CR: Calories Matter

I may be starting to sound like a broken record, but it should be obvious by now that many of the problems we want to address or avoid stem from consuming calories in excess of what we can use or safely store. If we take in more energy than we require, the surplus ends up in our adipose tissue, one way or another. If this imbalance continues, we exceed the capacity of our “safe” subcutaneous fat tissue, and excess fat spills over into our liver, our viscera, and our muscles, as we discussed in chapter 6.

How many calories you consume has a huge impact on everything else we’re talking about in this book. If you’re ingesting one thousand extra calories a day, of anything, you’re going to have problems sooner or later. In prior chapters, we’ve seen how excess calories contribute to many chronic diseases, not only metabolic disorders but also heart disease, cancer, and Alzheimer’s disease. We also know from decades of experimental data (chapter 5) that eating fewer calories tends to lengthen lifespan, at least in lab animals such as rats and mice—although there is debate over whether this represents true lifespan extension or an elimination of the known hazards of overfeeding, the default state of the control animals in most of these experiments. (And also, of many modern humans.)

In human beings, as opposed to laboratory animals, caloric restriction typically goes by a different name: calorie counting. There is plenty of research showing that people who count their calories and limit them can and do lose weight, the primary end point of such studies. This is how Weight Watchers works. The biggest obstacles to doing this successfully are first of all hunger and second the requirement that you track what you eat in meticulous detail. The apps that help you do this today are better than ten years ago, but it’s still not easy. For the right person, this approach works incredibly well—it’s a favorite of bodybuilders and athletes—but for many, the requirement of constant tracking makes it unfeasible.

One slight advantage is that calorie counting is agnostic to food choices; you can eat whatever you want so long as you stay within your daily allowance. But if you make too many poor decisions, you will be very hungry, so buyer beware. You can lose weight on a restricted-calorie diet consisting only of Snickers bars, but you will feel much better if you opt for steamed broccoli and chicken breasts instead.

There has been a long-running controversy over whether caloric restriction could or should be applied to humans as a tool to enhance longevity. It did seem to work for Luigi Cornaro, the dieting Italian gentleman from the sixteenth century—he claimed to have lived to one hundred, although he was probably actually in his eighties when he died. This supposed longevity benefit is, obviously, a difficult proposition to study in human beings over the long term, for some of the reasons I’ve just outlined. So the hypothesis was tested in monkeys, in two long-running primate studies. The results were so surprising that they are still being debated.

In July of 2009, a study published in Science found that rhesus monkeys that had been fed a reduced-calorie diet for more than two decades had lived markedly longer than those who were allowed to eat freely. “Dieting Monkeys Offer Hope for Living Longer,” declared the headline on the front page of The New York Times. The accompanying photos told the story: on the left was a monkey named Canto, looking trim and spry at the relatively advanced age of twenty-seven, while on the right sat Owen, just two years older but looking like Canto’s flabby, dissipated uncle. Canto had been on a calorically restricted diet for most of his life, while Owen had eaten just about as much food as he wanted.

Owen and Canto were two of seventy-six monkeys in this study, begun two decades earlier at the University of Wisconsin–Madison. Half of the monkeys (the control group) were fed ad libitum, meaning they could eat as much food as they wanted, while the other half were placed on a “diet” allowing them about 25 percent fewer calories than the controls. They then lived out their lives as the researchers observed them growing older.

Aging studies tend to be about as exciting as watching paint dry, but the end results were pretty dramatic. In the end, the calorically restricted monkeys lived significantly longer and proved far less likely to die of age-related diseases than the ad libitum–fed control monkeys. They were healthier by many other measures, such as insulin sensitivity. Even their brains were in better shape than those of the controls, retaining more gray matter as they aged. “These data demonstrate that caloric restriction slows aging in a primate species,” the study authors concluded.

Case closed, or so it seemed.

Three years later, in August 2012, another monkey study made the front page of the Times, but with a markedly different headline: “Severe Diet Doesn’t Prolong Life,” the paper declared grimly, adding, “At Least in Monkeys.” This study, also begun in the 1980s, was conducted under the auspices of the National Institute on Aging, one of the National Institutes of Health, and the study design was nearly identical to the Wisconsin study, with one group of monkeys being fed about 25 to 30 percent less than the other. Yet the NIH researchers found that their calorically restricted monkeys had not lived longer than the controls. There was no statistically significant difference in the lifespans of the two groups. From a headline writer’s point of view, caloric restriction had not “worked.”

Journalists love it when a study contradicts whatever the last well-publicized study said. In the small world of people who study aging, the NIH results caused consternation. Everyone had expected that the NIH monkey study would confirm the results seen in Wisconsin. Now it appeared as if the two research teams had spent tens of millions of dollars in federal grant money to demonstrate that caloric restriction lengthens monkey lifespans in Wisconsin but not in Maryland, where the NIH monkeys were kept.

But sometimes science tells us more when an experiment “fails” than when it yields the expected results, and so it was with the monkeys. When examined side by side, the two monkey studies had some seemingly minor differences that turned out to be hugely significant—and very pertinent to our strategy as well. Together, the dueling monkey studies constitute one of the most rigorous experiments ever done about the complex relationship between nutrition and long-term health. And like many of the best scientific experiments, this one happened at least partly by accident.

The most profound difference between the two studies was also the most fundamental, for a diet study: the food that the monkeys ate. The Wisconsin animals ate an off-the-shelf commercial monkey chow that was “semipurified,” meaning its ingredients were highly processed and rigorously titrated. The NIH monkeys were fed a diet that was similar in its basic macronutrient profile, but their chow was “natural” and less refined, custom formulated from whole ingredients by an in-house primate nutritionist at NIH. The most glaring contrast: while the NIH monkey chow contained about 4 percent sugar, the Wisconsin diet comprised an astonishing 28.5 percent sucrose, by weight. That is a greater proportion of sugar than you’ll find in vanilla Häagen-Dazs ice cream.

Could that alone have explained the difference in survival outcomes? Possibly: more than 40 percent of the Wisconsin control monkeys, the ones not subject to calorie limitations, developed insulin resistance and prediabetes, while just one in seven of the NIH controls became diabetic.[*1] And the Wisconsin control monkeys proved far more likely to die from cardiovascular causes and cancer than monkeys from any other group. This could suggest that caloric restriction was eliminating early deaths because of the bad Wisconsin diet more than it was actually slowing aging—which is still useful information, as avoiding diabetes and related metabolic disorders is important to our strategy.

The Wisconsin researchers defended their diet as more similar to what Americans actually eat, which is a fair point. The comparison is not exact by any means, but in human terms the Wisconsin monkeys were more or less living on fast food, while the NIH monkeys were eating at the salad bar. The Wisconsin control monkeys ate the most calories, of the worst food, and their health suffered. Makes sense; if your diet consists mostly of cheeseburgers and milkshakes, then eating fewer cheeseburgers and milkshakes is going to help you.

The NIH diet was much higher in quality. Instead of ultraprocessed ingredients like corn oil and cornstarch (another 30 percent of the Wisconsin diet), the NIH monkey chow contained ground whole wheat and corn, and thus more phytochemicals and other possibly beneficial micronutrients like those typically found in fresh food. While not exactly natural, it was at least closer to what rhesus monkeys would actually eat in the wild. So giving the NIH monkeys more or less of that feed may have had less of an impact because the diet was not as harmful to begin with. Upshot: the quality of your diet may matter as much as the quantity.

Taken together, then, what do these two monkey studies have to tell us about nutritional biochemistry?

1. Avoiding diabetes and related metabolic dysfunction—especially by eliminating or reducing junk food—is very important to longevity.

2. 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.

3. 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.

4. Conversely, if your diet is high quality to begin with, and you are metabolically healthy, then only a slight degree of caloric restriction—or simply not eating to excess—can still be beneficial.

I think this last point is key. These two studies suggest that if you are eating a higher-quality diet—and are metabolically healthy to begin with—then severe caloric restriction may not even be necessary. The NIH control monkeys ate as much as they wanted of their better diet and still lived nearly as long as the CR monkeys in both studies. Interestingly, the post facto analyses also revealed that the NIH control monkeys naturally consumed about 10 percent fewer calories per day than the Wisconsin controls, likely because their higher-quality diet left them feeling less hungry. The researchers speculated that even this very slight degree of caloric reduction may have been significant—certainly, it supports our thesis that it is better to avoid being overnourished.

Note that these study results do not suggest that everyone needs to undertake a drastic, severe reduction in caloric intake. Limiting calories can be helpful for people who are metabolically unhealthy and/or overnourished. But I’m not convinced that whatever longevity boost long-term, deep caloric restriction may confer is worth some of the trade-offs—including potentially weakened immunity and greater susceptibility to cachexia and sarcopenia (muscle loss), not to mention constant hunger. These unwanted side effects would accelerate some of the negative processes that already go along with aging, suggesting that in older people especially, caloric restriction might do more harm than good.

The monkeys teach us that if you are metabolically healthy and not over-nourished, like the NIH animals, then avoiding a crap diet may be all you need. Some of the NIH CR monkeys ended up with some of the longest lifespans ever recorded in rhesus monkeys. It seems quite clear, then, that even for monkeys, limiting caloric intake and improving diet quality “works”—it’s how you pull it off that is tricky. As we’ll see in the next section, there are many other strategies we can adopt to limit the calories we consume and to tailor our food consumption to suit our metabolism and way of life.

DR: The Nutritional Biochemistry “Diet”

Dietary restriction (DR) represents the land of conventional “diets,” where 90 percent of the attention—and research funding, and energy, and anger, and, of course, arguing—over nutritional biochemistry is focused. But it is pretty simple, when you get down to it: identify one or more bogeymen in your nutrition world, such as wheat gluten (for example), and exclude it. The more ubiquitous the bogeyman, the more restrictive the “diet,” and the more likely you are to reduce your overall caloric intake. Even if you decided to eat nothing but potatoes, you would still lose weight, because a human being can only choke down so many potatoes in a day. I’ve seen people do this, and it works. The hard part is figuring out what foods to eliminate or restrict.

This wasn’t an issue for our ancestors. There is ample evidence to suggest that they were opportunistic omnivores, out of necessity. They ate anything and everything they could get their hands on: lots of plants, lots of starch, animal protein whenever they could, honey and berries whenever possible. They also seemed to be, at least on the basis of the study of the few remaining hunter-gatherer societies, very metabolically healthy.

Should we do the same? Should we be opportunistic omnivores eating anything and everything we can get our hands on? That’s how evolution has formed us, but our modern food environment makes it a little too easy to find food. Thus, being overnourished and metabolically unhealthy is now commonplace. We have too many choices and too many delicious ways to take calories into our body. Hence the need for dietary restriction. We need to erect walls around what we can and cannot (or should not) eat.

The advantage of DR is that it is highly individualized; you can impose varying degrees of restriction, depending on your needs. For example, you could decide to eliminate all sugar-sweetened beverages, and that would be a great first step (and a relatively easy one). You could go a step further and quit drinking sweet fruit juices as well. You could quit eating other foods with added sugar. Or you could go as far as reducing or eliminating carbohydrates in general.

One reason carbohydrate restriction is so effective for many people is that it tends to reduce appetite as well as food choices. But some people have a harder time maintaining it than others. (Even I am pretty sure I could never go back to a ketogenic diet for more than a few days.) While fat restriction also limits food choices, it can be less effective at reducing appetite if you pick the wrong low-fat foods to eat (e.g., high-carb junk food). If you consume most of your carbohydrates in the form of Fruit Loops, for example, you will still be very hungry all the time.

A major risk with DR is that you can still easily end up overnourished if you are not deliberate about it. People tend to (erroneously) assume you can’t eat too much if you’re just restricting fill-in-the-blank (e.g., carbohydrates). This is incorrect. Even if done correctly and strictly, DR can still result in overnutrition. If you cut out carbohydrates altogether but overdo it on the Wagyu steaks and bacon, you will fairly easily find yourself in a state of caloric excess. The key is to pick a strategy to which you can adhere but that also helps achieve your goals. This takes patience, some willpower, and a willingness to experiment.

We also want to be sure we’re not compromising our other goals along the way. Any form of DR that restricts protein, for example, is probably a bad idea for most people, because it likely also impairs the maintenance or growth of muscle. Similarly, replacing carbohydrates with lots of saturated fats can backfire if it sends your apoB concentration (and thus your cardiovascular disease risk) sky-high.

A more significant issue with DR is that everyone’s metabolism is different. Some people will lose tremendous amounts of weight and improve their metabolic markers on a low-carbohydrate or ketogenic diet, while others will actually gain weight and see their lipid markers go haywire—on the exact same diet. Conversely, some people might lose weight on a low-fat diet, while others will gain weight. I have seen this happen time and again in my own practice, where similar diets yield very different outcomes, depending on the individual.

For example, when my patient Eduardo came to see me a few years ago with what turned out to be a case of full-blown type 2 diabetes, cutting his carbohydrate intake was clearly the way to go. Type 2 diabetes is a condition of impaired carbohydrate metabolism, after all. From the outside, Eduardo seemed like a pretty healthy guy, with a soccer player’s build and a physical job in construction. He certainly did not fit the (bogus) stereotype of the lazy, gluttonous diabetic. 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. Being Latino meant that Eduardo was at a higher risk of NAFLD and diabetes to begin with, thanks to his genes. He wasn’t even forty, but unless we did something drastic, he more than likely was going to die a painful and early death.

The obvious first step was to wean Eduardo off carbohydrates almost entirely. No more tortillas, rice, or starchy beans—and no Gatorade, either. Because he worked outside in the heat, he was pounding about three or four liters of “sports drinks” each day. I never once described this diet as “ketogenic,” and Eduardo certainly wasn’t telling the guys on the job site about his new trendy keto diet. He just wasn’t drinking Gatorade anymore. (I also put him on the diabetes drug metformin, which is cheap as well as effective.) Within about five months, Eduardo’s markers had all normalized, and his diabetes seemed to have been reversed; his hemoglobin A1c was now a completely normal 5.3 percent, just thanks to dietary changes and metformin. And along the way he lost about twenty-five pounds. I’m not saying this diet was the only possible path to this result, but this relatively simple and achievable form of DR created enough of an energy imbalance that he lost weight, and everything else improved in lockstep.

In the past, I was a huge proponent of ketogenic diets, finding them particularly useful to manage or prevent diabetes in patients like Eduardo. I also like that they have a strict definition, unlike “low carb” or “low fat.” A ketogenic diet means restricting carbohydrates to such an extent that the body begins metabolizing fat into “ketone bodies” that the muscles and brain can utilize as fuel. A ketogenic diet helped fix Not-Thin Peter, and it had likely saved Eduardo’s life. I thought it was the medicine that every metabolically unhealthy person needed.

But my patients brought me back to earth, as they so often do. As a physician, one often receives feedback in a very direct, personal way. If I give someone a medication or a recommendation, I will find out pretty quickly whether it is working. It’s not “data” in the strict sense, but it can be equally powerful. I’ve had more than one patient for whom a ketogenic diet has completely failed. They didn’t lose weight, and their liver enzymes and other biomarkers failed to improve. Or they found it impossible to sustain. I’ve had other patients who were able to stick to the diet, but then their lipid numbers (especially their apoB) went through the roof, probably because of all the saturated fats they were eating.

At the time, this confused me. What was wrong with them? Why couldn’t they just follow the diet correctly? I had to remind myself of what Steve Rosenberg used to say when a patient’s cancer progressed despite treatment: The patient has not failed the treatment; the treatment has failed the patient.

These patients needed a different treatment.

The real art to dietary restriction, Nutrition 3.0–style, is not picking which evil foods we’re eliminating. Rather, it’s finding the best mix of macronutrients for our patient—coming up with an eating pattern that helps them achieve their goals, in a way that they can sustain. This is a tricky balancing act, and it requires us (once again) to forget about labels and viewpoints and drill down into nutritional biochemistry. The way we do this is by manipulating our four macronutrients: alcohol, carbohydrates, protein, and fat. How well do you tolerate carbohydrates? How much protein do you require? What sorts of fats suit you best? How many calories do you require each day? What is the optimal combination for you?

Let’s now look at each of the four macronutrients in more detail.

Alcohol

It’s easy to overlook, but alcohol should be considered as its own category of macronutrient because it is so widely consumed, it has such potent effects on our metabolism, and it is so calorically dense at 7 kcal/g (closer to the 9 kcal/g of fat than the 4 kcal/g of both protein and carbohydrate).

Alcohol serves no nutritional or health purpose but is a purely hedonic pleasure that needs to be managed. 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.

While I certainly enjoy an occasional glass of my favorite Belgian beer, Spanish red wine, or Mexican tequila (never in the same sitting, obviously), I also believe that drinking alcohol is a net negative for longevity. Ethanol is a potent carcinogen, and chronic drinking has strong associations with Alzheimer’s disease, mainly via its negative effect on sleep, but possibly via additional mechanisms. Like fructose, alcohol is preferentially metabolized in the liver, with well-known long-term consequences in those who drink to excess. Last, it loosens inhibitions around other kinds of food consumption; give me a few drinks, and the next thing you know I’m elbow-deep in the Pringles can as I pace around the pantry looking for my next snack.

There have been numerous well-publicized studies suggesting that moderate levels of alcohol consumption can be beneficial, for example by improving endothelial function and reducing clotting factors, both of which would reduce cardiovascular disease risk. But heavier drinking tends to reverse those effects. And as shown by the Mendelian randomization study in JAMA that we talked about in the previous chapter, “moderate drinking” is so confounded by healthy user bias that it is impossible to put much faith in these studies purporting to show a health benefit for drinking.

Nevertheless, for many of my patients, the lifestyle around moderate drinking (e.g., a nice glass of wine with a non-SAD dinner) helps them dissipate stress. My personal bottom line: if you drink, try to be mindful about it. You’ll enjoy it more and suffer fewer consequences. Don’t just keep drinking because they’re serving it on the plane. I strongly urge my patients to limit alcohol to fewer than seven servings per week, and ideally no more than two on any given day, and I manage to do a pretty good job adhering to this rule myself.

Carbohydrates

The balance of our nonalcohol diet consists of carbohydrates, protein, and fat, and it’s largely a job of finding the right mix for you as an individual. In the days of labeled diets, we would assemble our macronutrients and sort out the different types of foods, using rules and arbitrary boundaries—you can eat this, but not that; these, but not those. We would basically be guessing at the right mix. And then we would wait to see whether it “worked,” typically defined in terms of whether the person lost weight over a period of weeks or months. Now we have more sophisticated ways of looking at macronutrients, beginning with the most abundant: carbohydrates.

Carbs probably create more confusion than any other macro. They are neither “good” nor “bad”—although some types are better than others. Overall, it’s more a question of matching dose to tolerance and demand, which is much less tricky than it used to be. Thanks to advancements in technology, we no longer need to guess; we now have data.

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. Excess glucose, beyond what we need immediately, can be stored in the liver or muscles as glycogen for near-term use or socked away in adipose tissue (or other places) as fat. This decision is made with the help of the hormone insulin, which surges in response to the increase in blood glucose.

We already know that it’s not good to consume excessive calories. In the form of carbohydrates, those extra calories can cause a multitude of problems, from NAFLD to insulin resistance to type 2 diabetes, as we saw in chapter 6. We know that elevated blood glucose, over a long enough period of time, amplifies the risk of all the Horsemen. But there is also evidence suggesting that repeated blood glucose spikes, and the accompanying rise(s) in insulin, may have negative consequences in and of themselves.

Each person will respond differently to an influx of glucose. Too much glucose (or carbohydrate) for one person might be barely enough for another. An athlete who is training or competing in high-level endurance events might easily take in—and burn up—six hundred or eight hundred grams of carbohydrates per day. If I consumed that much now, day to day, it would probably render me a diabetic within a year. So how much is too much? And what about quality? Obviously that piece of pie is going to affect an endurance athlete differently from a sedentary person—and the pie will also have a different effect than a baked potato or french fries.

Now we have a tool to help us understand our own individual carbohydrate tolerance and how we respond to specific foods. This is called continuous glucose monitoring, or CGM, and it has become a very important part of my armamentarium in recent years.[*2]

The device consists of a microscopic filament sensor that is implanted in the upper arm, attached to a fingertip-sized transmitter that sends data[*3] to the patient’s phone in real time. As its name suggests, CGM gives continuous, real-time information on blood glucose levels, which is extraordinary: the patient can see, moment by moment, how their blood sugar levels are responding to whatever they eat, whether a doughnut, a steak, or a handful of Raisinets. More importantly, it also keeps track of glucose levels over time, capturing historical averages and variance, and registering each and every time that blood glucose spikes upward or crashes downward.

CGM represents a huge improvement over the Medicine 2.0 standard of one fasting glucose test per year, which in my opinion tells you almost nothing of value. Think back to my self-driving cars analogy from Part I: fasting blood glucose, annually, does tell us something, but it’s not too far from strapping a brick to the gas pedal. With CGM, you start to approximate the sensors currently found on cars with elaborate driver-assistance tools.

The power of CGM is that it enables us to view a person’s response to carbohydrate consumption in real time and make changes rapidly to flatten the curve and lower the average. Real-time blood glucose serves as a decent proxy for the insulin response, which we also look to minimize. And, last, I find that it is much more accurate, and more actionable, than HbA1c, the traditional blood test used to estimate average blood glucose over time.

At the moment, CGM is available only by prescription and is most commonly worn by patients diagnosed with type 1 or type 2 diabetes, who need to monitor their glucose levels from moment to moment. For these people, CGM is an essential tool that can protect them from life-threatening swings in blood glucose. But I think nearly every adult could benefit from it, at least for a few weeks, and it will likely be available to consumers without a prescription in the not-too-distant future.[*4] It’s currently fairly easy for a nondiabetic to obtain a CGM from one of several online metabolic health start-ups.

Yet some experts and evidence-based medicine types have criticized the growing use of CGM in nondiabetic people. They argue, as these sorts of people always do, that the “cost” is excessive. CGM costs about $120 a month, which is not insignificant—but I would argue that even this is still far cheaper than allowing someone to slide into metabolic dysfunction and eventually type 2 diabetes. Insulin treatment alone can cost hundreds of dollars a month. Also, as CGM becomes more common, and more readily available without a prescription, the cost is sure to come down. Typically, my healthy patients need to use CGM only for a month or two before they begin to understand what foods are spiking their glucose (and insulin) and how to adjust their eating pattern to obtain a more stable glucose curve. Once they have this knowledge, many of them no longer need CGM. It’s a worthwhile investment.

The second argument against using CGM in healthy patients is also pretty typical: There are no randomized clinical trials showing a benefit from the technology. This is true, strictly speaking, but it is also a weak argument. For one thing, use of CGM is growing so fast and the technology is advancing so much that by the time you are reading this there may very well be published RCTs (assuming a study can be designed to test the metrics that matter most over a long enough period of time).

I am confident that such studies will show a benefit, if done correctly, because there are already ample data showing how important it is to keep blood glucose low and stable. A 2011 study looking at twenty thousand people, mostly without type 2 diabetes, found that their risk of mortality increased monotonically with their average blood glucose levels (measured via HbA1c). The higher their blood glucose, the greater their risk of death—even in the nondiabetic range of blood glucose. Another study in 2019 looked at the degree of variation in subjects’ blood glucose levels and found that the people in the highest quartile of glucose variability had a 2.67 times greater risk of mortality than those in the lowest (most stable) quartile. From these studies, it seems quite clear that we want to lower average blood glucose and reduce the amount of variability from day to day and hour to hour. CGM is a tool that can help us achieve that. We use it in healthy people in order to help them stay healthy. That shouldn’t be controversial.

When I’ve put my patients on CGM, I’ve observed that there are two distinct phases to the process. The first is the insight phase, where you learn how different foods, exercise, sleep (especially lack thereof), and stress affect your glucose readings in real time. The benefit of this information can’t be overstated. Almost always, patients are stunned to see how some of their favorite foods send their glucose soaring, then crashing back to earth. This leads to the second phase, which is what I call the behavior phase. Here you mostly know how your glucose is going to respond to that bag of potato chips, and that knowledge is what prevents you from mindlessly eating it. I’ve found that CGM powerfully activates the Hawthorne effect, the long-observed phenomenon whereby people modify their behavior when they are being watched. (The Hawthorne effect is also what makes it difficult to study what people actually eat, for the same reason.)

Typically, the first month or so of using CGM is dominated by insights. Thereafter, it’s really dominated by behavior modification. But both are quite powerful, and even after my patients stop using CGM, I find that the Hawthorne effect persists, because they know what that bag of potato chips will do to their glucose levels. (Those who need more “training” to break their snacking habit will typically need to use CGM for longer.) CGM has proved especially useful in patients with APOE e4, where we often see big glucose spikes, even in relatively young people. In these patients, the behavior modification that CGM prompts is an important part of their Alzheimer’s disease prevention strategy.

The real beauty of CGM is that it allows me to titrate a patient’s diet while remaining flexible. No longer do we need to try to hit some arbitrary target for carbohydrate or fat intake and hope for the best. Instead, we can observe in real time how their body handles the food they are eating. Is their average blood glucose a little bit high? Are they “spiking” above 160 mg/dL more often than I would like? Or could they perhaps tolerate a little bit more carbohydrate in their diet? Not everyone needs to restrict carbohydrates; some people can handle more than others, and some have a hard time sticking to severe carbohydrate restriction. Overall, I like to keep average glucose at or below 100 mg/dL, with a standard deviation of less than 15 mg/dL.[*5] These are aggressive goals: 100 mg/dL corresponds to an HbA1c of 5.1 percent, which is quite low. But I believe that the reward, in terms of lower risk of mortality and disease, is well worth it given the ample evidence in nondiabetics and diabetics alike.

All of this takes experimentation and iteration; dietary restriction has to be adaptive, changing with the patient’s lifestyle, age, exercise habits, and so on. It’s always interesting to see which specific foods cause elevated CGM readings in some patients but not in others. The SAD sends most people’s CGM readings through the roof, as all the sugar and processed carbohydrates dump into the bloodstream at once, provoking a strong insulin response, which is what we don’t want. But seemingly “healthy” meals, for example certain kinds of vegetarian tacos, can also send glucose levels soaring in some people but not others. It also depends on when those carbs are eaten. If you eat 150 grams of carbohydrates as a serving of rice and beans in one sitting, that has a different effect than eating the same amount of rice and beans spread out over the day (and, obviously, much different from ingesting 150 grams of carbs in the form of Frosted MiniWheats). 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.

One thing CGM pretty quickly teaches you is that your carbohydrate tolerance is heavily influenced by other factors, especially your activity level and sleep. An ultraendurance athlete, someone who is training for long rides or swims or runs, can eat many more grams of carbs per day because they are blowing through those carbs every time they train—and they are also vastly increasing their ability to dispose of glucose via the muscles and their more-efficient mitochondria.[*6] Also, sleep disruption or reduction dramatically impairs glucose homeostasis over time. From years of experience with my own CGM and that of my patients, it still amazes me how much even one night of horrible sleep cripples our ability to dispose of glucose the next 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, 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.

This doesn’t need to be an exercise in deprivation: one patient of mine gleefully confessed that his CGM, which he had only reluctantly agreed to wear, had given him a “superpower” to cheat. By eating certain “forbidden” types of carbohydrates only at certain times, either mixed with other foods or after exercising, he had figured out how he could hit his average glucose goals while still enjoying all the foods he loved. He was gaming his CGM, but he had also unwittingly discovered another rule of nutrition, which is that timing is important: If you scarf a large baked potato before working out, it will leave much less of a footprint on your daily glucose profile than if you eat it right before bedtime.

It is important to remember the limitations of CGM—chiefly, that it measures one variable. This variable happens to be very important, but it is not the only one. Thus, CGM data alone are not going to help you find the ideal diet. Eating bacon for breakfast, lunch, and dinner might give you a great CGM tracing, even though it’s obviously not an optimal diet. Similarly, a bathroom scale will suggest that smoking is good for you because you lost weight. This is why I monitor my patients’ other biomarkers closely as well, to ensure that their CGM-driven choices are not increasing their risk of something else, such as cardiovascular disease. 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. All of these taken together start to give us a better way to evaluate our progress than any one in isolation.

Protein

Why is protein so important? One clue lies in the name, which is derived from the Greek word proteios, meaning “primary.” Protein and amino acids are the essential building blocks of life. Without them, we simply cannot build or maintain the lean muscle mass that we need. As we saw in chapter 11, this is absolutely critical to our strategy, because the older we get, the more easily we lose muscle, and the more difficult it becomes to rebuild it.

Remember the study we discussed in chapter 11 that looked at the effect of strength training in sixty-two frail seniors? The subjects who did only strength training for six months gained no muscle mass. 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. The extra protein likely made the difference.[*7]

Unlike carbs and fat, protein is not a primary source of energy. We do not rely on it in order to make ATP,[*8] nor do we store it the way we store fat (in fat cells) or glucose (as glycogen). If you consume more protein than you can synthesize into lean mass, you will simply excrete the excess in your urine as urea. Protein is all about structure. The twenty amino acids that make up proteins are the building blocks for our muscles, our enzymes, and many of the most important hormones in our body. They go into everything from growing and maintaining our hair, skin, and nails to helping form the antibodies in our immune system. On top of this, we must obtain nine of the twenty amino acids that we require from our diet, because we can’t synthesize them.

The first thing you need to know about protein is that the standard recommendations for daily consumption are a joke. Right now the US recommended dietary allowance (RDA) for protein is 0.8 g/kg of body weight. This may reflect how much protein we need to stay alive, but it is a far cry from what we need to thrive. There is ample evidence showing that we require more than this—and that consuming less leads to worse outcomes. More than one study has found that elderly people consuming that RDA of protein (0.8 g/kg/day) end up losing muscle mass, even in as short a period as two weeks. It’s simply not enough.

On a related note, some of you may have the impression that low-protein diets are helpful for longevity purposes. Certainly, a number of mouse studies have suggested that restricting protein can improve mouse lifespan. I am not convinced that these results are applicable to humans, however. Mice and human beings respond very differently to low protein, and numerous studies suggest that low protein in the elderly leads to low muscle mass, yielding greater mortality and worse quality of life. I am more persuaded by this human data than I am by studies in mice, who are simply not the same as us.

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.

So if someone weighs 180 pounds, they need to consume a minimum of 130 grams of protein per day, and ideally closer to 180 grams, especially if they are trying to add muscle mass. 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.

Most people don’t need to worry about consuming too much protein. It would require an overwhelming effort to eat more than 3.7 g/kg/day (or ~1.7 g/lb of body weight), defined as the safe upper limit of protein consumption (too much stress on the kidneys, for one). For someone my size, that maximum amount would be nearly 300 grams per day, or the equivalent of seven or eight chicken breasts.

How much protein you need depends on your sex, body weight and lean body mass, activity level, and other factors, including age. There is some evidence that older people might require more protein because of the anabolic resistance that develops with age—that is, their greater difficulty in gaining muscle. Unfortunately, there’s no CGM for protein, so it becomes a bit of a process of trial and error. I try to consume enough to maintain muscle mass as I train. If I find that I’m losing muscle mass, then I endeavor to eat more. Older people in particular should try to keep track of their lean mass, such as via a body-composition-measuring scale (or better yet, DEXA scan), and adjust their protein intake upwards if lean mass declines. For me and my patients, this works out to four servings, as described, with at least one of them being a whey protein shake. (It’s very difficult for me to consume four actual meals. Typically, I will consume a protein shake, a high-protein snack, and two protein meals.)

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, and an expert on protein.

Some of this can be overcome by cooking the plants, but that still leaves us with the second issue. The distribution of amino acids is not the same as in animal protein. In particular, plant protein has less of the essential amino acids methionine, lysine, and tryptophan, potentially leading to reduced protein synthesis. Taken together, these two factors tell us that the overall quality of protein derived from plants is significantly lower than that from animal products.

The same is true of protein supplements. Whey protein isolate (from dairy) is richer in available amino acids than soy protein isolate. So if you forgo protein from animal sources, you need to do the math on your protein quality score. In truth, this can get pretty complicated pretty quick, because you get wrapped around the axle of something called the Digestible Indispensable Amino Acid Score (DIAAS) and the Protein Digestibility-Corrected Amino Acid Score (PDCAAS). These are great if you have the time to comb through databases all day, but for those of us with day jobs, Layman suggests focusing on a handful of important amino acids, such as leucine, lycine, and methionine. Focus on the absolute amount of these amino acids found in each meal, and be sure to get about three to four grams per day of leucine and lycine and at least one gram per day of methionine for maintenance of lean mass. 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.

Multiple studies suggest that the more protein we consume, in general, the better. A large prospective study called the Healthy Aging and Body Composition Study, with more than two thousand elderly subjects, found that those who ate the most protein (about 18 percent of caloric intake) kept more of their lean body mass over three years than those in the lowest quintile of protein consumption (10 percent of calories). The difference was significant: the low-protein group lost 40 percent more muscle than the high-protein group.

You could make the case that protein is a performance-enhancing macronutrient. Other studies have found that boosting protein intake even moderately above the RDA can slow the progressive loss of muscle mass in older people, including patients with heart failure and cachexia (wasting). Adding thirty grams of milk protein to the diet of frail elderly people, in another study, significantly improved their physical performance.

Beyond its role in building muscle, protein may have beneficial effects on our metabolism. One study found that giving elderly people supplements containing essential amino acids (that is, mimicking some effects of increasing dietary protein) lowered their levels of liver fat and circulating triglycerides. Another study in men with type 2 diabetes found that doubling their protein intake from 15 to 30 percent of total calories, while cutting carbohydrates by half, improved their insulin sensitivity and glucose control. Eating protein also helps us feel satiated, inhibiting the release of the hunger-inducing hormone ghrelin, so we eat fewer calories overall.

In case my point here isn’t clear enough, let me restate it: don’t ignore protein. It’s the one macronutrient that is absolutely essential to our goals. There’s no minimum requirement for carbohydrates or fats (in practical terms), but if you shortchange protein, you will most certainly pay a price, particularly as you age.

Fat

The balance of our diet is composed of fat—or rather fats, plural. Fat is essential, but too much can be problematic both in terms of total energy intake and also metabolically. It should be relatively straightforward, but dietary fat has a sordid past that also creates a lot of confusion.

Fats have long had a bad rap, on two counts: their high caloric content (9 kcal/g) and their role in raising LDL cholesterol and thus heart disease risk. Like carbohydrates, fats are often labeled “good” or “bad” on the basis of one’s tribal or political stripes; in actuality, of course, it’s not that black and white. Fats have an important place in any diet, and therefore it’s important to understand them.

While carbohydrates are primarily a source of fuel and amino acids are primarily building blocks, fats are both. They are very efficient fuel for oxidation (think: slow-burning logs) and also the building blocks for many of our hormones (in the form of cholesterol) and cell membranes. 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.

There are (broadly) three types of fats: saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA).[*9] The differences between these have to do with differences in their chemical structure; a “saturated” fat simply has more hydrogen atoms attached to its carbon chain.[*10] Within PUFA, we make one more important distinction, which is to separate the omega-6 from the omega-3 variants (also a chemical distinction having to do with the position of the first double bond). 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.

The key thing to remember—and somehow this is almost always overlooked—is that virtually no food belongs to just one group of fats. Olive oil and safflower oil might be as close as you can get to a pure monounsaturated fat, while palm and coconut oil might be as close as you can get to a pure saturated fat, but all foods that contain fats typically contain all three categories of fat: PUFA, MUFA, and SFA. Even a ribeye steak contains a lot of monounsaturated fats.

So it’s not really possible or feasible to try to eliminate certain categories of fatty acids from the diet entirely; instead, we try to tweak the ratios. The default fat state of most of my patients (i.e., their baseline fat consumption when they come to me) works out to about 30–40 percent each of MUFA and SFA, and 20–30 percent PUFA—and within that PUFA group, they are generally consuming about six to ten times more omega-6 than omega-3s and usually scant amounts of EPA and DHA.

From our empirical observations and what I consider the most relevant literature, which is less than perfect, we try to boost MUFA closer to 50–55 percent, while cutting SFA down to 15–20 percent and adjusting total PUFA to fill the gap. We also boost EPA and DHA, those fatty acids that are likely important to brain and cardiovascular health, with marine fat sources and/or supplementation. 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.[*11] Our target depends on a person’s APOE genotype and other risk factors for neurodegenerative and cardiovascular disease, but for most patients the range we look for is between 8 and 12 percent of RBC membrane composed of EPA and DHA.

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.[*12]

But once again, this is where the SAD, our modern food environment, comes in to complicate things. A hundred years ago, our ancestors would have gotten all their fat from animals, in the form of butter, lard, and tallow, and/or fruits, such as olives, coconuts, and avocados. They would have done so mostly by consuming these foods in their relatively natural state, and achieving a reasonable balance of fatty acids would have come fairly easily. Over the course of the twentieth century, advances in food-processing technology enabled us to chemically and mechanically extract oil from vegetables and seeds that otherwise would have been impossible to get. These new technologies suddenly allowed vast quantities of oils high in polyunsaturated fats, such as corn and cottonseed oil (aka linoleic acid, a PUFA), to flood into the food supply. Our per capita consumption of soybean oil, for example, has increased over a thousand-fold since 1909; meanwhile, studies have found that levels of linoleic acid found in human fat tissue have also increased, by 136 percent over the last half century.

This industrial fat revolution also helped create trans fats, listed on ingredient labels as “partially hydrogenated vegetable oils” (think: margarine), which in turn helped enable the proliferation of the SAD, in part because they allowed foods to remain shelf stable for longer periods. But trans fats also contributed to atherosclerosis (by raising apoB) and have been banned by the FDA.

It is tempting to indict this massive proliferation of soybean and other seed oils as the dietary bad guy responsible for our obesity and metabolic syndrome epidemic. Anything that goes up by a thousand-fold in the same few decades in which our health goes to hell in a handbasket can’t be good, right? Even just a few years ago, I used to think this was the case. But the closer and closer I look at the data, the less and less sure I am that we can say much in this regard.

In fact, the most comprehensive review of this topic, Polyunsaturated Fatty Acids for the Primary and Secondary Prevention of Cardiovascular Disease, published by the Cochrane Collaboration in 2018—a 422-page summation of all relevant literature from forty-nine studies, randomizing over twenty-four thousand patients—drew the following conclusion: “Increasing PUFA probably makes little or no difference (neither benefit nor harm) to our risk of death, and may make little or no difference to our risk of dying from cardiovascular disease. However, increasing PUFA probably slightly reduces our risk of heart disease events and of combined heart and stroke events (moderate-quality evidence).”

Slight advantage to increasing PUFA, noted. A more recent publication by the Cochrane Collaboration, published in 2020 as a 287-page treatise titled Reduction in Saturated Fat Intake for Cardiovascular Disease, looked at fifteen RCTs in over fifty-six thousand patients and found, among other things, that “reducing dietary saturated fat reduced the risk of combined cardiovascular events by 17%.” Interesting. But the same review also found “little or no effect of reducing saturated fat on all-cause mortality or cardiovascular mortality.” Furthermore, “There was little or no effect on cancer mortality, cancer diagnoses, diabetes diagnosis, HDL cholesterol, serum triglycerides or blood pressure, and small reductions in weight, serum total cholesterol, LDL cholesterol and BMI.”

Slight disadvantage to saturated fats, but no observed effect on mortality. Last, yet another recent review, published in late 2020, titled Total Dietary Fat Intake, Fat Quality, and Health Outcomes: A Scoping Review of Systematic Reviews of Prospective Studies, examined fifty-nine systematic reviews of RCTs or prospective cohort studies and found “mainly no association of total fat, monounsaturated fatty acid (MUFA), polyunsaturated fatty acid (PUFA), and saturated fatty acid (SFA) with risk of chronic diseases.”

I could go on, but I think you get the point. The data are very unclear on this question, at least at the population level. As we discussed in the introduction to Medicine 3.0 and earlier in this chapter, any hope of using broad insights from evidence-based medicine is bound to fail when it comes to nutrition, because such population-level data cannot provide much value at the individual level when the effect sizes are so small, as they clearly are here. All Medicine 2.0 has to offer is broad contours: MUFA seems to be the “best” fat of the bunch (based on PREDIMED and the Lyon Heart study), and after that the meta-analyses suggest PUFA has a slight advantage over SFA. But beyond that, we are on our own.

Medicine 3.0 asks, what is the “best” mix of fats for our patient? I use an expanded lipid panel to keep track of how changes in fatty acid consumption may affect my patients’ cholesterol synthesis and reabsorption, and their overall lipid and inflammatory response. Subtle changes in fat intake, particularly of saturated fats, can make a significant difference in lipid levels in some people, as I have learned over and over again—but not in others. Some people (like me)[*13] can consume saturated fats with near impunity, while others can hardly even look at a slice of bacon without their apoB number jumping to the 90th percentile.

Medicine 2.0 says this proves that nobody should eat saturated fats, period. Medicine 3.0 takes these data and says, “While it is obviously not good that our patient’s apoB has gone up this much, it now presents us with a choice: Should we consider medication to lower their apoB, or reduce their intake of saturated fats? Or both?” There is no obvious or uniform answer here, and addressing this not-too-uncommon situation comes down to a judgment call.

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.

TR: The Case for (and Against) Fasting

Fasting, or time-restricted (TR) eating (regulating when you eat), presents us with a tactical conundrum. On the one hand, it is a powerful tool for accomplishing some of our goals, large and small. On the other, fasting has some potentially serious downsides that limit its usefulness. While intermittent fasting and eating “windows” have become popular and even trendy in recent years, I’ve grown skeptical of their effectiveness. And frequent longer-term fasting has enough negatives attached to it that I am reluctant to use it in all but the most metabolically sick patients. The jury is still out on the utility of infrequent (e.g., yearly) prolonged fasts. Overall, I’ve come to believe that fasting-based interventions must be utilized carefully and with precision.

There is no denying that some good things happen when we are not eating. Insulin drops dramatically because there are no incoming calories to trigger an insulin response. The liver is emptied of fat in fairly short order. Over time, within three days or so, the body enters a state called “starvation ketosis,” where fat stores are mobilized to fulfill the need for energy—yet at the same time, as I often noticed when I was undergoing regular lengthy fasts, hunger virtually disappears. This paradoxical phenomenon is likely due to the ultrahigh levels of ketones that this state produces, which tamp down feelings of hunger.

Fasting over long periods also turns down mTOR, the pro-growth and pro-aging pathway we discussed in chapter 5. This would also be desirable, one might think, at least for some tissues. At the same time, lack of nutrients accelerates autophagy, the cellular “recycling” process that helps our cells become more resilient, and it activates FOXO, the cellular repair genes that may help centenarians live so long. In short, fasting triggers many of the physiological and cellular mechanisms that we want to see. So why don’t I recommend it to all my patients?

It’s a tricky question, because the scientific literature on fasting is still relatively weak, notwithstanding the many popular books that have been written about fasting in its various forms. I have recommended (and practiced) different forms of fasting myself, from time-restricted feeding (eating in a defined time period each day) to water-only fasting for up to ten days. Because my thinking about fasting has evolved considerably, I feel that I need to address the topic here. I still think it can be useful sometimes, in some patients—typically the ones with the most severe metabolic dysfunction—but I am less persuaded that it is the panacea that some believe it to be.

There are really three distinct categories of time-restricted feeding, and we’ll look at each of them in order. First, we have the short-term eating windows that we’ve mentioned previously, where someone will limit their consumption of food to a specific time frame, such as six or eight hours out of the day. In practice, that could mean skipping breakfast, eating a first meal at 11 a.m. and finishing dinner by 7 p.m. every evening; or someone could eat breakfast at 8 a.m., another meal at 2 p.m., and nothing thereafter.

There are an almost infinite number of variations on this, but the trick is that it works only provided you make the feeding window small enough. The standard 16/8 (sixteen hours of fasting, eight hours to eat) is barely enough for most people, but it can work. Usually a narrower window, such as 18/6 or 20/4, is needed to eke out enough of a caloric deficit. For a time, I was experimenting with a two-hour eating window, which basically meant that I would eat one huge meal per day. I always enjoyed the look on a waiter’s face when I would order multiple entrees.

In my experience, most people find this to be the easiest way to reduce their caloric intake, by focusing on when they are eating rather than how much and/or what they are eating. But I am not convinced that short-term time-restricted feeding has much of a benefit beyond this.

The original 16/8 model came from a study conducted in mice. This study found that mice fed in only eight hours out of the day, and fasted for the other sixteen, were healthier than mice fed continuously. The time-restricted mice gained less weight than the mice that ate whenever they wanted, even though the two groups consumed the same number of calories. This study gave birth to the eight-hour diet fad, but somehow people lost sight of the fact that this is a big extrapolation from research in mice. Because a mouse lives for only about two to three years—and will die after just forty-eight hours without food—a sixteen-hour fast for a mouse is akin to a multiday fast for a human. It’s just not a valid comparison.

Human trials of this eating pattern have failed to find much of a benefit. A 2020 clinical trial by Ethan Weiss and colleagues found no weight loss or cardiometabolic benefits in a group of 116 volunteers on a 16/8 eating pattern. Two similar studies also found minimal benefit. One other study did find that shifting the eating window to early in the day, from 8 a.m. to 2 p.m., actually did result in lower twenty-four-hour glucose levels, reduced glucose excursions, and lower insulin levels compared to controls. 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.

Another drawback is that you are virtually guaranteed to miss your protein target with this approach (see “Protein,” above). This means that a person who needs to gain lean body mass (i.e., undernourished or undermuscled), should either abandon this approach completely or consume a pure protein source outside their feeding window (which more or less defeats the purpose of time-restricted feeding). Also, it’s very easy to fall into the trap of overindulgence during your feeding window and mindlessly consume, say, a half gallon of ice cream in one sitting. Taken together, this combo of too little protein and too many calories can have the exact opposite effect we want: gaining fat and losing lean body mass. In my clinical experience, this result is quite common.

As I said, I will sometimes put certain patients on a time-restricted eating pattern because I’ve found it helps them reduce their overall caloric intake with minimal hunger. But it’s more of a disciplinary measure than a diet. Setting time limits around food consumption helps foil a key feature of the SAD, which is that it’s difficult to stop eating it. Time-restricted feeding is a way of putting the brakes on snacking and late-night meals—the type of mindless eating-just-to-eat that the Japanese call kuchisabishii, for “lonely mouth.” But beyond that, I don’t think it’s particularly useful.

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Next, we have alternate-day fasting (ADF), which has also become popular. This is where you eat normally or even a bit more than normal one day, and then very little (or nothing) the next. There is more extensive research into this eating pattern in humans—and, of course, there have been books written about it too—but the results are not particularly appealing. Some studies have found that subjects can indeed lose weight on alternate-day fasting diets, but more nuanced research suggests there are some significant downsides. One small but revealing study found that subjects on an alternate-day fasting diet did lose weight—but they also lost more lean mass (i.e., muscle) than subjects who simply ate 25 percent fewer calories every day.

This study was limited because of its small size and short duration, but it suggests that fasting might cause some people, especially lean people, to lose too much muscle.[*14] On top of this, the ADF group had much lower activity levels during the study, which suggests that they were not feeling very good on the days they were not eating. With longer-term fasting, these effects only become more pronounced, particularly the loss of muscle mass. Therefore, I am inclined to agree with lead investigator James Betts: “If you are following a fasting diet, it is worth thinking about whether prolonged fasting periods [are] actually making it harder to maintain muscle mass and physical activity levels, which are known to be very important factors for long-term health.”

As a result of this and other research, I have become convinced that frequent, prolonged fasting may be neither necessary nor wise for most patients. The cost, in terms of lost lean mass (muscle) and reduced activity levels, simply does not justify whatever benefits it may bring. My rule of thumb for any eating pattern, in fact, is that you must eat enough to maintain lean mass (muscle) and long-term activity patterns. That is part of what makes any diet sustainable. If we are going to use a powerful tool like fasting, we must do so carefully and deliberately.

But fasting can still prove useful sometimes, in some patients—generally, patients for whom no other dietary intervention has worked. Case in point: my friend Tom Dayspring, the lipidologist whom we met in chapter 7. Tom became a patient of mine a few years ago because I was so concerned about his metabolic health. Then in his midsixties, he was carrying 240 pounds on his five-eight frame, giving him a BMI of 36.5, well into the obese range. Blood tests revealed that he was also working on a serious case of NAFLD, if not outright NASH. Over the years, I had nagged him constantly until he finally agreed to try to do something about it. Given his issues, a ketogenic diet was the obvious place to start. If we limited his carb intake, I figured, he’d lose weight and hopefully his NAFLD would have a chance to dissipate, and his biomarkers and weight would also come under control.

But they didn’t. After Tom struggled for six months to stay on the diet, his liver enzymes, and his weight, had failed to budge. A year later, same story. Two years, three years, nothing had changed. In the meantime, his health continued to deteriorate, to the point where he had difficulty walking a single city block. He eventually required both a hip replacement and spinal fusion. The problem was that Tom was simply unable to stay on the strict ketogenic diet for very long. He would be fine for two weeks or so, but then he would break down and eat a sandwich or a plate of pasta. It simply wasn’t sustainable for him.

Tom clearly required some sort of stronger medicine, and I concluded that he needed to try fasting. Unfortunately, like many SAD-trained North Americans, Tom hated the very thought of hunger. This was why he had 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 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 lose any fat. Clearly, he needed to break out of this vicious cycle.

At first, Tom was horrified by the very notion of fasting. But he is also a scientist, and after delving into some of the research on nutrient deprivation and putting that together with what he already knew about lipids and metabolism and disease risk, he agreed to give it a try. His scientific mind was persuaded, but I think at some point he also realized that he was staring down the barrel of what might be the last five years of his life unless he made some drastic changes. We came up with an aggressive plan, at the limit of what he thought he could tolerate: one week per month, Monday through Friday, Tom would subsist on a drastically reduced diet of about seven hundred calories per day, comprising mostly fat, with a little protein and almost no carbohydrates.

This kind of fasting is called “hypocaloric” because you are not truly fasting in the sense of eating no food at all. You are eating just enough to quell the worst hunger pangs, but not so much that your body thinks you are fully fed. For twenty-five days out of each month, Tom ate a “normal” diet (though in his case, very starch- and sugar-restricted), and only between noon and 8 p.m.; during his fasting week, a typical day’s menu might consist of a salad with light dressing, an avocado, and some macadamia nuts or olives. He was surprised at how good he felt. “It wasn’t as horrific as I thought it was going to be,” he told me later. “After day three, the hunger disappears.”

It did not take long for his blood biomarkers to improve dramatically: where his complete blood chemistry report used to be largely yellow and red—meaning, most of his values were borderline to “bad”—it is now almost entirely green. His lipids are under control, and his liver enzymes have plummeted back to safe, normal ranges. After several cycles of this, he was able to do things like climb a flight of steps or walk several city blocks again without feeling out of breath. His blood pressure is lower, and he has been able to stop taking many of the countless medications he was on. Last, he now weighs sixty-seven pounds less than he used to, a sign that his metabolic health really is back on track, and a powerful incentive for him to keep at it. “The weight just poured off,” he told me.

Fasting had effectively reset or rebooted his crashed metabolism in a way that no other dietary intervention was able to achieve. Because it has such deleterious effects on muscle mass, I only use it in hard-to-fix patients like Tom. Tom was so overweight to begin with that he could tolerate the loss of muscle because he was losing so much fat at the same time. But most people can’t safely lose muscle mass, so fasting is a tool that we can only really use in extremis, when there are no other viable options.

Conclusion

In the last two chapters, we have explored the impact of what we eat—and sometimes what we do not eat—on our health, and the importance of moving our thinking toward a Nutrition 3.0 mindset, based on feedback and data rather than labels and trends and ideology.

I once believed that diet and nutrition could cure almost all ills, but I no longer feel that strongly about it. Nutritional biochemistry is an important component of our tactics, but it is not the only path to longevity, or even the most powerful one. I see it more as a rescue tactic, particularly for patients like Eduardo and Tom, with really severe metabolic problems such as NAFLD and type 2 diabetes. It is also essential for older people who need to build or maintain muscle mass. But its power to leverage increased lifespan and healthspan is more limited. 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.

I know this seems hard to believe, after all we’ve been conditioned to think and given all the grandstanding that goes into promoting this diet versus that one. But in reality, the first-, second-, and third-order terms in this problem come down to energy balance. CR, DR, and TR are just tools to reduce energy intake, to correct the state of being overnourished and/or metabolically unhealthy.

The bad news is that most Americans are not metabolically healthy, so they need to pay attention to nutrition. In most cases, addressing the problem means reducing overall energy intake—cutting calories—but in a way that is sustainable for the individual person. We also have to focus on eliminating those types of foods that raise blood glucose too much, but in a way that also does not compromise protein intake and lean body mass.

This is where it can get tricky. Protein is actually the most important macronutrient, the one macro that should not be compromised. Remember, most people will be overnourished—but also undermuscled. It is counterproductive for them to limit calories at the expense of protein and hence muscle mass.

This is also where other tactics can play a role. As we saw in chapter 12, zone 2 aerobic training can have a huge impact on our ability to dispose of glucose safely, and also on our ability to access energy we have stored as fat. And the more muscle mass we have, the more capacity we have to use and store excess glucose, and utilize stored fat. In the next chapter, we will see how important good sleep can be to maintaining metabolic balance.

If your issues fall more in the domain of lipoproteins and cardiovascular risk, then it makes sense to focus on the fats side of the equation as well, meaning mostly saturated fats, which raise apoB in some people, although this is relatively easy to control pharmacologically. Excessive carbohydrate intake can also have spillover effects on apoB, in the form of elevated triglycerides. (If there is one type of food that I would eliminate from everyone’s diet if I could, it would be fructose-sweetened drinks, including both sodas and fruit juices, which deliver too much fructose, too quickly, to a gut and liver that much prefer to process fructose slowly. Just eat fruit and let nature provide the right amount of fiber and water.)

In the end, the best nutrition plan is the one that we can sustain. How you manipulate the three levers of diet—calorie restriction, dietary restriction, and time restriction—is up to you. Ideally, your plan improves or maintains all the parameters we care about—not only blood glucose and insulin but also muscle mass and lipid levels, and possibly even weight—while reducing your risk of your most proximate Horseman or Horsemen. Your nutrition goals depend on your individual risk profile: Are you more at risk of metabolic dysfunction, or cardiovascular disease? There is no one right answer for everyone; each patient finds their own balance, their own best approach. Hopefully, in this chapter I’ve given you some tools with which to come up with a plan that works for you.

And, one last thing. If, after reading this chapter, you’re upset because you don’t quite agree with some detail I’ve covered—be it the ratio of MUFA to PUFA to SFA, or the exact bioavailability of soy protein, the role of seed oils and lectins, or the ideal target for average blood glucose levels—or if I have offended your sensibilities because I didn’t say your diet is the best diet, I have one final piece of advice. Stop overthinking nutrition so much. Put the book down. Go outside and exercise.