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Peter Attia, MD, Outlive

Sep 09, 202450 min read

Outlive

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Highlights

  • INTRODUCTION
  • whizzing
    • Note: move quickly through the air with a whirring sound.
  • CHAPTER 1 The Long Game
  • Each one of the Horsemen is cumulative, the product of multiple risk factors adding up and compounding over time. Many of these same individual risk factors, it turns out, are relatively easy to reduce or even eliminate. Even better, they share certain features or drivers in common that make them vulnerable to some of the same tactics and behavioral changes we will discuss in this book. Medicine’s biggest failing is in attempting to treat all these conditions at the wrong end of the timescale—after they are entrenched—rather than before they take root. As a result, we ignore important warning signs and miss opportunities to intervene at a point where we still have a chance to beat back these diseases, improve health, and potentially extend lifespan.
  • 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
  • EKG
    • Note: Electrocardiogram. From Google (Wikipedia): “Electrocardiography is the process of producing an electrocardiogram, a recording of the heart’s electrical activity through repeated cardiac cycles. It is an electrogram of the heart which is a graph of voltage versus time of the electrical activity of the heart using electrodes placed on the skin.”
  • pulmonary embolism
    • Note: From Mayo Clinic: “A pulmonary embolism (PE) occurs when a blood clot gets stuck in an artery in the lung, blocking blood flow to part of the lung.”
  • meted out
    • Note: From Merriam Webster. To give out or distribute something.
  • 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.
  • duck out
    • Note: From Merriam Webster: “To leave suddenly and usually without telling anyone that one is leaving. We ducked out after the first act of the play. often + on or of. They ducked out on us without even saying goodbye.”
  • 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.
  • notching
    • Note: Score or achieve something.
  • This is what happened to a hapless mythical Greek named Tithonus, who asked the gods for eternal life. To his joy, the gods granted his wish. But because he forgot to ask for eternal youth as well, his body continued to decay. Oops.
  • 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.
  • 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
  • Healthspan is typically defined as the period of life when we are free from disability or disease
  • the only way to create a better future for yourself—to set yourself on a better trajectory—is to start thinking about it and taking action now.
    • Note: One of Peter Attia’s core principles.
  • One of the main obstacles in anyone’s quest for longevity is the fact that the skills that my colleagues and I acquired during our medical training have proved to be far more effective against fast death than slow death. We learned to fix broken bones, wipe out infections with powerful antibiotics, support and even replace damaged organs, and decompress serious spine or brain injuries. We had an amazing ability to save lives and restore full function to broken bodies, even reviving patients who were nearly dead. But we were markedly less successful at helping our patients with chronic conditions, such as cancer, cardiovascular disease, or neurological disease, evade slow death. We could relieve their symptoms, and often delay the end slightly, but it didn’t seem as if we could reset the clock the way we could with acute problems.
  • The problem is not that we aren’t trying. Modern medicine has thrown an unbelievable amount of effort and resources at each of these diseases. But our progress has been less than stellar, with the possible exception of cardiovascular disease, where we have cut mortality rates by two-thirds in the industrialized world in about sixty years (although there’s more yet to do, as we will see). Death rates from cancer, on the other hand, have hardly budged in the more than fifty years since the War on Cancer was declared, despite hundreds of billions of dollars’ worth of public and private spending on research. Type 2 diabetes remains a raging public health crisis, showing no sign of abating, and Alzheimer’s disease and related neurodegenerative diseases stalk our growing elderly population, with virtually no effective treatments on the horizon.
  • While the prevalence of each of the Horsemen diseases increases sharply with age, they typically begin much earlier than we recognize, and they generally take a very long time to kill you. Even when someone dies “suddenly” of a heart attack, the disease had likely been progressing in their coronary arteries for two decades. Slow death moves even more slowly than we realize.
  • The logical conclusion is that we need to step in sooner to try to stop the Horsemen in their tracks—or better yet, prevent them altogether.
  • The standard-of-care treatment guidelines of the American Diabetes Association specify that a patient can be diagnosed with diabetes mellitus when they return a hemoglobin A1c (HbA1c) test result[*1] of 6.5 percent or higher, corresponding to an average blood glucose level of 140 mg/dL (normal is more like 100 mg/dL, or an HbA1c of 5.1 percent).
    • Note: 1. HbA1 c measures the amount of glycosylated hemoglobin in the blood, which allows us to estimate the patient’s average level of blood glucose over the past ninety days or so.
  • I believe that our goal should be to act as early as possible, to try to prevent people from developing type 2 diabetes and all the other Horsemen. We should be proactive instead of reactive in our approach. Changing that mindset must be our first step in attacking slow death. We want to delay or prevent these conditions so that we can live longer without disease, rather than lingering with disease.
  • atherosclerosis
    • Note: A disease of the arteries characterized by the deposition of plaques of fatty material on their inner walls. See also atheroma and arteriosclerosis.
  • gerontology
    • Note: The scientific study of old age, the process of aging, and the particular problems of old people.
  • 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.
  • The typical cholesterol panel that you receive and discuss at your annual physical, along with many of the underlying assumptions behind it (e.g., “good” and “bad” cholesterol), is misleading and oversimplified to the point of uselessness. It doesn’t tell us nearly enough about your actual risk of dying from heart disease—and we don’t do nearly enough to stop this killer.
  • Millions of people are suffering from a little-known and underdiagnosed liver condition that is a potential precursor to type 2 diabetes. Yet people at the early stages of this metabolic derangement will often return blood test results in the “normal” range. Unfortunately, in today’s unhealthy society, “normal” or “average” is not the same as “optimal.”
  • The metabolic derangement that leads to type 2 diabetes also helps foster and promote heart disease, cancer, and Alzheimer’s disease. Addressing our metabolic health can lower the risk of each of the Horsemen.
  • Almost all “diets” are similar: they may help some people but prove useless for most. Instead of arguing about diets, we will focus on nutritional biochemistry—how the combinations of nutrients that you eat affect your own metabolism and physiology, and how to use data and technology to come up with the best eating pattern for you.
  • 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.
  • 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.
  • My goal is to create an actionable operating manual for the practice of longevity. A guide that will help you Outlive. I hope to convince you that with enough time and effort, you can potentially extend your lifespan by a decade and your healthspan possibly by two, meaning you might hope to function like someone twenty years younger than you.
  • CHAPTER 2 Medicine 3.0
  • During one of the last trauma calls I took as a resident, a seventeen-year-old kid came in with a single stab wound in his upper abdomen, just below his xiphoid process, the little piece of cartilage at the bottom end of his sternum. He seemed to be stable when he rolled in, but then he started acting odd, becoming very anxious. A quick ultrasound suggested he might have some fluid in his pericardium, the tough fibrous sac around the heart. This was now a full-blown emergency, because if enough fluid collected in there, it would stop his heart and kill him within a minute or two. There was no time to take him up to the OR; he could easily die on the elevator ride. As he lost consciousness, I had to make a split-second decision to cut into his chest right then and there and slice open his pericardium to relieve the pressure on his heart. It was stressful and bloody, but it worked, and his vital signs soon stabilized. No doubt the procedure was hugely risky and caused him great short-term harm, but had I not done it, he might have died[…]
  • edifice
    • Note: A complex system of beliefs.
  • dissuading
    • Note: From New Oxford American Dictionary. Persuade (someone) not to take a particular course of action.
  • McKinsey originally hired me into their healthcare practice, but because of my quantitative background (I had studied applied math and mechanical engineering in college, planning to pursue a PhD in aerospace engineering), they moved me over to credit risk.
    • Note: This dude… lol
  • posh
    • Note: From New Oxford American Dictionary. Elegant or stylishly luxurious.
  • In finance and banking, understanding risk is key to survival. Great investors do not take on risk blindly; they do so with a thorough knowledge of both risk and reward.
  • The trouble began with Hippocrates. Most people are familiar with the ancient Greek’s famous dictum: “First, do no harm.” It succinctly states the physician’s primary responsibility, which is to not kill our patients or do anything that might make their condition worse instead of better. Makes sense. There are only three problems with this: (a) Hippocrates never actually said these words,[*1] (b) it’s sanctimonious bullshit, and (c) it’s unhelpful on multiple levels.
  • Risk is not something to be avoided at all costs; rather, it’s something we need to understand, analyze, and work with. Every single thing we do, in medicine and in life, is based on some calculation of risk versus reward.
  • sometimes doing nothing is the riskiest choice of all.
  • opined
    • Note: Hold and state as one’s opinion.
  • You can’t use a tool that has not yet been invented.
  • slog
    • Note: New Oxford American Dictionary. Work hard over a period of time.
  • Consider the case of poor Ignaz Semmelweis, a Viennese obstetrician who was troubled by the fact that so many new mothers were dying in the hospital where he worked. He concluded that their strange “childbed fever” might somehow be linked to the autopsies that he and his colleagues performed in the mornings, before delivering babies in the afternoons—without washing their hands in between. The existence of germs had not yet been discovered, but Semmelweis nonetheless believed that the doctors were transmitting something to these women that caused their illness. His observations were most unwelcome. His colleagues ostracized him, and Semmelweis died in an insane asylum in 1865.
  • The next step is crucial: rigorously testing that hypothesis/guess to determine whether it is correct, also known as experimenting.
  • Toward Medicine 3.0
  • 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. Atherosclerosis, for example, begins many decades before the person has a coronary “event” that could result in their death. But that event, often a heart attack, too often marks the point where treatment begins.
  • we need a new way of thinking about chronic diseases, their treatment, and how to maintain long-term health. 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.
  • The horizontal or x-axis of the graph represents your lifespan, how long you will live, while the vertical or y-axis represents a kind of sum total of your physical and cognitive function, the two age-dependent dimensions of healthspan. (Obviously, healthspan is not really quantifiable, but bear with my oversimplification.)
  • For many people, like Sophie, the last ten years of life are not a particularly happy time. They typically suffer from one or more of the Horsemen diseases and the effects of the requisite treatments. Their cognitive and physical abilities may be weakening or gone. Generally, they are unable to participate in the activities they once loved, whether that means gardening, or playing chess, or riding a bicycle, or whatever else in their life gave them joy. I call this the Marginal Decade, and for many, if not most, it is a period of diminishment and limitation.
  • Economists call this “hyperbolic discounting,” the natural tendency for people to choose immediate gratification over potential future gains, especially if those gains entail hard work.
  • You remain relatively robust until about the fifth decade of life, at which point your cognitive and physical health will likely begin a gradual but steady decline, until you die (healthspan = zero) sometime in your sixties or early seventies. This would have been a not untypical lifespan for someone born into a hunter-gatherer or primitive agrarian tribe, provided they managed to avoid early death thanks to infectious disease or another calamity.
  • in midlife, you will gradually begin to feel some changes. You will lose a bit of your youthful strength and stamina. You might notice that you occasionally forget passwords, or the names of people you meet, or the names of actors in movies you watched long ago. Your friends and peers will begin to be diagnosed with cancer, cardiovascular disease and related conditions like high blood pressure, and diabetes or prediabetes. You will attend memorial services for friends from school.
  • Moreover, when you do begin to decline, the descent is steep but relatively brief. This is called squaring the longevity curve.
    • Note: I need to learn more about this. What is “squaring the longevity curve”, exactly? And how does it look like?
  • The big mistake people often make is to conflate strategy and tactics, thinking they are the same. They are not.
  • hree-part approach to longevity: objective → strategy → tactics.
  • 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.
  • time is definitely not on our side. Every moment we are alive, our risk of disease and death is tugging at us, the way gravity pulls a long jumper toward earth.
  • 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.
  • what do we mean by “aging,” exactly? It’s not merely the passage of time, but what is happening inside us, beneath the surface, in our organs and our cells, as time passes. Entropy is working on us every single day.
  • Someone who drops dead of a heart attack did not just get sick an hour earlier. The disease was working inside them, silently and invisibly, for decades. As they grew older, their own internal defense mechanisms weakened, and disease gained the upper hand.
  • I think about healthspan and its deterioration in terms of three categories, or vectors. The first vector of deterioration is cognitive decline.
  • The second vector of deterioration is the decline and eventual loss of function of our physical body.
  • The third and final category of deterioration, I believe, has to do with emotional health.
  • 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.
  • 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.
  • lifespan and healthspan are not independent variables; they are tightly intertwined. If you increase your muscle strength and improve your cardiorespiratory fitness, you have also reduced your risk of dying from all causes by a far greater magnitude than you could achieve by taking any cocktail of medications.
  • The actions we take to improve our healthspan will almost always result in a longer lifespan.
  • “Isn’t it ironic that your entire professional life is predicated around trying to make people live longer,” she mused, “yet you’re putting no energy into being less miserable, into suffering less emotionally?” She continued: “Why would you want to live longer if you’re so unhappy?”
  • Typically, Medicine 2.0 steps in only when something is acutely wrong, like an infection or a broken bone, with short-term fixes for the immediate problem. In Medicine 3.0, our tactics must become interwoven into our daily lives. We eat, breathe, and sleep them—literally.
  • strength, stability, aerobic efficiency, and peak aerobic capacity.
    • Note: 4 important areas to focus on in the tactical domain of exercise.
  • The data are unambiguous: exercise not only delays actual death but also prevents both cognitive and physical decline, better than any other intervention.
  • 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.
  • Our second domain is nutrition.
    • Note: The second tactical domain.
  • A good strategy allows us to adopt new tactics and discard old ones in service of our objectives.
  • Next is sleep, which I and many others had ignored for far too long
    • Note: The third tactical domain.
  • 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.
  • I am now convinced that Not-Thin Peter’s biggest problem was less what he ate than how little he slept.
    • Note: I really want to know more about the relationship of metabolic health and sleep.
  • Finally, we will explore the importance of emotional health, which I believe is every bit as important a component of healthspan as the others.
    • Note: The fourth tactical domain.
  • For example, some epidemiologic studies have suggested an inverse relationship between LDL cholesterol and cancer risk. That is, people with lower LDL cholesterol appear to have a higher risk of cancer. But is the relationship causal? That’s a tricky but important question. If true, it would imply that lowering LDL cholesterol, such as with statins, increases the risk of cancer, which would obviously be bad news. Epidemiology does not tell us the direction of causality, so we turn to MR. With MR, we can look at genetic variations that result in low, medium, and high levels of LDL cholesterol. These genes are randomly occurring, so they serve as a proxy for a randomized natural experiment. By examining the relationship between the resulting LDL cholesterol levels and cancer incidence, we can answer the question without the usual confounders that plague traditional epidemiology. And lo and behold, it turns out that low LDL cholesterol does not cause cancer or increase its risk. If we use the same technique to look at the effect of LDL levels on cardiovascular disease (our dependent variable), it turns out that higher LDL cholesterol is causally linked to the development of cardiovascular disease (as we’ll discuss[…]
    • Note: Re-read and distill this.
  • My rule of thumb is that if a given intervention can be shown to extend lifespan or healthspan in multiple species spanning a billion years of evolution, for example, from worms to monkeys, then I am inclined to take it seriously.
  • In the absence of multiple, repeated, decades-long randomized clinical trials that might answer our questions with certainty, we are forced to think in terms of probabilities and risk. In a sense it’s a bit like charting an investment strategy: we are seeking the tactics that are likeliest, based on what we know now, to deliver a better-than-average return on our capital, while operating within our own individual tolerance for risk.
  • Your personal tactics should never be static, but will evolve as needed, as you journey through life with all its uncertainties—and as we learn more about the science of aging and the workings of diseases like cancer.
  • 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.
  • While your genome is immutable, at least for the near future, gene expression can be influenced by your environment and your behaviors. For example, 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.
  • According to research by Thomas Perls of Boston University and his colleagues, who run the New England Centenarian Study, one in five people in the general population will have received some type of cancer diagnosis by age seventy-two. Among centenarians, that one-in-five threshold is not reached until age one hundred, nearly three decades later. Similarly, one-quarter of the general population will have been diagnosed with clinically apparent cardiovascular disease by age seventy-five; among centenarians, that prevalence is reached only at age ninety-two. The same pattern holds for bone loss, or osteoporosis, which strikes centenarians sixteen years later than average, as well as for stroke, dementia, and hypertension: centenarians succumb to these conditions much later, if at all.
  • compression of morbidity, and it basically means shrinking or shortening the period of decline at the end of life and lengthening the period of healthy life, or healthspan.
  • The centenarians not only live longer but live longer in a healthier state, meaning many of them get to enjoy one, or two, or even three Bonus Decades. They are often healthier at ninety than the average person in their sixties. And when they do decline, their decline is typically brief. This is what we want for ourselves: to live longer with good function and without chronic disease, and with a briefer period of morbidity at the end of our lives.
  • You may have heard of this gene, which is called APOE, because of its known effect on Alzheimer’s disease risk. It codes for a protein called APOE (apolipoprotein E) that is involved in cholesterol transport and processing, and it has three variants: e2, e3, and e4. Of these, e3 is the most common by far, but having one or two copies of the e4 variant seems to multiply one’s risk of developing Alzheimer’s disease by a factor of between two and twelve. This is why I test all my patients for their APOE genotype, as we’ll discuss in chapter 9.
  • The e2 variant of APOE, on the other hand, seems to protect its carriers against dementia—and it also turns out to be very highly associated with longevity. According to a large 2019 meta-analysis of seven separate longevity studies, with a total of nearly thirty thousand participants, people who carried at least one copy of 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. That’s a pretty big swing.
  • Researchers have identified two other cholesterol-related genes, known as CETP and APOC3, that are also correlated with extreme longevity (and may explain why centenarians rarely die from heart disease). But one individual gene, or even three dozen genes, is unlikely to be responsible for centenarians’ extreme longevity and healthspan. Broader genetic studies suggest that hundreds, if not thousands, of genes could be involved, each making its own small contribution—and that there is no such thing as a “perfect” centenarian genome.
  • if we want to outlive our life expectancy and live better longer, we will have to work hard to earn it—through small, incremental changes.
  • One other possible longevity gene that has emerged, in multiple studies of centenarians worldwide, also provides some possible clues to inform our strategy. These are variants in a particular gene called FOXO3 that seem to be directly relevant to human longevity.
  • FOXO3 belongs to a family of “transcription factors,” which regulate how other genes are expressed—meaning whether they are activated or “silenced.” I think of it as rather like the cellular maintenance department. Its responsibilities are vast, encompassing a variety of cellular repair tasks, regulating metabolism, caring for stem cells, and various other kinds of housekeeping, including helping with disposal of cellular waste or junk. But it doesn’t do the heavy lifting itself, like the mopping, the scrubbing, the minor drywall repairs, and so on. Rather, it delegates the work to other, more specialized genes—its subcontractors, if you will. 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.
  • 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.
  • We must focus on delaying the onset rather than extending the duration of disease—and not just one disease but all chronic diseases. Our goal is to live longer without disease.
  • We treat diabetes as if it were unrelated to cancer and Alzheimer’s, for example, even though it is a major risk factor for both.
  • The steps we take to improve metabolic health and prevent type 2 diabetes almost certainly reduce the risk of cardiovascular disease, cancer, and Alzheimer’s simultaneously.
  • rapamycin had been demonstrated to do something that no other drug had ever done before: extend maximum lifespan in a mammal.
  • It proved to have powerful effects on the immune system, and in 1999 it was approved by the US Food and Drug Administration (FDA) to help transplant patients accept their new organs.
    • Note: In the context of rapamycin.
  • rapamycin acted directly on a very important intracellular protein complex called mTOR (pronounced “em-tor”), for “mechanistic target of rapamycin.”
  • 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.
  • The authors of the study, published in Nature, speculated that rapamycin might extend lifespan “by postponing death from cancer, by retarding mechanisms of aging, or both.”
  • ad libitum
    • Note: As much or as necessary as needed.
  • 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.
  • 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.
  • long-term severe caloric restriction is difficult if not impossible for most humans to sustain.
  • 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.
  • 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.
  • Imagine if you stopped taking out the garbage (or the recycling); your house would soon become uninhabitable. Except instead of trash bags, this cellular cleanup is carried out by specialized organelles called lysosomes, which package up the old proteins and other detritus, including pathogens, and grind them down (via enzymes) for reuse. In addition, the lysosomes also break up and destroy things called aggregates, which are clumps of damaged proteins that accumulate over time. Protein aggregates have been implicated in diseases such as Parkinson’s and Alzheimer’s disease, so getting rid of them is good; impaired autophagy has been linked to Alzheimer’s disease–related pathology and also to amyotrophic lateral sclerosis (ALS), Parkinson’s disease, and other neurodegenerative disorders. Mice who lack one specific autophagy gene succumb to neurodegeneration within two to three months.
  • By cleansing our cells of damaged proteins and other cellular junk, autophagy allows cells to run more cleanly and efficiently and helps make them more resistant to stress.
  • The Nobel Committee shares this fascination, having awarded the 2016 Nobel Prize in Physiology or Medicine to Japanese scientist Yoshinori Ohsumi for his work in elucidating the genetic regulation of autophagy.
  • Kaeberlein found that rapamycin actually seemed to improve cardiac function in older animals. “One thing that’s been surprising to me,” he says, “is the different ways that rapamycin not only seems to delay the decline but seems to make things better. There clearly seems to be, at least in some organs, a rejuvenating function.”
  • rapamycin seems to reduce systemic inflammation, perhaps by tamping down the activity of so-called senescent cells, which are “older” cells that have stopped dividing but have not died; these cells secrete a toxic cocktail of inflammatory cytokines, chemicals that can harm surrounding cells.
  • The main phase of the Dog Aging Project, involving some 600 pet dogs, is now under way; results from this larger clinical trial are expected in 2026. (Disclosure: I am a partial funder of this research.)
  • A small but growing number of people, including me and a handful of my patients, already take rapamycin off-label for its potential geroprotective benefits. I can’t speak for everyone, but taking it cyclically does appear to reduce unwanted side effects, in my experience
    • Note: I wonder where I can buy rapamycin in the Philippines.
  • Metformin has been taken by millions of people for years. Over time, researchers noticed (and studies appeared to confirm) that patients on metformin appeared to have a lower incidence of cancer than the general population. One large 2014 analysis seemed to show that diabetics on metformin actually lived longer than nondiabetics, which is striking. But none of these observations “prove” that metformin is geroprotective—hence the need for a clinical trial.
  • what we eat and how we metabolize it appear to play an outsize role in longevity.
  • 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. Source: Tchernof and DesprĂŠs (2013).
  • You have fat accumulating in many places where it should not be, such as in your liver, between your abdominal organs, even around your heart—regardless of your actual weight. But one of the first places where this overflowing fat will cause problems is in your muscle, as it worms its way in between your muscle fibers, like marbling on a steak. As this continues, microscopic fat droplets even appear inside your muscle cells. This is where insulin resistance likely begins, Gerald Shulman concludes from three decades’ worth of investigation.
  • Avoidable human misery is more often caused not so much by stupidity as by ignorance, particularly our ignorance about ourselves. —Carl Sagan
  • mottled
    • Note: From New Oxford Dictionary: Marked with spots or smears of color.
  • fessing up
    • Note: Confess or own up.
  • 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
  • According to Labcorp, a leading testing company, the acceptable range for ALT is below 33 IU/L for women and below 45 IU/L for men (although the ranges can vary from lab to lab). But “normal” is not the same as “healthy.
  • 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.
  • care about NAFLD and NASH—and you should too—because they represent the tip of the iceberg of a global epidemic of metabolic disorders, ranging from insulin resistance to type 2 diabetes.
  • even in the early stages of NAFLD, you are likely also en route to one or more of the other three Horsemen diseases (cardiovascular disease, cancer, and Alzheimer’s disease).
  • you can’t fight the Horsemen without taking on metabolic dysfunction first.
  • 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)
  • being obese means someone is at greater risk of chronic disease
  • heart attack patients often had both high fasting glucose levels and high triglycerides, as well as elevated blood pressure and abdominal obesity. The more of these boxes a patient checked, the greater their risk of cardiovascular disease.
  • 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)
    • Note: Criteria for metabolic syndrome
  • Studies have found that approximately one-third of those folks who are obese by BMI are actually metabolically healthy, by many of the same parameters used to define the metabolic syndrome (blood pressure, triglycerides, cholesterol, and fasting glucose, among others).
  • Source: Internal analysis based on data from National Institute of Diabetes and Digestive and Kidney Diseases (2021). Relative prevalence of metabolic dysfunction (“MetSyn”) across the obese and nonobese segments of the population.
  • Out of a conservatively estimated 100 million Americans who meet the criteria for the metabolic syndrome (i.e., metabolically unhealthy), almost exactly one-third are not obese.
  • upshot
    • Note: From Oxford Dictionary: the final or eventual outcome or conclusion of a discussion, action, or series of events. “the upshot of the meeting was that he was on the next plane to New York”
  • it’s not only obesity that drives bad health outcomes; it’s metabolic dysfunction.
  • One of the liver’s many important jobs is to convert this stored glycogen back to glucose and then to release it as needed to maintain blood glucose levels at a steady state, known as glucose homeostasis
  • five grams of glucose, spread out across one’s entire circulatory system, is normal, while seven grams—a teaspoon and a half—means you have diabetes
  • Even a relatively lean adult may carry ten kilograms of fat in their body, representing a whopping ninety thousand calories of stored energy.
  • fat—that is, subcutaneous fat, the layer of fat just beneath our skin—is actually the safest place to store excess energy.
  • Think of fat as acting like a kind of metabolic buffer zone, absorbing excess energy and storing it safely until it is needed.
  • 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.
    • Note: The good news here is that visceral fat is easily managed through cardiovascular exercises (which I like) such as running.
  • Individual fat-storage capacity seems to be influenced by genetic factors.
  • 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.
  • 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.)
  • stress levels and sleep, both of which affect cortisol release, are pertinent to metabolism.
  • when insulin resistance begins to develop, the train is already well down the track toward type 2 diabetes, which brings a multitude of unpleasant consequences.
  • Our slowly dawning awareness of NAFLD and NASH mirrors the emergence of the global epidemic of type 2 diabetes a century ago. Like cancer, Alzheimer’s, and heart disease, type 2 diabetes is known as a “disease of civilization,” meaning it has only come to prominence in the modern era.
  • As type 2 diabetes emerged, beginning in the early 1700s, it was at first largely a disease of the superelite, popes and artists and wealthy merchants and nobles who could afford this newly fashionable luxury food known as sugar. The composer Johann Sebastian Bach is thought to have been afflicted, among other notable personages. It also overlapped with gout, a more commonly recognized complaint of the decadent upper classes. This, as we’ll soon see, was not a coincidence.
  • Today over 11 percent of the US adult population, one in nine, has clinical type 2 diabetes, according to a 2022 CDC report, including more than 29 percent of adults over age sixty-five. Another 38 percent of US adults—more than one in three—meet at least one of the criteria for prediabetes. That means that nearly half of the population is either on the road to type 2 diabetes or already there.
  • 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.
  • 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.
  • One abundant source of calories in our present diet, fructose, also turns out to be a very powerful driver of metabolic dysfunction if consumed to excess.
  • fructose is metabolized in a manner different from other sugars. When we metabolize fructose, along with certain other types of foods, it produces large amounts of uric acid, which is best known as a cause of gout but which has also been associated with elevated blood pressure.
  • More than two decades ago, a University of Colorado nephrologist named Rick Johnson noticed that fructose consumption appeared to be an especially powerful driver not only of high blood pressure but also of fat gain. “We realized fructose was having effects that could not be explained by its calorie content,” Johnson says. The culprit seemed to be uric acid. Other mammals, and even some other primates, possess an enzyme called uricase, which helps them clear uric acid. But we humans lack this important and apparently beneficial enzyme, so uric acid builds up, with all its negative consequences.
    • Note: From Cleveland Clinic: A nephrologist is a medical doctor who specializes in diagnosing and treating kidney conditions. You should see a nephrologist if you have any signs of kidney disease or other conditions that may damage your kidneys.
  • millions of years ago, our primate ancestors migrated north from Africa into what is now Europe. Back then, Europe was lush and semitropical, but as the climate slowly cooled, the forest changed. Deciduous trees and open meadows replaced the tropical forest, and the fruit trees on which the apes depended for food began to disappear, especially the fig trees, a staple of their diets. Even worse, the apes now had to endure a new and uncomfortably cold season, which we know as “winter.” In order to survive, these apes now needed to be able to store some of the calories they did eat as fat. But storing fat did not come naturally to them because they had evolved in Africa, where food was always available. Thus, their metabolism did not prioritize fat storage.
    • Note: From Johnson and Andrews, in case I need it in the future.
  • Thanks to the miracles of modern food technology, we are almost literally swimming in a sea of fructose, especially in the form of soft drinks, but also hidden in more innocent-seeming foods like bottled salad dressing and yogurt cups.
  • 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
  • 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
  • High uric acid is an early warning sign that we need to address a patient’s metabolic health, their diet, or both.
  • 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
    • Note: How annoying!
  • 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.
  • 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).
  • As we’ll see in chapter 8, obesity and metabolic dysfunction are both powerful risk factors for cancer
  • Why wait until someone has three of the five markers? Any one of them is generally a bad sign. A Medicine 3.0 approach would be to look for the warning signs years earlier. We want to intervene before a patient actually develops metabolic syndrome.
  • In my patients, 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.
  • canary in the coal mine
    • Note: Early indication of danger or failure.
  • the insulin in someone at the early stages of insulin resistance will rise very dramatically in the first thirty minutes and then remain elevated, or even rise further, over the next hour. This postprandial insulin spike is one of the biggest early warning signs that all is not well.
  • diabetes is only one danger: Studies have found that insulin resistance itself is associated with huge increases in one’s risk of cancer (up to twelvefold), Alzheimer’s disease (fivefold), and death from cardiovascular disease (almost sixfold)
  • the logical first step in our quest to delay death is to get our metabolic house in order.
  • Changing how we exercise, what we eat, and how we sleep (see Part III) can completely turn the tables in our favor. The bad news is that these things require effort to escape the default modern environment that has conspired against our ancient (and formerly helpful) fat-storing genes, by overfeeding, undermoving, and undersleeping us all.
  • Brief Overview of Lipid-Lowering Medications While there are seven statins on the market, I tend to start with rosuvastatin (Crestor) and only pivot from that if there is some negative effect from the drug (e.g., a symptom or biomarker). My goal is aggressive: as rationalized by Peter Libby, I want to knock someone’s apoB concentration down to 20 or 30 mg/dL, about where it would be for a child. For people who can’t tolerate statins, I like to use a newer drug, called bempedoic acid (Nexletol), which manipulates a different pathway to accomplish much the same end: inhibiting cholesterol synthesis as a way to force the liver to increase LDLR and therefore LDL clearance. But where statins inhibit cholesterol synthesis throughout the body, and most notably in the muscles, bempedoic acid does so only in the liver. Therefore, it does not cause the side effects associated with statins, especially muscle soreness. The main issue with this drug is cost. Another drug called ezetimibe (Zetia) blocks absorption of cholesterol in the GI tract.[*10] That in turn depletes the amount of cholesterol in the liver, leading once again to increased LDLR expression and greater clearance of apoB particles[…]
  • There is some risk involved in action, there always is. But there is far more risk in failure to act. —Harry S. Truman
  • too much knowledge can become its own kind of curse.
  • even though my cholesterol profile is excellent, and I eat sensibly, never smoke, have normal blood pressure, and rarely drink alcohol, I’m still at risk.
  • Globally, heart disease and stroke (or cerebrovascular disease), which I lump together under the single heading of atherosclerotic cardiovascular disease, or ASCVD, represent the leading cause of death, killing an estimated 2,300 people every day in the United States, according to the CDC—more than any other cause, including cancer.
  • American women are up to ten times more likely to die from atherosclerotic disease than from breast cancer (not a typo: one in three versus one in thirty).
  • My score of 6 meant that I had more calcium in my coronary arteries than 75 to 90 percent of people my age.
  • While heart disease is the most prevalent age-related condition, it is also more easily prevented than either cancer or Alzheimer’s disease
  • In spite of how well we understand atherosclerotic disease and its progression, and how many tools we have to prevent it, it still kills more people than cancer in the United States each year, many of them completely out of the blue.
  • If one vessel is injured, others regrow to take its place, ensuring continuous blood flow throughout the body.
  • HDL particles are wrapped in a type of molecule called apolipoprotein A (or apoA), while LDL is encased in apolipoprotein B (or apoB). This distinction may seem trivial, but it goes to the very root cause of atherosclerotic disease: every single lipoprotein that contributes to atherosclerosis—not only LDL but several others[*1]—carries this apoB protein signature.
  • Each lipoprotein particle is enwrapped by one or more large molecules, called apolipoproteins, that provide structure, stability, and, most importantly solubility to the particle
  • 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
  • Even Ancel Keys, the famed nutrition scientist who was one of the founding fathers of the notion that saturated fat causes heart disease, knew this was nonsense. The problem he recognized was that much of the basic research into cholesterol and atherosclerosis had been conducted in rabbits, which have a unique ability to absorb cholesterol into their blood from their food and form atherosclerotic plaques from it; the mistake was to assume that humans also absorb dietary cholesterol as readily. “There’s no connection whatsoever between cholesterol in food and cholesterol in blood,” Keys said in a 1997 interview. “None. And we’ve known that all along. Cholesterol in the diet doesn’t matter at all unless you happen to be a chicken or a rabbit.”
  • The final myth that we need to confront is the notion that cardiovascular disease primarily strikes “old” people and that therefore we don’t need to worry much about prevention in patients who are in their twenties and thirties and forties. Not true. I’ll never forget the one-question pop quiz that Allan Sniderman dropped on me over dinner at Dulles Airport, back in 2014: “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.
  • This is what HDL particles generally do: particles tagged with apoA (HDL) can cross the endothelial barrier easily in both directions, in and out. LDL particles and other particles with the apoB protein are far more prone to getting stuck inside.
  • It is not an accident that the two biggest risk factors for heart disease, smoking and high blood pressure, cause damage to the endothelium. Smoking damages it chemically, while high blood pressure does so mechanically, but the end result is endothelial harm that, in turn, leads to greater retention of LDL. As oxidized LDL accumulates, it causes still more damage to the endothelium.
  • I’ve been saying LDL, but the key factor here is actually exposure to apoB-tagged particles, over time. The more of these particles that you have in your circulation, not only LDL but VLDL and some others, the greater the risk that some of them will penetrate the endothelium and get stuck.
  • Autopsy data from young people who died from accidents, homicides, or other noncardiovascular causes have revealed that as many as a third of sixteen- to twenty-year-olds already had actual atherosclerotic lesions or plaques in their coronary arteries when they died. As teenagers.
  • The fatty streak is a precursor of an atherosclerotic plaque, and if you are reading this and are older than fifteen or so, there is a good chance you already have some of these lurking in your arteries.
  • Source: Stary, (2003). This is a cross-sectional view of the proximal left anterior descending artery, one of the key vessels supplying blood to the heart, from a twenty-three-year-old male homicide victim. Note that he already has extensive atherosclerotic damage in the wall of this artery: a significant core (“core”) of accumulated lipids, and macrophages and foam cells (“fo”) in the subendothelial space, beginning to encroach on the lumen, the passage where blood flows. He would likely not suffer a heart attack anytime soon, but this is very advanced disease nonetheless.
  • Clearly, Not-Thin Peter was already on the road to heart disease. My waist size was on track to hit 40 by the time I turned forty, a clear sign of my metabolic dysfunction. Underneath my belt, I was likely accumulating visceral fat. I was also insulin resistant, an enormous risk driver for cardiovascular disease. Though my blood pressure was fine, I suspect it would have deteriorated fairly rapidly as I aged, as hypertension seems rampant in my family. I probably also had high levels of uric acid, which as we saw in the previous chapter is often found in the company of high blood pressure and other signs of metabolic dysfunction. All of these contribute to another necessary (but not sufficient) condition that is required for atherosclerosis to develop, and that is inflammation. The endothelial barrier, in particular, is uniquely vulnerable to damage from inflammation.
  • most atherosclerotic plaques are fairly undramatic. They grow silently and invisibly, gradually occluding the blood vessel until one day the obstruction, due to the plaque itself or a plaque-induced clot, becomes a problem.
    • Note: Oxford: Occlude means to stop, close up or obstruct.
  • atherogenic
    • Note: From Oxford: tending to promote the formation of fatty plaques in the arteries.
  • 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).
  • 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.)
  • junket
    • Note: From Oxford Languages: INFORMAL an extravagant trip or celebration, in particular one enjoyed by a government official at public expense. “the latest row over city council junkets”
  • badgered
    • Note: From Oxford Languages: repeatedly ask (someone) to do something; pester. “Tom had finally badgered her into going”
  • because of its structure, Lp(a) may be even more likely than a normal LDL particle to get stuck, with its extra cargo of lipids gone bad. Even worse, once in there, it acts partly as a thrombotic or proclotting factor, which helps to speed the formation of arterial plaques.
  • when a patient comes to me and says their father or grandfather or aunt, or all three, died of “premature” heart disease, elevated Lp(a) is the first thing I look for. It is the most prevalent hereditary risk factor for heart disease, and its danger is amplified by the fact that it is still largely flying under the radar of Medicine 2.0, although that is beginning to change.
  • if you have a history of premature heart attacks in your family, you should definitely ask for an Lp(a) test. We test every single patient for Lp(a) during their first blood draw. Because elevated Lp(a) is largely genetic, the test need only be done once (and cardiovascular disease guidelines are beginning to advise a once-a-lifetime test for it anyway).
  • atherosclerotic disease shouldn’t even be in the top ten causes of death, if we treated it more aggressively. Instead, we have over eighteen million cases of fatal atherosclerotic disease per year globally.
  • if we all maintained the apoB levels we had when we were babies, there wouldn’t be enough heart disease on the planet for people to know what it was.
  • For more on specific statin and other apoB-lowering medications, see the sidebar on this page.
    • Note: I’ll go back to this as needed.
  • Nearly all adults are coping with some degree of vascular damage, no matter how young and vital they may seem, or how pristine their arteries appear on scans. There is always damage, especially in regions of shear stress and elevated local blood pressure, such as curves and splits in the vasculature.
  • Sniderman and colleagues’ analysis found that looking at a thirty-year time frame rather than the standard ten years and taking aggressive precautionary measures early—like beginning statin treatment earlier in certain patients—could prevent hundreds of thousands more cardiac events, and by implication could save many lives.
  • risk is proportional to apoB exposure over time. The sooner we lower apoB exposure, thus lowering risk, the more the benefits compound over time—and the greater our overall risk reduction.
  • Once you understand that apoB particles—LDL, VLDL, Lp(a)—are causally linked to ASCVD, the game completely changes. The only way to stop the disease is to remove the cause, and the best time to do that is now.

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