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Outlive by Peter Attia

Outlive by Peter Attia

by Parker · 384 things on Twos

The Science and Art of Longevity
Part 1
Chapter 1: The Long Game: From Fast Death to Slow Death
“There comes a point where we need to stop just pulling people out of the river. We need to go upstream and find out why they’re falling in.” - Bishop Desmond Tutu
Cancer doesn’t care how rich you are. Or who your surgeon is, really. If it wants to find a way to kill you, it will.
Longevity does not mean living forever. Barring some major breakthrough that, somehow, someway, reverses two billion years of evolutionary history and frees us from time’s arrow, everyone and everything that is alive today will inevitably die. It’s a one-way street.
The majority of people reading this book can expect to die somewhere in their seventies or eighties, give or take, and almost all from “slow” causes. 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.
Longevity has two components. The first is how long you live, your chronological lifespan, but the second and equally important part is how well you live—the quality of your years. This is called healthspan, and it is what Tithonus forgot to ask for. Healthspan is typically defined as the period of life when we are free from disability or disease, but I find this too simplistic.
One macronutrient, in particular, demands more of our attention than most people realize: not carbs, not fat, but protein becomes critically important as we age.
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.
Striving for physical health and longevity is meaningless if we ignore our emotional health. Emotional suffering can decimate our health on all fronts, and it must be addressed.
Chapter 2: Medicine 3.0: Rethinking Medicine for the Age of Chronic Disease
“The time to repair the roof is when the sun is shining.” - John F. Kennedy
“First, do no harm.” - Hippocrates
The goal of this new medicine—which I call Medicine 3.0—is not to patch people up and get them out the door, removing their tumors and hoping for the best, but rather to prevent the tumors from appearing and spreading in the first place. Or to avoid that first heart attack. Or to divert someone from the path to Alzheimer’s disease. Our treatments, and our prevention and detection strategies, need to change to fit the nature of these diseases, with their long, slow prologues.
Medicine 3.0 places a far greater emphasis on prevention than treatment.
Medicine 3.0 considers the patient as a unique individual.
In Medicine 3.0, our starting point is the honest assessment, and acceptance, of risk—including the risk of doing nothing.
At the level of the individual patient, we should be willing to ask deeper questions of risk versus reward versus cost for this therapy—and for almost anything else we might do.
Medicine 3.0 pays far more attention to maintaining healthspan, the quality of life.
We want more out of life than simply the absence of sickness or disability. We want to be thriving, in every way, throughout the latter half of our lives.
Health insurance companies won’t pay a doctor very much to tell a patient to change the way he eats, or to monitor his blood glucose levels in order to help prevent him from developing type 2 diabetes. Yet insurance will pay for this same patient’s (very expensive) insulin after he has been diagnosed. Similarly, there’s no billing code for putting a patient on a comprehensive exercise program designed to maintain her muscle mass and sense of balance while building her resistance to injury. But if she falls and breaks her hip, then her surgery and physical therapy will be covered. Nearly all the money flows to treatment rather than prevention—and when I say “prevention,” I mean prevention of human suffering. Continuing to ignore healthspan, as we’ve been doing, not only condemns people to a sick and miserable older age but is guaranteed to bankrupt us eventually.
In Medicine 2.0, you are a passenger on the ship, being carried along somewhat passively. Medicine 3.0 demands much more from you, the patient: You must be well informed, medically literate to a reasonable degree, clear-eyed about your goals, and cognizant of the true nature of risk. You must be willing to change ingrained habits, accept new challenges, and venture outside of your comfort zone if necessary. You are always participating, never passive. You confront problems, even uncomfortable or scary ones, rather than ignoring them until it’s too late. You have skin in the game, in a very literal sense. And you make important decisions.
Chapter 3: Objective, Strategy, Tactics: A Road Map for Reading This Book
“Strategy without tactics is the slowest route to victory. Tactics without strategy is the noise before defeat.” - Sun Tzu
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.
You don’t need a strategy if your objective is, say, to avoid getting a sunburn. Your straightforward tactical options are to put on sunblock, long sleeves and pants, and perhaps a big hat, or to stay out of the sun altogether. But we need a strategy in order to live longer and better, because longevity is a far more complex problem than sunburn.
Living longer means delaying death from all four of the Horsemen. The Horsemen do have one powerful risk factor in common, and that is age. As you grow older, the risk grows exponentially that one or more of these diseases has begun to take hold in your body.
Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases.
Without an understanding of the strategy, and the science that informs it, our tactics will not mean much, and you’ll forever ride the merry-go-round of fad diets and trendy workouts and miracle supplements.
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. The second vector of deterioration is the decline and eventual loss of function of our physical body. This may precede or follow cognitive decline; there is no predetermined order. But as we grow older, frailty stalks us. We lose muscle mass and strength, along with bone density, stamina, stability, and balance, until it becomes almost impossible to carry a bag of groceries into the house. Chronic pains prevent us from doing things we once did with ease. At the same time, the inexorable progression of atherosclerotic disease might leave us gasping for breath when we walk to the end of the driveway to fetch the newspaper. The third and final category of deterioration, I believe, has to do with emotional health. Unlike the others, this one is largely independent of age; it can afflict outwardly healthy young people in their twenties, or it can creep up on you in middle age, as it did with me. Or it can descend later in life. Surveys show that happiness tends to reach its nadir in our forties (age forty-seven, to be exact), but as I learned through painful experience, middle-aged distress often has its roots much earlier, in adolescence or childhood. And we may not recognize that we are in danger until we reach a crisis point, as I did. How we deal with it has a huge bearing on our physical health, our happiness, and our very survival.
Our tactics in Medicine 3.0 fall into five broad domains: exercise, nutrition, sleep, emotional health, and exogenous molecules, meaning drugs, hormones, or supplements.
I used to prioritize nutrition over everything else, but I now consider exercise to be the most potent longevity “drug” in our arsenal, in terms of lifespan and healthspan. 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.
The best science out there says that what you eat matters, but the first-order term is how much you eat: how many calories you take into your body.
Good sleep is critical to our innate physiological repair processes, especially in the brain, while poor sleep triggers a cascade of negative downstream consequences, from insulin resistance to cognitive decline, as well as mental health issues.
Part 2
Chapter 4: Centenarians: The Older You Get, the Healthier You Have Been
“Whiskey’s a good medicine. It keeps your muscles tender.” - Richard Overton
Never inhale smoke.
The oldest person to have ever lived was 122.
Despite the fact that female centenarians outnumber males by at least four to one, the men generally scored higher on both cognitive and functional tests.
APOE can determine if you are going to get Alzheimer's disease.
APOE e2 (and no e4) were about 30 percent more likely to reach extreme old age (defined as ninety-seven for men, one hundred for women) than people with the standard e3/e3 combination. Meanwhile, those with two copies of e4, one from each parent, were 81 percent less likely to live that long, according to the analysis.
When we are slightly deprived of nutrients, or when we are exercising, FOXO3 tends to be more activated, which is what we want.
A 2007 study found that older people who were put on a regular exercise program shifted to a more youthful pattern of gene expression after six months. This suggests that genetics and environment both play a role in longevity and that it may be possible to implement interventions that replicate at least some of the centenarians’ good genetic luck.
Our goal is to live longer without disease.
I think that the centenarians’ secret comes down to one word: resilience. They are able to resist and avoid cancer and cardiovascular disease, even when they have smoked for decades. They are able to maintain ideal metabolic health, often despite a lousy diet. And they resist cognitive and physical decline long after their peers succumb. It is this resilience that we want to cultivate.
Chapter 5: Eat Less, Live Longer?: The Science of Hunger and Health
“Scientists who play by someone else’s rules don’t have much chance of making discoveries.” - Jack Horner
Rapamycin slows down the process of cellular growth and division.
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.
When resveratrol was subjected to the same sort of rigorous testing as rapamycin, as part of a National Institute on Aging program to test potential antiaging interventions, it did not extend lifespan in a similar diverse population of normal mice.
Modern experiments have demonstrated, over and over, that reducing the food intake of lab animals could lengthen their lives.
Discourses on the Sober Life by Alvise Cornaro
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.
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.
Chapter 6: The Crisis of Abundance: Can Our Ancient Genes Cope with Our Modern Diet?
“Avoidable human misery is more often caused not so much by stupidity as by ignorance, particularly our ignorance about ourselves.” - Carl Sagan
Signs of metabolic syndrome
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)
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.
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.
Insulin is all about fat storage, not fat utilization.
Evolution wants us to get fat when nutrients are abundant: the more energy we could store, in our ancestral past, the greater our chances of survival and successful reproduction. We needed to be able to endure periods of time without much food, and natural selection obliged, endowing us with genes that helped us conserve and store energy in the form of fat. That enabled our distant ancestors to survive periods of famine, cold climates, and physiologic stressors such as illness and pregnancy. But these genes have proved less advantageous in our present environment, where many people in the developed world have access to almost unlimited calories.
Fructose isn’t the only thing that creates uric acid; foods high in chemicals called purines, such as certain meats, cheeses, anchovies, and beer, also generate uric acid. This is why gout, a condition of excess uric acid, was so common among gluttonous aristocrats in the olden days (and still today).
I monitor several biomarkers related to metabolism, keeping a watchful eye for things like elevated uric acid, elevated homocysteine, chronic inflammation, and even mildly elevated ALT liver enzymes.
Chapter 7: The Ticker: Confronting—and Preventing—Heart Disease, the Deadliest Killer on the Planet
“There is some risk involved in action, there always is. But there is far more risk in failure to act.” - Harry S. Truman
Cholesterol is essential to life. It is required to produce some of the most important structures in the body, including cell membranes; hormones such as testosterone, progesterone, estrogen, and cortisol; and bile acids, which are necessary for digesting food.
Cholesterol is not a nutrient of concern for overconsumption.
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.
Atlas of Atherosclerosis Progression and Regression, by Herbert C. Stary
Evidence has piled up pointing to apoB as far more predictive of cardiovascular disease than simply LDL-C, the standard “bad cholesterol” measure. According to an analysis published in JAMA Cardiology in 2021, each standard-deviation increase in apoB raises the risk of myocardial infarction by 38 percent in patients without a history of cardiac events or a diagnosis of cardiovascular disease (i.e., primary prevention). That’s a powerful correlation. Yet even now, the American Heart Association guidelines still favor LDL-C testing instead of apoB. I have all my patients tested for apoB regularly, and you should ask for the same test the next time you see your doctor. (Don’t be waved off by nonsensical arguments about “cost”: It’s about twenty to thirty dollars.)
If you have a history of premature heart attacks in your family, you should definitely ask for an Lp(a) test.
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.
Medicine 3.0 takes a much longer view—and more importantly seeks to identify and eliminate the primary causative agent in the disease process: apoB.
The sooner you cut the head off the snake, the lower the risk that it will bite you.
Chapter 8: The Runaway Cell: New Ways to Address the Killer That Is Cancer
“You may have to fight a battle more than once to win it.” - Margaret Thatcher
We need to try to detect cancer as early as possible so that our treatments can be deployed more effectively. I advocate early, aggressive, and broad screening for my patients—such as colonoscopy (or other colorectal cancer screening) at age forty, as opposed to the standard recommendation of forty-five or fifty—because the evidence is overwhelming that it’s much easier to deal with most cancers in their early stages.
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.
Metabolic therapies, including dietary manipulations that lower insulin levels, could potentially help slow the growth of some cancers and reduce cancer risk. There is already some evidence that tinkering with metabolism can affect cancer rates. As we have seen, 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.
She had concluded that a diet that reduced insulin and IGF-1 would aid in her treatment. So she worked out a regimen that consisted primarily of leafy vegetables, olive oil, avocados, nuts, and modest amounts of protein, mostly from fish, eggs, and poultry. The diet was just as notable for what it did not contain: added sugar and refined carbohydrates. All along, she underwent frequent blood tests to make sure her insulin and IGF-1 levels stayed low, which they did.
This flies in the face of traditional practice, which is to try to get patients on chemotherapy to eat as much as they can tolerate, typically in the form of high-calorie and even high-sugar diets. The American Cancer Society suggests using ice cream “as a topping on cake.
Too many cancers are detected too late, after they’ve grown and spread via metastasis.
Out of dozens of different types of cancers, we have agreed-upon, reliable screening methods for only five: lung (for smokers), breast, prostate, colorectal, and cervical. Even so, mainstream guidelines have been waving people away from some types of early screening, such as mammography in women and blood testing for PSA, prostate-specific antigen, in men. In part this has to do with cost, and in part this has to do with the risk of false positives that may lead to unnecessary or even dangerous treatment.
Typically encouraging average-risk individuals to get a colonoscopy by age forty—and even sooner if anything in their history suggests they may be at higher risk. We then repeat the procedure as often as every two to three years, depending on the findings from the previous colonoscopy. If a sessile (flat) polyp is found, for example, we’re inclined to do it sooner than if the endoscopist finds nothing at all. Two or three years might seem like a very short window of time to repeat such an involved procedure, but colon cancer has been documented to appear within the span of as little as six months to two years after a normal colonoscopy. Better safe than sorry.
It’s possible that not screening early and frequently enough is the most dangerous option.
Other cancers that are relatively easy to spot on visual examination include skin cancer and melanomas. The pap smear for cervical cancer is another well-established, minimally invasive test that I recommend my patients do yearly.
Chapter 9: Chasing Memory: Understanding Alzheimer's Disease and Other Neurodegenerative Diseases
“The greatest obstacle to discovery is not ignorance—it is the illusion of knowledge.” - Daniel J. Boorstin
We set up another appointment for a week later to review her initial blood work. I rely as much as one can on biomarkers, so we run a comprehensive array of tests, but there are a few things that I immediately scan for when I get a new patient’s results back. Among them is their level of Lp(a), the high-risk lipoprotein that we talked about in chapter 7, along with their apoB concentration. A third thing that I always check is their APOE genotype, the gene related to Alzheimer’s disease risk that we mentioned in chapter 4.
Alzheimer’s disease is perhaps the most difficult, most intractable of the Horsemen diseases. We have a much more limited understanding of how and why it begins, and how to slow or prevent it, than we do with atherosclerosis. Unlike with cancer, we currently have no way to treat it once symptoms begin. And unlike type 2 diabetes and metabolic dysfunction, it does not appear to be readily reversible (although the jury is still out on that). This is why, almost without exception, my patients fear dementia more than any other consequence of aging, including death. They would rather die from cancer or heart disease than lose their minds, their very selves.
Plato believed that because advancing age seemingly “gives rise to all manners of forgetfulness as well as stupidity,” older men were unsuited for leadership positions requiring acumen or judgment. William Shakespeare gave us an unforgettable portrayal of an old man struggling with his failing mind in King Lear.
While those of African descent are at an overall increased risk of developing Alzheimer’s disease, for unclear reasons, APOE e4 seems to present less risk to them than to people of Caucasian, Asian, and Hispanic descent.
Alzheimer’s disease is almost twice as common in women than in men.
Other reproductive history factors, such as the number of children the woman has had, age of first menstruation, and exposure to oral contraceptives, may also have a significant impact on Alzheimer’s risk and later life cognition. And new research suggests that women are more prone to accumulate tau, the neurotoxic protein we mentioned earlier. The end result is that women have a greater age-adjusted risk of Alzheimer’s, as well as faster rates of disease progression overall, regardless of age and educational level.
While female Alzheimer’s patients outnumber men by two to one, the reverse holds true for Lewy body dementia and Parkinson’s, both of which are twice as prevalent in men. Yet Parkinson’s also appears to progress more rapidly in women than in men, for reasons that are not clear.
These are clinically validated, highly complex tests that cover every domain of cognition and memory, including executive function, attention, processing speed, verbal fluency and memory (recalling a list of words), logical memory (recalling a phrase in the middle of a paragraph), associative memory (linking a name to a face), spatial memory (location of items in a room), and semantic memory (how many animals you can name in a minute, for example).
Frontal and vascular dementias primarily affect the frontal lobe, a region of the brain responsible for executive functioning such as attention, organization, processing speed, and problem solving. So these forms of dementia rob an individual of such higher-order cognitive features. Alzheimer’s disease, on the other hand, predominantly affects the temporal lobes, so the most distinct symptoms relate to memory, language, and auditory processing (forming and comprehending speech)—although researchers are beginning to identify different possible subtypes of Alzheimer’s disease, based on which brain regions are most affected. Parkinson’s is a bit different in that it manifests primarily as a movement disorder, resulting from (in part) a deficiency in producing dopamine, a key neurotransmitter. While Alzheimer’s can be confirmed by testing for amyloid in the cerebrospinal fluid, these other forms of neurodegeneration are largely clinical diagnoses, based on testing and interpretation. Thus, they can be more subjective, but with all these conditions it is critical to identify them as soon as possible, to allow more time for preventive strategies to work.
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.
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.
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.
Dancing appears to be more effective than walking at delaying symptoms of Parkinson’s disease, possibly because it involves more complex movement.
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.
Alzheimer’s is more likely to be diagnosed in patients who have suffered a stroke, which typically results from a sudden blockage of blood flow in specific regions of the brain.
In all, some two dozen known risk factors for Alzheimer’s disease also happen to reduce blood flow, including high blood pressure, smoking, head injury, and depression, among others.
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.
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.
A woman with one copy of e4 is four times more likely to develop the disease than a man with the same genotype.
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.
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.
In Stephanie’s case, she cut out not only added sugar and highly refined carbohydrates but also alcohol. The precise role of alcohol in relation to Alzheimer’s disease remains somewhat controversial: some evidence suggests that alcohol may be slightly protective against Alzheimer’s, while other evidence shows that heavier drinking is itself a risk factor for the disease, and e4 carriers may be more susceptible to alcohol’s deleterious effects. I’m inclined to err on the side of caution, and so is Stephanie.
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.
Endurance exercise produces factors that directly target regions of the brain responsible for cognition and memory. It also helps lower inflammation and oxidative stress.
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.
There appeared to be no upper limit or “plateau” to this relationship; the greater someone’s grip strength, the lower their risk of dementia.
I now tell patients that exercise is, full stop and hands down, the best tool we have in the neurodegeneration prevention tool kit.
Sleep is also a very powerful tool against Alzheimer’s disease, as we’ll see in chapter 16. Sleep is when our brain heals itself; while we are in deep sleep our brains are essentially “cleaning house,” sweeping away intracellular waste that can build up between our neurons. Sleep disruptions and poor sleep are potential drivers of increased risk of dementia. If poor sleep is accompanied by high stress and elevated cortisol levels, as in Stephanie’s case, that acts almost as a multiplier of risk, as it contributes to insulin resistance and damaging the hippocampus at the same time. Furthermore, hypercortisolemia (excess cortisol due to stress) impairs the release of melatonin, the hormone that normally signals to our brains that it is time to go to sleep (and that may also help prevent neuronal loss and cognitive impairment). Addressing Stephanie’s difficulties with sleep was therefore urgent. Her divorce and her work situation were making it almost impossible for her to get more than four hours of uninterrupted sleep on any given night.
Another somewhat surprising risk factor that has emerged is hearing loss. Studies have found that hearing loss is clearly associated with Alzheimer’s disease, but it’s not a direct symptom. Rather, it seems hearing loss may be causally linked to cognitive decline, because folks with hearing loss tend to pull back and withdraw from interactions with others. When the brain is deprived of inputs—in this case auditory inputs—it withers. Patients with hearing loss miss out on socializing, intellectual stimulation, and feeling connected; prescribing them hearing aids may help relieve some symptoms. This is just a hypothesis for the moment, but it is being tested right now in a clinical trial called ACHIEVE (Aging and Cognitive Health Evaluation in Elders) that is currently ongoing.
Another surprising intervention that may help reduce systemic inflammation, and possibly Alzheimer’s disease risk, is brushing and flossing one’s teeth. (You heard me: Floss.) There is a growing body of research linking oral health, particularly the state of one’s gum tissue, with overall health. Researchers have found that one pathogen in particular, a microbe called P. gingivalis that commonly causes gum disease, is responsible for large increases in levels of inflammatory markers such as IL-6.
The best interpretation I can draw from the literature suggests that at least four sessions per week, of at least twenty minutes per session, at 179 degrees Fahrenheit (82 degrees Celsius) or hotter seems to be the sweet spot to reduce the risk of Alzheimer’s by about 65 percent (and the risk of ASCVD by 50 percent).
Other potential interventions that have shown some promise in studies include lowering homocysteine with B vitamins, while optimizing omega-3 fatty acids. Higher vitamin D levels have been correlated with better memory in e4/e4 patients but it’s difficult to know from the current literature if this means supplementing with vitamin D will reduce risk of AD. And as mentioned earlier, hormone replacement therapy for women during the transition from perimenopause to menopause seems promising, especially for women with at least one copy of e4.
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.
Part 3
Chapter 10: Thinking Tactically: Building a Framework of Principles That Work for You
“Absorb what is useful, discard what is useless, and add what is specifically your own.” - Bruce Lee
“Cancer, like insanity, seems to increase with the progress of civilization.” - Stanislas Tanchou
Eventually cancer, as well as heart disease, type 2 diabetes, and dementia (along with a few others), became collectively known as “diseases of civilization,” because they seemed to have spread in lockstep with the industrialization and urbanization of Europe and the United States.
This doesn’t mean that civilization is somehow “bad” and that we all need to return to a hunter-gatherer lifestyle. I would much rather live in our modern world, where I worry about losing my iPhone or missing a plane flight, than endure the rampant disease, random violence, and lawlessness that our ancestors suffered through for millennia (and that people in some parts of our world still experience).
In Medicine 3.0, we have five tactical domains that we can address in order to alter someone’s health. The first is exercise, which I consider to be by far the most potent domain in terms of its impact on both lifespan and healthspan. Of course, exercise is not just one thing, so I break it down into its components of aerobic efficiency, maximum aerobic output (VO2 max), strength, and stability, all of which we’ll discuss in more detail. Next is diet or nutrition—or as I prefer to call it, nutritional biochemistry. The third domain is sleep, which has gone underappreciated by Medicine 2.0 until relatively recently. The fourth domain encompasses a set of tools and techniques to manage and improve emotional health. Our fifth and final domain consists of the various drugs, supplements, and hormones that doctors learn about in medical school and beyond. I lump these into one bucket called exogenous molecules, meaning molecules we ingest that come from outside the body.
The obvious tactics we already know about to not die while driving: wear a seat belt, don’t text and drive (seemingly difficult for many people), and don’t drink and drive, since alcohol is a factor in up to a third of fatalities. Automotive fatality statistics also reveal that almost 30 percent of deaths involve excessive speed.
A very high proportion of fatalities occur at intersections. The most common way to be killed, as a driver, is by another car that hits yours from the left, on the driver’s side, having run a red light or traveling at high speed. It’s typically a T-bone or broadside crash, and often the driver who dies is not the one at fault.
We are most concerned about cars coming from our left, toward our driver’s side door, so we should pay special attention to that side. At busy intersections, it makes sense to look left, then right, then left again, in case we missed something the first time.
When I evaluate new patients, I’m always asking three key questions:
Are they overnourished or undernourished? That is, are they taking in too many or too few calories?
Are they undermuscled or adequately muscled?
Are they metabolically healthy or not?”
But if they are also undermuscled, which is common, we want to be careful to make sure they are still getting enough protein, since the goal is not weight loss but fat loss coupled with muscle gain.
The action part is their responsibility; not much of this stuff is easy. It requires them to change their habits and do the work.
Our only goal is to live longer and live better—to outlive.
Chapter 11: Exercise: The Most Powerful Longevity Drug
“I never won a fight in the ring; I always won in preparation.” - Muhammad Ali
More than any other tactical domain we discuss in this book, 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. (It also has benefits in terms of emotional health, although those are harder to quantify.)
If you adopt only one new set of habits based on reading this book, it must be in the realm of exercise.
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.
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.
The benefits of exercise begin with any amount of activity north of zero—even brisk walking—and go up from there.
It turns out that peak aerobic cardiorespiratory fitness, measured in terms of VO2 max, is perhaps the single most powerful marker for longevity. VO2 max represents the maximum rate at which a person can utilize oxygen. This is measured, naturally, while a person is exercising at essentially their upper limit of effort.
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.
Muscle may be almost as powerfully correlated with living longer as a high V02 max.
A ten-year observational study of roughly 4,500 subjects ages fifty and older found that those with low muscle mass were at 40 to 50 percent greater risk of mortality than controls, over the study period.
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.
In numerous randomized clinical trials, exercise-based interventions performed as well as or better than multiple classes of pharmaceutical drugs at reducing mortality from coronary heart disease, prediabetes or diabetes, and stroke.
Exercise strengthens the heart and helps maintain the circulatory system. It also improves the health of the mitochondria, the crucial little organelles that produce energy in our cells (among other things). That, in turn, improves our ability to metabolize both glucose and fat. Having more muscle mass and stronger muscles helps support and protect the body—and also maintains metabolic health, because those muscles consume energy efficiently. The list goes on and on, but simply put, exercise helps the human “machine” perform far better for longer.
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.
Both physical activity levels and muscle mass decline steeply after about age sixty-five, and then even more steeply after about seventy-five.
Seniors with the least muscle mass (also known as lean mass) are at the greatest risk of dying from all causes.
It is never too late to start; my mom did not begin lifting weights until she was sixty-seven, and it has changed her life.
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.
The Centenarian Decathlon is the ten most important physical tasks you will want to be able to do for the rest of your life.
Hike 1.5 miles on a hilly trail.
Get up off the floor under your own power, using a maximum of one arm for support.
Pick up a young child from the floor.
Carry two five-pound bags of groceries for five blocks.
Lift a twenty-pound suitcase into the overhead compartment of a plane.
Balance on one leg for thirty seconds, eyes open. (Bonus points: eyes closed, fifteen seconds.)
Have sex.
Climb four flights of stairs in three minutes.
Open a jar.
Do thirty consecutive jump-rope skips.
Swim half a mile in twenty minutes.
Walk with a thirty-pound dumbbell in each hand for one minute.
Draw back and fire a fifty-pound compound bow.
Do five pull-ups.
Climb ninety steps in two minutes (VO2 max = 32).
Dead-hang for one minute.
Drive a race car within 5 to 8 percent of the pace I can do so today.
Hike with a twenty-pound backpack for an hour.
Carry my own luggage.
Walk up a steep hill.
The full list is much longer, with more than fifty different items.
In every case, you need to be doing much more now, to armor yourself against the natural and precipitous decline in strength and aerobic capacity that you will undergo as you age.
Chapter 12: Training 101: How to Prepare for the Centenarian Decathlon
“It is impossible to produce superior performance unless you do something different from the majority.” - Sir John Templeton
The three dimensions in which we want to optimize our fitness are aerobic endurance and efficiency (aka cardio), strength, and stability.
For cardio, 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.
How we utilize different fuels, glucose and fatty acids, is critical not only to our fitness but also to our metabolic and overall health. Aerobic exercise, done in a very specific way, improves our ability to utilize glucose and especially fat as fuel.
Typically, zone 1 is a walk in the park and zone 5 (or 6, or 7) is an all-out sprint. Zone 2 is more or less the same in all training models: going at a speed slow enough that one can still maintain a conversation but fast enough that the conversation might be a little strained. It translates to aerobic activity at a pace somewhere between easy and moderate.
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. This ability to use both fuels, fat and glucose, is called “metabolic flexibility,” and it is what we want.