The Neuroscience of Intermittent Fasting – A Simplified Guide to the Metabolic Switch and Neuroprotective Effects

TYPES OF FASTING

Fasting is the implementation of a specified and periodic energy restriction sufficient for the body to switch from carbohydrates to ketones as the primary sources of fuel, also known as the Glucose to Ketone Switch (G-K switch).

Two broad types of fasting techniques highlighted in the medical literature are: [Mattson et al., 2018] 

Alternate day fasting (ADF)

• Alternating days of 24-hour fasts are separated by average feeding days. It is suggested that one or two 24-hour fasts can be incorporated into a single week.

Time-restricted feeding (TRF):

• This form of fasting permits energy intake during a specified and periodic (4 to 8 hours) time period during a single day. For example, TRF could be incorporated with a daily feeding window from 12 pm to 8 pm.

Various fasting methods incorporate the broad principles: [Vasim et al., 2022].

• 16/8: Daily 16-hour fast and an 8-hour eating window for 2, 3, or more meals.
• The 5:2 diet: Eating on a routine 5 days a week and restricting calorie intake to 500-600 on the remaining 2 days.
• 20:4: Fast for 20 hours, eat within a window of 4 hrs.
• Whole day (24 hr) fasting
• Intermittent Very low-calorie diet (VLCD) therapy: 1 day a week VLCD and 5-day VLCD (5 consecutive days a week, repeated every five weeks)
• Intermittent, very low-calorie diet (VLCD) therapy is not intermittent fasting as the subject consumes a very low caloric dietary intake daily without any fasting period.
• Time-restricted feeding: Every day. Duration 14-18 hr. Food consumed over 6hr period.
• Alternate day fasting: Duration 24 hr.
• Eat, Stop, Eat: Involves a 24-hour fast once or twice weekly.
• The Warrior Diet: Involves eating small amounts of raw fruits and vegetables during the day and eating one large meal at night.

THE FASTED STATE

Fasting is a metabolic state that occurs after approximately 12 to 14 hours (or sooner if exercising) when the energy stores in the liver have been depleted. The fasting process leads to a G-K switch.

G to K Switch:

• The transition from the utilisation of carbohydrates and glucose to fatty acids and ketones as the primary cellular fuel source
• The G to K switch is hastened by exercise.
• At this time, circulating glucose levels are low and adipose cells are signalled to release fatty acids, which are metabolised in the liver to ketone bodies, primarily acetoacetate (AcAc) and β-hydroxybutyrate (BHB).
• Ketones can then be used as an alternative energy source by metabolically active tissues such as the muscles and the brain. [Maalouf et al., 2009] 
• Ketones also modulate signalling pathways and modify gene expression levels as the body’s cellular metabolism adapts to the environmental pressure of energy restriction. [Newman and Verdin, 2014]

K to G Switch:

Upon food consumption after a fast, the primary energy source for cells switches back to glucose (‘K-to-G switch’).

Intermittent Metabolic Switching [IMS]: 

• When an individual’s eating and exercise patterns result in periodic G-to-K switches, the process is known as intermittent metabolic switching.

Evidence suggests that switching between periods of negative energy balance (short fasts and/or exercise) and positive energy balance (eating and resting) can optimise general health and brain health.

Benefits of IMS: 

• Increased insulin sensitivity
• Reduced abdominal fat
• Maintenance of muscle mass
• Reduced resting heart rate and blood pressure

Fasting and Hormesis:

Fasting, much like exercise, is a mildly stressful challenge that activates adaptive cellular stress responses. This adaptive effect benefits the cell or organism and is known as hormesis. [Mattson, 2008] 

Hormesis is described as a biphasic dose response whereby a high dose induces a toxic effect, but a low dose induces a beneficial effect.

In an evolutionary context, hormesis is a fundamental concept of survival with benefits such as: [Calabrese et al., 2007]

• Reduced oxidative stress
• Improved cellular energy metabolism
• Reduced inflammation
• Reduced DNA damage

CELLULAR AND MOLECULAR CHANGES IN INTERMITTENT METABOLIC SWITCHING

ADF and TRF incorporate periods of fasting followed by periods of feeding, and this transition between the two states is known as intermittent metabolic switching (IMS). [Mattson et al., 2018] 

It refers to how the body switches between a negative energy balance and a positive energy balance.

Physiology of IMS and its beneficial impacts on health: 

Neurotransmitter modulation: 

• Ketones, particularly BHB, upregulate GABAergic tone, which can protect against seizures.
• The switch may modulate neurotransmitters such as serotonin, noradrenaline and dopamine, enhancing neuronal network activity.
• Promotion of parasympathetic tone with reductions in resting heart rate and blood pressure.

Antioxidant effects:

• Mitochondria are the primary source of intracellular ROS. During fasting-induced oxidative stress, mitochondria adapt by reducing the production of ROS through the activation of an uncoupling protein (UCP3) that dissipates the proton gradient across the inner membrane of the mitochondria. [Seifert et al., 2008]

Metabolic efficiency:

• In addition to reduced ROS production, fasting promotes mitochondrial biogenesis, increasing a cell’s mitochondrial mass and number, which enhances the metabolic output of a cell.
• This protects the cell against the cumulative effects of mitochondrial damage and dysfunction caused by ageing. [Maalouf et al., 2009]

Neurotrophic factor activity:

• Neurotrophic factors play essential roles in the central and peripheral nervous systems’ development, maintenance and plasticity.
• Fasting promotes the expression of neurotrophic factors such as BDNF, which is known as a master regulator of energy homeostasis.
• BDNF mediates neurogenesis, thus facilitating synaptic plasticity, learning and memory. [Lazarov et al., 2010]
• BDNF also increases insulin sensitivity and improves peripheral energy metabolism. [Marosi and Mattson, 2015]
• BHB and AcAc are precursors to membrane lipids in brain cells, neurons and oligodendrocytes, thus promoting axonal myelination.

Anti-inflammatory activity:

• The NRLP3 inflammasome is an integral part of the immune system, and chronic inflammation is implicated in several disorders, including diabetes, neurodegenerative disorders and autoimmune diseases.
• BHB has been shown to inhibit NLRP3-mediated inflammation directly. [Youm et al., 2015]

Enhanced autophagy:

• This is an evolutionarily conserved quality control process by which cells can degrade proteins and organelles. It is a protective process that, when compromised, is related to age-related diseases. [Martinez-Lopez et al., 2015]
• During fasting, decreased insulin signalling activates many genes involved in autophagy. [Liu et al., 2009]
• In addition, mTOR is inactivated by the decreased insulin signalling, which is necessary for the stimulation of autophagy [Hansen et al., 2008]

Antidepressant (AD) Effects: 

• Recent evidence suggests that ADs may exert their beneficial effects via the TRkB BDNF receptor.
• BHB induces BDNF expression in hippocampal and cortical neurons, suggesting that ketones may mediate the antidepressant effects of exercise and IF.

FASTING AND BRAIN HEALTH

Many reports show how exercise, fasting and intellectual enrichment enhance cellular stress response pathways that enhance neuroplasticity. [Mattson, 2015]

This includes how the brain responds to acute injuries as well as how resistant the brain is to developing neurological disorders.

Fasting promotes neuronal resistance through neurotrophic factor signalling, down-regulation of pro-inflammatory cytokine signalling, DNA repair, and improved antioxidant defences. Several studies using animal models have shown the positive effects of fasting in ischemic stroke and traumatic brain injury (TBI):

• The outcome of TBI can be improved by initiating fasting post-injury with notable improvements in both brain damage severity and subsequent cognitive deficits. [Davis et al., 2008]
• Prophylactic fasting regimens can help reduce the risk of death after experiencing a stroke. It is hypothesised that the presence of elevated circulating levels of BHB. [Fann et al., 2017]

For centuries, fasting has been used as an effective anticonvulsant therapy and today is recommended for certain types of treatment-resistant childhood epilepsies. [Hartman and Vining, 2007]

Fasting may show some therapeutic potential in individuals with Alzheimer’s Dementia as brain cell uptake of glucose is severely impaired in patients with AD while the cells can utilise ketones. Positron emission tomography (PET) has shown that within 48 hours of the onset of fasting, there is a sevenfold to eightfold increase in brain uptake of ketones. [Mattson et al., 2018]

There is some evidence that a ketogenic diet may improve symptoms of Autism spectrum disorder. [El Rashidy. et al. 2017].

It is suggested that the neurotrophic factor, BDNF, is responsible for enhanced neuroprotection and electrophysiological integrity; however, the precise mechanism is unknown. [Duan et al., 2001]

OPTIMISING BRAIN HEALTH

Intermittent metabolic switching not only improves brain health directly through enhanced neuroplasticity, but it also independently improves brain health via the beneficial effects of reduced energy intake and improved weight loss. [Anson et al., 2003] 

Obesity has numerous neurological consequences with negative effects on cognition through impaired synaptic plasticity and neurogenesis. [Mattson, 2012]

• Fasting lowers blood pressure and heart rate [Mager et al., 2006]
• Fasting prevents obesity and other related metabolic morbidities even in the presence of a high-fat diet. [Hatori et al., 2012]
• Fasting increases the expres­sion of the neurotrophic factor, BDNF while obesity is associated with a reduced expres­sion BDNF.^,[Stranahan, 2015], [O’Brien et al., 2017]
• IMS and increased exercise can effectively counteract the adverse effects of excessive energy intake on hippocampal plasticity. [Mattson, 2012]

RISKS OF INTERMITTENT FASTING

SUMMARY

Sedentary and overindulgent lifestyles exacerbate the risk of developing neurodegenerative and psy­chiatric disorders.

The incorporation of IMS involves cyclical periods of improved neuroprotection when fasting and exercising and adaptive growth periods when feeding and resting.

It is hoped that a better understanding of the neurobiology of IMS could lead to new approaches for improving brain health as we age.