*Outlive*

Table of Contents

Part I

1. From fast death to slow death
2. Rethinking medicine for the age of chronic disease
3. A road map for reading this book

Part II

4. The older you get, the healthier you have been
5. The science of hunger and health
6. Can our ancient genes cope with our modern diet?
7. Confronting—and preventing—heart disease
8. New ways to address the killer that is cancer
9. Understanding Alzheimer's Disease and other neurodegenerative diseases

Part III

10. Building a framework of principles that work for you
11. The most powerful logevity drug
12. How to prepare for the centenarian decathlon
13. Relearning how to move to prevent injury
14. You say potato, I say "nutritional biochemistry"
15. How to find the right eating pattern for you
16. How to learn to love sleep, the best medicine for your brain
17. The high price of ignoring emotional health

1. From fast death to slow death

Medicine has focused mostly on fast death (accidents, injuries, infection) and not slow death from aging. The Four Horsemen are: heart disease, cancer, neurodegenerative disease, and type 2 diabetes and metabolic dysfunction.

Not only should we think about how long we live (lifespan), we must also think about how well we live (healthspan).

Dealing with slow death requires early preventive measures. The difference between prediabetic (137 mg/dL blood glucose) and Type 2 diabetes (140 mg/dL) is just 3 points. Prediabetics are usually under "annual monitoring," while diabetics are given extensive treatment. But "normal" is more like 100 mg/dL, so prediabetes is already pretty late in the game.

2. Rethinking medicine for the age of chronic disease

Medicine 1.0 began when people realized that diseases were caused by nature and not the actions of gods. Its conclusions were based on observation and guesswork.

Medicine 2.0 arrived in the mid-1800s with the germ theory of disease. It was prompted by the scientific method way of thinking. While it is great at creating new antibiotics and sanitary practices, it is not very successful against the Horsemen.

Medicine 3.0 should emphasize preventive, personalized, risk-adjusted care. It should also focus more on healthspan than in the past.

3. A road map for reading this book

Medicine 2.0 has two tactics: procedures (surgery) and medications.

Medicine 3.0 should have more domains: exercise, nutrition, sleep, emotional health, and exogenous molecules (drugs, hormones, or supplements).

Hard to study longevity with randomized controlled trials (RCT). Instead we can look at different sources of data: centenarians, animal models, human studies of the Horsemen, molecular and cellular science, and Mendelian randomization (MR).

MR is able to find causal relationships between risk factors and outcomes in situations where it is hard to do RCT. It does this by considering random variation in genes and comparing them to the observed results. This eliminates many of the biases in pure epidemiology.

4. The older you get, the healthier you have been

Lots of centenarians have bad habits. There probably isn't a shared genetic bases for their longevity either, since natural selection doesn't necessarily favor longer lifespans.

APOE affects cholesterol and glucose metabolism, and it is linked to delaying (or not delaying) Alzheimer's disease.

FOXO3 governs gene expression. Some variants of FOXO3 is also associated with longevity. Although we cannot change our genotypes, we can affect our phenotypes (gene expression) through our environment and behaviors.

5. The science of hunger and health

mTOR ("mechanistic target of Rapamycin") regulates cellular growth with nutrient availability

• When there is a lot of food, mTOR promotes protein synthesis and cell division
• When there is little food, mTOR activity decreases, slowing dow cell division and enhancing autophagy (the process of recyling amino acids from old or damaged proteins)

Caloric restriction without malnutrition (CR) consistently lengthens both healthspan and lifespan in many species.

• It is not recommended for humans, since we live in a more complex environment and may be more affected by infections, trauma, and fraility.
• It does show that how much food we eat seems to correlate with how long we live

AMPK (AMP-activated protein kinase) is activated in low-nutrient conditions.

• It stimulates mitochondrial biogenesis (the creation of new mitochondria)
• It also inhibits mTOR, further promoting autophagy and conserving energy

Rapamycin is a drug that inhibits mTOR activity, mimicking some effects of caloric restriction

• In animal studies, rapamycin has extended lifespan across multiple species, including mice
• Its use in humans is not yet verified by scientific studies

6. Can our ancient genes cope with our modern diet?

Metabolic dysfunction underlies many major diseases:

• 12x increased risk of cancer
• 5x increased risk of Alzheimer's disease
• 6x increased risk of cardiovascular disease.

This is why diabetes is matters despite only being the 7th or 8th leading cause of death in the US.

Type 2 diabetes is merely the last stop on a line of metabolic disorders, which include

• Hyperinsulinemia (elevated insulin levels)
• Prediabetes
• NAFLD (nonalcoholic fatty liver disease) and NASH (nonalcoholic steatohepatitis)

Metabolic syndrone (MetSyn) is defined by meeting 3 or more of these 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)

Metabolic dysfunction is not the same as obesity. It is a stronger predictor of bad health outcomes

• 1/3 of obese people are actually metabolically healthy
• 20-40% of nonobese people are metabolically unhealthy, and may be at higher risk than metabolically healthy but obese people

When we eat carbohydrates, two things can happen:

1. Carbs are converted into glycogen for near-term use

   • 75% goes into skeletal muscle and 25% into the liver
   • An adult male can store up to 1600 calories here (2 hours of exercise)
   • The liver turns glycogen into glucose and releases it to maintain glucose homeostasis in the blood
   • Healthy blood glucose is 5 grams (1 tsp); diabetes is 7 grams (1.5 tsp)

2. Carbs are converted into fat

   • Subcutaneous fat (just beneath our skin) is good. It acts as a metabolic buffer zone to absorb excess energy. But if you fill up the subcutaneous fat cells, surplus floods into other parts of the body.
   • Visceral fat (around the organs) is bad. It causes inflammation and is linked to increased risk of cancer and cardiovascular disease. You can check on your levels of visceral fat with a DEXA scan.

Hormones, notably insulin, determine where we put the carbs

• Insulin is secreted by the pancreas to help shuttle glucose to where it is needed, like cells. When cells contain too much glucose, it takes more insulin to fit even more glucose in them, causing insulin resistence. Insulin resistence seems to start in muscles and is prompted by physical inactivity. It is widely accepted as the main cause of Type 2 diabetes.
• Cortisol depletes subcutaneous fat and replaces it with visceral fat. This is why stress levels and sleep affect metabolism.
• Other hormones involved include testosterone and estrogen.

Ancient genes favored fat storage to survive famines. With access to almost unlimited food, these genes contribute to disease.

Fructose is a major problem because it is metabolized different from other sugars.

• When it is metabolized, it produces large amounts of uric acid. Other mammals can produce an enzyme called uricase, which helps them clear uric acid. But we don't, because our distant ancestors found it useful to store fructose calories as fat. Now high uric acid is associated with fat storage and high blood preasure.
• When other sugars are metabolized, cells must expend a bit of ATP to get more ATP. A specific enzyme prevents the cell from spending too much of its ATP on metabolism. When fructose is metabolized, another enzyme takes over and allows ATP levels in the cell to drop rapidly. This makes us feel like we need to still take in more food for energy.
• Liquid fructose (notably fruit smoothies) can also overwhelm the gut and get sent to the liver

7. Confronting—and preventing—heart disease

Most heart disease and stroke is caused by atherosclerosis (plaque buildup in arteries). We can lump them under the term atherosclerotic cardiovascular disease (ASCVD). It is the leading cause of death in the US.

Atherosclerosis happens when the endothelial barrier (which lines arteries and veins) is damaged by:

1. How blood traffics cholesterol molecules
2. Chemical injury from smoking
3. Mechanical stress from high blood pressure

Heart disease is not caused by the cholesterol we eat in our diet. It's just that studies on this were on chicken or rabbits, which absorb dietary cholesterol in a different way than humans.

Only certain cholesterol (apoB) damages the endothelial barrier

• Since cholesterol is a lipid, it needs to be carted around in a protein (forming a lipoprotein). Lipoproteins themselves are wrapped in apolipoproteins that provide structure and solubility
• High-density lipoproteins (HDL) are wrapped in apoA. ApoA particles pass easily through the endothelium and are generally harmless.
• Low-density lipoproteins (LDL, VLDL) and lipoprotein(a) (Lp(a)) are wrapped in apoB. ApoB particles tend to get stuck inside the endothelium.

It takes a long time for apoB damage to be discovered:

1. First, the apoB particles oxidize and get stuck in clumps.
2. The endothelium responds to this by sending monocytes (large white blood cells), which transform into macrophages which swallow up the apoB particles.
3. If macrophages consumes too much cholesterol, it blows up into a foam cell and and forms a "fatty streak." Most young people already have these lesions or plaques in their arteries.
4. At some point, this plaque may start to become calcified. This is what finally shows up on a calcium scan.
5. Plaques, at some point, form clots. That is when you might get a heart attack or stroke.

LDL-C targets are typically 100 mg/dL for patients at normal risk and 70 mg/dL for patients with high risk. But the lower the better; aiming for 10-20 mg/dL might be right. This can be done by controlling diet and using statins drugs.

8. New ways to address the killer that is cancer

Properties of cancer cells:

1. Cancer cells don't stop growing when they are supposed to, likely because of genetic mutations. But this is highly complex, and there are hundreds of different mutations that combine to cause cancers.
2. Cancer cells can travel from one part of the body to another part of the body in metastasis. This is what makes cancer deadly. While local, solid-tumor cancers can be treated by combining surgery and radiation therapy, this stops working as well on metastatic cancers.
3. Many cancer cells have an altered metabolism. In normal aerobic conditions, cells consume oxygen and produce a lot of ATP. Cancer cells act like they are in anaerobic conditions, so they consume glucose and produce less ATP. This is called the Warburg effect (anaerobic glycolysis). Its possible that cancer cells do that because they also get more chemical buildings, which can be used to build new cells.

The only modifiable risk factor for cancer is smoking, insulin resistance, and obesity. There is an association between obesity, diabetes, and cancer. This is likely because inflammation creates an environment that could cause cells to be cancerous. Additionally, insulin itself seems to help cancer cells devour glucose at a higher rate (through PI3K). Thus, you do not want to have poor metabolic health when dealing with cancer.

New treatments

1. There have been some drugs that target cancer metabolism, specifically by inhibiting PI3K. However, it hasn't been very effective, since it also has the side-effect of raising blood glucose levels. It might be that an additional insulin-minimizing diet is needed.
2. Chemotherapy attacks the replicative cycle of cells. This hurts cancer cells, but also hair follicies and the lining of the gut. It might be that having a fasting diet might increase the ability of normal cells to resist chemotherapy, while making cancer cells more vulnerable.
3. Immunotherapy is a technique of getting the immune system to recognize and attack cancer cells. One approach is to genetically engineering T cells (CAR-T) to attack the tumor. Another approach is to block specific checkpoints so that T cells would recognize cancer cells. Another is adoptive cell therapy (ACT), which involves transferring supplemental T cells into the patient.

9. Understanding Alzheimer's Disease and other neurodegenerative diseases

There is no cure for any neurodegenerative disease, including Alzheimer's disease and dementia with Lewy bodies (Lewy body dementia and Parkinson's disease). Lewy body dementia affects cognition; Parkinson's disease primarily affects movement.

Alzheimer's disease is defined by the accumulation of amyloid and tau.

• Amyloid-beta proteins are found accumulating between neurons. Amyloid-beta is created when amyloid precursor protein (APP) is split into three pieces instead of two. Then one of the pieces loses its structure and starts aggregating in clumps.
• The amyloid also causes the protein tau to clump, causing inflammation and brain shrinkage. This causes neurons to be entangled and coated with a white substance.
• However, it appears be that amyloid-beta plaques are neither necessary nor sufficient for the development of the symptoms of Alzheimer's disease.

Other theories of Alzheimer's disease:

1. Cerebral blood flow (perfusion) is reduced in Alzheimer's disease, which causes the brain to not get enough oxygen and nutrients. This causes the dementia symptoms.
2. Abonormal glucose metabolism in the brain causes a drop of energy delivered to the brain, causing dementia symptoms. Having Type 2 diabetes doubles your risk of developing Alzheimer's disease.

The APOE genotype is highly correlated with Alzheimer's disease

• APOE (apolipoprotein E) carries cholesterol across the brain barrier to the neurons
• People with e4 alleles appear to have defects in both cholesterol transport and glucose metabolism. e4 alleles are associated with greater risk, e3 alleles are standard, and e2 alleles are associated with lower risk.
• Since APOE is also highly correlated with Lewy body dementia and Parkinson's disease, this indicates that these conditions may be related on some level.

Lewy body dementia and Parkinson's disease is defined by the buildup of alpha-synuclein proteins into Lewy bodies. Exercise is the only intervention shown to delay progression of Parkinson's.

11. Exercise

Aerobic fitness is how efficiently your body can get, deliver, and use oxygen. Its measured in terms of VO2 max.

When we exercise, cytokines send signals to strengthen the immune system and grow new muscles and stronger bones. Endurance exercise generates brain-derived neurotrophic factor (BDNF) that improves the health of the hippocampus. Additionally, it stimulates mitochondrial biogenesis and mitophagy, improving our mitochondrial health.

Fat-free mass (muscle mass) and activity lefts remain relatively constant from the 20s to the 50s but decline steeply after 65, and even more steeply after 75. By 80, the average person would have lost 18 lbs of muscle. But active people lose less muscle—8 lbs on average.

Activities that are easy become impossible as you get older.

1. If you want to be able to pick up a 30 lb grandchild when you're 80, you're going to have to be able to lift 55 lbs now
2. If you want to be able to climb 4 flights of stairs, you need to be able to sprint up the stairs now
3. A 35-year-old with average fitness should be able to run at a 10-min mile pace. But by age 70, only 5% of people will be able to do this

If you want to do things in old age, you must be able to do them better now.

12. Training 101

Three dimensions: cardio (aerobic exercise), strength, and stability.

Cardio is a continuum: endurance, zone 2, and the maximum aerobic output.

The ability to use both glucose and fat (metabolic flexibility) is important

• At lower intensity you burn more fat, and at higher intensities more glucose
• While professional cyclists burned mostly fat even at high speeds, nonathletes relied primarily on glucose even at lower speeds
• While glucose can be metabolized in many different ways, fatty acids can be converted to energy only in mitochondria
• The people with the most amount of fat are unable to unlock virtually any of that fat to use as energy

The solution is to spend more time exercising in Zone 2.

• Zone 2 is the speed where one could have strained conversation. Professional cyclists spend 80% of their training in Zone 2.
• In Zone 2, most of the work is being done by type 1 "slow-twitch" muscle fibers. These are dense with mitochondria. If you go faster, you will use more type 2 ("fast-twitch") muscle fibers, which are less efficient but more forceful. They also produce lactate, which becomes lactic acid and causes the burning feeling. Thus, you can also think of Zone 2 as the maximum amount of effort that you can maintain without accumulating lactate.
• Zone 2 exercise also keeps glucose levels in check. By creating more mitochondria, we increase our ability to dispose glycogen in muscles. It activates a non-insulin-mediated glucose uptake (NIMGU) pathway, allowing glucose to be transported without insulin. The overall glucose uptake increases.
• Spend at least 4 hrs/week in Zone 2.

Maximum aerobic output involves hitting VO2 max

• Do 1-2 VO2 max workouts per week
• Go 4 min at maximum pace, 4 min at easy jog, and repeat this 4-6 times
• You want to be as close to fully recovered as possible before the next set. Otherwise, you will not be able to reach peak effort.

Fun facts

Conserved elements are things that are relatively unchanged across different species for a long period of time. Highly conserved features are probably found to be important by evolution.

The liver is highly regenerative; when a liver a donated, both the donor and the recipient end up with a full-sized liver within weeks.