Cancer doesn’t care how rich you are. Or who your surgeon is, really. If it wants to find a way to kill you, it will. (Location 125)
the Four Horsemen: heart disease, cancer, neurodegenerative disease, or type 2 diabetes and related metabolic dysfunction. (Location 157)
Even when someone dies “suddenly” of a heart attack, the disease had likely been progressing in their coronary arteries for two decades. (Location 210)
Because I am an insatiably curious person by nature, I reached out to the leading experts in these fields and persuaded them to mentor me on my quest for knowledge. (Location 266)
Unfortunately, in today’s unhealthy society, “normal” or “average” is not the same as “optimal.” (Location 295)
The metabolic derangement that leads to type 2 diabetes also helps foster and promote heart disease, cancer, and Alzheimer’s disease. (Location 296)
This is called squaring the longevity curve. In this scenario, we live longer, and we live better for longer . We outlive our life expectancy, and we also exceed society’s expectations of what our later life is supposed to look like. (Location 761)
Someone who drops dead of a heart attack did not just get sick an hour earlier. The disease was working inside them, silently and invisibly, for decades. (Location 825)
Without an understanding of the strategy, and the science that informs it, our tactics will not mean much, and you’ll forever ride the merry-go-round of fad diets and trendy workouts and miracle supplements. (Location 834)
And to retain good health as we age, but without love and friendship and purpose, is a purgatory I would not wish on my worst enemy. (Location 892)
This is why our tactics are largely aimed at improving healthspan first; the lifespan benefits will follow. (Location 903)
Our tactics in Medicine 3.0 fall into five broad domains: exercise, nutrition, sleep, emotional health, and exogenous molecules, meaning drugs, hormones, or supplements. (Location 909)
Hair loss is not terribly relevant to longevity, luckily for me. (Location 1235)
One of the most potent individual genes yet discovered is related to cholesterol metabolism, glucose metabolism—and Alzheimer’s disease risk. 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 (Location 1251)
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. (Location 1257)
ancestry had identified three SNPs (or variants) in FOXO3 that were strongly associated with healthy aging and longevity. (Location 1285)
FOXO3 belongs to a family of “transcription factors,” which regulate how other genes are expressed—meaning whether they are activated or “silenced.” (Location 1291)
For example, when we are slightly deprived of nutrients, or when we are exercising, FOXO3 tends to be more activated, which is what we want. (Location 1299)
Ultimately, he and others discovered that rapamycin acted directly on a very important intracellular protein complex called mTOR (pronounced “em-tor”), for “mechanistic target of rapamycin.” [*2] Why do we care about mTOR? Because this mechanism turns out to be one of the most important mediators of longevity at the cellular level. (Location 1429)
Furthermore, there is no evidence that extreme CR would truly maximize the longevity function in an organism as complex as we humans, (Location 1526)
Reducing the amount of nutrients available to a cell seems to trigger a group of innate pathways that enhance the cell’s stress resistance and metabolic efficiency—all of them related, in some way, to mTOR. (Location 1532)
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. (Location 1542)
from mTOR and rapamycin to caloric restriction, points in one direction: that what we eat and how we metabolize it appear to play an outsize role in longevity. (Location 1659)
More than one in four people on this planet have some degree of NASH or its precursor, known as nonalcoholic fatty liver disease, (Location 1730)
Next question: What is normal? According to Labcorp, a leading testing company, the acceptable range for ALT is below 33 IU/L for women and below 45 IU/L for men (Location 1739)
In the late 1970s, the average American adult male weighed 173 pounds. Now the average American man tips the scale at nearly 200 pounds. (Location 1744)
I care about NAFLD and NASH—and you should too—because they represent the tip of the iceberg of a global epidemic of metabolic disorders, ranging from insulin resistance to type 2 diabetes. (Location 1770)
As we will see in the next few chapters, metabolic dysfunction vastly increases your risk for all of these. (Location 1776)
The upshot is that it’s not only obesity that drives bad health outcomes; it’s metabolic dysfunction. That’s what we’re concerned with here. (Location 1821)
Even if just 4.5 pounds of that is visceral fat, you would be considered at exceptionally high risk for cardiovascular disease and type 2 diabetes, in the top 5 percent of risk for your age and sex. This is why I insist my patients undergo a DEXA scan annually—and I am far more interested in their visceral fat than their total body fat. (Location 1897)
Patients with diabetes have a much greater risk of cardiovascular disease, as well as cancer and Alzheimer’s disease and other dementias; (Location 1965)
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. (Location 2008)
It will hopefully become clear to you, as it is to me, that the logical first step in our quest to delay death is to get our metabolic house in order. (Location 2113)
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, (Location 2241)
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. (Location 2252)
If you look at the coronary arteries with a CT scan at this very early stage, you will likely miss this if you’re looking only for calcium buildup. (You have a better chance of spotting this level of damage if using a more advanced type of CT scan, called a CT angiogram, which I much prefer to a garden-variety calcium scan[*4] because it can also identify the noncalcified or “soft” plaque that precedes calcification.) (Location 2401)
Since then, evidence has piled up pointing to apoB as far more predictive of cardiovascular disease than simply LDL-C, the standard “bad cholesterol” measure. (Location 2446)
so I suggested that he should probably also get a calcium scan, as I had done, so we could get a better sense of the state of his arteries. That’s where things got interesting. (Location 2474)
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. It is the most prevalent hereditary risk factor for heart disease, (Location 2497)
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 (Location 2505)
Note: blood test for lpa!
When I look at a patient’s blood panel for the first time, my eyes immediately dart to two numbers: apoB and Lp(a). (Location 2532)
Many doctors, and in fact many of you reading this, might be shocked to see such a low LDL-C target: 10 to 20 mg/dL? Most guidelines consider lowering LDL-C to 70 mg/dL to be “aggressive,” (Location 2553)
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. [*8] 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. (Location 2585)
(Amazingly, the longest statin trials to date have lasted just seven years.) But looking at their risk reduction potential over a thirty-year time frame, as the Sniderman study did, reduces the NNT down to less than 7: (Location 2654)
Rather, our best hope likely lies in figuring out better ways to attack cancer on all three of these fronts: prevention, more targeted and effective treatments, and comprehensive and accurate early detection. (Location 2821)
The first such hallmark is the fact that many cancer cells have an altered metabolism, consuming huge amounts of glucose . Second, cancer cells seem to have an uncanny ability to evade the immune system, (Location 2902)
Getting our metabolic health in order is essential to our anticancer strategy. (Location 2997)
Nature in 2018, with Mukherjee and Cantley as senior authors, the study found that a combination of a ketogenic diet and PI3K inhibitors improved the responses to treatment of mice that had been implanted with human cancer tumors. (Location 3039)
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. (Location 3050)
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. (Location 3061)
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. (Location 3211)
Not all polyps become cancer, but all colon cancers came from polyps. This is what makes a colonoscopy such a powerful tool. (Location 3307)
Why do I generally recommend a colonoscopy before the guidelines do? Mostly because, of all the major cancers, colorectal cancer is one of the easiest to detect, (Location 3329)
One newer technique that can enhance the ability of a screening MRI to differentiate between a cancer and noncancer is something called diffusion-weighted imaging with background subtraction, or DWI for short. (Location 3348)
Those imaging-based tests require “seeing” the tumor, which can happen only when the tumor reaches a certain size. (Location 3412)
With Galleri, the test is looking at cell-free DNA, which can come from any size tumor—even ones that remain invisible to imaging tests. (Location 3413)
If the first rule of cancer is “Don’t get cancer,” the second rule is “Catch it as soon as possible.” (Location 3443)
there are a few things that 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 (Location 3502)
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. (Location 3508)
they have other genes that protect them from e4; for example, a certain variant of the gene Klotho (KL), called kl-vs, seems to protect carriers of e4 from developing dementia. (Location 3553)
The APOE e4 variant not only increases someone’s risk for Alzheimer’s but also significantly raises their risk of Lewy body dementia as well as Parkinson’s disease with dementia, further supporting the notion that these conditions are related on some level. (Location 3672)
Exercise is the only intervention shown to delay the progression of Parkinson’s. (Location 3830)
The key insight was that robust blood flow seemed to be critical to maintaining brain health. (Location 3865)
vascular dementia is currently considered distinct from dementia (Location 3904)
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. (Location 3910)
Even young patients with e4 show dramatic blood glucose spikes after eating carbohydrate-rich foods, although the clinical significance of this is unclear. (Location 3962)
the greater someone’s grip strength, the lower their risk of dementia. (Location 4021)
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. (Location 4052)
One other somewhat recent addition to my thinking on dementia (and ASCVD while we’re at it) prevention is the use of dry saunas. (Location 4061)
The longer we can go without developing dementia, the better our odds of living longer, and living in better health. (Location 4083)
The most common way to be killed, as a driver, is by another car that hits yours from the left, on the driver’s side, having run a red light or traveling at high speed. (Location 4173)
We are not “keto” or “low-fat,” and we do not emphasize aerobic training at the expense of strength, or vice versa. We range widely and pick and choose and test tactics that will hopefully work for us. (Location 4229)
An average forty-five-year-old man will have a VO2 max around 40 ml/kg/min, while an elite endurance athlete will likely score in the high 60s and above. (Location 4331)
But I can say with a very high degree of certainty that having a higher VO2 max is better for your overall health and longevity than having a lower VO2 max. Period. (Location 4374)
Seniors with the least muscle mass (also known as lean mass) are at the greatest risk of dying from all causes. (Location 4433)
Think of the Centenarian Decathlon as the ten most important physical tasks you will want to be able to do for the rest of your life. Some of the items on the list resemble actual athletic events, while some are closer to activities of daily living, and still others might reflect your own personal interests. (Location 4533)
Over the next thirty or forty years, your muscle strength will decline by about 8 to 17 percent per decade—accelerating as time goes on. (Location 4552)
It’s a bit hard to define, but I think of stability as the solid foundation that enables us to do everything else that we do, without getting injured. (Location 4639)
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. (Location 4662)
You take your average wattage output for a zone 2 session and divide it by your weight to get your watts per kilogram, which is the number we care about. (Location 4797)
Even if you are not competing in high-level endurance sports, your VO2 max is an important number that you can and should know. (Location 4821)
VO2 max. We have all our patients do the test at least annually, (Location 4827)
Activities that are easy when we are young or middle-aged become difficult if not impossible as we get older. (Location 4838)
Our goal is to become elite athletes of aging. (Location 4885)
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. (Location 4909)
study of twelve healthy volunteers with an average age of sixty-seven found that after just ten days of bed rest, which is about what a person would experience from a major illness (Location 4965)
it is very difficult to put on muscle mass later in life. (Location 4979)
We measure BMD in every patient, every year, looking at both of their hips and their lumbar spine using DEXA. (Location 4981)
I think of strength training as a form of retirement saving. Just as we want to retire with enough money saved up to sustain us for the rest of our lives, we want to reach older age with enough of a “reserve” of muscle (and bone density) (Location 5011)
Yet unlike some guys in the gym, I’m less concerned with how big my biceps are (Location 5018)
life). A far more important measure of strength, I’ve concluded, is how much heavy stuff you can carry. (Location 5021)
You’re setting yourself up to age well. It’s not about how much weight you can deadlift now, but how well you will function in twenty or thirty or forty years. (Location 5067)
Note: Think about the future when going to the gym
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, (Location 5089)
The final foundational element of strength is hip-hinging, which is what it sounds like: (Location 5130)
But I think the missing X factor that explains why so many people just stop moving is something else: injury. (Location 5177)
botched), followed by a long and very difficult recovery. For (Location 5182)
we need to be able to anticipate and avoid any potential injuries that lie in our path, like icebergs at sea. (Location 5220)
My problem, as these photos make painfully clear, was that I lacked stability. It even hurts to look at it now, because it reminds me of the thousands of atrocious, strain-inducing squats I’d committed in this awkward position. (Location 5281)
This is how it works, as I would learn: We try to cheat or work around our existing injuries and limitations and end up creating new problems. (Location 5285)
suggest visiting the websites for DNS (www.rehabps.com) and the Postural Restoration Institute (PRI) (www.posturalrestoration.com), the two leading exponents of what I’m talking about here. (Location 5339)
I practice this 360- degree abdominal breathing every day, not only in the gym but also while I am at my desk. (Location 5429)
I’ve posted a video demonstration of this and other exercises at www.peterattiamd.com/ outlive/ videos. (Location 5475)
I have made is that I am no longer a dogmatic advocate of any particular way of eating, such as a ketogenic diet or any form of fasting. (Location 5773)
I think it boils down to the simple questions that we posited in chapter 10: 1. Are you under nourished, or over nourished? 2. Are you under muscled, or adequately muscled? 3. Are you metabolically healthy or not? (Location 5792)
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. (Location 5798)
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. (Location 5814)
Our knowledge of nutrition comes primarily from two types of studies: epidemiology and clinical trials. (Location 5836)
The point is that humans are terrible study subjects for nutrition (or just about anything else) because we are unruly, disobedient, messy, forgetful, confounding, hungry, and complicated creatures. (Location 5866)
Our goal in the next chapter is to help you figure out the best eating plan for you, as an individual. To do that, we must move beyond labels and dive into nutritional biochemistry. (Location 6021)
My doctor told me to stop having intimate dinners for four. Unless there are three other people. (Location 6046)
For example, cheese is a processed food, invented as a way to preserve milk, which would otherwise spoil quickly without refrigeration. (Location 6075)
Similarly, replacing carbohydrates with lots of saturated fats can backfire if it sends your apoB concentration (and thus your cardiovascular disease risk) sky-high. (Location 6276)
But tests showed that he had almost no ability to store excess sugar that he consumed. His hemoglobin A1c was 9.7 percent, well into the diabetic red zone. (Location 6287)
nutritional biochemistry. The way we do this is by manipulating our four macronutrients: alcohol, carbohydrates, protein, and fat. (Location 6320)
Alcohol (Location 6324)
It’s especially disruptive for people who are overnourished, for three reasons: it’s an “empty” calorie source that offers zero nutrition value; the oxidation of ethanol delays fat oxidation, which is the exact opposite of what we want if we’re trying to lose fat mass; and drinking alcohol very often leads to mindless eating. (Location 6328)
My personal bottom line: if you drink, try to be mindful about it. You’ll enjoy it more and suffer fewer consequences. (Location 6345)
strongly urge my patients to limit alcohol to fewer than seven servings per week, and ideally no more than two on any given day, (Location 6346)
CGM has proved especially useful in patients with APOE e4, where we often see big glucose spikes, even in relatively young people. (Location 6432)
One thing CGM pretty quickly teaches you is that your carbohydrate tolerance is heavily influenced by other factors, especially your activity level and sleep. (Location 6455)
If she goes to bed at, say, 80 mg/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. (Location 6462)
We also monitor other variables that are relevant to diet, beginning with weight (obviously) but continuing with body composition, the ratios of lean mass and fat mass, and how they change. We can also look at biomarkers such as lipids, uric acid, insulin, and liver enzymes. (Location 6479)
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. (Location 6493)
I’ve come to appreciate the fact that CGM creates its own Hawthorne effect, a phenomenon where study subjects change their behavior because they are being observed. (Location 6508)
Protein (Location 6511)
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. (Location 6517)
The first thing you need to know about protein is that the standard recommendations for daily consumption are a joke. (Location 6527)
In my patients I typically set 1.6 g/kg/day as the minimum, (Location 6539)
130 grams of protein per day, and ideally closer to 180 grams, especially if they are trying to add muscle mass. (Location 6543)
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 (Location 6544)
Typically, I will consume a protein shake, a high-protein snack, and two protein meals.) (Location 6563)
Layman suggests focusing on a handful of important amino acids, such as leucine, lycine, and methionine. (Location 6580)
If you are trying to increase lean mass, you’ll need even more leucine, closer to two to three grams per serving, four times per day. (Location 6583)
Fat (Location 6604)
There are (broadly) three types of fats: saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA). (Location 6616)
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. (Location 6621)
We titrate the level of EPA and DHA in our patients’ diets by measuring the amount of each found in the membranes of their red blood cells (RBC), using a specialized but readily available blood test. (Location 6635)
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. (Location 6702)
So perhaps an early-day feeding window could be effective, but in my view sixteen hours without food simply isn’t long enough to activate autophagy or inhibit chronic mTOR elevation, or engage any of the other longer-term benefits of fasting that we would want to obtain. (Location 6754)
difficulty adhering to the strict ketogenic diet for very long—he felt hungry, and he craved his old familiar carb-heavy foods. Thus, he was never able (Location 6805)
craved his old familiar carb-heavy foods. Thus, he was never able to switch his metabolism into ketosis and drive down his hunger. Because of his persistently high insulin, his fat cells were refusing to give up the energy they had stored. So he felt hungry all the time, and he could not (Location 6806)
Bad nutrition can hurt us more than good nutrition can help us. If you’re already metabolically healthy, nutritional interventions can only do so much. (Location 6844)
Protein is actually the most important macronutrient, the one macro that should not be compromised. (Location 6853)
I have one final piece of advice. Stop overthinking nutrition so much. Put the book down. Go outside and exercise. (Location 6878)
Now I recognize that sleep, diet, and risk of long-term diseases are all intimately connected to each other. (Location 7066)
Higher stress levels can make us sleep poorly, as we all know, but poor sleep also makes us more stressed. It’s a feedback loop. (Location 7089)
When we sleep poorly, we can be desperately, irrationally hungry the next day, and more likely to reach for high-calorie and sugary foods than their healthy alternatives. (Location 7101)
It’s also worth reiterating that long sleep is also often a sign not only of poor sleep quality, but other potential health problems. (Location 7298)
Probably the best-validated sleep questionnaire is the Pittsburgh Sleep Quality Index, (Location 7300)
We all have different relationships to the circadian cycle, and much of that relationship is genetic: a morning person and a night owl will have different circadian genes. (Location 7317)
Everyone differs in their caffeine tolerance, based on genes and other factors (23andMe tests for one common caffeine-related gene). (Location 7406)
Alcohol probably impairs sleep quality more than any other factor we can control. Don’t confuse the drowsiness it produces with quality sleep. (Location 7440)
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.) (Location 7448)
Fix your wake-up time—and don’t deviate from it, even on weekends. (Location 7459)
Emotional health and physical health are closely intertwined, (Location 7586)
This is why I’ve come to believe that emotional health may represent the most important component of healthspan. (Location 7614)
Even just living alone, or feeling lonely, is linked to a much higher risk of mortality. (Location 7618)
It took me a while to recognize this, but feeling connected and having healthy relationships with others, and with oneself, is as imperative as maintaining efficient glucose metabolism or an optimal lipoprotein profile. (Location 7624)
It is just as important to get your emotional house in order as it is to have a colonoscopy or an Lp(a) test, if not more so. (Location 7625)
Trauma generally falls into five categories: (1) abuse (physical or sexual, but also emotional or spiritual); (2) neglect; (3) abandonment; (4) enmeshment (the blurring of boundaries between adults and children); and (5) witnessing tragic events. Most of the things that wound children fit into these five categories. (Location 7695)
Our Medicine 3.0 thesis is that if we address our emotional health, and do so early on, we will have a better chance of avoiding clinical mental health issues such as depression and chronic anxiety—and our overall health will benefit as well. (Location 7765)
I was ready to give up when Esther suggested that I read Terrence Real’s book I Don’t Want to Talk About It, (Location 7788)
I learned that children don’t respond to a parent’s anger in a logical way. If they see me screaming at a driver who just cut me off, they internalize that rage as though it were directed to them. (Location 7818)
One of the most powerful exercises I learned was to simply listen to my self-talk. I would record voice memos to myself on my phone, after I did anything that could produce self-judgment, (Location 8062)
simply thinking about problems might not help if our thinking itself is disordered. (Location 8110)
For the first time in my life, I felt that I could be a good father. I could be a good husband. I could be a good person. After all, this is the whole point of living. And the whole point of outliving. (Location 8155)