Apr, 2023

The Big Idea: As a leader, it’s your job to design and build your organization’s culture. A well-designed culture can overcome a poor product or service in the long-term, but not in the short-term. (Product-market fit probably matters more than culture for a startup trying to survive past the early stages.)

The culture you design should reflect you who you are, not who you aspire to be.

Make sure your culture supports your strategy.

Develop virtues (eg. Samurai honor code.)

Be inclusive (eg. Genghis Khan.)

Model and reinforce the culture (eg. Toussaint Louverture.)

Never stop improving your culture (eg. Shaka Senghor.)

Chapter 1: The Long Game

Longevity has two components; how long you live and how well you live.

The four main chronic diseases of aging (aka Four Horsemen) are: heart disease, cancer, neurodegenerative disease, metabolic disorder (diabetes.)

A single, preventative measure (not smoking) saves more lives than any late stage intervention that medicine has devised.

By the time medicine intervenes, it’s often too late.

The typical cholesterol panel is misleading and oversimplified to the point of uselessness.

Protein is more important than carbs as we age.

Exercise is the most potent longevity drug.

Chapter 2: Medicine 3.0

The evolution of medicine, Medicine 3.0, will place a far greater emphasis on prevention than treatment.

Medicine 3.0 will consider the patient as a unique individual.

Medicine 3.0 will consider risk differently, including the risk of doing nothing.

Medicine 3.0 will pay far more attention to maintaining quality of life.

Chapter 3: Objective, Strategy, and Tactics

What is our goal? To delay death and to get the most out of the extra years.

What is our strategy? To understand the Four Horsemen and how they lead to decline.

What are our tactics? Exercise, nutrition, sleep, emotional health, and exogenous molecules (drugs, hormones, supplements.)

Randomized clinical trials are of limited use in longevity because they work best for simple interventions, over a short time period.

Centenarian studies are very useful for learning about longevity, even though the data is observational.

Other sources of useful longevity information: animal models, human studies, cellular mechanisms, Mendelian randomization.

Chapter 4: Centenarians

Genetics is a strong predictor of centenarian longevity.

Centenarians not only live longer, but tend to be healthier.

The path to reaching 100 is likely a lot of small interventions, compounded over time.

We must focus on delaying the onset of chronic disease, not extending the duration of the disease.

Chapter 5: Hunger and Health

Studies show that extreme caloric restriction improves health and longevity in animals but not necessarily in humans.

Reduction of nutrients does trigger a group of pathways that enhance a cell’s stress resistance and metabolic efficiency.

Fasting activates AMPK, which stimulates new mitochondria and inhibits the activity of mTOR, activating autophagy.

Chapter 6: Modern Diets

42% of Americans are obese.

It’s not actually obesity that drives bad health outcomes, it’s metabolic dysfunction (high blood pressure, high triglycerides, low HDL, large waist circumference, high glucose.)

Excess calories enters into fat tissue, then blood, then liver, then muscle, then heart and pancreas.

Visceral fat cells secrete inflammatory cytokines which increase risk of cancer and heart disease.

Everyone interested in longevity should get a DEXA scan annually to monitor their visceral fat.

When you have high fasting blood glucose, it means your cells are becoming insulin resistant.

Insulin resistance leads to obesity, atherosclerosis, and potentially cancer.

Fructose also drives high blood pressure and fat gain, unless consumed as part of a whole fruit.

It’s far better to intervene before HbA1C rises above 6.5 and the patient already has diabetes. Look out for liver enzymes and signs of NAFLD. Look out for elevated lipids.

Most importantly, look out for elevated insulin, in the form of an oral glucose test.

Chapter 7: Heart Disease

Dietary cholesterol doesn’t impact cholesterol blood levels.

ApoB particles are the strongest predictor of cardiovascular disease.

One third of 16-20 yo in one study already have actual atherosclerotic plaques in their coronary arteries.

HDL is poorly understood but it serves some protective function. Drugs that raise HDL don’t lower risk of cardiovascular disease.

CT angiogram is preferred over standard calcium heart scan because it can detect soft plaque.

Lp(a) is another marker highly predictive of heart disease, but only needs to be tested once.

Get apoB and LDL-C as low as possible, even if it requires drugs such as statins.

A ketogenic diet will improve lipids for most people, but will actually worsen apoB in about 1/3 of people.

Medicine 2.0 starts treating heart disease much too late, based on 10 year risk calculations. We should start taking aggressive preventative measure when patients are in their 40s, if not earlier.

Statins: Crestor (rosuvastatin), sometimes paired with Zetia (ezetimibe) to get apoB to 20 or 30 mg/dL. Also, Vascepa, is a helpful prescription grade fish oil.

Chapter 8: Cancer

Cancer is second leading cause of death in the U.S., behind heart disease.

By the time most cancer is detected, it’s been progressing for years, if not decades.

Metastatic cancers can be slowed by chemo, but they usually come back.

We need to detect cancers as early as possible.

12-13 percent of all cancer is attributable to obesity.

Chronic inflammation creates an environment that could induce cells to become cancerous.

Promising new treatments for cancers: fasting, immunotherapy, adoptive cell therapy.

It’s always best to detect cancer early. We already screen for five cancers: lung, breast, prostate, colorectal, and cervical.

Medicine 3.0 will encourage more aggressive screening (MRI, liquid biopsies, ultrasound) while understanding the result will be false positives, which leads to more screening.

Chapter 9: Neurogenerative Diseases

People with one or two APOE e4 allele have an increased risk of Alzheimer’s.

Neurodegenerative diseases have no cure, but we can try and prevent them.

Amyloid beta plaques are probably not necessary nor sufficient to cause Alzheimer’s.

Lewy bodies accumulate in Lewy body dementia and in Parkinson’s.

Alzheimer’s is twice as common in women versus men. The opposite is true for Lewy body dementia and Parkinson’s.

Dementia can go unnoticed for years, as patients learn how to counteract.

Exercise with complex movements is the only intervention shown to delay Parkinson’s.

We still don’t know exactly what causes Alzheimer’s, but theories include: vascular disease and impaired glucose metabolism.

To prevent or delay Alzheimer’s: steady cardio to improve mitochondrial efficiency, strength training, sleep, brushing/flossing, sauna.

Chapter 10: Thinking Tactically

Our genes no longer match our environment.

Exercise, nutrition, sleep, emotional health, exogenous molecules.

Focus on effective tactics, driven by logic and data.

Eg. the most common way to be killed, as a driver, is by another car coming from the left, resulting in a T-bone crash. Always look left, even if you have the green light.

Exercise and nutrition are the most complex and impactful domains.

Most people will need to lose fat and gain muscle.

Chapter 11: Exercise

Exercise is the most powerful longevity drug.

Peak aerobic fitness, measured by VO2 max, is the most powerful marker for longevity.

In one study, muscle strength was more important than aerobic fitness.

Don’t specialize in one physical activity. Be a centenarian decathlete and cross-train.

Jack LaLanne kept doing his usual rigorous daily workout until his death at age ninety-six. He built and maintained a high level of fitness throughout his life.

Chapter 12: Centenarian Olympics

Training for centenarian olympics has three key dimensions: cardio, strength, and stability. You must train all three.

Your cardio training should be mostly in zone 2, to optimize mitochondrial health and keep fat accumulation in check.

Zone 2 is 70-80% of your max heart rate, or a pace where you can still hold a conversation. Do at least three hours per week of zone 2, or four 45-minute sessions.

VO2 max is a strong predictor of cardiovascular disease. Aim to get your VO2 max in the top 2%.

Train your VO2 max with a 4/4/4 protocol. 4 minutes at all out effort, 4 minutes of easy effort, repeated 4 times.

Aging muscle preferentially loses type 2 (fast-twitch) muscles. Strength training is required to prevent muscle loss.

Strength is critical for injury prevention and recovery. The one year mortality from a hip or femur fracture at age 65 is about one-third.

Rucking combines VO2 max training and ability to carry medium-heavy loads long distances.

Strength train to build: grip strength, concentric/eccentric loading, pulling, hip hinging.

Chapter 13: Stability

More than 27% of Americans over 45yo have chronic pain.

Stability is about injury prevention, not just core strength.

Infant movement patterns are ideal. As adults, primary sitting in chairs, we unlearn these movement patterns.

Stability training comes before strength or cardio training.

Resources: https://rehabps.com and https://posturalrestoration.com.

Stability training begins with the breath. Spend some time on breath training.

Stability training continues with the feet. Practice “toe yoga”, try lifting barefoot or in minimal shoes.

Stability training continues with the spine and shoulders, which can be trained with yoga.

Stability training culminates in the hands. Train your grip using carries.

Chapter 14: Nutrition 3.0

Diet and nutrition are poorly understood by science. Epidemiological studies are usually useless. Clinical trials are usually flawed.

Extreme tribalism prevails among diet cults, such as vegan, carnivore, paleo, low-carb.

Old cliches are probably true: if your grandmother would not recognize it, you probably shouldn’t eat it; avoid the front and middle of the store where junk food and processed food live; plants are good; animal protein is ok; most of us will do well as omnivores.

The Mediterranean diet is one of the best diets, based on well-designed clinical trials.

Chapter 15: Nutritional Biochemistry

Avoid the Standard American Diet at all costs.

Excess calories end up as excess fat.

Animal studies show that extreme calorie restriction extends life, but human lives are more complex. Plus, there are undesireable consequences to undernourishment.

Quality of food matters as much as quantity of food.

Everyone’s metabolism is different, so there is no best diet for everyone.

Keto diets can make a dramatic impact on biomarkers for some people, but can fail for others.

Alcohol is a net negative for longevity, but moderate drinking is probably fine if it encourages social connection.

Continuous glucose monitors (CGM) are useful to understand your body’s response to carbohydrates and specific foods and personalize your diet.

Almost everyone is not eating enough protein. Active people should aim for 1 gram of protein per pound of body weight. Older people might even require more protein.

Plant protein is okay, but less bioavailable than animal protein, so you’ll need even more.

Try to boost monounsaturated fat intake (50%+) and lower saturated fat intake (15%).

Boost omega-3, EPA and DHA, through fish and fish oil.

The data on time-restricted eating is inconclusive. Just remember to get enough protein and maintain lean muscle mass.

The best nutrition plan is one we can sustain. Don’t be dogmatic.

First, avoid the Standard American Diet. Then, prioritize exercise over nutrition.

Chapter 16: Sleep

Poor sleep is linked to diabetes, Alzheimer’s, stress, heart disease.

Sleep is essential. Good sleep is restorative. Deep sleep cleanses the brain.

Ambien, Lunesta, etc, promote a sleep like state of unconsciousness that is not sleep.

Ways to improve sleep: CPAP (sleep apnea), darkness, quiet, avoid screens at night, keep bedroom cool (65), cut back on alcohol, no coffee after mid-day, exercise, reduce stress, meditation, no late night snacks.

Chapter 17: Emotional Health

Take care of your emotional health by healing past trauma.

Read The Road to Character by David Brook’s.

Consider MDMA and psilocybin, administered by a skilled guide.

Dialectical behavior therapy (DBT) is also an effective approach.

Epilogue

Don’t get obsessed with biohacks, in order to live to 120, as if longevity was another engineering problem to be solved and optimized.

Longevity is meaningless if your life sucks.

As you work to extend your life, remember that we still must live in the present.