# Outlive  ## Metadata - Author: [[Peter Attia MD]] - Full Title: Outlive - Category: #books ## Highlights - Assuming that you’re not someone who engages in ultrarisky behaviors like BASE jumping, motorcycle racing, or texting and driving, the odds are overwhelming that you will die as a result of one of the chronic diseases of aging that I call the Four Horsemen: heart disease, cancer, neurodegenerative disease, or type 2 diabetes and related metabolic dysfunction. To achieve longevity—to live longer and live better for longer—we must understand and confront these causes of slow death. ([Location 152](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=152)) - Tags: [[blue]] - Exercise is by far the most potent longevity “drug.” No other intervention does nearly as much to prolong our lifespan and preserve our cognitive and physical function. But most people don’t do nearly enough—and exercising the wrong way can do as much harm as good. ([Location 270](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=270)) - Tags: [[blue]] - The shift from Medicine 1.0 to Medicine 2.0 was prompted in part by new technologies such as the microscope, but it was more about a new way of thinking. The foundation was laid back in 1628, when Sir Francis Bacon first articulated what we now know as the scientific method. This represented a major philosophical shift, from observing and guessing to observing, and then forming a hypothesis, which as Richard Feynman pointed out is basically a fancy word for a guess. The next step is crucial: rigorously testing that hypothesis/guess to determine whether it is correct, also known as experimenting. Instead of using treatments that they believed might work, often despite ample anecdotal evidence to the contrary, scientists and physicians could systematically test and evaluate potential cures, then choose the ones that had performed best in experiments. Yet three centuries elapsed between Bacon’s essay and the discovery of penicillin, the true game-changer of Medicine 2.0. ([Location 424](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=424)) - Tags: [[blue]] - Yet Medicine 2.0 has proved far less successful against long-term diseases such as cancer. While books like this always trumpet the fact that lifespans have nearly doubled since the late 1800s, the lion’s share of that progress may have resulted entirely from antibiotics and improved sanitation, as Steven Johnson points out in his book Extra Life. The Northwestern University economist Robert J. Gordon analyzed mortality data going back to 1900 (see figure 1) and found that if you subtract out deaths from the eight top infectious diseases, which were largely brought under control by the advent of antibiotics in the 1930s, overall mortality rates declined relatively little over the course of the twentieth century. That means that Medicine 2.0 has made scant progress against the Horsemen. ([Location 440](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=440)) - Tags: [[blue]] - This actually wasn’t so obvious until I’d spent my little sabbatical immersed in the worlds of mathematics and finance, thinking every day about the nature of risk. The banks’ problem was not all that different from the situation faced by some of my patients: their seemingly minor risk factors had, over time, compounded into an unstoppable, asymmetric catastrophe. Chronic diseases work in a similar fashion, building over years and decades—and once they become entrenched, it’s hard to make them go away. ([Location 454](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=454)) - Tags: [[blue]] - First, Medicine 3.0 places a far greater emphasis on prevention than treatment. ([Location 495](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=495)) - Tags: [[blue]] - Second, Medicine 3.0 considers the patient as a unique individual. ([Location 498](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=498)) - Tags: [[blue]] - The third philosophical shift has to do with our attitude toward risk. In Medicine 3.0, our starting point is the honest assessment, and acceptance, of risk—including the risk of doing nothing. ([Location 504](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=504)) - Tags: [[blue]] - The fourth and perhaps largest shift is that where Medicine 2.0 focuses largely on lifespan, and is almost entirely geared toward staving off death, Medicine 3.0 pays far more attention to maintaining healthspan, the quality of life. ([Location 528](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=528)) - Tags: [[blue]] - Take another look at the Sun Tzu quote that opens this chapter: “Tactics without strategy is the noise before defeat.” He was talking about war, but it applies here as well. To achieve our objectives, we first need to have a strategy: an overall approach, a conceptual scaffolding or mental model that is informed by science, is tailored to our goals, and gives us options. Our specific tactics flow from our strategy, and the strategy derives from our objective. ([Location 660](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=660)) - Tags: [[blue]] - The point is that the tactics are what you do when you are actually in the ring. The strategy is the harder part, because it requires careful study of one’s opponent, identifying his strengths and weaknesses, and figuring out how to use both to your advantage, well before actually stepping in the ring. In this book, we will apply this three-part approach to longevity: objective → strategy → tactics. ([Location 682](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=682)) - Tags: [[blue]] - that we barely perceive the change. I think about healthspan and its deterioration in terms of three categories, or vectors. The first vector of deterioration is cognitive decline. Our processing speed slows down. We can’t solve complex problems with the quickness and ease that we once did. Our memory begins to fade. Our executive function is less reliable. Our personality changes, and if it goes on for long enough, even our sentient self is lost. ([Location 722](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=722)) - Tags: [[blue]] - The important distinction here is that while actual death is inevitable, this deterioration that we’re talking about is less so. Not everyone who dies in their eighties or nineties passes through the valleys of cognitive, physical, or emotional destruction on the way there. They are preventable—and I believe that they are largely optional, despite their ever-increasing gravitational pull over time. As we will see in later chapters, cognitive, physical, and even emotional deterioration can all be slowed and even reversed in some cases with the application of the proper tactics. ([Location 755](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=755)) - Tags: [[blue]] - Medicine 2.0 relies on two types of tactics, broadly speaking: procedures (e.g., surgery) and medications. Our tactics in Medicine 3.0 fall into five broad domains: exercise, nutrition, sleep, emotional health, and exogenous molecules, meaning drugs, hormones, or supplements. ([Location 767](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=767)) - Tags: [[blue]] - The data are unambiguous: exercise not only delays actual death but also prevents both cognitive and physical decline, better than any other intervention. We also tend to feel better when we exercise, so it probably has some harder-to-measure effect on emotional health as well. ([Location 781](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=781)) - Tags: [[blue]] ## New highlights added April 23, 2025 at 4:11 PM - Studies of Scandinavian twins have found that genes may be responsible for only about 20 to 30 percent of the overall variation in human lifespan. The catch is that the older you get, the more genes start to matter. For centenarians, they seem to matter a lot. Being the sister of a centenarian makes you eight times more likely to reach that age yourself, while brothers of centenarians are seventeen times as likely to celebrate their hundredth birthday, according to data from the one-thousand-subject New England Centenarian Study, which has been tracking extremely long-lived individuals since 1995 (although because these subjects grew up in the same families, with presumably similar lifestyles and habits, this finding could be due to some environmental factors as well). If you don’t happen to have centenarian siblings, the next best option is to choose long-lived parents. ([Location 947](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=947)) - Tags: [[blue]] - Because we are probing a more relevant question: Can we, through our behaviors, somehow reap the same benefits that centenarians get for “free” via their genes? Or to put it more technically, can we mimic the centenarians’ phenotype, the physical traits that enable them to resist disease and survive for so long, even if we lack their genotype? Is it possible to outlive our own life expectancy if we are smart and strategic and deliberate about it? If the answer to this question is yes, as I believe it is, then understanding the inner workings of these actuarial lottery winners—how they achieve their extreme longevity—is a worthwhile endeavor that can inform our strategy. ([Location 958](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=958)) - Tags: [[blue]] - In mathematical terms, the centenarians’ genes have bought them a phase shift in time—that is, their entire lifespan and healthspan curve has been shifted a decade or two (or three!) to the right. Not only do they live longer, but these are people who have been healthier than their peers, and biologically younger than them, for virtually their entire lives. When they were sixty, their coronary arteries were as healthy as those of thirty-five-year-olds. At eighty-five, they likely looked and felt and functioned as if they were in their sixties. They seemed like people a generation younger than the age on their driver’s license. This is the effect that we are seeking to mimic. ([Location 1000](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1000)) - Tags: [[blue]] - When FOXO3 is activated, it in turn activates genes that generally keep our cells healthier. It seems to play an important role in preventing cells from becoming cancerous as well. Here’s where we start to see some hope, because FOXO3 can be activated or suppressed by our own behaviors. For example, when we are slightly deprived of nutrients, or when we are exercising, FOXO3 tends to be more activated, which is what we want. ([Location 1084](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1084)) - Tags: [[blue]] - “We’re trying to attack heart disease, cancer, stroke, and Alzheimer’s one disease at a time, as if somehow these diseases are all unrelated to each other,” says S. Jay Olshansky, who studies the demography of aging at the University of Illinois–Chicago, “when in fact the underlying risk factor for almost everything that goes wrong with us as we grow older, both in terms of diseases we experience, and of the frailty and disability associated with it, is related to the underlying biological process of aging.” ([Location 1113](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1113)) - Tags: [[blue]] - The reason rapamycin has so many diverse applications is thanks to a property that Sehgal had observed, but never explored, which is that it tends to slow down the process of cellular growth and division. David Sabatini was one of a handful of scientists who picked up the baton from Sehgal, seeking to explain this phenomenon. Understanding rapamycin became his life’s work. Beginning when he was a graduate student, working from a sheaf of papers that Sehgal himself had photocopied, Sabatini helped to elucidate how this unique compound worked on the cell. Ultimately, he and others discovered that rapamycin acted directly on a very important intracellular protein complex called mTOR (pronounced “em-tor”), for “mechanistic target of rapamycin.”[*2] Why do we care about mTOR? Because this mechanism turns out to be one of the most important mediators of longevity at the cellular level. Not only that, but it is highly “conserved,” meaning it is found in virtually all forms of life, ranging from yeast to flies to worms and right on up to us humans. In biology, “conserved” means that something has been passed on via natural selection, across multiple species and classes of organisms—a sign that evolution has deemed it to be very important. It was uncanny: this exotic molecule, found only on an isolated scrap of land in the middle of the ocean, acts almost like a switch that inhibits a very specific cellular mechanism that exists in nearly everything that lives. It was a perfect fit, and this fact still blows my mind every time I think about it. The job of mTOR is basically to balance an organism’s need to grow and reproduce against the availability of nutrients. When food is plentiful, mTOR is activated and the cell (or the organism) goes into growth mode, producing new proteins and undergoing cell division, as with the ultimate goal of reproduction. When nutrients are scarce, mTOR is suppressed and cells go into a kind of “recycling” mode, breaking down cellular components and generally cleaning house. Cell division and growth slow down or stop, and reproduction is put on hold to allow the organism to conserve energy. ([Location 1189](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1189)) - Tags: [[blue]] - more modern experiments have demonstrated, over and over, that reducing the food intake of lab animals could lengthen their lives. ([Location 1236](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1236)) - Tags: [[blue]] - Studies dating back to the 1930s have found that limiting caloric intake can lengthen the lifespan of a mouse or a rat by anywhere from 15 to 45 percent, depending on the age of onset and degree of restriction. Not only that, but the underfed animals also seem to be markedly healthier for their age, developing fewer spontaneous tumors than normally fed mice. CR seems to improve their healthspan in addition to their lifespan. You’d think that hunger might be unhealthy, but the scientists have actually found that the less they feed the animals, the longer they live. Its effects seem to be dose dependent, up to a point, almost like a drug. The life-extending effect of CR seems to be almost universal. Numerous labs have found that restricting caloric intake lengthens lifespan not only in rats and mice (usually) but also in yeast, worms, flies, fish, hamsters, dogs, and even, weirdly, spiders. It has been found to extend lifespan in just about every model organism on which it has been tried, with the odd exception of houseflies. It seems that, across the board, hungry animals become more resilient and better able to survive, at least inside a well-controlled, germ-free laboratory. ([Location 1259](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1259)) - Tags: [[blue]] - Reducing the amount of nutrients available to a cell seems to trigger a group of innate pathways that enhance the cell’s stress resistance and metabolic efficiency—all of them related, in some way, to mTOR. The first of these is an enzyme called AMP-activated protein kinase, or AMPK for short. AMPK is like the low-fuel light on the dashboard of your car: when it senses low levels of nutrients (fuel), it activates, triggering a cascade of actions. While this typically happens as a response to lack of nutrients, AMPK is also activated when we exercise, responding to the transient drop in nutrient levels. Just as you would change your itinerary if your fuel light came on, heading for the nearest gas station rather than Grandma’s house, AMPK prompts the cell to conserve and seek alternative sources of energy. It does this first by stimulating the production of new mitochondria, the tiny organelles that produce energy in the cell, via a process called mitochondrial biogenesis. Over time—or with disuse—our mitochondria become vulnerable to oxidative stress and genomic damage, leading to dysfunction and failure. Restricting the amount of nutrients that are available, via dietary restriction or exercise, triggers the production of newer, more efficient mitochondria to replace old and damaged ones. These fresh mitochondria help the cell produce more ATP, the cellular energy currency, with the fuel it does have. AMPK also prompts the body to provide more fuel for these new mitochondria, by producing glucose in the liver (which we’ll talk about in the next chapter) and releasing energy stored in fat cells. More importantly, AMPK works to inhibit the activity of mTOR, the cellular growth regulator. Specifically, it seems to be a drop in amino acids that induces mTOR to shut down, and with it all the anabolic (growth) processes that mTOR controls. Instead of making new proteins and undergoing cell division, the cell goes into a more fuel-efficient and stress-resistant mode, activating an important cellular recycling process called autophagy, which means “self-eating” (or better yet, “self-devouring”). Autophagy represents the catabolic side of metabolism, when the cell stops producing new proteins and instead begins to break down old proteins and other cellular structures into their amino acid components, using the scavenged materials to build new ones. It’s a form of cellular recycling, cleaning out the accumulated junk in the cell and repurposing it or disposing of it. Instead of going to Home Depot to buy more lumber and drywall and screws, the cellular “contractor” scavenges through the debris from the house he just tore down for spare materials that he can reuse, either to build and repair the cell or to burn to produce energy. ([Location 1276](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1276)) - Tags: [[blue]] - had assumed that its apparent immunosuppressive effects were too serious. But this very well-done and well-controlled study actually suggested the opposite. It appeared that the immune suppression resulted from daily use of rapamycin at low to moderate doses. The study subjects had been given moderate to high doses followed by a rest period, and this cyclical administration had had an opposite, immune-enhancing effect. It seems odd that giving different doses of the same drug could have such disparate effects, but it makes sense if you understand the structure of mTOR, which is actually composed of two separate complexes, called mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The two complexes have different jobs, but (at risk of oversimplifying) the longevity-related benefits seem to result from inhibiting complex 1. Giving the drug daily, as is typically done with transplant patients, appears to inhibit both complexes, while dosing the drug briefly or cyclically inhibits mainly mTORC1, unlocking its longevity-related benefits, with fewer unwanted side effects. (A rapamycin analog or “rapalog” that selectively inhibited mTORC1 but not mTORC2 would thus be more ideal for longevity purposes, but no one has successfully developed one yet.) ([Location 1328](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1328)) - Tags: [[blue]] - In 1980, a team at the Mayo Clinic dubbed this “hitherto unnamed disease” nonalcoholic steatohepatitis, or NASH. Since then, it has blossomed into a global plague. More than one in four people on this planet have some degree of NASH or its precursor, known as nonalcoholic fatty liver disease, or NAFLD, which is what we had observed in our patient that day in the operating room. NAFLD is highly correlated with both obesity and hyperlipidemia (excessive cholesterol), yet it often flies under the radar, especially in its early stages. Most patients are unaware that they have it—and so are their doctors, because NAFLD and NASH have no obvious symptoms. ([Location 1438](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1438)) - Tags: [[blue]] - NAFLD and NASH are basically two stages of the same disease. NAFLD is the first stage, caused by (in short) more fat entering the liver or being produced there than exiting it. The next step down the metabolic gangplank is NASH, which is basically NAFLD plus inflammation, similar to hepatitis but without a viral infection. This inflammation causes scarring in the liver, but again, there are no obvious symptoms. This may sound scary, but all is not yet lost. Both NAFLD and NASH are still reversible. If you can somehow remove the fat from the liver (most commonly via weight loss), the inflammation will resolve, and liver function returns to normal. The liver is a highly resilient organ, almost miraculously so. It may be the most regenerative organ in the human body. When a healthy person donates a portion of their liver, both donor and recipient end up with an almost full-sized, fully functional liver within about eight weeks of the surgery, and the majority of that growth takes place in just the first two weeks. In other words, your liver can recover from fairly extensive damage, up to and including partial removal. But if NASH is not kept in check or reversed, the damage and the scarring may progress into cirrhosis. This happens in about 11 percent of patients with NASH and is obviously far more serious. It now begins to affect the cellular architecture of the organ, making it much more difficult to reverse. A patient with cirrhosis is likely to die from various complications of their failing liver unless they receive a liver transplant. ([Location 1458](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1458)) - Tags: [[blue]] - According to the Centers for Disease Control (CDC), more than 40 percent of the US population is obese (defined as having a BMI[*2] greater than 30), while roughly another third is overweight (BMI of 25 to 30). Statistically, being obese means someone is at greater risk of chronic disease, so a lot of attention is focused on the “obesity problem,” but I take a broader view: obesity is merely one symptom of an underlying metabolic derangement, such as hyperinsulinemia, that also happens to cause us to gain weight. But not everyone who is obese is metabolically unhealthy, and not everyone who is metabolically unhealthy is obese. There’s more to metabolic health than meets the eye. ([Location 1479](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1479)) - Tags: [[blue]] - In the 1980s, Reaven labeled this collection of related disorders “Syndrome X”—where the X factor, he eventually determined, was insulin resistance. Today we call this cluster of problems “metabolic syndrome” (or MetSyn), and it is defined in terms of the following five criteria: high blood pressure (>130/85) high triglycerides (>150 mg/dL) low HDL cholesterol (<40 mg/dL in men or <50 mg/dL in women) central adiposity (waist circumference >40 inches in men or >35 in women) elevated fasting glucose (>110 mg/dL) If you meet three or more of these criteria, then you have the metabolic syndrome—along with as many as 120 million other Americans, according to a 2020 article in JAMA. About 90 percent of the US population ticks at least one of these boxes. But notice that obesity is merely one of the criteria; it is not required for the metabolic syndrome to be diagnosed. Clearly the problem runs deeper than simply unwanted weight gain. This tends to support my view that obesity itself is not the issue but is merely a symptom of other problems. ([Location 1489](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1489)) - Tags: [[blue]] - Metabolism is the process by which we take in nutrients and break them down for use in the body. In someone who is metabolically healthy, those nutrients are processed and sent to their proper destinations. But when someone is metabolically unhealthy, many of the calories they consume end up where they are not needed, at best—or outright harmful, at worst. ([Location 1517](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1517)) - Tags: [[blue]] - That decision—where to put the energy from the doughnut—is made via hormones, chief among them insulin, which is secreted by the pancreas when the body senses the presence of glucose, the final breakdown product of most carbohydrates (such as those in the doughnut). Insulin helps shuttle the glucose to where it’s needed, while maintaining glucose homeostasis. If you happen to be riding a stage of the Tour de France while you eat the doughnut, or are engaged in other intense exercise, those calories will be consumed almost instantly in the muscles. But in a typical sedentary person, who is not depleting muscle glycogen rapidly, the excess energy from the doughnut will largely end up in fat cells (or more specifically, as triglycerides contained within fat cells). ([Location 1534](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1534)) - Tags: [[blue]] - Think of fat as acting like a kind of metabolic buffer zone, absorbing excess energy and storing it safely until it is needed. If we eat extra doughnuts, those calories are stored in our subcutaneous fat; when we go on, say, a long hike or swim, some of that fat is then released for use by the muscles. This fat flux goes on continually, and as long as you haven’t exceeded your own fat storage capacity, things are pretty much fine. But if you continue to consume energy in excess of your needs, those subcutaneous fat cells will slowly fill up, particularly if little of that stored energy is being utilized. When someone reaches the limit of their capacity to store energy in their subcutaneous fat, yet they continue to take on excess calories, all that energy still has to go somewhere. The doughnuts or whatever they might be eating are probably still getting converted into fat, but now the body has to find other places to store it. It’s almost as if you have a bathtub, and you’re filling it up from the faucet. If you keep the faucet running even after the tub is full and the drain is closed (i.e., you’re sedentary), water begins spilling over the rim of the tub, flowing into places where it’s not wanted or needed, like onto the bathroom floor, into the heating vents or down the stairs. It’s the same with excess fat. As more calories flood into your subcutaneous fat tissue, it eventually reaches capacity and the surplus begins spilling over into other areas of your body: into your blood, as excess triglycerides; into your liver, contributing to NAFLD; into your muscle tissue, contributing directly to insulin resistance in the muscle (as we’ll see); and even around your heart and your pancreas (figure 4). None of these, obviously, are ideal places for fat to collect; NAFLD is just one of many undesirable consequences of this fat spillover. ([Location 1546](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1546)) - Tags: [[blue]] - Fat also begins to infiltrate your abdomen, accumulating in between your organs. Where subcutaneous fat is thought to be relatively harmless, this “visceral fat” is anything but. These fat cells secrete inflammatory cytokines such as TNF-alpha and IL-6, key markers and drivers of inflammation, in close proximity to your most important bodily organs. This may be why visceral fat is linked to increased risk of both cancer and cardiovascular disease. ([Location 1561](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1561)) - Tags: [[blue]] - Individual fat-storage capacity seems to be influenced by genetic factors. This is a generalization, but people of Asian descent (for example), tend to have much lower capacity to store fat, on average, than Caucasians. There are other factors at play here as well, but this explains in part why some people can be obese but metabolically healthy, while others can appear “skinny” while still walking around with three or more markers of metabolic syndrome. It’s these people who are most at risk, according to research by Mitch Lazar at the University of Pennsylvania, because a “thin” person may simply have a much lower capacity to safely store fat. All other things… ([Location 1568](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1568)) - Tags: [[blue]] - It doesn’t take much visceral fat to cause problems. Let’s say you are a forty-year-old man who weighs two hundred pounds. If you have 20 percent body fat, making you more or less average (50th percentile) for your age and sex, that means you are carrying 40 pounds of fat throughout your body. Even if just 4.5 pounds of that is visceral fat, you would be considered at exceptionally high risk for cardiovascular disease and type 2 diabetes, in the top 5 percent of risk for your age and sex. This is why… ([Location 1575](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1575)) - Tags: [[blue]] - It’s worth noting that one key ingredient in this process seems to be inactivity. If a person is not physically active, and they are not consuming energy via their muscles, then this fat-spillover-driven insulin resistance develops much more quickly. (This is why Shulman requires his study subjects, mostly young college students, to refrain from physical activity, in order to push them towards insulin resistance.) ([Location 1589](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1589)) - Tags: [[blue]] - Insulin resistance is a term that we hear a lot, but what does it really mean? Technically, it means that cells, initially muscle cells, have stopped listening to insulin’s signals, but another way to visualize it is to imagine the cell as a balloon being blown up with air. Eventually, the balloon expands to the point where it gets more difficult to force more air inside. You have to blow harder and harder. This is where insulin comes in, to help facilitate the process of blowing air into the balloon. The pancreas begins to secrete even more insulin, to try to remove excess glucose from the bloodstream and cram it into cells. For the time being it works, and blood glucose levels remain normal, but eventually you reach a limit where the “balloon” (cells) cannot accept any more “air” (glucose). This is when the trouble shows up on a standard blood test, as fasting blood glucose begins to rise. This means you have high insulin levels and high blood glucose, and your cells are shutting the gates to glucose entry. If things continue in this way, then the pancreas becomes fatigued and less able to mount an insulin response. This is made worse by, you guessed it, the fat now residing in the pancreas itself. You can see the vicious spiral forming here: fat spillover helps initiate insulin resistance, which results in the accumulation of still more fat, eventually impairing our ability to store calories as anything other than fat. There are many other hormones involved in the production and distribution of fat, including testosterone, estrogen, hormone-sensitive lipase[*3] and cortisol. Cortisol is especially potent, with a double-edged effect of depleting subcutaneous fat (which is generally beneficial) and replacing it with more harmful visceral fat. This is one reason why stress levels and sleep, both of which affect cortisol release, are pertinent to metabolism. But insulin seems to be the most potent as far as promoting fat accumulation because it acts as kind of a one-way gate, allowing fat to enter the cell while impairing the release of energy from fat cells (via a process called lipolysis). Insulin is all about fat storage, not fat utilization. ([Location 1592](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1592)) - Tags: [[blue]] - In 2020, a little more than one hundred thousand deaths were attributed to type 2 diabetes, a fraction of the number due to either cardiovascular disease or cancer. By the numbers, it barely qualifies as a Horseman. But I believe that the actual death toll due to type 2 diabetes is much greater and that we undercount its true impact. Patients with diabetes have a much greater risk of cardiovascular disease, as well as cancer and Alzheimer’s disease and other dementias; one could argue that diabetes with related metabolic dysfunction is one thing that all these conditions have in common. This is why I place such emphasis on metabolic health, and why I have long been concerned about the epidemic of metabolic disease not only in the United States but around the world. ([Location 1629](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1629)) - Tags: [[blue]] - Whatever form it takes, fructose does not pose a problem when consumed the way that our ancestors did, before sugar became a ubiquitous commodity: mostly in the form of actual fruit. It is very difficult to get fat from eating too many apples, for example, because the fructose in the apple enters our system relatively slowly, mixed with fiber and water, and our gut and our metabolism can handle it normally. But if we are drinking quarts of apple juice, it’s a different story, as I’ll explain in a moment. ([Location 1676](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1676)) - Tags: [[blue]] - Another issue is that glucose and fructose are metabolized very differently at the cellular level. When a brain cell, muscle cell, gut cell, or any other type of cell breaks down glucose, it will almost instantly have more ATP (adenosine triphosphate), the cellular energy “currency,” at its disposal. But this energy is not free: the cell must expend a small amount of ATP in order to make more ATP, in the same way that you sometimes have to spend money to make money. In glucose metabolism, this energy expenditure is regulated by a specific enzyme that prevents the cell from “spending” too much of its ATP on metabolism. But when we metabolize fructose in large quantities, a different enzyme takes over, and this enzyme does not put the brakes on ATP “spending.” Instead, energy (ATP) levels inside the cell drop rapidly and dramatically. This rapid drop in energy levels makes the cell think that we are still hungry. The mechanisms are a bit complicated, but the bottom line is that even though it is rich in energy, fructose basically tricks our metabolism into thinking that we are depleting energy—and need to take in still more food and store more energy as fat.[*5] ([Location 1684](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1684)) - Tags: [[blue]] - On a more macro level, consuming large quantities of liquid fructose simply overwhelms the ability of the gut to handle it; the excess is shunted to the liver, where many of those calories are likely to end up as fat. I’ve seen patients work themselves into NAFLD by drinking too many “healthy” fruit smoothies, for the same reason: they are taking in too much fructose, too quickly. Thus, the almost infinite availability of liquid fructose in our already high-calorie modern diet sets us up for metabolic failure if we’re not careful (and especially if we are not physically active). ([Location 1694](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1694)) - Tags: [[blue]] - But the first thing I look for, the canary in the coal mine of metabolic disorder, is elevated insulin. As we’ve seen, the body’s first response to incipient insulin resistance is to produce more insulin. Think back to our analogy with the balloon: as it gets harder to get air (glucose) into the balloon (the cell), we have to blow harder and harder (i.e., produce more insulin). At first, this appears to be successful: the body is still able to maintain glucose homeostasis, a steady blood glucose level. But insulin, especially postprandial insulin, is already on the rise. ([Location 1724](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1724)) - Tags: [[blue]] - When I was in medical school, my first-year pathology professor liked to ask a trick question: What is the most common “presentation” (or symptom) of heart disease? It wasn’t chest pain, left arm pain, or shortness of breath, the most common answers; it was sudden death. You know the patient has heart disease because he or she has just died from it. This is why, he claimed, the only doctors who truly understand cardiovascular disease are pathologists. His point: by the time a pathologist sees your arterial tissue, you are dead. ([Location 1794](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1794)) - Tags: [[blue]] - I was in great shape, I thought. But I was nevertheless worried, on account of my family history. So I insisted that my doctor order a CT scan of my heart, and it wound up changing my whole outlook on life. The scan was calibrated to detect calcification in my coronary arteries, a sign of advanced atherosclerosis. The results showed that I had a calcium “score” of 6. That sounds low, and in absolute terms it was; someone with severe disease could return a score well over 1,000. But for someone age thirty-six, it should have been zero. My score of 6 meant that I had more calcium in my coronary arteries than 75 to 90 percent of people my age. As I dug deeper into the pathology of this disease, I was dismayed to learn that it was already fairly late in the game. A calcium score is treated as a predictor of future risk, which it is, but it is also a measure of historical and existing damage. And I was already off the charts. I was only in my midthirties, but I had the arteries of a fifty-five-year-old. ([Location 1815](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1815)) - Tags: [[blue]] - Eating lots of saturated fat can increase levels of atherosclerosis-causing lipoproteins in blood, but most of the actual cholesterol that we consume in our food ends up being excreted out our backsides. The vast majority of the cholesterol in our circulation is actually produced by our own cells. Nevertheless, US dietary guidelines warned Americans away from consuming foods high in cholesterol for decades, and nutrition labels still inform American consumers about how much cholesterol is contained in each serving of packaged foods. ([Location 1891](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1891)) - Tags: [[blue]] - “What proportion of heart attacks occur in people younger than age sixty-five?” I guessed high, one in four, but I was way low. Fully half of all major adverse cardiovascular events in men (and a third of those in women), such as heart attack, stroke, or any procedure involving a stent or a graft, occur before the age of sixty-five. In men, one-quarter of all events occur before age fifty-four. ([Location 1906](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=1906)) - Tags: [[blue]] ## New highlights added April 24, 2025 at 4:11 PM - I was still in my thirties, yet I likely already had all three of the major prerequisites for heart disease: significant lipoprotein burden or apoB, LDL oxidation or modification (leading to the plaques that my calcium scan revealed), and a high level of background inflammation. None of these is enough to guarantee that someone will develop heart disease, but all three are necessary to develop it. ([Location 2039](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=2039)) - Tags: [[blue]] - We’ll talk about nutrition in much more detail, but my first step in controlling my own cardiovascular risk was to begin to change my own diet, so as to lower my triglycerides (a contributor to apoB when they are high, as mine were), but more importantly to manage my insulin levels. I needed to get my metabolic house in order. I should note that my own solution at the time, a ketogenic diet, might not work for everyone, nor is it a diet to which I continue to adhere. In my clinical experience, about a third to half of people who consume high amounts of saturated fats (which sometimes goes hand in hand with a ketogenic diet) will experience a dramatic increase in apoB particles, which we obviously don’t want.[*8] Monounsaturated fats, found in high quantities in extra virgin olive oil, macadamia nuts, and avocados (among other foods), do not have this effect, so I tend to push my patients to consume more of these, up to about 60 percent of total fat intake. The point is not necessarily to limit fat overall but to shift to fats that promote a better lipid profile. But for many patients, if not for most, lowering apoB to the levels we aim for—the physiologic levels found in children—cannot be accomplished with diet alone, so we need to use nutritional interventions in tandem with drugs. ([Location 2143](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=2143)) - Tags: [[blue]] - The problem we face is that once cancer is established, we lack highly effective treatments for it. Our toolbox is limited. Many (though not all) solid tumors can be removed surgically, a tactic that dates back to ancient Egypt. Combining surgery and radiation therapy is pretty effective against most local, solid-tumor cancers. But while we’ve gotten fairly good at this approach, we have essentially maxed out our ability to treat cancers this way. We are not getting any more juice from the squeeze. And surgery is of limited value when cancer has metastasized, or spread. Metastatic cancers can be slowed by chemotherapy, but they virtually always come back, often more resistant to treatment than ever. Our benchmark for success in a patient, or remission, is typically five-year survival, nothing more. We don’t dare utter the word cure. ([Location 2338](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=2338)) - Tags: [[blue]] - Cancer cells are different from normal cells in two important ways. Contrary to popular belief, cancer cells don’t grow faster than their noncancerous counterparts; they just don’t stop growing when they are supposed to. For some reason, they stop listening to the body’s signals that tell them when to grow and when to stop growing. This process is thought to begin when normal cells acquire certain genetic mutations. ([Location 2364](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=2364)) - Tags: [[blue]] - The second property that defines cancer cells is their ability to travel from one part of the body to a distant site where they should not be. This is called metastasis, and it is what enables a cancerous cell in the breast to spread to the lung. This spreading is what turns a cancer from a local, manageable problem to a fatal, systemic disease. ([Location 2370](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=2370)) - Tags: [[blue]] - very few if any of these well-known mutations were shared across all tumors. In fact, there didn’t seem to be any individual genes that “caused” cancer at all; instead, it seemed to be random somatic mutations that combined to cause cancers. So not only is breast cancer genetically distinct from colon cancer (as the researchers expected), but no two breast cancer tumors are very much alike. If two women have breast cancer, at the same stage, their tumor genomes are likely to be very different from each other. Therefore, it would be difficult if not impossible to devise one treatment for both women based on the genetic profile of their tumors. ([Location 2383](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=2383)) - Tags: [[blue]] - Traditional chemotherapy occupies a fuzzy region between poison and medicine; the mustard gas used as a weapon during World War I was a direct precursor to some of the earliest chemotherapy agents, some of which are still in use. These drugs attack the replicative cycle of cells, and because cancer cells are rapidly dividing, the chemo agents harm them more severely than normal cells. But many important noncancerous cells are also dividing frequently, such as those in the lining of the mouth and gut, the hair follicles, and the nails, which is why typical chemotherapy agents cause side effects like hair loss and gastrointestinal misery. Meanwhile, as cancer researcher Robert Gatenby points out, those cancer cells that do manage to survive chemotherapy often end up acquiring mutations that make them stronger, like cockroaches that develop resistance to insecticides. ([Location 2408](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=2408)) - Tags: [[blue]] - In the 1920s, a German physiologist named Otto Warburg discovered that cancer cells had a strangely gluttonous appetite for glucose, devouring it at up to forty times the rate of healthy tissues. But these cancer cells weren’t “respiring” the way normal cells do, consuming oxygen and producing lots of ATP, the energy currency of the cell, via the mitochondria. Rather, they appeared to be using a different pathway that cells normally use to produce energy under anaerobic conditions, meaning without sufficient oxygen, such as when we are sprinting. The strange thing was that these cancer cells were resorting to this inefficient metabolic pathway despite having plenty of oxygen available to them. ([Location 2434](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=2434)) - Tags: [[blue]] - While it may not yield much in the way of energy, they found, the Warburg effect generates lots of by-products, such as lactate, a substance that is also produced during intense exercise. In fact, turning glucose into lactate creates so many extra molecules that the authors argued that the relatively small amount of energy it produces may actually be the “by-product.” There’s a logic to this seeming madness: when a cell divides, it doesn’t simply split into two smaller cells. The process requires not only the division of the nucleus, and all that stuff we learned in high school biology, but the actual physical materials required to construct a whole new cell. Those don’t just appear out of nowhere. Normal aerobic cellular respiration produces only energy, in the form of ATP, plus water and carbon dioxide, which aren’t much use as building materials (also, we exhale the latter two). The Warburg effect, also known as anaerobic glycolysis, turns the same amount of glucose into a little bit of energy and a whole lot of chemical building blocks—which are then used to build new cells rapidly. Thus, the Warburg effect is how cancer cells fuel their own proliferation. But it also represents a potential vulnerability in cancer’s armor.[*1] ([Location 2459](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=2459)) - Tags: [[blue]] ## New highlights added June 10, 2025 at 1:00 PM - I suspect that the association between obesity, diabetes, and cancer is primarily driven by inflammation and growth factors such as insulin. Obesity, especially when accompanied by accumulation of visceral fat (and other fat outside of subcutaneous storage depots), helps promote inflammation, as dying fat cells secrete an array of inflammatory cytokines into the circulation (see figure 4 in chapter 6). This chronic inflammation helps create an environment that could induce cells to become cancerous. It also contributes to the development of insulin resistance, causing insulin levels to creep upwards—and, as we’ll see shortly, insulin itself is a bad actor in cancer metabolism. ([Location 2479](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=2479)) - Tags: [[blue]] - laboratory animals on calorically restricted (CR) diets tend to die from cancer at far lower rates than control animals on an ad libitum (all-they-can-eat) diet. Eating less appears to give them some degree of protection. The same may hold true in people: one study of caloric restriction in humans found that limiting caloric intake directly turns down the PI3K-associated pathway, albeit in muscle (which is not susceptible to cancer). This may be a function of lowered insulin rather than lower glucose levels. ([Location 2494](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=2494)) - Tags: [[blue]] - the results of these studies suggest that maybe it’s not such a good idea to increase the level of insulin in someone who has cancer. More studies need to be done, but the working hypothesis is that because cancer cells are so metabolically greedy, they are therefore more vulnerable than normal cells to a reduction in nutrients—or more likely, a reduction in insulin, which activates the PI3K pathway essential to the Warburg effect. ([Location 2551](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=2551)) - Tags: [[blue]] - Genetic analysis reveals that some 80 percent of epithelial cancers (that is, solid organ tumors) possess mutations that the immune system can recognize—thus making them potentially vulnerable to immune-based treatments. ([Location 2655](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=2655)) - Tags: [[blue]] - One very promising technique is called adoptive cell therapy (or adoptive cell transfer, ACT). ACT is a class of immunotherapy whereby supplemental T cells are transferred into a patient, like adding reinforcements to an army, to bolster their ability to fight their own tumor. These T cells have been genetically programmed with antigens specifically targeted at the patient’s individual tumor type. It is similar to CAR-T cell therapy, which we discussed earlier, but much broader in scope. As cancer grows, it quickly outruns the immune system’s ability to detect and kill it; there simply aren’t enough T cells to do the job, particularly when the cancer reaches the point of clinical detection. This is why spontaneous remission, as happened with James DeAngelo, is so rare. The idea behind ACT is basically to overwhelm the cancer with a huge number of targeted T cells, like supplementing an army with a brigade of trained assassins. ([Location 2657](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=2657)) - Tags: [[blue]] - So what explains it? The difference has to do with the overall burden of cancer cells in each patient. In advanced, metastatic cancer there are tens if not hundreds of billions of cancer cells in need of treatment. In less advanced cancers, while there are undoubtedly still millions, if not billions, of cancer cells that have escaped the surgeon’s scalpel, the far lower population means they will also have fewer mutations and thus less resistance to the treatment. ([Location 2709](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=2709)) - Tags: [[blue]] - Of all the Horsemen, cancer is probably the hardest to prevent. It is probably also the one where bad luck in various forms plays the greatest role, such as in the form of accumulated somatic mutations. The only modifiable risks that really stand out in the data are smoking, insulin resistance, and obesity (all to be avoided)—and maybe pollution (air, water, etc.), but the data here are less clear. ([Location 2855](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=2855)) - Tags: [[blue]] - Just as Alzheimer’s disease is defined (rightly or wrongly) by accumulations of amyloid and tau, Lewy body dementia and Parkinson’s disease are associated with the accumulation of a neurotoxic protein called alpha-synuclein, which builds up in aggregates known as Lewy bodies (first observed by a colleague of Alois Alzheimer’s named Friedrich Lewy). The APOE e4 variant not only increases someone’s risk for Alzheimer’s but also significantly raises their risk of Lewy body dementia as well as Parkinson’s disease with dementia, further supporting the notion that these conditions are related on some level. ([Location 3062](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3062)) - Tags: [[blue]] - The more of these networks and subnetworks that we have built up over our lifetime, via education or experience, or by developing complex skills such as speaking a foreign language or playing a musical instrument, the more resistant to cognitive decline we will tend to be. The brain can continue functioning more or less normally, even as some of these networks begin to fail. This is called “cognitive reserve,” and it has been shown to help some patients to resist the symptoms of Alzheimer’s disease. It seems to take a longer time for the disease to affect their ability to function. “People that have Alzheimer’s disease and are very cognitively engaged, and have a good backup pathway, they’re not going to decline as quickly,” Richard says. ([Location 3181](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3181)) - Tags: [[blue]] - There is a parallel concept known as “movement reserve” that becomes relevant with Parkinson’s disease. People with better movement patterns, and a longer history of moving their bodies, such as trained or frequent athletes, tend to resist or slow the progression of the disease as compared to sedentary people. This is also why movement and exercise, not merely aerobic exercise but also more complex activities like boxing workouts, are a primary treatment/prevention strategy for Parkinson’s. Exercise is the only intervention shown to delay the progression of Parkinson’s. ([Location 3186](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3186)) - Tags: [[blue]] - The evidence suggests that tasks or activities that present more varied challenges, requiring more nimble thinking and processing, are more productive at building and maintaining cognitive reserve. Simply doing a crossword puzzle every day, on the other hand, seems only to make people better at doing crossword puzzles. The same goes for movement reserve: dancing appears to be more effective than walking at delaying symptoms of Parkinson’s disease, possibly because it involves more complex movement. ([Location 3195](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3195)) - Tags: [[blue]] - The brain is a greedy organ. It makes up just 2 percent of our body weight, yet it accounts for about 20 percent of our total energy expenditure. Its eighty-six billion neurons each have between one thousand and ten thousand synapses connecting them to other neurons or target cells, ([Location 3220](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3220)) - Tags: [[blue]] - brain cells metabolize glucose in a different way from the rest of the body; they do not depend on insulin, instead absorbing circulating glucose directly, via transporters that essentially open a gate in the cell membrane. This enables the brain to take top priority to fuel itself when blood glucose levels are low. If we lack new sources of glucose, the brain’s preferred fuel, the liver converts our fat into ketone bodies, as an alternative energy source that can sustain us for a very long time, depending on the extent of our fat stores. (Unlike muscle or liver, the brain itself does not store energy.) When our fat runs out, we will begin to consume our own muscle tissue, then our other organs, and even bone, all in order to keep the brain running at all costs. The brain is the last thing to shut off. ([Location 3227](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3227)) - Tags: [[blue]] - another. His “barf bag theory,” as he jokingly called it, was that Alzheimer’s disease is primarily a vascular disorder of the brain. The dementia symptoms that we see result from a gradual reduction in blood flow, which eventually creates what he calls a “neuronal energy crisis,” which in turn triggers a cascade of unfortunate events that harms the neurons and ultimately causes neurodegeneration. The amyloid plaques and tangles come later, as a consequence rather than a cause. “We believed, and still do, that amyloid-beta is an important pathological product of neurodegeneration,” de la Torre wrote recently, “…[but] it is not the cause of Alzheimer’s disease.” ([Location 3234](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3234)) - Tags: [[blue]] - Another compelling and perhaps parallel theory of Alzheimer’s disease says that it stems from abnormal glucose metabolism in the brain. Scientists and physicians have long noted a connection between Alzheimer’s disease and metabolic dysfunction. Having type 2 diabetes doubles or triples your risk of developing Alzheimer’s disease, about the same as having one copy of the APOE e4 gene. On a purely mechanistic level, chronically elevated blood glucose, as seen in type 2 diabetes and prediabetes/insulin resistance, can directly damage the vasculature of the brain. But insulin resistance alone is enough to elevate one’s risk. ([Location 3252](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3252)) - Tags: [[blue]] - Insulin seems to play a key role in memory function. Insulin receptors are highly concentrated in the hippocampus, the memory center of the brain. Several studies have found that spraying insulin right into subjects’ noses—administering it as directly as possible into their brains—quickly improves cognitive performance and memory, even in people who have already been diagnosed with Alzheimer’s disease. One study found that intranasal insulin helped preserve brain volume in Alzheimer’s patients. Clearly, it is helpful to get glucose into neurons; insulin resistance blocks this. As the authors wrote, “Several lines of evidence converge to suggest that central insulin resistance plays a causal role in the development and progression of Alzheimer’s disease.” ([Location 3257](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3257)) - Tags: [[blue]] - Because metabolism plays such an outsize role with at-risk e4 patients like Stephanie, our first step is to address any metabolic issues they may have. Our goal is to improve glucose metabolism, inflammation, and oxidative stress. One possible recommendation for someone like her would be to switch to a Mediterranean-style diet, relying on more monounsaturated fats and fewer refined carbohydrates, in addition to regular consumption of fatty fish. There is some evidence that supplementation with the omega-3 fatty acid DHA, found in fish oil, may help maintain brain health, especially in e4/e4 carriers. Higher doses of DHA may be required because of e4-induced metabolic changes and dysfunction of the blood-brain barrier. ([Location 3317](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3317)) - Tags: [[blue]] - This is also one area where a ketogenic diet may offer a real functional advantage: when someone is in ketosis, their brain relies on a mix of ketones and glucose for fuel. Studies in Alzheimer’s patients find that while their brains become less able to utilize glucose, their ability to metabolize ketones does not decline. So it may make sense to try to diversify the brain’s fuel source from only glucose to both glucose and ketones. A systematic review of randomized controlled trials found that ketogenic therapies improved general cognition and memory in subjects with mild cognitive impairment and early-stage Alzheimer’s disease. Think of it as a flex-fuel strategy. ([Location 3322](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3322)) - Tags: [[blue]] - The single most powerful item in our preventive tool kit is exercise, which has a two-pronged impact on Alzheimer’s disease risk: it helps maintain glucose homeostasis, and it improves the health of our vasculature. So along with changing Stephanie’s diet, we put her back on a regular exercise program, focusing on steady endurance exercise to improve her mitochondrial efficiency. This had a side benefit in that it helped manage her off-the-charts high cortisol levels, due to stress; stress and anxiety-related risk seem more significant in females. As we’ll see in chapter 11, endurance exercise produces factors that directly target regions of the brain responsible for cognition and memory. It also helps lower inflammation and oxidative stress. ([Location 3331](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3331)) - Tags: [[blue]] - Strength training is likely just as important. A study looking at nearly half a million patients in the United Kingdom found that grip strength, an excellent proxy for overall strength, was strongly and inversely associated with the incidence of dementia (see figure 8). People in the lowest quartile of grip strength (i.e., the weakest) had a 72 percent higher incidence of dementia, compared to those in the top quartile. The authors found that this association held up even after adjusting for the usual confounders such as age, sex, socioeconomic status, diseases such as diabetes and cancer, smoking, and lifestyle factors such as sleep patterns, walking pace, and time spent watching TV. And there appeared to be no upper limit or “plateau” to this relationship; the greater someone’s grip strength, the lower their risk of dementia. ([Location 3337](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3337)) - Tags: [[blue]] - Broadly, our strategy should be based on the following principles: WHAT’S GOOD FOR THE HEART IS GOOD FOR THE BRAIN. That is, vascular health (meaning low apoB, low inflammation, and low oxidative stress) is crucial to brain health. WHAT’S GOOD FOR THE LIVER (AND PANCREAS) IS GOOD FOR THE BRAIN. Metabolic health is crucial to brain health. TIME IS KEY. We need to think about prevention early, and the more the deck is stacked against you genetically, the harder you need to work and the sooner you need to start. As with cardiovascular disease, we need to play a very long game. OUR MOST POWERFUL TOOL FOR PREVENTING COGNITIVE DECLINE IS EXERCISE. We’ve talked a lot about diet and metabolism, but exercise appears to act in multiple ways (vascular, metabolic) to preserve brain health; we’ll get into more detail in Part III, but exercise—lots of it—is a foundation of our Alzheimer’s-prevention program. ([Location 3397](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3397)) - Tags: [[blue]] - exercise has the greatest power to determine how you will live out the rest of your life. There are reams of data supporting the notion that even a fairly minimal amount of exercise can lengthen your life by several years. It delays the onset of chronic diseases, pretty much across the board, but it is also amazingly effective at extending and improving healthspan. Not only does it reverse physical decline, which I suppose is somewhat obvious, but it can slow or reverse cognitive decline as well. ([Location 3557](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3557)) - Tags: [[blue]] - Even a little bit of daily activity is much better than nothing. Going from zero weekly exercise to just ninety minutes per week can reduce your risk of dying from all causes by 14 percent. It’s very hard to find a drug that can do that. ([Location 3564](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3564)) - Tags: [[blue]] - It’s obviously not a revelation that exercise is good for you; so is chicken soup if you have a sore throat. But not many people realize how profound its effects really are. Study after study has found that regular exercisers live as much as a decade longer than sedentary people. Not only do habitual runners and cyclists tend to live longer, but they stay in better health, with less morbidity from causes related to metabolic dysfunction. ([Location 3571](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3571)) - Tags: [[blue]] - It turns out that peak aerobic cardiorespiratory fitness, measured in terms of VO2 max, is perhaps the single most powerful marker for longevity. ([Location 3596](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3596)) - Tags: [[blue]] - VO2 max is typically expressed in terms of the volume of oxygen a person can use, per kilogram of body weight, per minute. An average forty-five-year-old man will have a VO2 max around 40 ml/kg/min, while an elite endurance athlete will likely score in the high 60s and above. An unfit person in their thirties or forties, on the other hand, might score only in the high 20s on a VO2 max test, ([Location 3611](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3611)) - Tags: [[blue]] - A 2018 study in JAMA that followed more than 120,000 people found that higher VO2 max (measured via a treadmill test) was associated with lower mortality across the board. The fittest people had the lowest mortality rates—by a surprising margin. Consider this: A person who smokes has a 40 percent greater risk of all-cause mortality (that is, risk of dying at any moment) than someone who does not smoke, representing a hazard ratio or (HR) of 1.40. This study found that someone of below-average VO2 max for their age and sex (that is, between the 25th and 50th percentiles) is at double the risk of all-cause mortality compared to someone in the top quartile (75th to 97.6th percentiles). Thus, poor cardiorespiratory fitness carries a greater relative risk of death than smoking. ([Location 3619](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3619)) - Tags: [[blue]] - Someone in the bottom quartile of VO2 max for their age group (i.e., the least fit 25 percent) is nearly four times likelier to die than someone in the top quartile—and five times likelier to die than a person with elite-level (top 2.3 percent) VO2 max. That’s stunning. These benefits are not limited to the very fittest people either; even just climbing from the bottom 25 percent into the 25th to 50th percentile (e.g., least fit to below average) means you have cut your risk of death nearly in half, according to this study. ([Location 3625](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3625)) - Tags: [[blue]] - These results were confirmed by a much larger and more recent study, published in 2022 in the Journal of the American College of Cardiology, looking at data from 750,000 US veterans ages thirty to ninety-five (see figure 9). This was a completely different population that encompassed both sexes and all races, yet the researchers found a nearly identical result: someone in the least fit 20 percent has a 4.09 times greater risk of dying than a person in the top 2 percent of their age and sex category. Even someone of moderate fitness (40th to 60th percentile) is still at more than double the risk of all-cause mortality than the fittest group, this study found. “Being unfit carried a greater risk than any of the cardiac risk factors examined,” the authors concluded. ([Location 3630](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3630)) - Tags: [[blue]] - As the authors of the JAMA study concluded, “Cardiorespiratory fitness is inversely associated with long-term mortality with no observed upper limit of benefit [emphasis mine]. Extremely high aerobic fitness was associated with the greatest survival.” ([Location 3649](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3649)) - Tags: [[blue]] - Subjects with low muscle strength were at double the risk of death, while those with low muscle mass and/or low muscle strength, plus metabolic syndrome, had a 3 to 3.33 times greater risk of all-cause mortality. ([Location 3662](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3662)) - Tags: [[blue]] - Strength may even trump cardiorespiratory fitness, at least one study suggests. Researchers following a group of approximately 1,500 men over forty with hypertension, for an average of about eighteen years, found that even if a man was in the bottom half of cardiorespiratory fitness, his risk of all-cause mortality was still almost 48 percent lower if he was in the top third of the group in terms of strength versus the bottom third.[*4] ([Location 3664](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3664)) - Tags: [[blue]] - At a deeper biochemical level, exercise really does act like a drug. To be more precise, it prompts the body to produce its own, endogenous drug-like chemicals. When we are exercising, our muscles generate molecules known as cytokines that send signals to other parts of our bodies, helping to strengthen our immune system and stimulate the growth of new muscle and stronger bones. Endurance exercise such as running or cycling helps generate another potent molecule called brain-derived neurotrophic factor, or BDNF, that improves the health and function of the hippocampus, a part of the brain that plays an essential role in memory. Exercise helps keep the brain vasculature healthy, and it may also help preserve brain volume. This is why I view exercise as a particularly important part of the tool kit for patients at risk of developing Alzheimer’s disease—such ([Location 3680](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3680)) - Tags: [[blue]] - One of the prime hallmarks of aging is that our physical capacity erodes. Our cardiorespiratory fitness declines for various reasons that begin with lower cardiac output, primarily due to reduced maximum heart rate. We lose strength and muscle mass with each passing decade, our bones grow fragile and our joints stiffen, and our balance falters, a fact that many men and women discover the hard way, by falling off a ladder or while stepping off a curb. ([Location 3692](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3692)) - Tags: [[blue]] - I will find a way to lift heavy weights in some way, shape, or form four times per week, no matter what else I am doing or where I might be traveling. ([Location 3734](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3734)) - Tags: [[blue]] - When we say “cardio,” we are talking about not one thing, but a physiologic continuum, ranging from an easy walk to an all-out sprint. The various levels of intensity all count as cardio but are fueled by multiple different energy systems. For our purposes, we are interested in two particular regions of this continuum: long, steady endurance work, such as jogging or cycling or swimming, where we are training in what physiologists call zone 2, and maximal aerobic efforts, where VO2 max comes into play. ([Location 3876](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3876)) - Tags: [[blue]] - Aerobic exercise, done in a very specific way, improves our ability to utilize glucose and especially fat as fuel. The key here are the mitochondria, those tiny little intracellular organelles that produce much of our energy. These cellular “engines” can burn both glucose and fat, and thus they are fundamental to our metabolic health. Healthy mitochondria are also important to maintaining the health of our brain, and to controlling potential bad actors like oxidative stress and inflammation. ([Location 3895](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3895)) - Tags: [[blue]] - In San Millán’s view, healthy mitochondria are key to both athletic performance and metabolic health. Our mitochondria can convert both glucose and fatty acids to energy—but while glucose can be metabolized in multiple different ways, fatty acids can be converted to energy only in the mitochondria. Typically, someone working at a lower relative intensity will be burning more fat, while at higher intensities they would rely more on glucose. The healthier and more efficient your mitochondria, the greater your ability to utilize fat, which is by far the body’s most efficient and abundant fuel source. ([Location 3917](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3917)) - Tags: [[blue]] - The differences they found were striking. The professional cyclists could zoom along, producing a huge amount of power while still burning primarily fat. But the subjects with metabolic syndrome relied almost entirely on glucose for their fuel source, even from the first pedal stroke. They had virtually zero ability to tap into their fat stores, meaning they were metabolically inflexible: able to use only glucose but not fat. ([Location 3929](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3929)) - Tags: [[blue]] - As fundamental as zone 2 training is for professional cyclists, however, San Millán believes that it’s even more important for nonathletes, for two reasons. First, it builds a base of endurance for anything else you do in life, whether that is riding your bike in a one-hundred-mile century ride or playing with your kids or grandkids. The other reason is that he believes it plays a crucial role in preventing chronic disease by improving the health and efficiency of your mitochondria, which is why training aerobic endurance and efficiency (i.e., zone 2 work) is the first element of my Centenarian Decathlon training program. ([Location 3936](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3936)) - Tags: [[blue]] - In technical terms, San Millán describes zone 2 as the maximum level of effort that we can maintain without accumulating lactate. We still produce it, but we’re able to match production with clearance. The more efficient our mitochondrial “engine,” the more rapidly we can clear lactate, and the greater effort we can sustain while remaining in zone 2. If we are “feeling the burn” in this type of workout, then we are likely going too hard, creating more lactate than we can eliminate. ([Location 3948](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3948)) - Tags: [[blue]] - If you know your maximum heart rate—not estimated, but your actual maximum, the highest number you’ve ever seen on a heart rate monitor—your zone 2 will correspond to between approximately 70 and 85 percent of that peak number, depending on your fitness levels. That’s a big range, so when starting people out, I prefer they rely on their rate of perceived exertion, or RPE, also known as the “talk test.” How hard are you working? How easy is it to speak? If you’re at the top of zone 2, you should be able to talk but not particularly interested in holding a conversation. If you can’t speak in complete sentences at all, you’re likely into zone 3, which means you’re going too hard, but if you can comfortably converse, you’re likely in zone 1, which is too easy. ([Location 3957](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3957)) - Tags: [[blue]] - Zone 2 output is highly variable, depending on one’s fitness. In San Millán and Brooks’s study, the professional cyclists produced about three hundred watts of power in zone 2, while the sedentary, metabolically unhealthy subjects could generate only about one hundred watts at the same relative level of intensity. ([Location 3963](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3963)) - Tags: [[blue]] - It seems unjust, but the people who most need to burn their fat, the people with the most of it, are unable to unlock virtually any of that fat to use as energy, while the lean, well-trained professional athletes are able to do so easily because they possess greater metabolic flexibility (and healthier mitochondria).[*2] ([Location 3978](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3978)) - Tags: [[blue]] - Mitochondrial health becomes especially important as we grow older, because one of the most significant hallmarks of aging is a decline in the number and quality of our mitochondria. But the decline is not necessarily a one-way street. Mitochondria are incredibly plastic, and when we do aerobic exercise, it stimulates the creation of many new and more efficient mitochondria through a process called mitochondrial biogenesis, while eliminating ones that have become dysfunctional via a recycling process called mitophagy ([Location 3982](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3982)) - Tags: [[blue]] - This is another reason why zone 2 is such a powerful mediator of metabolic health and glucose homeostasis. Muscle is the largest glycogen storage sink in the body, and as we create more mitochondria, we greatly increase our capacity for disposing of that stored fuel, rather than having it end up as fat or remaining in our plasma. ([Location 3987](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3987)) - Tags: [[blue]] - This in turn explains why exercise, especially in zone 2, can be so effective in managing both type 1 and type 2 diabetes: It enables the body to essentially bypass insulin resistance in the muscles to draw down blood glucose levels. I have one patient with type 1 diabetes, meaning he produces zero insulin, who keeps his glucose in check almost entirely by walking briskly for six to ten miles every day, and sometimes more. As he walks, his muscle cells are vacuuming glucose out of his bloodstream via NIMGU. He still needs to inject himself with insulin, but only a tiny fraction of the amount that he would otherwise require. ([Location 3995](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=3995)) - Tags: [[blue]] - How much zone 2 training you need depends on who you are. Someone who is just being introduced to this type of training will derive enormous benefit from even two 30-minute sessions per week to start with. Based on multiple discussions with San Millán and other exercise physiologists, it seems that about three hours per week of zone 2, or four 45-minute sessions, is the minimum required for most people to derive a benefit and make improvements, once you get over the initial hump of trying it for the first time. (People who are training for major endurance events, such as running a marathon, obviously need to do more than this.) I am so persuaded of the benefits of zone 2 that it has become a cornerstone of my training plan. Four times a week, I will spend about an hour riding my stationary bike at my zone 2 threshold. ([Location 4004](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4004)) - Tags: [[blue]] - One way to track your progression in zone 2 is to measure your output in watts at this level of intensity. (Many stationary bikes can measure your wattage as you ride.) You take your average wattage output for a zone 2 session and divide it by your weight to get your watts per kilogram, which is the number we care about. So if you weigh 60 kilos (about 132 pounds) and can generate 125 watts in zone 2, that works out to a bit more than 2 watts/kg, which is about what one would expect from a reasonably fit person. These are rough benchmarks, but someone who is very fit will be able to produce 3 watts/kg, while professional cyclists put out 4 watts/kg and up. It’s not the number that matters, but how much you are improving over time. ([Location 4010](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4010)) - Tags: [[blue]] - Typically, for patients who are new to exercising, we introduce VO2 max training after about five or six months of steady zone 2 work. ([Location 4029](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4029)) - Tags: [[blue]] - For example, a thirty-five-year-old man with average fitness for his age—a VO2 max in the mid-30s—should be able to run at a ten-minute mile pace (6 mph). But by age seventy, only the very fittest 5 percent of people will still be able to manage this. Similarly, an average forty-five- to fifty-year-old will be able to climb stairs briskly (VO2 max = 32), but at seventy-five, such a feat demands that a person be in the top tier of their age group. Activities that are easy when we are young or middle-aged become difficult if not impossible as we get older. This explains why so many people are miserable in their Marginal Decade. They simply can’t do much of anything. ([Location 4043](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4043)) - Tags: [[blue]] - I push my patients to train for as high a VO2 max as possible, so that they can maintain a high level of physical function as they age. Ideally, I want them to target the “elite” range for their age and sex (roughly the top 2 percent). If they achieve that level, I say good job—now let’s reach for the elite level for your sex, but two decades younger. This may seem like an extreme goal, but I like to aim high, in case you haven’t noticed. ([Location 4051](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4051)) - Tags: [[blue]] - Keep in mind, increasing your VO2 max by any amount is going to improve your life, not only in terms of how long you live but also how well you live, today and in the future. Improving your VO2 max from the very bottom quartile to the quartile above (i.e., below average) is associated with almost a 50 percent reduction in all-cause mortality, as we saw earlier. I believe that almost anyone is capable of achieving this—and they should, because the alternative is so unacceptable. Once maximal oxygen consumption or VO2 max drops below a certain level (typically about 18 ml/kg/min in men, and 15 in women), it begins to threaten your ability to live on your own. Your engine is beginning to fail. ([Location 4068](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4068)) - Tags: [[blue]] - The payoff is that increasing your VO2 max makes you functionally younger. One study found that boosting elderly subjects’ VO2 max by 6 ml/kg/min, or about 25 percent, was equivalent to subtracting twelve years from their age. If you are a man in your sixties and you are starting with a VO2 max of 30, you are more or less average for your age group (see figure 12). (Women typically have a somewhat lower average VO2 max by age, because of various factors, so an “average” woman in her sixties would be at about 25 ml/kg/min.) If you can boost that up to 35 via training, you will be squarely in the top 25 percent of your age group. Nice work. Now, here’s another way to look at it: In your sixties, you will have achieved the aerobic fitness of an average man in his fifties, a decade younger than you. If you can get it still higher, to 38 or 39, you will be the aerobic equivalent of an average thirty-something. This means you will have bought yourself a phase shift, like we talked about with the centenarians: you now have the fitness of someone decades younger than you. So give yourself a pat on the back; you’ve earned it. ([Location 4089](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4089)) - Tags: [[blue]] - the way we train VO2 max is pretty similar to the way elite athletes do it: by supplementing our zone 2 work with one or two VO2 max workouts per week. ([Location 4105](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4105)) - Tags: [[blue]] - Where HIIT intervals are very short, typically measured in seconds, VO2 max intervals are a bit longer, ranging from three to eight minutes—and a notch less intense. I do these workouts on my road bike, mounted to a stationary trainer, or on a rowing machine, but running on a treadmill (or a track) could also work. The tried-and-true formula for these intervals is to go four minutes at the maximum pace you can sustain for this amount of time—not an all-out sprint, but still a very hard effort. Then ride or jog four minutes easy, which should be enough time for your heart rate to come back down to below about one hundred beats per minute. Repeat this four to six times and cool down.[*4] ([Location 4107](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4107)) - Tags: [[blue]] - According to Andy Galpin, a professor of kinesiology at California State University, Fullerton, and one of the foremost authorities on strength and performance, we lose muscle strength about two to three times more quickly than we lose muscle mass. And we lose power (strength x speed) two to three times faster than we lose strength. This is because the biggest single change in the aging muscle is the atrophy of our fast twitch or type 2 muscle fibers. Ergo, our training must be geared towards improving these with heavy resistance training. Daily life and zone 2 endurance work may be enough to prevent atrophy of type 1 fibers—but unless you are working against significant resistance, your type 2 muscle fibers will wither away. ([Location 4149](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4149)) - Tags: [[blue]] - It takes much less time to lose muscle mass and strength than to gain it, particularly if we are sedentary. Even if someone has been training diligently, a short period of inactivity can erase many of those gains. If that inactivity stems from a fall or a broken bone, and lasts longer than a few days, it can often kick off a steep decline from which we may never fully recover, which is pretty much what happened with Sophie. A study of twelve healthy volunteers with an average age of sixty-seven found that after just ten days of bed rest, which is about what a person would experience from a major illness or orthopedic injury, study participants lost an average of 3.3 pounds of lean mass (muscle). That’s substantial, and it shows just how dangerous inactivity can be. If someone is sedentary and consuming excess calories, muscle loss accelerates, because one of the primary destinations of fat spillover is into muscle. ([Location 4154](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4154)) - Tags: [[blue]] - Regaining that muscle, once we’ve gotten to this state, is no easy task. One study looked at sixty-two frail seniors (average age seventy-eight) who engaged in a program of strength training and found that even after six months of pure strength training, half of the subjects did not gain any muscle mass. They also didn’t lose any muscle mass, likely thanks to the weight training, but the upshot is, it is very difficult to put on muscle mass later in life. ([Location 4165](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4165)) - Tags: [[blue]] - I think of strength training as a form of retirement saving. Just as we want to retire with enough money saved up to sustain us for the rest of our lives, we want to reach older age with enough of a “reserve” of muscle (and bone density) to protect us from injury and allow us to continue to pursue the activities that we enjoy. ([Location 4195](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4195)) - Tags: [[blue]] - unlike some guys in the gym, I’m less concerned with how big my biceps are or how much I can bench press. Those might matter if you’re a bodybuilder or a powerlifter, but I’d argue they matter less in the Centenarian Decathlon (or in real life). A far more important measure of strength, I’ve concluded, is how much heavy stuff you can carry. I say this on the basis of my intuition but also research into hunter-gatherers and human evolution. Carrying is our superpower as a species. It’s one reason why we have thumbs, as well as long legs (and arms). No other animal is capable of carrying large objects from one place to another with any efficiency. (And the ones that can, like horses and other livestock, do so only because we bred and trained and harnessed them.) This frames how I view strength training in general. It’s largely about improving your ability to carry things. ([Location 4201](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4201)) - Tags: [[blue]] - I was introduced to this pastime by Michael Easter in his eye-opening book The Comfort Crisis. His intriguing thesis is that because we have removed all discomfort of any kind from modern life, we have lost touch with the fundamental skills (not to mention the frequent suffering) that once defined what it meant to be human. Carrying stuff over long distances is one of these skills; our ancestors likely had to range far and wide to hunt food for their families and then carry their kills back to camp to feed everyone. But it’s so effective that the military has incorporated it into their training. ([Location 4215](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4215)) - Tags: [[blue]] - As great as rucking is, it’s not the only thing I rely on to build my strength. Fundamentally I structure my training around exercises that improve the following: Grip strength, how hard you can grip with your hands, which involves everything from your hands to your lats (the large muscles on your back). Almost all actions begin with the grip. Attention to both concentric and eccentric loading for all movements, meaning when our muscles are shortening (concentric) and when they are lengthening (eccentric). In other words, we need to be able to lift the weight up and put it back down, slowly and with control. Rucking down hills is a great way to work on eccentric strength, because it forces you to put on the “brakes.” Pulling motions, at all angles from overhead to in front of you, which also requires grip strength (e.g., pull-ups and rows). Hip-hinging movements, such as the deadlift and squat, but also step-ups, hip-thrusters, and countless single-leg variants of exercises that strengthen the legs, glutes, and lower back. ([Location 4227](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4227)) - Tags: [[blue]] - Training grip strength is not overly complicated. One of my favorite ways to do it is the classic farmer’s carry, where you walk for a minute or so with a loaded hex bar or a dumbbell or kettlebell in each hand. (Bonus points: Hold the kettlebell up vertically, keeping your wrist perfectly straight and elbow cocked at ninety degrees, as though you were carrying it through a crowded room.) One of the standards we ask of our male patients is that they can carry half their body weight in each hand (so full body weight in total) for at least one minute, and for our female patients we push for 75 percent of that weight. This is, obviously, a lofty goal—please don’t try to do it on your next visit to the gym. Some of our patients need as much as a year of training before they can even attempt this test. ([Location 4256](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4256)) - Tags: [[blue]] - One of the tests we have our patients perform is stepping onto and off an eighteen-inch block and taking three full seconds to reach the ground (a forward step down, like descending a very tall step). The stepping up part is comparatively easy, but most people initially struggle with a controlled three-second descent. That requires eccentric strength and control. ([Location 4273](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4273)) - Tags: [[blue]] - Training eccentric strength is relatively simple. Big picture, it means focusing on the “down” phase of lifts ranging from pull-ups or pull-downs to deadlifts to rows; rucking downhill, carrying a weighted pack, is a great way to build both eccentric strength as well as spatial awareness and control, which are important parts of stability training (next chapter). It also helps protect against knee pain. ([Location 4281](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4281)) - Tags: [[blue]] - One thing that stability training has taught me is that most “acute” injuries, such as a torn ACL or a hamstring tear, are rarely sudden. While their onset may be rapid—instantaneous back or neck or knee pain—there was likely a chronic weakness or lack of stability at the foundation of the joint that was the true culprit. This is the real iceberg in the water. The “acute” injury is just the part you see, the manifestation of the underlying weakness. So if we are to complete the goals we have set in our own Centenarian Decathlon, we need to be able to anticipate and avoid any potential injuries that lie in our path, like icebergs at sea. This means understanding stability and incorporating it into our routine. ([Location 4370](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4370)) - Tags: [[blue]] - Stability is tricky to define precisely, but we intuitively know what it is. A technical definition might be: stability is the subconscious ability to harness, decelerate, or stop force. A stable person can react to internal or external stimuli to adjust position and muscular tension appropriately without a tremendous amount of conscious thought. ([Location 4376](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4376)) - Tags: [[blue]] - When this happens in our bodies, this force dissipation (as it’s called) leaks out via the path of least resistance—typically via joints like knees, elbows, and shoulders, and/or the spine, any or all of which will give out at some point. Joint injuries are almost always the result of this kind of energy leak. ([Location 4403](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4403)) - Tags: [[blue]] - In sum, stability lets us create the most force in the safest manner possible, connecting our body’s different muscle groups with much less risk of injury to our joints, our soft tissue, and especially our vulnerable spine. The goal is to be strong, fluid, flexible, and agile as you move through your world. ([Location 4405](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4405)) - Tags: [[blue]] - DNS. Short for dynamic neuromuscular stabilization, DNS sounds complicated, but it is based on the simplest, most natural movements we make: the way we moved when we were babies. The theory behind DNS is that the sequence of movements that young children undergo on their way to learning how to walk is not random or accidental but part of a program of neuromuscular development that is essential to our ability to move correctly. As we go through this sequence of motions, our brain learns how to control our body and develop ideal patterns of movement. ([Location 4434](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4434)) - Tags: [[blue]] - Instead of diet, we should be talking about nutritional biochemistry. That takes it out of the realm of ideology and religion—and above all, emotion—and places it firmly back into the realm of science. ([Location 4848](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4848)) - Tags: [[blue]] - The correlation between poor metabolic health and being overnourished and undermuscled is very high. Hence, for a majority of patients the goal is to reduce energy intake while adding lean mass. This means we need to find ways to get them to consume fewer calories while also increasing their protein intake, and to pair this with proper exercise. This is the most common problem we are trying to solve around nutrition. ([Location 4857](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4857)) - Tags: [[blue]] - Nutritional interventions can be powerful tools with which to restore someone’s metabolic equilibrium and reduce risk of chronic disease. But can they extend and improve lifespan and healthspan, almost magically, the way exercise does? I’m no longer convinced that they can. ([Location 4864](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4864)) - Tags: [[blue]] - Nutrition is relatively simple, actually. It boils down to a few basic rules: don’t eat too many calories, or too few; consume sufficient protein and essential fats; obtain the vitamins and minerals you need; and avoid pathogens like E. coli and toxins like mercury or lead. Beyond that, we know relatively little with complete certainty. ([Location 4872](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4872)) - Tags: [[blue]] - The problem is that epidemiology is incapable of distinguishing between correlation and causation. This, aided and abetted by bad journalism, creates confusion. For example, multiple studies have found a strong association between drinking diet sodas and abdominal fat, hyperinsulinemia, and cardiovascular risk. Sounds like diet soda is bad stuff that causes obesity, right? But that is not what those studies actually demonstrate, because they fail to ask an important question: Who drinks diet soda? People who are concerned about their weight or their diabetes risk, that’s who. They may drink diet soda because they are heavy, or worried about becoming heavy. The problem is that epidemiology is not equipped to determine the direction of causality between a given behavior (e.g., drinking diet soda) and a particular outcome (e.g., obesity) any more than one of my chickens is able to scramble the egg she has just laid for me. ([Location 4902](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4902)) - Tags: [[blue]] - While the epidemiology of smoking (like exercise) easily passes the Bradford Hill tests because the effect size is so overwhelming, in nutrition the effect sizes are typically so small that they could easily be the product of other, confounding factors. ([Location 4922](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4922)) - Tags: [[blue]] - Case in point: The claim that eating red meats and processed meats “causes” colorectal cancer. According to a very well-publicized 2017 study from the Harvard School of Public Health and the World Health Organization, eating those kinds of meats raises one’s risk of colon cancer by 17 percent (HR = 1.17). That does sound scary—but does it pass the Bradford Hill tests? I don’t think so, because the association is so weak. For comparison’s sake, someone who smokes cigarettes is at more like 1,000 to 2,500 percent (ten to twenty-five times) increased risk of lung cancer, depending on the population being studied. This suggests that there might actually be some sort of causation at work. Yet very few published epidemiological studies show a risk increase of even 50 percent (HR = 1.50) for any given type of food. ([Location 4924](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4924)) - Tags: [[blue]] - The true weakness of epidemiology, at least as a tool to extract reliable, causal information about human nutrition, is that such studies are almost always hopelessly confounded. The factors that determine our food choices and eating habits are unfathomably complex. They include genetics, social influences, economic factors, education, metabolic health, marketing, religion, and everything in between—and they are almost impossible to disentangle from the biochemical effects of the foods themselves. ([Location 4949](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4949)) - Tags: [[blue]] - A few years ago, a scientist and statistician named David Allison ran an elegant experiment that illustrates how epidemiological methods can lead us astray, even in the most tightly controlled research model possible: laboratory mice, which are genetically identical and housed in identical conditions. Allison created a randomized experiment using these mice, similar to the caloric restriction experiments we discussed in chapter 5. He split them into three groups, differing only in the quantity of food they were given: a low-calorie group, a medium-calorie group, and a high-calorie, ad libitum group of animals who were allowed to eat as much as they wanted. The low-calorie mice were found to live the longest, followed by medium-calorie mice, and the high-calorie mice lived the shortest, on average. This was the expected result that had been well established in many previous studies. But then Allison did something very clever. He looked more closely at the high-calorie group, the mice with no maximum limit on food intake, and analyzed this group separately, as its own nonrandomized epidemiological cohort. Within this group, Allison found that some mice chose to eat more than others—and that these hungrier mice actually lived longer than the high-calorie mice who chose to eat less. This was exactly the opposite of the result found in the larger, more reliable, and more widely repeated randomized trial. There was a simple explanation for this: the mice that were strongest and healthiest had the largest appetites, and thus they ate more. Because they were healthiest to begin with, they also lived the longest. But if all we had to go on was Allison’s epidemiological analysis of this particular subgroup, and not the larger and better-designed clinical trial, we might conclude that eating more calories causes all mice to live longer, which we are pretty certain is not the case. ([Location 4952](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4952)) - Tags: [[blue]] - it is to be misled by epidemiology. One reason is because general health is a massive confounder in these kinds of studies. This is also known as healthy user bias, meaning that study results sometimes reflect the baseline health of the subjects more than the influence of whatever input is being studied—as ([Location 4967](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=4967)) - Tags: [[blue]] - it is so important to evaluate any intervention, nutritional or otherwise, through the lens of efficacy versus effectiveness. Efficacy tests how well the intervention works under perfect conditions and adherence (i.e., if one does everything exactly as prescribed). Effectiveness tests how well the intervention works under real-world conditions, in real people. Most people confuse these and therefore fail to appreciate this nuance of clinical trials. ([Location 5009](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5009)) - Tags: [[blue]] - On one level, it’s brilliant, a solution to four problems that have plagued humanity since the beginning: (1) how to produce enough food to feed almost everyone; (2) how to do so inexpensively; (3) how to preserve that food so it can be stored and transported safely; and (4) how to make it highly palatable. If you optimize for all four of these characteristics, you’re pretty much guaranteed to end up with the SAD, which is not so much a diet as a business model for how to feed the world efficiently. Two cheers for modern industrial food systems. ([Location 5090](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5090)) - Tags: [[blue]] - The basic problem we face is that, for perhaps the first time in human history, ample calories are available to many if not most people on the planet. But evolution has not prepared us for this situation. Nature is quite happy for us to be fat and frankly doesn’t care if we get diabetes. Thus, the SAD foils our key objectives with regard to nutrition: it induces us to eat more than we need to, becoming overnourished, while its preponderance of low-quality, ultraprocessed ingredients tends to displace other nutrients that we need, such as protein, to maintain optimal health. ([Location 5103](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5103)) - Tags: [[blue]] - The SAD disrupts the body’s metabolic equilibrium. It places enormous strain on our ability to control our blood glucose levels, and causes us to store fat when we should be utilizing it. The leading source of calories that Americans consume is a category called “grain-based desserts,” like pies, cakes, and cookies, according to the US Department of Agriculture. That is our number one “food group.” If we consume a bunch of grain-based desserts in a Cheesecake Factory binge, our blood glucose levels will surge. And if we do it over and over and over again, as we saw in previous chapters, we will eventually overwhelm our ability to handle all those calories in a safe way. The SAD essentially wages war on our metabolic health, and, given enough time, most of us will lose the war. ([Location 5107](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5107)) - Tags: [[blue]] - Once you strip away the labels and the ideology, almost all diets rely on at least one of the following three strategies to accomplish this: CALORIC RESTRICTION, or CR: eating less in total, but without attention to what is being eaten or when it’s being eaten DIETARY RESTRICTION, or DR: eating less of some particular element(s) within the diet (e.g., meat, sugar, fats) TIME RESTRICTION, or TR: restricting eating to certain times, up to and including multiday fasting In other words, if you are overnourished, and statistically speaking about two-thirds of us are, you will need to apply at least one of these methods of… ([Location 5115](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5115)) - Tags: [[blue]] - Each of these approaches has its pros and cons, as I’ve observed over a decade of working on nutrition issues with countless patients. These will be covered in more detail below, but here is the tl;dr: From the standpoint of pure efficacy, CR or caloric restriction is the winner, hands down. This is how bodybuilders shed weight while holding on to muscle mass, and it also allows the most flexibility with food choices. The catch is that you have to do it perfectly—tracking every single thing you eat, and not succumbing to the urge to cheat or snack—or it doesn’t work. Many people have a hard time sticking with it. DR or dietary restriction is probably the most common strategy employed for reducing energy intake. It is conceptually simple: pick a type of food, and then don’t eat that food. It only works, obviously, if that food is both plentiful and significant enough that eliminating it will create a caloric deficit. Saying you’re going on the “no lettuce” diet is pretty much doomed to fail. And you can still overeat while adhering perfectly to a particular DR, as I found out when I attempted to go vegan. TR or time restriction—also known as intermittent fasting—is the latest trend in ways to cut calories. In some ways I think it’s the easiest. When I was a cyclist, and I was trying to drop that six final pounds from my already very light (for me) frame, this became my jam. I would allow myself only one meal per day, despite doing about three hours per day of training. But this can still backfire if you overeat. I have, much to my amusement, watched patients gain weight on a one-meal-a-day approach by turning their meal into a contest to see who… ([Location 5125](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5125)) - Tags: [[blue]] - One slight advantage is that calorie counting is agnostic to food choices; you can eat whatever you want so long as you stay within your daily allowance. But if you make too many poor decisions, you will be very hungry, so buyer beware. You can lose weight on a restricted-calorie diet consisting only of Snickers bars, but you will feel much better if you opt for steamed broccoli and chicken breasts instead. ([Location 5158](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5158)) - Tags: [[blue]] - The most profound difference between the two studies was also the most fundamental, for a diet study: the food that the monkeys ate. The Wisconsin animals ate an off-the-shelf commercial monkey chow that was “semipurified,” meaning its ingredients were highly processed and rigorously titrated. The NIH monkeys were fed a diet that was similar in its basic macronutrient profile, but their chow was “natural” and less refined, custom formulated from whole ingredients by an in-house primate nutritionist at NIH. The most glaring contrast: while the NIH monkey chow contained about 4 percent sugar, the Wisconsin diet comprised an astonishing 28.5 percent sucrose, by weight. That is a greater proportion of sugar than you’ll find in vanilla Häagen-Dazs ice cream. Could that alone have explained the difference in survival outcomes? Possibly: more than 40 percent of the Wisconsin control monkeys, the ones not subject to calorie limitations, developed insulin resistance and prediabetes, while just one in seven of the NIH controls became diabetic.[*1] And the Wisconsin control monkeys proved far more likely to die from cardiovascular causes and cancer than monkeys from any other group. This could suggest that caloric restriction was eliminating early deaths because of the bad Wisconsin diet more than it was actually slowing aging—which is still useful information, as avoiding diabetes and related metabolic disorders is important to our strategy. ([Location 5194](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5194)) - Tags: [[blue]] - The NIH diet was much higher in quality. Instead of ultraprocessed ingredients like corn oil and cornstarch (another 30 percent of the Wisconsin diet), the NIH monkey chow contained ground whole wheat and corn, and thus more phytochemicals and other possibly beneficial micronutrients like those typically found in fresh food. While not exactly natural, it was at least closer to what rhesus monkeys would actually eat in the wild. So giving the NIH monkeys more or less of that feed may have had less of an impact because the diet was not as harmful to begin with. Upshot: the quality of your diet may matter as much as the quantity. ([Location 5209](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5209)) - Tags: [[blue]] - Taken together, then, what do these two monkey studies have to tell us about nutritional biochemistry? Avoiding diabetes and related metabolic dysfunction—especially by eliminating or reducing junk food—is very important to longevity. There appears to be a strong link between calories and cancer, the leading cause of death in the control monkeys in both studies. The CR monkeys had a 50 percent lower incidence of cancer. The quality of the food you eat could be as important as the quantity. If you’re eating the SAD, then you should eat much less of it. Conversely, if your diet is high quality to begin with, and you are metabolically healthy, then only a slight degree of caloric restriction—or simply not eating to excess—can still be beneficial. I think this last point is key. These two studies suggest that if you are eating a higher-quality diet—and are metabolically healthy to begin with—then severe caloric restriction may not even be necessary. ([Location 5214](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5214)) - Tags: [[blue]] - The monkeys teach us that if you are metabolically healthy and not over-nourished, like the NIH animals, then avoiding a crap diet may be all you need. Some of the NIH CR monkeys ended up with some of the longest lifespans ever recorded in rhesus monkeys. It seems quite clear, then, that even for monkeys, limiting caloric intake and improving diet quality “works”—it’s how you pull it off that is tricky. ([Location 5232](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5232)) - Tags: [[blue]] - A major risk with DR is that you can still easily end up overnourished if you are not deliberate about it. People tend to (erroneously) assume you can’t eat too much if you’re just restricting fill-in-the-blank (e.g., carbohydrates). This is incorrect. Even if done correctly and strictly, DR can still result in overnutrition. If you cut out carbohydrates altogether but overdo it on the Wagyu steaks and bacon, you will fairly easily find yourself in a state of caloric excess. The key is to pick a strategy to which you can adhere but that also helps achieve your goals. This takes patience, some willpower, and a willingness to experiment. ([Location 5258](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5258)) - Tags: [[blue]] - The real art to dietary restriction, Nutrition 3.0–style, is not picking which evil foods we’re eliminating. Rather, it’s finding the best mix of macronutrients for our patient—coming up with an eating pattern that helps them achieve their goals, in a way that they can sustain. This is a tricky balancing act, and it requires us (once again) to forget about labels and viewpoints and drill down into nutritional biochemistry. The way we do this is by manipulating our four macronutrients: alcohol, carbohydrates, protein, and fat. How well do you tolerate carbohydrates? How much protein do you require? What sorts of fats suit you best? How many calories do you require each day? What is the optimal combination for you? ([Location 5296](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5296)) - Tags: [[blue]] - Alcohol serves no nutritional or health purpose but is a purely hedonic pleasure that needs to be managed. It’s especially disruptive for people who are overnourished, for three reasons: it’s an “empty” calorie source that offers zero nutrition value; the oxidation of ethanol delays fat oxidation, which is the exact opposite of what we want if we’re trying to lose fat mass; and drinking alcohol very often leads to mindless eating. ([Location 5305](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5305)) - Tags: [[blue]] - Ethanol is a potent carcinogen, and chronic drinking has strong associations with Alzheimer’s disease, mainly via its negative effect on sleep, but possibly via additional mechanisms. Like fructose, alcohol is preferentially metabolized in the liver, with well-known long-term consequences in those who drink to excess. Last, it loosens inhibitions around other kinds of food consumption; give me a few drinks, and the next thing you know I’m elbow-deep in the Pringles can as I pace around the pantry looking for my next snack. ([Location 5310](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5310)) - Tags: [[blue]] - I strongly urge my patients to limit alcohol to fewer than seven servings per week, and ideally no more than two on any given day, and I manage to do a pretty good job adhering to this rule myself. ([Location 5321](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5321)) - Tags: [[blue]] - Carbohydrates are our primary energy source. In digestion, most carbohydrates are broken down to glucose, which is consumed by all cells to create energy in the form of ATP. Excess glucose, beyond what we need immediately, can be stored in the liver or muscles as glycogen for near-term use or socked away in adipose tissue (or other places) as fat. This decision is made with the help of the hormone insulin, which surges in response to the increase in blood glucose. ([Location 5331](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5331)) - Tags: [[blue]] - Each person will respond differently to an influx of glucose. Too much glucose (or carbohydrate) for one person might be barely enough for another. An athlete who is training or competing in high-level endurance events might easily take in—and burn up—six hundred or eight hundred grams of carbohydrates per day. If I consumed that much now, day to day, it would probably render me a diabetic within a year. So how much is too much? And what about quality? Obviously that piece of pie is going to affect an endurance athlete differently from a sedentary person—and the pie will also have a different effect than a baked potato or french fries. ([Location 5338](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5338)) - Tags: [[blue]] - I am confident that such studies will show a benefit, if done correctly, because there are already ample data showing how important it is to keep blood glucose low and stable. A 2011 study looking at twenty thousand people, mostly without type 2 diabetes, found that their risk of mortality increased monotonically with their average blood glucose levels (measured via HbA1c). The higher their blood glucose, the greater their risk of death—even in the nondiabetic range of blood glucose. Another study in 2019 looked at the degree of variation in subjects’ blood glucose levels and found that the people in the highest quartile of glucose variability had a 2.67 times greater risk of mortality than those in the lowest (most stable) quartile. From these studies, it seems quite clear that we want to lower average blood glucose and reduce the amount of variability from day to day and hour to hour. ([Location 5374](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5374)) - Tags: [[blue]] - Overall, I like to keep average glucose at or below 100 mg/dL, with a standard deviation of less than 15 mg/dL.[*5] These are aggressive goals: 100 mg/dL corresponds to an HbA1c of 5.1 percent, which is quite low. But I believe that the reward, in terms of lower risk of mortality and disease, is well worth it given the ample evidence in nondiabetics and diabetics alike. ([Location 5398](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5398)) - Tags: [[blue]] - One thing CGM pretty quickly teaches you is that your carbohydrate tolerance is heavily influenced by other factors, especially your activity level and sleep. An ultraendurance athlete, someone who is training for long rides or swims or runs, can eat many more grams of carbs per day because they are blowing through those carbs every time they train—and they are also vastly increasing their ability to dispose of glucose via the muscles and their more-efficient mitochondria.[*6] Also, sleep disruption or reduction dramatically impairs glucose homeostasis over time. From years of experience with my own CGM and that of my patients, it still amazes me how much even one night of horrible sleep cripples our ability to dispose of glucose the next day. ([Location 5410](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5410)) - Tags: [[blue]] - Remember the study we discussed in chapter 11 that looked at the effect of strength training in sixty-two frail seniors? The subjects who did only strength training for six months gained no muscle mass. What I didn’t mention there was that another group of subjects was given protein supplementation (via a protein shake); those subjects added an average of about three pounds of lean mass. The extra protein likely made the difference.[*7] ([Location 5464](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5464)) - Tags: [[blue]] - Unlike carbs and fat, protein is not a primary source of energy. We do not rely on it in order to make ATP,[*8] nor do we store it the way we store fat (in fat cells) or glucose (as glycogen). If you consume more protein than you can synthesize into lean mass, you will simply excrete the excess in your urine as urea. Protein is all about structure. The twenty amino acids that make up proteins are the building blocks for our muscles, our enzymes, and many of the most important hormones in our body. They go into everything from growing and maintaining our hair, skin, and nails to helping form the antibodies in our immune system. On top of this, we must obtain nine of the twenty amino acids that we require from our diet, because we can’t synthesize them. ([Location 5468](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5468)) - Tags: [[blue]] - How much protein do we actually need? It varies from person to person. In my patients I typically set 1.6 g/kg/day as the minimum, which is twice the RDA. The ideal amount can vary from person to person, but the data suggest that for active people with normal kidney function, one gram per pound of body weight per day (or 2.2 g/kg/day) is a good place to start—nearly triple the minimal recommendation. ([Location 5484](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5484)) - Tags: [[blue]] - The literature suggests that the ideal way to achieve this is by consuming four servings of protein per day, each at ~0.25 g/lb of body weight. A six-ounce serving of chicken, fish, or meat will provide about 40 to 45 grams (at about 7 grams of actual protein per ounce of meat), so our hypothetical 180-pound person should eat four such servings a day. ([Location 5490](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5490)) - Tags: [[blue]] - There is some evidence that older people might require more protein because of the anabolic resistance that develops with age—that is, their greater difficulty in gaining muscle. ([Location 5497](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5497)) - Tags: [[blue]] - Older people in particular should try to keep track of their lean mass, such as via a body-composition-measuring scale (or better yet, DEXA scan), and adjust their protein intake upwards if lean mass declines. ([Location 5500](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5500)) - Tags: [[blue]] - Multiple studies suggest that the more protein we consume, in general, the better. A large prospective study called the Healthy Aging and Body Composition Study, with more than two thousand elderly subjects, found that those who ate the most protein (about 18 percent of caloric intake) kept more of their lean body mass over three years than those in the lowest quintile of protein consumption (10 percent of calories). The difference was significant: the low-protein group lost 40 percent more muscle than the high-protein group. You could make the case that protein is a performance-enhancing macronutrient. Other studies have found that boosting protein intake even moderately above the RDA can slow the progressive loss of muscle mass in older people, including patients with heart failure and cachexia (wasting). Adding thirty grams of milk protein to the diet of frail elderly people, in another study, significantly improved their physical performance. ([Location 5520](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5520)) - Tags: [[blue]] - Beyond its role in building muscle, protein may have beneficial effects on our metabolism. One study found that giving elderly people supplements containing essential amino acids (that is, mimicking some effects of increasing dietary protein) lowered their levels of liver fat and circulating triglycerides. Another study in men with type 2 diabetes found that doubling their protein intake from 15 to 30 percent of total calories, while cutting carbohydrates by half, improved their insulin sensitivity and glucose control. Eating protein also helps us feel satiated, inhibiting the release of the hunger-inducing hormone ghrelin, so we eat fewer calories overall. ([Location 5527](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5527)) - Tags: [[blue]] - In case my point here isn’t clear enough, let me restate it: don’t ignore protein. It’s the one macronutrient that is absolutely essential to our goals. There’s no minimum requirement for carbohydrates or fats (in practical terms), but if you shortchange protein, you will most certainly pay a price, particularly as you age. ([Location 5532](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5532)) - Tags: [[blue]] - While carbohydrates are primarily a source of fuel and amino acids are primarily building blocks, fats are both. They are very efficient fuel for oxidation (think: slow-burning logs) and also the building blocks for many of our hormones (in the form of cholesterol) and cell membranes. Eating the right mix of fats can help maintain metabolic balance, but it is also important for the health of our brain, much of which is composed of fatty acids. ([Location 5541](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5541)) - Tags: [[blue]] - There are (broadly) three types of fats: saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA).[*9] The differences between these have to do with differences in their chemical structure; a “saturated” fat simply has more hydrogen atoms attached to its carbon chain.[*10] Within PUFA, we make one more important distinction, which is to separate the omega-6 from the omega-3 variants (also a chemical distinction having to do with the position of the first double bond). We can further subdivide omega-3 PUFA into marine (EPA, DHA) and nonmarine sources (ALA). Salmon and other oil-rich seafood provide the former, nuts and flaxseed the latter. ([Location 5545](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5545)) - Tags: [[blue]] - The key thing to remember—and somehow this is almost always overlooked—is that virtually no food belongs to just one group of fats. Olive oil and safflower oil might be as close as you can get to a pure monounsaturated fat, while palm and coconut oil might be as close as you can get to a pure saturated fat, but all foods that contain fats typically contain all three categories of fat: PUFA, MUFA, and SFA. Even a ribeye steak contains a lot of monounsaturated fats. ([Location 5552](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5552)) - Tags: [[blue]] - From our empirical observations and what I consider the most relevant literature, which is less than perfect, we try to boost MUFA closer to 50–55 percent, while cutting SFA down to 15–20 percent and adjusting total PUFA to fill the gap. We also boost EPA and DHA, those fatty acids that are likely important to brain and cardiovascular health, with marine fat sources and/or supplementation. We titrate the level of EPA and DHA in our patients’ diets by measuring the amount of each found in the membranes of their red blood cells (RBC), using a specialized but readily available blood test.[*11] Our target depends on a person’s APOE genotype and other risk factors for neurodegenerative and cardiovascular disease, but for most patients the range we look for is between 8 and 12 percent of RBC membrane composed of EPA and DHA. Putting all these changes into practice typically means eating more olive oil and avocados and nuts, cutting back on (but not necessarily eliminating) things like butter and lard, and reducing the omega-6-rich corn, soybean, and sunflower oils—while also looking for ways to increase high-omega-3 marine PUFAs from sources such as salmon and anchovies.[*12] ([Location 5559](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5559)) - Tags: [[blue]] - MUFA seems to be the “best” fat of the bunch (based on PREDIMED and the Lyon Heart study), and after that the meta-analyses suggest PUFA has a slight advantage over SFA. But beyond that, we are on our own. ([Location 5603](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5603)) - Tags: [[blue]] - frequent longer-term fasting has enough negatives attached to it that I am reluctant to use it in all but the most metabolically sick patients. The jury is still out on the utility of infrequent (e.g., yearly) prolonged fasts. ([Location 5623](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5623)) - Tags: [[blue]] - There is no denying that some good things happen when we are not eating. Insulin drops dramatically because there are no incoming calories to trigger an insulin response. The liver is emptied of fat in fairly short order. Over time, within three days or so, the body enters a state called “starvation ketosis,” where fat stores are mobilized to fulfill the need for energy—yet at the same time, as I often noticed when I was undergoing regular lengthy fasts, hunger virtually disappears. This paradoxical phenomenon is likely due to the ultrahigh levels of ketones that this state produces, which tamp down feelings of hunger. Fasting over long periods also turns down mTOR, the pro-growth and pro-aging pathway we discussed in chapter 5. This would also be desirable, one might think, at least for some tissues. At the same time, lack of nutrients accelerates autophagy, the cellular “recycling” process that helps our cells become more resilient, and it activates FOXO, the cellular repair genes that may help centenarians live so long. In short, fasting triggers many of the physiological and cellular mechanisms that we want to see. ([Location 5625](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5625)) - Tags: [[blue]] - in my view sixteen hours without food simply isn’t long enough to activate autophagy or inhibit chronic mTOR elevation, or engage any of the other longer-term benefits of fasting that we would want to obtain. ([Location 5659](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5659)) - Tags: [[blue]] - Taken together, this combo of too little protein and too many calories can have the exact opposite effect we want: gaining fat and losing lean body mass. In my clinical experience, this result is quite common. ([Location 5665](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5665)) - Tags: [[blue]] - One small but revealing study found that subjects on an alternate-day fasting diet did lose weight—but they also lost more lean mass (i.e., muscle) than subjects who simply ate 25 percent fewer calories every day. ([Location 5676](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5676)) - Tags: [[blue]] - fasting can still prove useful sometimes, in some patients—generally, patients for whom no other dietary intervention has worked. ([Location 5688](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5688)) - Tags: [[blue]] - Fasting had effectively reset or rebooted his crashed metabolism in a way that no other dietary intervention was able to achieve. Because it has such deleterious effects on muscle mass, I only use it in hard-to-fix patients like Tom. Tom was so overweight to begin with that he could tolerate the loss of muscle because he was losing so much fat at the same time. But most people can’t safely lose muscle mass, so fasting is a tool that we can only really use in extremis, when there are no other viable options. ([Location 5721](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5721)) - Tags: [[blue]] - I once believed that diet and nutrition could cure almost all ills, but I no longer feel that strongly about it. Nutritional biochemistry is an important component of our tactics, but it is not the only path to longevity, or even the most powerful one. I see it more as a rescue tactic, particularly for patients like Eduardo and Tom, with really severe metabolic problems such as NAFLD and type 2 diabetes. It is also essential for older people who need to build or maintain muscle mass. But its power to leverage increased lifespan and healthspan is more limited. Bad nutrition can hurt us more than good nutrition can help us. If you’re already metabolically healthy, nutritional interventions can only do so much. ([Location 5727](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5727)) - Tags: [[blue]] - Protein is actually the most important macronutrient, the one macro that should not be compromised. Remember, most people will be overnourished—but also undermuscled. It is counterproductive for them to limit calories at the expense of protein and hence muscle mass. ([Location 5739](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5739)) - Tags: [[blue]] - We now know that chronic sleep debt is a far more insidious killer than the acute sleep deprivation that results in falling asleep at stop signs. Many studies have found powerful associations between insufficient sleep (less than seven hours a night, on average) and adverse health outcomes ranging from increased susceptibility to the common cold to dying of a heart attack. Poor sleep dramatically increases one’s propensity for metabolic dysfunction, up to and including type 2 diabetes, and it can wreak havoc with the body’s hormonal balance. ([Location 5849](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5849)) - Tags: [[blue]] - As important as sleep is for the body, it may even be more so for the brain. Good sleep, in terms of not only quantity but quality, is critical to our cognitive function, our memory, and even our emotional equilibrium. We feel better, in every way, after a night of good sleep. Even while we are unconscious, our brain is still working, processing thoughts and memories and emotions (hence, dreams). It even cleans itself, in a manner similar to a city sweeping the streets. Relatedly, there is a growing body of evidence that sleeping well is essential to preserving our cognition as we age and staving off Alzheimer’s disease. ([Location 5854](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5854)) - Tags: [[blue]] - many, many studies have confirmed what your mother told you: We need to sleep about seven and a half to eight and a half hours a night. There is even some evidence, from studies conducted in dark caves, that our eight-ish-hour sleep cycle may be hard-wired to some extent, suggesting that this requirement is non-negotiable. Getting significantly less sleep than this, or significantly more, will almost inevitably cause problems in the long run. ([Location 5898](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5898)) - Tags: [[blue]] - Good sleep is like a performance-enhancing drug. In one study, Stanford basketball players were encouraged to strive for ten hours of sleep per day, with or without naps, and to abstain from alcohol or caffeine. After five weeks, their shooting accuracy had improved by 9 percent, and their sprint times had also gotten faster.[*1] LeBron James makes sleep a key part of his recovery routine, always trying for nine and sometimes ten hours of sleep per night, plus a daily nap. “When you get in that good sleep, you just wake up, and you feel fresh,” he has said. “You don’t need an alarm clock. You just feel like, okay, I can tackle this day at the highest level that you can get to.” ([Location 5906](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5906)) - Tags: [[blue]] - poor sleep wreaks havoc on our metabolism. Even in the short term, sleep deprivation can cause profound insulin resistance. Sleep researcher Eve van Cauter of the University of Chicago subjected healthy young people to severely restricted sleep, just 4.5 hours a night, and found that after four days they had the elevated insulin levels of obese middle-aged diabetics and, worse yet, approximately a 50 percent reduction in their capacity for glucose disposal. This turns out to be one of the most consistent findings in all of sleep research. No fewer than nine different studies have found that sleep deprivation increases insulin resistance by up to a third. Very rarely in medicine do we see such consistent findings, with experimental evidence confirming the epidemiology so powerfully, so it’s worth paying attention. It seems quite clear that poor or inadequate sleep can help tilt us into metabolic dysfunction. ([Location 5938](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5938)) - Tags: [[blue]] - long sleep is also a sign of problems. People who sleep eleven hours or more nightly have a nearly 50 percent higher risk of all-cause mortality, likely because long sleep = poor quality sleep, but it may also reflect an underlying illness. ([Location 5947](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5947)) - Tags: [[blue]] - poor sleep has much the same effect, putting the sympathetic nervous system on permanent alert; we get stuck in fight-or-flight mode, and our blood pressure and heart rate remain elevated. This, in turn, multiplies the stress placed on our vasculature. I’ve noticed this myself, via some of the self-tracking devices that I like to play with: During a night of poor sleep, my resting heart rate will be higher (bad), and my heart rate variability will be lower (also bad). ([Location 5971](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5971)) - Tags: [[blue]] - Sleep plays a major role in brain health, especially as we get older, not only in terms of daily cognitive function but also in terms of our long-term cognitive health, a crucial pillar of healthspan. ([Location 5988](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5988)) - Tags: [[blue]] - good sleep is essential to long-term brain health—and how bad sleep inflicts major damage. Poor sleep was long considered to be one of the first symptoms of incipient Alzheimer’s disease. Subsequent research, however, has pointed to chronic bad sleep as a powerful potential cause of Alzheimer’s disease and dementia. Sleep, it turns out, is as crucial to maintaining brain health as it is to brain function. ([Location 5991](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=5991)) - Tags: [[blue]] - Both REM and deep NREM sleep (which we’ll call “deep sleep” for convenience) are crucial to learning and memory, but in different ways. Deep sleep is when the brain clears out its cache of short-term memories in the hippocampus and selects the important ones for long-term storage in the cortex, helping us to store and reinforce our most important memories of the day. Researchers have observed a direct, linear relationship between how much deep sleep we get in a given night and how well we will perform on a memory test the next day. When we are young, REM sleep is important in helping our brains grow and develop. Even while we are asleep, our brain is forming new connections, expanding our neural network; this is why younger people spend more time in REM. In adulthood, our REM sleep time tends to plateau, but it remains important, especially for creativity and problem solving. By generating seemingly random associations between facts and memories, and by sorting out the promising connections from the meaningless ones, the brain can often come up with solutions to problems that stumped us the previous day. Research has also found that REM sleep is especially helpful with what is called procedural memory, learning new ways of moving the body, for athletes and for musicians. ([Location 6016](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6016)) - Tags: [[blue]] - A few years ago, researchers in Rochester discovered that while we are in deep sleep, the brain activates a kind of internal waste disposal system that allows cerebrospinal fluid to flood in between the neurons and sweep away intercellular junk; while this happens, the neurons themselves pull back to allow this to happen, the way city residents are sometimes required to move their cars to allow street sweepers to pass through. This cleansing process flushes out detritus, including both amyloid-beta and tau, the two proteins linked to neurodegeneration. But if we do not spend enough time in deep sleep, the system cannot work as effectively, and amyloid and tau build up among the neurons. Broader studies have found that people who have generally slept less than seven hours per night, over decades, tend to have much more amyloid-beta and tau built up in their brains than people who sleep for seven hours or more per night. Tau, the protein that collects in “tangles” inside unhealthy neurons, is itself correlated to sleep disturbances in cognitively normal people and in those with MCI, or mild cognitive impairment, an early stage of dementia. ([Location 6039](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6039)) - Tags: [[blue]] - sleep disturbances, in turn, may help create conditions that allow Alzheimer’s to progress. Insomnia affects 30 to 50 percent of older adults, and there is ample research showing that sleep disturbances often precede the diagnosis of dementia by several years; they may even appear before cognitive decline. One study linked poor sleep quality in cognitively normal people with the onset of cognitive impairment—just one year later. ([Location 6051](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6051)) - Tags: [[blue]] - superior sleep quality in older adults is associated with a lower risk of developing MCI and Alzheimer’s disease, and with maintaining a higher level of cognitive function. Successfully treating sleep disturbance may delay the age of onset into MCI—by about eleven years, according to one study—and may improve cognitive function in patients already diagnosed with Alzheimer’s disease. ([Location 6054](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6054)) - Tags: [[blue]] - More research points to the forties and sixties as the decades of life when deep sleep is especially important for the prevention of Alzheimer’s disease. People who have slept less during those decades seem to be at higher risk of developing dementia later on. Thus, good sleep in middle age appears to be especially important for maintaining cognitive health. ([Location 6070](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6070)) - Tags: [[blue]] - One study found that Ambien actually decreased slow-wave sleep (deep sleep) without increasing REM, meaning people who take it are basically trading high-quality sleep for low-quality sleep. Meanwhile, Ambien has the well-publicized side effect that some users have been known to walk around and do things while “sleeping,” leading to all sorts of problems. ([Location 6089](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6089)) - Tags: [[blue]] - One drug that we do find helpful for assisting with sleep is trazodone, a fairly old anti-depressant (approved in 1981) that never really took off. At the doses used to treat depression, two hundred to three hundred milligrams per day, it had the unwanted side effect of causing users to fall asleep. But one man’s trash is another man’s treasure. That side effect is what we want in a sleep medication, especially if it also improves sleep architecture, which is exactly what trazodone does—and most other sleep meds do not.[*4] We typically use it at much lower doses, from one hundred milligrams down to fifty milligrams or even less; the optimal dosing depends on the individual, but the goal is to find the amount that improves their sleep quality without next-day grogginess. (We have also had good results with the supplement ashwagandha.) ([Location 6104](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6104)) - Tags: [[blue]] - The first step in this process echoes the first step in a recovery program: we must renounce our “addiction” to chronic sleep deprivation and admit that we need more sleep, in sufficient quality and quantity. We are giving ourselves permission to sleep. ([Location 6116](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6116)) - Tags: [[blue]] - The next step is to assess your own sleep habits. There are numerous sleep trackers out there that can give you a pretty good idea about how well you are actually sleeping. They work by measuring variables such as heart rate, heart rate variability (HRV), movement, breathing rate, and more. These inputs are used to estimate sleep duration and stage and do so with reasonable (but not perfect) accuracy. While I’ve found these to be quite helpful in optimizing my own sleep, some people get worked up over poor sleep scores—which can further impair their sleep. In these situations I insist that my patients take a tracker holiday for a few months. It’s also worth reiterating that long sleep is also often a sign not only of poor sleep quality, but other potential health problems. ([Location 6119](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6119)) - Tags: [[blue]] - In parallel, you should make a longer-term assessment of your sleep quality over the last month. Probably the best-validated sleep questionnaire is the Pittsburgh Sleep Quality Index, a four-page document that asks questions about your sleep patterns over the last month: for example, how often you have had trouble falling asleep within thirty minutes, have woken up during the night, have had difficulty breathing (i.e., snoring), have had trouble staying awake during the day (such as while driving), or have “felt a lack of enthusiasm for getting things done.” ([Location 6125](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6125)) - Tags: [[blue]] - you must create an environment for yourself that is conducive to sleeping well. The first requirement for good sleep is darkness. Light is the enemy of sleep, full stop. Thus, you want to make your bedroom itself as dark as possible—installing room-darkening curtains if you live somewhere with a lot of outdoor evening light, and removing all light sources in the bedroom, even down to electronic equipment like TVs and cable boxes and such. Their little pinpoint LEDs are more than bright enough to keep you from sleeping well. Digital clocks are especially deadly, not only because of their bright numerals but also because if you wake up and see that it’s 3:31 a.m., you might start worrying about your 7 a.m. flight and never fall back asleep. ([Location 6164](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6164)) - Tags: [[blue]] - I am increasingly persuaded that our 24-7 addiction to screens and social media is perhaps our most destructive habit, not only to our ability to sleep but to our mental health in general. So I banish those from my evenings (or at least, I try to). Turn off the computer and put away your phone at least an hour before bedtime. Do NOT bring your laptop or phone into bed with you. ([Location 6184](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6184)) - Tags: [[blue]] - Another very important environmental factor is temperature. Many people associate sleep with warmth, but in fact the opposite is true: One of the signal events as we are falling asleep is that our body temperature drops by about one degree Celsius. To help that happen, try to keep your bedroom cool—around sixty-five degrees Fahrenheit seems to be optimal. A warm bath before bed may actually help with this process, not only because the bath itself is relaxing but also because when we get out of the bath and climb into our cool bed, our core temperature drops, which signals to our brain that it is time to fall asleep. (There are also a variety of cooling mattresses and mattress toppers out there that could help people who like to sleep cool.) ([Location 6187](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6187)) - Tags: [[blue]] - Coffee is not a solution to the problem of poor sleep, especially if consumed to excess or (especially) at the wrong time. Most people think of caffeine as a stimulant that somehow gives us energy, but actually it functions more as a sleep blocker. It works by inhibiting the receptor for a chemical called adenosine, which normally helps us go to sleep every night. Over the course of the day, adenosine builds up in our brain, creating what scientists call “sleep pressure,” or the drive to sleep. We may be tired and needing sleep, but if we ingest caffeine it effectively takes the phone off the hook, so our brain never gets the message. This is obviously helpful in the morning, particularly if our “chronotype” is telling us we should still be asleep at 6 a.m. But the half-life of caffeine in the body is up to six hours, so if we drink a cup of coffee at noon, we will still have half a cup’s worth of caffeine in our system at 6 p.m. Now multiply this by the number of cups of coffee you drink in a day and work forward from the time of your last cup. If you down one last double espresso at 3 p.m., you will still have a full shot’s worth of caffeine in your system at 9. What you won’t have, most likely, is much of an urge to fall asleep anytime soon. ([Location 6206](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6206)) - Tags: [[blue]] - Another way to help cultivate sleep pressure is via exercise, particularly sustained endurance exercise (e.g., zone 2), ideally not within two or three hours of bedtime. My patients often find that a thirty-minute zone 2 session can do wonders for their ability to fall asleep. Even better is exercise that entails some exposure to sunlight (i.e., outdoors). While blue light late in the evening can interfere with sleep, a half-hour dose of strong daylight, during the day, helps keep our circadian cycle on track, setting us up for a good night of sleep. ([Location 6225](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6225)) - Tags: [[blue]] - The following are some rules or suggestions that I try to follow to help me sleep better. These are not magic bullets but are mostly about creating better conditions for sleeping and letting your brain and body do the rest. The closer you can come to these operating conditions, the better your sleep will be. Of course, I’m not suggesting that it’s necessary to do all these things—in general, it’s best not to obsess over sleep. But the more of these you can check off, the better your odds of a good night of sleep. Don’t drink any alcohol, period—and if you absolutely, positively must, limit yourself to one drink before about 6 p.m. Alcohol probably impairs sleep quality more than any other factor we can control. Don’t confuse the drowsiness it produces with quality sleep. Don’t eat anything less than three hours before bedtime—and ideally longer. It’s best to go to bed with just a little bit of hunger (although being ravenous can be distracting.) Abstain from stimulating electronics, beginning two hours before bed. Try to avoid anything involving a screen if you’re having trouble falling asleep. If you must, use a setting that reduces the blue light from your screen. For at least one hour before bed, if not more, avoid doing anything that is anxiety-producing or stimulating, such as reading work email or, God help you, checking social media. These get the ruminative, worry-prone areas of our brain humming, which is not what you want. For folks who have access, spend time in a sauna or hot tub prior to bed. Once you get into the cool bed, your lowering body temperature will signal to your brain that it’s time to sleep. (A hot bath or shower works too.) The room should be cool, ideally in the midsixties. The bed should be cool too. Use a “cool” mattress or one of the many bed-cooling devices out there. These are also great tools for couples who prefer different temperatures at night, since both sides of the mattress can be controlled individually. Darken the room completely. Make it dark enough that you can’t see your hand in front of your face with your eyes open, if possible. If that is not achievable, use an eye shade. I use a silky one called Alaska Bear that costs about $8 and works better than the fancier versions I’ve tried. Give yourself enough time to sleep—what sleep scientists call a sleep opportunity. This means going to bed at least eight hours before you need to wake up, preferably nine. If you don’t even give yourself a chance to get adequate sleep, then the rest of this chapter is moot. Fix your wake-up time—and don’t deviate from it, even on weekends. If you need flexibility, you can vary your bedtime, but make it a priority to budget for at least eight hours in bed each night. Don’t obsess over your sleep, especially if you’re having problems. If you need an alarm clock, make sure it’s turned away from you so you can’t see the numbers. Clock-watching makes it harder to fall asleep. And if you find yourself worrying about poor… ([Location 6239](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6239)) - Tags: [[blue]] - I also want to make an important distinction between trauma and adversity. They are not the same. I am not suggesting that it is ideal for children to grow up without experiencing any adversity at all, which sometimes seems to be a primary goal of modern parenting. Many stressors can be beneficial, while others are not. ([Location 6478](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6478)) - Tags: [[blue]] - Just as an aside, a 2019 study provides an elegant demonstration of the principle that setbacks can be net positive. The researchers looked at junior scientists who had applied for NIH grants and separated them into two groups: One group had scored just above the threshold for funding, while the other had scored just below the funding line, meaning their grants were not funded. While the near-miss group were more likely to drop out of science in the immediate aftermath, those who stuck with it eventually outperformed their peers who had received funding on their first try. The early setback had not impaired their careers but may have had an opposite effect. ([Location 6485](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6485)) - Tags: [[blue]] - Our Medicine 3.0 thesis is that if we address our emotional health, and do so early on, we will have a better chance of avoiding clinical mental health issues such as depression and chronic anxiety—and our overall health will benefit as well. ([Location 6521](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6521)) - Tags: [[blue]] - As Terry had written: “Family pathology rolls from generation to generation like a fire in the woods taking down everything in its path until one person, in one generation, has the courage to turn and face the flames. That person brings peace to his ancestors and spares the children that follow.” ([Location 6566](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6566)) - Tags: [[blue]] - The way in which I do this, the tools that I use, derive from a school of psychology known as dialectical behavior therapy, or DBT, developed in the 1990s by Marsha Linehan. Based on the principles of cognitive behavioral therapy, which seeks to teach patients new ways of thinking about or acting on their problems, DBT was developed to help individuals with more serious and potentially dangerous issues, such as an inability to regulate their emotions and a propensity to harm themselves or even attempt suicide. These people are lumped into something called borderline personality disorder, which is a bit of a catch-all diagnosis, but DBT has also been found to be helpful in patients with less dramatic and dangerous emotional health issues, a category that encompasses many more of us. I liken it, naturally, to Formula One: the race circuit is a high-stakes, high-risk laboratory where car manufacturers develop and test technologies that trickle down to our everyday street cars. ([Location 6713](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6713)) - Tags: [[blue]] - DBT consists of four pillars joined by one overarching theme. The overarching theme is mindfulness, which gives you the ability to work through the other four: emotional regulation (getting control over our emotions), distress tolerance (our ability to handle emotional stressors), interpersonal effectiveness (how well we make our needs and feelings known to others), and self-management (taking care of ourselves, beginning with basic tasks like getting up in time to go to work or school). The first two—emotion regulation and distress tolerance—are the ones I need to work on most, so that’s where I’ve focused with my DBT therapist, Andy White. ([Location 6725](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6725)) - Tags: [[blue]] - too, was an enormous revelation to me. Simply put, I experience less pain because I am able to recognize when the source of that pain is inside my own head. This was not an original insight, but it was nevertheless profound. I was about 2,500 years behind the Buddha, who said that “your worst enemy cannot harm you as much as your own unguarded thoughts.” Seneca improved on that in the first century AD, observing that “we suffer more often in imagination than in reality.” And later, in the sixteenth century, Shakespeare’s Hamlet noted, “There is nothing either good or bad, but thinking makes it so.” ([Location 6756](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6756)) - Tags: [[blue]] - DBT teaches a variety of techniques to enable people to maintain and improve their distress tolerance, and to recognize and cope with their emotions—and not be controlled by them, as I had been for so long. One simple tactic that I use to cope with mounting emotional distress is inducing an abrupt sensory change—typically, by throwing ice water on my face or, if I’m really struggling, taking a cold shower or stepping into an ice bath. This simple intervention stimulates an important cranial nerve, the vagus nerve, which causes our heart rate and respiratory rate to slow and switches us into a calm, parasympathetic mode (and out of our fight-or-flight sympathetic mode). Interventions like these are often enough to help refocus and think about a situation more calmly and constructively. Another technique I have grown very fond of is slow, deep breathing: four seconds to inhale, six seconds to exhale. Repeat. As the breath goes, the nervous system follows. ([Location 6779](https://readwise.io/to_kindle?action=open&asin=B0B1BTJLJN&location=6779)) - Tags: [[blue]]