Outlive Part 2: The Four Horsemen
Outlive Part 2: The Four Horsemen
Meet your opponents
This is part two of our three-part summary of Peter Attia's Outlive. You can read part one here. This is also probably a good place to say that I am 100% not a medical professional—not even close to one. I’ve tried to research everything carefully but obviously you should not take what I say as any kind of medical advice.
All I want to know is where I'm going to die so I'll never go there. —Charlie Munger1
Imagine if you could peek into the future and see exactly what might threaten your health decades from now.
Actually you don’t have to imagine; odds are you know a lot of them already; heart disease, cancer, stroke.2
In Outlive, Attia groups the leading causes into groups he calls the Four Horsemen:
Metabolic syndrome or dysfunction
Heart disease
Cancer
Neurodegenerative disease, like Alzheimer’s
It turns out the Four Horsemen are not equally easy to fight. We have much more control over the first two: metabolic syndrome and heart disease. If we can nail those two, it'll go a long way towards fighting all four. That starts with understanding each one in a bit more detail, so let’s dive in.
Metabolic Syndrome: The Silent Threat
Ever heard of metabolic syndrome? If not, you’re not alone. Despite it being number one on Attia’s Four Horsemen list, it’s often overshadowed by its more famous cousins like heart disease and cancer.3
What Is Metabolic Syndrome (aka MetSyn)?
Also known as insulin resistance syndrome, MetSyn is a cluster of conditions that together raise your risk for all other diseases. You are defined as having metabolic syndrome if you have at least three of the following five criteria:
high blood pressure (>130/85)
high triglycerides (>150 mg/dL)
low HDL cholesterol (<40 mg/dL in men or <50 mg/dL in women)
central adiposity (waist circumference >40 inches in men or >35 in women)
elevated fasting glucose (>110 mg/dL)
MetSyn is highly correlated with obesity, but they are not the same thing. (Note that it's not one of the five criteria, though central adiposity is clearly highly correlated!) Not everyone who is obese is metabolically unhealthy, and vice versa. Just because you appear skinny does not make you immune to this problem!4
Insulin Resistance
Understanding MetSyn requires understanding how energy storage in the body works. When we eat or drink, glucose is the final form of most carbs after being processed by the body. (This is true whether you are eating sugar or pasta.) When the body senses glucose, insulin is secreted. Insulin moves glucose to where it’s needed (like your muscles lifting weights, or your brain solving chess puzzles), and maintains your blood glucose levels at a roughly steady amount.
When you eat a giant slice of cake, your body responds by pumping out insulin to manage the sudden glucose spike.5 Now, imagine doing this repeatedly, day after day, year after year. Your cells start to tune out insulin's signals, like a teenager ignoring their parent's hundredth request to clean their room.
This is insulin resistance, and it's at the heart of metabolic syndrome.
Insulin resistance is a term that we hear a lot, but what does it really mean? Technically, it means that cells, initially muscle cells, have stopped listening to insulin’s signals, but another way to visualize it is to imagine the cell as a balloon being blown up with air. Eventually, the balloon expands to the point where it gets more difficult to force more air inside. You have to blow harder and harder. This is where insulin comes in, to help facilitate the process of blowing air into the balloon. The pancreas begins to secrete even more insulin, to try to remove excess glucose from the bloodstream and cram it into cells. 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. If things continue in this way, then the pancreas becomes fatigued and less able to mount an insulin response. This is made worse by, you guessed it, the fat now residing in the pancreas itself. You can see the vicious spiral forming here: fat spillover helps initiate insulin resistance, which results in the accumulation of still more fat, eventually impairing our ability to store calories as anything other than fat.
Why Should You Care?
You might be thinking, “I’m not diabetic, so why should I worry?” Here's why: insulin resistance is the silent force behind the other three horsemen. It increases your risk of:
Cancer (up to 12 times!)
Alzheimer's disease (5 times)
Death from cardiovascular disease (almost 6 times)
So, while you're busy worrying about heart attacks or cancer, metabolic syndrome might be setting the stage for all of them.
Diabetes ranks behind things like Alzheimer's as a cause of death in the US, but Peter believes it's because we underaccount for the true impact. People with diabetes are far more vulnerable to other diseases that end up killing you.6
This is why even if you are not at risk of Type 2 diabetes any time soon, metabolic syndrome remains key to longevity. Of all four horsemen, MetSyn receives by far the most coverage in Outlive. I was surprised, since I would not have guessed that it was the number one thing to combat for longevity—heart disease seems to get much more press. The good news is between nutrition and exercise, we have a tremendous set of tools to ensure we stay metabolically healthy, which we will cover in part three.
Heart Disease: The One Everyone Knows
Heat disease is probably what most people think of first when they think of the most common causes of death. Unlike metabolic syndrome, it needs no introduction. But there are still a few surprising things to learn here.
Cholesterol: The Good, The Bad, and The Misunderstood
When we think of heart disease, we of course think of cholesterol. There are a few misconceptions around heart disease that Outlive discusses.
First, most people have heard of “good” cholesterol (HDLs) and “bad” cholesterol (LDLs), but cholesterol itself is not problematic. The problem is due to the nature of the particle that carries the cholesterol itself. LDL is encased in a protein called apolipoprotein B (or apoB), whereas HDL is wrapped in apoA. Every single lipoprotein that contributes to atherosclerosis (not only LDL, but several others) is wrapped in apoB. This is why when we get to testing, Attia considers apoB a more valuable to test for as an indicator of risk, than the markers we historically measure like LDL and HDL counts.
Second, dietary cholesterol doesn't seem to have much to do with heart disease:
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.
In 2015, the US advisory committee for nutrition guidelines conceded “cholesterol is not a nutrient of concern for overconsumption.” It's a little confusing because, when talking about nutrition, Attia does talk about how diet affects cholesterol. But it seems like the total cholesterol amount of the foods you eat doesn't matter much, whereas the kinds of cholesterol (saturated fats, polyunsaturated fats, monounsaturated fats) does. We'll get to that in part three.
Not Just For The Elderly
When we think about heart disease, most of us picture an elderly person clutching their chest. But half of major cardiovascular events (heart attack, stroke, etc) occur in men before age 65. A third occur before then for women.
Critically cardiovascular disease is a slowly building process that starts long before you are old, in some cases as early as in your teens! (As a teenager who ate a lot of Chik-fil-A in Texas growing up, I am probably in this category.) But it's also not a one-way street. HDL cholesterol, through better nutrition, can clear away cholesterol clinging to arterial walls.
For many people nutrition is not enough. The good news is that unlike for cancer or neurodegenerative diseases (spoilers), we have excellent drugs to fight heart disease. We have a host of statins that can be prescribed for cholesterol, and notably most people can handle them with minimal side effects. For those people, Attia (per his Medicine 3.0 philosophy) advocates using statins early and often. This is because it's all about total exposure to apoB over time. If the side effects are minimal, and we know that statins can push apoB numbers down, why shouldn't we utilize them earlier to fight back?
This is an aggressive view of health management, and (as far as I can tell) not widely adopted. But who knows, perhaps this will change over the coming years. Until then, there’s plenty we can still do to fight the good fight.
Cancer: The Wild Card of the Four Horsemen
Of all the health topics out there, cancer might be the scariest. It's the bogeyman of diseases, the thing that lurks in our anxieties.
Unfortunately, unlike metabolic dysfunction and heart disease, cancer is an area we have much less control over. Some of us will simply be unlucky.
Screen Early, Screen Often
The main takeaway for cancer from Outlive is that once it is established in the body, we have crappy tools to fight it. Breast cancer and prostate cancer only kill when they become metastatic and spread.
The good news? You can live without breasts or a prostate organs, which means if we catch these cancers early, our chances of survival skyrocket. While we can hope for better treatments in the future, currently our best hope remains to try and catch them as early as possible, when are treatments can be most effective. Because of this, Attia’s strategy for cancer is centered around aggressive screening.
What Can We Actually Do?
Besides screening, there does not seem like there is a lot we can do to prevent cancer. The only risks we have some control over seem to be not smoking (smoking puts you at 10-25x more risk for lung cancer), insulin resistance, and obesity. Remember our old friend metabolic syndrome? Turns out it might be playing for team cancer too. While the evidence for the link between insulin resistance, obesity, and cancer is less strong, it's still just another reason to focus on metabolic health.
Beyond this, there isn't much else to say. Outlive covers a bunch of possible new treatments, which will hopefully bear fruit some day, but that don't really affect those of us without cancer right now.
Neurodegenerative Diseases: The Final Frontier
If you thought our lack of tools to combat cancer was depressing, get ready for more. We do have some genetic screens that can indicate a higher likelihood of developing a disease, but by and large we are worse off here both for screening and treatment than for cancer.
Partly this is because we are generally not that good at understanding this horseman, which limits our ability to come up with effective treatment and prevention plans.
Possible Theories
One theory of the cause of neurodegenerative disease is vascular disease resulting reduced blood flow, for which there is strong circumstantial evidence. If true, then doing all the things we already want to do to fight heart disease will help our brains too.
Another theory is—you guessed it, the recurring scourge—insulin resistance. Having type 2 diabetes greatly increases the risk of developing Alzheimer's disease. (He says "doubles or triples" here but there's no footnote.) If this is the case, doing what's good for metabolic health, will also help the brain.
So while things may look bleak for this horseman, the best weapons we have are ones we were going to deploy anyway against the other horsemen. Yay, I guess? No extra homework!
Attia does mention exercise as the most important tool we have for fighting neurodegenerative diseases, but it also seems to be the most effective thing for fighting, well… everything, as we’ll discover in part three.
tl;dr
To summarize:
Metabolic syndrome is very, very bad. DO NOT GET DIABETES. It is a source of cascading problems that buffs every other horseman. If the Four Horsemen had a leader, it would be MetSyn.
Heart disease is also bad, but we have very good drugs in statins to help us.
We can do a lot to combat both MetSyn and heart disease through exercise and nutrition, which we're about to get into next.
Cancer and neurodegenerative diseases are less well understood and we have much weaker tools to fight them. For cancer our best bet is early detection. If we succeed at fighting MetSyn and heart disease, we'll incidentally be improving our odds against both of them as well, which is kind of nice because frankly this is a lot already.
Now on to the good stuff: what the hell do we do about all this?
Charlie Munger said a lot of witty little quips bordering on trite like, “It’s been my experience in life, if you just keep thinking and reading, you don’t have to work.” But he did live to be 99, so maybe he was onto something.
COVID is also up there in the 2022 data, but if you go back to 2019, the rankings are basically the same, minus COVID.
While Type 2 diabetes is the most well-known disease in this category, metabolic syndrome takes many forms. You have probably not heard of NASH (nonalcoholic steatohepatitis) or NAFLD (nonalcoholic fatty liver disease, pronounced “naffel-dee”), but more than 25% of people have it to some degree. Type 2 diabetes is simply an endpoint on a sequence of diseases that include NAFLD and NASH.
And actually despite Outlive being published in 2023, the terms NAFLD and NASH are already out of date. In a recent interview with Julia Wattacheril, she shares that doctors are trying to shift the nomenclature to Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD), due to stigma around the world “alcoholic” in NAFLD, even though the acronym stands for non-alcoholic fatty liver disease.
It turns out being “skinny fat” is a thing (and one that I am definitely afflicted with):
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.
A crazy fact I wrote down from Outlive: “The leading source of calories that Americans consume is a category called “grain-based desserts,” like pies, cakes, and cookies, according to the US Department of Agriculture.”
In a review of Outlive by an ER doctor, he reinforces this:
The last thing I will say is what I’ve learned as an ER doctor for the past 16 years: do not get diabetes. Almost every other disease is worse or more prevalent or higher-risk if you have diabetes, and I am not exaggerating when I say that easily half of my patients I see in the ER have it. It is that bad of a disease. (They’re not necessarily in the ER due to their diabetes, but due to the other diseases that track along closely like heart disease, kidney disease, etc.)