Outlive

Medical Approach & Philosophy

• If the results are positive, it would not surprise me if the use of rapamycin for longevity purposes becomes more common. A small but growing number of people, including me and a handful of my patients, already take rapamycin off-label for its potential geroprotective benefits. I can’t speak for everyone, but taking it cyclically does appear to reduce unwanted side effects, in my experience.

Exercise & Physical Performance

• So we will break down this thing called exercise into its most important components: strength, stability, aerobic efficiency, and peak aerobic capacity.
• The data are unambiguous: exercise not only delays actual death but also prevents both cognitive and physical decline, better than any other intervention. We also tend to feel better when we exercise, so it probably has some harder-to-measure effect on emotional health as well.
• I never won a fight in the ring; I always won in preparation.
• VO2 max, is perhaps the single most powerful marker for longevity. VO2 max represents the maximum rate at which a person can utilize oxygen. This is measured, naturally, while a person is exercising at essentially their upper limit of effort. (If you’ve ever had this test done, you will know just how unpleasant it is.) The more oxygen your body is able to use, the higher your VO2 max. Our human body has an amazing ability to respond to the demands placed on it. Let’s say I’m just sitting on the couch, watching a movie. At rest, someone my size might require about 300 ml of oxygen per minute in order to generate enough ATP, the chemical “fuel” that powers our cells, to perform all the physiological functions necessary to stay alive and watch the movie. This is a pretty low level of energy demand, but if I go outside and jog around my neighborhood, the energy demands ramp up. My breathing quickens, and my heart rate accelerates to help me extract and utilize ever more oxygen from the air I breathe, in order to keep my muscles working. At this level of intensity, someone my size might require 2,500 to 3,000 ml of oxygen per minute, an eight- to tenfold increase from when I was sitting on the couch. Now, if I start running up a hill as fast as I can, my body’s oxygen demand will increase from there: 4,000 ml, 4,500 ml, even 5,000 ml or more depending on the pace and my fitness level. The fitter I am, the more oxygen I can consume to make ATP, and the faster I can run up that hill.
• A ten-year observational study of roughly 4,500 subjects ages fifty and older found that those with low muscle mass were at 40 to 50 percent greater risk of mortality than controls, over the study period. Further analysis revealed that it’s not the mere muscle mass that matters but the strength of those muscles, their ability to generate force. It’s not enough to build up big pecs or biceps in the gym—those muscles also have to be strong. They have to be capable of creating force. Subjects with low muscle strength were at double the risk of death, while those with low muscle mass and/or low muscle strength, plus metabolic syndrome, had a 3 to 3.33 times greater risk of all-cause mortality.
• Even better: You don’t need a doctor to prescribe exercise for you.
• I tell my patients that even if exercise shortened your life by a year (which it clearly does not), it would still be worthwhile purely for the healthspan benefits, especially in middle age and beyond.
• For our purposes, 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.
• 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 goal is to keep lactate levels constant, ideally between 1.7 and 2.0 millimoles. This is the zone 2 threshold for most people. If I’m working too hard, lactate levels will rise, so I’ll slow down. (It’s sometimes tempting to go too hard in zone 2, because the workout feels relatively “easy” on good days.) I make a point of this because lactate is literally what defines zone 2. It’s all about keeping lactate levels steady in this range, and the effort sustainable.
• 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.
• Typically, for patients who are new to exercising, we introduce VO2 max training after about five or six months of steady zone 2 work.
• Once maximal oxygen consumption or VO2 max drops below a certain level (typically about 18 ml/kg/min in men, and 15 in women), it begins to threaten your ability to live on your own. Your engine is beginning to fail.
• I’ve always been a fan of carrying heavy objects with my hands. As a teenager working on a construction site over the summers, I always volunteered to haul tools and materials across the site, and today I still incorporate some kind of carrying, typically with dumbbells, kettlebells, or sandbags, into most of my workouts. I’ve also become semiobsessed with an activity called rucking, which basically means hiking or walking at a fast pace with a loaded pack on your back. Three or four days a week, I’ll spend an hour rucking around my neighborhood, up and down hills, typically climbing and descending several hundred feet over the course of three or four miles. The fifty- to sixty-pound pack on my back makes it quite challenging, so I’m strengthening my legs and my trunk while also getting in a solid cardiovascular session. The best part is that I never take my phone on these outings; it’s just me, in nature, or maybe with a friend or a family member or a houseguest (for whom rucking is mandatory; I keep two extra rucksacks in the garage).
• 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.
• One of the standards we ask of our male patients is that they can carry half their body weight in each hand (so full body weight in total) for at least one minute,
• The final foundational element of strength is hip-hinging,
• It’s extremely subtle, but the way in which someone breathes gives tremendous insight to how they move their body and, more importantly, how they stabilize their movements. We run our patients through a series of respiration and movement tests to get the full picture of their respiration strategy and how it relates to their strength and stability issues.
• To help reacquaint us with our feet, Beth Lewis likes to put me, and our patients, through a routine she calls “toe yoga.” Toe yoga (which I hate, by the way) is a series of exercises intended to improve the dexterity and intrinsic strength of our toes, as well as our ability to control them with our mind.
• Now try to put just your big toe back on the floor, while keeping your other toes lifted. Trickier than you’d think, right? Now do the opposite: keep four toes on the floor and lift only your big toe. Then lift all five toes, and try to drop them one by one, starting with your big toe. (You get the idea.)[*3] If you can do this at all, it likely takes a concerted mental effort, your brain telling that big toe to drop or rise—which is exactly the point. One of the goals of stability training is to regain mental control, conscious or not, over key muscles and body parts. Because our feet spend so much time crammed into shoes that may or may not fit properly, and likely have a lot of padding in their soles, many of us have lost touch with our feet, or have worked them into unhelpful contortions over time.
• (Also important: I prefer to lift barefoot or in minimal shoes, with little to no cushioning in the soles because it allows me feel the full surface of my feet at all times.)
• One key test in our movement assessment is to have our patients stand with one foot in front of the other and try to balance. Now close your eyes and see how long you can hold the position. Ten seconds is a respectable time; in fact, the ability to balance on one leg at ages fifty and older has been correlated with future longevity, just like grip strength. (Pro tip: balancing becomes a lot easier if you first focus on grounding your feet, as described above.)
• The structure we most want to protect—and a major focus of stability training in general—is the spine. We spend so much of our time in car seats, in desk chairs, at computers, and peering at our various devices that modern life sometimes seems like an all-out assault on the integrity of our spine.
• That’s what stability is about: safe and powerful transmission of force through muscles and bones, and not joints or spinal hinge points.
• Our hands are quite amazing, actually, in that they are powerful enough to crush the juice out of a lemon yet dexterous enough to play a Beethoven sonata on the piano. Our grip can be firm yet feathery, transmitting force with finesse.
• One way that Beth likes to illustrate the importance of this is via a basic bicep curl with a (light) dumbbell. First, try the curl with your wrist bent slightly backward, just a bit out of line with your forearm. Now try the same bicep curl with your wrist straight. Which one felt stronger and more powerful? Which one felt like the fingers were more involved? It’s about building awareness of the importance of your fingers, as the last link in the chain.
• Balance is the real challenge with swimming, because our center of mass is way off from our center of volume, causing our hips to sink. Good swimmers learn to overcome this imbalance with training. But if you never take off the wetsuit, you will never learn how to fix this problem.
• Timing, duration, and intensity of exercise matter a lot. In general, aerobic exercise seems most efficacious at removing glucose from circulation, while high-intensity exercise and strength training tend to increase glucose transiently, because the liver is sending more glucose into the circulation to fuel the muscles. Don’t be alarmed by glucose spikes when you are exercising.

Metabolic Health & Nutrition

• Millions of people are suffering from a little-known and underdiagnosed liver condition that is a potential precursor to type 2 diabetes. Yet people at the early stages of this metabolic derangement will often return blood test results in the “normal” range. Unfortunately, in today’s unhealthy society, “normal” or “average” is not the same as “optimal.”
• Thus, I find it fascinating that this very important cellular mechanism can be triggered by certain kinds of interventions, such as a temporary reduction in nutrients (as when we are exercising or fasting)—and the drug rapamycin.
• 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.
• Whatever form it takes, fructose does not pose a problem when consumed the way that our ancestors did, before sugar became a ubiquitous commodity: mostly in the form of actual fruit. It is very difficult to get fat from eating too many apples, for example, because the fructose in the apple enters our system relatively slowly, mixed with fiber and water, and our gut and our metabolism can handle it normally. But if we are drinking quarts of apple juice, it’s a different story, as I’ll explain in a moment.
• I’ve seen patients work themselves into NAFLD by drinking too many “healthy” fruit smoothies, for the same reason: they are taking in too much fructose, too quickly. Thus, the almost infinite availability of liquid fructose in our already high-calorie modern diet sets us up for metabolic failure if we’re not careful (and especially if we are not physically active).
• “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.”
• 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.
• Another drug called ezetimibe (Zetia) blocks absorption of cholesterol in the GI tract.
• Ethyl eicosapentaenoic acid (Vascepa), a drug derived from fish oil and consisting of four grams of pharmaceutical-grade eicosapentaenoic acid (EPA), also has FDA approval to reduce LDL in patients with elevated triglycerides.
• WHAT’S GOOD FOR THE LIVER (AND PANCREAS) IS GOOD FOR THE BRAIN. Metabolic health is crucial to brain health.
• The correlation between poor metabolic health and being overnourished and undermuscled is very high. Hence, for a majority of patients the goal is to reduce energy intake while adding lean mass. This means we need to find ways to get them to consume fewer calories while also increasing their protein intake, and to pair this with proper exercise. This is the most common problem we are trying to solve around nutrition. When my patients are undernourished, it’s typically because they are not taking in enough protein to sustain muscle mass, which as we saw in the previous chapters is a crucial determinant of both lifespan and healthspan. So any dietary intervention that compromises muscle, or lean body mass, is a nonstarter—for both the under- and overnourished groups.
• 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.
• One of the best, or least bad, clinical trials ever executed seemed to show a clear advantage for the Mediterranean diet—or at least, for nuts and olive oil. This study also focused on the role of dietary fats.
• The basic problem we face is that, for perhaps the first time in human history, ample calories are available to many if not most people on the planet. But evolution has not prepared us for this situation. Nature is quite happy for us to be fat and frankly doesn’t care if we get diabetes.
• The farther away we get from the SAD, the better off we will be. This is the common goal of most “diets”—to help us break free of the powerful gravitational pull of the SAD so that we can eat less, and hopefully eat better. But eating less is the primary aim.
• From the standpoint of pure efficacy, CR or caloric restriction is the winner, hands down. This is how bodybuilders shed weight while holding on to muscle mass, and it also allows the most flexibility with food choices. The catch is that you have to do it perfectly—tracking every single thing you eat, and not succumbing to the urge to cheat or snack—or it doesn’t work. Many people have a hard time sticking with it.
• Upshot: the quality of your diet may matter as much as the quantity.
• Avoiding diabetes and related metabolic dysfunction—especially by eliminating or reducing junk food—is very important to longevity.
• 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.
• Carbohydrates are our primary energy source. In digestion, most carbohydrates are broken down to glucose, which is consumed by all cells to create energy in the form of ATP.
• Also, everyone tends to be more insulin sensitive in the morning than in the evening, so it makes sense to front-load our carb consumption earlier in the day.
• Another surprising thing I’ve learned thanks to CGM is about what happens to a patient’s glucose levels during the night. If she goes to bed at, say, 80mg/dL, but then her glucose ramps up to 110 for most of the night, that tells me that she is likely dealing with psychological stress. Stress prompts an elevation in cortisol, which in turn stimulates the liver to drip more glucose into circulation. This tells me that we need to address her stress levels and probably also her sleep quality.
• 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. I try to eat more than fifty grams of fiber per day.
• Fructose does not get measured by CGM, but because fructose is almost always consumed in combination with glucose, fructose-heavy foods will still likely cause blood-glucose spikes.
• 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).
• Stacking the above insights—in both directions, positive or negative—is very powerful. So if you’re stressed out, sleeping poorly, and unable to make time to exercise, be as careful as possible with what you eat.
• The first thing you need to know about protein is that the standard recommendations for daily consumption are a joke.
• How much protein do we actually need? It varies from person to person. In my patients I typically set 1.6 g/kg/day as the minimum, which is twice the RDA. The ideal amount can vary from person to person, but the data suggest that for active people with normal kidney function, one gram per pound of body weight per day (or 2.2 g/kg/day) is a good place to start—nearly triple the minimal recommendation.
• 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. A six-ounce serving of chicken, fish, or meat will provide about 40 to 45 grams (at about 7 grams of actual protein per ounce of meat), so our hypothetical 180-pound person should eat four such servings a day.
• Now, a word on plant protein. Do you need to eat meat, fish, and dairy to get sufficient protein? No. But if you choose to get all your protein from plants, you need to understand two things. First, the protein found in plants is there for the benefit of the plant, which means it is largely tied up in indigestible fiber, and therefore less bioavailable to the person eating it. Because much of the plant’s protein is tied to its roots, leaves, and other structures, only about 60 to 70 percent of what you consume is contributing to your needs, according to Don Layman, professor emeritus of food science and human nutrition at the University of Illinois Urbana-Champaign,
• Whey protein isolate (from dairy) is richer in available amino acids than soy protein isolate.
• Eating the right mix of fats can help maintain metabolic balance, but it is also important for the health of our brain, much of which is composed of fatty acids. On a practical level, dietary fat also tends to leave one feeling more satiated than many types of carbohydrates, especially when combined with protein.
• 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.
• In the final analysis, I tell my patients that on the basis of the least bad, least ambiguous data available, MUFAs are probably the fat that should make up most of our dietary fat mix, which means extra virgin olive oil and high-MUFA vegetable oils. After that, it’s kind of a toss-up, and the actual ratio of SFA and PUFA probably comes down to individual factors such as lipid response and measured inflammation. Finally, unless they are eating a lot of fatty fish, filling their coffers with marine omega-3 PUFA, they almost always need to take EPA and DHA supplements in capsule or oil form.

Sleep & Recovery

• A good versus bad night of sleep makes a world of difference in terms of glucose control. All things equal, it appears that sleeping just five to six hours (versus eight hours) accounts for about a 10 to 20 mg/dL (that’s a lot!) jump in peak glucose response, and about 5 to 10 mg/dL in overall levels.
• How long do we need to sleep? This question is tricky, because our sleep cycles are powerfully influenced by external cues such as sunlight, noise, and artificial lighting, not to mention our own emotions and stresses. Also, we are quite good at adapting to inadequate sleep, at least for a while. But many, many studies have confirmed what your mother told you: We need to sleep about seven and a half to eight and a half hours a night. There is even some evidence, from studies conducted in dark caves, that our eight-ish-hour sleep cycle may be hard-wired to some extent, suggesting that this requirement is non-negotiable.
• Translation: good sleep may help mitigate some of the genetic risk of heart disease faced by people like me. All of the above has convinced me to make sleep a top priority in my own life, and to pay attention to my patients’ sleep habits.
• sleep is to help us process our emotional memories, helping separate our emotions from the memory of the negative (or positive) experience that triggered those emotions. This is why, if we go to bed upset about something, it almost always seems better in the morning.
• One drug that we do find helpful for assisting with sleep is trazodone, a fairly old anti-depressant (approved in 1981) that never really took off. At the doses used to treat depression, two hundred to three hundred milligrams per day, it had the unwanted side effect of causing users to fall asleep. But one man’s trash is another man’s treasure. That side effect is what we want in a sleep medication, especially if it also improves sleep architecture, which is exactly what trazodone does—and most other sleep meds do not.[*4] We typically use it at much lower doses, from one hundred milligrams down to fifty milligrams or even less; the optimal dosing depends on the individual, but the goal is to find the amount that improves their sleep quality without next-day grogginess. (We have also had good results with the supplement ashwagandha.)
• Digital clocks are especially deadly, not only because of their bright numerals but also because if you wake up and see that it’s 3:31 a.m., you might start worrying about your 7 a.m. flight and never fall back asleep.
• One large-scale survey found that the more interactive devices subjects used during the hour before bedtime, the more difficulties they had falling asleep and staying asleep—whereas passive devices such as TV, electronic music players, and, best of all, books were less likely to be associated with poor sleep. This may partially explain why watching TV before bed does not seem to affect sleep quite as negatively as playing video games or scrolling social media does, according to research by Michael Gradisar, a sleep researcher and professor of psychology at Flinders University in Australia.
• Many people associate sleep with warmth, but in fact the opposite is true: One of the signal events as we are falling asleep is that our body temperature drops by about one degree Celsius. To help that happen, try to keep your bedroom cool—around sixty-five degrees Fahrenheit seems to be optimal. A warm bath before bed may actually help with this process, not only because the bath itself is relaxing but also because when we get out of the bath and climb into our cool bed, our core temperature drops, which signals to our brain that it is time to fall asleep. (There are also a variety of cooling mattresses and mattress toppers out there that could help people who like to sleep cool.)
• Don’t eat anything less than three hours before bedtime—and ideally longer. It’s best to go to bed with just a little bit of hunger (although being ravenous can be distracting.)
• For folks who have access, spend time in a sauna or hot tub prior to bed. Once you get into the cool bed, your lowering body temperature will signal to your brain that it’s time to sleep. (A hot bath or shower works too.)
• Darken the room completely. Make it dark enough that you can’t see your hand in front of your face with your eyes open, if possible. If that is not achievable, use an eye shade. I use a silky one called Alaska Bear that costs about $8 and works better than the fancier versions I’ve tried.

Cognitive Health & Brain Function

• You may have heard of this gene, which is called APOE, because of its known effect on Alzheimer’s disease risk. It codes for a protein called APOE (apolipoprotein E) that is involved in cholesterol transport and processing, and it has three variants: e2, e3, and e4. Of these, e3 is the most common by far, but having one or two copies of the e4 variant seems to multiply one’s risk of developing Alzheimer’s disease by a factor of between two and twelve. This is why I test all my patients for their APOE genotype, as we’ll discuss in chapter 9. The e2 variant of APOE, on the other hand, seems to protect its carriers against dementia—and it also turns out to be very highly associated with longevity. According to a large 2019 meta-analysis of seven separate longevity studies, with a total of nearly thirty thousand participants, people who carried at least one copy of APOE e2 (and no e4) were about 30 percent more likely to reach extreme old age (defined as ninety-seven for men, one hundred for women) than people with the standard e3/e3 combination. Meanwhile, those with two copies of e4, one from each parent, were 81 percent less likely to live that long, according to the analysis. That’s a pretty big swing.
• The greatest obstacle to discovery is not ignorance—it is the illusion of knowledge.
• I immediately scan for when I get a new patient’s results back. Among them is their level of Lp(a), the high-risk lipoprotein that we talked about in chapter 7, along with their apoB concentration. A third thing that I always check is their APOE genotype, the gene related to Alzheimer’s disease risk that we mentioned in chapter 4. Stephanie’s labs revealed that she had the APOE e4 allele, which is associated with a greater risk of Alzheimer’s disease—and not just one copy, but two (e4/e4), which meant her risk of developing Alzheimer’s disease was up to twelve times greater than that of someone with two copies of the common e3 allele. The e2 version of APOE appears to protect carriers against Alzheimer’s disease: 10 percent reduced risk for someone with e2/e3, and about 20 percent for e2/e2. Stephanie was unlucky.
• These are clinically validated, highly complex tests that cover every domain of cognition and memory, including executive function, attention, processing speed, verbal fluency and memory (recalling a list of words), logical memory (recalling a phrase in the middle of a paragraph), associative memory (linking a name to a face), spatial memory (location of items in a room), and semantic memory (how many animals you can name in a minute, for example). My patients almost always come back complaining about the difficulty of the tests. I just smile and nod.
• Can they correctly identify scents such as coffee, for example? Olfactory neurons are among the first to be affected by Alzheimer’s disease.
• 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. It seems to take a longer time for the disease to affect their ability to function. “People that have Alzheimer’s disease and are very cognitively engaged, and have a good backup pathway, they’re not going to decline as quickly,” Richard says.
• 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.
• There are computers that are bigger and faster, but no machine yet made by man can match the brain’s ability to intuit and learn, much less feel or create. No computer possesses anything approaching the multidimensionality of the human self.
• This enables the brain to take top priority to fuel itself when blood glucose levels are low. If we lack new sources of glucose, the brain’s preferred fuel, the liver converts our fat into ketone bodies, as an alternative energy source that can sustain us for a very long time, depending on the extent of our fat stores. (Unlike muscle or liver, the brain itself does not store energy.) When our fat runs out, we will begin to consume our own muscle tissue, then our other organs, and even bone, all in order to keep the brain running at all costs. The brain is the last thing to shut off.
• 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.
• Insulin seems to play a key role in memory function. Insulin receptors are highly concentrated in the hippocampus, the memory center of the brain. Several studies have found that spraying insulin right into subjects’ noses—administering it as directly as possible into their brains—quickly improves cognitive performance and memory, even in people who have already been diagnosed with Alzheimer’s disease.
• This graph shows how the incidence of dementia declines with increasing handgrip strength. Note that data are presented as hazard ratios in comparison with the weakest group; e.g., 0.4 = 40 percent. Thus someone with 40 kg grip strength has about 40 percent as much risk of dementia as someone with 10 kg.
• 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.
• 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.
• Endurance exercise such as running or cycling helps generate another potent molecule called brain-derived neurotrophic factor, or BDNF, that improves the health and function of the hippocampus, a part of the brain that plays an essential role in memory.

Biomarkers & Testing

• One test that I like to give patients is the oral glucose tolerance test, or OGTT, where the patient swallows ten ounces of a sickly-sweet, almost undrinkable beverage called Glucola that contains seventy-five grams of pure glucose, or about twice as much sugar as in a regular Coca-Cola.[*6] We then measure the patient’s glucose and their insulin, every thirty minutes over the next two hours. Typically, their blood glucose levels will rise, followed by a peak in insulin, but then the glucose will steadily decrease as insulin does its job and removes it from circulation.
• The takeaway for readers here is that your BMD is important, demanding at least as much attention as muscle mass, so you should at least check your BMD every few years. (Particularly if your primary sports are nonweight-bearing, like cycling or swimming.)
• This is called continuous glucose monitoring, or CGM, and it has become a very important part of my armamentarium in recent years.

Disease Prevention

• Researchers have identified two other cholesterol-related genes, known as CETP and APOC3, that are also correlated with extreme longevity (and may explain why centenarians rarely die from heart disease). But one individual gene, or even three dozen genes, is unlikely to be responsible for centenarians’ extreme longevity and healthspan. Broader genetic studies suggest that hundreds, if not thousands, of genes could be involved, each making its own small contribution—and that there is no such thing as a “perfect” centenarian genome.
• the seventh or eighth leading cause of death in the United States, behind things like kidney disease, accidents, and Alzheimer’s disease. In 2020, a little more than one hundred thousand
• At a certain point in this process, the plaque may start to become calcified. This is what (finally) shows up on a regular calcium scan. Calcification is merely another way in which the body is trying to repair the damage, by stabilizing the plaque to protect the all-important arteries.
• Brief Overview of Lipid-Lowering Medications 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.
• I tell patients, if you’re going to have a whole-body screening MRI, there is a good chance we’ll be chasing down an insignificant thyroid (or other) nodule in exchange for getting such a good look at your other organs. As a result of this, about a quarter of my patients, understandably, elect not to undergo such screening.
• This does come at significant cost, which is why Medicine 2.0 tends to be more conservative about screening. There is a financial cost, of course, but there is also an emotional cost, particularly of tests that may generate false positives. And there are other, incidental risks, such as the slight risk from a colonoscopy or the more significant risk from an unnecessary biopsy. These three costs must be weighed against the cost of missing a cancer, or not spotting it early, when it is still susceptible to treatment. Nobody said this was going to be easy. We still have a very long way to go.
• I now tell patients that exercise is, full stop and hands down, the best tool we have in the neurodegeneration prevention tool kit.
• (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.)
• Study after study has found that regular exercisers live as much as a decade longer than sedentary people.
• The spine has three parts: lumbar (lower back), thoracic (midback), and cervical (neck) spine. Radiologists see so much degeneration in the cervical spine, brought on by years of hunching forward to look at phones, that they have a name for it: “tech neck.”
• The authors concluded that there is no dose of alcohol that is “healthy.”
• The group receiving the olive oil had about a one-third lower incidence (31 percent) of stroke, heart attack, and death than the low-fat group, and the mixed-nuts group showed a similar reduced risk (28 percent).
• There appears to be a strong link between calories and cancer, the leading cause of death in the control monkeys in both studies. The CR monkeys had a 50 percent lower incidence of cancer.Lifestyle & Behavioral Changes
• There comes a point where we need to stop just pulling people out of the river. We need to go upstream and find out why they’re falling in.
• Our tactics in Medicine 3.0 fall into five broad domains: exercise, nutrition, sleep, emotional health, and exogenous molecules, meaning drugs, hormones, or supplements.
• “Isn’t it ironic that your entire professional life is predicated around trying to make people live longer,” she mused, “yet you’re putting no energy into being less miserable, into suffering less emotionally?”
• There is some risk involved in action, there always is. But there is far more risk in failure to act.
• Absorb what is useful, discard what is useless, and add what is specifically your own.
• Religion is a culture of faith; science is a culture of doubt.
• I am increasingly persuaded that our 24-7 addiction to screens and social media is perhaps our most destructive habit, not only to our ability to sleep but to our mental health in general.
• Why do we want to live longer? For what? For whom? My obsession with longevity was really about my fear of dying.