Book Notes: Outlive

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Big Idea
“Medicine 2.0” was quite a bit successful in reducing immediate death. If you are infected with a nasty bug, it is often able to treat you and make a recovery. However, with four horsemen — type 2 diabetes, heart disease, cancer, and neurodegenerative diseases — each of which is more like a long process than an instant reaction to a germ, it is failing us. Dr Attia proposes a framework for “Medicine 3.0”, that also includes mental health, so we can effectively increase our healthspan. i.e., we not only live longer, but enjoy that added life being healthy, active and joyful.

Brief Review
Excellent framework and right narrative:data ratio (moderate!). However, a few chapters — later in the book — were bloated. Namely, mental health, diet and exercise. Despite that, the accessibility and solid call-to-action gets this at least 4 stars.

Interesting Takeaways

• Exercise is the most potent longevity drug.
• Author calls diet “nutritional biochemistry”.
• Many of the high level tests routinely done by Medicine 2.0, like lipid panels, are not sufficient enough nor even reliable to weed out two types of issues — you have a problem and it fails to detect, or you don’t have a problem and it overmedicates.
• Hippocratic oath — “first, do not harm”, taken to its extreme, could force toward inaction. Even optimally, it fails to provide a risk-reward probabilistic spectrum to either doctors or patients.
• Mortality rates since 1900, minus the top 8 contagious diseases, barely dropped. Medicine 2.0, originated from ‘germ theory’, was massively successful with antibiotics alone. Medicine 2.0 is more tactical, we need a strategic gambit to fight the four horsemen that culminate over a set of complex variables, including genetics, lifestyle, laws of biology and randomness.
• Healthspan deteriorates over one or more of three vectors — one, cognitive decline; two, loss of physical function; three — emotional health. Healthspan is “compression of morbidity”.
• The key difference between centenarians and rest is they develop key four diseases much later in life. E.g., cancer 30 years later, bone loss about 16 years later.
• Longevity Genes -

APOE is one of the longevity genes that affects Alzheimer’s disease risk. The protein it codes (also known as APOE) has three variants — e2, e3 and e4. While e3 is most common, and e2 lowers the risk, the e4 variant significantly multiplies the risk.

Two cholesterol related genes — CETP and APOC3 — are also associated with longevity.

FOXO3 is another family of “transcribing genes” — regulating others — that is strongly associated with longevity. This gene can be activated or suppressed by our behavior — like exercising.

• Rapamycin — a molecule originally discovered from Easter Island soil — acts directly on a very important intracellular protein complex called mTOR . This is one of the most important mediators of longevity at cellular level and is found in virtually all forms of life. mTOR is like a “general contractor” of the cell and has “a finger in every major process” there.
• Calorie restriction improved our understanding of aging, especially wrt mTOR mechanism. Essentially, when our cells are starved they flash “low fuel” and an enzyme called AMPK helps conserve and seek alternate sources of energy by producing new mitochondria. It also inhibits the mTOR — when there is no fuel, you cannot grow. And it is the continuous growth — cell divisions et al — that increases the probability that random “errors” could start dogpiling into something far more egregious.
• Metformin — a common diabetes drug — has also been found to have been associated with low cancer rates among its users.
• A cluster of problems called MetSync (metabolic syndrome) contributes to insulin resistance -

High Blood pressure (> 130/85)

High triglycerides (>150 mg/dL)

Low HDL cholesterol (< 40mg/dL in men or < 50 mg/dL in women)

Abdominal fat (waist > 40 inches in men or > 35 in women)

Elevated fasting glucose (>110 mg/dL)

i.e., being obese is only one of the five criteria for diabetes. There are about half as many non-obese people as obese who suffer from MetSyn.

• 75% of glycogen ends up in skeletal muscle and 25% goes to the liver. An adult male can store about 1600 calories worth of glycogen between these two sites — about 2 hours of energy for vigorous exercise. Any excess and it starts stored as fat. Subcutaneous fat is the safest place to store excess energy.
• Lipid overflow, first, goes to be stored per capacity as visceral fat, liver fat (fatty liver disease!), epi/peri/myo-cardial fat, kidney fat and pancreatic fat. The first four lead to insulin resistance and cardiac risk, while the last leads to impaired insulin secretion and thus directly contributes to type 2 diabetes.
• Dietary cholesterol almost does not matter.
• Elevated Lp(a), a combination of LDL fused with a rare protein called apo(a), looks like Danish pastry and could get easily lodged in the artery wall. This often leads to sudden cardiac attack.
• The only safe concentration of apoB is 20–30 mg/DL — a baby’s level, and can be reached by Crestor/statins. Nexletol inhibits cholesterol synthesis in the liver. Zetia blocks absorption of cholesterol in the GI tract. Another type of medicine called PCSK9 inhibitors degrades LDL receptors.
• “..there didn’t seem to be any individual genes that “caused” cancer at all; instead, it seemed to be random somatic mutations that combined to cause cancers.”
• Most cancers, other than glioblastoma or certain lung and liver cancers, kill only when they spread beyond the organ — they metastasize. Yet only 5–8% of research funds go to study metastasis.
• In the 1940s, biology’s top dogs were biochemists. Now they are molecular biologists.
• In all diagnostic tests, the trade-off is between sensitivity (true positive rate) and specificity ( true negative rate).
• A good hypothesis to fight dementia is to build a “memory reserve” — e.g., learning a new language — a vast pool of experience that grows enough network within the brain that the disease finds difficult to prune. Our memory palace can never have enough bricks!
• Strong handgrip strength and regular flossing are inversely related to dementia incidence.
• Zone 2 training — where we are exercising but can continue a conversation — is the optimal way to promote mitochondrial health. That, in turn, has a serial effect on glucose homeostasis by effective generation of energy (ATP).
• Three reductive strategies to eat effectively -

Caloric restriction — eat less;

Dietary restriction — not eat everything;

Time restriction — eat at very selective times.

• 1.6g/kg/day protein consumption is good, per Dr Attia.
• Whey protein is richer than Soy protein.
• Trauma falls into five categories

Abuse

Neglect

Abandonment

Enmeshment

Witnessing tragedy

Tests one could do

1. APOE genotype
2. Annual DEXA scan — to measure visceral fat.
3. OGTT — Oral Glucose Tolerance test
4. CT angiogram is more effective to find out soft plaque in arteries
5. apoB and Lp(a) — latter largely genetic, so can be done just once. ApoB tells the concentration of LDL and VLDL.
6. VO2 max
7. CGM — continuous glucose monitoring0

Great Quotes:

‘There comes a point where we need to stop just pulling people out of the river. We need to go upstream and find out why they’re falling in.’ — Bishop Tutu

‘There is some risk involved in action, there always is. But there is far more risk in failure to act.’ — Harry Truman

“Maybe the journey isn’t so much about becoming anything, maybe it’s about unbecoming everything that isn’t really you, so you can be who you were meant to be in the first place” — Paulo Coelho