Muller H, De Toledo FW, Resch KL (2001) Fasting followed by vegetarian diet in patients with rheumatoid arthritis: a systematic review. Scand J Rheumatol 30:1–10PubMedGoogle Scholar
  54. Palop JJ, Chin J, Mucke LA (2006) Network dysfunction perspective on neurodegenerative diseases. Nature 443:768–773CrossRefPubMedGoogle Scholar
  55. Patel NV, Gordon MN, Connor KE et al (2005) Caloric restriction attenuates Abeta-deposition in Alzheimer transgenic models. Neurobiol Aging 26:995–1000CrossRefPubMedGoogle Scholar
  56. Przedborski S, Vila M, Jackson-Lewis V (2003) Neurodegeneration: what is it and where are we? J Clin Invest 111:3–10CrossRefPubMedPubMedCentralGoogle Scholar
  57. Qasrawi SO, Pandi-Perumal SR, Bahammam AS (2017) The effect of intermittent fasting during Ramadan on sleep, sleepiness, cognitive function, and circadian rhythm. Sleep Breath 21:577CrossRefPubMedGoogle Scholar
  58. Qin W, Chachich M, Lane M et al (2006) Calorie restriction attenuates Alzheimer’s disease type brain amyloidosis in Squirrel monkeys (Saimiri sciureus). J Alzheimers Dis 10:417–422CrossRefPubMedGoogle Scholar
  59. Rashotte ME, Pastukhov IF, Poliakov EL et al (1998) Vigilance states and body temperature during the circadian cycle in fed and fasted pigeons (Columba livia). Am J Phys 275:R1690–R1702Google Scholar
  60. Roky R, Iraki L, Hajkhlifa R et al (2000) Daytime alertness, mood, psychomotor performances, and oral temperature during Ramadan intermittent fasting. Ann Nutr Metab 44:101–107CrossRefPubMedGoogle Scholar
  61. Roky R, Chapotot F, Benchekroun MT et al (2003) Daytime sleepiness during Ramadan intermittent fasting: polysomnographic and quantitative waking EEG study. J Sleep Res 12:95–101CrossRefPubMedGoogle Scholar
  62. Shettleworth SJ (2009) Cognition, evolution, and behavior. Oxford University Press, OxfordGoogle Scholar
  63. Singh R, Lakhanpal D, Kumar S et al (2012) Late-onset intermittent fasting dietary restriction as a potential intervention to retard age-associated brain function impairments in male rats. Age (Dordr) 34:917–933CrossRefGoogle Scholar
  64. Soares-Simi SL, Pastrello DM, Ferreira ZS et al (2013) Changes in CREB activation in the prefrontal cortex and hippocampus blunt ethanol-induced behavioral sensitization in adolescent mice. Front Integr Neurosci 7:94CrossRefPubMedPubMedCentralGoogle Scholar
  65. Tian HH, Aziz AR, Png W et al (2011) Effects of fasting during ramadan month on cognitive function in muslim athletes. Asian J Sports Med 2:145–153CrossRefPubMedPubMedCentralGoogle Scholar
  66. Vasconcelos AR, Yshii LM, Viel TA et al (2014) Intermittent fasting attenuates lipopolysaccharide-induced neuroinflammation and memory impairment. J Neuroinflammation 11:85CrossRefPubMedPubMedCentralGoogle Scholar
  67. Wang J, Ho L, Qin W et al (2005) Caloric restriction attenuates beta-amyloid neuropathology in a mouse model of Alzheimer’s disease. FASEB J 19:659–661CrossRefPubMedGoogle Scholar
  68. Waqanivalu T, Nederveen L (2015) Fiscal policies for diet and prevention of noncommunicable diseases. World Health Organization. Accessed 10 Nov 2017
  69. Weindruch R, Sohal RS (1997) Seminars in medicine of the Beth Israel Deaconess Medical Center. Caloric intake and aging. N Engl J Med 337:986–994CrossRefPubMedPubMedCentralGoogle Scholar
  70. Witte AV, Fobker M, Gellner R et al (2009) Caloric restriction improves memory in elderly humans. Proc Natl Acad Sci U S A 106:1255–1260CrossRefPubMedPubMedCentralGoogle Scholar
  71. Wu A, Sun X, Liu Y (2003) Effects of caloric restriction on cognition and behavior in developing mice. Neurosci Lett 339:166–168CrossRefPubMedGoogle Scholar
  72. Xu BL, Wang R, Ma LN et al (2015) Effects of caloric intake on learning and memory function in juvenile C57BL/6J mice. Biomed Res Int 2015:759803PubMedPubMedCentralGoogle Scholar
  73. Yuan XZ, Sun S, Tan CC et al (2017) The role of ADAM10 in Alzheimer’s disease. J Alzheimers Dis 58:303–322CrossRefPubMedGoogle Scholar
  74. Zainuddin MS, Thuret S (2012) Nutrition, adult hippocampal neurogenesis and mental health. Br Med Bull 103:89–114CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Andrea Rodrigues Vasconcelos
    • 1
  • Ana Maria Marques Orellana
    • 1
  • Amanda Galvão Paixão
    • 1
  • Cristoforo Scavone
    • 1
  • Elisa Mitiko Kawamoto
    • 1
    Email author
  1. 1.Department of PharmacologyUniversity of São PauloButantãBrazil

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