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

by Peter Attia

It turned out that the culprit was a little-known but very deadly type of particle called Lp(a) (pronounced “el-pee-little-A”). This hot mess of a lipoprotein is formed when a garden-variety LDL particle is fused with another, rarer type of protein called apolipoprotein(a), or apo(a) for short (not to be confused with apolipoprotein A or apoA, the protein that marks HDL particles). The apo(a) wraps loosely around the LDL particle, with multiple looping amino acid segments called “kringles,” so named because their structure resembles the ring-shaped Danish pastry by that name. The kringles are what make Lp(a) so dangerous: as the LDL particle passes through the bloodstream, they scoop up bits of oxidized lipid molecules and carry them along.

because Lp(a) is a member of the apoB particle family, it also has the potential to penetrate the endothelium and get lodged in an artery wall; 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.

Often, the way Lp(a) announces itself is via a sudden, seemingly premature heart attack. This is what happened to Biggest Loser host Bob Harper, who suffered cardiac arrest at a gym in New York in 2017, at age fifty-two. Harper’s life was saved by a bystander who performed CPR until the paramedics arrived.

This is why, 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).

There was no quick fix for Anahad, or anyone else with 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.

Together, our stories illustrate 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

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.

Our first order of business is to reduce the burden of apoB particles, primarily LDLs but also VLDLs, which can be dangerous in their own right. And do so dramatically, not marginally or incrementally. We want it as low as possible, sooner rather than later.

Lipoproteins aren’t the only significant risk factors for cardiovascular disease; as noted earlier, smoking and high blood pressure both damage the endothelium directly. Smoking cessation and blood pressure control are thus non-negotiable first steps in reducing cardiovascular risk.

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.

Typically our first line of defense (or attack), 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.

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. Atherosclerosis is with us, in some form, throughout our life course.

The median age of a cancer diagnosis is sixty-six, but in 2017 there were more cancer deaths3 among people between forty-five and sixty-four than from heart disease, liver disease, and stroke combined.

Our toolbox is limited. Many (though not all) solid tumors can be removed surgically, a tactic that dates back to ancient Egypt. 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.

This experience informs our three-part strategy for dealing with cancer. 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.

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.

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. I advocate early, aggressive, and broad screening for my patients

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.

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.

In the 1920s, a German physiologist named Otto Warburg10 discovered that 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.

This remains a controversial view in mainstream cancer circles, but it has gotten harder and harder to ignore the link between cancer and metabolic dysfunction.

the association between obesity, diabetes, and cancer is primarily driven by inflammation and growth factors such as insulin. Obesity, especially when accompanied by accumulation of visceral fat (and other fat outside of subcutaneous storage depots), helps promote inflammation, as dying fat cells secrete an array of inflammatory cytokines into the circulation (see figure 4 in chapter 6). This chronic inflammation helps create an environment that could induce cells to become cancerous.

This in turn suggests that metabolic therapies, including dietary manipulations that lower insulin levels, could potentially help slow the growth of some cancers and reduce cancer risk. There is already some evidence that tinkering with metabolism can affect cancer rates. As we have seen, 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.

I’m not suggesting that it’s possible to “starve” cancer or that any particular diet will magically make cancer go away; cancer cells always seem to be able to obtain the energy supply they need. What I am saying is that we don’t want to be anywhere on that spectrum of insulin resistance to type 2 diabetes, where our cancer risk is clearly elevated. To me, this is the low-hanging fruit of cancer prevention, right up there with quitting smoking.

Work by Valter Longo of the University of Southern California and others has found that fasting, or a fasting-like diet, increases the ability of normal cells to resist chemotherapy, while rendering cancer cells more vulnerable to the treatment. It may seem counterintuitive to recommend fasting to cancer patients, but researchers have found that it caused no major adverse events in chemotherapy patients, and in some cases it may have improved the patients’ quality of life.

Rosenberg and his team23 adapted a technique that had been developed in Israel that involved taking T cells from a patient’s blood, then using genetic engineering to add antigen receptors that were specifically targeted to the patient’s tumors. Now the T cells were programmed to attack the patient’s cancer. Known as chimeric antigen receptor T cells (or CAR-T), these modified T cells could be multiplied in the lab and then infused back into the patient.

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. Unfortunately, we have not yet identified a similar marker for other cancers.

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, according to an analysis by oncologists25 Nathan Gay and Vinay Prasad.

One very promising technique is called adoptive cell therapy (or adoptive cell transfer, ACT). ACT is a class of immunotherapy whereby supplemental T cells are transferred into a patient, like adding reinforcements to an army, to bolster their ability to fight their own tumor.

One striking feature of immune-based cancer treatment is that when it works, it really works. It is not uncommon for a patient with metastatic cancer to enter remission after chemotherapy. The problem is that it virtually never lasts. The cancer almost always comes back in some form. But when patients do respond to immunotherapy, and go into complete remission, they often stay in remission.

Liquid biopsies could be viewed as having two functions: first, to determine cancer’s presence or absence, a binary question; and second and perhaps more important, to gain insight into the specific cancer’s biology.

Until we learn how to prevent or “cure” cancer entirely, something I do not see happening in our lifetime, short of some miraculous breakthroughs, we need to focus far more energy on early detection of cancer, to enable better targeting of specific treatments at specific cancers while they are at their most vulnerable stages. If the first rule of cancer is “Don’t get cancer,” the second rule is “Catch it as soon as possible.”

in the early 1980s, other researchers identified the substance in the plaques as a peptide called amyloid-beta. Because it is often found at the scene of the crime, amyloid-beta was immediately suspected to be a primary cause of Alzheimer’s disease.

At the same time, amyloid also triggers the aggregation of another protein called tau, which in turn leads to neuronal inflammation and, ultimately, brain shrinkage. Tau was likely responsible for the neuronal “tangles” that Alois Alzheimer observed in Auguste Deter.

It was not a huge leap to conclude, on the basis of available evidence, that Alzheimer’s disease is caused directly by this accumulation of amyloid-beta in the brain. The “amyloid hypothesis,” as it’s called, has been the dominant theory of Alzheimer’s disease since the 1980s, and it has driven the research priorities of the National Institutes of Health and the pharmaceutical industry alike.

Still other studies have found only a weak correlation between the degree of amyloid burden and the severity of disease. It appears, then, that the presence of amyloid-beta plaques may be neither necessary for the development of Alzheimer’s disease nor sufficient to cause it.

Frontal and vascular dementias primarily affect the frontal lobe, a region of the brain responsible for executive functioning such as attention, organization, processing speed, and problem solving. So these forms of dementia rob an individual of such higher-order cognitive features. Alzheimer’s disease, on the other hand, predominantly affects the temporal lobes, so the most distinct symptoms relate to memory, language, and auditory processing (forming and comprehending speech)—although researchers are beginning to identify different possible subtypes of Alzheimer’s disease, based on which brain regions are most affected. Parkinson’s is a bit different in that it manifests primarily as a movement disorder, resulting from (in part) a deficiency in producing dopamine, a key neurotransmitter.

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.

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.

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.

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. 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 enough27 to elevate one’s risk

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,38 may help maintain brain health, especially in e4/e4 carriers.

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. So along with changing Stephanie’s diet, we put her back on a regular exercise program, focusing on steady endurance exercise to improve her mitochondrial efficiency.

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). People in the lowest quartile of grip strength (i.e., the weakest) had a 72 percent higher incidence of dementia, compared to those in the top quartile.

I now tell patients that exercise is, full stop and hands down, the best tool we have in the neurodegeneration prevention tool kit.

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 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.

Broadly, our strategy should be based on the following principles: 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.

More than any other tactical domain we discuss in this book, exercise has the greatest power to determine how you will live out the rest of your life. There are reams of data supporting the notion that even a fairly minimal amount of exercise can lengthen your life by several years. It delays the onset of chronic diseases, pretty much across the board, but it is also amazingly effective at extending and improving healthspan. Not only does it reverse physical decline, which I suppose is somewhat obvious, but it can slow or reverse cognitive decline as well.