What we eat obviously affects gut health such as the microbiome and through that, along with other mechanisms, it affects the rest of our body, the brain included (by way of permeability, immune system, vagus nerve, substances like glutamate and propionate, and much else). About general health, I might add that foods eaten in what combination (e.g., red meat and grains) is also an issue. Opposite of what you eat impacting neurocognition and mental health, not eating (i.e., fasting, whether intermittent or extended) or else caloric restriction and carbohydrate reduction, ketogenic or otherwise, alters it in other ways.
Fasting, for example, increases the level of neurotransmitters such as serotonin, dopamine, and norepinephrine while temporarily reducing the brains release and use of them; plus, serotonin and its precursor tryptophan are made more available to the brain. So, it allows your reserves of neurotransmitters to rebuild to higher levels. That is partly why a ketogenic diet, along with the brains efficient use of ketones, shows improvements in behavior, learning, memory, acuity, focus, vigilance, and mood (such as sense of well-being and sometimes euphoria); with specific benefits, to take a couple of examples, in cerebral blood flow and prefrontal-cortex-related cognitive functions (mental flexibility and set shifting); while also promoting stress resistance, inflammation reduction, weight loss, and metabolism, and while decreasing free radical damage, blood pressure, heart rate, and glucose levels. Many of these are similar benefits as seen with strenuous exercise.
We know so much about this because the ketogenic diet is the only diet that has been specifically and primarily studied in terms of neurological diseases, going back to early 20th century research on epileptic seizures and autism, was shown effective for other conditions later in the century (e.g., V. A. Angelillo et al, Effects of low and high carbohydrate feedings in ambulatory patients with chronic obstructive pulmonary disease and chronic hypercapnia), and more recently with positive results seen in numerous other conditions (Dr. Terry Wahl’s work on multiple sclerosis, Dr. Dale Bredesen’s work on Alzheimer’s, etc). By the way, the direction of causality can also go the other way around, from brain to gut: “Studies also suggest that overwhelming systemic stress and inflammation—such as that induced via severe burn injury—can also produce characteristic acute changes in the gut microbiota within just one day of the sustained insult .” (Rasnik K. Singh et al, Influence of diet on the gut microbiome and implications for human health). And see:
“Various afferent or efferent pathways are involved in the MGB axis. Antibiotics, environmental and infectious agents, intestinal neurotransmitters/neuromodulators, sensory vagal fibers, cytokines, essential metabolites, all convey information about the intestinal state to the CNS. Conversely, the HPA axis, the CNS regulatory areas of satiety and neuropeptides released from sensory nerve fibers affect the gut microbiota composition directly or through nutrient availability. Such interactions appear to influence the pathogenesis of a number of disorders in which inflammation is implicated such as mood disorder, autism-spectrum disorders (ASDs), attention-deficit hypersensitivity disorder (ADHD), multiple sclerosis (MS) and obesity.” (Anastasia I. Petra et al, Gut-Microbiota-Brain Axis and Its Effect on Neuropsychiatric Disorders With Suspected Immune Dysregulation)
There are many other positive effects. Fasting reduces the risk of neurocognitive diseases: Parkinson’s, Alzheimer’s, etc. And it increases the protein BDNF (brain-derived neurotrophic factor) that helps grow neuronal connections. Results include increased growth of nerve cells from stem cells (as stem cells are brought out of their dormant state) and increased number of mitochondria in cells (mitochondria are the energy factories), the former related to the ability of neurons to develop and maintain connections between each other. An extended fast will result in autophagy (cellular housekeeping), the complete replacement of your immune cells and clearing out damaged cells which improves the functioning of your entire body (it used to be thought to not to occur in the brain but we now know it does) — all interventions known to prolong youthful health, lessen and delay diseases of aging (diabetes, cancer, cardiovascular disease, etc), and extend lifespan in lab animals involve autophagy (James H. Catterson et al, Short-Term, Intermittent Fasting Induces Long-Lasting Gut Health and TOR-Independent Lifespan Extension). Even calorie restriction has no effect when autophagy is blocked (Fight Aging!, Autophagy Required For Calorie Restriction Benefits?). It cleans out the system, gives the body a rest from its normal functioning, and redirects energy toward healing and rebuilding.
As a non-human example, consider hibernation for bears. A study was done comparing bears with a natural diet (fruits, nuts, insects, and small mammals) and those that ate human garbage (i.e., high-carb processed foods). “A research team tracked 30 black bears near Durango, Colo., between 2011 and 2015, paying close attention to their eating and hibernation habits. The researchers found that bears who foraged on human food hibernated less during the winters — sometimes, by as much as 50 days — than bears who ate a natural diet. The researchers aren’t sure why human food is causing bears to spend less time in their dens. But they say shorter hibernation periods are accelerating bears’ rates of cellular aging” (Megan Schmidt, Human Food Might Be Making Bears Age Faster). As with humans who don’t follow fasting or a ketogenic diet, bears who hibernate less don’t live as long. Maybe a high-carb diet messes with hibernation similarly to how it messes with ketosis.
Even intermittent fasting shows many of these benefits. Of course, you can do dramatic changes to the body without fasting at all, if you’re on a ketogenic diet (though one could call it a carb fast since it is extremely low carb) or severe caloric restriction (by the way, caloric restriction has been an area of much mixed results and hence confusion — see two pieces by Peter Attia: Calorie restriction: Part I – an introduction & Part IIA – monkey studies; does intermittent fasting and ketosis mimic caloric restriction or the other way around?). I’d add a caveat: On any form of dietary limitation or strict regimen, results vary depending on specifics of test subjects and other factors: how restricted and for how long, micronutrient and macronutrient content of diet, fat-adaptation and metabolic flexibility, etc; humans, by the way, are designed for food variety and so it is hard to know the consequences of modern diet that often remains unchanged, season to season, year to year (Rachel Feltman, The Gut’s Microbiome Changes Rapidly with Diet). There is a vast difference between someone on a high-carb diet doing an occasional fast and someone on a ketogenic diet doing regular intermittent fasting. Even within a single factor such as a high-carb diet, there is little similarity between the average American eating processed foods and a vegetarian monk eating restricted calories. As another example, autophagy can take several days of fasting to be fully achieved; but how quickly this happens depends on the starting conditions such as how many carbs eaten beforehand and how much glucose in the blood and glycogen stores in the muscles, both of which need to be used up before ketosis begins.
Metabolic flexibility, closely related to fat-adaptation, requires flexibility of the microbiome. Research has found that certain hunter-gatherers have microbiomes that completely switch from season to season and so the gut somehow manages to maintain some kind of memory of previous states of microbial balance which allows them to be re-established as needed. This is seen more dramatically with the Inuit who eat an extremely low-carb diet, but they seasonally eat relatively larger amounts of plant matter such as seaweed and they temporarily have digestive issues until the needed microbes take hold again. Are these microbes dormant in the system or systematically reintroduced? In either case, the process is unknown, as far as I know. What we are clear about is how dramatically diet affects the microbiome, whatever the precise mechanisms.
For example, a ketogenic diet modulates the levels of the microbes Akkermansia muciniphila, Lactobacillus, and Desulfovibrio (Lucille M. Yanckello, Diet Alters Gut Microbiome and Improves Brain Functions). It is the microbes that mediate the influence on both epileptic seizures and autism, such that Akkermansia is decreased in the former and increased in the latter, that is to say the ketogenic diet helps the gut regain balance no matter which direction the imabalance is. In the case of epileptic seizures, Akkermansia spurs the growth of Parabacteroides which alters neurotransmission by elevating the GABA/glutamate ratio (there is glutamate again): “the hippocampus of the microbe-protected mice had increased levels of the neurotransmitter GABA, which silences neurons, relative to glutamate, which activates them” (Carolyn Beans, Mouse microbiome findings offer insights into why a high-fat, low-carb diet helps epileptic children), but no such effect was found in germ-free mice, that is to say with no microbiome (similar results were found in human studies: Y. Zhang, Altered gut microbiome composition in children with refractory epilepsy after ketogenic diet). Besides reducing seizures, “GABA is a neurotransmitter that calms the body. Higher GABA to glutamate ratios has been shown to alleviate depression, reduce anxiety levels, lessen insomnia, reduce the severity of PMS symptoms, increase growth hormone, improve focus, and reduce systemic inflammation” (MTHFR Support, Can Eating A Ketogenic Diet Change Our Microbiome?). To throw out the other interesting mechanism, consider Desulfovibrio. Ketosis reduces its numbers and that is a good thing since it causes leakiness of the gut barrier, and what causes leakiness in one part of the body can cause it elsewhere as well such as the brain barrier. Autoimmune responses and inflammation can follow. This is why ketosis has been found beneficial for preventing and treating neurodegenerative conditions like Alzheimer’s (plus, ketones are a useful alternative fuel for Alzheimer’s since their brain cells begin starving to death for loss of the capacity to use glucose as a fuel).
All of this involves the factors that increase and reduce inflammation: “KD also increased the relative abundance of putatively beneficial gut microbiota (Akkermansia muciniphila and Lactobacillus), and reduced that of putatively pro-inflammatory taxa (Desulfovibrio and Turicibacter).” (David Ma et al, Ketogenic diet enhances neurovascular function with altered gut microbiome in young healthy mice). Besides the microbiome itself, this has immense impact on leakiness and autoimmune conditions, with this allowing inflammation to show up in numerous areas of the body, including the brain of course. Inflammation is found in conditions such as depression and schizophrenia. Even without knowing this mechanism, much earlier research has long established that ketosis reduces inflammation.
It’s hard to know what this means, though. Hunter-gatherers tend to have much more diverse microbiomes, as compared to industrialized people. Yet the ketogenic diet that helps induce microbial balance simultaneously reduces diversity. So, diversity isn’t always a good thing, with another example being small intestinal bacterial overgrowth (SIBO). What matters is which microbes one has in abundance and in relation which microbes one lacks or has limitedly. And what determines that isn’t limited to diet in the simple sense of what foods we eat or don’t eat but the whole pattern involved. Also, keep in mind that in a society like ours most of the population is in varying states of gut dysbiosis. First eliminating the harmful microbes is most important before the body can heal and rebalance. That is indicated by a study on multiple sclerosis that found, after the subjects had an initial reduction in the microbiome, “They started to recover at week 12 and exceeded significantly the baseline values after 23–24 weeks on the ketogenic diet” (Alexander Swidsinski et al, Reduced Mass and Diversity of the Colonic Microbiome in Patients with Multiple Sclerosis and Their Improvement with Ketogenic Diet). As always, it’s complex. But the body knows what to do when you give it the tools its evolutionarily-adapted to.
In any case, all of the methods described can show a wide range of benefits and improvements in physical and mental health. They are potentially recommended for almost anyone who is in a healthy state or in some cases of disease, although as always seek medical advice before beginning any major dietary change, especially anyone with an eating disorder or malnourishment (admittedly, almost all people on a modern industrialized diet are to some degree malnourished, especially Americans, although most not to a degree of being immediately life-threatening). Proceed with caution. But you are free to take your life in your hands by taking responsibility for your own health through experimentation in finding out what happens (my preferred methodology), in which case the best case scenario is that you might gain benefit at no professional medical cost and the worst case scenario is that you might die (not that I’ve heard of anyone dying from a typical version of a diet involving fasting, ketosis, and such; you’re way more likely to die from the standard American diet; but individual health conditions aren’t necessarily predictable based on the experience of others, even the vast majority of others). Still, you’re going to die eventually, no matter what you do. I wish you well, until that time.
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Let me clarify one point of widespread confusion. Talk of ‘diets’, especially of the variety I’ve discussed here, are often thought of in terms of restriction and that word does come up quite a bit. I’m guilty of talking this way even in this post, as it is about impossible to avoid such language considering it is used in the scientific and medical literature. So, there is an implication of deprivation, of self-control and self-denial, as if we must struggle and suffer to be healthy. That couldn’t be further from the truth.
Once you are fat-adapted and have metabolic flexibility, you are less restricted than you were before, in that you can eat more carbs and sugars for a time and then more easily return back to ketosis, as is a common seasonal pattern for hunter-gatherers. And once you no longer are driven by food cravings and addictions, you’ll have a happier and healthier relationship to food — eating when genuinely hungry and going without for periods without irritation or weakness, as also is common among hunter-gatherers.
This is simply a return to the state in which most humans have existed for most of our historical and evolutionary past. It’s not restriction or deprivation, much less malnourishment. It’s normalcy or should be. But we need to remember what normalcy looks and feels like: “People around the world suffer from starvation and malnutrition, and it is not only because they lack food and nutrients. Instead they suffer from immature microbiomes, which can severely impact health” (AMI, The effects of fasting and starvation on the microbiome). Gut health is inseparable from the rest, and these diets heal and rebalance the gut.
We need to redefine what health means, in a society where sickness has become the norm.
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Here is a good discussion that is relevant here, even though the author never discusses ketosis anywhere in his book. He is pointing out that calorie intake and energy usage is approximately the same for urbanized humans as for hunter-gatherers. Yet the former have higher rates of obesity and the latter don’t. As many have noted, not all calories are the same and so calories-in/calories-out is a myth. This data makes more sense once you understand how profoundly different the body functions under ketogenic and non-ketogenic states.
100 Million Years of Food
by Stephen Le
At this point, a reader might conclude that the root of modern food-related ailments like obesity and diabetes lies in people eating a lot more food, due to the miracle of nitrogen fixation, and doing a lot less physical activity, due to the miracle of combustion engines and private vehicles. However, it turns out that neither of these common beliefs is supported by the evidence.
First, the food intake myth. The daily energy consumed through food in contemporary industrialized nations runs from about 2,300 kcal (kilocalories) among Japanese men and 1,800 kcal among Japanese women to 2,600 kcal among American men and 1,900 kcal among American women. 21 What is surprising is that the average daily caloric intake of these overweight industrialized societies is about the same as among hunter-gatherer groups, with some hunter-gatherer groups below and others above the calories consumed of industrialized nations. 22 Although hunter-gatherers ate about as much as we do today, they faced much greater variability in their food supply. In northern Australia, among the Anbarra, the daily energy intake dropped to 1,600 kcal during the rainy season and peaked at 2,500 kcal during the dry season. The calorie consumption of the Hiwi in the rainforests of Venezuela bounced between 1,400 and 2,800 kilocalories, depending on the season (plant foods were most plentiful at the end of the wet season). Thus, if any major pattern emerges in terms of caloric intake, it is that our hunter-gatherer ancestors lived on a dramatically varying diet, which swung between feast and famine according to the season and other hazards of fortune.
Another surprising finding concerns physical activity. Although it is commonly believed that people in hunter-gatherer societies expended much more energy than people in industrialized societies today, the evidence so far does not support this assumption. One common measure of physical activity level (PAL) expresses the total energy used in one day as a multiple of a person’s metabolic rate. For example, a PAL of 1 means that a person uses only his/her metabolic energy, i.e., the energy expended by breathing, thinking, digesting, etc. A PAL of 2 means that a person uses twice as much energy as his or her base metabolic rate. PAL allows us to adjust for the fact that people have varying levels of metabolism; a person who has a high metabolic rate can burn up a lot of energy by just sitting in one place compared to a person with low metabolism, so a good measure of physical activity needs to compensate for differences in metabolism. To determine the amount of energy used in a day, the best measure involves giving a person a drink of water that has been “tagged” with isotopes of hydrogen and oxygen. Measurement of these two tags in samples of saliva, urine, or blood allows measurement of exhaled carbon dioxide and hence the degree of respiration from metabolic processes.
Using tagged water, the average PAL among foragers was found to be 1.78 for men and 1.72 for women. Among industrialized contemporary societies with a high human development index (which measures income, literacy, and so on), the PAL of men was 1.79 for men and 1.71 for women. 23 In other words, the energy expenditure of overweight contemporary industrialized societies is roughly the same as that of lean hunter-gatherer societies once metabolism is taken into account; or to put it another way, the cause of obesity is unlikely to be lack of exercise, because people in industrialized societies today use about the same amount of energy as people in hunter-gatherer societies. 24
This finding has important implications for understanding obesity. All of us living in industrialized societies are aware of the stigma associated with obesity, and perhaps the longer-term health consequences of diabetes, high blood pressure, gout, and cancers associated with being overweight. Since food intake and energy expenditure levels today are roughly the same as during ancestral times (using the lifestyles of modern hunter-gatherers as a reasonable model for our ancestors’ lifestyles), why are obesity and diabetes so prevalent among industrialized societies and virtually nonexistent among our ancestors?
The first argument might be an objection that obesity has in fact been with us since the days of our earliest ancestors, so nothing has changed. It has been suggested that figurines of markedly obese women, found in Europe and dating to thirty thousand years ago, are proof that obesity existed at that time. However, no hunter-gatherer or small-scale horticultural group has ever manifested signs of obesity, despite having caloric intake and energy expenditure (adjusted for metabolism) within the range of contemporary industrialized populations. Thus the prehistoric statuettes may be representative of idealized feminine beauty, just as Barbie dolls and Japanese anime characters with huge eyes and exaggerated busts are fantasies more revealing of their creators than of real women.
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Become Smarter, Happier, and More Productive While Protecting Your Brain for Life
by Max Lugavere
Baby Fat Isn’t Just Cute—It’s a Battery
Have you seen a baby lately? I’m talking about a newborn, fresh out of the womb. They’re fat. And cute. But mostly fat. Packed with stored energy prior to birth in the third trimester, the fatness of human babies is unprecedented in the mammal world. While the newborns of most mammal species average 2 to 3 percent of birth weight as body fat, humans are born with a body fat percentage of nearly 15, surpassing the fatness of even newborn seals. Why is this so? Because humans are born half-baked.
When a healthy human baby emerges from the womb, she is born physically helpless ad with an underdeveloped brain. Unlike most animals at birth, a newborn human is not equipped with a full catalogue of instincts preinstalled. It is estimated that if a human were to be born at a similar stage of cognitive development to a newborn chimp, gestation would be at least double the length (that doesn’t sound fun—am I right ladies?). By being born “prematurely,” human brains complete their development not in the womb, but in the real world, with open eyes and open ears—this is probably why we’re so social and smart! And it is during this period for rapid brain growth, what some refer to as the “fourth trimester,” that our fast serves as an important ketone reservoir for the brain, which can account for nearly 90 percent of the newborn’s metabolism. Now you know: baby fat isn’t just there for pinching. It’s there for the brain.
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Mitochondria and the Future of Medicine:
The Key to Understanding Disease, Chronic Illness, Aging, and Life Itself
by Lee Know
Ketogenic Diets and Calorie Restriction
Ketone bodies, herein also referred to simply as ketones , are three water-soluble compounds that are produced as by-products when fatty acids are broken down for energy in the liver. These ketones can be used as a source of energy themselves, especially in the heart and brain, where they are a vital source of energy during periods of fasting.
The three endogenous ketones produced by the body are acetone , acetoacetic acid , and beta-hydroxybutyric acid (which is the only one that’s not technically a ketone, chemically speaking). They can be converted to acetyl-CoA, which then enters the TCA cycle to produce energy.
Fatty acids are so dense in energy, and the heart is one of the most energy-intensive organs, so under normal physiologic conditions, it preferentially uses fatty acids as its fuel source. However, under ketotic conditions, the heart can effectively utilize ketone bodies for energy.
The brain is also extremely energy-intensive, and usually relies on glucose for its energy. However, when glucose is in short supply, it gets a portion of its energy from ketone bodies (e.g., during fasting, strenuous exercise, low-carbohydrate, ketogenic diet, and in neonates). While most other tissues have alternate fuel sources (besides ketone bodies) when blood glucose is low, the brain does not. For the brain, this is when ketones become essential. After three days of low blood glucose, the brain gets 25 percent of its energy from ketone bodies. After about four days, this jumps to 70 percent!
In normal healthy individuals, there is a constant production of ketone bodies by the liver and utilization by other tissues. Their excretion in urine is normally very low and undetectable by routine urine tests. However, as blood glucose falls, the synthesis of ketones increases, and when it exceeds the rate of utilization, their blood concentration increases, followed by increased excretion in urine. This state is commonly referred to as ketosis , and the sweet, fruity smell of acetone in the breath is a common feature of ketosis.
Historically, this sweet smell was linked to diabetes and ketones were first discovered in the urine of diabetic patients in the mid-nineteenth century. For almost fifty years thereafter, they were thought to be abnormal and undesirable by-products of incomplete fat oxidation.
In the early twentieth century, however, they were recognized as normal circulating metabolites produced by the liver and readily utilized by the body’s tissues. In the 1920s, a drastic “hyperketogenic” diet was found to be remarkably effective for treating drug-resistant epilepsy in children. In 1967, circulating ketones were discovered to replace glucose as the brain’s major fuel during prolonged fasting. Until then, the adult human brain was thought to be entirely dependent upon glucose.
During the 1990s, diet-induced hyperketonemia (commonly called nutritional ketosis ) was found to be therapeutically effective for treating several rare genetic disorders involving impaired glucose utilization by nerve cells. Now, growing evidence suggests that mitochondrial dysfunction and reduced bioenergetic efficiency occur in brains of patients with Parkinson’s disease and Alzheimer’s disease. Since ketones are efficiently used by brain mitochondria for ATP generation and might also help protect vulnerable neurons from free-radical damage, ketogenic diets are being evaluated for their ability to benefit patients with Parkinson’s and Alzheimer’s diseases, and various other neurodegenerative disorders (with some cases reporting remarkable success).
There are various ways to induce ketosis, some easier than others. The best way is to use one of the various ketogenic diets (e.g., classic, modified Atkins, MCT or coconut oil, low-glycemic index diet), but calorie restriction is also proving its ability to achieve the same end results when carbohydrates are limited.
Features of Caloric Restriction
There are a number of important pieces to caloric restriction. First, and the most obvious, is that caloric intake is most critical. Typically, calories are restricted to about 40 percent of what a person would consume if food intake was unrestricted. For mice and rats, calorie restriction to this degree results in very different physical characteristics (size and body composition) than those of their control-fed counterparts. Regarding life extension, even smaller levels of caloric restriction (a reduction of only 10–20 percent of unrestricted calorie intake) produce longer-lived animals and disease-prevention effects.
In April of 2014, a twenty-five-year longitudinal study on rhesus monkeys showed positive results. The benefit of this study was that it was a long-term study done in primates—human’s closest relatives—and confirms positive data we previously saw from yeasts, insects, and rodents. The research team reported that monkeys in the control group (allowed to eat as much as they wanted) had a 2.9-fold increased risk of disease (e.g., diabetes) and a 3-fold increased risk of premature death, compared to calorie-restricted monkeys (that consumed a diet with 30 percent less calories).
If other data from studies on yeast, insects, and rodents can be confirmed in primates, it would indicate that calorie restriction could extend life span by up to 60 percent, making a human life span of 130–150 years a real possibility without fancy technology or supplements or medications. The clear inverse relationship between energy intake and longevity links its mechanism to mitochondria—energy metabolism and free-radical production.
Second, simply restricting the intake of fat, protein, or carbohydrates without overall calorie reduction does not increase the maximum life span of rodents. It’s the calories that count, not necessarily the type of calories (with the exception of those trying to reach ketosis, where type of calorie does count).
Third, calorie restriction has been shown to be effective in disease prevention and longevity in diverse species. Although most caloric restriction studies have been conducted on small mammals like rats or mice, caloric restriction also extends life span in single-celled protozoans, water fleas, fruit flies, spiders, and fish. It’s the only method of life extension that consistently achieves similar results across various species.
Fourth, these calorie-restricted animals stay “biologically younger” longer. Experimental mice and rats extended their youth and delayed (even prevented) most major diseases (e.g., cancers, cardiovascular diseases). About 90 percent of the age-related illnesses studied remained in a “younger” state for a longer period in calorie-restricted animals. Calorie restriction also greatly delayed cancers (including breast, colon, prostate, lymphoma), renal diseases, diabetes, hypertension, hyperlipidemia, lupus, and autoimmune hemolytic anemia, and a number of others.
Fifth, calorie restriction does not need to be started in early age to reap its benefits. Initiating it in middle-aged animals also slowed aging (this is good news for humans, because middle age is when most of us begin to think about our own health and longevity).
Of course, the benefits of calorie restriction relate back to mitochondria. Fewer calories mean less “fuel” (as electrons) entering the ETC, and a corresponding reduction in free radicals. As you know by now, that’s a good thing.
As just discussed, new research is showing that judicious calorie restriction and ketogenic diets (while preserving optimal nutritional intake) might slow down the normal aging process and, in turn, boost cardiovascular, brain, and cellular health. But how? We can theorize that the restriction results in fewer free radicals, but one step in confirming a theory is finding its mechanism.
In particular, researchers have identified the beneficial role of beta-hydroxybutyric acid (the one ketone body that’s not actually a ketone). It is produced by a low-calorie diet and might be the key to the reduced risk of age-related diseases seen with calorie restriction. Over the years, studies have found that restricting calories slows aging and increases longevity, but the mechanism behind this remained elusive. New studies are showing that beta-hydroxybutyric acid can block a class of enzymes, called histone deacetylases , which would otherwise promote free-radical damage.
While additional studies need to be conducted, it is known that those following calorie-restricted or ketogenic diets have lower blood pressure, heart rate, and glucose levels than the general population. More recently, there has been a lot of excitement around intermittent fasting as an abbreviated method of achieving the same end results.
However, self-prescribing a calorie-restricted or ketogenic diet is not recommended unless you’ve done a lot of research on the topic and know what to do. If not done properly, these diets can potentially increase mental and physical stress on the body. Health status should be improving, not declining, as a result of these types of diets, and when not done properly, these diets could lead to malnutrition and starvation. Health care practitioners also need to properly differentiate a patient who is in a deficiency state of anorexia or bulimia versus someone in a healthy state of ketosis or caloric restriction.
I’ll add a final word of caution: While ketogenic diets can be indispensable tools in treating certain diseases, their use in the presence of mitochondrial disease—at this point—is controversial and depends on the individual’s specific mitochondrial disease. In some cases, a ketogenic diet can help; in others it can be deleterious. So, of all the therapies listed in this book, the one for which I recommend specific expertise in its application is this diet, and only after a proper diagnosis.
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The Surprising Truth about Wheat, Carbs, and Sugar–Your Brain’s Silent Killers
by David Perlmutter
Another epigenetic factor that turns on the gene for BDNF production is calorie restriction. Extensive studies have clearly demonstrated that when animals are on a reduced-calorie diet (typically reduced by around 30 percent), their brain production of BDNF shoots up and they show dramatic improvements in memory and other cognitive functions. But it’s one thing to read experimental research studies involving rats in a controlled environment and quite another to make recommendations to people based upon animal research. Fortunately, we finally have ample human studies demonstrating the powerful effect of reducing caloric intake on brain function, and many of these studies have been published in our most well-respected medical journals. 13
In January 2009, for example, the Proceedings of the National Academy of Science published a study in which German researchers compared two groups of elderly individuals—one that reduced their calories by 30 percent and another that was allowed to eat whatever they wanted. The researchers were interested in whether changes could be measured between the two groups’ memory function. At the conclusion of the three-month study, those who were free to eat without restriction experienced a small but clearly defined decline in memory function, while memory function in the group on the reduced-calorie diet actually increased, and significantly so. Knowing that current pharmaceutical approaches to brain health are very limited, the authors concluded, “The present findings may help to develop new prevention and treatment strategies for maintaining cognitive health into old age.” 14
Further evidence supporting the role of calorie restriction in strengthening the brain and providing more resistance to degenerative disease comes from Dr. Mark P. Mattson, chief of the Laboratory of Neurosciences at the National Institute on Aging (NIA). He reported:
Epidemiological data suggest that individuals with a low calorie intake may have a reduced risk of stroke and neurodegenerative disorders. There is a strong correlation between per capita food consumption and risk for Alzheimer’s disease and stroke. Data from population-based case control studies showed that individuals with the lowest daily calorie intakes had the lowest risk of Alzheimer’s disease and Parkinson’s disease. 15
Mattson was referring to a population-based longitudinal prospective study of Nigerian families, in which some members moved to the United States. Many people believe that Alzheimer’s disease is something you “get” from your DNA, but this particular study told a different story. It was shown that the incidence of Alzheimer’s disease among Nigerian immigrants living in the United States was increased compared to their relatives who remained in Nigeria. Genetically, the Nigerians who moved to America were the same as their relatives who remained in Nigeria. 16 All that changed was their environment—specifically, their caloric intake. The research clearly focused on the detrimental effects that a higher caloric consumption has on brain health. In a 2016 study published in Johns Hopkins Health Review, Mattson again emphasized the value of caloric restriction in warding off neurodegenerative diseases while at the same time improving memory and mood. 17 One way to do that is through intermittent fasting, which we’ll fully explore in chapter 7 . Another way, obviously, is to trim back your daily consumption.
If the prospect of reducing your calorie intake by 30 percent seems daunting, consider the following: On average, we consume 23 percent more calories a day than we did in 1970. 18 Based on data from the Food and Agriculture Organization of the United Nations, the average American adult consumes more than 3,600 calories daily. 19 Most would consider “normal” calorie consumption to be around 2,000 calories daily for women and 2,500 for men (with higher requirements depending on level of activity/exercise). A 30 percent cut of calories from an average of 3,600 per day equals 1,080 calories.
We owe a lot of our increased calorie consumption to sugar. Remember, the average American consumes roughly 163 grams (652 calories) of refined sugars a day—reflecting upward of a 30 percent hike in just the last three decades. 20 And of that amount, about 76 grams (302 calories) are from high-fructose corn syrup. So focusing on just reducing sugar intake may go a long way toward achieving a meaningful reduction in calorie intake, and this would obviously help with weight loss. Indeed, obesity is associated with reduced levels of BDNF, as is elevation of blood sugar. Remember, too, that increasing BDNF provides the added benefit of actually reducing appetite. I call that a double bonus.
But if the figures above still aren’t enough to motivate you toward a diet destined to help your brain, in many respects, the same pathway that turns on BDNF production can be activated by intermittent fasting (which, again, I’ll detail in chapter 7 ).
The beneficial effects in treating neurologic conditions using caloric restriction actually aren’t news for modern science, though; they have been recognized since antiquity. Calorie restriction was the first effective treatment in medical history for epileptic seizures. But now we know how and why it’s so effective: It confers neuroprotection, increases the growth of new brain cells, and allows existing neural networks to expand their sphere of influence (i.e., neuroplasticity).
While low caloric intake is well documented in relation to promoting longevity in a variety of species—including roundworms, rodents, and monkeys—research has also demonstrated that lower caloric intake is associated with a decreased incidence of Alzheimer’s and Parkinson’s disease. And the mechanisms by which we think this happens are via improved mitochondrial function and controlling gene expression.
Consuming fewer calories decreases the generation of free radicals while at the same time enhancing energy production from the mitochondria, the tiny organelles in our cells that generate chemical energy in the form of ATP (adenosine triphosphate). Mitochondria have their own DNA, and we know now that they play a key role in degenerative diseases such as Alzheimer’s and cancer. Caloric restriction also has a dramatic effect on reducing apoptosis, the process by which cells undergo self-destruction. Apoptosis happens when genetic mechanisms within cells are turned on that culminate in the death of that cell. While it may seem puzzling at first as to why this should be looked upon as a positive event, apoptosis is a critical cellular function for life as we know it. Pre-programmed cell death is a normal and vital part of all living tissues, but a balance must be struck between effective and destructive apoptosis. In addition, caloric restriction triggers a decrease in inflammatory factors and an increase in neuroprotective factors, specifically BDNF. It also has been demonstrated to increase the body’s natural antioxidant defenses by boosting enzymes and molecules that are important in quenching excessive free radicals.
In 2008, Dr. Veronica Araya of the University of Chile in Santiago reported on a study she performed during which she placed overweight and obese subjects on a three-month calorie-restricted diet, with a total reduction of 25 percent of calories. 21 She and her colleagues measured an exceptional increase in BDNF production, which led to notable reductions in appetite. It’s also been shown that the opposite occurs: BDNF production is decreased in animals on a diet high in sugar. 22 Findings like this have since been replicated.
One of the most well-studied molecules associated with caloric restriction and the growth of new brain cells is sirtuin-1 (SIRT1), an enzyme that regulates gene expression. In monkeys, increased SIRT1 activation enhances an enzyme that degrades amyloid—the starch-like protein whose accumulation is the hallmark of diseases like Alzheimer’s. 23 In addition, SIRT1 activation changes certain receptors on cells, leading to reactions that have the overall effect of reducing inflammation. Perhaps most important, activation of the sirtuin pathway by caloric restriction enhances BDNF. BDNF not only increases the number of brain cells, but also enhances their differentiation into functional neurons (again, because of caloric restriction). For this reason, we say that BDNF enhances learning and memory. 24
The Benefits of a Ketogenic Diet
While caloric restriction is able to activate these diverse pathways, which are not only protective of the brain but enhance the growth of new neuronal networks, the same pathway can be activated by the consumption of special fats called ketones. By far the most important fat for brain energy utilization is beta-hydroxybutyrate (beta-HBA), and we’ll explore this unique fat in more detail in the next chapter. This is why the so-called ketogenic diet has been a treatment for epilepsy since the early 1920s and is now being reevaluated as a therapeutic option in the treatment of Parkinson’s disease, Alzheimer’s disease, ALS, depression, and even cancer and autism. 25 It’s also showing promise for weight loss and ending type 2 diabetes. In mice models, the diet rescues hippocampal memory deficits, and extends healthy lifespan.
Google the term “ketogenic diet” and well over a million results pop up. Between 2015 and 2017, Google searches for the term “keto” increased ninefold. But the studies demonstrating a ketogenic diet’s power date back further. In one 2005 study, for example, Parkinson’s patients actually had a notable improvement in symptoms that rivaled medications and even brain surgery after being on a ketogenic diet for just twenty-eight days. 26 Specifically, consuming ketogenic fats (i.e., medium-chain triglycerides, or MCT oil) has been shown to impart significant improvement in cognitive function in Alzheimer’s patients. 27 Coconut oil, from which we derive MCTs, is a rich source of an important precursor molecule for beta-hydroxybutyrate and is a helpful approach to treating Alzheimer’s disease. 28 A ketogenic diet has also been shown to reduce amyloid in the brain, 29 and it increases glutathione, the body’s natural brain-protective antioxidant, in the hippocampus. 30 What’s more, it stimulates the growth of mitochondria and thus increases metabolic efficiency. 31
Dominic D’Agostino is a researcher in neuroscience, molecular pharmacology, and physiology at the University of South Florida. He has written extensively on the benefits of a ketogenic diet, and in my Empowering Neurologist interview with him he stated: “Research shows that ketones are powerful energy substrates for the brain and protect the brain by enhancing antioxidant defenses while suppressing inflammation. No doubt, this is why nutritional ketosis is something pharmaceutical companies are aggressively trying to replicate.” I have also done a lot of homework in understanding the brain benefits of ketosis—a metabolic state whereby the body burns fat for energy and creates ketones in the process. Put simply, your body is in a state of ketosis when it’s creating ketones for fuel instead of relying on glucose. And the brain loves it.
While science typically has looked at the liver as the main source of ketone production in human physiology, it is now recognized that the brain can also produce ketones in special cells called astrocytes. These ketone bodies are profoundly neuroprotective. They decrease free radical production in the brain, increase mitochondrial biogenesis, and stimulate production of brain-related antioxidants. Furthermore, ketones block the apoptotic pathway that would otherwise lead to self-destruction of brain cells.
Unfortunately, ketones have gotten a bad rap. I remember in my internship being awakened by a nurse to treat a patient in “diabetic ketoacidosis.” Physicians, medical students, and interns become fearful when challenged by a patient in such a state, and with good reason. It happens in insulin-dependent type 1 diabetics when not enough insulin is available to metabolize glucose for fuel. The body turns to fat, which produces these ketones in dangerously high quantities that become toxic as they accumulate in the blood. At the same time, there is a profound loss of bicarbonate, and this leads to significant lowering of the pH (acidosis). Typically, as a result, patients lose a lot of water due to their elevated blood sugars, and a medical emergency develops.
This condition is exceedingly rare, and again, it occurs in type 1 diabetics who fail to regulate their insulin levels. Our normal physiology has evolved to handle some level of ketones in the blood; in fact, we are fairly unique in this ability among our comrades in the animal kingdom, possibly because of our large brain-to-body weight ratio and the high energy requirements of our brain. At rest, 20 percent of our oxygen consumption is used by the brain, which represents only 2 percent of the human body. In evolutionary terms, the ability to use ketones as fuel when blood sugar was exhausted and liver glycogen was no longer available (during starvation) became mandatory if we were to survive and continue hunting and gathering. Ketosis proved to be a critical step in human evolution, allowing us to persevere during times of food scarcity. To quote Gary Taubes, “In fact, we can define this mild ketosis as the normal state of human metabolism when we’re not eating the carbohydrates that didn’t exist in our diets for 99.9 percent of human history. As such, ketosis is arguably not just a natural condition but even a particularly healthful one.” 32
There is a relationship between ketosis and calorie restriction, and the two can pack a powerful punch in terms of enhancing brain health. When you restrict calories (and carbs in particular) while upping fat intake, you trigger ketosis and increase levels of ketones in the blood. In 2012, when researchers at the University of Cincinnati randomly assigned twenty-three older adults with mild cognitive impairment to either a high-carbohydrate or very low-carbohydrate diet for six weeks, they documented remarkable changes in the low-carb group. 33 They observed not only improved verbal memory performance but also reductions in weight, waist circumference, fasting glucose, and fasting insulin. Now here’s the important point: “Ketone levels were positively correlated with memory performance.”
German researchers back in 2009 demonstrated in fifty healthy, normal to overweight elderly individuals that when calories were restricted along with a 20 percent increase in dietary fat, there was a measurable increase in verbal memory scores. 34 Another small study, yes, but their findings were published in the respected Proceedings of the National Academy of Sciences and spurred further research like that of the 2012 experiment. These individuals, compared to those who did not restrict calories, demonstrated improvements in their insulin levels and decline in their C-reactive protein, the infamous marker of inflammation. As expected, the most pronounced improvements were in people who adhered the most to the dietary challenge.
Research and interest in ketosis have exploded in recent years and will continue. The key to achieving ketosis, as we’ll see later in detail, is to severely cut carbs and increase dietary fat. It’s that simple. You have to be carb restricted if you want to reach this brain-blissful state.
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Power Up Your Brain
by David Perlmutter and Alberto Villoldo
Your Brain’s Evolutionary Advantage
One of the most important features distinguishing humans from all other mammals is the size of our brain in proportion to the rest of our body. while it is certainly true that other mammals have larger brains, scientists recognize that larger animals must have larger brains simply to control their larger bodies. An elephant, for example, has a brain that weighs 7,500 grams, far larger than our 1,400-gram brain. So making comparisons about “brain power” or intelligence just based on brain size is obviously futile, Again, it’s the ratio of the brain size to total body size that attracts scientist’s interests when considering the brain’s functional capacity. An elephant’s brain represents 1/550 of its body weight, while the human brain weighs 1/40 of the total body weight. So our brain represents 2.5 percent of our total body weight as opposed to the large-brained elephant whose brain is just 0.18 percent of its total body weight.
But even more important than the fact that we are blessed with a lot of brain matter is the intriguing fact that, gram for gram, the human brain consumes a disproportionately huge amount of energy. While only representing 2.5 percent of our total body weight, the human brain consumes an incredible 22 percent of our body’s energy expenditure when at rest. this represents about 350 percent more energy consumption in relation to body weight compared with other anthropoids like gorillas, orangutans, and chimpanzees.
So it takes a lot of dietary calories to keep the human brain functioning. Fortunately, the very fact that we’ve developed such a large and powerful brain has provided us with the skills and intelligence to maintain adequate sustenance during times of scarcity and to make provisions for needed food supplies in the future. Indeed, the ability to conceive of and plan for the future is highly dependent upon the evolution not only of brain size but other unique aspects of the human brain.
It is a colorful image to conceptualize early Homo sapiens migrating across and arid plain and competing for survival among animals with smaller brains yet bigger claws and greater speed. But our earliest ancestors had one other powerful advantage compared to even our closest primate relatives. The human brain has developed a unique biochemical pathway that proves hugely advantageous during times of food scarcity. Unlike other mammals, our brain is able to utilize an alternative source of calories during times of starvation. Typically, we supply our brain with glucose form our daily food consumption. We continue to supply our brains with a steady stream of glucose (blood sugar) between meals by breaking down glycogen, a storage form of glucose primarily found in the liver and muscles.
But relying on glycogen stores provides only short-term availability of glucose. as glycogen stores are depleted, our metabolism shifts and we are actually able to create new molecules of glucose, a process aptly termed gluconeogenesis. this process involves the construction of new glucose molecules from amino acids harvested form the breakdown of protein primarily found in muscle. While gluconeogenesis adds needed glucose to the system, it does so at the cost of muscle breakdown, something less than favorable for a starving hunter-gatherer.
But human physiology offers one more pathway to provide vital fuel to the demanding brain during times of scarcity. When food is unavailable, after about three days the liver begins to use body fat to create chemicals called ketones. One ketone in particular, beta hydroxybutyrate (beta-HBA), actually serves as a highly efficient fuel source for the brain, allowing humans to function cognitively for extended periods during food scarcity.
Our unique ability to power our brains using this alternative fuel source helps reduce our dependence on gluconeogensis and therefore spares amino acids and the muscles they build and maintain. Reducing muscle breakdown provides obvious advantages for the hungry Homo sapiens in search of food. It is this unique ability to utilize beta-HBA as a brain fuel that sets us apart from our nearest animal relatives and has allowed humans to remain cognitively engaged and, therefore, more likely to survive the famines ever-present in our history.
This metabolic pathway, unique to Homo sapiens, may actually serve as an explanation for one of the most hotly debated questions in anthropology: what caused the disappearance of our Neanderthal relatives? Clearly, when it comes to brains, size does matter. Why then, with a brain some 20 percent larger than our own, did Neanderthals suddenly disappear in just a few thousand years between 40,000 and 30,000 years ago? the party line among scientists remains fixated on the notion that the demise of Neanderthals was a consequence of their hebetude, or mental lethargy. The neurobiologist William Calvin described Neanderthals in his book, A Brain for All Seasons: “Their way of life subjected them to more bone fractures; they seldom survived until forty years of age; and while making tools similar to [those of] overlapping species, there was little [of the] inventiveness that characterizes behaviorally modern Homo sapiens.”
While it is convenient and almost dogmatic to accept that Neanderthals were “wiped out” by clever Homo sapiens, many scientists now believe that food scarcity may have played a more prominent role in their disappearance. Perhaps the simple fact that Neanderthals, lacking the biochemical pathway to utilize beta-HBA as a fuel source for brain metabolism, lacked the “mental endurance” to persevere. Relying on gluconeogenesis to power their brains would have led to more rapid breakdown of muscle tissue, ultimately compromising their ability to stalk prey or migrate to areas where plant food sources were more readily available. their extinction may not have played out in direct combat with Homo sapiens but rather manifested as a consequence of a simple biochemical inadequacy.
Our ability to utilize beta-HBA as a brain fuel is far more important than simply a protective legacy of our hunter-gatherer heritage. George F. Cahill of Harvard Medical School stated, “Recent studies have shown that beta-hydroxybutyrate, the principle ‘ketone’ is not just a fuel, but a ‘superfuel’ more efficiently producing ATP energy than glucose. . . . It has also protected neuronal cells in tissue culture against exposure to toxins associated with Alzheimer’s or Parkinson’s.”
Indeed, well beyond serving as a brain superfuel, Dr. Cahill and other researchers have determined that beta-HBA has other profoundly positive effects on brain health and function. Essentially, beta-HBA is thought to mediate many of the positive effects of calorie reduction and fasting on the brain, including improved antioxidant function, increased mitochondrial energy production with an increased in mitochondrial energy production with an increase in mitochondrial population, increased cellular survival, and increased levels of BDNF leading to enhanced growth of new brain cells (neurogenesis).
Earlier, we explored the need to reduce caloric intake in order to increase BDNF as a means to stimulate the growth of new brain cells as well as to enhance the function of existing neurons. The idea of substantially reducing daily calorie intake will not appeal to many people despite the fact that it is a powerful approach to brain enhancement as well as overall health.
Interestingly, however, many people find the idea of intermittent fasting to be more appealing. Fasting is defined here as a complete abstinence from food for a defined period of time at regular intervals—our fasting program permits the drinking of water. Research demonstrates that many of the same health-providing and brain-enhancing genetic pathways activated by calorie reduction are similarly engaged by fasting—even for relatively short periods of time. Fasting actually speaks to your DNA, directing your genes to produce an astounding array of brain-enhancement factors.
Not only does fasting turn on the genetic machinery for the production of BDNF, but it also powers up the Nrf2 pathway, leading to enhanced detoxification, reduced inflammation, and increased production of brain-protective antioxidants. Fasting causes the brain to shift away from using glucose as a fuel to a metabolism that consumes ketones. When the brain metabolizes ketones for fuel, even the process of apoptosis is reduced, while mitochondrial genes turn their attention to mitochondrial replication. In this way, fasting shifts the brain’s basic metabolism and specifically targets the DNA of mitochondria, thus enhancing energy production and paving the way for better brain function and clarity . . .
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Ketone bodies mimic the life span extending properties of caloric restriction
by Richard L. Veech Patrick C. Bradshaw Kieran Clarke William Curtis Robert Pawlosky M. Todd King
Aging in man is accompanied by deterioration of a number of systems. Most notable are a gradual increase in blood sugar and blood lipids, increased narrowing of blood vessels, an increase in the incidence of malignancies, the deterioration and loss of elasticity in skin, loss of muscular strength and physiological exercise performance, deterioration of memory and cognitive performance, and in males decreases in erectile function. Many aging‐induced changes, such as the incidence of malignancies in mice 82, the increases in blood glucose and insulin caused by insulin resistance 39, 78, and the muscular weakness have been shown to be decreased by the metabolism of ketone bodies 18, 83, a normal metabolite produced from fatty acids by liver during periods of prolonged fasting or caloric restriction 12.
The unique ability of ketone bodies to supply energy to brain during periods of impairment of glucose metabolism make ketosis an effective treatment for a number of neurological conditions which are currently without effective therapies. Impairment of cognitive function has also been shown to be improved by the metabolism of ketone bodies 84. Additionally, Alzheimer’s disease, the major cause of which is aging 20 can be improved clinically by the induction of mild ketosis in a mouse model of the disease 85 and in humans 86. Ketosis also improves function in Parkinson’s disease 87 which is thought to be largely caused by mitochondrial free radical damage 19, 88. Ketone bodies are also useful in ameliorating the symptoms of amyotrophic lateral sclerosis 89. It is also recognized that ketosis could have important therapeutic applications in a wide variety of other diseases 90 including Glut 1 deficiency, type I diabetes 91, obesity 78, 92, and insulin resistance 20, 39, 93, and diseases of diverse etiology 90.
In addition to ameliorating a number of diseases associated with aging, the general deterioration of cellular systems independent of specific disease seems related to ROS toxicity and the inability to combat it. In contrast increases in life span occur across a number of species with a reduction in function of the IIS pathway and/or an activation of the FOXO transcription factors, inducing expression of the enzymes required for free radical detoxification (Figs. 1 and 2). In C. elegans, these results have been accomplished using RNA interference or mutant animals. Similar changes should be able to be achieved in higher animals, including humans, by the administration of d‐βHB itself or its esters.
In summary, decreased signaling through the insulin/IGF‐1 receptor pathway increases life span. Decreased insulin/IGF‐1 receptor activation leads to a decrease in PIP3, a decrease in the phosphorylation and activity of phosphoinositide‐dependent protein kinase (PDPK1), a decrease in the phosphorylation and activity of AKT, and a subsequent decrease in the phosphorylation of FOXO transcription factors, allowing them to continue to reside in the nucleus and to increase the transcription of the enzymes of the antioxidant pathway.
In mammals, many of these changes can be brought about by the metabolism of ketone bodies. The metabolism of ketones lowers the blood glucose and insulin thus decreasing the activity of the IIS and its attendant changes in the pathway described above. However, in addition ketone bodies act as a natural inhibitor of class I HDACs, inducing FOXO gene expression stimulating the synthesis of antioxidant and metabolic enzymes. An added important factor is that the metabolism of ketone bodies in mammals increases the reducing power of the NADP system providing the thermodynamic drive to destroy oxygen free radicals which are a major cause of the aging process.
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Insights into human evolution from ancient and contemporary microbiome studies
by Stephanie L Schnorr, Krithivasan Sankaranarayanan, Cecil M Lewis, Jr, and Christina Warinner
Brain growth, development, and behavior
The human brain is our defining species trait, and its developmental underpinnings are key foci of evolutionary genetics research. Recent research on brain development and social interaction in both humans and animal models has revealed that microbes exert a major impact on cognitive function and behavioral patterns . For example, a growing consensus recognizes that cognitive and behavioral pathogenesis are often co-expressed with functional bowel disorders . This hints at a shared communication or effector pathway between the brain and gut, termed the gutbrain-axis (GBA). The enteric environment is considered a third arm of the autonomic nervous system , and gut microbes produce more than 90% of the body’s serotonin (5-hydroxytryptamine or 5-HT) . Factors critical to learning and plasticity such as serotonin, γ-aminobutryic acid (GABA), short chain fatty acids (SCFAs), and brain derived neurotrophic factor (BDNF), which train amygdalin and hippocampal reactivity, can be mediated through gut-brain chemical signals that cross-activate bacterial and host receptors [86••, 106, 107]. Probiotic treatment is associated with positive neurological changes in the brain such as increased BDNF, altered expression of GABA receptors, increased circulating glutathione, and a reduction in inflammatory markers. This implicates the gut microbiome in early emotional training as well as in affecting long-term cognitive plasticity.
Critically, gut microbiota can modulate synthesis of metabolites affecting gene expression for myelin production in the prefrontal cortex (PFC), presumably influencing the oligodendrocyte transcriptome [110•, 111••]. Prosocial and risk associated behavior in probiotic treated mice, a mild analog for novelty-seeking and risk-seeking behaviors in humans, suggests a potential corollary between entrenched behavioral phenotypes and catecholamines (serotonin and dopamine) produced by the gut microbiota [108, 112, 113]. Evolutionary acceleration of the human PFC metabolome divergence from chimpanzees, particularly the dopaminergic synapse , reifies the notion that an exaggerated risk-reward complex characterizes human cognitive differentiation, which is facilitated by microbiome derived bioactive compounds. Therefore, quintessentially human behavioral phenotypes in stress, anxiety, and novelty-seeking is additionally reinforced by microbial production of neuroactive compounds. As neurological research expands to include the microbiome, it is increasingly clear that host–microbe interactions have likely played an important role in human brain evolution and development [115•].
Ancient human microbiomes
by Christina Warinner, Camilla Speller, Matthew J. Collins, and Cecil M. Lewis, Jr
Need for paleomicrobiology data
Although considerable effort has been invested in characterizing healthy gut and oral microbiomes, recent investigations of rural, non-Western populations (Lozupone et al., 2012; Yatsunenko et al., 2012) have raised questions about whether the microbiota we currently define as normal have been shaped by recent influences of modern Western diet, hygiene, antibiotic exposure, and lifestyle (Maslowski and Mackay, 2011). The process of industrialization has dramatically reduced our direct interaction with natural environments and fundamentally altered our relationship with food and food production. Situated at the entry point of our food, and the locus of food digestion, the human oral and gut microbiomes have evolved under conditions of regular exposure to a diverse range of environmental and zoonotic microbes that are no longer present in today’s globalized food chain. Additionally, the foods themselves have changed from the wild natural products consumed by our hunter-gatherer ancestors to today’s urban supermarkets stocked with an abundance of highly processed Western foodstuffs containing artificially enriched levels of sugar, oil, and salt, not to mention antimicrobial preservatives, petroleum-based colorants, and numerous other artificial ingredients. This dietary shift has altered selection pressure on our microbiomes. For example, under the ‘ecological plaque hypothesis’, diseases such as dental caries and periodontal disease are described as oral ecological catastrophes of cultural and lifestyle choices (Marsh, 2003).
Although it is now clear that the human microbiome plays a critical role in making us human, in keeping us healthy, and in making us sick, we know remarkably little about the diversity, variation, and evolution of the human microbiome both today and in the past. Instead, we are left with many questions: When and how did our bacterial communities become distinctly human? And what does this mean for our microbiomes today and in the future? How do we acquire and transmit microbiomes and to what degree is this affected by our cultural practices and built environments? How have modern Western diets, hygiene practices, and antibiotic exposure impacted ‘normal’ microbiome function? Are we still in mutualistic symbiosis with our microbiomes, or are the so-called ‘diseases of civilization’ – heart disease, obesity, type II diabetes, asthma, allergies, osteoporosis – evidence that our microbiomes are out of ecological balance and teetering on dysbiosis (Stecher et al., 2013)? At an even more fundamental level, who are the members of the human microbiome, how did they come to inhabit us, and how long have they been there? Who is ‘our microbial self’ (Gonzalez et al., 2011)?
Studies of remote and indigenous communities (Contreras et al., 2010; Yatsunenko et al., 2012; Schnorr et al., 2014) and crowdsourcing projects such as the American Gut (www.americangut.org), the Earth Microbiome Project (www.earthmicrobiome.org), and uBiome (www.uBiome.com) are attempting to characterize modern microbiomes across a range of contemporary environments. Nevertheless, even the most extensive sampling of modern microbiota will provide limited insight into Pre-Industrial microbiomes. By contrast, the direct investigation of ancient microbiomes from discrete locations and time points in the past would provide a unique view into the coevolution of microbes and hosts, host microbial ecology, and changing human health states through time. […]
Diet also plays a role in shaping the composition of oral microbiomes, most notably by the action of dietary sugar in promoting the growth of cariogenic bacteria such as lactobacilli and S. mutans (Vågstrand and Birkhed, 2007). Two recent papers have proposed that cariogenic bacteria, such as S. mutans, were absent in pre-Neolithic human populations, possibly indicating low carbohydrate diets (Soltysiak, 2012; Adler et al., 2013), while evolutionary genomic analyses of S. mutans suggest an expansion in this species approximately 10,000 years, coinciding with the onset of agriculture (Cornejo et al., 2013). […]
Ancient microbiome research provides an additional pathway to understanding human biology that cannot be achieved by studies of extant individuals and related species alone. Although reconstructing the ancestral microbiome by studying our ancestors directly is not without challenges (Tito et al., 2012), this approach provides a more direct picture of human-microbe coevolution. Likewise, ancient microbiome sources may reveal to what extent bacteria commonly considered ‘pathogenic’ in the modern world (for example, H. pylori) were endemic indigenous organisms in pre-Industrial microbiomes (Hadley, 2006).
The three paths to reconstructing the ancestral microbiomes are also complimentary. For example, analysis of the gut microbiome from extant, rural peoples in Africa and South America have revealed the presence of a common, potentially commensal, spirochete belonging to the genus Treponema (De Filippo et al., 2010; Yatsunenko et al., 2012). Such spirochetes have also been detected in extant hunter-gatherers (Schnorr et al., 2014), and in 1,000-year-old human coprolites from Mexico (Tito et al., 2012), but they are essentially absent from healthy urban populations, and they have not been reported in the gut microbiome of chimpanzees (Moeller et al., 2012). These multiple lines of evidence suggest that this poorly understood spirochete is a member of the ancestral human microbiome, yet not necessarily the broader primate microbiome. Future coprolite research may be able to answer the question of how long this microbe has co-associated with humans, and what niche it fills.
Exposure of the Host-Associated Microbiome to Nutrient-Rich Conditions May Lead to Dysbiosis and Disease Development—an Evolutionary Perspective
The gist of what the paper is about:
We here propose that overfeeding of the host-associated bacterial community, particularly with easily digestible, energy-dense, low-fiber-content foods, likely causes dysbiosis and the development of disease. Overfeeding uncouples natural host-microbe associations, leading to an increased activity and changed functionality of the associated microbiota.
This paper sheds light on an important, yet often overlooked facet of the recent assault on the human microbiome, namely the effects of overfeeding. While it’s widely recognized that fast food doesn’t do the microbiome good, it’s somewhat underappreciated that changes pertaining to our meal pattern and total caloric intake have also undermined human-microbe relations.
Whereas our primal ancestors often did things, like chasing game, on an empty stomach, many humans of the 21st century could be said to almost constantly be in a fed, as opposed to fasted, state. This paper helps draw attention to the microbiome-related implications of this mismatch and suggests that many of the health benefits of intermittent fasting are mediated by gut bacteria.
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Can Ketogenic Diets Work for Bodybuilding or Athletics?
by P. D. Mangan
Here’s how I’d summarize the ‘keto for sports’ evidence so far:
- The longer the study…or the longer its keto-adaptation phase…or the more keto-adapted the subjects are…the more likely the study is to find favorable performance results
- Keto is worth trying for anyone in any sport (but start in the off-season!)
- It’s highly unlikely keto is better for high-intensity
- It’s unlikely that keto is bad for high-intensity
- It’s likely that keto is neutral for high-intensity
- It’s likely that keto diets are better for endurance
- It’s very likely keto diets are better for body composition
- It’s very likely keto diets are generally healthier than standard high-carb diets for athletes
Does Fasting Make You Smarter?
by Derek Beres
Fasting Cleans the Brain
by P. D. Mangan
How Fasting Heals Your Brain
by Adriana Ayales
Effect of Intermittent Fasting on Brain Neurotransmitters, Neutrophils Phagocytic Activity, and Histopathological Finding in Some Organs in Rats
by Sherif M. Shawky, Anis M. Zaid, Sahar H. Orabi, Khaled M. Shoghy, and Wafaa A. Hassan
The Effects of Fasting During Ramadan on the Concentration of Serotonin, Dopamine, Brain-Derived Neurotrophic Factor and Nerve Growth Factor
by Abdolhossein Bastani, Sadegh Rajabi, and Fatemeh Kianimarkani
Gut microbiome, SCFAs, mood disorders, ketogenic diet and seizures
by Jonathan Miller
Study: Ketogenic diet appears to prevent cognitive decline in mice
by University of Kentucky
Low-carb Diet Alleviates Inherited Form of Intellectual Disability in Mice
by Johns Hopkins Medicine
Is the Keto Diet Bad for the Microbiome?
by David Jockers
Does a Ketogenic Diet Change Our Microbiome?
by Christie Rice
Can Health Issues Be Solved By Dietary Changes Altering the Microbiome?
by Russ Schierling
RHR: Is High Fat Healthy for the Gut Microbiota?
by Chris Kresser
A Comprehensive List of Low Carb Research
by Sarah Hallberg