Chronic Intermittent Fasting Improves Cognitive Functions and Brain Structures in Mice
Open accessAbstract
Obesity is a major health issue. Obesity started from teenagers has become a major health concern in recent years. Intermittent fasting increases the life span. However, it is not known whether obesity and intermittent fasting affect brain functions and structures before brain aging. Here, we subjected 7-week old CD-1 wild type male mice to intermittent (alternate-day) fasting or high fat diet (45% caloric supplied by fat) for 11 months. Mice on intermittent fasting had better learning and memory assessed by the Barnes maze and fear conditioning, thicker CA1 pyramidal cell layer, higher expression of drebrin, a dendritic protein, and lower oxidative stress than mice that had free access to regular diet (control mice). Mice fed with high fat diet was obese and with hyperlipidemia. They also had poorer exercise tolerance. However, these obese mice did not present significant learning and memory impairment or changes in brain structures or oxidative stress compared with control mice. These results suggest that intermittent fasting improves brain functions and structures and that high fat diet feeding started early in life does not cause significant changes in brain functions and structures in obese middle-aged animals.
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Intermittent fasting (IF) is a diet with salutary effects on cognitive aging, Alzheimer's disease (AD), and stroke.
“Intermittent fasting (IF) is a diet with salutary effects on cognitive aging, Alzheimer’s disease (AD), and stroke.”
From 2-Deoxyglucose drives plasticity via an adaptive ER stress-ATF4 pathway and elicits stroke recovery and Alzheimer’s resilience (2023) · cites this paper as [6]
The Results and Discussion report improved learning and memory and reduced cerebral-cortex oxidative stress in mice after intermittent fasting; the Discussion links oxidative stress to brain aging. The paper does not show that intermittent fasting benefits Alzheimer’s disease or stroke, and its findings in mice do not establish effects on cognitive aging more broadly. No page numbers are available in our copy. (LLM, conf=0.87)
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“One day after Barnes maze test, mice were subjected to fear conditioning test as we previously described [5, 19].”
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Mori Folium and Mori Fructus Mixture Attenuates High-Fat Diet-Induced Cognitive Deficits in Mice
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“Previous research has revealed that long-term dietary restriction modulates synaptic protein expression in the hippocampus [1].”
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“Alternate day fasting, for example, can slow the aging process [15, 16], reduce visceral adiposity [17], improve cognitive function [15, 18] and delay the development of chronic diseases [15, 19].”
BackgroundPrecision Nutrition and Gut–Brain Axis Modulation in the Prevention of Neurodegenerative Diseases
Tuigunov, D. N., Sinyavskiy, Y. A., Nurgozhin, T. S., Zholdassova, Z., Smagul, G., Omarov, Y., Dolmatova, O., Yeshmanova, A., & Omarova, I. (2025) · Nutrients · doi:10.3390/nu17193068 · Cited by 19 · see citing works
“Preclinical studies in animal models indicate positive effects of intermittent fasting on cognitive functions, including improved memory performance, stimulation of neurogenesis, and reduction in neuroinflammatory processes [244,245].”
Ebrahim, H., El-Gamal, R., & Sherif, R. N. (2021) · Cells Tissues Organs · doi:10.1159/000519088 · Cited by 20 · see citing works
“IF also has a positive effect on lowering the high-density lipoprotein, cholesterol, triglyceride, and low-density lipoprotein blood levels together with body weight reduction [Li et al., 2013].”
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SGLT2 inhibition to target kidney aging
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“It has also been shown that mitochondrial function is improved and amyloid plaque deposition in the brain is reduced, ameliorating age-related and neurodegeneration disease [52 , 53 ].”
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“Pertinent to our findings, undernutrition has been shown to positively impact behavior in that intermittent fasting has been shown to improve Barnes maze performance and fear conditioning [71].”
BackgroundMissong, H., Joshi, R., Khullar, N., Thareja, S., Navik, U., Bhatti, G. K., & Bhatti, J. S. (2024) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2024.109592 · Cited by 19 · see citing works
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“Furthermore, Li et al (1) reported that, for 11 months of ImF, significant body weight change in adult CD-1 mice (7-week old) appeared after 37 weeks (around 9 months) of ImF.”
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“Animals were fed commercially available rodent normal diet or IF (24 h fasting and 24 h feeding) was applied for 2 months according to method by published methods (9,12,17).”
MethodCao, J., Wang, Z., Mi, W., & Zuo, Z. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.04.049 · Cited by 16 · see citing works
“Fear conditioning test Fear conditioning was performed by using the Freeze Monitor from San Diego Instruments (San Diego, CA) as we described before (Lin and Zuo, 2011; Li et al., 2013).”
MethodSelf-citationAutophagy: Biology and Diseases: Clinical Science
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“Likewise, ANXA7 has become a leading compound for therapeutic drug development as it may have anti-atherosclerotic effects (Li et al. 2013a).”
BackgroundInfluentialTripolt, N. J., Hofer, S. J., Pferschy, P. N., Aziz, F., Durand, S., Aprahamian, F., Nirmalathasan, N., Waltenstorfer, M., Eisenberg, T., Obermayer, A. M., et al. (2023) · Nutrients · doi:10.3390/nu15030511 · Cited by 15 · see citing works
“Moreover, animal studies suggested neuroprotective effects [5] and an improvement of learning and memory after prolonged fasting in mice [6].”
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Yu, H., Deng, J., & Zuo, Z. (2014) · Obesity · doi:10.1002/oby.20879 · Cited by 13
“The cytosolic fraction of the whole hippocampus or hippocampal slices after being exposed to various experimental conditions was prepared as we previously described (20,21).”
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“Frequently, people in modern society attempt to reduce their body weight using a calorie-controlled diet and intermittent fasting over a short period [6,7].”
BackgroundIntermittent fasting alerts neurotransmitters and oxidant/antioxidant status in the brain of rats
Abdel-Rahman, M., Hussein, A. A., Ahmed-Farid, O. A.-H., Sawi, A. A., & Moneim, A. E. A. (2024) · Metabolic Brain Disease · doi:10.1007/s11011-024-01415-7 · Cited by 16 · see citing works
“Li et al. ( 2013 ) investigated how IF affected the expression of dopamine receptors.”
BackgroundIntermittent fasting—The new lifestyle?
Khedkar, P. H. (2020) · Acta Physiologica · doi:10.1111/apha.13518 · Cited by 13 · see citing works
Modulation of frailty syndrome by diet: A review of evidence from mouse studies
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García‐Juárez, M., García-Rodríguez, A., Cruz-Carrillo, G., Flores-Maldonado, O. E., Becerril-García, M. A., Garza‐Ocañas, L., Torre-Villalvazo, I., & Camacho‐Morales, A. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04340-z · Cited by 10 · see citing works
“This is consistent with other studies that reported fasting reduced oxidative stress in cortex and hippocampus, as well as improved memory and learning [126] and decreased JNK signaling in senescence-accelerated mice P8 (SAMP8) [127].”
Neuroprotective Effects of Intermittent Fasting in the Aging Brain
Dong, H., Wang, S., Hu, C., Wang, M., Zhou, T., & Zhou, Y. (2024) · Annals of Nutrition and Metabolism · doi:10.1159/000538782 · Cited by 19 · see citing works
Campos-Rodríguez, R., Godínez-Victoria, M., Reyna-Garfias, H., Arciniega-Martínez, I., Reséndiz-Albor, A., Abarca-Rojano, E., Cruz-Hernández, T., & Drago-Serrano, M. (2016) · AGE · doi:10.1007/s11357-016-9876-3 · Cited by 10
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“In the mouse model, 11 months of IF not only increased the thickness of the CA1 pyramidal cell layer and the expression of the dendritic protein drebrin in the hippocampus but also reduced the occurrence of oxidative stress [21].”
Food restriction modifies ultrastructure of hippocampal synapses
Babits, R., Szőke, B., Sótonyi, P., & Rácz, B. (2015) · Hippocampus · doi:10.1002/hipo.22533 · Cited by 10 · see citing works
“Intermittent fasting – a widely used form of dietary restriction – has been shown to improve learning and memory (Li et al., 2013), and dietary restriction has been shown to enhance performance in tests of learning and memory (Fontan-Lozano et al., 2007; Adams et al., 2008; Mattson, 2010), while…”
BackgroundSystemic and transcriptional response to intermittent fasting and fasting-mimicking diet in mice
Michenthaler, H., Duszka, K., Reinisch, I., Galhuber, M., Moyschewitz, E., Stryeck, S., Madl, T., Prokesch, A., & Krstić, J. (2024) · BMC Biology · doi:10.1186/s12915-024-02061-2 · Cited by 6 · see citing works
Elhessy, H. M., Berika, M. Y., Salem, Y. G., El-Desoky, M. M., Eldesoqui, M. B., Mostafa, N., Habotta, O. A., & Lashine, N. H. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e28436 · Cited by 7 · see citing works
Grundler, F., Mesnage, R., Cerrada, A., & de Toledo, F. W. (2023) · Frontiers in Nutrition · doi:10.3389/fnut.2023.1195270 · Cited by 11 · see citing works
“In the rodent brain, fasting reduced oxidative stress (29) and enhanced mitochondrial oxidative metabolism (30).”
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“Hence, this provides a plausible explanation of the observed non-significant difference of ROS production between IF groups while its effect on CYP1a1/a2 expression and other parameter differ significantly [62,63].”
BackgroundLong-Term Shaping of Corticostriatal Synaptic Activity by Acute Fasting
Campanelli, F., Laricchiuta, D., Natale, G., Marino, G., Calabrese, V., Picconi, B., Petrosini, L., Calabresi, P., & Ghiglieri, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041916 · Cited by 8 · see citing works
“Food restriction has mainly been tested as a tool to enhance hippocampal-dependent memory performance [9,10], leading to improvement in cognition and synaptic efficacy.”
MethodProgress of Anti-aging Drugs Targeting Autophagy.
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“As indicated by Li et al. (2013), who discovered that a 40% reduction in caloric intake lowers oxidative stress in several parts of the brain, IF-induced caloric restriction also enhances the level of the brain ’ s redox state.”
BackgroundInfluence of long-term fasting and intermittent fasting on the cognitive abilities
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“Intermittent fasting, as opposed to caloric restriction, increases the tolerance of the hippocampal neuron to excitotoxic stress in mice, which may indicate the neuroprotective effects (Anson et al. 2003) and improves learning and memory in mice (Li, Wang, and Zuo 2013).”
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Dietary restriction in senolysis and prevention and treatment of disease
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Intermittent fasting and mental and physical fatigue in obese and non-obese rats
Niepoetter, P., Butts‐Wilmsmeyer, C. J., & Gopalan, C. (2022) · PLoS ONE · doi:10.1371/journal.pone.0275684 · Cited by 6 · see citing works
“The mice in the fasting condition outperformed mice in the other groups [30].”
BackgroundPrevention of Neurologic Disease with Fasting
Macri, E., & Azhar, Y. (2022) · Seminars in Neurology · doi:10.1055/a-1957-8449 · Cited by 6 · see citing works
Pitchaimani, V., Arumugam, S., Thandavarayan, R., Karuppagounder, V., Afrin, M. R., Sreedhar, R., Harima, M., Nakamura, M., Watanabe, K., Kodama, S., et al. (2020) · Neurochemistry International · doi:10.1016/j.neuint.2020.104745 · Cited by 5 · see citing works
- Authors
- Li, L., Wang, Z., & Zuo, Z.
- Affiliations
- University of Virginia (US)
- Sun Yat-sen University (CN)
- Corresponding author
- Zuo, Zhiyi
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-06-03
- Volume
- 8
- Issue
- 6
- Pages
- e66069
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3670843
- OpenAlex
- W1974661288
- Cited by
- 147
- References
- 23
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 13 · 2023: 13 · 2022: 19 · 2021: 14 · 2020: 19 · 2019: 9 · 2018: 6 · 2017: 9 · 2016: 9 · 2015: 8 · 2014: 6
- FWCI
- 5.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- American Heart Association (10GRNT3900019)
- International Anesthesia Research Society (R01 GM065211)
- National Institutes of Health (GM098308)
- National Institute of General Medical Sciences (R01GM065211, R01GM098308)
- Topics
- Health Sciences › Medicine › Physiology › Dietary Effects on Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- intermittent fasting, alternate-day fasting, cognitive function, learning and memory, brain aging, high-fat diet, obesity, drebrin, oxidative stress, hyperlipidemia, exercise tolerance, Barnes maze, fear conditioning, middle-aged mice
- MeSH terms
- Aging, Animals, Cerebral Cortex, Cognition, Dietary Fats, Fasting, Male, Memory, Mice, Obese, Neuropeptides, Obesity, Exercise Tolerance, Oxidative Stress, Maze Learning, Mice, CA1 Region, Hippocampal, Diet, High-Fat
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