Outlive
The Science and Art of Longevity
Author: Peter Attia, M.D.
Publication Year: 2023
Link: https://www.amazon.com/Outlive-Longevity-Peter-Attia-MD/dp/0593236599
See also these notes and recommendations from another reader.
Notes
Part I
1. The Long Game: From Fast Death to Slow Death
Hemoglobin A1C (HbA1C) >= 6.5%, corresponding to an average blood glucose level of 140 mg/dL, results in a diagnosis of diabetes mellitus (type 2). Normal is 100 mg/dL, or 5.1% (p13, ¶3).
2. Medicine 3.0: Rethinking Medicine for the Age of Chronic Disease
Toward Medicine 3.0
Traditionally, a fasting glucose test, and HbA1C test, are used to assess a patient’s metabolic health once per year. Alternatively, a continuous glucose monitor (CGM) allows real-time monitoring to assess how diet impacts glucose uptake (p31, ¶1).
3. Objective, Strategy, Tactics: A Road Map for Reading This Book
Our Strategy
Tactics
Tactics fall into five broad categories: exercise, nutrition, sleep, emotional health, and exogenous molecules (p47, ¶4).
Exercise is the most potent longevity “drug” in our arsenal (p48, ¶3).
In terms of nutrition, quantity of food is the primary determinant (p48, ¶4).
Good sleep is critical to our innate physiological repair processes, especially in the brain; lack of sleep triggers a cascade of consequences (p49, ¶2).
From Evidence Based to Evidence Informed
Part II
4. Centenarians: The Older You Get, the Healthier You Have Been
Apolipoprotein E (APOE) is involved in cholesterol transport and processing. It comes in three type (e2, e3, and e4). e3 is the most common. One or two copies of e4 is associated with significantly higher risk of Alzheimer’s disease, but the e2 variant seems to protect against dementia (p67, ¶5).
The FOXO3 gene is strongly associated with healthy aging and longevity. It belongs to a family of “transcription factors,” which regulate how other genes are expressed, and it can be activated via caloric restriction (CR) and exercise (p69, ¶3).
Improving metabolic health significantly decreases the risk of cancer and cardiovascular and neurodegenerative diseases (p72, ¶1).
5. Eat Less, Live Longer: The Science of Hunger and Health
Mechanistic target of rapamycin (mTOR) is one of the most important mediators of longevity at the cellular level. It balances an organism’s need to grow against available nutrients. When food is plentiful, mTOR is activated, and cells go into growth mode; when scarce, mTOR is suppressed, and cells go into “recycling” mode (p77, ¶1).
AMP-activated protein kinase (AMPK) is the cellular low-fuel light. It’s activated by low nutrient levels and exercise, and prompts the cell to seek alternate sources of energy. This happens first by replacing old and damaged mitochondria with new ones, and then by stimulating glucose production in the liver and releasing energy stored in fat cells. This inhibits mTOR, shifting the cell into a more fuel-efficient and stress-resistant mode, and activating cellular recycling (autophagy) (p82, ¶2).
Cellular clean-up is carried out by lysosomes, which package up old proteins and other detritus (including pathogens and protein aggregates), and grind them up into base components for reuse. Aggregates are clumps of damaged proteins that accumulate over time, and their presence is linked to neurodegenerative diseases (p83, ¶2).
Impaired autophagy is likely a driver of neurodegeneration and osteoarthritis, but it can be improved via exercise, fasting, and rapamycin (though it’s not approved for this use in humans) (p83, ¶3).
6. The Crisis of Abundance: Can Our Ancient Genes Cope with Our Modern Diet?
Rising levels of alanine amino-transferase (ALT) are often the first clue that something is wrong with the liver—e.g., nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH)—though these diseases can already be present when ALT levels are still normal (p91, ¶3).
“Normal” ALT levels are below 33 IU/L for women and 45 IU/L for men, but normal (a statistical measure) is not necessarily healthy; better limits might be 19 and 30, respectively (p91, ¶4).
Obesity (having a body mass index greater than 30) is merely one symptom of an underlying metabolic derangement, such as hyperinsulinemia, that also happens to cause us to gain weight. But not everyone who is obese is metabolically unhealthy, and not everyone who is metabolically unhealthy is obese (p93, ¶3).
Metabolic syndrome (MetSyn) is defined as meeting three of the following five criteria (p94, ¶2):
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 inches in women)
Elevated fasting glucose (> 110 mg/dL)
Energy from carbohydrates can be converted to either glycogen or triglycerides contained within fat cells for long-term storage. About 3/4 of glycogen ends up in skeletal muscle, and the rest goes to the liver, which then converts it back to glucose to maintain glucose homeostatis within the circulatory system (p96, ¶2).
The decision to store energy in glycogen vs fat is made via hormones, primarily insulin, which helps shuttle the glucose to where it’s needed (p97, ¶1).
Subcutaneous fat, which plays an important role in regulating metabolic health, is actually the safest place to store excess energy, which is then consumed with sustained exercise (p97, ¶2).
When you exceed your body’s capacity for subcutaneous fat, the excess calories spill over elsewhere (p98, ¶2):
in your blood, as excess triglycerides
in your liver, contributing to NAFLD
in your muscle tissue, contributing to insulin resistance
around your heart and pancreas
as visceral fat, accumulating between your organs, which secretes inflammatory cytokines
You should undergo a DEXA scan annually (p100, ¶1).
Insulin resistance means cells have stopped listening to insulin’s signals (p101, ¶1).
There’s very little difference between high-fructose corn syrup (55% fructose, 45% glucose) and sugar/sucrose (50% fructose, 50% glucose) (p105, ¶4).
You should test your uric acid levels, because high levels promote fat storage, and are an early warning sign that we need to address diet or metabolic health (p106, ¶2).
Fructose is metabolized differently from glucose. When metabolizing fructose in large quantities, adenosine triphosphate (ATP, the cellular energy currency) levels drop rapidly, which triggers an enzyme called AMP deaminase (AMPD), which triggers fat storage, and also blocks the satiety hormone leptin, tricking us into thinking we’re still hungry. All that to say, consuming large quantities of liquid fructose simply overwhelms the ability of the gut to handle it (p106, ¶3).
You want to monitor several biomarkers related to metabolism, keeping an eye out for elevated uric acid, elevated homocysteine, chronic inflammation, and even mildly elevated ALT liver enzymes. The ratio of triglycerides to HDL cholesterol should be less than 2:1 (ideally less than 1:1). Track VLDL level as well (p108, ¶4).
An oral glucose tolerance test (OGTT) can indicate whether someone is in the early stages of insulin resistance (p109, ¶2).
7. The Ticker: Confronting—and Preventing—Heart Disease, the Deadliest Killer on the Planet
Order a CT scan of your heart, calibrated to detect calcification in your coronary arteries, a sign of advanced atherosclerosis. The resulting calcium score indicates the degree of concern (p113, ¶5).
Since cholesterol is a lipid, it can’t dissolve in our plasma; rather, it has to be transported around inside lipoproteins, which also carry triglycerides, phospholipids, vitamins, proteins, etc. They come in varying densities, referring to the amount of fat relative to protein that they carry. All these particles frequently exchange their cargo with one another throughout circulation. Each is enwrapped by one or more large molecules (apolipoproteins) that provide structure, stability, and solubility to the particle. Every lipoprotein that contributes to atherosclerosis carries the apolipoprotein B (apoB) signature (p116, ¶5).
High-density lipoproteins (HDL), enwrapped by apolipoprotein A (apoA)
Intermediate-density lipoproteins (IDL), enwrapped by apoB
Low-density lipoproteins (LDL), enwrapped by apoB
Very-low-density lipoproteins (VLDL), enwrapped by apoB
Particles tagged with apoA can cross the endothelial barrier easily in both directions; particles tagged with apoB are far more prone to get stuck inside. When they do, if they come into contact with a reactive oxygen species (ROS), they become oxidized, kicking off the atherosclerotic cascade. Smoking and high blood pressure damage the endothelium, which increases the risk of this. The more apoB-tagged particles you have in circulation, the higher the risk (p120, ¶2).
If enough apoB-tagged particles are oxidized at a site, monocytes (immune cells; large white blood cells) are summoned and become macrophages, attempting to eat the oxidized LDL (p121, ¶3).
HDL particles can suck the cholesterol back out of macrophages via delipidation, then transports it back to the liver and other tissues for reuse. Additionally, HDL help maintain the integrity of the endothelium, lowers inflammation, and neutralizes or stops the oxidation of LDL. That said, raising HDL concentration has not been shown to reduce cardiovascular risk. The key seems to be increasing the functionality of the particles, but we don’t know how to do that (p123, ¶1).
A CT angiogram is a more advanced CT scan, capable of identifying both noncalcified or “soft” plaque that precedes calcification, and stenosis, or narrowing of the lumen, the passage through which blood flows. It’s a bit more expensive, but it’ll find problems sooner than a standard calcium scan, giving you more time to address them (p124, ¶3).
Get tested for apoB regularly; it’s ~$20–$30 (p127, ¶1).
The most dangerous hereditary risk factor for heart disease is elevated Lp(a), which is when a LDL particle fuses with an apolipoprotein(a) particle (not the same as apoA). As Lp(a) circulates, it scoops up oxidized lipid molecules, but then if it penetrates the endothelium and gets stuck, it accelerates the formation of arterial plaques. If there’s a history of premature heart attacks in your family, you should definitely test your Lp(a) levels, though this only needs to be done once. There is no behavioral way to reduce Lp(a), though PCSK9 inhibitors do help some. The best thing is to keep apoB as low as possible (though keep an eye on antisense oligonucleotide drugs, ASOs, which are currently in clinical trials to reduce Lp(a) concentration) (p128, ¶3).
How to Reduce Cardiovascular Risk
Various treatment guidelines specify a target LDL concentration of 100 mg/dL, but in reality, we should probably be down in the 10–20 mg/dL range (which is what we have when we’re born) (p131, ¶2).
Low HDL does not causally increase the risk of myocardial infarction, and raising it does not causally lower the risk (p132, ¶3).
Prefer monounsaturated fats (extra virgin olive oil, macadamia nuts, avocados, etc.) over saturated fats (p133, ¶3).
To reduce apoB or LDL concentration, statins inhibit cholesterol synthesis, prompting the liver to increase the expression of LDL receptors (LDLR), taking more LDL out of circulation. That said, when drug intervention is needed, you likely want a combination of different classes of drugs that operate via distinct mechanisms (p134, ¶1).
Lipid-lowering medications include rosuvastatin (Crestor), bempedoic acid (Nexletol), ezetimibe (Zetia), PCSK9 inhibitors, fibrates, and ethyl eicosapentaenoic acid (Vascepa) (p137, ¶5).
8. The Runaway Cell: New Ways to Address the Killer That Is Cancer
What Is Cancer?
Cancer is not one single, simple, straightforward disease, but a condition with mind-boggling complexity (p146, ¶3).
With few exceptions, solid organ tumors typically kill you when they metastasize from their source (e.g., breast, prostate, pancreas, colon) to more critical organs (e.g., brain, lungs, liver, bones) (p147, ¶4).
Many cancer cells have an altered metabolism, consuming huge amounts of glucose. They also seem to have an uncanny ability to evade the immune system, which normally hunts down damaged and dangerous cells and targets them for destruction (p149, ¶2).
Cancer Metabolism
Injecting a patient with radioactively labeled glucose, and then doing a PET scan to see where most of the glucose is migrating, can indicate the possible presence of a tumor (p150, ¶2).
Excess weight is a leading risk factor for both cancer cases and deaths, second only to smoking. 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. This chronic inflammation helps create an environment that could induce cells to become cancerous. It also contributes to the development of insulin resistance, causing insulin levels to creep upward (p152, ¶1).
Metabolic therapies, including dietary manipulations that lower insulin levels, could potentially help slow the growth of some cancers and reduce cancer risk (p153, ¶2).
While it’s tricky to impossible to avoid or prevent the genetic mutations that help give rise to cancer, it is relatively easy to address the metabolic factors that feed it. We don’t want to be anywhere on the spectrum of insulin resistance to type 2 diabetes. This is the low-hanging fruit of cancer prevention, right up there with quitting smoking (p154, ¶2).
New Treatments
Nutritional interventions, such as a particular diet (leafy vegetables, olive oil, avocados, nuts, and modest mounts of protein, mostly from fish, eggs, and poultry, plus no added sugar or refined carbohydrates) or intermittent fasting, may increase the effectiveness of traditional treatments (e.g., chemotherapy), though research in this area is still in its infancy (p155, ¶3).
The Promise of Immunotherapy
It is not uncommon for a patient with metastatic cancer to enter remission after chemotherapy. The problem is that it virtually never lasts. The cancer almost always comes back in some form. But when patients respond to immunotherapy, and go into complete remission, they often stay in remission (p164, ¶4).
Early Detection
Out of dozens of different types of cancers, we have agreed-upon, reliable screening methods for only five: lung (for smokers), breast, prostate, colorectal, and cervical (p167, ¶2).
Get a colonoscopy by age 40, and repeat the procedure every 2–3 years, depending on the findings. Colorectal cancer is one of the easiest to detect, with the greatest payoff in terms of risk reduction. The deadliest cancers, in terms of number of deaths, are lung, breast/prostate, colon, pancreas, and liver (p170, ¶2).
You should ask what your endoscopist’s adenoma detection rate (ADR) is, which is the proportion of individuals undergoing a colonoscopy who have one or more adenomas (or colon polyps) detected. The benchmarks are greater than 30% in men and 20% in women. You should also ask your endoscopist how many perforations he or she has caused, as well as any other serious complications. You should also ask about their withdrawal time, the amount of time spent viewing as the colonoscope is withdrawn (six minutes is the current standard of care) (p171, footnote).
Skin cancer and melanomas are easy to spot on visual examination. The pap smear for cervical cancer is another well-established, minimally invasive test that I recommend my patients do yearly. CT scans can detect lung cancers, and we should use them on never-smokers as well, because lung cancer in never-smokers is the seventh leading cause of cancer death worldwide (p171, ¶2).
A whole body screening MRI can be a good means of cancer detection, but false positives are likely, and you might waste time/money chasing a problem that’s not really there (p172, ¶3).
Liquid biopsies are a promising means of early cancer detection. It’s worth keeping your eye on screenings like Galleri from the Grail company (p172, ¶4).
If the first rule of cancer is “Don’t get cancer,” the second rule is “Catch it as soon as possible.” This comes at significant financial and emotional cost, particularly when encountering false positives (p176, ¶2).
9. Chasing Memory: Understanding Alzheimer’s Disease and Other Neurodegenerative Diseases
In initial blood work, I’m looking at a patient’s level of Lp(a), their apoB concentration, and their APOE genotype. The APOE e4 allele is associated with greater risk of Alzheimer’s, with two copies (e4/e4) indicating a 12-times higher risk than someone with two copies of the e3 allele. The e2 version appears to protect against Alzheimer’s: e2/e3 is a 10% risk reduction over e3/e3; e2/e2 is a 20% reduction (p178, ¶1).
Neurodegenerative diseases (Alzheimer’s, Lewy body dementia, Parkinson’s, amyotrophic lateral sclerosis or ALS, Huntington’s) are the most intractable of the four horsemen, as they don’t appear to be readily reversible (p179, ¶2).
Understanding Alzheimer’s
Amyloid-beta is a by-product that is created when a normally occurring substance called amyloid precursor protein (APP), a membrane protein found in neuronal synapses, is cleaved in three pieces instead of the normal two. One of the three becomes “misfolded,” becoming chemically stickier and prone to aggregating in clumps. These amyloid-beta clumps also trigger the aggregation of another protein (tau), which leads to neuronal inflammation and brain shrinkage. Certain genetic mutations (APP, PSEN1, PSEN2) affect APP cleavage and promote rapid amyloid-beta accumulation (p182, ¶p2).
The “amyloid hypothesis” is that Alzheimer’s is caused directly by amyloid-beta accumulation. However, so far (as of 2023) any drugs attempting to clear amyloid-beta plaque, or slow its accumulation, haven’t benefited patients’ cognitive function or slowed the progression of the disease, though this may be because treatments have been administered too late. Some researchers think the disease might be reversible at the point where amyloid-beta is present but not tau (p182, ¶4).
Contrary to the amyloid hypothesis, numerous autopsies have shown that more than 25% of cognitively normal people had large deposits of amyloid in their brains when they died, and some patients with all the symptoms of Alzheimer’s disease have little to no amyloid in their brains. The presence of amyloid-beta plaques is neither necessary for the development of Alzheimer’s, nor sufficient to cause it (p184, ¶3).
Lewy body dementia and Parkinson’s are associated with the accumulation of a neurotoxic protein called alpha-synuclein, which builds up in aggregates called Lewy bodies. The APOE e4 variant increases one’s risk for Lewy body dementia and Parkinson’s as well (p185, ¶4).
Can Neurodegenerative Disease Be Prevented?
Alzheimer’s disease is almost twice as common in women as men. Some think this is simply because women tend to live longer, but that doesn’t fully account for the difference. There may be something about menopause, and the abrupt decline in hormonal signaling, that sharply increases the risk. Particularly, a rapid drop in estradiol in women with APOE e4 is a driver of risk, so perimenopausal hormone replacement therapy could play a role in prevention. Other reproductive history factors (number of children, age of first menstruation, exposure to oral contraceptives, etc.) may also have a significant impact on Alzheimer’s risk (p189, ¶1).
Any patient who may have cognitive issues should be subjected to a grueling battering of tests, administered by one specializing in preventive neurology. These tests cover every domain of cognition and memory, including executive function, attention, processing speed, verbal fluency, and logical, associative, spatial, and semantic memory (p191, ¶1).
When we have a thought or a perception, it’s not just one neural network that is responsible for that insight, or that decision, but many individual networks working simultaneously on the same problem. There’s redundancy built into the system. The more of these networks that we have built up over our lifetime, via education or experience, or by developing complex skills such as speaking in a foreign language or playing a musical instrument, the more resistant to cognitive decline we will tend to be. This is known as “cognitive reserve” (p192, ¶2).
There’s a parallel concept known as “movement reserve” that becomes relevant for Parkinson’s disease. People with better movement patterns, and a longer history of moving their bodies, such as trained or frequent athletes, tend to resist or slow the progression of the disease as compared to sedentary people. This is also why movement and exercise, not merely aerobic exercise but also more complex activities like boxing workouts, are a primary treatment/prevention strategy for Parkinson’s (p192, ¶4).
Tasks or activities that present more varied challenges, requiring more nimble thinking and processing, are more productive at building and maintaining cognitive reserve. The same goes for movement reserve: dancing appears to be more effective than walking, likely because it involves more complex movement (p193, ¶3).
Alternatives to Amyloid
For decades researchers have noted problems with cerebral blood flow (perfusion) in patients with dementia. Alzheimer’s brains often display marked calcification of the blood vessels and capillaries that feed them. Robust blood flow in the brain seems to be critical to maintaining mental health (p194, ¶1).
Brain cells metabolize glucose in a different way from the rest of the body; they don’t depend on insulin, but absorb circulating glucose directly. This enables the brain to take top priority to fuel itself when blood glucose levels are low. If we lack new sources of glucose, the liver converts our fat into ketone bodies. When our fat runs out, we begin to consume our own muscle tissue, then our other organs, even bone, all to keep the brain running at all costs. The dementia symptoms that we see result from a gradual reduction in blood flow, which eventually creates a “neuronal energy crisis,” which in turn triggers a cascade of unfortunate events that harms the neurons and ultimately causes neurodegeneration. Amyloid-beta is an important pathological product of neurodegeneration, but it’s not the cause (p195, ¶2).
People with a history of cardiovascular disease are at a higher risk of developing Alzheimer’s disease. Evidence also demonstrates a linear relationship between cognitive decline and increased intimal media thickness in the carotid artery, a major blood vessel that feeds the brain. Cerebral blood flow already declines naturally during the aging process, and this arterial thickening, a measure of arterial aging, could cause a further reduction in cerebral blood supply. High blood pressure, smoking, head injury, depression, and other problems that reduce blood flow are also risk factors (p196, ¶1).
Another compelling theory of Alzheimer’s disease says that it stems from abnormal glucose metabolism in the brain. Having type 2 diabetes doubles or triples your risk of developing Alzheimer’s disease, about the same as having one copy of the APOE e4 gene. Chronically elevated blood glucose can directly damage the vasculature of the brain, but insulin resistance alone is enough to elevate one’s risk. Insulin plays a key role in memory function, as insulin receptors are highly concentrated in the hippocampus, the memory center of the brain. Insulin nasal spray, to get insulin to the brain as quickly as possible, quickly improves cognitive performance and memory, and helps preserve brain volume. It’s helpful to get glucose into neurons, and insulin resistance blocks this. Reduced glucose metabolism essentially starves neurons of energy, provoking a cascade of responses that include inflammation, increased oxidative stress, mitochondrial dysfunction, and ultimately neurodegeneration (p196, ¶3).
The Role of APOE e4
We don’t know why, but APOE e4 seems to accelerate other risk factors and driver mechanisms for Alzheimer’s, simply making everything worse. APOE plays an important role in cholesterol transport and glucose metabolism. It’s the main cholesterol carrier in the brain, moving it across the blood-brain barrier. For some reason, people with the e4 allele have defects in both cholesterol transport and glucose metabolism. The e4 variant appears to be less efficient at moving cholesterol into and especially out of the brain (p197, ¶3).
The e4 variant also appears to be bad for dealing with modern diets. Carriers are more likely to develop metabolic syndrome, and this may be because APOE e4 disrupts the brain’s ability to regulate insulin levels and maintain glucose homeostasis in the body. Such patients on continuous glucose monitoring demonstrate dramatic blood glucose spikes after eating carbohydrate-rich foods. Therefore, e4 might drive the metabolic dysfunction that increases the risk of dementia, and it seems to intensify the damage done to the brain by that metablic dysfunction. In high-glucose environments, the aberrant form of the protein works to block insulin receptors in the brain, forming aggregates that prevent neurons from taking in energy. However, not everyone with e4 is affected in the same way; biological factors (sex, ethnicity) and lifestyle choices (diet, exercise) play a key role (p198, ¶4).
The Preventive Plan
The first step is to address any metabolic issues, seeking to improve glucose metabolism, inflammation, and oxidative stress. One possible recommendation is to switch to a Mediterranean diet, relying on more monounsaturated fats and fewer refined carbohydrates, in addition to regular consumption of fatty fish. Supplementation with the omega-3 fatty acid DHA may help (p200, ¶3).
A ketogenic diet may offer a real functional advantage, because when someone is in ketosis, their brain relies on a mix of ketones and glucose for fuel. While Alzheimer’s patients’ ability to utilize glucose in the brain is impaired, they can still metabolize ketones (p200, ¶4).
The most powerful item in our preventive toolkit is exercise, as it helps maintain glucose homeostasis, and improves the health of our vasculature. A focus on steady endurance exercise will improve mitochondrial efficiency, and help lower inflammation and oxidative stress. Strength training is likely just as important. Grip strength (shoot for 50+ kg), an excellent proxy for overall strength, is strongly inversely correlated with the incidence of dementia (p201, ¶2).
Sleep is also a very powerful tool, because that’s when our brains heal themselves. During deep sleep our cerebrospinal fluid sweeps away intracellular waste that builds up between neurons. Poor sleep combined with high stress and elevated cortisol levels is a multiplier of risk (p202, ¶2).
Another risk factor is hearing loss, which is clearly associated with Alzheimer’s, though not a direct symptom. Folks with hearing loss tend to pull back from social interactions, and when the brain is deprived of inputs, it withers. Socializing, intellectual stimulation, and feeling connected are essential to brain health (p203, ¶2).
Another intervention that may help reduce systemic inflammation, and, by extension, Alzheimer’s risk, is flossing your teeth. Microbes causing gum disease are responsible for large increases in inflammatory markers, and oral health is strongly correlated with overall health (p203, ¶4).
While the mechanisms are not yet fully understood, the use of dry saunas, four times per week, for 20 minutes at a time, at 179°F, is correlated with a reduction in Alzheimer’s risk by 65% and ASCVD risk by 50% (p204, ¶1).
Other potential interventions include lowering homocysteine with B vitamins, optimizing omega-3 fatty acids, increasing vitamin D levels, and hormone replacement therapy for women during the transition from perimenopause to menopause (p204, ¶2).
Broadly, our strategy should be based on the following principles (p205, ¶2):
What’s good for the heart is good for the brain. That is, vascular health (meaning low apoB, low inflammation, and low oxidative stress) is crucial to brain health.
What’d good forr the liver (and pancreas) is good for the brain. Metabolic health is crucial to brain health.
Time is key. We need to think about prevention early, and the more the deck is stacked against you genetically, the harder you need to work and the sooner you need to start. As with cardiovascular disease, we need to play a very long game.
Our most powerful tool for preventing cognitive decline is exercise. We’ve talked a lot about diet and metabolism, but exercise appears to act in multiple ways (vascular, metabolic) to preserve brain health, but exercise—lots of it—is a foundation of our Alzheimer’s-prevention program.
Part III
10. Thinking Tactically: Building a Framework of Principles That Work for You
The five tactical domains we can address are exercise, nutritional biochemistry (diet), sleep, emotional health, and exogenous molecules (drugs) (p211, ¶3).
Tactics are specific things you can do regularly to decrease risk. E.g., to reduce risk of death by car accident, wear a seat belt, don’t use a phone while driving, don’t drink and drive, and look left and right before entering an intersection (even if you have the right of way) (p212, ¶4).
When I evaluate new patients, I’m always asking three key questions (p213, ¶5):
Are they overnourished or undernourished? That is, are they taking in too many or too few calories?
Are they undermuscled or adequately muscled?
Are they metabolically healthy or not?
11. Exercise: The Most Powerful Longevity Drug
Peak aerobic cardiorespiratory fitness, measured in terms of VO2 max, is perhaps the single most powerful marker for longevity. VO2 max represents the maximum rate at which a person can utilize oxygen, and is expressed as a volume of oxygen, per kilogram of body weight, per minute (p220, ¶1).
Poor cardiorespiratory fitness carries a greater relative risk of death than smoking. Climing from the bottom to the second quartile of VO2 max cuts your risk of all-cause mortality nearly in half (p221, ¶2).
Those with low muscle mass are at ~50% greater risk of mortality than controls, and it’s not just the mass that matters, but the strength of those muscles, their ability to generate force (p223, ¶5).
Exercise strengthens the heart and helps maintain the circulatory system. It improves the health of mitochondria, which improves our ability to metabolize glucose and fat. When exercising, our muscles produce cytokines that send signals to other parts of our bodies, helping to strengthen the immune system and stimulate growth of new muscle and stronger bones. Endurance exercise helps generate brain-derived neurotrophic factor (BDNF), which improves the function of the hippocampus, a part of the brain that plays an essential role in memory. Exercise also keeps the brain vasculature healthy and may help preserve brain volume (p224, ¶5).
The Centenarian Decathlon
The centenarian decathlon is the 10 (or 15 or 20) activities that you want to be able to do in your eighth, ninth, or tenth decade. Examples include (p231, ¶3):
Hike 1.5 miles on a hilly trail.
Get up off the floor under your own power, using a maximum of one arm for support.
Pick up a young child from the floor.
Carry two five-pound bags of groceries for five blocks.
Lift a twenty-pound suitcase into the overhead compartment of a plane.
Balance on one leg for thirty seconds, eyes open. (Bonus points: eyes closed, fifteen seconds.)
Have sex.
Climb four flights of stairs in three minutes.
Open a jar.
Do thirty consecutive jump-rope skips.
Swim half a mile in twenty minutes.
Walk with a thirty-pound dumbbell in each hand for one minute.
Draw back and fire a fifty-pound compound bow.
Do five pull-ups.
Climb ninety steps in two minutes.
Dead-hang for one minute.
Drive a race car.
Hike with a twenty-pound backpack for an hour.
Carry your own luggage.
Walk up a steep hill.
These activities have certain requirements in terms of strength, stability, flexibility, and endurance. Your body will naturally degrade in these areas, so it’s insufficient to be able to do the activities now—you need to be able to do substantially more now to prepare for that decline. E.g., since muscle strength declines by ~8-17% per decade, if you want to be able to lift a 30-pound child at ninety, you need to be able to do a 50-pound goblet squat at sixty. If you want to be able to briskly climb stairs at seventy (VO2 max = 32), you need to be able to jog up a steep hill (10% grade) at forty (VO2 max = 48) (p232, ¶3).
12. Training 101: How to Prepare for the Centenarian Decathlon
Aerobic Efficiency: Zone 2
How we utilize different fuels, glucose and fatty acids, is critical to our fitness, and our metabolic and overall health. Our mitochondria burn glucose and fat, are fundamental to maintaining brain health, and control bad actors like oxidative stress and inflammation. Zone 2 aerobic exercise improves the ability of the mitochondria to use glucose, and especially fat, as fuel (p237, ¶1).
The levels of intensity used by trainers in endurance sports are (p237, ¶3):
A walk in the park.
Going at a speed slow enough that one can still maintain a conversation, but fast enough that the conversation might be a little strained.
Increasing the pace to the point where you can’t get through a whole sentence without pausing to breathe.
…
An all-out sprint.
Glucose can be metabolized in multiple different ways, but fatty acids can be converted to energy only in the mitochondria. Someone working at a lower intensity will be burning more fat, while at higher intensities they would rely more on glucose. The more efficient your mitochondria, the greater your ability to utilize fat, which is by far the body’s most efficient and abundant fuel source (p238, ¶3).
A professional athlete might spend 30–35 hours per week training, with 80% of that time (24–28 hours) spent in zone 2 (p239, ¶2).
Most of the work being done in zone 2 exercise is by type 1 (slow-twitch) muscle fibers, which are dense with mitochondria and well-suited for slow-paced, efficient endurance work. As we pick up the pace, we recruit more type 2 (fast-twitch) fibers, which are less efficient, but more forceful and generate more lactate. Zone 2 is the maximum level of effort we can maintain without accumulating lactate. We still produce it, but clearance—driven by the efficiency of our mitochondria—matches production. You can use a handheld lactate monitor when exercising to ensure your levels are between 1.7 and 2.0 millimoles (p239, ¶4).
Unhealthy mitochondria quickly switch over from aerobic respiration, burning fat and clucose with oxygen, to the much less efficient glycolysis, which consumes only glucose and produces loads of lactate. As lactate accumulates, our efforts quickly become unsustainable (p241, ¶3).
The number and quality of our mitochondria decline with age, if we don’t do anything about it, but aerobic exercise both recycles old/inefficient ones via mitophagy, and stimulates the creation of new and more efficient ones via mitochondrial biogenesis (p242, ¶2).
Muscle is the largest glycogen storage sink in the body, and the more mitochondria we have, the better we’re able to dispose of that stored fuel, so it doesn’t become fat or stay in our plasma. Chronic blood glucose elevation is bad for pretty much all our organs, but when we exercise, our glucose uptake increases by up to 100-fold. This happens via both the regular, insulin-signaled pathway, and via non-insulin-mediated glucose uptake (NIMGU), where glucose is transported directly across the cell membrane. Patients with type 1 diabetes are able to greatly reduce the amount of insulin they need via injections by clearance glucose from the bloodstream via NIMGU while exercising (p242, ¶3).