Outlive: The Science and Art of Longevity

by Peter Attia

The absolute risk increase was just 0.1 percentage point. HRT was linked to, potentially, one additional case of breast cancer in every thousand patients. Yet this tiny increase in absolute risk was deemed to outweigh any benefits, meaning menopausal women would potentially be subject to hot flashes and night sweats, as well as loss of bone density and muscle mass, and other unpleasant symptoms of menopause—not to mention a potentially increased risk of Alzheimer’s disease,

Medicine 2.0 relies on two types of tactics, broadly speaking: procedures (e.g., surgery) and medications. Our tactics in Medicine 3.0 fall into five broad domains: exercise, nutrition, sleep, emotional health, and exogenous molecules, meaning drugs, hormones, or supplements. I will not be talking much about molecules, because that would make this book twice as long as it already is, but one thing that I will say is that I do not shy away from pharmaceutical drugs because they are not “natural.” I consider many drugs and supplements, including lipid-lowering medications, to be essential items in our longevity tool kit, and I hope that in the not-too-distant future we will have many even more effective tools at our disposal.

So we will break down this thing called exercise into its most important components: strength, stability, aerobic efficiency, and peak aerobic capacity. Increasing your limits in each of these areas is necessary if you are hoping to reach your limit of lifespan and healthspan.

The job of mTOR is basically to balance an organism’s need to grow and reproduce against the availability of nutrients. When food is plentiful, mTOR is activated and the cell (or the organism) goes into growth mode, producing new proteins and undergoing cell division, as with the ultimate goal of reproduction. When nutrients are scarce, mTOR is suppressed and cells go into a kind of “recycling” mode, breaking down cellular components and generally cleaning house. Cell division and growth slow down or stop, and reproduction is put on hold to allow the organism to conserve energy.

AMPK is like the low-fuel light on the dashboard of your car: when it senses low levels of nutrients (fuel), it activates, triggering a cascade of actions. While this typically happens as a response to lack of nutrients, AMPK is also activated when we exercise, responding to the transient drop in nutrient levels. Just as you would change your itinerary if your fuel light came on, heading for the nearest gas station rather than Grandma’s house, AMPK prompts the cell to conserve and seek alternative sources of energy.

AMPK works to inhibit the activity of mTOR, the cellular growth regulator.

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) If you meet three or more of these criteria, then you have the metabolic syndrome—along with as many as 120 million other Americans, according to a 2020 article in JAMA. About 90 percent of the US population ticks at least one of these boxes.

glycogen, the storage form of glucose, suitable for use in the near term. About 75 percent of this glycogen ends up in skeletal muscle and the other 25 percent goes to the liver, although this ratio can vary. An adult male can typically store a total of about 1,600 calories worth of glycogen between these two sites,

One of the liver’s many important jobs is to convert this stored glycogen back to glucose and then to release it as needed to maintain blood glucose levels at a steady state, known as glucose homeostasis. This is an incredibly delicate task: an average adult male will have about five grams of glucose circulating in his bloodstream at any given time, or about a teaspoon. That teaspoon won’t last more than a few minutes, as glucose is taken up by the muscles and especially the brain, so the liver has to continually feed in more, titrating it precisely to maintain a more or less constant level. Consider that five grams of glucose, spread out across one’s entire circulatory system, is normal, while seven grams—a teaspoon and a half—means you have diabetes.

Fat also begins to infiltrate your abdomen, accumulating in between your organs. Where subcutaneous fat is thought to be relatively harmless, this “visceral fat” is anything but. These fat cells secrete inflammatory cytokines such as TNF-alpha and IL-6, key markers and drivers of inflammation, in close proximity to your most important bodily organs. This may be why visceral fat is linked to increased risk of both cancer and cardiovascular disease.

Individual fat-storage capacity seems to be influenced by genetic factors. This is a generalization, but people of Asian descent (for example), tend to have much lower capacity to store fat, on average, than Caucasians.

But one of the first places where this overflowing fat will cause problems is in your muscle, as it worms its way in between your muscle fibers, like marbling on a steak. As this continues, microscopic fat droplets even appear inside your muscle cells.

Insulin resistance is a term that we hear a lot, but what does it really mean? Technically, it means that cells, initially muscle cells, have stopped listening to insulin’s signals,

Each lipoprotein particle is enwrapped by one or more large molecules, called apolipoproteins, that provide structure, stability, and, most importantly solubility to the particle. HDL particles are wrapped in a type of molecule called apolipoprotein A (or apoA), while LDL is encased in apolipoprotein B (or apoB).

While there are seven statins on the market, I tend to start with rosuvastatin (Crestor) and only pivot from that if there is some negative effect from the drug (e.g., a symptom or biomarker). My goal is aggressive: as rationalized by Peter Libby, I want to knock someone’s apoB concentration down to 20 or 30 mg/dL, about where it would be for a child. For people who can’t tolerate statins, I like to use a newer drug, called bempedoic acid (Nexletol), which manipulates a different pathway to accomplish much the same end: inhibiting cholesterol synthesis as a way to force the liver to increase LDLR and therefore LDL clearance. But where statins inhibit cholesterol synthesis throughout the body, and most notably in the muscles, bempedoic acid does so only in the liver. Therefore, it does not cause the side effects associated with statins, especially muscle soreness. The main issue with this drug is cost. Another drug called ezetimibe (Zetia) blocks absorption of cholesterol in the GI tract.[*10] That in turn depletes the amount of cholesterol in the liver, leading once again to increased LDLR expression and greater clearance of apoB particles, which is what we want. Ezetimibe pairs very well with statins because statins, which block cholesterol synthesis, tend to cause the body to reflexively increase cholesterol reabsorption in the gut—exactly the thing that ezetimibe so effectively prevents.

Homocysteine is broken down by B vitamins,

advocate early, aggressive, and broad screening for my patients—such as colonoscopy (or other colorectal cancer screening) at age forty, as opposed to the standard recommendation of forty-five or fifty—because the evidence is overwhelming that it’s much easier to deal with most cancers in their early stages.

If two women have breast cancer, at the same stage, their tumor genomes are likely to be very different from each other.

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

In 2020, some 3,640 Americans died from colorectal cancer before they turned fifty—and given the slow-moving nature of the disease, it’s likely that many of those who died later than that already had the disease on their fiftieth birthday. This is why the American Cancer Society updated its guidelines in 2018, lowering the age to forty-five for people at average risk.

“Before you get your first colonoscopy, there are [a] few things you can do that may improve your risk-to-benefit ratio. You should ask what your endoscopist’s adenoma detection rate (ADR) is. The ADR is the proportion of individuals undergoing a colonoscopy who have one or more adenomas (or colon polyps) detected. The benchmarks for ADR are greater than 30% in men and greater than 20% in women. You should also ask your endoscopist how many perforations he or she has caused, specifically, as well as any other serious complications, like major intestinal bleeding episodes (in a routine screening setting). Another question you should ask is what is your endoscopist’s withdrawal time, defined as the amount of time spent viewing as the colonoscope is withdrawn during a colonoscopy. A longer withdrawal time suggests a more thorough inspection. A 6-minute withdrawal time is currently the standard of care.”

Exercise is the only intervention shown to delay the progression of Parkinson’s.