happen right

again feeds the vicious cycle. It is important to understand that weight loss needs to happen right now, as changes take place as soon as an individual begins to carry excess body fat. To some degree, we can predict whose brain will suffer thirty years from now simply by measuring body fat. In a 2008 report, California scientists combed through the records of more than sixty-five hundred people who were evaluated in the mid1960s to 1970s. 23 They wanted to know: Who got dementia? When these folks were first evaluated an average of thirty-six years earlier, various measurements were made of their bodies to determine how much fat they had. These included the size of the belly, thigh circumference, and height and weight. Roughly three decades later, those individuals who had more body fat had a dramatically increased risk for dementia. Of the original group, 1,049 were diagnosed as having dementia. When the scientists compared the group with the least body fat to the group with the highest body fat, they found that those in the highest body fat group had an almost twofold increased risk of dementia. The authors reported, “As is the case for diabetes and cardiovascular disease, central obesity [belly fat] is also a risk factor for dementia.” THE POWER OF WEIGHT LOSS (BESIDES WHAT YOU ALREADY KNOW) As study after study has proven, weight loss through dieting can have a dramatic effect on insulin signaling and insulin sensitivity. In one report, doctors evaluated 107 obese individuals at least sixtyfive years of age over a one-year period and studied how they responded in terms of insulin to an oral dose of glucose. 24 The researchers wanted to measure the difference among three distinct groups: those who were put on a weight-loss program, those who were assigned an exercise program, and those put on a diet and exercise program. A fourth group of people was designated as the control for purposes of further comparison. The results six months later? People in the weight-loss group had a 40 percent increase in their insulin sensitivity. This also happened in the group that went on a weight-loss program and exercised. The group that didn’t embark on a weight-loss program but did exercise, however, showed no change in insulin sensitivity. When the study was finally concluded after one year, insulin sensitivity had improved by a whopping 70 percent in those who lost weight; people who were exercising while on a diet and lost weight had an 86 percent improvement in their sensitivity to insulin. But the third group, the one that engaged in physical activity without dieting and losing weight, remained far behind. Even after one year they had absolutely no change in their insulin sensitivity. So the take-home lesson is clear: You can improve insulin sensitivity and reduce your risk of diabetes (not to mention all manner of brain diseases) simply by making lifestyle changes that melt that fat away. And if you add exercise to the dieting, you’ll stand to gain even bigger benefits. By now you should know that I’m going to prescribe a low-carb diet rich in healthy fats, including cholesterol. And don’t take my word for it. Just turn to the latest studies proving the power of this type of diet. Last year the Journal of the American Medical Association published the effects of three popular diets on a group of overweight or obese young adults. 25 Each of the participants tried each of the diets for a month—one was low-fat (60 percent of the calories came from carbohydrate, 20 percent from fat, and 20 percent from protein), one was low-glycemic (40 percent of the calories came from carbohydrate, 40 percent from fat, and 20 percent from protein), and the third was a very low carbohydrate diet (10 percent of the calories came from carbohydrates, 60 percent from fat, and 30 percent from protein). All of the diets provided the same number of calories, but those on the low-carb, high-fat diet burned the most calories. The study also looked at insulin sensitivity during the four-week period on each diet, finding that the low-carb diet triggered the biggest improvement in insulin sensitivity—almost twice that of the low-fat diet. Triglycerides, a powerful cardiovascular risk marker, averaged 66 in the low-carb group and 107 in the low-fat group. (As an aside, elevated triglyceride levels are also a hallmark of too many carbs in the diet.) The authors pointed out that the lab results they measured in the low-fat diet showed changes in people’s blood chemistry that left them vulnerable to weight gain. Clearly, the best diet for maintaining weight loss is a low-carbohydrate, high-fat one. Many other studies have arrived at the same conclusion: A low-carb, high-fat diet will outperform a low-fat, high-carb diet any day, and by virtually every measure in the body, from its internal chemistry to its external waistline. And when we consider all of the parameters that affect health, and specifically brain health, such as weight loss, insulin sensitivity, blood sugar control, and even Creactive protein, a low-carbohydrate diet is substantially more effective than any other diet. Those other diets will result in outcomes that heighten your risk for a multitude of brain dysfunctions, from daily nuisances like headaches to chronic migraines, anxiety disorders, ADHD, and depression. And if the thought of being as sharp as a whip until your last breath on earth isn’t enough to motivate you, then consider all the benefits that your heart (and virtually every organ in your body) will gain by ditching a low-fat diet. In March 2013, the New England Journal of Medicine published a large landmark study showing that people age fifty-five to eighty who ate a Mediterranean diet were at lower risk of heart disease and stroke—by as much as 30 percent—than those on a typical low-fat diet. 26 The results were so profound that scientists halted the study early because the low-fat diet proved too damaging for the people eating lots of commercially baked goods rather than sources of healthy fats. The Mediterranean diet is famous for being rich in olive oil, nuts, beans, fish, fruits and vegetables, and even wine with meals. Although it does allow room for grains, it’s very similar to my dietary protocol. In fact, if you modify the traditional Mediterranean diet by removing all glutencontaining foods and limiting sugary fruits and non-gluten carbs, you have yourself the perfect grainbrain-free diet. AN APPLE A DAY? No, an apple a day may not keep the doctor away. Now that I’ve held so many of your favorite foods in contempt, I can hear the uncertainty: “How can the body live on fat and never get fat?” Ah, it’s an excellent question. I’m going to tackle that very conundrum shortly and settle any confusion about how you can live—and thrive—on fats. It sounds absurd to think we can live on virtually no carbs but copious amounts of fat and cholesterol in our diet. But we can, and we should if we’re going to protect our genome. Despite what food marketers would have you believe, we’ve had a fat-based diet shaping our genome for the past 2.6 million years. Why change that? As you’ve already read, when we did we got fat. The story of reversing this trend and gaining back the lean, toned, lithe bodies we’re designed to have, and a sharp brain to boot, starts with a look at the brain’s fundamental properties. CHAPTER 5 The Gift of Neurogenesis and Controlling Master Switches How to Change Your Genetic Destiny The brain is a far more open system than we ever imagined, and nature has gone very far to help us perceive and take in the world around us. It has given us a brain that survives in a changing world by changing itself. —DR. NORMAN DOIDGE (THE BRAIN THAT CHANGES ITSELF) WE ARE DESIGNED to be smart people our entire lives. The brain is supposed to work well until our last breath. But most of us assume, wrongly, that with age comes cognitive decline. We think it’s an inevitable part of aging, much like hearing loss or wrinkles. This impression is a pernicious fallacy. The truth is that we’re living a life that’s not suited to what we’re genetically supposed to do. Period. The diseases we see nowadays are largely brought on by our lifestyle not being in harmony with our genetic predisposition. But we can change this and return our DNA back to its original programming. Better yet, we can re-program some of our DNA to function even more advantageously. And this isn’t science fiction. How often do we hear people say things like, “I’ll probably get [insert disease here] because it runs in my family.” No doubt our genetic heritage does play a role in determining our risk for various health conditions. But what leading-edge medical research now understands is that we have the power to change our genetic destiny. One of the hottest areas of research currently gaining momentum is epigenetics, the study of particular sections of your DNA (called “marks”) that essentially tell your genes when and how strongly to express themselves. Like conductors of an orchestra, these epigenetic marks are the remote control not only to your health and longevity but also to how you pass your genes on to future generations. Our day-to-day lifestyle choices have a profound effect on the activity of our genes. And this is empowering. We now know that the food choices we make, the stress we experience or avoid, the exercise we get or avoid, the quality of our sleep, and even the relationships we choose actually choreograph to a significant degree which of our genes are active and which remain suppressed. Here’s what is most compelling: We can change the expression of more than 70 percent of the genes that have a direct bearing on our health and longevity. This chapter explains how we can enhance the expression of our “healthy genes” while turning off those genes that trigger such detrimental events as inflammation and the production of free radicals. The genes involved in causing inflammation and free radical production are strongly influenced by fat and carbohydrate dietary choices, and this information will further support the recommendations made in the upcoming chapters. THE STORY OF NEUROGENESIS Does every cocktail you drink really kill thousands of brain cells? As it turns out, we are not stuck with the number of neurons we’re born with, or even those that develop in early childhood. We can grow new neurons throughout our entire lives. We can also fortify existing brain circuits and create entirely new and elaborate connections, too, with new brain cells. I’ve been lucky enough to participate in this discovery that has overturned generations of conventional wisdom in neuroscience, though many people still believe otherwise. During my college years I was given the opportunity to explore the brain using technology that was just in its infancy. It was in the early 1970s, and the Swiss had begun developing microscopes that could be used by neurosurgeons performing delicate brain procedures. While this technology was evolving and surgeons in the United States were eager to adopt this new approach to brain surgery, a problem soon became evident. While learning to actually use the operating microscope was relatively easy, the neurosurgeons found that they were becoming somewhat lost in terms of understanding the anatomy of the brain from this new microscopic perspective. I was nineteen years old and just starting my junior year in college when I received a phone call from Dr. Albert Rhoton, chairman of the Department of Neurological Surgery at Shands Teaching Hospital in Gainesville, Florida. Dr. Rhoton was leading the way for expansion of the use of the operating microscope in the United States and wanted to create the first anatomy text of the brain as seen through the microscope. He invited me to spend the following summer studying and mapping the brain, and it was from this research that we eventually published a series of research papers and book chapters that gave neurosurgeons the needed roadmap to more carefully operate on the brain. In addition to anatomy, we also had the opportunity to explore and develop other aspects of microneurosurgery, including innovative instruments and procedures. Spending so much time behind the microscope, I had become quite adept at manipulating and repairing extremely small blood vessels that, prior to the use of the microscope, would have been destroyed during brain operations, often with dire consequences. Our lab had gained international recognition for its achievements in this new and exciting field and often attracted visiting professors from around the world. And it was soon after a delegation of Spanish neurosurgeons had visited that I found myself accepting an invitation to continue my research at the prestigious Centro Ramón y Cajal in Madrid, Spain. Their microneurosurgery program was in its infancy, but their team was dedicated, and I felt honored to be assisting them in their groundwork efforts, especially those dealing with understanding the brain’s blood supply. The hospital was named in honor of Dr. Santiago Ramón y Cajal, a Spanish pathologist and neuroscientist working at the turn of the twentieth century, who is still regarded as the father of modern neurology; images of him on the walls were numerous and there was clearly a deep sense of pride among my Spanish colleagues that they could claim such an influential scientist as their own. In 1906 he won the Nobel Prize in medicine for his pioneering investigations of the microscopic structure of the brain. Today, hundreds of his handmade drawings are still used for educational purposes. During my visit to Madrid I was compelled to learn more about Dr. Cajal and came to deeply respect his explorations of human brain anatomy and function. One of his major tenets held that brain neurons were unique compared to other cells of the body, not only because of their function, but also because they lacked the ability to regenerate. The liver, for example, perpetually regenerates by growing new liver cells, and similar regeneration of cells occurs in virtually all other tissues, including skin, blood, bone, and intestines. I admit that I was pretty well sold on this theory that brain cells do not regenerate, but I did wonder back then why it wouldn’t make sense for the brain to retain the ability to regenerate—to have the ability to grow new brain neurons. After all, researchers at the Massachusetts Institute of Technology had shown previously that neurogenesis, the growth of new brain neurons, occurred throughout the entire lifetime in rats. And so much about the human body is regeneration; it relies on continuous selfrenewal to survive. For example, certain blood cells turn over every few hours, taste receptor cells get replaced every ten days, skin cells turn over every month, and muscle cells take about fifteen years to completely renew themselves. In the last decade, scientists have determined that the heart muscle—an organ that we long thought was “fixed” since birth—does in fact experience cellular turnover as well. 1 When we’re twenty-five years old, about 1 percent of our heart muscle cells are replaced every year; but by the age of seventy-five, that rate has fallen to less than half a percent per year. Hard to believe that we’ve only recently come to identify and understand this phenomenon in the body’s bloodpumping machine. And now we’ve finally decoded the brain and discovered its self-renewing qualities. Dr. Cajal couldn’t possibly have known just how malleable and “plastic” the brain could be given the technology he was working with. At that time, DNA hadn’t been decoded yet and there was little understanding of the impact genes could have on functionality. In his seminal 1928 book Degeneration and Regeneration of the Nervous System, Cajal stated: “In adult centers the nerve paths are something fixed, ended, immutable. Everything may die, nothing may be regenerated.” 2 If I could change his statement to reflect what we know today, I’d swap out the words fixed, ended, and immutable for the absolute opposite: pliable, open-ended, and alterable. I’d also say that brain cells may die, but they most certainly can be regenerated. Indeed, Cajal made great contributions to our knowledge of the brain and how neurons work; he was even ahead of his time in trying to understand the pathology of inflammation. But his belief that the brain was somehow stuck with its bill of goods is one that pervaded for most of human history—until modern science in the late twentieth century proved just how flexible the brain could be. In my previous book, Power Up Your Brain: The Neuroscience of Enlightenment, Dr. Alberto Villoldo and I told the story of how science has come to understand the gift of neurogenesis in humans. Although scientists have long proven neurogenesis in various other animals, it wasn’t until the 1990s that scientists began focusing exclusively on trying to demonstrate neurogenesis in humans. 3 In 1998, the journal Nature Medicine published a report by Swedish neurologist Peter Eriksson in which he claimed that within our brains exists a population of neural stem cells that are continually replenished and can differentiate into brain neurons. 4 And indeed, he was right: We all experience brain “stem cell therapy” every minute of our lives. This has led to a new science called neuroplasticity. The revelation that neurogenesis occurs in humans throughout our lifetimes has provided neuroscientists around the world an exciting new reference point, with implications spanning virtually the entire array of brain disorders. 5 It also has instilled hope among those searching for clues to stopping, reversing, or even curing progressive brain disease. The idea of regenerating brain neurons has established a new level of excitement in scientists dedicated to studying neurodegenerative disorders. It’s also paved the way for novel treatments, transforming the lives of people who have suffered from serious brain injuries or disease. Look no further than Norman Doidge’s The Brain That Changes Itself: Stories of Personal Triumph from the Frontiers of Brain Science to hear of real-life tales that prove just how pliable our brains—and our human potential—are. 6 If stroke victims can learn to speak again and people born with partial brains can train their brains to rewire themselves to work as a whole, imagine the possibilities for those of us who just hope to preserve our mental faculties. The burning question: How can we grow new brain neurons? In other words, what influences neurogenesis? And what can we do to enhance this natural process? The process, as one might expect, is controlled by our DNA. Specifically, a gene located on chromosome 11 codes for the production of a protein called “brain-derived neurotrophic factor,” or BDNF. BDNF plays a key role in creating new neurons. But beyond its role in neurogenesis, BDNF protects existing neurons, ensuring their survivability while encouraging synapse formation, the connection of one neuron to another—a process vital for thinking, learning, and higher levels of brain function. Studies have demonstrated decreased levels of BDNF in Alzheimer’s patients, which, based on an understanding of how BDNF works, should not come as a surprise. 7 What is perhaps more surprising is the association of BDNF with a variety of neurological conditions, including epilepsy, anorexia nervosa, depression, schizophrenia, and obsessive-compulsive disorder. We now have a firm understanding of the factors that influence our DNA to produce BDNF. And fortunately, these factors are mostly under our direct control. The gene that turns on BDNF is activated by a variety of lifestyle habits, including physical exercise, caloric restriction, following a ketogenic diet, and the addition of certain nutrients like curcumin and the omega-3 fat DHA. This is an empowering lesson because all of these factors are within our grasp, representing choices we can make to flip the switch that spurs the growth of new brain cells. Let’s explore them individually. THIS IS YOUR (NEW) BRAIN ON EXERCISE I’m going to save the bulk of this conversation for chapter 8, which explores in great depth the role of exercise in preventing cognitive decline. The science is stunning. Physical exercise is one of the most potent ways of changing your genes; put simply, when you exercise, you literally exercise your genes. Aerobic exercise in particular not only turns on genes linked to longevity, but also targets the BDNF gene, the brain’s “growth hormone.” More specifically, aerobic exercise has been shown to increase BDNF, reverse memory decline in elderly humans, and actually increase growth of new brain cells in the brain’s memory center. Exercise isn’t just for trim looks and a strong heart; perhaps its most powerful effects are going on silently in the upstairs room where our brains reside. The emerging scientific view of human evolution and role of physical activity gives a whole new meaning to the phrase “jog your memory.” A million years ago, we triumphed over long distances because we could outrun and outwalk most other animals. This ultimately helped make us the clever human beings we are today. The more we moved, the fitter our brain became. And even today our brain’s healthy functioning requires regular physical activity despite the passage of time and ills of the aging process. CALORIC RESTRICTION 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. 8 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 profoundly 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.” 9 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 at the National Institute on Aging, who 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. 10 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. 11 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. If the prospect of reducing your calorie intake by 30 percent seems daunting, consider the following: On average, we consume 523 more calories a day than we did in 1970. 12 Based on data from the Food and Agriculture Organization of the United Nations, the average American adult consumes 3,770 calories daily. 13 Most would consider “normal” calorie consumption to be around 2,000 calories daily for women and 2,550 for men (with higher requirements depending on level of activity/exercise). A 30 percent cut of calories from an average of 3,770 per day equals 2,640 calories. We owe a lot of our increased calorie consumption to sugar. The average American consumes between 100 and 160 pounds of refined sugar annually—reflecting upwards of a 25 percent hike in just the last three decades. 14 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. We’ll fully explore fasting 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 profound 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. Preprogrammed 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 from 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. 15 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. 16 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. 17 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. 18 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 very powerful therapeutic option in the treatment of Parkinson’s disease, Alzheimer’s disease, ALS, and even autism. 19, 20, 21 In one 2005 study, 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. 22 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. 23 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. 24 A ketogenic diet has also been shown to reduce amyloid in the brain, 25 and it increases glutathione, the body’s natural brain-protective antioxidant, in the hippocampus. 26 What’s more, it stimulates the growth of mitochondria and thus increases metabolic efficiency. 27 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 insulindependent 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 only represents 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.” 28 THE POWER OF MEDITATION Meditating is far from a passive activity. Studies show that people who meditate are at much less risk of developing brain disease, among other maladies. 29 Learning to meditate takes time and practice, but it has multiple proven benefits, all of which play into our longevity. Visit my website at www.DrPerlmutter.com for resources on how to learn this technique. CURCUMIN AND DHA Curcumin, the main active ingredient in the spice turmeric, is currently the subject of intense scientific inquiry, especially as it relates to the brain. It has been used in traditional Chinese and Indian (ayurvedic) medicine for thousands of years. Although it is well known for its antioxidant, antiinflammatory, anti-fungal, and antibacterial activities, its ability to increase BDNF in particular has attracted the interest of neuroscientists around the world, especially epidemiologists searching for clues to explain why the prevalence of dementia is markedly reduced in communities where turmeric is used in abundance. (More on curcumin in chapter 7.) Perhaps no other brain-boosting molecule is receiving as much attention lately as is docosahexaenoic acid (DHA). For the past several decades scientists have been aggressively studying this critical brain fat for at least three reasons. First, more than two-thirds of the dry weight of the human brain is fat, and of that fat, one quarter is DHA. Structurally, DHA is an important building block for the membranes surrounding brain cells, particularly the synapses, which lie at the heart of efficient brain function. Second, DHA is an important regulator of inflammation. It naturally reduces the activity of the COX-2 enzyme, which turns on the production of damaging inflammatory chemicals. DHA also acts like a warrior in many ways when it enters hostile territory brought on by poor diet. It can fight back inflammation when a war ensues within the intestinal lining of a gut that is gluten sensitive. And it can block the damaging effects of a high-sugar diet, especially fructose, and help prevent metabolic dysfunctions in the brain that can result from too many carbs in the diet. The third, and arguably most exciting, activity of DHA, is its role in regulating gene expression for the production of BDNF. Put simply, DHA helps orchestrate the production, connectivity, and viability of brain cells while at the same time enhancing function. In a recently completed double-blind interventional trial, now known by its acronym MIDAS (Memory Improvement with DHA Study), a group of 485 individuals whose average age was seventy and who had mild memory problems were given a supplement containing DHA from marine algae or a placebo for six months. 30 At the end of the study, not only did blood DHA levels double in the group receiving the DHA, but the effects upon brain function were outstanding. Lead researcher of the study, Dr. Karin Yurko-Mauro, commented: “In our study, healthy people with memory complaints who took algal DHA capsules for six months had almost double the reduction in errors on a test that measures learning and memory performance versus those who took a placebo…. The benefit is roughly equivalent to having the learning and memory skills of someone three years younger.” Another study done of 815 individuals aged sixty-five to ninety-four years found that those who consumed the highest amount of DHA had a breathtaking 60 percent reduction in risk for developing Alzheimer’s disease. 31 This level of protection beats other popular fatty acids such as EPA and linolenic acid. The Framingham Heart Study pointed to a magnificent protective effect, too. When researchers compared blood levels of DHA in 899 men and women over a nearly ten-year period, during which some people developed dementia and Alzheimer’s, they calculated a 47 percent lower risk for such diagnoses in those who maintained the highest levels of DHA in their blood. 32 The researchers also found that consuming more than two servings of fish per week was associated with a 59 percent reduction in the occurrence of Alzheimer’s disease. When parents bring kids with behavioral problems to see me, I typically test their DHA levels in addition to looking for gluten sensitivity. Because of DHA’s role in triggering BDNF, it is important in utero, as well as during infancy and childhood. But many kids today aren’t getting enough DHA, and this is partly why we are seeing so many cases of attention deficit hyperactivity disorder (ADHD). I can’t tell you how many times I’ve “cured” ADHD just by recommending a DHA supplement. In chapter 10, I’ll give you my dosage recommendations for this important supplement. How can we increase our DHA? Our bodies can manufacture small amounts of DHA, and we are able to synthesize it from a common dietary omega-3 fat, alpha-linolenic acid. But it’s hard to get all the DHA we need from the food we eat, and we can’t rely on our body’s natural production of it, either. We need at least 200 to 300 milligrams daily, but most Americans consume less than 25 percent of this target and would do well to go beyond this bare minimum. In chapter 10, I’ll offer my prescription for ensuring you’re getting enough, and show you how to do so easily through dietary and supplementary sources. INTELLECTUAL STIMULATION BOLSTERS NEW NETWORKS If common knowledge didn’t tell us that keeping the brain intellectually stimulated was a good thing for brain health, then crossword puzzles, continuing education courses, museum hunting, and even reading wouldn’t be so popular. And, as it turns out, we know that challenging the mind fortifies new neural networks. Much in the way our muscles gain strength and functionality when physically challenged through exercise, the brain similarly rises to the challenges of intellectual stimulation. The brain becomes not only faster and more efficient in its processing capacity, but also better able to store more information. Again, Dr. Mattson’s summary of the proof from the literature is informative: “In regards to aging and age-related neurodegenerative disorders, the available data suggest that those behaviors that enhance dendritic complexity and synaptic plasticity also promote successful aging and decrease risk of neurodegenerative disorders.” 33 He goes on to offer several examples. He notes that people with more education have a lower risk for Alzheimer’s disease, and that protection from agerelated neurodegenerative disorders in general likely begins during the first several decades of life. To this end, Dr. Mattson points to studies that show how individuals with the best linguistic abilities as young adults have a reduced risk for dementia. And he writes that “data from animal studies suggest that increased activity in neural circuits that results from intellectual activity stimulates the expression of genes that play a role in its neuroprotective effects.” THE ANTIOXIDANT HOAX 34 Advertisements proclaiming the virtues of an exotic fruit juice or extract that has the highest antioxidant content on earth are ubiquitous. You may wonder: Why all the hype? What is the benefit of ingesting an antioxidant? As you know by now, antioxidants help control marauding free radicals, and the brain generates tremendous amounts of free radicals but lacks the level of antioxidant protection found elsewhere in the body. Fortunately, we now understand how to compensate for this harmful disparity, but we can’t do this by consuming antioxidants themselves. Our DNA can actually turn on the production of protective antioxidants in the presence of specific signals, and this internal antioxidant system is far more powerful than any nutritional supplement. So if you’re eating exotic berries or downing vitamins E and C in a bid to outrun those free radicals, consider the following. In 1956, Dr. Denham Harman demonstrated that free radicals are “quenched” by antioxidants, and the whole antioxidant industry was born. 35 His theories became more refined in 1972 when he recognized that mitochondria, the actual source of free radicals, are themselves most at risk of free radical damage, and that when mitochondrial function is compromised because of such damage, aging results. 36 Understanding the powerfully damaging effects of free radicals, especially as they relate to the brain, has encouraged researchers to seek out better antioxidants to provide the brain with a measure of protection in an attempt to not only stave off disease but also enhance function. For example, the relationship between mild cognitive impairment and free radicals was well described in a 2007 report from Dr. William Markesbery of the University of Kentucky. In this report, Dr. Markesbery and colleagues demonstrated that cognitive function begins to decline early on—well before a brain disease is diagnosed. He also noted that elevated markers for oxidative damage to fat, protein, and even DNA correlate directly to the degree of mental impairment. Markesbery states, “These studies establish oxidative damage as an early event in the pathogenesis of Alzheimer’s disease that can serve as a therapeutic target to slow the progression or perhaps the onset of the disease.” 37 The authors continue, “Better antioxidants and agents used in combination to up-regulate defense mechanisms against oxidation will be required to neutralize the oxidative component of the pathogenesis of Alzheimer’s disease. It is most likely that to optimize these neuroprotective agents, they will have to be used in the pre-symptomatic phase of the disease.” In layman’s terms: We need to stimulate our body’s innate defense against free radicals long before the signs and symptoms of cognitive decline surface. And when we recognize that if we live to be eighty-five years or older, our risk for Alzheimer’s is an astounding 50 percent, there are a lot of people who should consider that they are “pre-symptomatic” right now. So if our brain tissue is being assaulted by free radicals, does it make sense to load up on antioxidants? To answer the question, we need to consider our cells’ energy suppliers, the mitochondria. In the normal process of producing energy, each mitochondrion produces hundreds if not thousands of free radical molecules each day. Multiply that by the ten million billion mitochondria that we each possess and you come up with an unfathomable number, ten followed by eighteen zeros. So one might ask, how effective would, say, a vitamin E capsule or a tablet of vitamin C be when confronted by this onslaught of free radicals? Common antioxidants work by sacrificing themselves to become oxidized when faced with free radicals. Thus, one molecule of vitamin C is oxidized by one free radical. (This one-to-one chemistry is called a stoichiometric reaction by chemists.) Can you imagine how much vitamin C or other oral antioxidant it would take to neutralize the untold number of free radicals generated by the body on a daily basis? Fortunately, and as one would expect, human physiology has developed its own biochemistry to create more protective antioxidants during times of high oxidative stress. Far from being entirely dependent on external food sources of antioxidants, our cells have their own innate ability to generate antioxidant enzymes on demand. High levels of free radicals turn on a specific protein in the nucleus called Nrf2, which essentially opens the door for the production of a vast array of not only our body’s most important antioxidants, but also detoxification enzymes. So if excessive free radicals induce better antioxidant production through this pathway, then the next obvious question is, what else activates Nrf2? Now this is where the story gets really exciting. New research has identified a variety of modifiable factors that can turn on the Nrf2 switch, activating genes that can produce powerful antioxidants and detoxification enzymes. Vanderbilt University’s Dr. Ling Gao has found that when the omega-3 fats EPA and DHA are oxidized, they significantly activate the Nrf2 pathway. For years researchers have noted decreased levels of free radical damage in individuals who consume fish oil (the source of EPA and DHA), but with this new research, the relationship between fish oil and antioxidant protection is now clear. As Dr. Gao reported, “Our data support the hypothesis that the formation of… compounds generated from oxidation of EPA and DHA in vivo can reach concentrations high enough to induce Nrf2-based antioxidant and… detoxification defense systems.” 38 DETOXIFICATION: WHAT IT MEANS FOR BRAIN HEALTH The human body produces an impressive array of enzymes that serve to combat the large number of toxins to which we are exposed in our external environments as well as those that are generated internally through the course of our normal metabolism. These enzymes are produced under the direction of our DNA and have evolved over hundreds of thousands of years. Glutathione is regarded as one of the most important detoxification agents in the human brain. A fairly simple chemical, glutathione is a tripeptide, meaning it consists of only three amino acids. But despite its simplicity, glutathione has farreaching roles in brain health. First, it serves as a major antioxidant in cellular physiology, not only helping to protect the cell from free radical damage, but also protecting the delicate and life-sustaining mitochondria. Glutathione is so important as an antioxidant that scientists often measure cellular glutathione levels as an overall indicator of cellular health. Glutathione is a powerful factor in detoxification chemistry as well, binding to various toxins to render them less noxious. Most important, glutathione serves as a substrate for the enzyme glutathione S-transferase, which is involved in transforming a multitude of toxins, making them more water soluble and thus more easily excreted. Deficiencies in the function of this enzyme are associated with a wide range of medical problems, including melanoma, diabetes, asthma, breast cancer, Alzheimer’s disease, glaucoma, lung cancer, Lou Gehrig’s disease, Parkinson’s disease, and migraine headaches, to name a few. With this understanding of the cardinal roles of glutathione as both an antioxidant and a major player in detoxification, it makes sense to do everything possible to maintain and even enhance glutathione levels, which is exactly what my protocol will help you to achieve. Not surprisingly, calorie restriction also has been demonstrated in a variety of laboratory models to induce Nrf2 activation. When calories are reduced in the diets of laboratory animals, they not only live longer (likely as a result of increased antioxidant protection), but also become remarkably resistant to the development of several cancers. And it is this attribute that further supports the fasting program described in the next chapter. Several natural compounds that turn on antioxidant and detoxification pathways through activation of the Nrf2 system have been identified. Among these are curcumin from turmeric, green tea extract, silymarin (milk thistle), bacopa extract, DHA, sulforaphane (contained in broccoli), and ashwagandha. Each of these substances is effective in turning on the body’s innate production of key antioxidants, including glutathione. And if none of these compounds sounds like something you’re used to having daily in your diet, then you’ll be happy to know that coffee is one of the most powerful Nrf2 activators in nature. Several molecules in coffee, some of which are partly present in the raw material while others are generated during the roasting process, are responsible for this positive effect. 39 Aside from antioxidant function, activation of the Nrf2 pathway turns on the genes to produce a vast array of protective chemicals that further support the body’s detoxification pathways while dampening inflammation—all good things for brain health. THE “ALZHEIMER’S GENE” Since decoding the entire human genome more than a decade ago, we’ve managed to accumulate a great deal of evidence about which genes map to which outcomes, good or bad. If you were paying attention to the news in the early to mid-1990s, you probably learned that science had discovered an “Alzheimer’s gene,” an association between a particular gene and the risk for Alzheimer’s disease.