Outlive: The Science and Art of Longevity: The Million-Copy Bestseller

by Peter Attia

About a third of cancers can be treated with immunotherapy, and of those patients, just one-quarter will actually benefit (i.e., survive). That means that only 8 percent of potential cancer deaths could be prevented by immunotherapy,

There are two ways to do ACT. First, we can take a sample of a patient’s tumor and isolate those T cells that do recognize the tumor as a threat. These are called tumor-infiltrating lymphocytes (TILs), but there may only be a few million of them, not enough to mount a complete response against the tumor. By removing the TILs from the body and multiplying them by a factor of 1,000 or so, and then reinfusing them into the patient, we can expect to see a much better response. Alternatively, T cells can be harvested from the patient’s blood and genetically modified to recognize his or her specific tumor. Each of these approaches has advantages and disadvantages,fn4 but the interesting part is that ACT effectively means designing a new, customized anticancer drug for each individual patient. This is obviously a costly proposition, and a very labor-intensive process, but it has a lot of promise.

Between 80 and 90 percent28 of so-called complete responders to immunotherapy remain disease-free fifteen years out. This is extraordinary—far better than the short-term, five-year time horizon at which we typically declare victory in conventional cancer treatment.

The problem is that we’re still not very good at detecting cancer in these early stages—yet. 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.

Why do I generally recommend a colonoscopy before the guidelines do? Mostly because, of all the major cancers, colorectal cancer is one of the easiest to detect, with the greatest payoff in terms of risk reduction. It remains one of the top five deadliest cancers in the United States, behind lung (#1) and breast/prostate (#2 for women/men), and just ahead of pancreas (#4) and liver (#5) cancers. Of these five, though, CRC is the one we have the best shot at catching early. As it grows in a relatively accessible location, the colon, we can see it without any need for imaging techniques or a surgical biopsy. Because it is so easily observed, we understand its progression from normal tissue to polyp to tumor. Finding it early makes a huge difference, since we can effectively eliminate polyps or growths on the spot.

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. When we’re talking about cancers that develop inside the body, in our internal organs, things get trickier. We can’t see them directly, so we must rely on imaging technologies such as low-dose CT scans for lung cancer. These scans are currently recommended in smokers and former smokers, but (as always) I think they should be used more widely,

I am cautiously optimistic about the emergence of so-called “liquid biopsies” that seek to detect the presence of cancers via a blood test.

Of all the Horsemen, cancer is probably the hardest to prevent. It is probably also the one where bad luck in various forms plays the greatest role, such as in the form of accumulated somatic mutations. The only modifiable risks that really stand out in the data are smoking, insulin resistance, and obesity (all to be avoided)—and maybe pollution (air, water, etc.), but the data here are less clear. We do have some treatment options for cancer, unlike with Alzheimer’s disease (as we’ll see in the next chapter), and immunotherapy in particular has great promise. Yet our treatment and prevention strategies remain far less effective than the tools that we have to address cardiovascular disease and the spectrum of metabolic dysfunction from insulin resistance to type 2 diabetes.

It’s a simple truth that treating smaller tumors with fewer mutations is far easier than if we wait for the cancer to advance and potentially acquire mutations that help it evade our treatments. The only way to catch it early is with aggressive screening.

More than fifty years into the War on Cancer, we can finally see a path to a world where a cancer diagnosis typically means an early detection of a treatable problem rather than a late discovery of a grim one. Thanks to better screening and more effective treatments such as immunotherapy, cancer could someday become a manageable disease, perhaps no longer even qualifying as a Horseman.

Amyloid-beta is a by-product that is created when a normally occurring substance called amyloid precursor protein, or APP, a membrane protein that is found in neuronal synapses, is cleaved into three pieces. Normally, APP is split into two pieces, and everything is fine. But when APP is cut in thirds, one of the resulting fragments then becomes “misfolded,” meaning it loses its normal structure (and thus its function) and becomes chemically stickier, prone to aggregating in clumps. This is amyloid-beta, and it is clearly bad stuff.

Several dozen drugs have been developed that target amyloid-beta in one way or another. But even when they succeed in clearing amyloid or slowing its production, these drugs have yet to show benefit in improving patients’ cognitive function or slowing the progression of the disease.

Researchers from the Memory and Aging Center7 at University of California San Francisco found via PET scans that close to one in three patients with mild to moderate dementia had no evidence of amyloid in their brains. Still other studies have found only a weak correlation between the degree of amyloid burden and the severity of disease.

Lewy body dementia and Parkinson’s disease are associated with the accumulation of a neurotoxic protein called alpha-synuclein, which builds up in aggregates known as Lewy bodies (first observed by a colleague of Alois Alzheimer’s named Friedrich Lewy).

interventions around nutrition, physical activity, and cognitive training helped maintain cognitive function and prevent cognitive decline among a group of more than 1,200 at-risk older adults. Two other large European13 trials have found that multidomain lifestyle-based interventions have improved cognitive performance among at-risk adults.

Alzheimer’s disease is almost twice as common in women than in men.

Some scientists believe there may be something about menopause, and the abrupt decline in hormonal signaling, that sharply increases the risk of neurodegeneration in older women. In particular, it appears that a rapid drop in estradiol in women14 with an e4 allele is a driver of risk; that, in turn, suggests a possible role for perimenopausal hormone replacement therapy in these women.

often the disease isn’t recognized until someone is well into its early stages. This is when their symptoms go beyond occasional lapses and forgetfulness to noticeable memory problems such as forgetting common words and frequently losing important objects (forgetting passwords becomes a problem too). Friends and loved ones notice changes, and performance on cognitive tests begins to slip.

Parkinson’s may show up as subtle changes in movement patterns, a frozen facial expression, stooped posture or shuffling gait, a mild tremor, or even changes in a person’s handwriting (which may become small and cramped). Someone in the early stages of Lewy body dementia may exhibit similar physical symptoms, but with slight cognitive changes as well; both may exhibit alterations in mood, such as depression or anxiety. Something seems “off,” but it’s hard for a layperson to pinpoint. This is why an important first step with any patient who may have cognitive issues is to subject them to a grueling battery of tests.

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).

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.

The more of these networks and subnetworks that we have built up over our lifetime, via education or experience, or by developing complex skills such as speaking a foreign language or playing a musical instrument, the more resistant to cognitive decline we will tend to be. The brain can continue functioning more or less normally, even as some of these networks begin to fail. This is called “cognitive reserve,” and it has been shown to help some patients to resist the symptoms of Alzheimer’s disease. It seems to take a longer time for the disease to affect their ability to function. “People that have Alzheimer’s disease and are very cognitively engaged, and have a good backup pathway, they’re not going to decline as quickly,” Richard says. There is a parallel concept known as “movement reserve” that becomes relevant with Parkinson’s disease. People with better movement patterns, and a longer history of moving their bodies, such as trained or frequent athletes, tend to resist or slow the progression of the disease as compared to sedentary people. This is also why movement and exercise, not merely aerobic exercise but also more complex activities like boxing workouts, are a primary treatment/prevention strategy for Parkinson’s.

The evidence suggests that tasks or activities that present more varied challenges, requiring more nimble thinking and processing, are more productive at building and maintaining cognitive reserve. Simply doing a crossword puzzle every day, on the other hand, seems only to make people better at doing crossword puzzles. The same goes for movement reserve: dancing appears to be more effective than walking at delaying symptoms of Parkinson’s disease, possibly because it involves more complex movement.

In their seminal 1968 paper21 that defined Alzheimer’s disease as a common age-related condition, Blessed, Tomlinson, and Roth had also noted severe vascular damage in the brains of their deceased study subjects.

the beautiful machine that is the human brain depends on a steady supply of glucose and oxygen, delivered via a huge and delicate network of blood vessels. Even slight disruptions to this vascular network can result in a crippling or even fatal stroke. On top of this, brain cells metabolize glucose in a different way from the rest of the body; they do not depend on insulin, instead absorbing circulating glucose directly, via transporters that essentially open a gate in the cell membrane. This enables the brain to take top priority to fuel itself when blood glucose levels are low. If we lack new sources of glucose, the brain’s preferred fuel, the liver converts our fat into ketone bodies, as an alternative energy source that can sustain us for a very long time, depending on the extent of our fat stores. (Unlike muscle or liver, the brain itself does not store energy.) When our fat runs out, we will begin to consume our own muscle tissue, then our other organs, and even bone, all in order to keep the brain running at all costs. The brain is the last thing to shut off.

The dementia symptoms that we see result from a gradual reduction in blood flow, which eventually creates what he calls a “neuronal energy crisis,” which in turn triggers a cascade of unfortunate events that harms the neurons and ultimately causes neurodegeneration. The amyloid plaques and tangles come later, as a consequence rather than a cause.

Cerebral blood flow already declines naturally during the aging process, and this arterial thickening, a measure of arterial aging, could cause a further reduction in cerebral blood supply. Vascular disease is not the only culprit here either. 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 risk26 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.

Brain imaging studies reveal31 lower brain glucose metabolism, decades before the onset of other symptoms of vascular dementia. Intriguingly, this reduction appears32 to be especially dramatic in brain regions that are also affected in Alzheimer’s disease, including the parietal lobe, which is important for processing and integrating sensory information; and the hippocampus of the temporal lobe, which is critical to memory. Just like reduced blood flow, reduced glucose metabolism essentially starves these neurons of energy, provoking a cascade of responses that include inflammation, increased oxidative stress, mitochondrial dysfunction—and ultimately neurodegeneration itself.

people with the e4 allele appear to have defects in both cholesterol transport and glucose metabolism, to a degree not seen in those with e2 or e3. Even though the higher risk APOE e4 protein differs from the harmless e3 one by just one amino acid, it appears to be less efficient at moving cholesterol into and especially out of the brain.

Curiously, APOE e4 was not always a bad actor. For millions of years, all our post-primate ancestors were e4/e4. It was the original human allele.35 The e3 mutation showed up about 225,000 years ago, while e2 is a relative latecomer, arriving only in the last 10,000 years. Data from present-day populations with a high prevalence of e4 suggest that it may have been helpful for survival in environments with high levels of infectious disease: children carrying APOE e436 in Brazilian favelas are more resistant to diarrhea and have stronger cognitive development, for example. In environments where infectious disease was a leading cause of death, APOE e4 carriers may have been the lucky ones, in terms of longevity.

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,38 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.

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.

stress and anxiety-related risk41 seem more significant in females. As we’ll see in chapter 11, endurance exercise produces factors that directly target regions of the brain responsible for cognition and memory. It also helps lower inflammation and oxidative stress. 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 proxy42 for overall strength, was strongly and inversely associated with the incidence of dementia (see figure 8

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 drivers43 of increased risk of dementia.

Another somewhat surprising risk factor that has emerged is hearing loss. Studies have found that hearing loss44 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.

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. Even stranger, P. gingivalis has also shown up45 inside the brains of patients with Alzheimer’s disease, although scientists are not certain that this bacterium is directly causing dementia,

One other somewhat recent addition to my thinking on dementia (and ASCVD while we’re at it) prevention is the use of dry saunas. Until about 2019 I was very skeptical of the data linking sauna use to brain and heart health. However, the more time I spend buried in this literature, the more I become convinced by the magnitude of the benefit, the uniformity of the studies, and the mechanisms providing plausibility.

The scariest aspect of Alzheimer’s disease boils down to this: Medicine 2.0 cannot help us. At all. The point at which Medicine 2.0 steps in, the point of diagnosis, is also likely near the point of no return for most Alzheimer’s patients,

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. I

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.

Our two most complex tactical domains are nutrition and exercise, and I find that most people need to make changes in both—rarely just one or the other. 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?

So if you adopt only one new set of habits based on reading this book, it must be in the realm of exercise. If you currently exercise, you will likely want to rethink and modify your program. And if exercise is not a part of your life at the moment, you are not alone—77 percent of the US population is like you.1 Now is the time to change that. Right now. Even a little bit of daily activity is much better than nothing. Going from zero weekly exercise2 to just ninety minutes per week can reduce your risk of dying from all causes by 14 percent. It’s very hard to find a drug that can do that.

Although my medical school classmates and I learned almost zilch about exercise, let alone how to “prescribe” it to patients, Medicine 2.0 does at least recognize its value. Unfortunately, the advice rarely goes beyond generic recommendations to move more and sit less. The US government’s physical activity guidelines6 suggest that “active adults” engage in at least 30 minutes of “moderate-intensity aerobic activity,” five times per week (or 150 minutes in total). This is to be supplemented with two days of strength training, targeting “all major muscle groups.”

Let’s start with cardiorespiratory or aerobic fitness. This means how efficiently your body can deliver oxygen to your muscles, and how efficiently your muscles can extract that oxygen, enabling you to run (or walk) or cycle or swim long distances. It also comes into play in daily life, manifesting as physical stamina.

Let’s say I’m just sitting on the couch, watching a movie. At rest, someone my size might require about 300 ml of oxygen per minute in order to generate enough ATP, the chemical “fuel” that powers our cells, to perform all the physiological functions necessary to stay alive and watch the movie. This is a pretty low level of energy demand, but if I go outside and jog around my neighborhood, the energy demands ramp up. My breathing quickens, and my heart rate accelerates to help me extract and utilize ever more oxygen from the air I breathe, in order to keep my muscles working. At this level of intensity, someone my size might require 2,500 to 3,000 ml of oxygen per minute, an eight-to tenfold increase from when I was sitting on the couch. Now, if I start running up a hill as fast as I can, my body’s oxygen demand will increase from there: 4,000 ml, 4,500 ml, even 5,000 ml or more depending on the pace and my fitness level. The fitter I am, the more oxygen I can consume to make ATP, and the faster I can run up that hill. Eventually, I will reach the point at which I just can’t produce any more energy via oxygen-dependent pathways, and I’ll be forced to switch over to less efficient, less sustainable ways of producing power, such as those used in sprinting. The amount of oxygen that I am using at this level of effort represents my VO2 max. (And not long after that, I will “fail,” meaning I am no longer able to continue running up the hill at that pace.)

poor cardiorespiratory fitness carries a greater relative risk of death than smoking.

“Cardiorespiratory fitness is inversely associated with long-term mortality with no observed upper limit of benefit [emphasis mine]. Extremely high aerobic fitness was associated with the greatest survival.”

A ten-year observational study13 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. Further analysis revealed that it’s not the mere muscle mass that matters but the strength of those muscles, their ability to generate force.