Dr. Mark Matson, an adjunct professor of neuroscience at Johns Hopkins University, is an expert on the understanding of plant phytochemicals and their genetic responses. He explains that organisms evolved in stressful environments and developed mechanisms to cope with stress. For example, they incorporated iron and selenium into proteins to benefit from them, even though high levels of these elements are toxic. Evolution also shaped nervous systems to overcome food scarcity, predation, and competition. However, in modern society, people have 24-hour access to food and do not need to exercise to obtain it. This lack of biological stress has made it difficult to achieve the benefits that stress can provide.
Continuous access to food without periods of scarcity may have detrimental consequences on overall health. The lack of need to exercise to obtain food may lead to complacency and reduced ability to cope with stressors that cause disease. Exercise stimulates gene programs that help cells cope with stress and become stronger and more resilient. Exercise increases antioxidant defenses, enhances the ability to clear out damaged proteins and dysfunctional organelles, and protects proteins from damage. Sedentary individuals have reduced intrinsic antioxidant defenses and accumulation of molecular garbage in their cells. Physical and mental exercise stimulate nerve cells, making them more electrically active and bolstering their antioxidant defenses and mitochondrial function. Animal studies suggest that regular exercise increases the number of healthy mitochondria in muscle cells, leading to better endurance and function. Similar effects are observed in nerve cells, though more research in humans is needed.
In animals, researchers have observed that environmental enrichment, such as running wheel exercise, can lead to an increase in the number of mitochondria in nerve cells. Additionally, there is evidence of an increase in the number of synapses between nerve cells under these conditions. These findings suggest that maintaining an active mind through exercise and mental stimulation can have positive effects on brain health.
Energetic stresses, whether through exercise or fasting, have been shown to play a role in signaling pathways and gene expression. For example, ketones, which are elevated during fasting and sustained exercise, have been found to modulate enzymes called acetylases, impacting gene expression.
Intermittent fasting is an eating pattern, not a diet. It involves intermittent periods of not eating, which leads to the depletion of glucose stores in the liver and a switch to the use of fats and ketones for energy. It typically takes at least 10 hours of not eating to deplete the glucose in the liver and trigger this metabolic switch.
Intermittent fasting involves various approaches, one of which is daily time-restricted eating. This method compresses eating into a 6-8 hour window, resulting in a fasting period of 16-18 hours. This allows for metabolic switching, which is believed to be important for health benefits.
Another approach is the 5-2 intermittent fasting, where two days a week only one moderate-sized meal is eaten, while the other five days are normal eating. This results in metabolic switching occurring two days a week.
Research has shown strong evidence that intermittent fasting is beneficial for heart health, brain function, and glucose regulation. However, its effects on athletic performance are still being studied.
Intermittent fasting has been popularized, and its benefits have been supported by scientific research. Studies have shown benefits for brain health, heart rate, blood pressure, and anti-inflammatory effects.
A study conducted on overweight asthma patients showed that a rigorous regimen of every other day fasting with 400 calories led to profound beneficial effects in improving symptoms and lung airflow. The study also measured indicators of oxidative stress and inflammation, which decreased between two and four weeks of initiating the regimen.
Following this, a study was conducted with 100 women at risk for breast cancer, who were assigned to either 5-2 intermittent fasting or a control group with reduced calorie intake over six months. Both groups showed weight loss and improvements in glucose regulation, but the intermittent fasting group had greater improvement in insulin sensitivity and lost more belly fat.
The BBC aired a documentary on intermittent fasting in 2013 or 14, which led to increased interest in the topic. While there is now more information on intermittent fasting available online, there is also a growing interest from mainstream medicine.
A review article on intermittent fasting was published in the New England Journal of Medicine due to the accumulation of human studies on intermittent fasting, particularly in overweight individuals. Many physicians lack knowledge on the science behind intermittent fasting and how to prescribe it to patients. Studies show that individuals may experience hunger, irritability, and difficulty concentrating during the initial weeks of switching their eating patterns, as it takes time for the body to adapt. Animal studies have shown that measurable changes in the brain, such as upregulation of antioxidant enzyme levels, occur after a couple of weeks of intermittent fasting. The adaptation to intermittent fasting is linked to changes in hunger and satiety hormones such as ghrelin and leptin, as well as the production of ketones and metabolic switching.
A study was conducted at the University of Kentucky in Lexington, where rats were randomly assigned to either intermittent fasting or not. The study revealed that every other day fasting can extend lifespan up to 50 percent in rats when initiated in young adults. In the study, intermittent fasting protected against epileptic seizures and protected the neurons from being excited to death. The role of ketones in protecting nerve cells against epileptic seizures was also explored. This information is important for understanding the potential benefits of intermittent fasting in neurological conditions.
The ketogenic diet may not provide all the benefits of intermittent fasting, as it does not increase neural network activity. However, the ketogenic diet has been shown to enhance the activity of the inhibitory transmitter called gaba. Glutamate is the most important neurotransmitter, with the majority of nerve cells in the brain deploying glutamate as a neurotransmitter. Gaba, the main inhibitory neurotransmitter, controls the excitability of glutamatergic neurons throughout the brain. Blocking the function of gaba-producing neurons could lead to brain circuit malfunction, while an excess of gaba can quiet down glutamatergic activity too much. An example of this is drugs called benzodiazepines like valium.
Activation of GABA receptors quiets down glutamatergic neurons, while excessive valium intake can negatively impact nerve cell circuits. Intermittent fasting, similar to intermittent exercise, activates the neural network. Exercise, intermittent fasting, and intellectual engagement increase the production of nerve cell growth factors, such as BDNF, which is essential for learning and memory. Ketogenic diet can switch neurons from using glucose to ketones, which is a more efficient energy source with less free radicals generated. However, the signaling functions of ketones are more limited than those activated by exercise, intermittent fasting, or brain activity. Animal studies show increased BDNF levels with metabolic stress, but translating these findings to humans must consider the differences in metabolic rates. Additive effects of exercise in animals have not yet been fully explored.
Two types of metabolic stress are intermittent fasting and exercise. Evidence shows that combining exercise and intermittent fasting can be more effective. One study, conducted by a former graduate student, involved normal and diabetic mice. The mice were divided into four groups: sedentary and fed ad libitum, running wheels and fed ad libitum, sedentary and every other day fasting, and running wheels and every other day fasting. After three months, their brains were studied, specifically the hippocampus, which is important for learning and memory. The hippocampus is also studied in relation to dysfunction and pathology, such as in Alzheimer’s disease, epileptic seizures, and stroke. The simplicity of its circuitry allows for easier study.
One study found that intermittent fasting and exercise led to an increase in the number of synapses in the brain. Additionally, the combination of intermittent fasting and exercise showed a further increase in synapse numbers. However, in diabetic mice, synapse levels did not return to normal.
Another study showed that daily treadmill training and every other day fasting led to an increase in maximum endurance in mice. The mice were also subjected to increasing treadmill work over two months.
A study was conducted to measure the effects of intermittent fasting and exercise on endurance in mice. The study found that mice on intermittent fasting had better endurance after two months of treadmill training. Additionally, ketone levels were elevated with intermittent fasting and exercise increased ketone levels further.
Metabolomics analysis and measurements on muscle cells from the mice suggested that intermittent fasting and exercise increased the number of mitochondria in the muscle cells, with the greatest increase occurring with the combination of intermittent fasting and exercise.
A meta-analysis of human studies also found that exercising in a fasted state led to metabolic adaptations such as enhanced mitochondrial fatty acid oxidation and biogenesis. However, it was noted that very long endurance training activities may impact performance if done in a fasted state.
Based on these findings, the speaker has adapted their exercise routine to include fasted workouts in order to potentially benefit from mitochondrial adaptations.
The number of mitochondria in muscle cells increases during rest periods, triggering mitochondrial biogenesis. Fasting and exercise are metabolic challenges, and recovery periods are essential for their effectiveness. Overdoing fasting or exercise can have adverse effects, and recovery is crucial. Refeeding after fasting is important, and a window of six to eight hours for eating is sufficient for recovery. Prolonged fasting may require more consideration of the refeeding process, especially in clinics that facilitate fasting for several days.
Supervised fasting centers have shown short-term improvements in health indicators, but long-term effects remain unclear. Walter Longo’s work on time-restricted eating has shown potential benefits, but the long-term sustainability of such eating patterns is a consideration. Diet composition is also a critical factor in long-term health, with emerging evidence challenging traditional ideas about antioxidants and the benefits of consuming fruits and vegetables. It is important to consider the evolutionary perspective on human and animal dietary habits when exploring the impact of diet on long-term health.
Plants produce their own pesticides as a defense mechanism against insects and other organisms. Humans have evolved to protect themselves from these naturally occurring pesticides. One way is through the bitter taste of certain plant parts, such as the skin of grapes and apples. Another way is through vomiting, and a third way is through the rapid removal of potentially toxic chemicals by enzymes in the liver.
Individual cells in our bodies have also evolved to respond to these chemicals by enhancing antioxidant defenses and the ability to extrude the chemicals. For example, sulforaphane in broccoli activates antioxidant defenses in our cells, similar to the effects of exercise and fasting. Curcumin in turmeric root also activates antioxidant defenses.
Caffeine is the most commonly consumed plant toxin. It has an extremely bitter taste and can be lethal in high doses. Even ants will avoid coffee and tea leaves due to the presence of caffeine. Humans have evolved to protect themselves from these plant toxins through various mechanisms.
The notion that fruits and vegetables are good for health is not solely due to their free radical scavenging properties, such as vitamin E or C. Instead, these foods trigger mild adaptive stress responses in cells, overlapping with the benefits of exercise and fasting. Chemicals that are good for health are concentrated in the exposed parts of fruits, such as the skin. For example, green tomatoes contain tomatidine, which declines as the tomato turns red. This chemical deters pests, allowing the seeds to propagate the species. Regular exercise and intermittent fasting can activate similar stress response pathways, but consuming plant phytochemicals may still provide additional benefits.
There is a need for further scientific studies on the combination of intermittent fasting, exercise, and specific dietary components. Epidemiological data from blue zones suggests that a mostly plant-based diet may contribute to exceptional longevity. Evidence also supports the negative impact of simple sugars on health, while complex carbohydrates are preferable. Additionally, there is strong evidence suggesting that fish is a better dietary choice than red meat. It is important to consider the overall diet composition, as relying solely on intermittent fasting and exercise to counteract poor dietary choices may not be effective. Furthermore, while exercise and intermittent fasting may activate certain pathways, it is important to acknowledge that different stressors may have a more robust effect on specific stress response pathways. Therefore, it is advisable to diversify the approach to stress response. Additionally, specific chemicals found in plants, such as sulforaphane, have targeted effects on pathways, compared to the broader impact of exercise and fasting. This suggests that a combination of dietary components, exercise, and fasting may be beneficial for overall health.
Research on intermittent fasting has primarily focused on its benefits for metabolically unhealthy individuals, such as those with type 2 diabetes or obesity. Studies in healthy individuals are limited, but have shown some potential benefits, including improved glucose regulation and insulin sensitivity. However, the magnitude of these effects is likely to be less significant in healthy individuals compared to those who are overweight or have metabolic issues. The production of ketone bodies and activation of autophagy are some of the mechanisms through which intermittent fasting may confer health benefits, even in healthy individuals, though further research is needed to fully understand the extent of these effects.
It is important to maintain muscle mass as you age. People need to be careful not to take insufficient energy to maintain their muscle mass. Calorie restriction can extend lifespan. However, excessive restriction can have negative effects. For example, intermittent fasting made a mouse model of ALS worse. This is important to consider when exploring the benefits of fasting. Additionally, personal experience has shown that daily time-restricted eating and a low BMI may not always be beneficial for everyone.
The importance of maintaining a healthy body weight and muscle mass during aging cannot be overstated. Studies in elderly people regarding intermittent fasting are still needed, but for now, the focus is on overweight individuals and those at risk for cancer. Resistance training and a healthy diet are key components of maintaining health in the elderly population.
Intermittent fasting has been shown to suppress tumor formation and reduce the growth of cancer cells in animals. It can also enhance the killing of cancer cells by chemotherapy drugs and radiation. Elderly people with good muscle mass and physical activity may consider intermittent fasting if they maintain their overall calorie intake. Pediatricians have shown interest in intermittent fasting for overweight children, with some success in helping them reduce their body weight. There is an increased risk of autism in children born to women with obesity and type 2 diabetes, which has been linked to the increased incidence of autism in recent years. This correlation tracks well with the increase in maternal obesity and type 2 diabetes.
The rapid growth of the brain in the embryo in the uterus is influenced by the mTOR pathways, which are activated by factors such as obesity, type 2 diabetes, and lack of exercise. This leads to hyperexcitability of neural networks, which has been observed in children with autism and a higher incidence of seizures in this population. Animal studies, such as those involving fragile X syndrome, have also shown hyperactivity in glutamatergic neuronal networks in the brain.
Exercise has been found to have positive effects on mood, and intermittent fasting and ketogenic diets have been shown to upregulate the GABA tone, which may have potential benefits for children with autism. However, there are questions about whether fasting affects women differently than men, particularly in relation to menstrual cycles and hormonal regulation. Further research is needed to fully understand the potential impacts of fasting on brain development and overall health.
A study was conducted on rats to determine the effects of various calorie restriction methods. Rats on 20% daily calorie restriction showed no changes in their reproductive cycles. Rats on 40% daily calorie restriction stopped cycling and lost significant body fat. Rats on every other day fasting showed increased irregularity in their cycles, but were still presumably fertile. Male rats did not experience changes in sperm count or body weight on 40% calorie restriction. Females on major calorie restriction became very active, potentially due to searching for food. This could be interpreted as a survival response to potential starvation. Intermittent fasting did not have as significant an impact on reproductive cycles or body fat compared to 40% calorie restriction. However, concerns about the potential for developing anorexia nervosa in adolescent girls on intermittent fasting remain.
There is a lack of studies in the field of studying hormones, aside from simple ones such as leptin and ghrelin. However, it is known that there is an increased activation of the hypothalamic pituitary adrenal stress response system in animals, resulting in increased levels of cortisol. This is a system that should be further studied in relation to anorexia nervosa. Additionally, there are studies in animals that suggest a potential link between calorie restriction and extended age of menopause, but this is purely speculative and should not be encouraged without further research.
Early animal studies showed that animals live longer with calorie restriction or intermittent fasting. However, they had elevated cortisol levels. Cortisol is known to suppress the immune system, but it also affects gene expression. There are two receptors for cortisol, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Chronic stress leads to changes in these receptors, but intermittent fasting showed a decrease in GR levels and sustained levels of MR. This suggests that intermittent fasting activates stress response pathways differently than chronic stress. It is important to note the distinction between severe caloric restriction and alternate day fasting. In rodents, alternate day fasting had minimal effects.
The differences between intermittent fasting and caloric restriction are significant. In rodents, a 24-hour fast is equivalent to a much longer fast in humans. The drop in igf-1 levels in humans takes much longer than in rodents. The effects of intermittent fasting on a woman’s cycle are influenced by caloric load. In general, there is an overlap between caloric restriction and intermittent fasting, but the extent of metabolic switching is unclear.
Studies have shown that there are clear beneficial effects of intermittent fasting on the brain, independent of calorie intake. Even when calorie intake remains unchanged, intermittent fasting has been shown to protect neurons and decrease IGF-1 levels. Additionally, research has shown that intermittent fasting can result in weight loss similar to traditional calorie counting, even with the same overall calorie intake. These findings highlight the potential benefits of intermittent fasting on brain health and weight management.
A human study on 5:2 intermittent fasting revealed significant reduction in belly fat and improved insulin sensitivity not attributable to calorie reduction. A study in mice also demonstrated uncoupling benefits of weight loss from intermittent fasting. Time-restricted eating studies have shown metabolic benefits with no weight loss. Stress response pathways, cytoprotective mechanisms, and metabolic switching are important factors in understanding these adaptations. Rats implanted with transmitters showed a decrease in heart rate and blood pressure with 30% caloric restriction and every other day fasting. These effects were reversed upon returning to ad libitum feeding. Low resting heart rate, low blood pressure, and increased heart rate variability are associated with aerobic exercise. High heart rate variability indicates adaptability to stress and changes. Endurance athletes typically have high heart rate variability, indicating greater adaptability in regulating their heart in response to stress.
Increased heart rate variability is a result of exercise over time, enhancing the parasympathetic nerves that innervate the heart and slow down heart rate. The sympathetic nervous system increases heart rate. Intermittent fasting has been found to enhance the parasympathetic nervous system through the vagus nerves, slowing down heart rate, increasing blood flow, dilation of blood vessels, and enhancing gut motility. Similar to exercise, it takes a few weeks to a month to see the clear effects of intermittent fasting on the cardiovascular system. Discontinuing exercise and intermittent fasting leads to a quick return to previous conditions. Sauna use has been shown to mimic cardiovascular effects of aerobic exercise, maintain muscle mass, and increase heat shock proteins. Hot baths can also increase heat shock proteins, protecting muscle mass and increasing heart rate. Caloric restriction or fasting mimetics like resveratrol, spermidine, hydroxycitrate, and polyphenols from coffee have been shown to increase autophagy. Speculation on combining these with intermittent fasting would be valuable. The speaker’s intermittent fasting routine before and after their injury may be different.
The discussion focused on the use of 2-deoxyglucose and dinitrophenol to mimic the effects of fasting. 2-deoxyglucose is a glucose analog that competes with glucose in cells and can lead to glucose deprivation, triggering the production of protein chaperones like grp78. Studies have shown that intermittent administration of 2-deoxyglucose can be neuroprotective in some models, but long-term use has adverse effects on the cardiovascular system and may shorten lifespan. It’s important to carefully consider the amount and duration of such interventions, as short-term benefits may not translate to long-term health. Instead, the speaker recommends sticking with exercise and intermittent fasting as potentially beneficial strategies for maintaining cognitive function and health.
There is insufficient data to support the use of nicotinamide riboside or rapamycin in humans. Rapamycin is prescribed to suppress the immune system, and its long-term effects on human health are unknown. Daily time-restricted eating may have an effect on human lifespan or health span. In animals, exercise alone has minimal effect on lifespan, while calorie restriction and intermittent fasting have a striking ability to extend lifespan. However, it is not safe to extrapolate animal studies to humans. Exercise has profound beneficial effects on mental health and may impact blood pressure.
Mark is a well-known figure in the field of biological stress and intermittent fasting. His research on glutamate, the brain’s most important neurotransmitter, has had a major influence on many people’s thinking. Mark’s work on glutamate has shown its important role in controlling the formation of synapses during brain development. Glutamate is also important in synaptic remodeling, learning, and memory. Additionally, there is evidence that glutamate is a factor in conditions such as epilepsy, excitotoxicity, Alzheimer’s, Parkinson’s, stroke, traumatic brain injury, and ALS. Mark’s upcoming book, “Sculptor and Destroyer: The Story of Glutamate”, will provide valuable insights into this important neurotransmitter.
The mitochondria’s production of ATP plays a key role in the function of neurons. ATP is essential for driving sodium and calcium pumps to regulate neuron activity. Aging and neurodegenerative diseases such as Alzheimer’s and Parkinson’s can lead to hyper excitability if mitochondria function is compromised.
Enhancing GABA tone through drugs or ketosis may have potential benefits in regulating neuron activity. Studies have shown that ketone esters can have beneficial effects on Alzheimer’s disease in mouse models, and imaging studies have indicated promising results in humans with mild cognitive impairment and Alzheimer’s.
Overall, the role of ketosis and GABA production in mitigating the effects of compromised mitochondria on neuron function is an area of ongoing research with potential therapeutic implications.
Recent studies have shown that brain cells switch to using more ketones than glucose when on a ketogenic diet. This is particularly relevant in the case of Alzheimer’s disease, where early research has indicated a reduction in glucose utilization by brain cells. However, preliminary studies suggest that brain cells in early Alzheimer’s disease may still be able to effectively use ketones.
Studies on intermittent fasting in individuals at risk for cognitive impairment are also underway, with potential implications for the use of ketone esters. While the cost of ketone esters may be prohibitive for most individuals, anecdotal evidence suggests potential benefits for those with cognitive decline or dementia. Additionally, there are reports of individuals with Parkinson’s disease experiencing rapid and clear beneficial effects from ketone esters.
These findings hold promise for further research and potential applications in the field of cognitive and neurological health.