— The Science & Art of Longevity
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Part I
Chapter 1: The Long Game: From Fast Death To Slow Death
As perverse as it sounds, the violence of the city was a “feature” of the training program. – Page 13
If longevity were simple, then there might not be a need for this book. – Page 14
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. – Page 16
None of our treatments for late-stage lung cancer has reduced mortality by nearly as much as the worldwide reduction in smoking that has occurred over the last two decades, thanks in part to widespread smoking bans. This simple preventive measure (not smoking) has saved more lives than any late-stage intervention that medicine has devised. – Page 18
We want to delay or prevent these conditions so that we can live longer without disease, rather than lingering with disease. – Page 19
Chapter 2: Medicine 3.0: Rethinking Medicine For The Age Of Chronic Disease
What bothers me most about “First, do no harm,” though, is its implication that the best treatment option is always the one with the least immediate downside risk—and, very often, doing nothing at all. – Page 31
Risk is not something to be avoided at all costs; rather, it’s something we need to understand, analyze, and work with. – Page 32
My point is that a physician who has never done any harm, or at least confronted the risk of harm, has probably never done much of anything to help a patient either. – Page 33
The first era, exemplified by Hippocrates but lasting almost two thousand years after his death, is what I call Medicine 1.0. Its conclusions were based on direct observation and abetted more or less by pure guesswork, some of which was on target and some not so much. Hippocrates advocated walking for exercise, for example, and opined that “in food excellent medicine can be found; in food bad medicine can be found,” which still holds up. But much of Medicine 1.0 missed the mark entirely, such as the notion of bodily “humors,” to cite just one example of many. Hippocrates’s major contribution was the insight that diseases are caused by nature and not by actions of the gods, as had previously been believed. That alone represented a huge step in the right direction. – Page 33
First, Medicine 3.0 places a far greater emphasis on prevention than treatment. – Page 40
Second, Medicine 3.0 considers the patient as a unique individual. Medicine 2.0 treats everyone as basically the same, obeying the findings of the clinical trials that underlie evidence-based medicine. – Page 41
This reported 24 percent risk increase sounded scary indeed. But nobody seemed to care that the absolute risk increase of breast cancer for women in the study remained minuscule. Roughly five out of every one thousand women in the HRT group developed breast cancer, versus four out of every one thousand in the control group, who received no hormones. – Page 42
Sleep was totally ignored, both in class and in residency, as we routinely worked twenty-four hours at a stretch. – Page 43
Another, related issue is that longevity itself, and healthspan in particular, doesn’t really fit into the business model of our current healthcare system. There are few insurance reimbursement codes for most of the largely preventive interventions that I believe are necessary to extend lifespan and healthspan. Health insurance companies won’t pay a doctor very much to tell a patient to change the way he eats, or to monitor his blood glucose levels in order to help prevent him from developing type 2 diabetes. Yet insurance will pay for this same patient’s (very expensive) insulin after he has been diagnosed. Similarly, there’s no billing code for putting a patient on a comprehensive exercise program designed to maintain her muscle mass and sense of balance while building her resistance to injury. But if she falls and breaks her hip, then her surgery and physical therapy will be covered. Nearly all the money flows to treatment rather than prevention— – Page 43
Chapter 3: Objective, Strategy, Tactics: A Road Map For Reading This Book
Because I am a math guy, I like to visualize lifespan and healthspan in terms of a mathematical function, as in figure 2 on the following page— – Page 49
“Tactics without strategy is the noise before defeat.” He was talking about war, but it applies here as well. To achieve our objectives, we first need to have a strategy: an overall approach, a conceptual scaffolding or mental model that is informed by science, is tailored to our goals, and gives us options. – Page 53
think about healthspan and its deterioration in terms of three categories, or vectors. The first vector of deterioration is cognitive decline. – Page 57
The second vector of deterioration is the decline and eventual loss of function of our physical body. – Page 57
My patients rarely expect this decline to affect them. I ask them to be very specific about their ideal future. What do they want to be doing when they are older? It’s striking how rosy their predictions tend to be. They feel supremely confident that they will still be snowboarding or kickboxing, or whatever else it is they enjoy doing now, when they’re in their seventies and eighties. – Page 58
The third and final category of deterioration, I believe, has to do with emotional health. Unlike the others, this one is largely independent of age; it can afflict outwardly healthy young people in their twenties, or it can creep up on you in middle age, as it did with me. Or it can descend later in life. Surveys show that happiness tends to reach its nadir in our forties (age forty-seven, to be exact), – Page 58
Part Ii
Chapter 4: Centenarians: The Older You Get, The Healthier You Have Been
What’s even more surprising is that Perls’s group has also found that the supercentenarians and the “semisupercentenarians” (ages 105 to 109) actually tend to be in even better health than garden-variety hundred-year-olds. These are the super survivors, and at those advanced ages, lifespan and healthspan are pretty much the same. As Perls and his colleagues put it in a paper title, “The Older You Get, the Healthier You Have Been.” – Page 77
Genes that prove unfavorable or even harmful in midlife and beyond are not weeded out because they have already been passed on. – Page 80
Chapter 5: Eat Less, Live Longer: The Science Of Hunger And Health
luminaries, – Page 96
Restricting the amount of nutrients that are available, via dietary restriction or exercise, triggers the production of newer, more efficient mitochondria to replace old and damaged ones. These fresh mitochondria help the cell produce more ATP, the cellular energy currency, with the fuel it does have. – Page 99
More importantly, AMPK works to inhibit the activity of mTOR, the cellular growth regulator. Specifically, it seems to be a drop in amino acids that induces mTOR to shut down, and with it all the anabolic (growth) processes that mTOR controls. Instead of making new proteins and undergoing cell division, the cell goes into a more fuel-efficient and stress-resistant mode, activating an important cellular recycling process called autophagy, which means “self-eating” (or better yet, “self-devouring”). – Page 99
Autophagy is essential to life. If it shuts down completely, the organism dies. Imagine if you stopped taking out the garbage (or the recycling); your house would soon become uninhabitable. – Page 99
Impaired autophagy is thought to be an important driver of numerous aging-related phenotypes and ailments, such as neurodegeneration and osteoarthritis. – Page 100
Chapter 6: The Crisis Of Abundance: Can Our Ancient Genes Cope With Our Modern Diet?
The liver is a highly resilient organ, almost miraculously so. It may be the most regenerative organ in the human body. When a healthy person donates a portion of their liver, both donor and recipient end up with an almost full-sized, fully functional liver within about eight weeks of the surgery, and the majority of that growth takes place in just the first two weeks. – Page 112
The twist here is that fat—that is, subcutaneous fat, the layer of fat just beneath our skin—is actually the safest place to store excess energy. – Page 117
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 – Page 119
Now, when these apes consumed fructose, they generated lots of uric acid, which caused them to store many more of those fructose calories as fat. This newfound ability to store fat enabled them to survive in the colder climate. – Page 128
Chapter 7: The Ticker: Confronting—And Preventing—Heart Disease, The Deadliest Killer On The Planet
What is the most common “presentation” (or symptom) of heart disease? It wasn’t chest pain, left arm pain, or shortness of breath, the most common answers; it was sudden death. You know the patient has heart disease because he or she has just died from it. – Page 136
The reason they’re called high-and low-density lipoproteins (HDL and LDL, respectively) has to do with the amount of fat relative to protein that each one carries. LDLs carry more lipids, while HDLs carry more protein in relation to fat, and are therefore more dense. Also, these particles (and other lipoproteins) frequently exchange cargo with one another, which is part of what drives me crazy about labeling them “good” and “bad.” When an HDL transfers its “good cholesterol” to an LDL particle, does that cholesterol suddenly become “bad”? The answer is no—because it’s not the cholesterol per se that causes problems but the nature of the particle in which it’s transported. – Page 142
The vast majority of the cholesterol in our circulation is actually produced by our own cells. – Page 143
“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.” – Page 143
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. – Page 156
macadamia nuts, – Page 161
Chapter 8: The Runaway Cell: New Ways To Address The Killer That Is Cancer
In normal aerobic respiration, a cell can turn one molecule of glucose into as many as thirty-six units of ATP. But under anaerobic conditions, that same amount of glucose yields only two net units of ATP. This phenomenon was dubbed the Warburg effect, and even today, one way to locate potential tumors is by injecting the patient with radioactively labeled glucose and then doing a PET scan to see where most of the glucose is migrating. Areas with abnormally high glucose concentrations indicate the possible presence of a tumor. – Page 181
The Warburg effect, also known as anaerobic glycolysis, turns the same amount of glucose into a little bit of energy and a whole lot of chemical building blocks—which are then used to build new cells rapidly. Thus, the Warburg effect is how cancer cells fuel their own proliferation. – Page 182
Siddhartha Mukherjee, who is a practicing oncologist, research scientist, and Pulitzer Prize–winning author of The Emperor of All Maladies, a “biography” of cancer. – Page 187
As elegant as they are, however, CAR-T treatments have proven successful only against one specific type of cancer called B-cell lymphoma. All B-cells, normal and cancerous alike, express a protein called CD19, which is the target used by the CAR-T cell to zero in and kill them. Since we can live without B-cells, CAR-T works by obliterating all CD19-bearing cells. – Page 193
Chapter 9: Chasing Memory: Understanding Alzheimer’S Disease And Other Neurodegenerative Diseases
They would rather die from cancer or heart disease than lose their minds, their very selves. – Page 216
When we have a thought or a perception, it’s not just one neural network that is responsible for that insight, or that decision, but many individual networks working simultaneously on the same problem, according to Francisco Gonzalez-Lima, a behavioral neuroscientist at the University of Texas in Austin. These parallel networks can reach different conclusions, so when we use the expression “I am of two minds about something,” that is not scientifically inaccurate. The brain then picks the most common response. There is redundancy built into the system. – Page 232
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. – Page 233
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. – Page 233
Its eighty-six billion neurons each have between one thousand and ten thousand synapses connecting them to other neurons or target cells, – Page 235
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. – Page 244
Part Iii
Chapter 11: Exercise: The Most Powerful Longevity Drug
It’s not that I was a passionate devotee of strength training over endurance, or vice versa; I’d done plenty of both. I was reacting to the binary nature of his question. In case you haven’t figured it out by now, I’m not fond of the way we reduce these complex, nuanced, vitally important questions down to simple either-ors. Cardio or weights? Low-carb or plant-based? Olive oil or beef tallow? – Page 261
Chapter 12: Training 101: How To Prepare For The Centenarian Decathlon
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] – Page 300
Chapter 14: Nutrition 3.0: You Say Potato, I Say “Nutritional Biochemistry”
Religion is a culture of faith; science is a culture of doubt.—Richard Feynman – Page 350
Wearing a cast on a perfectly normal arm will cause it to atrophy. While this example is obvious, it’s amazing how many people fail to translate it to nutrition. – Page 355
Nutrition is relatively simple, actually. It boils down to a few basic rules: don’t eat too many calories, or too few; consume sufficient protein and essential fats; obtain the vitamins and minerals you need; and avoid pathogens like E. coli and toxins like mercury or lead. Beyond that, we know relatively little with complete certainty. Read that sentence again, please. – Page 356
We evolved as omnivores; ergo, most of us can probably find excellent health as omnivores. – Page 356
One classic example of this, I believe, lies in the vast, well-publicized literature correlating “moderate” drinking with improved health outcomes. This notion has become almost an article of faith in the popular media, but these studies are also almost universally tainted by healthy user bias—that is, the people who are still drinking in older age tend to do so because they are healthy, and not the other way around. Similarly, people who drink zero alcohol often have some health-related reason, or addiction-related reason, for avoiding it. And such studies also obviously exclude those who have already died of the consequences of alcoholism. – Page 362
To me, perhaps the most vexing issue with diet and nutrition studies is the degree of variation between individuals that is found but often obscured. – Page 367
Chapter 15: Putting Nutritional Biochemistry Into Practice: How To Find The Right Eating Pattern For You
The quality of the food you eat could be as important as the quantity. If you’re eating the SAD, then you should eat much less of it. Conversely, if your diet is high quality to begin with, and you are metabolically healthy, then only a slight degree of caloric restriction—or simply not eating to excess—can still be beneficial. – Page 379
Not all carbs are created equal. The more refined the carb (think dinner roll, potato chips), the faster and higher the glucose spike. Less processed carbohydrates and those with more fiber, on the other hand, blunt the glucose impact. – Page 394
Nonstarchy veggies such as spinach or broccoli have virtually no impact on blood sugar. Have at them. Foods high in protein and fat (e.g., eggs, beef short ribs) have virtually no effect on blood sugar (assuming the short ribs are not coated in sweet sauce), but large amounts of lean protein (e.g., chicken breast) will elevate glucose slightly. Protein shakes, especially if low in fat, have a more pronounced effect (particularly if they contain sugar, obviously). – Page 395
What I didn’t mention there was that another group of subjects was given protein supplementation (via a protein shake); those subjects added an average of about three pounds of lean mass. The extra protein likely made the difference.[* – Page 396
This is a lot of protein to eat, and the added challenge is that it should not be taken in one sitting but rather spread out over the day to avoid losing amino acids to oxidation (i.e., using them to produce energy when we want them to be available for muscle protein synthesis). The literature suggests that the ideal way to achieve this is by consuming four servings of protein per day, each at ~ 0.25 g/ lb of body weight. – Page 397
In particular, plant protein has less of the essential amino acids methionine, lysine, and tryptophan, potentially leading to reduced protein synthesis. – Page 399
There are (broadly) three types of fats: saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA).[* 9] The differences between these have to do with differences in their chemical structure; a “saturated” fat simply has more hydrogen atoms attached to its carbon chain.[* 10] Within PUFA, we make one more important distinction, which is to separate the omega-6 from the omega-3 variants (also a chemical distinction having to do with the position of the first double bond). We can further subdivide omega-3 PUFA into marine (EPA, DHA) and nonmarine sources (ALA). Salmon and other oil-rich seafood provide the former, nuts and flaxseed the latter. – Page 401
From our empirical observations and what I consider the most relevant literature, which is less than perfect, we try to boost MUFA closer to 50–55 percent, while cutting SFA down to 15–20 percent and adjusting total PUFA to fill the gap. We also boost EPA and DHA, those fatty acids that are likely important to brain and cardiovascular health, with marine fat sources and/ or supplementation. – Page 402
Putting all these changes into practice typically means eating more olive oil and avocados and nuts, cutting back on (but not necessarily eliminating) things like butter and lard, and reducing the omega-6-rich corn, soybean, and sunflower oils—while also looking for ways to increase high-omega-3 marine PUFAs from sources such as salmon and anchovies.[* – Page 402
“Increasing PUFA probably makes little or no difference (neither benefit nor harm) to our risk of death, and may make little or no difference to our risk of dying from cardiovascular disease. However, increasing PUFA probably slightly reduces our risk of heart disease events and of combined heart and stroke events (moderate-quality evidence).” – Page 404
“mainly no association of total fat, monounsaturated fatty acid (MUFA), polyunsaturated fatty acid (PUFA), and saturated fatty acid (SFA) with risk of chronic diseases.” – Page 405
Fasting had effectively reset or rebooted his crashed metabolism in a way that no other dietary intervention was able to achieve. Because it has such deleterious effects on muscle mass, I only use it in hard-to-fix patients like Tom. – Page 413
(If there is one type of food that I would eliminate from everyone’s diet if I could, it would be fructose-sweetened drinks, including both sodas and fruit juices, which deliver too much fructose, too quickly, to a gut and liver that much prefer to process fructose slowly. – Page 415