Outlive: The Science and Art of Longevity

by Peter Attia

Thus, the evidence on whether cognitive reserve can be “trained” or used as a preventive strategy, such as by learning to play a musical instrument or other forms of “brain training,” is highly conflicted and not conclusive—although neither of these can hurt, so why not? 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.

Additionally, it has been established that people with a history of cardiovascular disease are at a higher risk of developing Alzheimer’s disease. Evidence also demonstrates a linear relationship between cognitive decline and increased intimal media thickness in the carotid artery, a major blood vessel that feeds the brain.

Another compelling and perhaps parallel theory of Alzheimer’s disease says that it stems from abnormal glucose metabolism in the brain. Scientists and physicians have long noted a connection between Alzheimer’s disease and metabolic dysfunction. Having type 2 diabetes doubles or triples your risk of developing Alzheimer’s disease, about the same as having one copy of the APOE e4 gene. On a purely mechanistic level, chronically elevated blood glucose, as seen in type 2 diabetes and prediabetes/insulin resistance, can directly damage the vasculature of the brain. But insulin resistance alone is enough to elevate one’s risk.

Insulin seems to play a key role in memory function.

One study found that intranasal insulin helped preserve brain volume in Alzheimer’s patients. Clearly, it is helpful to get glucose into neurons; insulin resistance blocks this. As the authors wrote, “Several lines of evidence converge to suggest that central insulin resistance plays a causal role in the development and progression of Alzheimer’s disease.”

Because metabolism plays such an outsize role with at-risk e4 patients like Stephanie, our first step is to address any metabolic issues they may have. Our goal is to improve glucose metabolism, inflammation, and oxidative stress. One possible recommendation for someone like her would be to switch to a Mediterranean-style diet, relying on more monounsaturated fats and fewer refined carbohydrates, in addition to regular consumption of fatty fish. There is some evidence that supplementation with the omega-3 fatty acid DHA, found in fish oil, may help maintain brain health, especially in e4/e4 carriers. Higher doses of DHA may be required because of e4-induced metabolic changes and dysfunction of the blood-brain barrier.

A systematic review of randomized controlled trials found that ketogenic therapies improved general cognition and memory in subjects with mild cognitive impairment and early-stage Alzheimer’s disease. Think of it as a flex-fuel strategy.

the epidemiology linking strength and cardiorespiratory fitness to lower risk for neurodegeneration is so uniform in its direction and magnitude that my own skepticism of the power of exercise, circa 2012, has slowly melted away. I now tell patients that exercise is, full stop and hands down, the best tool we have in the neurodegeneration prevention tool kit.

Nevertheless, the association is too strong to be ignored. (Also, better oral health correlates strongly with better overall health, particularly in terms of cardiovascular disease risk, so I pay much more attention to flossing and gum health than I used to.)

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.

But decades’ worth of auto accident data reveal that, in fact, 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.

with a patient who is overnourished, we want to find a way to reduce their caloric intake (there are three ways to do this, as you’ll see in chapter 15). 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. It can get complicated.

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. For those who are not habitual exercisers (yet), you’re in luck: The benefits of exercise begin with any amount of activity north of zero—even brisk walking—and go up from there. Just as almost any diet represents a vast improvement over eating only fast food, almost any exercise is better than remaining sedentary.

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.

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.

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

This was a completely different population that encompassed both sexes and all races, yet the researchers found a nearly identical result: someone in the least fit 20 percent has a 4.09 times greater risk of dying than a person in the top 2 percent of their age and sex category. Even someone of moderate fitness (40th to 60th percentile) is still at more than double the risk of all-cause mortality than the fittest group,

“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.”

Longitudinal and cross-sectional studies find that fat-free mass (meaning mostly muscle mass) and activity levels remain relatively consistent as people age from their twenties and thirties into middle age. But both physical activity levels and muscle mass decline steeply after about age sixty-five, and then even more steeply after about seventy-five. It’s as if people just fall off a cliff sometime in their mid-seventies.

One Chilean study looked at about one thousand men and four hundred women, with an average age of seventy-four at enrollment. The researchers divided the subjects into quartiles, based on their appendicular lean mass index (technically, the muscle mass of their extremities, arms and legs, normalized to height), and followed them over time. After twelve years, approximately 50 percent of those in the lowest quartile were dead, compared to only 20 percent of those in the highest quartile for lean mass.

I suspect that having more muscle mass delays death precisely because it also preserves healthspan.

Having more muscle mass on your exoskeleton appears to protect you from all kinds of trouble, even adverse outcomes following surgery—but most important, it is highly correlated with a lower risk of falling, a leading but oft-ignored cause of death and disability in the elderly. As figure 10 reveals, falls are by far the leading cause of accidental deaths in those ages sixty-five and older—and this is without even counting the people who die three or six or twelve months after their nonfatal but still serious fall pushed them into a long and painful decline.

Therefore, 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.

If we are to follow in LaLanne’s footsteps, we must stop pointlessly “exercising,” just because we think we are supposed to, banging away on the elliptical trainer at lunch hour. I promise, you can do better. I suggest you join me and start training, with a very specific purpose, which is to be kick-ass one-hundred-year-olds.

The three dimensions in which we want to optimize our fitness are aerobic endurance and efficiency (aka cardio), strength, and stability.

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.

I am convinced that it is impossible to be healthy without also having healthy mitochondria, which is why I place a great deal of emphasis on long, steady endurance training in zone 2.

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.

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:

They compared three groups of subjects: professional cyclists, moderately active healthy males, and sedentary men who met the criteria for the metabolic syndrome, meaning essentially that they were insulin resistant. They had each group ride a stationary bicycle at a given level of intensity relative to their fitness (about 80 percent of their maximum heart rate), while the scientists analyzed the amount of oxygen they consumed and the CO2 they exhaled in order to determine how efficiently they produced power—and what primary fuels they were using. The differences they found were striking. The professional cyclists could zoom along, producing a huge amount of power while still burning primarily fat. But the subjects with metabolic syndrome relied almost entirely on glucose for their fuel source, even from the first pedal stroke. They had virtually zero ability to tap into their fat stores, meaning they were metabolically inflexible: able to use only glucose but not fat.

training aerobic endurance and efficiency (i.e., zone 2 work) is the first element of my Centenarian Decathlon training program.

If you know your maximum heart rate—not estimated, but your actual maximum, the highest number you’ve ever seen on a heart rate monitor—your zone 2 will correspond to between approximately 70 and 85 percent of that peak number, depending on your fitness levels. That’s a big range, so when starting people out, I prefer they rely on their rate of perceived exertion, or RPE, also known as the “talk test.” How hard are you working? How easy is it to speak? If you’re at the top of zone 2, you should be able to talk but not particularly interested in holding a conversation. If you can’t speak in complete sentences at all, you’re likely into zone 3, which means you’re going too hard, but if you can comfortably converse, you’re likely in zone 1, which is too easy.

Mitochondria are incredibly plastic, and when we do aerobic exercise, it stimulates the creation of many new and more efficient mitochondria through a process called mitochondrial biogenesis, while eliminating ones that have become dysfunctional via a recycling process called mitophagy (which is like autophagy, touched on in chapter 5, but for mitochondria). A person who exercises frequently in zone 2 is improving their mitochondria with every run, swim, or bike ride. But if you don’t use them, you lose them.

This in turn explains why exercise, especially in zone 2, can be so effective in managing both type 1 and type 2 diabetes: It enables the body to essentially bypass insulin resistance in the muscles to draw down blood glucose levels.

The key is to find an activity that fits into your lifestyle, that you enjoy doing, and that enables you to work at a steady pace that meets the zone 2 test: You’re able to talk in full sentences, but just barely.

Based on multiple discussions with San Millán and other exercise physiologists, it seems that about three hours per week of zone 2, or four 45-minute sessions, is the minimum required for most people to derive a benefit and make improvements, once you get over the initial hump of trying it for the first time.

Besides improving mitochondrial health and glucose uptake and metabolic flexibility, and all those other good things, zone 2 training also increases your VO2 max somewhat. But if you really want to raise your VO2 max, you need to train this zone more specifically. Typically, for patients who are new to exercising, we introduce VO2 max training after about five or six months of steady zone 2 work.

This is why it’s so essential to train VO2 max in addition to zone 2. It’s a key to maintaining a fulfilling, independent life as you age. But it takes hard work over a long period of time to build it up and keep it up.

Where HIIT intervals are very short, typically measured in seconds, VO2 max intervals are a bit longer, ranging from three to eight minutes—and a notch less intense. I do these workouts on my road bike, mounted to a stationary trainer, or on a rowing machine, but running on a treadmill (or a track) could also work. The tried-and-true formula for these intervals is to go four minutes at the maximum pace you can sustain for this amount of time—not an all-out sprint, but still a very hard effort. Then ride or jog four minutes easy, which should be enough time for your heart rate to come back down to below about one hundred beats per minute. Repeat this four to six times and cool down.[*4]

you don’t need to spend very much time in the pain cave. Unless you are training to be competitive in elite endurance sports like cycling, swimming, running, triathlon, or cross-country skiing, a single workout per week in this zone will generally suffice. You’ll pretty quickly find that it boosts your performance across the rest of your exercise program as well—and, more importantly, in the rest of your life.

But muscle mass may be the least important metric here.

we lose muscle strength about two to three times more quickly than we lose muscle mass. And we lose power (strength x speed) two to three times faster than we lose strength. This is because the biggest single change in the aging muscle is the atrophy of our fast twitch or type 2 muscle fibers. Ergo, our training must be geared towards improving these with heavy resistance training. Daily life and zone 2 endurance work may be enough to prevent atrophy of type 1 fibers—but unless you are working against significant resistance, your type 2 muscle fibers will wither away.

If someone is sedentary and consuming excess calories, muscle loss accelerates, because one of the primary destinations of fat spillover is into muscle.

Regaining that muscle, once we’ve gotten to this state, is no easy task. One study looked at sixty-two frail seniors (average age seventy-eight) who engaged in a program of strength training and found that even after six months of pure strength training, half of the subjects did not gain any muscle mass. They also didn’t lose any muscle mass, likely thanks to the weight training, but the upshot is, it is very difficult to put on muscle mass later in life.

The mortality from a hip or femur fracture is staggering once you hit about the age of sixty-five.

Fundamentally I structure my training around exercises that improve the following: Grip strength, how hard you can grip with your hands, which involves everything from your hands to your lats (the large muscles on your back). Almost all actions begin with the grip. Attention to both concentric and eccentric loading for all movements, meaning when our muscles are shortening (concentric) and when they are lengthening (eccentric). In other words, we need to be able to lift the weight up and put it back down, slowly and with control. Rucking down hills is a great way to work on eccentric strength, because it forces you to put on the “brakes.” Pulling motions, at all angles from overhead to in front of you, which also requires grip strength (e.g., pull-ups and rows). Hip-hinging movements, such as the deadlift and squat, but also step-ups, hip-thrusters, and countless single-leg variants of exercises that strengthen the legs, glutes, and lower back.