PDF Summary:The Intermittent Fasting Revolution, by Mark P. Mattson

In The Intermittent Fasting Revolution, neuroscientist Mark P. Mattson explores how our bodies have evolved to function optimally during periods without food. He explains the biological mechanisms behind intermittent fasting's effects on metabolism, cellular repair, and brain function, showing how regular fasting periods can improve health outcomes and potentially prevent various diseases.

This guide examines research on intermittent fasting's role in managing conditions like diabetes, obesity, cardiovascular disease, and cancer. It details different fasting approaches and their effects on physical and mental performance. The summary also covers Mattson's insights on diet composition, particularly the impact of sugars and processed foods on brain health, and how certain plant compounds can benefit cellular function through hormetic mechanisms.

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Intermittent Fasting to Prevent and Manage Chronic Diseases

Mattson argues that intermittent fasting shows promise not only for preventing chronic diseases, but also treating them. He cites various research and trials exploring IF's efficacy in various conditions.

Intermittent Fasting Reverses Metabolic Issues and Conditions Like Diabetes and Obesity

Mattson presents IF as a potent intervention for obesity, diabetes type 2, and related metabolic disorders. He highlights its ability to promote weight loss, enhance blood sugar control, and restore insulin sensitivity.

Studies: Intermittent Fasting Promotes Weight Loss and Better Glucose Regulation

Mattson highlights the numerous RCTs showcasing IF's effectiveness in shedding pounds and enhancing metabolic well-being. He emphasizes that IF is not merely a diet but an eating pattern, focusing on the timing of food consumption rather than what is eaten. While diet composition remains important, when you eat plays a crucial role in regulating metabolism. The author points out that multiple IF regimens, including daily time-restricted eating (TRE) and the 5:2 approach, have demonstrated consistent results in weight loss and improved glucose control. These studies, Mattson explains, often involve comparing IF groups to control groups who either maintain their usual eating habits or follow calorie-restricted diets. He notes that even when people don't significantly cut their calories, IF can lead to improvements in metabolic markers, suggesting that the schedule of eating itself has unique benefits.

Mattson offers specific illustrations of this research to support his points. He cites research conducted by Zhihong Guo and Mike Anson at the NIA, which found that IF improved glucose regulation in rodents even without overall calorie restriction. Another example is shown in a study from Australia in which adolescents experienced weight loss and reduced abdominal fat following a 5:2 intermittent fasting protocol for several weeks. He also discusses an Australian study that demonstrated the long-term effectiveness of a modified 5:2 IF approach in teens with obesity. He mentions research conducted at the University of Oslo where obese participants showed sustained weight loss and metabolic improvements after a year of 5:2 IF. Mattson further mentions Krista Varady's research comparing every-other-day fasting to daily calorie restriction, showing comparable weight loss and enhancements in heart health markers. These examples, according to Mattson, demonstrate the robustness of IF's effects on shedding weight and metabolism across various populations and IF protocols.

Context

• Randomized Controlled Trials (RCTs) are considered the gold standard in clinical research. They involve randomly assigning participants to either an intervention group or a control group to objectively assess the effects of a treatment, in this case, intermittent fasting (IF).
• Fasting has been practiced for centuries in various cultures and religions, often for spiritual or health reasons, indicating its long-standing presence in human history.
• This approach involves eating normally for five days of the week and significantly reducing calorie intake (to about 500-600 calories) on the other two non-consecutive days. This method is designed to create a caloric deficit while allowing flexibility in eating habits.
• This refers to participants continuing their normal dietary patterns without any imposed changes. It serves as a baseline to assess the impact of the intervention.
• Metabolic markers are indicators used to assess metabolic health, including blood glucose levels, insulin sensitivity, cholesterol levels, and inflammatory markers. Improvements in these markers can reduce the risk of chronic diseases like diabetes and cardiovascular disease.
• This refers to the body's ability to maintain stable blood sugar levels. Proper glucose regulation is crucial for preventing conditions like insulin resistance and type 2 diabetes.
• Adolescents may be more susceptible to developing unhealthy relationships with food, so any fasting regimen should be approached with caution and ideally under professional guidance.
• Obesity in teens is a growing concern globally, linked to increased risks of type 2 diabetes, cardiovascular diseases, and psychological issues. Effective interventions are crucial for improving long-term health outcomes.
• Intermittent fasting, including the 5:2 method, may have psychological benefits, such as reduced stress about constant dieting and increased adherence due to its flexible nature.
• Studies often compare these methods to understand their effectiveness in different populations, considering factors like age, gender, and baseline health conditions.

Fasting Reverses Diabetes Type 2 by Restoring Insulin Sensitivity

Mattson asserts that IF can reverse type 2 diabetes by restoring the body's insulin sensitivity. He explains that insulin resistance, a hallmark of type 2 diabetes, impairs cells' capacity to use glucose, resulting in elevated blood sugar levels. IF, by improving how the body regulates glucose and cutting overall calorie intake, can break this cycle of being resistant to insulin. He points out that IF forces the body to utilize stored glucose when fasting, leading to lower baseline glucose levels and improved insulin responsiveness. This increase in how sensitive the body is to insulin allows cells to effectively take up glucose, restoring normal blood sugar control.

Mattson supports this statement by referencing clinical studies. He cites an Australian study in which 63 individuals with type 2 diabetes on a 5:2 IF regimen showed a significant decrease in hemoglobin A1c, a key marker of diabetes control. He also references studies showing increased insulin sensitivity and better blood sugar regulation in prediabetic individuals following IF protocols. These findings, according to Mattson, underscore IF's potential as a therapeutic intervention for not only preventing but also reversing diabetes type 2. He cautions, however, that individuals who have Type 1 diabetes, who require insulin injections, should talk to their doctor prior to starting IF, as it may increase the risk of hypoglycemia. He points to his lab’s research showing that IF may actually increase resistance to low blood sugar, but recommends caution and consulting a medical professional to tailor appropriate strategies. This is supported by findings by Wenzhen Duan, a neuroscientist in Mattson’s lab, who showed that mice on IF had greater resilience against hypoglycemia induced by insulin injections.

Practical Tips

• Monitor your blood sugar levels with a home glucose meter to understand how different foods affect you. By regularly checking your blood sugar before and after meals, you can identify which foods cause significant spikes and start to tailor your diet accordingly. For example, if you notice that eating white bread leads to higher glucose readings, you might experiment with whole grain alternatives or reduce your portion sizes.

Other Perspectives

• The reversal of type 2 diabetes through fasting may not be permanent, and individuals may experience a relapse of symptoms if they discontinue the fasting regimen or fail to maintain lifestyle changes.
• The clinical studies may not have adequately accounted for confounding variables such as medication changes, physical activity, or dietary composition, which could influence hemoglobin A1c levels.
• IF may not address all underlying causes of type 2 diabetes, such as genetic factors, which can play a significant role in the development and progression of the disease.
• While consulting a doctor is generally good advice, it may not be sufficient for individuals with Type 1 diabetes considering IF, as they require continuous and careful management of their insulin levels, which can be highly variable and influenced by many factors beyond fasting.
• The recommendation for caution could be perceived as overly cautious, potentially discouraging individuals who could safely benefit from IF under less stringent medical supervision, such as those with prediabetes or metabolic syndrome.
• The resilience against hypoglycemia in mice induced by insulin injections may not reflect the complex interplay of hormones and metabolism in humans with type 2 diabetes, who often have other health issues.

Fasting Protects Your Cardiovascular and Cerebrovascular Systems From Damage Due to Heart Attacks and Strokes

Mattson argues that IF not only lowers risk of strokes and heart attacks but also strengthens these organs, increasing their ability to withstand damage. This two-pronged approach makes IF a potent strategy for protecting heart and cerebrovascular health.

Intermittent Fasting Boosts Blood Vessel Function, Lowering Cardiovascular Risk Factors

Mattson discusses how IF improves cardiovascular health by boosting blood vessel function and lowering risk factors for heart disease and stroke. He explains that IF's positive effects on being overweight, reduced sensitivity to insulin, and blood pressure directly contribute to improved cardiovascular health. He explains that IF can counteract this group of risk factors, lowering the likelihood of these conditions. By reducing fat around the midsection, IF lowers chronic inflammation, a key driver of cardiovascular disease. Improved insulin responsiveness enhances glucose control, preventing damage to blood vasculature. Furthermore, Mattson notes that IF leads to healthier lipid levels, such as lower triglycerides and higher HDL cholesterol.

Mattson points to studies supporting IF's positive impacts on cardiovascular health. He references a University of Oslo study where obese patients on 5:2 IF experienced improved blood pressure, triglyceride levels, and HDL cholesterol. He also mentions research by Krista Varady showing similar cardiovascular risk factor enhancements in individuals using alternate-day fasting and reducing daily calories. These findings, coupled with IF's positive impact on metabolism, indicate that IF can protect against heart disease and cerebrovascular events. According to Mattson, these studies collectively demonstrate IF's potential as a non-pharmacological intervention for better heart health.

Other Perspectives

• Some research suggests that the timing of food intake during IF, such as eating late in the day, may affect circadian rhythms and potentially counteract some of the positive effects on cardiovascular health.
• Reducing fat around the midsection through IF without considering the overall quality of the diet may not lead to improved cardiovascular health if the diet remains high in processed foods, sugars, and unhealthy fats.
• Some studies have indicated that extreme calorie restriction or fasting can lead to hypoglycemia or other metabolic disturbances in certain populations, which could potentially counteract the benefits of improved insulin responsiveness.
• The studies mentioned may have limitations such as small sample sizes, short duration, or lack of diversity in the study population, which could affect the generalizability of the findings to the broader population.
• Some individuals may experience negative side effects from IF, such as fatigue, irritability, or hypoglycemia, which could indirectly affect cardiovascular health by reducing the ability or motivation to engage in heart-healthy behaviors.
• The effectiveness of IF may be influenced by other lifestyle factors such as physical activity, smoking, and stress management, which are also critical for heart health.

Fasting Protects the Cardiovascular and Nervous Systems During Attacks and Strokes

Mattson states that IF, due to its ability to increase stress resistance, may help reduce harm to the brain and heart during myocardial infarctions. He suggests that inducing brief periods of stress triggers adaptations that enhance the body's ability to withstand more significant stressors, such as those experienced during a heart attack. He notes that by activating pathways that respond to stress at the cellular level and improving mitochondrial function, the body can better withstand an ischemic insult such as a heart attack.

Mattson cites his own research to support this assertion. His studies on rats demonstrated that pre-stroke IF reduced neurological damage and improved motor function recovery after a simulated stroke. Lakatta and Ahmet further showed reduced heart damage and improved cardiac function in rats following a simulated heart attack, on an IF diet beforehand. He also describes his research in collaboration with Ed Lakatta, showing reduced heart tissue damage and improved ventricular function in rats that alternated fasting days before a simulated heart attack. Furthermore, he cites studies showing that IF, initiated even after a cardiovascular or cerebrovascular event, improved recovery in animal models. These results suggest that IF may offer a protective strategy for preventing and mitigating the damage from cardiovascular and cerebrovascular events, a proposition that, according to Mattson, requires further investigation in human clinical trials. He mentions Okoshi’s findings demonstrating enhanced recovery after heart attacks in rodents and Hu's findings showing improved cognitive recovery after cardiac arrest in rats kept on an IF regimen post-event as promising leads in the direction of post-event treatment and recovery.

Context

• A myocardial infarction, commonly known as a heart attack, occurs when blood flow to a part of the heart is blocked, causing damage to heart muscle. Enhancing stress resistance could theoretically help the heart muscle cope better with the reduced blood supply.
• Cellular stress pathways are mechanisms that cells use to respond to various stressors, such as oxidative stress or nutrient deprivation. These pathways often involve signaling molecules like AMP-activated protein kinase (AMPK) and sirtuins, which help regulate energy balance and promote cell survival.
• The idea of preconditioning involves exposing the body to mild stress to build resilience against more severe stress. IF acts as a form of metabolic preconditioning, potentially reducing damage during heart attacks.
• While rat models provide valuable insights, differences in physiology between humans and rats mean that results may not directly translate to humans. However, they offer a foundational understanding that can guide human studies.
• Post-event nutritional needs are critical, and fasting protocols must be carefully managed to ensure they do not deprive the body of essential nutrients needed for recovery.
• This is a process where brief episodes of ischemia (restricted blood flow) can protect against future ischemic events. IF may mimic this effect by conditioning the body to better handle reduced blood flow.
• Cardiac arrest can lead to brain damage due to lack of oxygen. Enhancing cognitive recovery involves improving brain function and reducing neurological deficits after such events.
• Human trials can control for placebo effects and biases that might influence outcomes, ensuring that observed benefits are truly due to IF and not other factors.

Using Intermittent Fasting to Prevent and Treat Cancer Shows Promise

Mattson explores the potential of IF in cancer prevention and treatment, citing research on animals and ongoing clinical trials.

Chemo and Radiotherapy's Impact on Cancer Cells Could Be Enhanced by Periodic Fasting

Mattson describes the present state of cancer research, including the employment of radio- and chemotherapies, and points to its limitations in damaging also healthy tissues. He describes p53 and other gene mutations within numerous cancers that could make these cells resist apoptosis, or programmed cell death. He notes that IF may be a safe addition to cancer therapies by increasing cancer cells' vulnerability to chemo and radiation's cell-killing effects, while simultaneously protecting normal cells from the potential damage. He posits that by decreasing tumor growth and making existing therapies more effective, IF holds promise as a potent adjunctive therapy in oncology care.

The author provides scientific support for these claims using research involving animals. He cites Morris Ross and Gerrit Bras's 1971 study showing reduced cancer incidence in rats with limited daily feeding windows. He also discusses research demonstrating IF's ability to inhibit tumor growth in animal studies of several cancer types, including cancers of the breast, prostate, colon, liver, pancreas, and brain. Mattson explains that IF may achieve this by several mechanisms, including improving DNA restoration in healthy cells, boosting immune function against cancer cells, and creating an energy-deficient environment (low glucose, elevated ketones) that is particularly harmful to some cancer cells that depend on glucose.

Practical Tips

• Start a digital journal to track your family's health history, specifically noting any instances of cancer or genetic disorders. This record can be a valuable tool for healthcare providers to assess your risk factors for mutations like p53 and offer personalized advice on monitoring and prevention.
• Educate yourself on the nutritional aspects of intermittent fasting by consulting a registered dietitian. A dietitian specializing in oncology can provide guidance on how to maintain a balanced diet during fasting periods, ensuring you get the necessary nutrients to support your body's needs while potentially enhancing the effectiveness of your cancer treatment.
• You can start a personal food diary to track your eating patterns and identify opportunities for introducing intermittent fasting (IF). By recording everything you eat and the times you eat, you'll be able to see your current eating habits and plan how to adjust them to incorporate IF. For example, if you notice you usually snack late at night, you might decide to stop eating after 7 PM to create a fasting window until breakfast.
• Experiment with different feeding window durations to find what works best for you. Begin with a 12-hour window, such as 7 a.m. to 7 p.m., and gradually reduce the window by an hour every week until you find a comfortable balance that fits your lifestyle and health goals.
• Create a simple meal plan that reduces glucose intake during your eating windows. Focus on foods that are low in simple sugars and high in fiber, such as vegetables, legumes, and whole grains. This approach may support the creation of an energy-deficient environment that could be less favorable to glucose-dependent cells.

Fasting Improves Immune Function in Fighting Cancer

Mattson argues that IF can improve how immunity fights cancer. He cites research showing that IF can stimulate certain immune cells, making them more effective at targeting and eliminating cancer cells. He mentions research by Valter Longo demonstrating IF’s ability to bolster T-cells, enhancing chemotherapy's effectiveness against breast cancer and melanoma in animal studies. These preclinical findings, according to Mattson, offer strong support for exploring the implementation of IF alongside cancer therapies.

Mattson explains several pathways through which IF may boost the immune response against cancer. First, through several pathways that include an increase in T lymphocytes activity, fasting could promote the elimination of precancerous cells via apoptosis, preventing the development of cancer. He mentions Valter Longo's research in which IF reduced mortality by preventing cancer incidence in mice lacking DNA repair abilities. Secondly, by lowering circulating sugar and increasing ketones, IF changes fuel availability, creating a potentially inhospitable environment for those cancers dependent on glucose growth. This was established in the 1920s by Otto Warburg, who found that low glucose concentrations make cancer cells much more sensitive. He notes that this impact is distinct from the general immunosuppressive outcomes of certain cancer therapies. These pathways, Mattson explains, could potentially improve the impact of chemo and radiation therapies. He notes that various clinical studies are presently exploring this idea. He suggests that IF may offer a cost-effective and safe strategy for improving outcomes in cancer therapy.

Context

• Apoptosis is a form of programmed cell death that helps eliminate damaged or potentially harmful cells, including precancerous cells, thereby preventing cancer development.
• Chemotherapy is a common cancer treatment that uses drugs to kill rapidly dividing cells. While effective, it can also suppress the immune system by reducing the number of white blood cells, including T-cells, which can make patients more susceptible to infections.
• IF can enhance the body's stress response pathways, which may improve the ability of cells to cope with damage and reduce the likelihood of cancerous transformations.
• Unlike normal cells, many cancer cells are less efficient at using ketones for energy. This inefficiency can hinder their growth and survival when glucose is scarce.
• The reference to Otto Warburg relates to his discovery that cancer cells often rely on glycolysis for energy production, even in the presence of oxygen, a phenomenon known as the Warburg effect. This reliance on glucose makes them potentially more vulnerable when glucose levels are reduced.
• The concept of hormesis suggests that low-level stressors, like fasting, can activate adaptive stress responses that enhance the resilience of normal cells to chemotherapy and radiation, potentially reducing side effects and improving overall treatment outcomes.
• Clinical studies must adhere to ethical guidelines and obtain regulatory approval to ensure patient safety and the integrity of the research process.
• IF is generally considered safe for most people, though it should be approached with caution in certain populations, such as those with diabetes or eating disorders. It is important to consult healthcare providers before starting IF, especially for cancer patients.

Intermittent Fasting's Effects on Mental and Physical Functioning

Mattson makes the case that IF not only benefits individuals with diseases but also boosts performance in healthy individuals, influencing both brain function and physical endurance.

Intermittent Fasting Enhances Neuronal Connections and Brain Cells at the Source

Mattson asserts that IF (intermittent fasting) improves brain health by increasing synaptic plasticity (creating new synapses), boosting neurogenesis (the generation of new neurons), and enhancing the stress resilience of neurons. These effects, according to Mattson, contribute significantly to improved cognition and memory, enhanced cognitive function, and greater protection against neurological diseases.

Fasting Boosts BDNF, Aiding the Creation of Synapses and Neurogenesis

Mattson posits that IF increases levels of brain-derived BDNF, a neurotrophic factor protein that plays a crucial role in promoting synaptic plasticity and neurogenesis. He explains that both IF and exercise trigger BDNF production in the brain, and this upregulation has significant impacts on neuroplasticity and neuronal health. Increased BDNF facilitates the growth of new synapses between neurons, increasing neuronal connectivity and strengthening communication within neuronal networks. Additionally, brain-derived neurotrophic factor supports the survival and integration of new neurons that stem cells create in the hippocampus, a crucial part of the brain for learning and memory. Mattson cites Alexis Stranahan’s finding of increased synaptic density in mice hippocampus related to IF and exercise, as well as Aiwu Cheng’s observation that BDNF boosts mitochondrial activity in neurons, all suggestive of a general improvement in neuronal health and function caused by IF.

Mattson expands on the roles of BDNF by relating it to its positive effects on Mood, by reducing stress and anxiety and on maintaining a healthy body weight by regulating appetite, as well as to its protective role in various neurological disorders, such as depression, Alzheimer's, and Parkinson's. He argues that by improving neuroplasticity, IF enhances the brain's adaptability and resilience, allowing it to learn, remember, and adapt to new situations more effectively. According to Mattson, these research findings are significant for enhancing brain performance in healthy people.

Other Perspectives

• The potential for negative effects of IF, such as stress on the body or exacerbation of certain health conditions, should be considered when evaluating its overall impact on neuronal health.
• While increased BDNF is associated with the growth of new synapses, it is not the sole factor in synaptic growth and neuronal connectivity; other factors such as neuronal activity, environmental stimuli, and the presence of other neurotrophic factors also play significant roles.
• There is evidence suggesting that chronic elevation of BDNF can lead to negative outcomes, such as increased anxiety-like behaviors in some animal studies, indicating that the relationship between BDNF levels and brain health is not straightforward.
• While IF and exercise may increase synaptic density and boost mitochondrial activity, it is important to consider individual variability in response to these interventions, as not all individuals may experience the same level of benefit.
• Some studies have shown that while BDNF may have a role in these areas, the effects can be context-dependent and influenced by factors such as age, sex, genetic background, and environmental conditions.
• The therapeutic use of BDNF as a treatment for neurological disorders is still in the experimental stages, and there is limited clinical evidence to support its efficacy and safety in humans.
• Some individuals may experience cognitive decline or impaired concentration during fasting periods due to low blood sugar levels, which could temporarily counteract any potential long-term benefits on learning and memory.

Intermittent Fasting Boosts Inhibitory Neuron Activity, Improving Network Balance and Stability

Mattson explains that IF increases the activity of inhibitory neurons in the brain, contributing to the stability of neural networks and improved cognitive function. He explains that inhibition of a neuronal circuit by GABA is an essential complement to the stimulation by glutamate in creating functional neuronal networks. Increased GABA activity can prevent seizures and lessen anxiety. These neurons, which inhibit and utilize GABA as a neurotransmitter, are crucial for regulating neuronal excitability, preventing excessive neuronal firing that can lead to seizures and other neurological problems. IF, he explains, enhances GABAergic activity and thereby improves neuronal network balance, improving information processing and reducing the risk of neuronal dysfunction.

Mattson relies on research from his lab and other relevant scientific findings to support this statement. He cites research he performed with Yong Liu which demonstrated that IF increases levels of SIRT3, a mitochondrial catalyst, in the hippocampus. This elevation in SIRT3, in turn, enhances the inhibitory effect of GABA, leading to behaviors in mice similar to reduced anxiety. Mattson further highlights the importance of this finding by explaining that an imbalance—excessive glutamate, not enough GABA—occurs in many brain disorders such as epilepsy, and neurodegenerative diseases. These findings, according to Mattson, help explain improvements in mood and cognitive function resulting from intermittent fasting.

Context

• Inhibitory neurons, which release GABA, play a key role in controlling the overall excitability of the brain. They help prevent overexcitation, which can lead to conditions such as seizures. By modulating the activity of excitatory neurons, they ensure that neural circuits function properly and efficiently.
• Certain dietary components, such as magnesium and zinc, can influence GABA activity. These nutrients are important for the synthesis and function of GABA in the brain.
• During brain development, GABAergic signaling plays a crucial role in the formation of neural circuits and the regulation of neurogenesis, synapse formation, and plasticity.
• Neuronal networks are complex circuits of neurons that communicate with each other to process information. Stability in these networks is essential for efficient information processing, learning, and memory. Disruptions in network stability can lead to cognitive impairments and neurological disorders.
• SIRT3 contributes to mitochondrial health by reducing oxidative stress and enhancing the efficiency of the electron transport chain, which is essential for ATP production. This can lead to improved energy availability for neurons.
• Increased GABA activity is associated with reduced anxiety and improved mood, as it helps calm the nervous system. This is why enhancing GABAergic activity can have anxiolytic (anxiety-reducing) effects.
• Mice are commonly used in neurological studies because their genetic, biological, and behavioral characteristics closely resemble those of humans, allowing researchers to infer potential effects in humans.
• Ongoing research is exploring how lifestyle interventions, like diet and exercise, can naturally modulate these neurotransmitters to support brain health and prevent disorders.

Intermittent Fasting Boosts Physical Endurance and Muscle Function

Mattson argues that IF improves physical endurance and muscle function, primarily by shifting the body's fuel source to ketones and enhancing mitochondrial function within muscle cells. This improves athletic performance and promotes overall physical health.

Fasting Boosts Muscle Use of Fat and Ketones For Exercise Fuel

Mattson explains that IF improves physical endurance by training the body to utilize fat and ketones as fuel during exercise. He notes that traditionally, athletes have emphasized carbohydrate loading before endurance events. However, Mattson argues that, from an evolutionary perspective, human bodies are adapted to perform well when fasting, relying on stored fat for energy. He notes that IF triggers a metabolic switch, where the body becomes more efficient at utilizing fats and ketones, an alternate fuel source produced during fasting, to power muscle activity. This shift in metabolism, Mattson asserts, can boost stamina by supplying a more sustained energy source compared to relying solely on sugar.

Mattson cites research to support his claims and notes that this adaptability in metabolism could benefit endurance events. He references research by Keelin Moehl and Krisztina Marosi where they found increased endurance in mice following alternate-day intermittent fasting when treadmill-trained in contrast with controls. He explains that this finding implies endurance capacity isn't limited by muscles' capacity to metabolize glucose through glycolysis and can be enhanced by training oneself to utilize ketones. He highlights his research with Krisztina Marosi and Keelin Moehl, showing that mice on IF during treadmill training performed better than those that had unrestricted feeding, demonstrating the link between higher ketone production and improved physical endurance. He suggests that for endurance athletes, training while fasting, thus increasing metabolic flexibility, could be beneficial in leveraging the body's ability to use ketones and fat as fuel during prolonged exertion.

Practical Tips

• Experiment with a mini-fasting workout by skipping breakfast and scheduling a morning jog or bike ride. This allows you to test your body's response to exercising in a fasted state, potentially tapping into fat stores for energy. Start with light to moderate exercise to gauge how you feel and gradually increase intensity based on your comfort and energy levels.
• Incorporate endurance-based exercises like swimming, cycling, or long-distance running into your weekly routine to encourage your body to adapt to using fat as a fuel source. Begin with shorter sessions and gradually increase the duration as your stamina improves. This physical adaptation complements the dietary changes and can help you experience sustained energy during activities.
• Try incorporating short, consistent fasting periods into your routine before engaging in endurance training. For example, choose a 16-hour fasting window that you can consistently maintain every other day, and schedule your endurance workouts shortly after this fasting period ends. Monitor how you feel during these workouts and whether you notice a subjective increase in stamina or performance.
• Incorporate coconut oil into your pre-workout routine as it contains medium-chain triglycerides (MCTs), which are more readily converted into ketones by the body. Start with a small amount, such as a teaspoon, taken with your pre-workout meal or snack, and observe any changes in your stamina and endurance during exercise sessions.
• Incorporate a low-carb, high-fat snack into your post-workout routine on training days. After a fasted workout, consuming a snack like avocado or nuts can help your body continue to utilize fats for recovery, rather than relying on quick carbohydrates. This practice can enhance your body's ability to switch between energy sources.

Fasting Boosts Muscle Mitochondrial Health and Metabolism

Mattson discusses how IF enhances how mitochondria work and metabolism within muscle tissue, boosting physical ability. He explains that mitochondria are the powerhouses of cells, responsible for generating ATP, or adenosine triphosphate. IF, he explains, triggers the creation of new mitochondria, a boost in their number, and also mitophagy, where damaged organelles are recycled for the components to be reused in generating fresh mitochondria. These effects collectively boost cells' energy capacity. He further explains that IF improves metabolic flexibility, allowing muscles to switch between different fuel sources, including glucose, fatty acids, and ketones, according to the body’s availability and needs. This adaptability, Mattson asserts, improves athletic ability and supports muscle health, an improvement comparable to what endurance training offers.

Mattson provides evidence and examples from scientific studies to substantiate this claim. He discusses his studies with Marosi and Moehl showcasing increased mitochondria density in the leg muscle cells of mice that also underwent treadmill training while on alternate day fasting. This supports the idea that IF’s benefits extend beyond shedding pounds and have direct effects on muscle cell function. Further, he points to research highlighting similarities between how fasting and working out affect muscle cells. Both stimulate mitochondrial biogenesis, enhance autophagy, and improve stress resistance, as Alexis Stranahan's work in his laboratory demonstrated. The research indicates that IF, similar to regular exercise, can enhance metabolism and improve physical performance.

Practical Tips

• Enhance your diet with foods known to support mitochondrial health, such as those rich in omega-3 fatty acids, antioxidants, and B vitamins. For example, include more fatty fish like salmon, nuts and seeds, leafy greens, and whole grains in your meals. These nutrients play a role in maintaining the integrity of the mitochondria and optimizing their function.

Other Perspectives

• The increase in mitochondrial number and function through IF may depend on the presence of other factors, such as adequate nutrition during non-fasting periods, to provide the necessary substrates for mitochondrial biogenesis and repair.
• IF may not be suitable for everyone, and in some cases, it could lead to negative outcomes such as disordered eating patterns, especially in individuals with a history of eating disorders.
• The ability of muscles to switch between fuel sources during IF may vary greatly among individuals, and some people might not experience the same level of metabolic flexibility.
• IF may not be suitable for all athletic disciplines, particularly those requiring consistent energy availability, such as endurance sports, where a regular intake of carbohydrates is essential for optimal performance.
• There is a possibility that the benefits of IF on muscle cell function could plateau or diminish over time, and the long-term effects are not yet fully understood.
• The improvements in metabolism and physical performance attributed to fasting and working out may be confounded by other interventions or placebo effects in the studies referenced.
• The long-term sustainability of IF as a lifestyle choice may be challenging for some individuals, whereas regular exercise can be more easily adapted to different lifestyles and preferences.

Diet's Role: Avoiding Sugary and Manufactured Items to Support Brain Health

Mattson emphasizes the crucial role of diet composition in brain health, advocating for minimizing or eliminating sugars, especially fructose, and foods that have been processed, while prioritizing a diverse, nutrient-rich diet. He explains how these dietary choices directly impact cognitive function, neuronal well-being, and the likelihood of getting neurological diseases.

Sugars, Fats, and Altered Foods Damage Thinking and Development of the Brain

Mattson argues that eating lots of sugars, unhealthy fats, and processed foods has detrimental effects on cognitive functioning and brain structure. These effects, according to Mattson, occur through various mechanisms, including inflammation, oxidative pressure, and alterations in synaptic adaptability.

High Intake of Glucose, Fructose, and Saturated Fats Damages the Hippocampus and Impairs Memory

Mattson asserts that a high intake of glucose, fructose, and saturated fats damages the hippocampus and impairs memory. He explains that the hippocampus, an area of the brain crucial for learning and memory, is particularly vulnerable to the detrimental effects of these elements of diet. Excessive consumption of these substances can lead to inflammation, oxidative pressure, and impaired synaptic plasticity, all of which contribute to hippocampal dysfunction and memory impairment. Mattson highlights studies demonstrating both the increase in eating basic sugars—especially corn syrup that's high in fructose—and the rise in obesity over the last several decades. He explains that fructose metabolism through various poorly understood processes can lead to a reduction in metabolic rate and a rise in fat accumulation, further lowering glucose tolerance. He advocates for decreasing sugar intake for overall health and cognitive well-being.

Mattson provides research examples to support his argument. He cites Alexis Stranahan's work in his lab, showing impaired learning and memory dependent on the hippocampus in rats fed a diet high in fructose and saturated fat. He also discusses Scott Kanoski's research demonstrating impaired cognition even months after exposure of adolescent rats to high-fructose corn syrup for a short period of time, suggesting that long-term effects may appear later in adulthood due to exposure to unhealthy diets during development. He points to similar findings in adolescents with obesity, according to Antonio Convit’s reports including changes in brain structure (smaller corpus callosum), associated with slower cognitive function and impairment of memory. According to Mattson, this research provides strong evidence linking intake of corn syrup with high fructose levels and saturated fats to impaired cognitive function and a higher likelihood of poorer academic achievement among adolescents.

Practical Tips

• Start a "brain-healthy" recipe exchange with friends or family members to expand your repertoire of meals that are low in glucose, fructose, and saturated fats. This can be a fun way to discover new dishes and encourage each other to eat foods that support cognitive health. You might even challenge each other to create recipes using brain-boosting ingredients like leafy greens, berries, and nuts.
• Experiment with anti-inflammatory ingredients in your cooking. Incorporate spices like turmeric, ginger, and cinnamon, which are known for their anti-inflammatory properties, into your meals. Try new recipes each week that feature these ingredients, and observe any changes in your well-being, such as improved energy levels or cognitive function.
• Create a swap list of fructose-laden foods with healthier alternatives to simplify making better food choices. For example, instead of a fruit-flavored yogurt that may contain added sugars, opt for plain Greek yogurt with a sprinkle of cinnamon. Having a ready list of swaps can make grocery shopping and meal planning easier, helping you to consistently choose options that support a healthier metabolic rate and fat accumulation profile.
• Engage with an online community focused on sugar reduction to exchange ideas and support. Being part of a group with similar goals can provide motivation and accountability. You could share sugar-free recipes, celebrate milestones, and discuss challenges with group members, which can help you stay committed to reducing your sugar intake. For instance, if you're struggling to find tasty, sugar-free snacks, a community member might suggest a recipe for homemade kale chips that satisfies your cravings without the added sugar.
• You can monitor your cognitive performance by using a free online brain training platform. By engaging in daily cognitive exercises, you can track any changes in your memory and learning abilities over time. For instance, if you alter your diet to include less fructose and saturated fats, you might observe an improvement in your performance on these brain games, which could serve as a personal gauge of the diet's impact on your cognitive health.
• Experiment with making your own snacks and drinks from scratch, using natural sweeteners like honey or maple syrup instead of processed products with high-fructose corn syrup. This hands-on approach allows you to control what goes into your food and can lead to healthier eating habits.

Obesity and Insulin Resistance Linked to Decreased Brain Size and Academic Struggles

Mattson extends his argument by linking excess weight and insulin resistance to smaller brain size and worse academic performance. He references studies demonstrating that obese youth, on average, have smaller brains and perform worse academically than their peers with average weight. He contends that the chronic inflammation and metabolic dysregulation associated with being obese and experiencing insulin resistance contribute to these negative consequences. He explains that the size of the hippocampus, a brain area crucial for memory, is reduced in those with obesity and diabetes.

Mattson draws upon various research findings to bolster this point. He refers to research demonstrating that smaller brain volume has a strong link to higher insulin resistance among obese, depressed youths, supporting the idea that there is a considerable risk for the developing brain when glucose tolerance is impaired. Further, he notes the link between obesity and increased risk of anxiety and depression among young people, as demonstrated in several research studies reviewed by Amy Reichelt, that include changes in the number and activity of GABAergic neurons in the mouse prefrontal cortex after administration of an unhealthy diet during adolescence. This suggests that IF's beneficial impact on BDNF concentrations could also positively influence mood and potentially reduce the propensity to conditions such as anxiety and depressive states. These studies collectively highlight the negative consequences that excess weight and insulin insensitivity have on brain growth and cognitive abilities in kids and teens.

Practical Tips

• Create a personal challenge to increase physical activity with a friend or family member who also wants to improve their health. Set a goal for daily steps or active minutes and use a simple pedometer or smartphone app to track your progress. Encourage each other by sharing your daily achievements and discussing how this might be affecting your mental clarity and academic or work-related tasks.
• Engage in a monthly "kitchen reset" to make healthier food choices more automatic. Each month, reorganize your kitchen by placing healthier options at eye level in your pantry and fridge, and prep vegetables and fruits for easy snacking. By making these items more accessible, you're more likely to reach for them when you're hungry, supporting better dietary habits that can reduce inflammation and improve insulin sensitivity.
• Incorporate regular physical activity into your routine that combines both aerobic exercises and strength training. Exercise is known to enhance insulin sensitivity and can be a valuable tool in managing weight and mental health. Start with activities you enjoy, like dancing, hiking, or bodyweight exercises, to ensure consistency and enjoyment.
• Combine intermittent fasting with a light exercise routine to potentially enhance mood-improving effects. Engage in a daily walk or a short yoga session during your fasting period, as physical activity is known to boost BDNF levels as well, which might amplify the benefits you're seeking from fasting.
• Experiment with 'theme nights' at home that combine healthy eating with learning activities. For example, have a 'Mediterranean Monday' where you cook a meal rich in vegetables, whole grains, and lean proteins, followed by a family trivia game about the region's history or geography. This not only improves diet quality but also engages the family in cognitive exercises, making learning fun and relevant to everyday life.

Phytochemicals Benefit the Brain Through Hormetic Mechanisms

Mattson explains how phytochemicals, beneficial compounds from plants, activate hormetic mechanisms, similar to physical activity and IF, leading to enhanced neurological well-being. These mechanisms, according to Mattson, involve slight stress reactions in cells that enhance resilience and shield neurons from damage.

Health-Promoting Compounds Evolved As Pesticides Inducing Beneficial Cellular Stress

Mattson notes that many of the same plant-derived chemicals (phytochemicals) that promote health also evolved as innate pesticides to protect plants from being eaten by herbivores and omnivores. He explains that these phytochemicals, often found in high concentrations in the vulnerable parts of plants (seeds, buds, roots, skin) tend to taste bitter because they evolved to act as natural deterrents. Ironically, these same chemicals, consumed in moderate amounts by humans, have health benefits, especially for brain health. According to Mattson, this apparent paradox can be clarified through the concept of "hormesis." He postulates that small amounts of stressors that could provoke severe symptoms at higher doses might elicit adaptive stress responses that are ultimately beneficial to the cells. He explains that these foods—such as produce, tea, coffee, and cacao—benefit health because they contain bitter compounds that trigger small but positive stress reactions in our cells. These hormetic responses, Mattson concludes enhance resilience.

Mattson elaborates how animals evolved various mechanisms that allow them to eat vegetation without falling ill from these substances, while still enjoying their hormetic effects. He explains that there are 4 complementary mechanisms in place: the chemicals taste bitter, which deters overeating at high doses; an animal could vomit if the dose is too high, thus ridding itself of the excess; the liver contains a variety of p450 enzymes that detoxify and then get rid of the noxious chemicals through urine; and cells have evolved a variety of hormetic responses to these chemicals, such as enhancing stress resistance. He supports the significance of hormesis with examples like caffeine, found in coffee and tea, that can improve memory and stimulate BDNF and PGC-1α. The compound found in turmeric called curcumin and the one in broccoli known as sulforaphane can activate a variety of stress-reducing antioxidant responses. Resveratrol, found in red grapes, can protect cells from stress, and quercetin, found in many fruits and berries, can stimulate autophagy. These examples show how the defense strategies of plants, honed over millennia, have unwittingly benefited human health through hormetic pathways.

Other Perspectives

• The idea that phytochemicals evolved as pesticides suggests a purpose-driven process, whereas evolution is not goal-oriented but rather a series of random mutations that can result in advantageous traits being passed on.
• The concentration of phytochemicals can vary significantly among different species of plants, and even within different parts of the same plant, suggesting that vulnerability is not the only factor determining phytochemical distribution.
• Not all phytochemicals taste bitter; some may be sweet or have no taste at all, which suggests that bitterness is not a universal strategy for deterring herbivores.
• The bioavailability of phytochemicals can be low, and the actual amount absorbed and utilized by the brain may be much less than what is consumed, potentially reducing the expected health benefits.
• Some stressors that are considered hormetic may also have a narrow window of benefit, beyond which they can become toxic, and identifying this window can be challenging in practical applications.
• Some individuals may have sensitivities or allergies to certain phytochemicals found in these foods, which could negate the positive stress reactions and lead to adverse health outcomes.
• The mechanisms that allow animals to eat vegetation without falling ill can sometimes fail, especially when introduced to non-native plants or when the concentration of phytochemicals is unusually high, leading to poisoning and illness.
• Vomiting as a response to high doses of certain substances may not always be effective in preventing toxicity, as some compounds can be absorbed quickly or may cause damage before they can be expelled.
• The beneficial effects of caffeine on BDNF and PGC-1α may be dose-dependent, with too little having no effect and too much potentially causing harm.
• There is a possibility that the stress-reducing antioxidant responses induced by curcumin and sulforaphane could interfere with the efficacy of certain medications or have unintended effects in the context of specific diseases or conditions.
• Resveratrol's protective effects may not be as potent in humans as they are in laboratory settings or animal models due to differences in metabolism and bioavailability.
• Quercetin's ability to stimulate autophagy may not be significant enough in the amounts typically consumed in a standard diet to have a measurable impact on health.