Reviewing the effects of intermittent fasting on neurological diseases and
cognition: For whom and when does intermittent fasting yield positive effects?
Jip Gudden
under supervision of Dr. Mirjam Bloemendaal January 2021
Institute for Interdisciplinary Studies, University of Amsterdam, Science Park 904, Amsterdam, The Netherlands
Abstract
The incidence of neurological disorders has risen in the past thirty years, whereas treatments are still lacking. Therefore, more attention has shifted towards the prevention of neurological disorders. For instance, the interplay between diets and their effect on the brain. Intermittent fasting (IF), the abstinence or strong limitation of calories for 12 to 48 hours, alternated with periods of regular food intake, has shown promising results. In this review article, we discuss the potential benefits of IF on cognitive function and the possible effects on the prevention and progress of neurological diseases. We do so by looking at the effects of IF that - through metabolic, cellular and circadian mechanisms - lead to anatomical and functional changes in the brain. Animal studies show clear mechanisms by which IF has positive effects on the prevention and progress of neurological diseases. Clinical studies show a similar picture for epilepsy, Alzheimer’s disease and multiple sclerosis, whereas future clinical trials have to shed light on Parkinson’s disease and ischaemic stroke. It seems as these positive effects can be further enhanced when the nutritional intake during feeding periods is also healthier. In contrast, there has not been clear evidence that IF has positive short-term effects on cognition in healthy subjects. Long-term effects of IF on neurological disease prevention in healthy subjects has not been longitudinally examined. However, there are indications that IF might yield protective effects on neurological diseases which appear to be independent of age, the presence of obesity or total caloric intake. Future longitudinal studies, initiated with subjects at middle age and continued until an age where neurological diseases commence, could provide a window into the long-term effects of IF on the development of neurological disorders.
© University of Amsterdam, All rights reserved.
Keywords: Intermittent fasting, cognition, neurological diseases, prevention and progress
Introduction
Higher-income countries are facing challenges with an increase of age-related neurological and neurodegenerative diseases (WHO, 2018). The incidence of neurological diseases in higher-income countries has grown by 39% in the past thirty years (Feigin et al. 2019). An explanation is that people become older, as the average human life span in higher-income countries has increased by fifteen years during the last century (Flanagan, Most, Mey, & Redman, 2020). But another cause for the enhanced number of neurological diseases is the growth of risk factors like overweight and obesity (Feigin et al., 2020). Despite the large number of studies that have been initiated to find possible treatments of neurological diseases, therapeutic options are still mostly based on symptom relief while cures have not yet been found. Therefore, epidemiological evidence supports a role for certain life style factors that can open new
potential avenues for the prevention of neurological diseases that could be more effective than finding cures and treatments (Solfrizzi et al., 2008). For instance, the interplay between diets and their effect on the brain has been heavily researched in the past years (Moore et al., 2018). Several diets have found to slow down cognitive decline, with most evidence pointing towards the Mediterranean diet, which is high in vegetables, fruits, legumes, nuts, beans, cereals, grains, fish, and olive oil (Scarmeas, Anastasiou, & Yannakoulia, 2018). Moreover, the DASH diet is designed to reduce cardiovascular risk, which consists of foods that are low in sodium, potassium, magnesium and calcium. The MIND diet is a combination of the Mediterranean diet and the DASH diet, specifically composed of nutrients that are known to slow down cognitive decline (Morris et al., 2015). At last, diets that involve a restriction on the total amount of calories that can be consumed have also
shown positive effects on resistance against cognitive decline (for an overview of clinical improvements see Yu et al., 2020). Although these diets have positive effects, caloric restrictions and nutritional diets are hard to sustain for most people and can have detrimental effects for people who already have low body weights or muscle mass (Walford, Mock, Verdery, & MacCallum, 2002; Vitousek, 2004). Interestingly, a growing body of evidence from animal studies as well as epidemiological and clinical studies suggest that fasting periods without caloric or nutritional changes could have similar effects on cognition and the prevention of neurological diseases (Mattson, Longo, & Harvie, 2017). So alongside a growing interest in examining the role of nutritional intake on cognition, there has also been a growing interest to examine the timing and frequency of when to eat (Di Francesco, Di Germanio, Bernier, & de Cabo, 2018). Namely, intermittent fasting (IF) is the abstinence or strong limitation of calories for 12 to 48 hours. These periods are alternated with periods of regular food intake where there are no restrictions.
From an evolutionary standpoint, alternations of food availability and scarcity have been normal for most of humans throughout history and could be coped by storing food as fat (Liao et al., 2011). As a result of periods of restricted food intake, the human body initiates a metabolic switch from glucose to stored lipids, which leads to a cascade of metabolic, cellular and circadian changes that are associated with numerous health benefits in animal models and humans (Longo & Panda, 2016; Mattson et al., 2017; Liu et al., 2020). For instance, periods of IF have not only been associated with weight- and metabolism- related diseases, but also with positive effects on neurological diseases (Mattson et al., 2014). In this review article, we will discuss the potential benefits of IF on cognitive function and the possible effects on the prevention and progress of neurological diseases. We will do so by looking at the effects of IF that - through metabolic, cellular and circadian mechanisms - lead to anatomical and functional changes in the brain. Furthermore, we will critically review the evidence from clinical and epidemiological studies by listing studies that used different age groups, patient groups and different dietary restrictions to obtain the most complete overview of the possible benefits of an intermittent fasting diet on cognition and neurological diseases.
Metabolic, cellular and circadian responses to IF
Different variants of IF
Three variants of IF can be distinguished (see Figure 1), namely time-restricted eating (TRE), which is called time-restricted feeding in animals (TRF), alternate day fasting (ADF) and the 5:2 diet or periodic fasting (PF). ADF entails that people alternate between eating regularly on one day and restrain from eating the next day. PF is characterized by cycles of abstinence or strong limitation of food for 2 days a week whereas food can be
eaten without restrictions for the other 5 days of the week. TRE/TRF is characterized by a time window of food intake that only lasts 8 hours per day (note that studies vary on this and that eating windows of 6-12 hours per day is also seen as TRE). There is also a distinction within TRF, namely eTRF (eating early during the day) and lTRF (eating late during the day).
Figure 1. Different forms of intermittent fasting.
Caloric restriction (CR) entails that people have to consume 30% less calories but without time restrictions. PF or the 5:2 diet allows eating without restrictions for 5 days of the week, with 2 days of complete fasting. ADF entails that people alternate between eating regularly on one day and restrain from eating the next day. TRF/TRE is characterized by a time window of food intake that only lasts 8 hours per day or less. Retrieved from Balasubramanian et al. (2020) with small modifications.
The metabolic switch
The different variants of IF differ in the duration of the fast and therefore also in their effects on the body. However, they all have in common that when IF is sustained long enough, a process called “flipping” the metabolic switch is initiated. This process occurs around 12 to 36 hours after the fast begins, depending on the liver glycogen content at the beginning of the fast, the composition of the preceding meal and an individual’s amount of energy expenditure during the fast (Anton et al., 2018). Flipping the metabolic switch entails that the body switches from its preference to extract energy through the process of glycogenolysis (breakdown of glycogen into glucose) to lipolysis (the utilization of stored fat in the form of lipids from adipose tissue). It is believed that through this mechanism, IF can have positive effects for the treatment of obesity, diabetes and cardiovascular diseases (Mattson et al., 2017). Moreover, during a fast, these lipids are metabolised to free fatty acids (FFAs) in the liver. These FFAs are – through the process of β-oxidation and the intermediate stage Acetyl CoA – transformed to the ketones; β‑hydroxybutyrate (BHB) and acetoacetate (AcAc)(Mattson et al., 2018).
What makes ketones particularly interesting for cognition is that ketones become the preferred fuel for the brain during a fast (Puchalska & Crawford, 2017). Namely, in addition to the role of ketones as an energy source, ketones also have signalling effects and regulate transcription factors in neurons (Wilhelmi de Toledo, Grundler, Sirtori, & Ruscica, 2020). BHB
3 and AcAc are transported from the liver to the brain where they
are metabolised to acetyl CoA and HMG-CoA, which results in the upregulation of brain-derived neurotrophic factors (BDNF). The upregulation of BDNF is related with the promotion of mitochondrial biogenesis, synaptic plasticity and cellular stress resistance in animal models (Mattson et al., 2018). Enhanced BDNF levels during IF are also found in humans (Jamshed et al., 2019) and hypothesized is that the proposed mechanism holds true for humans as well (Mattson et al., 2018). Moreover, the lowered levels of glucose during IF also leads to a reduction in the ATP:AMP ratio, which after some hours of fasting activates the kinases; AMPK and CaKMII. Activation of their downstream transcription factors (CREB and PGC1α) enables these kinases to inhibit anabolic processes, thus inhibiting cell growth and biosynthesis. This, in turn, triggers repair by stimulating autophagy, a process where neurons remove dysfunctional or damaged components (Kong et al., 2016; Kobilo et al., 2014).
Neurons are able to regulate the synthesis of proteins in response to fluctuations in the availability of nutrition, namely through the mTOR pathway (Johnson, Rabinovitch, & Kaeberlein, 2013). In a non-fasting state, activation of the mTOR pathway leads to protein- and lipid synthesis. In contrast, activity of the mTOR pathway decreases during fasting periods and this leads to global inhibition of protein synthesis and the recycling of dysfunctional proteins by autophagy (Alirezaei et al., 2010). Autophagy is also responsible for the body’s ability to cope with oxidative stress (the accumulation of harmful free radicals) which is associated with neurodegenerative diseases and decreases with age (Davies, 2000; Pham-Huy & Pham-Huy, 2008). Inhibition of the mTOR pathway leads to an improvement in antioxidant defences (molecules that prevent the oxidation of free radicals), DNA repair and stimulation of BDNF (Menzies et al., 2017). Astrocytes are also capable of metabolizing FFAs to ketones. Therefore, astrocytes could be an important local source of BHB for neurons due to their direct connection (Valdebenito et al., 2016).
Insulin sensitivity is decreased in diabetic patients, but also naturally decays with age (Kalyani & Egan, 2013). IF leads to decreased levels of circulating insulin in the blood, enhancing the sensitivity of insulin receptors and upregulation of the insulin/IGF-1 signalling (IIS) pathway (Rahmani et al., 2019). Upregulated IIS activity also decreases the activity of the mTOR pathway (Longo & Mattson, 2014) and is associated with enhancement of neuroplasticity and protection against oxidative stress (Rahmani et al., 2019). All in all, organisms respond to a sustained period of lowered energy availability by minimizing anabolic processes (such as protein synthesis or growth) and favouring processes that enhance stress resistance, tissue repair and recycling of damaged proteins and molecules (Di Francesco et al., 2018)(see Figure 2).
Figure 2. Biochemical pathways involved in the metabolic switch. During intermittent fasting, glucose levels drop and through the process of lipolysis, fats (triacylglycerols and diacylglycerols) are metabolized to free fatty acids (FFAs). These lipids are then transported to the liver where they - through the process of β-oxidation and the intermediate stages Acetyl CoA and HMG-CoA - are transformed into the ketones: acetoacetate (AcAc) and β-hydroxybutyrate (BHB). BHB and AcAc are transported from the blood into the brain and then into neurons. The reduction in availability of glucose and elevation of ketones lowers the AMP:ATP ratio in neurons, which activates the kinases AMPK and CaKMII and, in turn, through the activation of CREB and PGC1α stimulates autophagy. BHB can also upregulate the expression of brain-derived neurotrophic factor (BDNF) and may thereby promote mitochondrial biogenesis, synaptic plasticity and cellular stress resistance. In addition to ketones metabolized in the liver, astrocytes are also capable of ketogenesis, which may provide an important local source of BHB for neurons. IF also leads to lower levels of circulating insulin in the blood, which can enhance neuroplasticity and protection against metabolic and oxidative stress through the insulin/IGF signalling pathway. Retrieved from Mattson et al. (2017) with small modifications.
Circadian clock mechanisms
Organisms have evolved to optimize physiological processes, such as the hormonal secretion pattern, to an endogenous circadian clock that matches day and night oscillations (Panda, Hogenesch, & Kay, 2002). In humans, the brain area involved in regulating this circadian clock is the suprachiasmatic nucleus (SCN), which is entrained to light and dark. On a molecular level, the circadian clock is regulated by transcription factors who – when risen too strongly – inhibit their own expression through transcriptional-translational feedback loops (Longo & Panda, 2016). Specifically, the transcription activators (BMAL1 and CLOCK) bind to three Period (Per 1-3) and two Cryptochrome (Cry 1-2) genes, driving their transcription. The translated proteins CRY and PER then inhibit the expression of BMAL and CLOCK, thus inhibiting their own expression. This creates a negative feedback loop in which gene transcription, hormonal secretion and protein levels oscillate on a ~24-hour basis. The amplitude (the difference in levels of hormones, proteins, etc. between peaks and throughs) should be as large as possible to
optimally prepare the body for activity or rest (Manoogian & Panda, 2017).
Similar secondary clock oscillators have been found in peripheral tissues, such as the liver, with meal timing as the main regulator (Patterson & Sears, 2017). Ideally, central and peripheral oscillators act in synchrony to optimally prepare the body for rest or activity. In Western societies, 24-hour lighting, shift work and altered meal schedules lead to different input signals to the central and peripheral clocks (Oosterman, Wopereis, & Kalsbeek, 2020). For example, consuming food outside the normal eating phase (i.e. late-night eating) may set some peripheral clocks out of phase with central oscillators and dampens the amplitude. Deterioration in the amplitude of peripheral circadian oscillations is related with Alzheimer’s disease (Hofman & Swaab, 2006), haemorrhagic stroke vulnerability (Casetta, Granieri, Portaluppi, & Manfredini, 2002) and increases with age in humans (Manoogian & Panda, 2017).
Interestingly, TRF has the ability to alter peripheral oscillators by strengthening the amplitude and coupling its phase to central oscillations, which leads to optimal rhythms of behaviour, physiology and metabolism (Longo & Panda, 2016). This ensures that anabolic and catabolic types of mechanisms are regulated in harmony with someone’s activity and rest cycle (Longo & Panda, 2016). A mechanism by which fasting can alter circadian-driven processes is the result of downstream effects of the (due to TRF) inhibited mTOR pathway. During fasting, the expression of CRY1 and CRY2 is directly regulated by phosphorylated kinases (AMPK, CK1 and GSK3), which couples the phase of central and peripheral oscillators and strengthens their amplitude (Lamia et al., 2009; Longo & Panda, 2016). Similarly, the mTOR pathway also increases the circadian phosphorylation of CREB which can activate Per transcription, which also couples the circadian rhythms and strengthens the amplitude (Vollmers et al., 2009). In sum, deterioration in the amplitude of peripheral circadian oscillations and decoupling of peripheral oscillators with the central oscillator are associated with neurological diseases and increasing age. TRF exert its effects by strengthening the amplitude and changing the phase of secondary oscillators to match central oscillations of the SCN. Gut microbiota and the gut-brain axis
The human gastrointestinal tract (GT) is colonized by an enormous amount of microorganisms, collectively termed the gut microbiota. A higher diversity of microbiota is associated with a healthier gut microbiome (Le Chatelier et al., 2013). The diversity or richness in gut microbiota composition is not fixed, but dynamically oscillates in activity and abundance throughout the day (Thaiss et al., 2015). Unhealthy eating patterns dampen these fluctuations, leading to a less diverse gut microbiome (Zarrinpar, Chaix, Yooseph, & Panda, 2014). Interestingly, TRF restores these cyclical fluctuations and thereby contributes to a richer diversity of the gut microbiome, even when nutritional intake is unaltered (Zarrinpar et al., 2014). The gut microbiota
is particularly interesting for cognition and neurological disorders because there is increasing evidence that the composition of the gut microbiota directly influences the brain through the gut-brain axis (Sampson & Mazmanian, 2015).
The gut-brain axis has numerous mechanisms by which the gut microbiota can affect the brain. Firstly, the gut microbiota modulates the interaction between the enteric nervous system and the central nervous system through the vagus nerve (Fung et al., 2017). Secondly, the gut microbiota produces microbial neurometabolites, signalling molecules which exert their effect by functioning as substrates for metabolic reactions (e.g. the microorganisms Lactobacillus and Bifidobacterium are involved in the generation of GABA; Lyte, 2011). Thirdly, the gut microbiota also has an indirect effect on the brain and behaviour through the effects on T-cells of the immune system (Cryan & Dinan, 2012). A well-known example are symptoms of sickness during viral or bacterial infections; decreased motor activity, difficulty with memory and learning, appetite suppression and reduced cognition (Dantzer et al., 2008).
Several animal studies have found that IF changes the composition of the gut microbiota (Liu et al., 2020; Cignarella et al., 2018; Beli et al., 2018). In Liu et al. (2020), IF enriched the gut microbiome composition and altered microbial metabolites which led to improved cognitive functioning, for example on spatial memory. Antibiotics treatment, detrimental for the gut microbiota, suppressed this improvement (Liu et al., 2020). In a study of 80 healthy men, Zeb and colleagues (2020) found that TRF enriched the composition of gut microbiota, which led to up-regulated transcription of the Bmal1 and Clock genes and thereby improved circadian oscillations. The gut microbiota is also found to be involved in the pathogenesis of various central nervous system disorders in humans, like Alzheimer’s disease, Parkinson’s disease, epilepsy and multiple sclerosis (Vogt et al., 2017; Scheperjans et al., 2015; Lindefeldt et al., 2019; Choi et al., 2016). In two clinical studies that examined the role of the gut microbiota in multiple sclerosis, IF improved the abundance of gut microbiota that are known to have anti-inflammatory effects and lessen multiple sclerosis severity (Stanisavljević et al., 2016), which led to lowered self-reported multiple sclerosis disability (Choi et al., 2016; Cignarella et al., 2018).
Summary of the neurological mechanisms behind IF In sum, the human body initiates a metabolic switch from glucose to stored lipids after a period of restricted food intake. These lipids are then metabolised to ketones, which have signalling effects and regulate transcription factors in neurons in the brain. Namely, anabolic processes are minimized (such as protein synthesis and growth) and catabolic processes are favoured that enhance stress resistance, tissue repair and recycling of damaged proteins and molecules. Moreover, TRF ensures that anabolic and catabolic types of mechanisms are regulated in harmony with someone’s activity and rest cycle.
5 Namely, TRF has the ability to strengthen the amplitude and
change the phase of secondary oscillators to match central oscillations of the SCN. At last, IF enriches the diversity of the gut microbiome. There are multiple ways (through the vagus nerve, neurometabolites or an immune response) by which IF can have effects on the brain. All in all, metabolic, cellular and circadian mechanisms of fasting periods have direct and indirect influences on the brain which could improve cognitive functioning and the progress or prevention of neurological disorders.
IF in different groups
IF in people with neurological diseases
Neurological diseases are major causes of morbidity throughout the world. In general, available data on the direct effects of IF on mechanisms contributing to the development or protection of neurological diseases in humans are scarce. However, potential efficacy of IF on neurological diseases in humans can be deducted by comparing IF-related proteins and genes in fasting humans with those present in fasting animals. Namely, gut microbiota and signalling proteins during IF can be identified through faecal- and serum proteomics (analysis of protein levels in the faeces and the blood respectively) and gene expression can be identified through mRNA levels in the blood. But most importantly, when available, randomized controlled trials (RCTs) will give the most insight in the possible positive effects
of IF on neurological diseases in humans. The effects of IF on the most extensively examined neurological diseases from preclinical and clinical studies are summarized in the following section. More specifically, the results from IF interventions in animal and humans studies on epilepsy, ischaemic stroke, Alzheimer’s disease, Parkinson’s disease and multiple sclerosis, are summarized in table 1.
Epilepsy
Epilepsy is a neurological disorder characterized by recurrent bursts of abnormal excessive neuronal activity, named seizures, in which motor control and often consciousness is lost (Duncan, Sander, Sisodiya, & Walker, 2006). In an animal model of epilepsy, rats maintained on ADF for several months exhibited less neuronal hippocampal damage and showed improved performance on a spatial water maze after being induced with a seizure compared to seizure-induced rats fed ad libitum (Bruce‑Keller, Umberger, McFall, & Mattson, 1999). With regards to the cellular and molecular mechanism, a crucial role for the gut microbiota has been postulated to mediate the protective effects of IF against epileptic seizures (Olson et al., 2018). Namely, ADF elevates GABA levels and decrease glutamate levels in the brain, which decreases overexcitability in the hippocampus (Olson et al., 2018). In a large RCT (Neal et al., 2008), 145 children not responding to antiepileptic drugs were given a ketogenic diet, which due to its low carbohydrate intake is believed to have similar effects as IF (D’Andrea Meira et al., 2019). Neal and colleagues (2008) found that children
Table 1
Characteristics of different preclinical and clinical studies on epilepsy, ischaemic stroke, Alzheimer’s disease and Parkinson’s disease. The species on which the study is conducted, the type of IF, and the duration of the diet are shown in columns two to four. The references of the studies are shown in the fifth column. At last, the findings of each study are reported in the last column. Ongoing studies are shown in italic.
Neurological disease Species Type of IF Duration Reference Findings
Epilepsy Ischaemic stroke Rodents Rodents Humans Humans Rodents Rodents Rodents Humans Humans ADF Ketogenic diet Ketogenic diet PF ADF ADF fasting Ramadan IF TRF 2-4 months 14 days 3 months 2 months 3 months 3 months 24 hours 13 years 6 months Bruce‑Keller et al. (1999) Olson et al. (2018) Neal et al. (2008) Hartman et al. (2013) Arumugan et al., 2010 Roberge et al. (2008) Davis et al. (2008) Bener et al. (2006)
Ulsan University hospital
less neuronal hippocampal damage and improved spatial navigation Decreased overexcitability in the hippocampus
Significantly less seizures than a control group Improved seizure control in children
Reduced cortical neuronal loss and reduced cognitive decline Recovery of spatial memory deficits
Reduced neuronal loss when fasting is initiated after injury and maintained for 24h
No differences in the number of hospitalisations for stroke between Ramadan and non-fasting months assessed in an epidemiological study
Ongoing random clinical trial to assess the effects of TRF after stroke
Alzheimer’s disease Rodents Ketogenic diet 4-7 months Kashiwaya et al. (2013) Improved performance on learning and memory tests and decreased Aβ
and tau pathologies
Humans fasting 12-16h Reger et al. (2004) Injected BHB leads to improved cognitive functioning
Parkinson’s disease Multiple sclerosis Humans Humans Humans Rodents Macaques Rodents Rodents Humans Humans TRF PF FMD FMD TRF FMD ADF FMD/Ketogenic ADF 30 days 3 years Unknown 3 cycles 6-10 months 3 cycles 4 weeks 7/30 days 15 days Mindikoglu et al. (2020) Ooi et al. (2020) University of Genova Zhou et al. (2019) Maswood et al. (2004) Choi et al. (2016) Cignarella et al. (2018) Choi et al. (2016) Cignarella et al. (2018)
Reduced amyloid precursor protein
Ongoing random clinical trial to assess the effectiveness of FMD in patients with mild cognitive impairment
Greater retention of motor skills and less dopaminergic neuronal loss in the SN Reduced motor deficiencies and attenuated dopamine depletion
Reversed disease progression
Increased gut microbiota richness and lowered levels of T lymphocytes Lowered self-reports of MS disability
after a 3-month ketogenic diet experienced significantly less seizures than a control group. In children with epilepsy not responding to antiepileptic treatment, a PF regimen for two months improved seizure control in four out six children (Hartman, Rubenstein, & Kossoff, 2013).
Ischaemic stroke
Ischaemic stroke is characterized by neuronal death and cognitive decline, caused by a blockage of blood flow to a part of the brain (Dirnagl, Iadecola, & Moskowitz, 1999). In animal models of focal ischaemic stroke, rodents on a 3-month ADF diet prior to cerebral vessel occlusion exhibited reduced cortical neuronal loss and reduced cognitive decline in comparison with animals fed ad libitum (Arumugan et al., 2010). Same results were obtained for the recovery of spatial memory deficits in rats maintained on a 3-month TRF diet before cerebral vessel occlusion compared with rats fed ad libitum (Roberge, Messier, Staines, & Plamondon, 2008). In an epidemiological study, Bener et al. (2006) reviewed the number of ischaemic stroke hospitalisations for Muslims while fasting during the Ramadan (which is a type of IF) and compared this incidence to non-fasting months. However, they found no differences in the number of hospitalisations for stroke between Ramadan and non-fasting months. During an ischaemic attack, quick reperfusion of blood flow is associated with better clinical outcomes, but reperfusion is contradictorily associated with exacerbation of tissue injury (Eltzschig & Eckle, 2011). Reactive oxygen species (ROS), a type of free radicals, have a critical role in initiating cell death and therefore enlarge tissue injury. Enhanced levels of ketones during a fast are thought to mediate the excitoprotective effects of IF by decreasing the levels of ROS (Gibson, Murphy, & Murphy, 2012). Injected ketones after cerebral vessel occlusion in rats were found to decrease levels of ROS, which led to enhanced stress resistance as well as suppression of neuroinflammation, which are both positive for cell survival (Prins, Lee, Fujima, & Hovda, 2004; Rahman et al., 2014; Yin, Han, Tang, Liu, & Shi, 2015). Interestingly, fasting initiated just after injury and maintained for 24 hours reduced neuronal loss in rats (Davis et al., 2008), which could be clinically relevant for humans but – up to this date - has not yet been tested in clinical or randomized controlled trials. However, the Ulsan University Hospital of South Korea is currently examining the efficacy of TRF in a RCT by randomly assigning ischaemic stroke patients to a 6-months TRF group or a control group (ClinicalTrials.gov, 2020).
Alzheimer’s disease
Alzheimer’s disease (AD) is a neurodegenerative disease that – due to the increase of life span worldwide – affects more people every year. The exact mechanism that causes AD is unknown. It is known, however, that AD is pathologically characterized by beta-amyloid (Aβ) plaques and neurofibrillary tangles, leading to neuronal death, which is clinically characterized by a decay in
cognitive abilities. Several studies using animal models have indicated that IF could reduce the accumulation of Aβ plaques and slow down cognitive decline (Halagappa et al., 2007; Zhang et al., 2017; Stewart, Mitchell & Kalant, 1989). Since the exact mechanism of AD is not yet fully understood, the mechanisms by which IF can have effects on AD is also only open for speculation. Argued is that IF can decrease neuropathology and cognitive decline of AD by upregulating neuronal stress-resistance pathways and suppress inflammation processes through decreased activity of the mTOR pathway (Mattson et al., 2018). In the brain, there is a reduction in glucose metabolism rates with age, which can be present long before the onset of AD and is associated with Aβ plaque density (Cunnane et al., 2016; Meier-Ruge, Bertoni-Freddari, & Iwangoff, 1994). Ketones might be alternative sources of fuel for the brain, suggested by studies that showed that ketone uptake in the brain is not different for AD patients than for healthy age‑matched controls (Croteau et al., 2018; Castellano et al., 2015; Ogawa, Fukuyama, Ouchi, Yamauchi, & Kimura, 1996). In mice, ketogenic diets have shown to counteract AD pathogenesis and cognitive decline as indicated by improved performance on learning and memory tests and decreased Aβ and tau pathologies (Kashiwaya et al., 2013). In patients suffering from AD or mild cognitive impairment, injected BHB after approximately 12 to 16 hours of fasting has led to improved cognitive functioning, assessed in various neuropsychological tests administered 90 minutes after injection (Reger et al., 2004). Moreover, a 14-hour TRF diet for 30 consecutive days has shown to reduce amyloid precursor protein (APP), the precursor of Aβ, in the blood of fourteen healthy subjects (Mindikoglu et al., 2020). Ooi and colleagues (2020) found that a 3-year PF diet enhanced cognitive functioning in older adults with mild cognitive impairment compared with age-matched adults who irregularly practice PF and age-matched adults who do not practice PF. In addition, a two-year phase I/II clinical trial is initiated in which AD patients will undergo a fasting-mimicking diet (FMD), a variation of PF in which fasting is practiced five consecutive days a month, to assess its efficacy as a treatment. (L-nutra, 2020).
Parkinson’s disease
Parkinson’s disease (PD) is characterized by the presence of α-synuclein-containing Lewy bodies and the loss of dopaminergic neurons in the substantia nigra (SN), which is clinically manifested by motor control problems (i.e. rigidity, bradykinesia, and tremor) and less frequently accompanied by cognitive deficiencies (Tysnes & Storstein, 2017). An animal model of PD, in which the degeneration of nigrostriatal neurons causes PD-like behaviour, can be induced by the administration of mitochondrial toxins that accumulate in dopaminergic neurons (Mattson et al., 2018). Using this model, neurotoxic-induced PD mice on a FMD showed greater retention of motor skills and less dopaminergic neuronal loss in the SN (Zhou et al.,
7 2019). Specifically, a FMD reshaped the composition of the gut
microbiota which – through the signalling effects of metabolites – restored the balance of BDNF and levels of astrocytes and microglia in the SN which are believed to be responsible for the inflammatory reactions in PD. Reduced motor deficiencies and attenuated dopamine depletion were also obtained in macaque monkeys on a TRF regimen who were neurotoxically injected to mimic PD (Maswood et al., 2004). In humans, no clinical trials are yet initiated early in the disease process and continued long enough (1 year or longer) to detect a disease-modifying effect of IF.
Multiple sclerosis
Multiple sclerosis (MS) is an autoimmune disorder in which abnormal T-cell mediated inflammatory response of the body causes demyelination and axonal damage, leading to neuronal death (Choi et al., 2016; Raine & Wu, 1993). MS is more common in Western countries with nutrition being a potential contributing factor, which led researchers to examine the role between IF and MS (Choi et al., 2016; Cignarella et al., 2018). Three cycles of a FMD completely reversed disease progression in MS-induced mice (Choi et al., 2016). A possible mechanism of IF on MS might be modulation of the gut microbiota, as 4 weeks of ADF activated microbial metabolic pathways and increased gut microbiota richness in a MS animal model (Cignarella et al., 2018). This, in turn, led to lowered levels of T lymphocytes, which are believed to be causative of MS pathogenesis (Legroux, & Arbour, 2015). Interestingly, transplantation of gut microbiota of MS-mice on an IF diet reduced MS pathogenesis for MS-mice without an IF diet (Cignarella et al., 2018). In humans, both a 30-day ketogenic diet and one 7-day cycle of FMD led to lowered self-reports of MS disability in 60 MS patients (Choi et al., 2016). In a small RCT with 5 MS patients and 9 controls, a 15-day ADF induced changes to the gut microbiota that are similar to what was observed in mice (Cignarella et al., 2018).
IF in healthy people
An outstanding question is whether IF has positive effects on cognition for people not suffering from neurological diseases. In healthy subjects, cognitive functioning has been heavily researched during Ramadan IF (Tian et al., 2011; Qasrawi, Pandi-Perumal, & BaHammam, 2017; Chamari et al., 2017). Qasrawi and colleagues (2017) reviewed studies that examined cognitive functioning during Ramadan IF and reported mix results for psychomotor functioning, memory, and visual- and verbal learning with poorer performances observed later in the day. An important confound for Ramadan IF is that it partially reverses the normal circadian pattern of eating and drinking with the circadian clock regulated by day light. As mentioned before in this review, it is known that desynchronized circadian rhythms have detrimental effects on cognition (Hofman &
Swaab, 2006). Therefore, we are not going to focus on studies with Ramadan IF as the intervention.
Benau and colleagues (2014) did a systematic review on 10 studies wherein the effects of IF on cognition were examined when the eating window took place during the day. These studies showed an inconsistent profile, with either no changes due to IF or negative effects on executive function, psychomotor speed or mental rotation. These studies only examined young adults (aged 18 – 28). It could be that healthy young subjects already show a ceiling effect when their cognition is tested. Moreover, the studies mentioned in the Benau et al. (2014) review paper have in common that subjects suddenly have to change to a fasting regimen. This period is long enough to flip the metabolic switch, but too short to couple peripheral and central oscillators and therefore is often accompanied by sensations of hunger (Hoddy et al., 2016). Hunger is associated with a decrease in cognitive performance (Rampersaud, Pereira, Girard, Adams, & Metzl, 2005) and could therefore be counter effective for the effects of IF in short trials. Namely, the subjective experience of hunger during fasting periods decreases as someone has regular fasts for a prolonged time (Bhutani et al., 2013). In a pilot study, Anton et al. (2019) showed that ten older adults with mobility impairments improved their cognitive and physical functioning after a TRE diet of 4 weeks. A 3-month RCT with 38 healthy subjects (age 20 – 68 years) showed that a FMD lowers the serum levels of C-reactive protein, a biomarker of inflammation and a risk factor for ischaemic stroke (Brandhorst et al., 2015). In addition, four weeks of ADF and >6 months of ADF reduced risk factors for the development of stroke for 29 and 30 healthy non-obese subjects, respectively (Stekovic et al., 2019). However, the studies reviewed above did not find any short-term effects of IF on cognitive functioning in healthy people, only that the risk for ischaemic stroke decreases. There are more studies that report indications of a reduced risk for neurological diseases due to IF in healthy people. For instance, lowered APP levels (Mindikoglu et al., 2020), enhanced hippocampal neurogenesis (Kim et al., 2020), and decreased mTOR pathway activity (Jamshed et al., 2019), which are all protective of developing AD (Moreno-Jiménez et al., 2019). So an interesting question to ask is whether IF might have substantial effects on the prevention of neurological diseases in healthy people when people maintain IF for a longer period of time.
Prevention of neurological diseases
IF initiated in different age groups
In order to understand the long-term effects of IF on the prevention of neurological diseases, we first have to compare studies that initiated IF in different ages. Namely, is IF similarly effective in every age group? If this would be true, this could mean that IF initiated at a young age leads to cognitive or
neurological health benefits later in life. In rats, ADF initiated when rats are young leads to a life span nearly twice as long (Goodrick et al., 1982). When ADF was initiated in middle age, the rats lived 30–40% longer than rats fed ad libitum (Goodrick et al., 1983). In two non-human primate studies, it was found that a decrease in caloric intake (while imposing TRF as well) is also effective in delaying neurological disease onset and mortality (Colman et al., 2009; Mattison et al., 2012). However, the age of onset is an important factor in determining the extent to which beneficial effects of IF might be induced. In contrast to what was found in rodents, IF initiated in early age in non-human primates might even be counter effective for delaying the onset of neurological disease and enhancing life span (Mattison et al., 2017). But IF onset in adult or advanced age yields clear benefits for survival in non-human primates.
In humans, there has not yet been a study that directly compares the effects of IF on the prevention of neurological diseases by looking at different age groups. However, there might be signs that IF is only effective later in life. As mentioned before, IF restores circadian rhythmicity and leads to decreased levels of circulating insulin in the blood, which enhances the sensitivity of insulin receptors (Longo & Panda, 2016; Rahmani et al., 2019). Circadian rhythmicity and glucose metabolism rates in the brain are known to decline with age in healthy adults (Kalyani & Egan, 2013; Manoogian & Panda, 2017). Therefore, this could indicate that IF might only have positive effects on cognition later in life when insulin sensitivity and glucose metabolism decays. However, Kim et al. (2020) did not find any improvement differences in neurogenesis-associated memory after a PF diet between healthy younger subjects (from 35 years old) and healthy older subjects (till 75 years old). In addition, Brandhorst et al. (2015) also did not find age differences on reduced risk factors for age-related diseases and stroke vulnerability in heathy subjects after a 3-month FMD. Therefore, it seems that IF is similarly effective for people of different ages. However, this does not provide a window into the question whether it is more beneficial for neurological disease protection to start IF at a young age in comparison with starting IF later in life. Future longitudinal studies with different age groups might be able to resolve this question.
IF initiated in obese and non-obese people
A next question we have to examine is whether it could be that the possible protective effects of IF on neurological diseases might lie in the specific subject group that most studies use; people with or at risk for obesity. IF is most often examined in the context of a weight-loss diet for obese subjects (Harris et al., 2018). The effects of IF on neurological disease prevention for obese subjects might trigger different mechanisms than it does for non-obese subjects. Firstly, obesity is associated with a greater risk of developing neurological diseases (O'Brien, Hinder, Callaghan, & Feldman, 2017). Secondly, epidemiological studies indicate that obesity is also associated with reduced
cognitive functioning and cognitive impairment in older age, regardless of the presence of neurological diseases (Feinkohl et al., 2018). Thirdly, obesity is also a risk factor to develop type 2 diabetes (Hossain, Kawar, & El Nahas, 2007), which contributes to the development of AD (Sims-Robinson, Kim, Rosko, & Feldman, 2010; Ahtiluoto et al., 2010). So it could be that the neurological disease prevention effects of IF might mainly be the result of the effects IF has on weight loss (Harris et al., 2018) and insulin sensitivity (Arnason, Bowen, & Mansell, 2017). Namely, these would then indirectly lead to improved cognitive functioning and neurological disease prevention. Three clinical trials reviewed in this study have solely looked at the protective effects of IF on neurological diseases in obese subjects (Anton et al., 2019; Kim et al., 2020; Jamshed et al., 2019). However, two clinical trials reviewed in this study have also found similar protective effects on neurological diseases in healthy non-obese subjects (Brandhorst et al. 2015; Mindikoglu et al., 2020). Thus, it can be hypothesized that IF is similarly protective for neurological diseases in both obese and non-obese subjects as there does not appear to be a difference between clinical studies with the two groups.
IF in regards to other dietary interventions
IF and caloric restriction
An important question to address is whether positive effects of IF on neurological diseases progress and protection are due to the proposed metabolic, cellular and circadian responses during fasting. Namely, a confound could be that people have less time to eat during the day and therefore eat less calories. It has been known for a long time that caloric restriction (CR) is associated with health and survival. For instance, rats fed a limited amount of food lived much longer than ad libitum-fed rats (McCay, Crowell, & Maynard, 1935), which has been replicated in many different species (Speakman & Mitchell, 2011). In non-obese humans, similar results have been found in epidemiological studies of centenarians living in Okinawa who have been exposed to CR most of their lives (Willcox et al., 2007) and in a 2-year clinical trial (Ravussin et al., 2015). CR even has signalling effects comparable to IF, such as upregulation of the IGF pathway, downregulation of the mTOR pathway, gut microbiota composition changes, and activation of AMPK and its effects on cell autophagy (Gillette-Guyonnet & Vellas, 2008; Fabbiano et al., 2018). In many animal models of CR, however, food is only provided once a day and animals tend to eat all of their food as soon as it is made available (Acosta-Rodríguez et al., 2017). Thus, the reduction of caloric intake automatically leads to a longer fasting period, making it a form of IF as well. So to address the question whether IF is in itself beneficial, Mitchell et al. (2019) compared life-span and disease onset for ad libitum-fed mice, mice on CR fed several meals a day, and CR mice fed once a day while keeping caloric intake
9 similar to the mice fed multiple times a day. Interestingly, the
time spent fasting was directly related to the health- and life span extension for all mice in that study, with the single meal-fed mice living significantly longer and having delayed disease onset than the multiple-meal-fed mice. In addition to life-span extension and delayed disease onset, IF also leads to improved preservation of cognitive-, sensory- and motor function in IF-fed rodents compared to CR-fed rodents (Singh et al., 2015).
In humans, difficulties in distinguishing between CR and IF poses similar problems, as people eat on average 25-33% less during ADF and PF, which holds true regardless of gender, presence of obesity, or age (Harvie et al., 2011; Harvie et al., 2013; Martens et al., 2020). So studies that keep the caloric intake of the control group similar to the ADF or the PF group are necessary to examine the specific benefits of IF. In contrast, TRE does not lead to a net reduction in calories while it imposes a prolonged fasting period (Balasubramanian et al., 2020). So studies directly comparing TRE with a no-diet control group are also informative to examine the specific benefits of IF. Jamshed et al. (2019) compared early-TRF (eating between 08:00 and 14:00) with a non-fasting control group, keeping the caloric and nutritional intake over the day exactly the same between both groups. The researchers found that TRF, in contrast to the control group, led to an increase in the expression of several genes associated with autophagy (LC3A), the circadian clock (PER1, CRY1, CRY2 and BMAL1) and insulin sensitivity (SIRT1; Sun et al., 2007). Furthermore, they found an increase in BNDF and an increase in the expression of mTOR in the TRF group compared to the control group. From this study, we can conclude that the fasting period itself is effective in neurological disease protection and progress, similarly to what was found in animal models. But this does not mean that CR during IF is therefore disadvantageous. As IF and CR trigger the same mechanisms (Fabbiano et al., 2018), it could be that a caloric reduction during IF might add to neurological health benefits. Moreover, overweight inevitably has harmful effects (Stockman et al., 2018). Thus, CR during IF might lead to more positive results for obese subjects since all types of IF (except TRF) lead to weight loss.
The effects of a healthier nutritional intake during IF A next question to ask is whether any possible effects of IF on the prevention and progress of neurological diseases further improves when the nutritional intake during the fed-period is also healthier. Namely, it has been found that diets like the Mediterranean diet, the MIND diet and the DASH diet prevent cognitive impairment (Scarmeas et al., 2018) and lower the chance to develop neurological diseases like PD (Maraki et al., 2018), AD (Berti et al., 2018) and ischaemic stroke (Larsson, Wallin, & Wolk, 2016). Unfortunately, there have not yet been studies initiated that directly compare the effects of IF with or without one of the previously mentioned diets. However, there
is a type of IF which also involves a change in the nutritional intake, namely the FMD. The FMD entails that people fast for 5 days a month, in which they eat a low protein/amino acid diet which is rich in fat and complex carbohydrates (Brandhorst et al., 2015). In a 2-arm cross-over RCT, Wei and colleagues (2017) found a reduction in IGF-1, which upregulates IIS-pathway activity and leads to enhancement of neuroplasticity and protection against oxidative stress (Rahmani et al., 2019). In contrast, 6 months of IF (Harvie et al. 2011) or 6 years of 20% CR (Fontana et al. 2008) does not lead to a net reduction in IGF-1. Therefore, Wei et al. (2017) claim that the nutritional composition of the FMD, in combination with its fasting component, leads to better results than IF alone. Specifically, Brandhorst and Longo (2019) highlight the possible complementary role of a low-protein intake (as is the case in the FMD) and fasting periods.
There might be a difference in the effectiveness of TRF on neurological disease protection and progress which depends on the nutritional intake during fed periods (Oosterman et al., 2020) and whether the eating window is early or late during the day (Sutton et al., 2018). Carbohydrate oxidation is the highest during the morning (Zitting et al., 2018), which means that the largest proportion of carbohydrates can best be consumed during the morning (Oosterman et al. 2020). In individuals with type 2 diabetes, a high-energy breakfast and low-energy dinner increased GLP-1 levels throughout the day (Jakubowicz et al. 2015). High levels of GLP-1 are associated with improved cognitive functioning, for instance in AD (Simsir, Soyaltin, & Cetinkalp, 2018). In contrast, a low-energy breakfast and high-energy dinner decreased GLP-1 levels. So besides the timing of eating, the nutritional intake during fed periods might also be of influence for cognitive functioning in neurological diseases like AD. Sutton et al. (2018) highlight the beneficial effects of eTRF in comparison with lTRF. However, there have not yet been clinical studies that directly compare the differences between eTRF and lTRF for the prevention and progress of neurological diseases.
Another possibility is that IF itself leads to a healthier eating pattern. For instance, the time window in which people can eat is narrowed during TRF. Snacks, low in nutrients but high in “empty calories”, are most frequently consumed during the evening (Bellisle et al., 2003). In a study with 13 healthy participants, the TRF group consumed significantly less snacks, especially during the evening (Antoni, Robertson, Robertson, & Johnston, 2018). Moreover, unhealthy snacks and drinks are more often consumed during social events which take place during the evening (Bellisle et al., 2003). Stockman et al. (2018) have highlighted the fact that IF might lead to skipping social events, thus indirectly leads to healthier eating patterns.
Discussion
This review study looked into the effects of IF on cognition and the protection and progress of neurological diseases by giving a complete interdisciplinary overview of the studies in this field. More specifically, a comprehensive image can only be achieved when knowledge about mechanisms on the molecular and cellular level are combined with insights on the clinical and psychosocial effects when fasting. The metabolic, cellular and circadian mechanisms by which IF can lead to structural and functional changes in the brain are well described in animal models. In humans, the tools to directly infer the effects of IF in the brain are limited. However, it is possible in humans to examine richness of the gut microbiota and signalling proteins through serum and faecal samples and to examine gene expression through mRNA levels in the blood. With these techniques, gut microbial richness and IF-induced changes in gene- and protein levels during fasting periods are found to be similar between humans and rodents (Brandhorst et al., 2015; Jamshed et al., 2019; Zeb et al., 2020). We can therefore hypothesize that clinical findings of IF are likely the result of the same mechanisms in humans as they are in rodents. This entails that findings from animal studies give perspective to replicate the same IF protocols in human clinical studies.
Although the number of clinical studies which examine the effects of IF on neurological diseases is still limited, positive findings have been found for several neurological diseases. Namely, clinical trials show that different types of IF (TRF, PF, ADF and FMD) have positive effects on epilepsy, AD and MS. Furthermore, animal studies indicate that IF has positive effects on PD and ischaemic stroke. A clinical trial is currently taking place in which patients recovering from an ischaemic stroke adhere to a TRF diet for six months (ClinicalTrials.gov, 2020). In contrast, IF does not lead to any short-term benefits for cognition in healthy people and long-term clinical trials to examine the effects of IF on cognition or neurological disease protection have not yet been initiated. However, there are indications that IF might be protective of developing neurological disorders, as studies report a lowered risk for ischaemic stroke or AD in healthy subjects (Stekovic et al., 2019; Brandhorst et al., 2015; Kim et al., 2020; Jamshed et al., 2019; Mindikoglu et al., 2020).
The role of age, obesity and nutrition for IF efficacy We examined the question for whom and when IF yields positive effects on the prevention and progress of neurological diseases. We first looked into the differences with obese and non-obese subjects. Obesity is associated with a greater risk of developing neurological diseases and is a risk factor to develop type 2 diabetes (Hossain, Kawar, & El Nahas, 2007), which contributes to the development of AD (Sims-Robinson, Kim, Rosko, & Feldman, 2010; Ahtiluoto et al., 2010). So IF might lead to improvements in weight loss and insulin sensitivity, which
indirectly lead to an improved neurological disease prevention. However, we did not find differences between clinical studies with obese and non-obese subjects. Moreover, fasting itself is responsible for the positive effects of IF, and not a net reduction in caloric intake that leads to weight loss (Jamshed et al., 2019). Therefore, we conclude that IF is effective for both obese and non-obese subjects. However, overweight inevitably has harmful effects (Stockman et al., 2018). Thus, IF might has more positive effects on neurological disease prevention for obese subjects than for non-obese subjects since all types of IF (except TRF) lead to weight loss.
We also looked into the role of age in the efficacy of IF on the prevention of neurological diseases. Namely, IF might only have substantial effects on the prevention of neurological diseases when it is practiced later in life. For instance, IF could exert its effects by enhancing insulin receptor sensitivity and improving circadian gene expression, but this might only be efficient later in life when circadian rhythmicity and insulin sensitivity decay (Kalyani & Egan, 2013; Manoogian & Panda, 2017). There has not been a study that directly compared the effects of IF on different age groups. However, there were no differences of IF effectiveness for specific age groups in studies that examined subjects with a wide age-range (Kim et al., 2020; Brandhorst et al., 2015). Unfortunately, there is no longitudinal study that follows subjects as they practice a form of IF for a longer period of time. That would be interesting, since it might be that IF has positive effects when it is initiated early in life, but beneficial effects are only noticeable later in life. For instance, rodents that start fasting from birth live significantly longer than rodents that start later in life (Goodrick et al., 1982; Mitchell et al., 2019). In contrast, IF initiated at an early age in non-human primates is found to be counter effective in delaying the onset of neurological disease and enhancing life span (Mattison et al., 2017). Therefore, large longitudinal RCTs with different age groups are necessary to understand the long-term effects of IF in humans and whether these are effective for everyone, or solely for older adults with or at risk for neurological disorders.
At last, we examined whether IF is more effective on neurological disease onset and progress when the nutritional intake is also healthier. Intuitively, an IF diet combined with a diet composed of nutrients that promote brain health (e.g. Mediterranean diet or the MIND diet) would be expected to give even more positive results. Unfortunately, there have not been studies that directly examined this. There have been positive results for a FMD, which involves fasting combined with a diet specifically composed of nutrients that are good for the brain. However, the contribution of nutrition is still unknown because there are no studies that directly compared a FMD with another type of IF. There might also be a difference in the effectiveness of IF on neurological disease protection and progress which depends on the nutritional intake during fed periods (Oosterman et al., 2020) and whether the eating window for
11 TRF is early or late during the day (Sutton et al., 2018). For
instance, high levels of GLP-1 are associated with improved cognitive functioning in AD and are stimulated through a high-energy breakfast and low-high-energy dinner (Jakubowicz et al. 2015). In addition, it might be that IF itself leads to a healthier eating pattern. Namely, the time window in which people can eat is narrowed during TRF. This leads to less snacking and skipping social events, which indirectly leads to a healthier eating pattern (Bellisle et al., 2003; Stockman et al., 2018). Conclusion and future direction
All in all, animal studies show a clear mechanism by which IF has positive effects on the prevention and progress of neurological diseases. Clinical studies show a similar picture for epilepsy, AD and MS, whereas future clinical trials have to shed light on PD and ischaemic stroke. IF does not lead to any short-term benefits for cognition in healthy people. However, there are indications that IF might be protective of developing neurological disorders, as studies report a lowered risk for ischaemic stroke or AD in healthy subjects. This appears to hold true, regardless of age, the presence of obesity or total caloric intake. It seems as these positive effects can be further enhanced when the nutritional intake during feeding periods is also healthier. In future research, it would be interesting to combine fasting with a nutritional diet that slows down cognitive decline (i.e. the MIND diet) to examine the effects on neurological disease protection and progress.
This review has started with the growing incidence of neurological disorders in the past thirty years. Prevention of the development of neurological disorders has become more important since treatments are still mostly lacking. If the findings from animal studies could be replicated in humans, this would mean a large step forward. However, humans live in a much more complex world; social cues, advertisements and unlimited access to food change our circadian rhythmicity and gut microbiota composition. Therefore, findings from animal studies are no guarantee to be similarly effective in humans. However, the promising effects of IF on neurological diseases makes the effort of longitudinal studies worth it.
References
● Acosta-Rodríguez, V. A., de Groot, M. H., Rijo-Ferreira, F., Green, C. B., & Takahashi, J. S. (2017). Mice under caloric restriction self-impose a temporal restriction of food intake as revealed by an automated feeder system. Cell metabolism,
26(1), 267-277.
● Ahtiluoto, S., Polvikoski, T., Peltonen, M., Solomon, A., Tuomilehto, J., Winblad, B., ... & Kivipelto, M. (2010). Diabetes, Alzheimer disease, and vascular dementia: a population-based neuropathologic study. Neurology, 75(13), 1195-1202. ● Alirezaei, M., Kemball, C. C., Flynn, C. T., Wood, M. R., Whitton, J. L., & Kiosses, W. B. (2010). Short-term fasting induces profound neuronal autophagy. Autophagy, 6(6), 702-710.
● Anton, S. D., Lee, S. A., Donahoo, W. T., McLaren, C., Manini, T., Leeuwenburgh, C., & Pahor, M. (2019). The effects of time restricted feeding on overweight, older adults: a pilot study.
Nutrients, 11(7), 1500.
● Anton, S. D., Moehl, K., Donahoo, W. T., Marosi, K., Lee, S. A., Mainous III, A. G., ... & Mattson, M. P. (2018). Flipping the metabolic switch: understanding and applying the health benefits of fasting. Obesity, 26(2), 254-268.
● Antoni, R., Robertson, T. M., Robertson, M. D., & Johnston, J. D. (2018). A pilot feasibility study exploring the effects of a moderate time-restricted feeding intervention on energy intake, adiposity and metabolic physiology in free-living human subjects. Journal of Nutritional Science, 7.
● Arnason, T. G., Bowen, M. W., & Mansell, K. D. (2017). Effects of intermittent fasting on health markers in those with type 2 diabetes: A pilot study. World journal of diabetes, 8(4), 154. ● Arumugam, T. V., Phillips, T. M., Cheng, A., Morrell, C. H., Mattson, M. P., & Wan, R. (2010). Age and energy intake interact to modify cell stress pathways and stroke outcome.
Annals of neurology, 67(1), 41-52.
● Balasubramanian, P., DelFavero, J., Ungvari, A., Papp, M., Tarantini, A., Price, N., ... & Tarantini, S. (2020). Time-restricted feeding (TRF) for prevention of age-related vascular cognitive impairment and dementia. Ageing
Research Reviews, 64(12), 101189.
● Beli, E., Yan, Y., Moldovan, L., Vieira, C. P., Gao, R., Duan, Y., ... & Chan, L. (2018). Restructuring of the gut microbiome by intermittent fasting prevents retinopathy and prolongs survival in db/db mice. Diabetes, 67(9), 1867-1879. ● Bellisle, F., Dalix, A. M., Mennen, L., Galan, P., Hercberg, S., De
Castro, J. M., & Gausseres, N. (2003). Contribution of snacks and meals in the diet of French adults: a diet-diary study.
Physiology & behavior, 79(2), 183-189.
● Benau, E. M., Orloff, N. C., Janke, E. A., Serpell, L., & Timko, C. A. (2014). A systematic review of the effects of experimental fasting on cognition. Appetite, 77, 52-61.
● Bener, A., Hamad, A., Fares, A., Al-Sayed, H. M., & Al-Suwaidi, J. (2006). Is there any effect of Ramadan fasting on stroke incidence? Singapore medical journal, 47(5), 404.
● Berti, V., Walters, M., Sterling, J., Quinn, C. G., Logue, M., Andrews, R., ... & Isaacson, R. S. (2018). Mediterranean diet and 3-year Alzheimer brain biomarker changes in middle-aged adults. Neurology, 90(20), e1789-e1798.
● Bhutani, S., Klempel, M. C., Kroeger, C. M., Aggour, E., Calvo, Y., Trepanowski, J. F., ... & Varady, K. A. (2013). Effect of exercising while fasting on eating behaviors and food intake.
Journal of the International Society of Sports Nutrition, 10(1),
50.
● Brandhorst, S., Choi, I. Y., Wei, M., Cheng, C. W., Sedrakyan, S., Navarrete, G., ... & Di Biase, S. (2015). A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan. Cell
metabolism, 22(1), 86-99.
● Bruce‑Keller, A. J., Umberger, G., McFall, R., & Mattson, M. P. (1999). Food restriction reduces brain damage and improves behavioral outcome following excitotoxic and metabolic insults. Annals of Neurology: Official Journal of the American
Neurological Association and the Child Neurology Society, 45(1), 8-15.
● Casetta, I., Granieri, E., Portaluppi, F., & Manfredini, R. (2002). Circadian variability in hemorrhagic stroke. Jama, 287(10), 1266-1267.
● Castellano, C. A., Nugent, S., Paquet, N., Tremblay, S., Bocti, C., Lacombe, G., ... & Cunnane, S. C. (2015). Lower brain 18F-fluorodeoxyglucose uptake but normal 11C-acetoacetate metabolism in mild Alzheimer's disease dementia. Journal of
Alzheimer's Disease, 43(4), 1343-1353.
● Chamari, K., Briki, W., Farooq, A., Patrick, T., Belfekih, T., & Herrera, C. P. (2016). Impact of Ramadan intermittent fasting on cognitive function in trained cyclists: a pilot study. Biology
of sport, 33(1), 49.
● Choi, I. Y., Piccio, L., Childress, P., Bollman, B., Ghosh, A., Brandhorst, S., ... & Longo, V. D. (2016). A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms. Cell reports, 15(10), 2136-2146.
● Cignarella, F., Cantoni, C., Ghezzi, L., Salter, A., Dorsett, Y., Chen, L., ... & Zhou, Y. (2018). Intermittent fasting confers protection in CNS autoimmunity by altering the gut microbiota. Cell metabolism, 27(6), 1222-1235.
● ClinicalTrials.gov (2020, November 25). Intermittent Fasting Following Acute Ischemic Stroke. Retrieved from
https://clinicaltrials.gov/ct2/show/NCT03789409?cond=in termittent+fasting&draw=2&rank=1.
● Colman, R. J., Anderson, R. M., Johnson, S. C., Kastman, E. K., Kosmatka, K. J., Beasley, T. M., ... & Weindruch, R. (2009). Caloric restriction delays disease onset and mortality in rhesus monkeys. Science, 325(5937), 201-204.
● Croteau, E., Castellano, C. A., Fortier, M., Bocti, C., Fulop, T., Paquet, N., & Cunnane, S. C. (2018). A cross-sectional comparison of brain glucose and ketone metabolism in cognitively healthy older adults, mild cognitive impairment and early Alzheimer's disease. Experimental gerontology, 107, 18-26.
● Cryan, J. F., & Dinan, T. G. (2012). Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nature reviews neuroscience, 13(10), 701-712. ● Cunnane, S. C., Courchesne‑Loyer, A., St‑Pierre, V., Vandenberghe, C., Pierotti, T., Fortier, M., ... & Castellano, C. A. (2016). Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer's disease. Annals of the New York
Academy of Sciences, 1367(1), 12-20.
● D’Andrea Meira, I., Romão, T. T., Pires do Prado, H. J., Krüger, L. T., Pires, M. E. P., & da Conceição, P. O. (2019). Ketogenic diet and epilepsy: what we know so far. Frontiers in
neuroscience, 13, 5.
● Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2008). From inflammation to sickness and depression: when the immune system subjugates the brain.
Nature reviews neuroscience, 9(1), 46-56.
● Davies, K. J. (2000). Oxidative stress, antioxidant defenses, and damage removal, repair, and replacement systems.
IUBMB life, 50(4‑5), 279-289.
● Davis, L. M., Pauly, J. R., Readnower, R. D., Rho, J. M., & Sullivan, P. G. (2008). Fasting is neuroprotective following traumatic brain injury. Journal of neuroscience research, 86(8), 1812-1822.
● Di Francesco, A., Di Germanio, C., Bernier, M., & de Cabo, R. (2018). A time to fast. Science, 362(6416), 770-775. ● Dirnagl, U., Iadecola, C., & Moskowitz, M. A. (1999).
Pathobiology of ischaemic stroke: an integrated view. Trends
in neurosciences, 22(9), 391-397.
● Duncan, J. S., Sander, J. W., Sisodiya, S. M., & Walker, M. C. (2006). Adult epilepsy. The Lancet, 367(9516), 1087-1100. ● Eltzschig, H. K., & Eckle, T. (2011). Ischemia and
reperfusion—from mechanism to translation. Nature
medicine, 17(11), 1391-1401.
● Fabbiano, S., Suárez-Zamorano, N., Chevalier, C., Lazarević, V., Kieser, S., Rigo, D., ... & Merkler, D. (2018). Functional gut microbiota remodeling contributes to the caloric restriction-induced metabolic improvements. Cell metabolism, 28(6), 907-921.
● Feigin, V. L., Nichols, E., Alam, T., Bannick, M. S., Beghi, E., Blake, N., ... & Fischer, F. (2019). Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. The
Lancet Neurology, 18(5), 459-480.
● Feigin, V. L., Vos, T., Nichols, E., Owolabi, M. O., Carroll, W. M., Dichgans, M., ... & Murray, C. (2020). The global burden of neurological disorders: translating evidence into policy. The
Lancet Neurology, 19(3), 255-265.
● Feinkohl, I., Lachmann, G., Brockhaus, W. R., Borchers, F., Piper, S. K., Ottens, T. H., ... & van Dijk, D. (2018). Association of obesity, diabetes and hypertension with cognitive impairment in older age. Clinical epidemiology, 10, 853. ● Flanagan, E. W., Most, J., Mey, J. T., & Redman, L. M. (2020).
Calorie Restriction and Aging in Humans. Annual Review of
Nutrition, 40, 105-133.
● Fontana, L., Weiss, E. P., Villareal, D. T., Klein, S., & Holloszy, J. O. (2008). Long‑term effects of calorie or protein restriction on serum IGF‑1 and IGFBP‑3 concentration in humans. Aging
cell, 7(5), 681-687.
● Fung, T. C., Olson, C. A., & Hsiao, E. Y. (2017). Interactions between the microbiota, immune and nervous systems in health and disease. Nature neuroscience, 20(2), 145. ● Gibson, C. L., Murphy, A. N., & Murphy, S. P. (2012). Stroke
outcome in the ketogenic state–a systematic review of the animal data. Journal of neurochemistry, 123, 52-57.
● Gillette-Guyonnet, S., & Vellas, B. (2008). Caloric restriction and brain function. Current Opinion in Clinical Nutrition &
Metabolic Care, 11(6), 686-692.
● Goodrick, C. L., Ingram, D. K., Reynolds, M. A., Freeman, J. R., & Cider, N. L. (1982). Effects of intermittent feeding upon growth and life span in rats. Gerontology, 28(4), 233-241. ● Goodrick, C. L., Ingram, D. K., Reynolds, M. A., Freeman, J. R.,
& Cider, N. L. (1983). Differential effects of intermittent feeding and voluntary exercise on body weight and lifespan in adult rats. Journal of gerontology, 38(1), 36-45.
● Halagappa, V. K. M., Guo, Z., Pearson, M., Matsuoka, Y., Cutler, R. G., LaFerla, F. M., & Mattson, M. P. (2007). Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the triple-transgenic mouse model of Alzheimer's disease. Neurobiology of disease, 26(1), 212-220. ● Harris, L., Hamilton, S., Azevedo, L. B., Olajide, J., De Brún, C., Waller, G., ... & Ells, L. (2018). Intermittent fasting interventions for treatment of overweight and obesity in
