Medicine 3.0: Rethinking medicine for the age of chronic disease
The first era, exemplified by Hippocrates but lasting almost two thousand years after his death, is what I call Medicine 1.0. Its conclusions were based on direct observation and abetted more or less by pure guesswork, some of which was on target and some not so much. Hippocrates advocated walking for exercise, for example, and opined that “in food excellent medicine can be found; in food bad medicine can be found,” which still holds up. But much of Medicine 1.0 missed the mark entirely, such as the notion of bodily “humors,” to cite just one example of many. Hippocrates’s major contribution was the insight that diseases are caused by nature and not by actions of the gods, as had previously been believed.
Medicine 2.0 arrived in the mid-nineteenth century with the advent of the germ theory of disease, which supplanted the idea that most illness was spread by “miasmas,” or bad air.
The next step is crucial: rigorously testing that hypothesis/guess to determine whether it is correct, also known as experimenting. Instead of using treatments that they believed might work, often despite ample anecdotal evidence to the contrary, scientists and physicians could systematically test and evaluate potential cures, then choose the ones that had performed best in experiments.
The goal of this new medicine—which I call Medicine 3.0—is not to patch people up and get them out the door, removing their tumors and hoping for the best, but rather to prevent the tumors from appearing and spreading in the first place.
Medicine 3.0 places a far greater emphasis on prevention than treatment.
Medicine 3.0 considers the patient as a unique individual.
In Medicine 3.0, our starting point is the honest assessment, and acceptance, of risk—including the risk of doing nothing.
Medicine 3.0 pays far more attention to maintaining healthspan, the quality of life.
Medicine 3.0 demands much more from you, the patient: You must be well informed, medically literate to a reasonable degree, clear-eyed about your goals, and cognizant of the true nature of risk. You must be willing to change ingrained habits, accept new challenges, and venture outside of your comfort zone if necessary. You are always participating, never passive.
Objective, strategy, tactics
Medicine 2.0 relies on two types of tactics, broadly speaking: procedures (e.g., surgery) and medications. Our tactics in Medicine 3.0 fall into five broad domains: exercise, nutrition, sleep, emotional health, and exogenous molecules, meaning drugs, hormones, or supplements.
Break down this thing called exercise into its most important components: strength, stability, aerobic efficiency, and peak aerobic capacity. Increasing your limits in each of these areas is necessary if you are hoping to reach your limit of lifespan and healthspan.
Mendelian randomization helps tease out causal relationships between modifiable risk factors (e.g., LDL cholesterol) and an outcome of interest (e.g., cancer) in situations where actual randomized experiments cannot easily be done. It accomplishes this by letting nature do the randomization. By considering the random variation in relevant genes and comparing them against the observed results, it eliminates many of the biases and confounders that limit the usefulness of pure epidemiology.
Centenarians: The older you get, the healthier you have been
Studies of Scandinavian twins have found that genes may be responsible for only about 20 to 30 percent of the overall variation in human lifespan. The catch is that the older you get, the more genes start to matter. For centenarians, they seem to matter a lot. Being the sister of a centenarian makes you eight times more likely to reach that age yourself, while brothers of centenarians are seventeen times as likely to celebrate their hundredth birthday,
FOXO3 belongs to a family of “transcription factors,” which regulate how other genes are expressed—meaning whether they are activated or “silenced.” I think of it as rather like the cellular maintenance department. Its responsibilities are vast, encompassing a variety of cellular repair tasks, regulating metabolism, caring for stem cells, and various other kinds of housekeeping, including helping with disposal of cellular waste or junk. But it doesn’t do the heavy lifting itself, like the mopping, the scrubbing, the minor drywall repairs, and so on. Rather, it delegates the work to other, more specialized genes—its subcontractors, if you will. When FOXO3 is activated, it in turn activates genes that generally keep our cells healthier. It seems to play an important role in preventing cells from becoming cancerous as well.
Here’s where we start to see some hope, because FOXO3 can be activated or suppressed by our own behaviors. 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.
Eat less, live longer: The science of hunger and health
The job of mTOR3 is basically to balance an organism’s need to grow and reproduce against the availability of nutrients. When food is plentiful, mTOR is activated and the cell (or the organism) goes into growth mode, producing new proteins and undergoing cell division, as with the ultimate goal of reproduction. When nutrients are scarce, mTOR is suppressed and cells go into a kind of “recycling” mode, breaking down cellular components and generally cleaning house. Cell division and growth slow down or stop, and reproduction is put on hold to allow the organism to conserve energy.
Furthermore, there is no evidence that extreme CR would truly maximize the longevity function in an organism as complex as we humans, who live in a more variable environment than the animals described above. While it seems likely that it would reduce the risk of succumbing to at least some of the Horsemen, it seems equally likely that the uptick in mortality due to infections, trauma, and frailty might offset those gains.
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.
The first of these is an enzyme called AMP-activated protein kinase, or AMPK for short. AMPK is like the low-fuel light on the dashboard of your car: when it senses low levels of nutrients (fuel), it activates, triggering a cascade of actions. While this typically happens as a response to lack of nutrients, AMPK is also activated when we exercise, responding to the transient drop in nutrient levels. Just as you would change your itinerary if your fuel light came on, heading for the nearest gas station rather than Grandma’s house, AMPK prompts the cell to conserve and seek alternative sources of energy.
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. These fresh mitochondria help the cell produce more ATP, the cellular energy currency, with the fuel it does have. AMPK also prompts the body to provide more fuel for these new mitochondria, by producing glucose in the liver (which we’ll talk about in the next chapter) and releasing energy stored in fat cells.
More importantly, AMPK works to inhibit the activity of mTOR, the cellular growth regulator. Specifically, it seems to be a drop in amino acids that induces mTOR to shut down, and with it all the anabolic (growth) processes that mTOR controls.
Autophagy represents the catabolic side of metabolism, when the cell stops producing new proteins and instead begins to break down old proteins and other cellular structures into their amino acid components, using the scavenged materials to build new ones. It’s a form of cellular recycling, cleaning out the accumulated junk in the cell and repurposing it or disposing of it.
As we get older, autophagy declines. Impaired autophagy is thought to be an important driver of numerous aging-related phenotypes and ailments, such as neurodegeneration and osteoarthritis. Thus, I find it fascinating that this very important cellular mechanism can be triggered by certain kinds of interventions, such as a temporary reduction in nutrients (as when we are exercising or fasting)—and the drug rapamycin.**
One large 2014 analysis seemed to show that diabetics on metformin actually lived longer than nondiabetics, which is striking. But none of these observations “prove” that metformin is geroprotective—hence the need for a clinical trial.
The crisis of abundance: Can our ancient genes cope with our modern diet?
Where subcutaneous fat is thought to be relatively harmless, this “visceral fat” is anything but. These fat cells secrete inflammatory cytokines such alpha and IL-6, key markers and drivers of inflammation, in close proximity to your most important bodily organs. This may be why visceral fat is linked to increased risk of both cancer and cardiovascular disease.
Individual fat-storage capacity seems to be influenced by genetic factors. This is a generalization, but people of Asian descent (for example), tend to have much lower capacity to store fat, on average, than Caucasians. There are other factors at play here as well, but this explains in part why some people can be obese but metabolically healthy, while others can appear “skinny” while still walking around with three or more markers of metabolic syndrome.
But one of the first places where this overflowing fat will cause problems is in your muscle, as it worms its way in between your muscle fibers, like marbling on a steak. As this continues, microscopic fat droplets even appear inside your muscle cells.
These fat droplets may be among the first destinations of excess energy/fat spillover, and as they accumulate they begin to disrupt the complex network of insulin-dependent transport mechanisms that normally bring glucose in to fuel the muscle cell. When these mechanisms lose their function, the cell becomes “deaf” to insulin’s signals.
For the time being it works, and blood glucose levels remain normal, but eventually you reach a limit where the “balloon” (cells) cannot accept any more “air” (glucose). This is when the trouble shows up on a standard blood test, as fasting blood glucose begins to rise. This means you have high insulin levels and high blood glucose, and your cells are shutting the gates to glucose entry.
When insulin is chronically elevated, more problems arise. Fat gain and ultimately obesity are merely one symptom of this condition, known as hyperinsulinemia. I would argue that they are hardly even the most serious symptoms: as we’ll see in the coming chapters, insulin is also a potent growth-signaling hormone that helps foster both atherosclerosis and cancer.
Patients with diabetes have a much greater risk of cardiovascular disease, as well as cancer and Alzheimer’s disease and other dementias; one could argue that diabetes with related metabolic dysfunction is one thing that all these conditions have in common.
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. Now, when these apes consumed fructose, they generated lots of uric acid, which caused them to store many more of those fructose calories as fat. This newfound ability to store fat enabled them to survive in the colder climate. They could spend the summer gorging themselves on fruit, fattening up for the winter.
In my patients, I monitor several biomarkers related to metabolism, keeping a watchful eye for things like elevated uric acid, elevated homocysteine, chronic inflammation, and even mildly elevated ALT liver enzymes. Lipoproteins, which we will discuss in detail in the next chapter, are also important, especially triglycerides; I watch the ratio of triglycerides to HDL cholesterol (it should be less than 2:1 or better yet, less than 1:1), as well as levels of VLDL, a lipoprotein that carries triglycerides—all of which may show up many years before a patient would meet the textbook definition of metabolic syndrome.
But the first thing I look for, the canary in the coal mine of metabolic disorder, is elevated insulin. As we’ve seen, the body’s first response to incipient insulin resistance is to produce more insulin.
Confronting and preventing heart disease
Because cholesterol belongs to the lipid family (that is, fats), it is not water soluble and thus cannot dissolve in our plasma like glucose or sodium and travel freely through our circulation. So it must be carted around in tiny spherical particles called lipoproteins—the final “L” in LDL and HDL—which act like little cargo submarines. As their name suggests, these lipoproteins are part lipid (inside) and part protein (outside).
LDLs carry more lipids, while HDLs carry more protein in relation to fat, and are therefore more dense.
Each lipoprotein particle is enwrapped by one or more large molecules, called apolipoproteins, that provide structure, stability, and, most importantly solubility to the particle. HDL particles are wrapped in a type of molecule called apolipoprotein A (or apoA), while LDL is encased in apolipoprotein B (or apoB). This distinction may seem trivial, but it goes to the very root cause of atherosclerotic disease: every single lipoprotein that contributes to atherosclerosis—not only LDL but several others—carries this apoB protein signature.
Eating lots of saturated fat can increase levels of atherosclerosis-causing lipoproteins in blood, but most of the actual cholesterol that we consume in our food ends up being excreted out our backsides. The vast majority of the cholesterol in our circulation is actually produced by our own cells.
Particles tagged with apoA (HDL) can cross the endothelial barrier easily in both directions, in and out. LDL particles and other particles with the apoB protein are far more prone to getting stuck inside.
This is what actually makes HDL particles potentially “good” and LDL particles potentially “bad”—not the cholesterol, but the particles that carry it. The trouble starts when LDL particles stick in the arterial wall and subsequently become oxidized, meaning the cholesterol (and phospholipid) molecules they contain come into contact with a highly reactive molecule known as a reactive oxygen species, or ROS, the cause of oxidative stress.
It is not an accident that the two biggest risk factors for heart disease, smoking and high blood pressure, cause damage to the endothelium. Smoking damages it chemically, while high blood pressure does so mechanically, but the end result is endothelial harm that, in turn, leads to greater retention of LDL. As oxidized LDL accumulates, it causes still more damage to the endothelium.
Going back to our street analogy, imagine that we have, say, one ton of cholesterol moving down the street, divided among four pickup trucks. The chance of an accident is fairly small. But if that same total amount of cholesterol is being carried on five hundred of those little rental scooters that swarm around cities like Austin, where I live, we are going to have absolute mayhem on our hands. So to gauge the true extent of your risk, we have to know how many of these apoB particles are circulating in your bloodstream. That number is much more relevant than the total quantity of cholesterol that these particles are carrying.
If you take a healthy coronary artery and expose it to high enough concentrations of apoB particles, over a long enough time, a certain amount of LDL (and VLDL) will get stuck in that subendothelial space and become oxidized, which then leads to it sticking together in clumps or aggregates. In response to this incursion, the endothelium dials up the biochemical equivalent of 911, summoning specialized immune cells called monocytes to the scene to confront the intruders.
The macrophage, whose name means “big eater,” swallows up the aggregated or oxidized LDL, trying to remove it from the artery wall. But if it consumes too much cholesterol, then it blows up into a foam cell, a term that you may have heard—so named because under a microscope it looks foamy or soapy. When enough foam cells gather together, they form a “fatty streak”—literally a streak of fat that you can see with your naked eye
The fatty streak is a precursor of an atherosclerotic plaque, and if you are reading this and are older than fifteen or so, there is a good chance you already have some of these lurking in your arteries.
Back at the crime scene, the ever-growing number of foam cells begin to sort of ooze together into a mass of lipids, like the liquefying contents of a pile of trash bags that have been dumped on the front lawn. This is what becomes the core of our atherosclerotic plaque. And this is the point where breaking and entering tilts over into full-scale looting. In an attempt to control the damage, the “smooth muscle” cells in the artery wall then migrate to this toxic waste site and secrete a kind of matrix in an attempt to build a kind of barrier around it, like a scar. This matrix ends up as the fibrous cap on your brand-new arterial plaque.
As this maladaptive repair or remodeling process continues, the plaque will continue to grow. At first, this expansion is directed toward the outer arterial wall, but as it continues it may encroach on the lumen, the passage through which blood flows—in our analogy, blocking traffic in the street itself. This luminal narrowing, known as stenosis, can also be seen in an angiogram.
At a certain point in this process, the plaque may start to become calcified. This is what (finally) shows up on a regular calcium scan. Calcification is merely another way in which the body is trying to repair the damage, by stabilizing the plaque to protect the all-important arteries. But it’s like pouring concrete on the Chernobyl reactor: you’re glad it’s there, but you know there’s been an awful lot of damage in the area to warrant such an intervention. A positive calcium score is really telling us that there are almost certainly other plaques around that may or may not be stabilized (calcified).
If the plaque does become unstable, eroding or even rupturing, you’ve really got problems. The damaged plaque may ultimately cause the formation of a clot, which can narrow and ultimately block the lumen of the blood vessel—or worse, break free and cause a heart attack or stroke.
This is why, if you have a history of premature heart attacks in your family, you should definitely ask for an Lp(a) test. We test every single patient for Lp(a) during their first blood draw. Because elevated Lp(a) is largely genetic, the test need only be done once (and cardiovascular disease guidelines are beginning to advise a once-a-lifetime test for it anyway).
There was no quick fix for Anahad, or anyone else with elevated Lp(a). It does not seem to respond to behavioral interventions such as exercise and dietary changes the way that, say, LDL-C does. A class of drug called PCSK917 inhibitors, aimed at lowering apoB concentrations, does seem to be able to reduce Lp(a) levels by approximately 30 percent, but as yet there are no data suggesting that they reduce the excess events (heart attacks) attributable to that particle. Thus, the only real treatment for elevated Lp(a) right now is aggressive management of apoB overall. Though we can’t reduce Lp(a) directly, beyond what a PCSK9 inhibitor can do, we can lower the remaining apoB concentration sufficiently that we can reduce a patient’s overall risk.
In my clinical experience, about a third to half of people who consume high amounts of saturated fats (which sometimes goes hand in hand with a ketogenic diet) will experience a dramatic increase in apoB particles, which we obviously don’t want. 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. The point is not necessarily to limit fat overall but to shift to fats that promote a better lipid profile.
Different drugs arrive at this effect via different paths. Typically our first line of defense (or attack), statins inhibit cholesterol synthesis, prompting the liver to increase the expression of LDLR, taking more LDL out of circulation. They may have other benefits too, including an apparent anti-inflammatory effect,
Cancer
With a few exceptions, such as glioblastoma or other aggressive brain tumors, as well as certain lung and liver cancers, solid organ tumors typically kill you only when they spread to other organs. Breast cancer kills only when it becomes metastatic. Prostate cancer kills only when it becomes metastatic.
I suspect that the association between obesity, diabetes, and cancer is primarily driven by inflammation and growth factors such as insulin. Obesity, especially when accompanied by accumulation of visceral fat (and other fat outside of subcutaneous storage depots), helps promote inflammation, as dying fat cells secrete an array of inflammatory cytokines into the circulation
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.
Exercise: The most powerful longevity drug
As the authors of the JAMA study concluded, “Cardiorespiratory fitness is inversely associated with long-term mortality with no observed upper limit of benefit. Extremely high aerobic fitness was associated with the greatest survival.”
Further analysis revealed that it’s not the mere muscle mass that matters but the strength of those muscles, their ability to generate force. It’s not enough to build up big pecs or biceps in the gym—those muscles also have to be strong. They have to be capable of creating force.
How to prepare for the centenarian olympics
Most people think that one of the primary benefits of exercise, if not the primary benefit, is that it “burns calories.” And it does, but we are more interested in a finer distinction—not calories, but fuels. How we utilize different fuels, glucose and fatty acids, is critical not only to our fitness but also to our metabolic and overall health. Aerobic exercise, done in a very specific way, improves our ability to utilize glucose and especially fat as fuel.
Healthy mitochondria are also important to maintaining the health of our brain, and to controlling potential bad actors like oxidative stress and inflammation. I am convinced that it is impossible to be healthy without also having healthy mitochondria, which is why I place a great deal of emphasis on long, steady endurance training in zone 2.
Typically, someone working at a lower relative intensity will be burning more fat, while at higher intensities they would rely more on glucose. The healthier and more efficient your mitochondria, the greater your ability to utilize fat, which is by far the body’s most efficient and abundant fuel source. This ability to use both fuels, fat and glucose, is called “metabolic flexibility,” and it is what we want:
San Millán describes zone 2 as the maximum level of effort that we can maintain without accumulating lactate. We still produce it, but we’re able to match production with clearance.
Mitochondria are incredibly plastic, and when we do aerobic exercise, it stimulates the creation of many new and more efficient mitochondria through a process called mitochondrial biogenesis, while eliminating ones that have become dysfunctional via a recycling process called mitophagy (which is like autophagy, touched on in chapter 5, but for mitochondria). A person who exercises frequently in zone 2 is improving their mitochondria with every run, swim, or bike ride. But if you don’t use them, you lose them.
Muscle is the largest glycogen storage sink in the body, and as we create more mitochondria, we greatly increase our capacity for disposing of that stored fuel, rather than having it end up as fat or remaining in our plasma.
Based on multiple discussions with San Millán and other exercise physiologists, it seems that about three hours per week of zone 2, or four 45-minute sessions, is the minimum required for most people to derive a benefit and make improvements,
The beauty of this is that VO2 max can always be improved by training, no matter how old you are.
Where HIIT intervals are very short, typically measured in seconds, VO2 max intervals are a bit longer, ranging from three to eight minutes—and a notch less intense. I do these workouts on my road bike, mounted to a stationary trainer, or on a rowing machine, but running on a treadmill (or a track) could also work. 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.fn4
A far more important measure of strength, I’ve concluded, is how much heavy stuff you can carry.
Fundamentally I structure my training around exercises that improve the following:
Grip strength, how hard you can grip with your hands, which involves everything from your hands to your lats (the large muscles on your back). Almost all actions begin with the grip. Attention to both concentric and eccentric loading for all movements, meaning when our muscles are shortening (concentric) and when they are lengthening (eccentric). In other words, we need to be able to lift the weight up and put it back down, slowly and with control.
Rucking down hills is a great way to work on eccentric strength, because it forces you to put on the “brakes.”
Pulling motions, at all angles from overhead to in front of you, which also requires grip strength (e.g., pull-ups and rows).
Hip-hinging movements, such as the deadlift and squat, but also step-ups, hip-thrusters, and countless single-leg variants of exercises that strengthen the legs, glutes, and lower back.
Training grip strength is not overly complicated. One of my favorite ways to do it is the classic farmer’s carry, where you walk for a minute or so with a loaded hex bar or a dumbbell or kettlebell in each hand. (Bonus points: Hold the kettlebell up vertically, keeping your wrist perfectly straight and elbow cocked at ninety degrees, as though you were carrying it through a crowded room.) 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, and for our female patients we push for 75 percent of that weight. This is, obviously, a lofty goal—please don’t try to do it on your next visit to the gym.
Another way to test your grip is by dead-hanging from a pull-up bar for as long as you can. (This is not an everyday exercise; rather, it’s a once-in-a-while test set.) You grab the bar and just hang there, supporting your body weight. This is a simple but sneakily difficult exercise that also helps strengthen the critically important scapular (shoulder) stabilizer muscles, which we will talk about in the next chapter. Here we like to see men hang for at least two minutes and women for at least ninety seconds at the age of forty. (We reduce the goal slightly for each decade past forty.)
Relearning how to move to prevent injury
In sum, stability lets us create the most force in the safest manner possible, connecting our body’s different muscle groups with much less risk of injury to our joints, our soft tissue, and especially our vulnerable spine. The goal is to be strong, fluid, flexible, and agile as you move through your world.
Nutrition 3.0
The problem is that epidemiology is incapable of distinguishing between correlation and causation. This, aided and abetted by bad journalism, creates confusion.
The true weakness of epidemiology, at least as a tool to extract reliable, causal information about human nutrition, is that such studies are almost always hopelessly confounded. The factors that determine our food choices and eating habits are unfathomably complex. They include genetics, social influences, economic factors, education, metabolic health, marketing, religion, and everything in between—and they are almost impossible to disentangle from the biochemical effects of the foods themselves.
The WHI study does provide a clear example of why it is so important to evaluate any intervention, nutritional or otherwise, through the lens of efficacy versus effectiveness. Efficacy tests how well the intervention works under perfect conditions and adherence (i.e., if one does everything exactly as prescribed). Effectiveness tests how well the intervention works under real-world conditions, in real people. Most people confuse these and therefore fail to appreciate this nuance of clinical trials.
How to find the right eating pattern for you
Once you strip away the labels and the ideology, almost all diets rely on at least one of the following three strategies to accomplish this:
CALORIC RESTRICTION, or CR: eating less in total, but without attention to what is being eaten or when it’s being eaten
DIETARY RESTRICTION, or DR: eating less of some particular element(s) within the diet (e.g., meat, sugar, fats)
TIME RESTRICTION, or TR: restricting eating to certain times, up to and including multiday fasting
Taken together, then, what do these two monkey studies have to tell us about nutritional biochemistry? Avoiding diabetes and related metabolic dysfunction—especially by eliminating or reducing junk food—is very important to longevity. 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. 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.
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.
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.
Overall, I like to keep average glucose at or below 100 mg/dL, with a standard deviation of less than 15 mg/dL. 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.
Lessons from Continuous Glucose Monitoring
In the years that I have used CGM, I have gleaned the following insights—some of which may seem obvious, but the power of confirmation cannot be ignored: Not all carbs are created equal. The more refined the carb (think dinner roll, potato chips), the faster and higher the glucose spike. Less processed carbohydrates and those with more fiber, on the other hand, blunt the glucose impact.
I try to eat more than fifty grams of fiber per day.
Rice and oatmeal are surprisingly glycemic (meaning they cause a sharp rise in glucose levels), despite not being particularly refined; more surprising is that brown rice is only slightly less glycemic than long-grain white rice.
Fructose does not get measured by CGM, but because fructose is almost always consumed in combination with glucose, fructose-heavy foods will still likely cause blood-glucose spikes.
Timing, duration, and intensity of exercise matter a lot. In general, aerobic exercise seems most efficacious at removing glucose from circulation, while high-intensity exercise and strength training tend to increase glucose transiently, because the liver is sending more glucose into the circulation to fuel the muscles. Don’t be alarmed by glucose spikes when you are exercising.
A good versus bad night of sleep makes a world of difference in terms of glucose control. All things equal, it appears that sleeping just five to six hours (versus eight hours) accounts for about a 10 to 20 mg/dL (that’s a lot!) jump in peak glucose response, and about 5 to 10 mg/dL in overall levels.
Stress, presumably, via cortisol and other stress hormones, has a surprising impact on blood glucose, even while one is fasting or restricting carbohydrates. It’s difficult to quantify, but the effect is most visible during sleep or periods long after meals.
Nonstarchy veggies such as spinach or broccoli have virtually no impact on blood sugar. Have at them.
Foods high in protein and fat (e.g., eggs, beef short ribs) have virtually no effect on blood sugar (assuming the short ribs are not coated in sweet sauce), but large amounts of lean protein (e.g., chicken breast) will elevate glucose slightly. Protein shakes, especially if low in fat, have a more pronounced effect (particularly if they contain sugar, obviously).
Stacking the above insights—in both directions, positive or negative—is very powerful. So if you’re stressed out, sleeping poorly, and unable to make time to exercise, be as careful as possible with what you eat.
Perhaps the most important insight of them all? Simply tracking my glucose has a positive impact on my eating behavior. 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. It makes me think twice when I see the bag of chocolate-covered raisins in the pantry, or anything else that might raise my blood glucose levels.
Protein
Unlike carbs and fat, protein is not a primary source of energy. We do not rely on it in order to make ATP, 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.
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 day19 (or 2.2 g/kg/day) is a good place to start—nearly triple the minimal recommendation.
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.
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
How to learn how to love sleep
Deep sleep is when the brain clears out its cache of short-term memories in the hippocampus and selects the important ones for long-term storage in the cortex, helping us to store and reinforce our most important memories of the day.
REM sleep is important in helping our brains grow and develop. Even while we are asleep, our brain is forming new connections, expanding our neural network; this is why younger people spend more time in REM.
Another very important function of REM sleep is to help us process our emotional memories, helping separate our emotions from the memory of the negative (or positive) experience that triggered those emotions. This is why, if we go to bed upset about something, it almost always seems better in the morning.
One large-scale survey found that the more interactive devices subjects used during the hour before bedtime, the more difficulties they had falling asleep and staying asleep—whereas passive devices such as TV, electronic music players, and, best of all, books were less likely to be associated with poor sleep.
Epilogue
“I think people get old when they stop thinking about the future,” Ric told me. “If you want to find someone’s true age, listen to them. If they talk about the past and they talk about all the things that happened that they did, they’ve gotten old. If they think about their dreams, their aspirations, what they’re still looking forward to—they’re young.” Here’s to staying young, even as we grow older.
