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

by Peter Attia

Both NAFLD and NASH are still reversible. 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. 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.

he eventually determined, was insulin resistance. Today we call this cluster of problems “metabolic syndrome” (or MetSyn), and it is defined in terms of the following five criteria: 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)

nearly 10 million Americans are normal weight (BMI 19-24.9) but metabolically unhealthy. Some research suggests that these people might be in the most serious danger. A large meta-analysis of studies11 with a mean follow-up time of 11.5 years showed that people in this category have more than triple the risk of all-cause mortality and/or cardiovascular events than metabolically healthy normal-weight individuals.

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 is no longer our friend, because our environment has changed much faster than our genome ever could. Evolution wants us to get fat when nutrients are abundant: the more energy we could store, in our ancestral past, the greater our chances of survival and successful reproduction. We needed to be able to endure periods of time without much food, and natural selection obliged, endowing us with genes that helped us conserve and store energy in the form of fat. That enabled our distant ancestors to survive periods of famine, cold climates, and physiologic stressors such as illness and pregnancy. But these genes have proved less advantageous in our present environment, where many people in the developed world have access to almost unlimited calories.

The key factor here is that 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.

At some point, our primate ancestors underwent a random genetic mutation that effectively switched on their ability to turn fructose into fat: the gene for the uricase enzyme was “silenced,” or lost. 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.

Another issue is that glucose and fructose are metabolized very differently at the cellular level. When a brain cell, muscle cell, gut cell, or any other type of cell breaks down glucose, it will almost instantly have more ATP (adenosine triphosphate), the cellular energy “currency,” at its disposal. But this energy is not free: the cell must expend a small amount of ATP in order to make more ATP, in the same way that you sometimes have to spend money to make money. In glucose metabolism, this energy expenditure is regulated by a specific enzyme that prevents the cell from “spending” too much of its ATP on metabolism. But when we metabolize fructose in large quantities, a different enzyme takes over, and this enzyme does not put the brakes on ATP “spending.”28 Instead, energy (ATP) levels inside the cell drop rapidly and dramatically. This rapid drop in energy levels makes the cell think that we are still hungry. The mechanisms are a bit complicated, but the bottom line is that 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.

One reason I find value in the concept of metabolic syndrome is that it helps us see these disorders as part of a continuum and not a single, binary condition. Its five relatively simple criteria are useful for predicting risk at the population level. But I still feel that reliance on it means waiting too long to declare that there is a problem.

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. Lipoproteins, which we will discuss in detail in the next chapter, are also important, especially triglycerides; I watch the ratio of triglycerides to HDL cholesterol (it should be less than 2:1 or better yet, less than 1:1), as well as levels of VLDL, a lipoprotein that carries triglycerides—all of which may show up many years before a patient would meet the textbook definition of metabolic syndrome. These biomarkers help give us a clearer picture of a patient’s overall metabolic health than HbA1c, which is not very specific by itself. But the first thing I look for, the canary in the coal mine of metabolic disorder, is elevated insulin.

Studies have found that insulin resistance itself is associated with huge increases29 in one’s risk of cancer (up to twelvefold), Alzheimer’s disease (fivefold), and death from cardiovascular disease (almost sixfold)—all of which underscores why addressing, and ideally preventing, metabolic dysfunction is a cornerstone of my approach to longevity.

Globally, heart disease and stroke1 (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 people2 every day in the United States, according to the CDC—more than any other cause, including cancer. It’s not just men who are at risk:3 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).

classic Medicine 2.0: guidelines for managing cardiovascular risk are based on an overly short time horizon, compared to the time line of the disease. We need to begin treating it, and preventing it, much earlier.

It is a wondrous organ, a tireless muscle that pumps blood around the body every moment of our lives. It pounds hard when we are exercising, slows down when we sleep, and even microadjusts its rate between beats, a hugely important phenomenon called heart rate variability. And when it stops, we stop. Our vascular network is equally miraculous,5,6 a web of veins, arteries, and capillaries that, if stretched out and laid end to end, would wrap around the earth more than twice (about sixty thousand miles, if you’re keeping score). Each individual blood vessel is a marvel of material science and engineering, capable of expanding and contracting dozens of times per minute, allowing vital substances to pass through its membranes, and accommodating huge swings in fluid pressure, with minimal fatigue. No material created by man can even come close to matching this. If one vessel is injured, others regrow to take its place, ensuring continuous blood flow throughout the body.

It’s practically a dirty word, cholesterol. Your doctor will probably utter it with a frown, because as everyone knows, cholesterol is evil stuff. Well, some of it is—you know, the LDL or “bad” cholesterol, which is inevitably counterpoised against the HDL, or “good” cholesterol. I practically need to be restrained when I hear these terms, because they’re so meaningless. And your “total cholesterol,” the first number that people offer up when we’re talking about heart disease, is only slightly more relevant to your cardiovascular risk than the color of your eyes.

Cholesterol is essential to life. It is required to produce some of the most important structures in the body, including cell membranes; hormones such as testosterone, progesterone, estrogen, and cortisol; and bile acids, which are necessary for digesting food. All cells can synthesize their own cholesterol, but some 20 percent of our body’s (large) supply is found in the liver, which acts as a sort of cholesterol repository, shipping it out to cells that need it and receiving it back via the circulation. Because cholesterol belongs to the lipid family (that is, fats), it is not water soluble and thus cannot dissolve in our plasma like glucose or sodium and travel freely through our circulation. So it must be carted around in tiny spherical particles called lipoproteins—the final “L” in LDL and HDL—which act like little cargo submarines. As their name suggests, these lipoproteins are part lipid (inside) and part protein (outside); the protein is essentially the vessel that allows them to travel in our plasma while carrying their water-insoluble cargo of lipids, including cholesterol, triglycerides, and phospholipids, plus vitamins and other proteins that need to be distributed to our distant tissues. 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.

it’s not the cholesterol per se that causes problems but the nature of the particle in which it’s transported.

Another major misconception about heart disease is that it is somehow caused by the cholesterol that we eat in our diet.

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.

Fully half of all major adverse cardiovascular events11 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.

The risk builds throughout our lives, and the critical factor is time. Therefore it is critical that we understand how it develops, and progresses, so we can develop a strategy to try to slow or stop it.

This is what actually makes HDL particles potentially “good” and LDL particles potentially “bad”—not the cholesterol, but the particles that carry it. The trouble starts when LDL particles stick in the arterial wall and subsequently become oxidized, meaning the cholesterol (and phospholipid) molecules they contain come into contact with a highly reactive molecule known as a reactive oxygen species, or ROS, the cause of oxidative stress. It’s the oxidation of the lipids on the LDL that kicks off the entire atherosclerotic cascade.

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.

So to gauge the true extent of your risk, we have to know how many of these apoB particles are circulating in your bloodstream.

evidence has piled up pointing to apoB as far more predictive of cardiovascular disease than simply LDL-C, the standard “bad cholesterol” measure. According to an analysis published in JAMA Cardiology15 in 2021, each standard-deviation increase in apoB raises the risk of myocardial infarction by 38 percent in patients without a history of cardiac events or a diagnosis of cardiovascular disease (i.e., primary prevention). That’s a powerful correlation. Yet even now, the American Heart Association guidelines still favor LDL-C testing instead of apoB. I have all my patients tested for apoB regularly, and you should ask for the same test the next time you see your doctor.

three of the major prerequisites for heart disease: significant lipoprotein burden or apoB, LDL oxidation or modification (leading to the plaques that my calcium scan revealed), and a high level of background inflammation. None of these is enough to guarantee that someone will develop heart disease, but all three are necessary to develop it. We are fortunate that many of these conditions can be modulated or nearly eliminated—including apoB, by the way—via lifestyle changes and medications.

elevated Lp(a). It does not seem to respond to behavioral interventions such as exercise and dietary changes the way that, say, LDL-C does. A class of drug called PCSK917 inhibitors, aimed at lowering apoB concentrations, does seem to be able to reduce Lp(a) levels by approximately 30 percent, but as yet there are no data suggesting that they reduce the excess events (heart attacks) attributable to that particle. Thus, the only real treatment for elevated Lp(a) right now is aggressive management of apoB overall.

three blind spots of Medicine 2.0 when it comes to dealing with atherosclerotic disease: first, an overly simplistic view of lipids that fails to understand the importance of total lipoprotein burden (apoB) and how much one needs to reduce it in order to truly reduce risk; second, a general lack of knowledge about other bad actors such as Lp(a); and third, a failure to fully grasp the lengthy time course of atherosclerotic disease, and the implications this carries if we seek true prevention. When I look at a patient’s blood panel for the first time, my eyes immediately dart to two numbers: apoB and Lp(a). I look at the other numbers, too, but these two tell me the most when it comes to predicting their risk of ASCVD. ApoB not only tells me the concentration of LDL particles (which, you’ll recall, is more predictive of disease than the concentration of cholesterol found within LDL particles, LDL-C), but it also captures the concentration of VLDL particles, which as members of the apoB family can also contribute to atherosclerosis. Furthermore, even someone whose apoB is low can still have a dangerously elevated Lp(a).

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.

ketogenic diet, might not work for everyone, nor is it a diet to which I continue to adhere. In my clinical experience, about a third to half of people who consume high amounts of saturated fats (which sometimes goes hand in hand with a ketogenic diet) will experience a dramatic increase in apoB particles, which we obviously don’t want.fn8 Monounsaturated fats, found in high quantities in extra virgin olive oil, macadamia nuts, and avocados (among other foods), do not have this effect, so I tend to push my patients to consume more of these, up to about 60 percent of total fat intake. The point is not necessarily to limit fat overall but to shift to fats that promote a better lipid profile.

statins inhibit cholesterol synthesis, prompting the liver to increase the expression of LDLR, taking more LDL out of circulation. They may have other benefits too, including an apparent anti-inflammatory effect, so while I don’t think statins should be dissolved into the drinking water, as some have suggested, I do think they are very helpful drugs for reducing apoB or LDL concentration in many patients. Not everyone can take statins comfortably; about 5 percent of patients experience deal-breaking side effects,24 most notably statin-related muscle pain. Also, a smaller but nonzero subset of patients taking statins experience a disruption in glucose homeostasis, which may explain why statins are associated with a small increase25 in the risk for type 2 diabetes. Another fraction of patients experience an asymptomatic rise in liver enzymes,

Combining surgery and radiation therapy is pretty effective against most local, solid-tumor cancers. But while we’ve gotten fairly good at this approach, we have essentially maxed out our ability to treat cancers this way. We are not getting any more juice from the squeeze. And surgery is of limited value when cancer has metastasized, or spread. Metastatic cancers can be slowed by chemotherapy, but they virtually always come back, often more resistant to treatment than ever.

The second problem is that our ability to detect cancer at an early stage remains very weak. Far too often, we discover tumors only when they cause other symptoms, by which point they are often too locally advanced to be removed

Our first and most obvious wish is to avoid getting cancer at all, like the centenarians—in other words, prevention. But cancer prevention is tricky, because we do not yet fully understand what drives the initiation and progression of the disease with the same resolution that we have for atherosclerosis. Further, plain bad luck seems to play a major role in this largely stochastic process. But we do have some clues, which is what we’ll talk about in the next two sections. Next is the use of newer and smarter treatments targeting cancer’s manifold weaknesses, including the insatiable metabolic hunger of fast-growing cancer cells and their vulnerability to new immune-based therapies, the outcome of decades of work by scientists like Steve Rosenberg. I feel that immunotherapy, in particular, has enormous promise. Third, and perhaps most importantly, we need to try to detect cancer as early as possible so that our treatments can be deployed more effectively.

Cancer cells are different from normal cells in two important ways. Contrary to popular belief, cancer cells don’t grow faster than their noncancerous counterparts; they just don’t stop growing when they are supposed to. For some reason, they stop listening to the body’s signals that tell them when to grow and when to stop growing. This process is thought to begin when normal cells acquire certain genetic mutations.

The second property that defines cancer cells is their ability to travel from one part of the body to a distant site where they should not be. This is called metastasis, and it is what enables a cancerous cell in the breast to spread to the lung.

One of the biggest obstacles to a “cure” is the fact that cancer is not one single, simple, straightforward disease, but a condition with mind-boggling complexity.

In fact, there didn’t seem to be any individual genes that “caused” cancer at all; instead, it seemed to be random somatic mutations that combined to cause cancers. So not only is breast cancer genetically distinct from colon cancer (as the researchers expected), but no two breast cancer tumors are very much alike.

Most of our energy has been focused on treating metastatic cancer, which is an extremely difficult problem. Once cancer has spread, the entire game changes: we need to treat it systemically rather than locally.

cancer cells had a strangely gluttonous appetite for glucose, devouring it at up to forty times the rate of healthy tissues. But these cancer cells weren’t “respiring” the way normal cells do, consuming oxygen and producing lots of ATP, the energy currency of the cell, via the mitochondria. Rather, they appeared to be using a different pathway that cells normally use to produce energy under anaerobic conditions, meaning without sufficient oxygen, such as when we are sprinting. The strange thing was that these cancer cells were resorting to this inefficient metabolic pathway despite having plenty of oxygen available to them.

Normal aerobic cellular respiration produces only energy, in the form of ATP, plus water and carbon dioxide, which aren’t much use as building materials (also, we exhale the latter two). 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. But it also represents a potential vulnerability in cancer’s armor.

The American Cancer Society reports that excess weight is a leading risk factor for both cancer cases and deaths, second only to smoking. Globally, about 12 to 13 percent15 of all cancer cases are thought to be attributable to obesity. Obesity itself is strongly associated with thirteen different types of cancers, including pancreatic, esophageal, renal, ovarian, and breast cancers, as well as multiple myeloma (see figure 7). Type 2 diabetes also16 increases the risk of certain cancers, by as much as double in some cases (such as pancreatic and endometrial cancers). And extreme obesity (BMI ≥ 40) is associated with a 52 percent greater risk of death from all cancers in men, and 62 percent in women.

PI3K, that play a major role in fueling the Warburg effect by speeding up glucose uptake into the cell. In effect, PI3K helps to open a gate in the cell wall, allowing glucose to flood in to fuel its growth. Cancer cells possess specific mutations that turn up PI3K activity while shutting down the tumor-suppressing protein PTEN, which we talked about earlier in this chapter. When PI3K is activated by insulin and IGF-1, the insulin-like growth factor, the cell is able to devour glucose at a great rate to fuel its growth. Thus, insulin acts as a kind of cancer enabler, accelerating its growth.

metabolic therapies, including dietary manipulations that lower insulin levels, could potentially help slow the growth of some cancers and reduce cancer risk.

laboratory animals on calorically restricted (CR) diets tend to die from cancer at far lower rates than control animals on an ad libitum (all-they-can-eat) diet. Eating less appears to give them some degree of protection. The same may hold true in people: one study of caloric restriction in humans18 found that limiting caloric intake directly turns down the PI3K-associated pathway, albeit in muscle (which is not susceptible to cancer). This may be a function of lowered insulin rather than lower glucose levels.

More studies need to be done, but the working hypothesis is that because cancer cells are so metabolically greedy, they are therefore more vulnerable than normal cells to a reduction in nutrients—or more likely, a reduction in insulin, which activates the PI3K pathway essential to the Warburg effect.

the best strategy to target cancer is likely by targeting multiple vulnerabilities of the disease at one time, or in sequence. By stacking different therapies, such as combining a PI3K inhibitor with a ketogenic diet, we can attack cancer on multiple fronts, while also minimizing the likelihood of the cancer developing resistance (via mutations) to any single treatment.

So for a cancer immunotherapy to succeed, we essentially need to teach the immune system to recognize and kill our own cells that have turned cancerous. It needs to be able to distinguish “bad self” (cancer) from “good self” (everything else).

in 2017, the first two CAR-T-based treatments were approved by the FDA (making them the first cell and gene therapies ever approved by the FDA), one for adult lymphoma and another for acute lymphoblastic leukemia,

there is a class of drugs called “checkpoint inhibitors,” which take an opposite approach to the T cell–based therapies. Instead of activating T cells to go kill the cancer, the checkpoint inhibitors help make the cancer visible to the immune system.