“Outlive” Book Summary and Biology Primer

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“Outlive” Book Summary and Biology Primer

Last Update: March 4, 2025   

{wymhacks – Introduction} 

This article summarizes my key learnings from each chapter of the book “Outlive” but also offers “deep dives” into various human biological concepts.

“Outlive” (written by Peter Attia with Bill Gifford; Published in 2023) explores tactics and strategies for living a longer, healthier life. 

Even though my hard cover copy was 411 pages long, I found myself frequently hitting the web to get a better understanding of several of the topics.  

So, I thought I would make the article more meaningful by weaving in additional information on human biology, biochemistry and a few other related topics.

Think of this article as a human biology primer (albeit incomplete) that uses the chapters of the book as a roadmap.

Any errors or misinterpretations (of the book Outlive or any other topic) are my own.

The author of “Outlive” (Peter Attia) does not necessarily endorse what I have written. 

Structure/Organization

Interspersed among the book related material are numerous links and text describing topics that are mentioned (or implied) in the book.

I tried to differentiate my comments / additions from the book material by bracketing my comments as follows:  {wymhacks: my comments}

Regardless, even my summaries of the book are my own and are not endorsed or approved by the author (Peter Attia) of “Outlive”.  

Biology References

Here are some of the sources I used:

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Part I. Chapter 1 – The Long Game

  • You’re going to eventually die.
    • {wymhacks: Bryan Johnson (Blueprint Protocol) believes that explosive non linear growth of human biological knowledge could very soon make step change impacts on human longevity.
    • He’s been described as “eccentric”,  but I think It’s worth a podcast or two to learn more about his measurement based learnings (and his protocols) }       
  • You’ll probably die from one of the following (1) Heart Disease (2) Cancer (3) Neurodegenerative Disease (4) Metabolic dysfunction
    • Call them the “4 Horsemen”. 

{wymhacks: Death Statistics}

Check out the two charts below showing Global and USA causes of deaths.

Although Deaths from Diabetes are not at the top of the list, the book “Outlive” strongly makes the case that people with Diabetes (or are developing Diabetes) have an increased risk of dying from the other “Horsemen”.

Table_Causes of Death Globally in 2019 – Source: Our World in Data

Global Causes of Death 2019 from "Our World in Data"

Graph_10 Leading Causes of Death in the USA 2021/2022 – Source: CDC.gov

USA 10 Leading Causes of Death 2021 2022

  • Traditional medicine has been most effective at preventing “fast death” from injuries, infections etc.
  • Traditional medicine  has not been as effective against “slow death” from the “4 Horsemen”.
    • “Slow death” timeline includes development and progression of the disease which probably has taken years before symptoms are felt or detected. 
  • “We need to step in sooner to stop the 4 Horsemen in their tracks”
  • Consider Type-2 Diabetes
    • Normal blood glucose is 100 mg/dL ; Hemoglobin A1c (HbA1c) = 5.1%
    • Only when blood glucose >=140 mg/dL (HbA1c >=6.5%) do ADA standard-of-care treatment guidelines kick in.
    • A measurement slightly less (e.g. HbA1c =6.4%) results in less rigorous treatment (Pre-Diabetes).
    • But even Pre-Diabetes is an almost “end of the line” symptom that took a long time to develop. 
    • This is not the proper approach. It should not be treated like a “cold or a broken bone”.
    • Action should be taken way before any “end of the line” symptoms appear. 
  • The focus of this book is to advocate for a proactive approach to longevity with the goal of
    • increasing Lifespan (living longer) but also
    • increasing Healthspan (higher quality of living, especially the back end years).    

Part I. Chapter 2 – Medicine 3.0

Medicine 1.0 – From Hippocrates + next 2000 years: 

  • {wymhacks: Not the best for most of this time…think Bloodletting, Trepanation (hole in the Skull), Lobotomy, Mercury treatments, Thalidomide, etc.}

Medicine 2.0 – (Mid 19th C.) Three milestones paved the way for Medicine 2.0.

Life expectancy from 1900 to 2000 doubled but was caused almost entirely by reductions in contagious and infectious diseases. 

“Slow death” diseases (i.e. the 4 Horsemen) are more prevalent in our times , and Medicine 2.0 is not best equipped to deal with them.

  • Medicine 2.0 best deals with acute illness and injury. 

Goal of Medicine 3.0 is to prevent or mitigate the onset of these diseases which tend to be “detected or intentionally identified as an issue” too late with Medicine 2.0. 

Idea is to have Medicine 3.0 (versus Medicine 2.0)
  • be more preventative.
  • be more personalized.
  • have a different attitude towards risk.
  • be more focused on quality of life.

Issues and challenges:

  • Insurance companies often don’t insure preventative stuff.
  • It’s possible your doctor is not going to be able to help you do Medicine 3.0
    • Especially if they are “older”. 
    • Medical Training is still primarily a Medicine 2.0 Construct.  
  • You have to be much more proactive in decisions on your health.
  • You need to be well informed.
  • You need to be medically / biologically / scientifically literate. 

Part I. Chapter 3 – Objectives, Strategy, Tactics

Objective

Medicine 2.0 intervenes too late.

  • The duration from the intervention to death could be low quality (painful etc.). 

Ideally, in Medicine 3.0, you live a high quality life for most of your life;  and in the end your quality of life drops quickly and you die quickly.

  • So, you suffer less in those last years. 

“Outlive” applies an Objective – Strategy – Tactic approach.

The Objective is to delay death and to get high quality years while doing it (live longer and better).

  • i.e. optimal Healthspan and longevity
Picture – Ideal life is a Steep and Quick Demise (long Healthspan)

Healthspan Trajectory Drawing from Peter Attia Outlive Figure 2 in book Outlive

Strategy

Part II of the book is dedicated to Strategy.  

Strategy: To gain a deeper understanding of the science and evidence surrounding 

  • The 4 Horsemen 
  • Aging 
  • Healthspan deterioration 
    • Cognitive decline
    • Loss of physical function (see “activities of daily living” checklist)
    • Emotional health

Tactics

Part III. of “Outlive” is dedicated to Tactics

Medicine 2.0 tactics:  

  • Procedure (e.g. surgery)
  • Medications

Medicine 3.0 tactics:

  • Exercise
  • Nutrition
  • Sleep
  • Emotional health
  • Exogenous molecules (drugs, hormones, supplements) – not covered in this book (too big of a topic)

“Outlive” Uses an Evidence Informed (vs Based) Strategy

Randomized Controlled Trials (RCTs) are the gold standard but are difficult to apply to the long durations and complex interventions regarding the 4 Horsemen. 

{wymhacks – Pyramid Graph – Hierarchy of Research} 

“Outlive” uses an evidence informed approach and combines insights from 5 sources:

  1. Study of centenarians – observational not experimental
  2. Lifespan data from animal models (e.g. mice)
  3. Human studies of the 4 Horsemen
  4. Molecular and mechanistic insights from aging studies
  5. Mendelian Randomization (MR) 

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{wymhacks – Macro / Micro Nutrients}  

At this point, you should probably brush up on your knowledge of Macro-Molecules , Minerals, and Vitamins.

So read and refer to my dedicated post on this topic:

Macro Molecules, Minerals, and Vitamins – A Primer 

It will introduce you to the major “macro” and “micro” nutrient categories. 

Here are some very high level descriptions: 

Carbohydrates

Carbohydrates are a major source of energy for the body and break down into simple sugars like Glucose.

Proteins

Proteins are the major building blocks of cells and tissues and break down into Amino Acids.

Lipids (a broad category that includes Fats)

Lipids are a major energy source and structural component of cells, and they break down into Fatty Acids and Glycerol.

Nucleic Acids

Nucleic Acids are the genetic materials of organism.

They are molecules found in meat, seafood, yeast etc. which break down to Nucleotides.  

Vitamins

Vitamins are important micronutrients that are absorbed directly into the bloodstream and used for various metabolic processes.

Minerals

Minerals are inorganic elements that the body needs in small amounts. 

They are needed for building bones, regulating fluid balance, and other bodily functions.

 

{wymhacks – Human Cell Components}

To understand the human body you need to start with the structure of the cell. 

Most cells of the body will contain the components shown in the schematic below. 

Picture_Animal Cell Components

Animal Cell Components

You can refer to my post linked below for a refresher:

Human Cell Structure and Components

Here’s a brief summary of some of the key components (organelles) within human cells that are crucial for energy / metabolism and genetics:

note: I used Google Gemeni to construct the below sentences (regarding cell organelles).

Mitochondria are
  • “powerhouses” of the cell that are central to metabolism. 
  • responsible for cellular respiration (the process that generates energy from Nutrients).
The Nucleus
  • houses the cell’s DNA, which contains the genetic code.
  • controls gene expression (regulate protein synthesis, which is essential for all cellular functions).
Ribosomes 
  • are the protein synthesis factories of the cell.  
  • play a key role in metabolism (Since they make proteins called Enzymes, which catalyze metabolic reactions). 
  • play a role in translating genetic information into proteins.
Endoplasmic Reticulum (ER) and Golgi Apparatus
  • are involved in protein processing, modification, and transport.
  • take part in the production of proteins needed for metabolism and
  • play a role in lipid and carbohydrate metabolism.
Cytoplasm is
  • the gel-like substance inside the cell that contains all the organelles.
  • is the site of many metabolic reactions.
The Cell’s organelles work together to 
  • maintain the cell’s energy levels,
  • carry out metabolic processes, and
  • ensure the accurate transmission and expression of genetic information.

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{wymhacks – Genetics Refresher}

A full ‘set’ of 46 Chromosomes are located in almost all your cells of which you have Trillions (30 Trillion according to this source).

Picture_Genetic Material Simplified DrawingCell Chromosome NDA Gene Simplified Drawing

You should learn a little bit about genetics.

According to the CDC,

  • “Genes play a role in almost every human trait and disease.”
  • “Advances in our understanding of how genes work have led to improvements in health care and public health.”

So click on the link to my post below and learn! 

Genetics Basics

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Part II. Chapter 4 – Centenarians

Your odds of living longer are correlated to siblings or parents who live longer. 

Genotype and Phenotype: (see this great video on Heredity):

  • Genotype: The complete genetic information inherited from your parents (contains your potential traits). 
  • Phenotype: The observable characteristics of an organism (the expression of your genes which is the result of the interaction between the genotype and the environment).

Centenarians tend to develop disease much later in life.

Morbidity is the period of disease / disability at end of life.

Medicine 2.0 tends to lengthen the morbidity span.

Generally when centenarians die, they have been sick / disabled for a much shorter time.

  • We want this: to live longer, with good function, without chronic disease and with shorter morbidity period. 

But, there doesn’t seem to be a fixed set of genes or gene characteristic that does this for centenarians.

  • Some “Dumb luck involved”. 

Potential Longevity Genes

ApoE Gene – Affects Alzheimer’s; Codes (provides instructions for creating) a protein called ApoE (Apolipoprotein E) which helps cholesterol transport and processing (in brain especially).

  • ApoEe4 version (an Allele) multiplies risk of getting Alzheimer’s by a factor of 2 or more.  
  • You can learn more about Lipoproteins here. 

Another Allele, ApoEe2 protects against dementia.

Seems that Lipoproteins (carriers of Cholesterol) are big players.

ApoE also seems to impact Glucose (carbohydrate foods break down to a sugar called glucose in your body) metabolism.

Two other cholesterol related genes CETP and ApoC3 are associated with extreme longevity.

Another one is FOXO3 (a transcription factor that regulates how other genes are expressed).

  • Three variants or SNPs (Single Nucleotide Polymorphism) of FOXO3 seem to improve longevity.
  • When activated , it activates Genes that keep cells healthier and possibly cancer free.
  • Exercise and slight deprivation of nutrients activate these. 

It seems that gene expression can be influenced by environment and behaviors (genome immutable but gene expression maybe not).

{wymhacks – Reasons for centenarian longevity}

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{wymhacks – Enzyme Primer}

Many important biological reactions require an energy push or impetus to get started and proceed.

This “required energy” is called the Activation Energy.

Whether a reaction will occur or not depends

  • on the collisions among the molecules and 
  • whether the collisions have sufficient energy and orientation.  

Without some assistance to overcome their Activation Energy,

  • many critical reactions in our bodies would not occur or
  • would occur so slowly as to render them ineffective.

More than 1,000 different types of proteins in the human body (called Enzymes) serve this purpose by

  • reducing the Activation Energy and
  • thus catalyzing the formation of Products from Reactants. 

Now, do yourself a favor and learn much more about enzymes in my post:

Enzyme Primer

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Part II. Chapter 5 – Eat Less, Live Longer?

The main point of this chapter is:

  • Diet restriction seems to have positive effects on the body.
  • It’s not necessarily a main tactic advocated by Attia, but it is a great example of how diet affects health. 

Rapamycin (Sirolimus)

Rapamycin is an antifungal agent produced by a soil bacterium (originally found in Easter Island; 1964)

  1. A Macrocyclic Lactone; MW = 914;  C51H79NO13
  2. Macrocyclic means large ring structure.
  3. Lactone is a Cyclic Ester.
  4. See a 2D structure here.
  5. Slows down cellular growth and division.
  6. Blocks or inhibits the activity of mTOR (pronounced “emptor”).

mTOR

  1. mTOR is a large Protein which has distinct functional regions called domains.
  2. mTOR Stands for Mechanistic Target Of Rapamycin.
  3. It affects longevity and is highly conserved (found in virtually all forms of life).
  4. mTOR controls cell growth and division based on nutrient availability.
  5. Food plentiful = high growth and division.
  6. Food less plentiful = mTOR suppressed and  cells go into recycling cleaning mode. (to allow conservation of energy) – See Chapter 15
  7. mTOR is the “general contractor” of the cell and is an integral part of cell metabolism. 
  8. Studies have shown that Rapamycin (which inhibits mTOR) can reliably extend mice lifespans.
  9. Reduction of food intake in animals can lengthen their lives (numerous studies have shown).
  10. Reducing the amount of nutrients available to cell triggers pathways that enhance a cell’s “stress resistance and metabolic efficiency”. 

AMPK 

There is an Enzyme called AMPK (AMP-activated Protein Kinase).

  1. Lack of nutrition triggers it.
  2. Exercise triggers it.
AMPK
  1. AMPK prompts cell to conserve and seek alternative sources of energy.
  2. It stimulates production of new mitochondria (the power generation part of  most of your cells).
  3. It prompts delivery of more fuel to these mitochondria.
  4. AMPK inhibits the activity of mTOR so anabolic (i.e. energy consuming building up process) processes are inhibited.
  5. With inhibition of mTOR, cells go into a fuel efficient and stress resistant mode, activating an important cellular recycling process called autophagy .
  6. Autophagy is a catabolic or breaking down process which is typically an energy producing process.
  7. Autophagy is carried out by specialized cell organelles called lysosomes. 
  8. Learn a little bit about the organelles in human cells here and here.  
  9. and take a closer look at lysosomes here. 
  10. Autophagy is very important.
    1. It Grinds old proteins down for re-use and destroys protein aggregates that have been implicated in Parkinson’s disease and Alzheimer’s.
    2. Impaired autophagy is linked to Alzheimer’s and ALS (amyotrophic lateral sclerosis) and Parkinson’s. 
  11. With age , autophagy declines.
  12. Autophagy plays big into age related neurodegeneration and osteoarthritis. 

Back to Rapamycin

  1. So, Rapamycin would promote Autophagy because it inhibits mTOR. 
  2. But Rapamycin is also an immunosuppressant (used on organ transplant patients to prevent body’s rejection of organ). 
  3. New research however suggests that immunosuppressive properties can be controlled by dose amount.
  4. Seems to reduce systemic inflammation (Caused by older cells that have stopped dividing but produce inflammation causing Cytokines).
  5. Metformin (diabetes drug) might be gero-protective as well (i.e. protecting older folks). 
  6. Attia is not necessarily advocating diet restriction as a general tactic but there seem to be positive effects (like autophagy) produced by it. 

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{wymhacks – Metabolism Defined} 

Metabolism can be broadly defined as “chemical reactions that occur in the body that support / sustain / maintain life”. 

We eat food and our Gastro Intestinal (GI) Tract breaks it down and utilizes the micro-components in various ways.

Picture_Digestive System (Gastro-Intestinal Tract)

Digestive System

Read my introductory post,

Metabolism Defined 

In this article, I introduce Metabolism in the context of the

  • breaking down of nutrients (Catabolism),
  • energy production (Cellular Respiration), and
  • molecule building (Anabolism).

We can’t introduce Metabolism without talking about ATP. 

So , let’s do that now.

 

{wymhacks – ATP – Adenosine Triphosphate (Tri-Phosphate)}

Adenosine Triphosphate (ATP) is the “energy currency” of the cell because it contains the energy needed to fuel cellular processes.

Picture_Adenosine Tri-Phosphate (ATP) C10H16N5O13P3
ATP Structure

ATP (along with RNA and DNA) are the rock stars of the biochemical world (there are a few others we’ll discuss later).

ATP has 3 phosphate groups, a Ribose (sugar) group, and a nitrogenous base (Adenine).

We’ve seen a structure very familiar to this already.

Yes!, that’s right, ATP is a three phosphate version of the single phosphate nucleotide we see in an RNA molecule.

Picture_RNA Nucleotide

Nucleotide - Structure of Adenosine Monophosphate AMP

Link to my post below, and learn more about this amazing molecule’s structure and hydrolysis by water. 

ATP (Adenosine Triphosphate)

Also, check out this great general description of ATP by Sal Khan:

We said that ATP is the energy currency of the cell.

Cellular Respiration is the process by which cells generate ATP by breaking down glucose and other molecules.

So, let’s take a closer look at Cellular Respiration.

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{wymhacks – Cellular Respiration} 

Cellular Respiration Icon Picture

I’ve written separate posts for each stage of Cellular Respiration.

You can access these via the links below as well as view a general summary of each stage.  

Cellular Respiration (I) Overview 

Cellular Respiration is a metabolic process that occurs (mostly) in the Mitochondria of cells to produce ATP, the primary energy source for cellular processes.

Through four major chemical reaction stages, roughly 32 molecules (30 – 32) of ATP are produced for each molecule of Glucose.

  1. Glycolysis breaks down molecules and generates energy carrying molecules like NADH and ATP.
  2. Pyruvate reacts to Acetyl CoA which enters the Krebs Cycle.     
  3. The Krebs Cycle builds up and breaks down molecules to generate more energy carrying molecules like NADH, FADH2, and ATP. 
  4. Oxidative Phosphorylation (Electron Transport Chain and Chemiosmosis) takes the energy from NADH and FADH2 and creates (a lot) more ATP.

Cellular Respiration (II) Glycolysis

Glycolysis is a metabolic pathway that breaks down simple sugars into Pyruvate molecules. 

These reactions occur in the cytoplasm of cells and don’t require oxygen. 

Glycolysis produces 2 NADH and 2 ATP.

The NADH is an electron carrier and is used in the last stage of Cellular Respiration to make more ATP.

Cellular Respiration (III) Pyruvate to Acetyl CoA

Stage 2 of Cellular Respiration is called the Transition Step,  

  • where 2 Pyruvates (produced for each Glucose) are converted to 2 Acetyl CoA molecules, and where
  • 2 NADHs and 2 CO2s are also produced. 

Acetyl CoA is a versatile Nucleotide containing molecule: 

  • It delivers an Acetyl group to the 3rd Stage of of Cellular Respiration, the Krebs Cycle. 
  • Acetyl CoA also plays a role in other metabolic pathways (e.g. biosynthesis involving Fatty Acids and Amino Acids etc. )

Cellular Respiration (IV) Krebs Cycle

The Krebs Cycle, the 3rd Stage of Cellular respiration, produces, per molecule of glucose,

  • 2 ATP
  • 6 NADH and 
  • 2 FADH2

FADH2 is yet another important Adenine Nucleotide molecule. The NADH and FADH2 molecules are electron carriers to be used in the 4th and final stage of Cellular Respiration.

Cellular Respiration (V) Oxidative Phosphorylation

The majority of ATP, the powerhouse cell of the body, is produced by Oxidative Phosphorylation.

This occurs in the final stage of Cellular Respiration. 

The Oxidation occurs to the electron carriers NADH and FADH2 which are produced in the earlier phases of Cellular Respiration. 

The released electrons move through a series of proteins , resulting in the creation of a proton gradient between the Mitochondrial Matrix and the Intermembrane of a Mitochondrion. 

This is sometimes described as the Electron Transport Chain. 

At the end of the electron cascade, electrons react with hydrogen and oxygen to form water. 

Through Chemiosmosis of the protons through the enzyme ATP synthase, ATP is produced from the Phosphorylation of ADP.  

For every molecule of Glucose about 27 to 38 molecules of ATP are formed.

References

{wymhacks – Cellular Respiration Atomic Balance}

Here is some bonus material for you. 

Let’s go through a material balance exercise where we account for the inflowing and outflowing molecules in the major cellular respiration reactions.  

Read this post, 

Cellular Respiration Atomic Balance ,

for the details.

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{wymhacks – Cellular Respiration References}

Videos

Here a lot more excellent external Cellular Respiration articles and videos.

Documents

{wymhacks – Metabolic Pathways}

The chemical reactions that run and maintain life are varied and often interrelated. 

Collectively we describe these as Metabolism. 

The core mechanism of Metabolism is the Cellular Respiration reaction pathway.

It is sometimes described as Central Metabolism because practically all metabolic paths for different nutrients pass through it or are connected to it in some way. 

That is,

  • Carbohydrates, Proteins, and Fats can all undergo Cellular Respiration to produce energy, but
  • they can all be used to create molecules as well.
Picture_Metabolism

Metabolism Defined Icon

For an in depth exploration of  Central Metabolism and its many reaction pathways, please click the link below. 

Metabolic Pathways

This article will teach you that the Cellular Respiration Pathway 

  • serves as a central hub for several critical biochemical reactions.
  • allows your body to extract energy not only from carbohydrates (e.g. Glucose) but also from Proteins (Amino Acids) and Fats (Glycerol and Fatty acids). 
  • “intermediates” also play critical roles in anabolic processes (i.e. building molecules needed for life like tissues, organs, enzymes, hormones etc.)

On the surface it seems relatively simple…You ingest nutrients and oxygen and you reject carbon dioxide, water, and waste. 

But all the time, an incredibly complicated blend of biochemical reactions are going on in your body. 

The reactions are tightly regulated and controlled (via enzymes and hormones) to ensure your body stays alive and nourished.

Part II. Chapter 6 – The Crisis of Abundance

Ok, back to Attia’s book “Outlive” (Part II. Chapter 6).

NASH 

  • 1980s: Mayo Clinic named it: NonAlcoholic SteatoHepatitus {wymhacks: NASH}. 
  • It’s the progressive form of its precursor, Non Alcoholic Fatty Liver Disease {wymhacks: NAFLD}.
  • So, NAFLD -> NASH
  • NASH can cause inflammation, scarring of the liver and could lead to Cirrhosis. {wymhacks: See  liverfoundation.org for more on NAFLD and NASH}.
  • So, NASH is not caused by alcohol.
  • It’s Caused by too much fat buildup in liver. 
  • NAFLD / NASH is highly correlated with obesity and high cholesterol {wymhacks: hyperlipidemia}.
  • No obvious symptoms make this dangerous.
  • Blood ALT test (for liver enzyme alanine aminotransferase) might pick it up but not in the early stages.
Acceptable ALT range:
    • <33 IU/L (women); IU = International Unit
    • <45 IU/L (men).
    • These might be too high.
    • You might have an unhealthy liver even if these numbers are lower. 
  • The Liver is a resilient and regenerative organ.
    • You can reverse effects of NASH and NAFLD (up to a point ; most commonly by weight loss)
  • NAFLD / NASH are the “tip of the iceberg of a global epidemic of metabolic disorders,
    • ranging from Insulin Resistance to Type-2 Diabetes.”
    • {wymhacks: Insulin Resistance – Muscle / Fat/ Lever cells can’t efficiently take up glucose from your blood or store it}
    • {wymhacks: Type-2 Diabetes – chronic condition of high blood sugar levels (Hyperglycemia). }
Type-2 Diabetes is the “last stop on a railway line passing through”
    • Hyperinsulinemia (high insulin in blood)-> Pre-Diabetes -> NAFLD / NASH 
    • If you are anywhere on this disease “train”, you are susceptible
    • to the other Horseman diseases (Cardiovascular Disease, Cancer, Alzheimer’s Disease). 
  • {wymhacks: According to liverfoundation.org ,
    • “Nonalcoholic fatty liver disease tends to develop in people who are overweight or obese or have diabetes, high cholesterol, or high triglycerides.
    • These conditions combined are known as Metabolic Syndrome.”}
  • {wymhacks: Metabolic Dysfunction is a broad term describing one or more abnormal metabolic issues involving:
    • breaking down nutrients, 
    • using nutrients for energy,
    • disrupted or abnormal enzymatic or hormonal activity
    • etc.  }
  • { wymhacks: Metabolic Dysfunction/s lead/s to Metabolic Syndrome (and/or other isolated effects):
    • For example, Insulin Resistance is a Metabolic Dysfunction that leads to 
    • high blood Glucose, which is a Metabolic Syndrome.}
Obesity
    • According to CDC, > 40% of US population is obese (BMI; Body Mass Index >30).
    • Another 30% are overweight (BMI 25-30)
    • An Obese person has a higher risk for chronic disease.
    • Obesity is one symptom of a Metabolic Dysfunction like hyperinsulinemia (high blood insulin).
    • But,
      • Not everyone who is obese is metabolically unhealthy and
      • Not everyone who is metabolically unhealthy is obese

Metabolic Syndrome (MetSyn)

  • A 1980s concept by Gerald Reaven at Stanford. Named MetSyn eventually.  
  • Metabolic Syndrome or MetSyn defined in terms of  the following criteria:
  • {wymhacks: A mg (milligram) is 1000th of a gram and a dL (deciliter) = 100 cubic centimeters = a cube with 4.64 cm sides or 1.83 inch sides (basically a cube that fits comfortably in your hand)}
IF YOU MEET 3 OR MORE OF THESE CRITERIA, THEN YOU HAVE METABOLIC SYNDROME 
  1. Each of these criteria can be described as a Metabolic Dysfunction.
  2. Possibly 100s of millions of American adults have Metabolic Syndrome.
  3. {wymhacks: One article claims that “ Less than one-third of normal weight adults were metabolically healthy and the prevalence decreased to 8.0% and 0.5% in overweight and obese individuals, respectively.”}
  4. {wymhacks: According to this article, about ∼20% of the normal weight adult population is metabolically unhealthy.
    1. So metabolic dysfunction affects non-fat people as well.}
  5. So understand it’s not only obesity that increases the risk of bad health outcomes.
  6. More broadly, Metabolic Dysfunctions increase the risk of bad health outcomes.  
  7. {wymhacks: According to the NIH,  “Metabolic syndrome is a group of conditions that together raise your risk of
    1. coronary heart disease,
    2. diabetes,
    3. stroke, and
    4. other serious health problems.”} 
{wymhacks: Causes and Risks of MetSyn}:
  1. Being inactive,
  2. Eating an unhealthy diet and large portion sizes,
  3. Not getting enough good quality sleep,
  4. Smoking,
  5. Drinking a lot of alcohol,
  6. Shift work. 

Carbohydrate Metabolism

{wymhacks – Carbohydrates according to my.clevelendclinic.org are fibers, starches and sugars that your body converts into glucose (blood sugar) to give you the energy you need to function.} 

Metabolism is the “process of taking in nutrients and breaking them down for use in our body.” 

Let’s understand how our body metabolizes carbohydrates (or carbs for short).   

Route 1 – Carbs Converted to Glycogen (For Near Term Use)

{wymhacks: Glycogen is a polymer ,i.e. repeating subunits, of glucose}

75% of glycogen ends up in muscle, and 25% of glycogen to the liver.  

About 1600 calorie capacity between these two sites

  • {wymhacks: Not A lot! If I’m swimming, calorie use might be 280×2 = 560 cal/hr = 1120 for 2 hours}
  • {wymhacks: a thermal kcal (kilo calorie or 1000 calories) is equal to a dietary Calorie.
    • So, technically 1 dietary Calorie = 1 kilo calorie or kcal.
    • A kcal is the amount of energy required to raise the temperature of 1 kg of water one degree centigrade at sea level.}
  • {wymhacks: Protein and Carbohydrates contain ~4 kcal/g
  • Pure fat contains ~9 kcal/g
    • Technically adipose tissue is not 100% fat so the heat content of adipose will be less than 9). }

The Liver maintains glucose balance in the blood.

  • Called Glucose Homeostasis
  • The average adult male has only 5 grams (1 teaspoon) of glucose in blood.
  • Glucose is used up quickly by muscles and brain, so the liver is essentially continuously squirting converted glycogen (glucose) into the blood.
  • 7 grams of glucose in blood means you have Diabetes!!! This is a very delicate balance. 
Route 2 – Carbs Converted to Fat (for Energy Storage)

Unlike our limited glycogen capacity, we have a lot of fat capacity.

  • A Relatively lean adult could be carrying 10 kg of fat (3500/lb x 2.205 lb/kg x 10 kg = 77,175 calories)
  • Compare that to 1600 calories.
  • That is, our energy from fat storage capacity  is ~ 48x the capacity of energy storage via glycogen.

{wymhacks: Hormone Primer}

I think you’ll appreciate the following sections on Insulin and Glucagon much more if you first review these great references.  

The Pancreas Maintains Glucose Homeostasis in the Blood

  • The body senses Glucose levels in the blood and the Pancreas releases Insulin to control it.
  • Intense exercise results in immediate uptake of glucose by your muscles whereas
  • being sedentary results in Glucose conversion to Fat.
    • Fat is not bad fundamentally (depends on where it is)
    • Subcutaneous (under skin) fat is safest place to store energy
    • Subcutaneous fat plays an important role in maintaining metabolic health 
  • Fat is like a “metabolic buffer zone”.
    • The body safely uses it for energy storage and extracts energy from it as needed

{wymhacks: Additional notes on Insulin and Glucagon}

  • Read my post Metabolic Pathways.
  • The Pancreas Islets of Langerhans secrete two hormones: 
    • Insulin: reduces blood glucose and
    • Glucagon: increases blood glucose. 
  • From khanacademy.org 
    • The body maintains glucose in blood between 70 and 120 mg/dL.
    • A mg is 1000th of a gram.
    • A dL = deciliter = 100 cubic centimeters = a cube with 4.64 cm sides or 1.83 inch sides.
    • Too high, you could get Hyperglycemia (eye, nerve, kidney disease….i.e. diabetes). 
    • Too low you get Hypoglycemia (fatigue and worse).
  • To Reduce Glucose in Blood, Insulin Initiates Conversion of
    • Glucose to energy via Glycolysis
      • Glycolysis – First phase of  how your body extracts energy from glucose.  
    • Glucose to Glycogen (polymer of Glucose) via Glycogenesis in the liver and muscle and
    • Glucose to Lipids (fats are one form of lipid)  
      • This is a multi-step process resulting in Fatty Acids 
      • Glucose-> Pyruvate-> Acetyl-CoA-> Fatty Acids
      • Fatty acids react to form fat (triglycerides or TAGs) by Lipogenesis.
        • In a Fasting State, Fatty Acids can also convert to Ketone Bodies
        • Ketone Bodies are other energetic molecules
      • Usually stored in adipose or fat tissue of body.
      • Sometimes called De Novo Lipogenesis. 

Fat Storage in The Body (Bathtub Analogy)

Consuming energy in excess of your needs eventually

  • Exceeds the capacity of subcutaneous fat and
  • Results in fat “spillover” into other bodily regions.

{wymhacks – see the picture below showing a bathtub analogy of this energy balance.} 

{wymhacks – Picture_Bathtub Analogy of Bodily Fat (Energy) Balance}

Too much fat ingested from diet and/or too little energy demand (Fat -> Energy)
  • Eventually results in the subcutaneous fat reservoir (the bathtub) overfilling.
  • Subcutaneous fat capacity differs widely among individuals.
    • Possibly influenced by genetic factors.
    • e.g. Asian subcutaneous fat capacity much lower than Caucasian capacity
    • One explanation for why some people are “skinny” but still have metabolic dysfunctions. 
    • Suggests that having some fat versus being leaner might offer some metabolic protection.
  • When the “reservoir” is full, fat spills over into various organs and tissues
    • Like the liver, heart, muscles, kidneys, pancreas, and visceral regions.
  • This fat buildup can cause NAFLD, insulin resistance and inflammation
  • The Pancreas’s ability to secrete insulin can be impaired and lead to Type-2 Diabetes. 
  • Visceral fat (accumulating among the organs) can be dangerous.
    • Inflammatory Cytokines (TNF-alpha, IL-6)  are released.  (see my post: The Immune System – A Primer)
    • Cytokines are key markers and drivers of inflammation.
    • It’s linked to cancer and cardiovascular disease

Visceral Fat

If you have 20% body fat and about 11% or of that is visceral fat, you might be at high risk for cardiovascular risk and Type-2 Diabetes.

  • Attia patients take annual DEXA scans to determine visceral fat
  • DEXA determines bone density, visceral fat, body fat, and muscle mass

Insulin Resistance

One of the first places fat-overspill will go to is your muscles.

  • like marbling in a steak! 
  • Insulin Resistance likely begins here and spreads to organs like the liver
  • This Fat disrupts cellular insulin transport mechanisms
  • Inactivity (lack of physical activity) enables/speeds this process

Insulin Resistance means cells, initially muscle cells, stop responding to insulin’s signals. 

  • Cellular Glucose uptake eventually decreases.
  • The Pancreas responds by injecting more insulin
  • Eventually (fasting) blood glucose begins to rise (as well as insulin)
  • The Pancreas can eventually fatigue.
  • All the while more fat is being produced (remember insulin enables glucose to fat conversion)
  • Many hormones affect fat distribution and fat use but Insulin is the big one
    • Cortisol release caused by stress and lack of sleep can also contribute to visceral fat accumulation
  • High insulin (Hyperinsulinemia) results in
    • Fat gain
    • Increase risks for atherosclerosis and cancer
    • On the way to Type-2 Diabetes

Type-2 Diabetes

The “disease of civilization”.

  • {wymhacks: Type-1 Diabetes is much less prevalent (maybe 5% of total Diabetes Cases)}.
  • {wymhacks: Type-1 Diabetes: The body can’t make insulin, usually starting in childhood.}
  • {wymhacks: Type-2 Diabetes is the most common type of Diabetes (90% to 95% of Diabetes cases)
    • With Type-2 Diabetes, the body doesn’t use insulin properly
    • It’s linked to lifestyle factors
    • Type-2 Diabetes is more common in adults and is sometimes called Adult Onset Diabetes. }
  • (2022 CDC) – Over 11% of US adult population (1 in 9) has type-2 Diabetes
  • Over 29% of adults over 65 have it. 
  • Almost 50% of adult population is pre-diabetic or has Type-2 Diabetes
  • Patients with Diabetes have a much greater risk of cardiovascular disease, cancer, Alzheimer’s and other Dementias
  • Why is this epidemic happening?
    • (Possibly) Our metabolism, evolved over millennia, cannot cope with our modern diet.
    • The environment has changed much faster than our Genome. 
    • Evolution still wants us to get fat (not so useful in our era of unlimited calories)

Fructose

Let’s talk Fructose.  See my post Fructose Metabolism Chart also. 

Fructose is the common sugar found in , you guessed it, fruits. It has the same molecular formula as Glucose but has a different structure (they are isomers of each other).

{wymhacks: Fructose is one of a number of monosaccharides. You’ve already seen some of these and know how important they are

  • DNA and RNA molecules contain deoxyribose and ribose sugar groups
  • Glucose is a key energy source for most cells in the body (the brain needs glucose) }
{wymhacks – Picture_Common Monosaccharides}

Common Monosaccharides

{wymhacks: See the simple picture showing Fructose metabolism below.  

Recall that the Cellular Respiration pathway is described as Central Metabolism  because practically all metabolic paths for different nutrients pass through it in some way. } 

{wymhacks – Picture_Cellular Respiration Pathway with Fructose Entry Point}

Simplified Cellular Respiration Pathway with Fructose

 
{wymhacks: Fructose metabolism (happening mostly in the liver) skips the first phase (investment phase) of glycolysis and enters the glycolysis pathway via the intermediates DHAP and GA3P: 
  • Dihydroxyacetone phosphate (DHAP)
  • Glyceraldehyde 3-phosphate (G3P)

But the more interesting (and dangerous route for humans) is the production of Uric Acid. 

  • Fructose is directly phosphorylated to fructose-1-phosphate by the enzyme fructokinase.
  • Without the investment phase, fructose metabolism is less regulated and proceeds more rapidly (than the more regulated glucose metabolism)
    • Insulin does not regulate Fructose like it does Glucose
  • The Krebs cycle is also disrupted by Uric Acid , causing more production of fat
    • Fatty acids are produced from Acetyl CoA
    • In a later section we will see how central metabolism plays a role in numerous metabolic routes 
  • The liver is the primary site for fructose metabolism. 
  • This rapid conversion favors fat synthesis and can lead to insulin resistance and metabolic disorders. }
Fructose Metabolism and Uric Acid

In the picture above, recall that every intermediate molecule represented by the circles is regulated by enzymes. 

Due to the rapid depletion of ATP due to fast Fructose metabolism,

  • the enzyme AMP Deaminase (AMPD) is activated.
  • By converting AMP to IMP, AMPD helps to conserve phosphate indirectly.
  • Uric Acid is ultimately formed.
  • Uric Acid causes Gout, disrupts the Krebs Cycle, and causes more Fat production.  
  • Notice that Uric Acid is a more oxygenated form of the purine section (nitrogenous base) of the AMP molecule.
  • Here again we see how key nucleotides are in human biochemistry. 
  • AMPD then sends us down the pathway towards more Uric Acid and more fat storage and metabolic distress.
  • Fascinating evolutionary theory:
    • Evolution eliminated the enzyme Uricase from our bodies (other animals still have this).
    • Uricase helps reject Uric Acid from our bodies.
    • Fruit sources lessened as the climate cooled and
    • Eventually we genetically adapted by eliminating Uricase.
    • This allowed our human bodies to store more fat (via Uric Acid) in preparation for Winter.
AMPD is the Evil Twin of AMPK
  • Recall that AMPK stands for AMP-activated protein kinase.
  • Activated AMPK triggers the burning of stored fat while
  • AMPD sends us down the path of fat storage. 
  • AMPD also triggers hunger by blocking the satiety hormone Leptin. 
Fructose Forms

Just because fruits have Fructose doesn’t mean you need to stop eating fruits.

  • Fructose enters our system relatively slowly when consumed from fruits
  • In fruits, Fructose comes in mixed with fiber and Water.
  • You’re not going to get fat eating fruit (well odds are , you’re not).
  • Bigger risk comes from consuming concentrated sugar drinks including fruit juices
    • where you are consuming a lot more fructose than you would via an apple for example

High Fructose Corn Syrup (HFCS) is a very widely used and cheap commodity. It is found in lots of processed foods. 

  • Most people believe this is a major contributor to modern metabolic dysfunctions
  • Don’t let the name HFCS scare you off:
    • HFCS is composed of 55% Fructose and 45% Glucose (Predominant in USA)
    • Sucrose (Table Sugar) is 50% Fructose and 50% Glucose (Predominant in Europe but slowly changing)
    • i.e. Fructose is found in all the regular standard sweeteners
    • Fructose is being overconsumed today
{wymhacks: Uric Acid Measurement/Management}

High Uric Acid in the blood is bad (called Hyperuricemia when > ~ 7.2 mg/dl in blood per Medlineplus).

It Can cause Gout, increased fat, and metabolic dysfunction.

Foods that increase Uric Acid in the blood (Source: My.Clevelendclinic.org)

  • Red meat.
  • Organ meats like liver.
  • Seafood (especially salmon, shrimp, lobster and sardines).
  • Food and drinks with high fructose corn syrup.
  • Alcohol (especially beer, including nonalcoholic beer).

Other good references:

Monitoring /Biomarkers /Tests 

Attia’s patients are monitored for various metabolism biomarkers

  • Insulin
    • Elevated Insulin – Canary in a coal mine of metabolic disorder
  • Oral Glucose Tolerance Test (OGTT)
    • Patient swallows ten oz. of a very sweet Glucola drink
    • Rise and fall of insulin and glucose is then monitored
    • Insulin rise/fall can be an early indicator of insulin resistance
  • Blood Uric Acid
  • Chronic Inflammation
  • Elevated Homocysteine
  • Elevated ALT liver enzymes
  • Ratio of Triglycerides to HDL cholesterol (should be <2:1; target <1:1)
  • VLDLs (Very Low Density Lipoproteins)
  • HbA1c test;  >=6.5% means Type-2 Diabetes

Insulin Resistance / Hyperinsulinemia

Attia sees preventing Metabolic Dysfunction as a cornerstone of his approach to longevity.

Studies have found that Insulin Resistance is associated with huge increases in the risk of  

  • Cancer (12x)
  • Alzheimer’s (5x)
  • Death from Cardiovascular Disease (6x)

Hyperinsulinemia is not really considered a bona fide endocrine disorder on its own.

Only after the advent of Type-2 Diabetes is any serious action taken. 

So, since they play a major part in cancer, cardiovascular disease, and neurodegenerative disease, Metabolic Dysfunctions must be addressed first.

Part II. Chapter 7 – The Ticker

  • Heart attacks are fatal roughly 1/3 of the time.
  • Atherosclerotic Cardiovascular Disease (ASCVD)
    • ASCVD = Heart Disease and Stroke (Cerebrovascular Disease )
    • Leading cause of death in the US (more than cancer)
    • Kills ~2300 people a day in the United States
      • {wymhacks: See CDC for latest statistics (May 15,2024: 33 deaths per second)}
    • American women are 10x more likely to die from ASCVD than from breast cancer.
  • Attia mentored in this area by following experts
    • Tom Dayspring
    • Allan Sniderman
    • Ron Krauss
  • ASCVD is “relatively easy to delay if you’re smart and get on the case early”
    • Classic Medicine 2.0 treats cardiovascular disease over an “overly short time horizon”

Vascular Network 

Our Vascular Network comprises arteries, veins and capillaries.

{wymhacks: Let’s learn a little about these vessels (Source: Khanacademy.org): 

  • Arteries
    • Carry blood away from the heart.
    • Typically carry oxygenated blood (except for the Pulmonary Artery).
    • Have thick, muscular walls to withstand the pressure of blood pumped from the heart.
  • Veins
    • Carry blood back to the heart.
    • Typically carry deoxygenated blood (except for the Pulmonary Vein).
    • Have thinner walls than arteries and often contain valves to prevent blood from flowing backward.
  • Capillaries
    • Tiny blood vessels that connect arteries to veins.
    • Have very thin walls to allow for the exchange of oxygen, nutrients, and waste products between the blood and tissues.
    • Most of the body’s exchange of substances takes place in capillaries.  }

If “stretched out and laid end to end”, we would have a 60,000 mile network of vessels. {wymhacks: ~2.5 x the earth’s circumference}

In addition to transporting 0xygen and nutrients to our tissues and carrying away waste, the Vascular Network also traffics Cholesterol between cells

Cholesterol

{wymhacks:  Cholesterol is a lipid. Recall from an earlier section that fats are lipids as well. 

Lipid Structure

Cholesterol is “essential to life“. It’s used to make  
  • cell membranes
    • {wymhacks: Your body has roughly 30 Trillion Cells! 
    • According to this NCBI NIH article: “Cholesterol is the 
    • major sterol component of animal cell membranes,
    • which makes up about 30% of the lipid bilayer on average.
    • …Cholesterol plays pivotal roles in maintaining the structural integrity and regulating the fluidity of cell membranes” }
{wymhacks – Picture_Cell Membrane Cholesterol} 

Cholesterol in Cell Membrane

  • Hormones (e.g. testosterone, progesterone, estrogen, cortisol, aldosterone)  
{wymhacks – Picture_Examples of Cholesterol Derivatives}

Some Cholesterol Derivatives

  • Vitamin D
    • {wymhacks: According to NIH.gov, “Type B UV (UVB) radiation with a wavelength of approximately 290–320 nanometers penetrates uncovered skin and converts cutaneous 7-dehydrocholesterol to Pre-Vitamin D3, which in turn becomes Vitamin D3”.}
    • {wymhacks – Picture_Vitamin D3}

All cells make Cholesterol but about 20% is stored in the liver. 

  • The Liver is a Cholesterol repository, distributing and receiving it.

Because Cholesterol is a Lipid (think fat), it’s not soluble in water or blood.

It therefore has to be carried around in spherical particles called Lipoproteins. {wymhacks: see my post Metabolic Pathways where I describe Lipoproteins called Chylomicrons}

Lipoproteins

Lipoproteins are

  • little “cargo submarines” that move via the blood and
  • distribute their lipid contents (Cholesterol, Phospholipids, and Triglycerides) to the body’s tissues.
  • Lipoproteins can even transfer their cargos among each other.

See the generic picture of a lipoprotein below.

{wymhacks – Picture_Lipoprotein Structure}
Lipoprotein Structure

A lipoprotein consists of three parts:

  • A lipid (cholesterol and other lipids) cargo on the inside.
  • A surface monolayer that contains Phospholipids and “free Cholesterol”
  • An outer non-continuous layer
    • Called an Apolipoprotein.
    • It wraps around the spherical structure.
    • There are several types of Apolipoproteins.
The Apolipoprotein type is the most critical differentiator among the different types of Lipoproteins.
  • High Density Lipoproteins (HDLs)
    • They are are more dense than other Lipoproteins, meaning
    • they have more fat relative to protein.
    • HDLs are wrapped with Apolipoprotein A or ApoA
  • Low Density Lipoproteins (LDLs)
    • are less dense than HDLs. 
    • are wrapped with Apolipoprotein B or ApoB
  • There are other Lipoproteins (IDLs, VLDLs)
    • IDL = Intermediate Density Lipoprotein
    • VLDL = Very Low Density Lipoprotein
    • These are also wrapped with Apolipoprotein B or ApoB

There are other types of Apolipoproteins , but it’s the ApoB that’s probably the most important.

LDLs, IDLs, and VLDLs contribute to Atherosclerosis and all carry this ApoB signature.
  • LDLs, IDLs, VLDLs all contain ApoB
{wymhacks – Picture_Classes of Lipoproteins}
  Classes of Lipoproteins

 

Our Current Understandings Dispel Some old Myths 

  • {wymhacks: According to this Harvard Article,
    • your body manufactures most of its cholesterol with only about 20% coming in via food.”} 
  • Eating lots of saturated fats will increase bad lipoproteins but not true for cholesterol.  
  • Most of ingested cholesterol is excreted from out bodies.
  • Eggs were vilified for years due to their cholesterol content, but since 2015,
    • “the US Government Dietary Guidelines ” finally conceded that “cholesterol is not a nutrient of concern for overconsumption“”
  • Cardiovascular disease does not only strike old people
    • In men, 25% of cardiovascular events (heart attack, stroke, stent, graft) occur before age 54!

Atherosclerosis

Take a look at the two pictures below as you read this section. 

{wymhacks: According the American Heart Association, 

  • “Atherosclerosis is a condition that develops when a substance called plaque builds up in the walls of the arteries.
  • This buildup narrows the arteries, making it harder for blood to flow through.
  • If a blood clot forms, it can block the blood flow. This can cause a heart attack or stroke.”  }

{wymhacks: Blood vessels comprise three sections (we are oversimplifying quite a bit)

  • The Artery Wall
  • A thin layer covering the wall called the Endothelium
  • The flow space which is called the Lumen 

The Endothelium

  • is a semipermeable barrier that controls the movement of molecules into and out of the blood.
  • maintains our “electrolyte and fluid balance”
  • expands and contracts the vessel based on blood flow (modulated by Nitric Oxide (NO)) }
 
{wymhacks – Picture_Atherosclerosis (Planar Arterial View)}
Atherosclerosis shown on a planar view of an artery
Endothelium Penetration

Lipoproteins, all kinds, will penetrate in and out of the endothelium (into the subendothelial space)

  • but LDL particles will tend to stick. 
  • Other lipoproteins with ApoB will also stick (IDL, VLDL for example)
  • These will react and be oxidized by reactive oxygen species (ROS).
  • This causes oxidative stress (causing inflammation etc.)
  • The accumulating ApoB laden lipoproteins begin to damage the Endothelium

A much better indicator of your exposure to risk from endothelial damage and ultimately Atherosclerosis

  • is your ApoB count. 
  • ApoB is much more relevant than your cholesterol count.
Atherosclerosis Progression

Other heart disease risk factors like high blood pressure and smoking can also damage the Endothelium.

As the Subendothelial space starts getting engorged with ApoB particles (LDLs, IDLs, VLDLs, etc.)

  • Immune cells called Monocytes are released and ultimately transform into
  • Macrophages (“larger and hungrier immune cells”).
  • Engorged Macrophages “blow up” into “foam cells“.
  • Foam cell accumulation results in “fatty streaks“.
  • Fatty streaks are precursors to Atherosclerotic Plaque. 
  • All of this begins developing in most of us at an early age.

HDL are considered “good lipoproteins” because they have “atheroprotective functions”

  • HDLs sweep out excess lipids from the subendothelial space back into the bloodstream.
  • New research suggests they maintain the structure of the Endothelium,  
  • lowering inflammation, and 
  • stopping the oxidation of LDL
  • Measuring cholesterol content in LDLs (LDL-C) correlates well with heart disease risk,
    • But knowing the concentration of LDL particles might be even more correlative
  • Measuring cholesterol content in HDL (HDL-C) however, does not correlate well. 
 
{wymhacks – Picture_Atherosclerosis (Cross Sectional Arterial View)}
Atherosclerosis shown on an artery cross section
Atherosclerotic Plaque and Blood Clots

The growing plaque (accumulated foam) is eventually sealed from the arterial wall by a matrix barrier. It keeps growing though. 

  • It’s still not easily detectible (CT Angiogram might catch it)
  • The plaque tends to grow towards walls but will eventually start squeezing the lumen passageway (called Stenosis).
  • The Plaque begins to calcify. A regular calcium scan will detect this. 
  • Unstable Plaque can form blood clots, or worse, break free and cause a heart attach or a stroke. 
  • Normally the result is restricted/blocked veins/arteries which can lead to
    • Ischemia (heart attach due to low blood flow) or
    • Infarction (stoke due to no blood flow) 

ApoB

Necessary (but not guaranteed) criteria for developing heart disease
  • High ApoB
  • LDL oxidation (modification) i.e. plaque and calcium
  • High inflammation
The ApoB blood test is more predictive of cardiovascular disease than LDL-C
  • More and more evidence to support this
  • Attia: “I have all my patients tested for ApoB regularly…”

Lp(a)

Another lipoprotein called Lipoprotein (a) or  Lp(a) is wrapped with a protein called Apolipoprotein a or Apo(a)

  • Not to be confused with ApoA
  • Apo(a) is stickier than ApoB
  • Speeds the formation of Plaque
  • If you have a family history of premature attacks, check your Lp(a) levels

How to Reduce Cardiovascular Risk

Attia mainly looks at ApoB and Lp(a) in his patients for indicators of cardiovascular risk. 

ApoB also shows 
  • concentration  of LDL particles
  • concentration of VLDL particles
LDL-C as a proxy for ApoB

Treatment guidelines suggest

  • 100 mg/dL LDL-C for patients at normal risk
  • 70 mg/dL LDL-C for patients with high risk

Attia thinks these are too high:

  • They should be much lower. 
  • See article by Peter Libby in Nature.
  • 10 – 20 mg/dL LDL-C  (levels we have when we were babies)
  • these low levels don’t appear to be harmful
Attia Approach 
  • Smoking and high blood pressure damage the endothelium
    • So, stop smoking !
    • Control your blood pressure!
  • Reduce ApoB, i.e. reduce LDLs and VLDLs via diet
    • Consider lowering triglycerides
    • Reduce saturated fats (shift to monounsaturated fats)
  • Monitor other metabolic health indicators
      • Insulin
      • Visceral fat
      • Homocystein (strongly correlated to increased risk of
        • Heart attack
        • Stroke
        • Dementia
  • HDL-C not that useful (HDL function seems more important but cant be tested)
  • Reduce ApoB with Drugs
    • Statins, lower LDL cholesterol levels by
    • reducing the amount of LDL the liver produces and
    • by helping the liver remove LDL from the bloodstream.
    • Cannot be used by everyone due to side effects and specific conditions
  • Prevention needs to start with people in their 30s and 40s!

References

Part II. Chapter 8 – The Runaway Cell

{wymhacks: Cancer Statistics}

Picture_Top 10 Cancers by Rate (USA, 2018-2022)

USA Cancer Death Rates 2022 CDC.gov

Outlive Chapter 8 Introductory Material

  • The book “The Transformed Cell” by Steve Rosenberg influenced Attia’s decision to go into surgical oncology.
  • Cancer is the second leading cause of death {wymhacks: In USA and Globally}
  • Cancer is a disease of aging.
  • Two problems with Cancer
    • Not many effective treatments
      • We can remove tumors but
      • If Cancer spreads (metastasized), its very tough to treat
    • Hard to detect cancer in early stages
  • Three part strategy for dealing with Cancer
    • Avoid getting cancer (we mostly don’t know how to do this)
    • Use of newer, smarter treatments to target cancer characteristics
      • Insatiable hunger for glucose 
      • Vulnerability to immune base therapies
    • Detect cancer early
      • early, aggressive and broad screening
      • Colonoscopy at 40
      • Pair these with Liquid Biopsies (detecting cancer via blood tests)

What is Cancer?

  • Cancer cells don’t stop growing (they don’t grow faster than other cells, they just don’t stop growing)
    • Gene Markers: e.g. Damaged Cell growth suppressor gene PTEN  (often mutated or lost in people who have cancer)
  • They can spread or metastasize
    • Often turns a manageable disease into a deadly one
  • The Cancer Genome Atlas
    • Ambitious project started 20 years ago
    • Couldn’t find much genetic similarity even for same cancer cases
    • Cancer mechanisms are extremely complex
  • Even if treated successfully, cant tell if cancer will come back or not
  • Metastasis is still not understood and very little research goes into understanding it
  • Once Metastasized cancer has to be treated systemically
    • With chemotherapy (Chemo) typically.
    • Chemo medicines are also poisons.
    • Earliest chemo medicines were Mustard Gas derivatives.
    • Hope is to selectively kill cancer cells.
  • Metabolism and immune surveillance
    • Two key cancer hallmarks discovered
    • Cancers have altered metabolism (consume huge amounts of glucose)
    • Cancers able to evade the immune system
    • Potentially promising learnings and treatments might come out of these.

Cancer Metabolism

  • 1920’s: Auto Warburg (Cancers love glucose)
    • Cancer can consume 40x more glucose than normal cells, but
    • they don’t respire normally (more anaerobically than aerobically) – even with plenty of oxygen
    • Called the Warburg Effect (Anaerobic Glycolysis) 
  • Lew Cantley – Harvard – metabolic aspects of cancer
  • Cancer fuels it proliferation via the Warburg Effect (less energy but lots of by product building blocks e.g. lactate)
  • Also the acidic byproduct environment might prevent or slow immune cells from acting
  • Obesity and Type 2 Diabetes fueling increased risks of cancer
  • PI3 Kinases (PI3K) fuel Warburg Effect
    • Cancer cells turn PI3K activity (speeds up glucose uptake)
    • Cancer cells shut down PTEN (Cell growth suppressor gene)
    • PI3K also turned up by Insulin and IGF-1 (insulin like growth factor)
    • So Insulin acts as a kind of cancer enabler
  • So, metabolic therapies (e.g. dietary adjustments) could lower insulin which could lower cancer risk
  • Caloric restriction might have this effect of lowering insulin
  • Bottom line: Avoid being anywhere on the spectrum of insulin resistance to Type 2 Diabetes because these elevate cancer risk

New Treatments

  • New class of drugs, PI3K inhibitors, that fight cancer metabolism, don’t work as well as expected.
  • They end up raising insulin
  • Combined with a ketogenic diet ,  PI3K therapy might work better. 
  • Drug treatment combined with nutritional interventions are being actively explored. 
  • Concept/theory: Cancer cells are metabolically greedy so they might be more vulnerable to a reduction in nutrients (i.e. insulin).
  • Stacking different therapies might be more effective (e.g. ketogenic diet + PI3K)

The Promise of Immunotherapy

  • “The immune system is programmed to distinguish “non-self” from “self”
    • It identifies pathogens and foreign bodies and attacks them 
  • Check out my post The Immune System – A Primer to learn more about B and T White Blood Cells. 
  • Immunotherapy is anything that trys to harness the immune system to combat an infection or other condition
  • For cancer immunotherapy to work, immune system needs to recognize “bad self” from “good self.”
  • Interluekin-2 (IL-2) – amplifies activity of lymphocytes (white blood cells). Marginally successful in cancer treatment.
  • T-Cells are a type of white blood cell that play a central role identifying and destroying infected (or cancerous cells).
  • Can take T-Cells, mark them with cancer cell antigens, and thus program them to attack those cancer cells.
    • See the section titled “The Roll of T-Cells in Adaptive Cell Mediated Immune Responses” in the Immune System Primer. 
    • These T Cells are called Chimeric Antigen Receptor T Cells or CAR-T. (Approved for use by FDA in 2017)
    • CAR-T only good against B-Cell Lymphoma.
    • {wymhacks: T Cytotoxic Cells (see Immune System Primer for more information)}

T Cytotoxic T Cell Immune Process

  • Another treatment called “Checkpoint Inhibitors” make the cancer visible to the immune system.
    • Checkpoints like CTLA-4 and PD-1 regulate and limit T Cells attacking our own cells. 
    • Inhibiting these allow the T Cells to see and attack cancer cells
  • About 1/3 of cancers can be treated with immunotherapy and about 25% of those patients will benefit(so only 8.3% potential cancer deaths are prevented).
  • Combining (Stacking) immunotherapies is being explored these days. 
  • Adaptive Cell Therapy – ACT – In this approach, a large amount of CAR-T cells are injected into the body to try to overwhelm the cancer. 
  • These developing therapies are very expensive at this time. 
  • Immunotherapy when it works seems to reduce the odds of remission compared to traditional treatments.
  • There is Hope these will be more successful going forward. 

Early Detection

  • Early aggressive screening is most important prevention tool
  • Too many cancers are detected too late
  • 10 year survival rate with people who have metastatic cancer is 0 (same as it was 50 years ago)
  • Cancer detection at Stage 1 mean your chances of survival skyrocket.
  • Out of dozens of cancers only 5 have reliable screening methods
    • lung
    • breast
    • prostate
    • colorectal
    • cervical
  • Possible false positives make some people reluctant to test for cancer (cost issue)
  • Diagnostic tests: tradeoff between Sensitivity and Specificity
    • Sensitivity: ability of test to detect an existing condition
    • Specificity: ability of test to determine someone does not have that condition
    • Together, they represent test’s accuracy
    • Must also consider prevalence of disease in our target population
    • i.e. is this test being done on someone from a relatively low risk or high risk population? 
  • Mammography: Sensitivity (mid 80s), Specificity (low 90s)
    • If from low risk population (lets say 1% have cancer), your going to get a lot of false positives.
    • In fact, “Positive Predictive Value” (PPV) of mammography is about 10% (i.e. if you test positive, there is only a 10% chance you actually have cancer).
    • For a high risk population, the test has a higher PPV.
    • Should stack tests to avoid misdiagnosis or improve “resolution” of diagnosis
    • i.e. Use Ultrasound and/or MRI in addition to mammography
  • Prostate Cancer Screening
    • This single test not enough to justify a very painful biopsy
    • Must look at PSA Velocity, PSA Density, and Free PSA
    • Could also do 4K blood test
    • Doctor needs to answer: “Will our patient die with prostate cancer (as many men do) or will he die from it?”
    • Can also use Multiparametric MRI imaging.
    • Stacked together these tests avoid do unnecessary biopsies or surgeries.
  • Colorectal Cancer Screening
    • Colonoscopy looks for tumors and polyps.
    • “not all polyps become cancer but all colon cancers come from polyps”.
    • Colonoscopy is excellent tool: does screening but also does surgery (can remove the polyps).
    • There is some evidence that getting screened at 50 might be too late (even with patients with average risk factors).
    • There are other screening tests (e.g. from stool samples) but Attia things “no other test compares to a colonoscopy”.
    • 2018 American Cancer Society guidelines: get tested at 45 for people of average risk
    • Attia recommends to get the test at age 40 (if you are above average risk – family history  and certain medical conditions you might have).
    • “Colon cancer has been documented to appear within the span of as little as 6 months to 2 years after a normal colonoscopy”
    • For more guidelines and details see:   peterattiamd.com – colorectal cancer screening
  • Scan Cancer and Melanomas
    • Cancers are easy to spot visually
  • Cervical Cancer
    • Pap smear: well established, minimally invasive
  • Inside body cancers are tougher to screen
  • Can use low dose CT scans or MRI scans for Lung Cancer
    • 15% of lung cancers occur to people who don’t smoke
    • Lung Cancer is the #1 cause of cancer deaths
    • MRI good to use also (less ionizing radiation than CTs)
    • DWI MRI (diffusion weighted imaging with back ground subtraction) 
    • Imaging tests not perfect : have high sensitivity but low specificity
    • Whole body MRI for example to screen for cancers might produce a lot of false positives
  • Liquid Biopsies (blood testing for cancers): Very promising
    • As opposed to solid tissue biopsies
    • Multicancer early detection – fast growing area
    • Cancer cells tend to shed cellular matter including DNA
    • Next generation high throughput DNA screening technology can detect these
  • A company called Grail (subsidiary of Illumina) offers the Galleri Test
  • Attia sees stacking (combining tests)  as the solution (wym: well sure…when I used to trick or treat, I wanted to take all the candy but I couldn’t)

Chapter Concluding Remarks

  • Of the Four Horsemen, cancer is the hardest to prevent.
  • Aggressive screening is your best bet today.
  • Only “modifiable” risks are
    • smoking
    • insulin resistance
    • obesity
    • pollution (maybe)
  • “Treatment and prevention strategies are far less effective than tools available to address
    • cardiovascular disease and 
    • the spectrum of metabolic dysfunction”

References

Part II. Chapter 9 – Chasing Memory

Introductory Section

  • Attia runs many tests on patients interested in longevity  
  • high interest measurements would be
    • Lp(a) – high risk lipoprotein (Chapter 7)
    • ApoB concentration – heart disease indicator –  (Chapter 7)
    • ApoE genotype (Chapter 4) – gene related to Alzheimer’s Disease
  • The e4 allele of ApoE indicates a greater risk for Alzheimer’s Disease.
    • It means increased risk. It doesn’t mean you’ll get it. 
  • We still don’t know much about Alzheimer’s (origins, prevention, treatment)
  • At this time Alzheimer’s doesn’t seem reversible.  – No cure
  • Other Neurodegenerative diseases  – No cure
    • Lewy Body Dementia – affects cognition (1.4 million US citizens have it)
    • Parkinson’s Disease – a movement disorder (1 million US citizens have it)
    • Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig’s Disease) – less common
    • Huntington’s Disease – less common
  • About 6 million US citizens have Alzheimer’s
  • At this time best (only) strategy is to try to prevent them
  • There are common threads among all these neurodegenerative diseases (so prevention strategies could benefit more than one)
  • Alzheimer’s rarely reaches a clinical stage before age 65.

Understanding Alzheimer’s

  • Identified as a disease by Dr. Alois Alzheimer (1906, German).
  • He observed that a patient who had died with these symptoms had a brain whose neurons were “entangled and spider-web like, coated with a strange white dental substance”.
  • The disease was Ignored / forgotten for 50 years – afflicted people were often institutionalized.
  • Doctors began describing senile dementia as a disease in the 1960s
    • Doctors observed the same “kinds of plaques and tangles”.
  • 1980s: Doctors identified plaque as a peptide called Amyloid-Beta. (my post Macro Molecules, Minerals, and Vitamins –  A Primer)
  • Amyloid-Beta also triggers production of Tau which also contributes to neuronal inflammation.
  • So theory has been than Alzheimer’s is caused by accumulation of Amyloid-Beta and tau. 
  • Currently (based on various tests and issues discovered with old data) it seems like Amyloid-Beta might not be necessary or sufficient to cause Alzheimer‘s
  • So lots more work needs to be done to figure this out (its causes, etc.)

Can Neurodegenerative Disease Be Prevented?

  • Dr. Richard Isaacson – pioneer in this area
  • 2015 – 2 year Randomized Controlled Trial in Finland
    • nutrition, physical activity, cognitive training helped (maintain and avoid degradation of cognitive function) for 1200 at risk adults
  • Alzheimer’s disease is twice as common in women than in men (possibly to do with menopause and certain hormones).
  • Lewy Body and Parkinson’s is more prevalent in men.
  • MCI – Mild Cognitive Impairment – early clinical stage of Alzheimer’s
  • Earlier symptoms are categorized as Stage I Preclinical Alzheimer’s Disease  (46 million Americans might have this?)
  • Pre-Dementia can lurk beneath the surface for years
  • When a patient exhibits cognitive issues
    • do a “grueling battery of tests” – they are “clinically validated , highly complex tests”
    • Ability to smell affected by Alzheimer’s disease
    • difficult to interpret results
    • hard to detect certain symptoms because brain can compensate for them
  • Alzheimer’s disease primarily affects the temporal lobes (memory, language, auditory)
  • Parkinson’s: a movement disease.  In part due to deficiency in producing dopamine. 
  • Cognitive Reserve
    • Brain can develop more neural networks if one learns a different language or plays music etc.
    • These tend to resist effects of Alzheimer’s (not conclusive though).
    • The more complicated and nimble the more they seem to help.
    • As a prevention, do cognitive reserve building exercises (things requiring deep or quick thinking etc.)
  • Movement Reserve (analogy for people with Parkinson’s Disease)
    • Exercise is the only “intervention shows to delay the progression of Parkinson’s”

Alternatives to Amyloid

  • Alzheimer’s seems to cause issues with cerebral blood flow (called perfusion). 
  • Alzheimer’s brains often display “marked calcification of the blood vessels and capillaries that feed them”.
  • The Brain is greedy. It makes up 2% of  body weight but consumes about 20% of our total energy use.
    • Its 86 billion neurons each have 1 to 10 thousand synapses (connecting them to other “neurons or target cells”)
    • The Brain needs a steady supply of glucose and oxygen delivered by a dense network of blood vessels
    • Disruptions to this vascular network is really bad
  • Brain cells metabolize glucose differently than other cells – does not depend on insulin (uses certain GLUT transporter proteins to do it)
  • If glucose low, brain will get energy from ketone bodies produced by fat (in the liver).
  • If fat runs out, muscle and other organs will get consumed to satisfy your brain’s energy demand. 
  • Perfusion Theory: Alzheimer’s is “primarily a vascular disorder of the brain.”
    • Dementia caused by lower blood flow
    • Amyloids develop after this
    • Evidence: Stroke victims, people with cardiovascular disease
    • Evidence: some ” 2 dozen known risk factors for Alzheimer’s also…reduce blood flow”
    • Categorized as Vascular Dementia but really applies to Alzheimer’s also. 
  • Glucose Theory: “Abnormal glucose metabolism in the brain”
    • Having Type 2 Diabetes doubles/triples risk of getting Alzheimer’s.
    • Chronically high glucose can damage brain vasculature (blood vessels).
    • “Insulin seems to play a key role in memory function”: High concentration of insulin receptors are in Hippocampus.
    • Main issue: lower glucose metabolism
  • Perfusion and Glucose theories both result in reduced neuron energy consumption

The Role of ApoE e4

  • ApoE (apolipoprotein E)
    • “Main cholesterol carrier in brain.”
    • e4 allele version disrupts cholesterol transport and glucose metabolism.
    • e4 allele might be damaging the blood-brain barrier
    • e4 allele promotes inflammation (good in some cases light fighting disease)
    • “…inflammation promotes atherosclerotic damage to our blood vessels setting the stage for Alzheimer’s disease and dementia”
    • Markers of high inflammation are found in Alzheimer’s patients (Cytokines TNF-alpha and IL-6)
    • e4 carriers can also have “higher levels of neuroinflammation”.
    • e4 carriers are more likely to develop metabolic syndrome.
    • ApoE e4 can block brain insulin receptors.
    • Complicated. Other genes (e.g. Klotho) might be in play at the same time.

The Preventive Plan

  • Alzheimer’s prevention strategies are their infancy
  • Attia approach
    • Address any metabolic issue with patient
    • Mediterranean style diets;
    • Omega 3 Fatty Acid DHA supplementation
    • Ketogenic diet (more ketones, less glucose that might not be being consumed efficiently)
    • Reduce added sugar and refined Carbs and alcohol
    • Exercise might be the most powerful tool (for glucose homeostasis and vascular health)
    • Endurance Exercises (improve mitochondrial health)
    • Exercise benefits cognition and memory.
    • Exercise reduces inflammation and oxidative stress.
    • Strength training is important also (low grip strength correlated with higher dementia).
    • Attia: “exercise is, full stop and hands down, the best tool we have in the neurodegeneration prevention tool kit”.
    • Must get adequate sleep. During sleep the brain “sweeps away intracellular waste” that build among your neurons. (see Chapter 16)
    • Theory: Hearing Loss (via cognitive decline) is associated with Alzheimer’s disease (less social interactions)
    • Treating depression might alleviate alleviate cognitive decline.
    • Brush and Floss your Teeth. Gum health (P.Gingivalis microbe) correlates with overall health. 
    • P.Gingivalis can increase inflammation.
    • Dry saunas might help
    • B vitamins (lower homocysteine levels)
    • Vitamin D (have been correlated to improved memory)
  • So in Summary:
    • “Vascular health (low ApoB, low inflammation, low oxidative stress) is crucial to Brain health.”
    • “Metabolic health is crucial to Brain health.”
    • Start early with prevention, especially if you have markers.
    • Exercise a lot for strength and endurance

References

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Part III – Chapter 10 – Thinking Tactically

In the last 100 years or two, our living has changed in so many ways eg. 
  • food supply and quality,
  • eating habits,
  • activity levels,
  • sleeping habits, 
  • socializing,  
but our genes have not. 
 
That is, we are not “designed” for today’s world. This leave’s our minds and bodies susceptible to a lot of modern hazards. 
 
So we have to apply the right tactics for optimal survival. 
 
5 “Tactical Domains”:
  • Exercise
  • Diet
  • Sleep
  • Emotional Health
  • “Exogenous Molecules” (i.e. drugs, supplements, other)

When Attia evaluates new patients, he is trying to answer 3 main questions: Are they

  1.  overnourished / undernourished
  2. undermuscled / overmuscled
  3. metabolically healthy or not

In Attia’s experience, poor metabolic health means you are probably undermuscled

Attia goal for his patients (and readers of this book):  “live longer and better” (i.e. outlive).

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Part III – Chapter 11 – Exercise

  • Exercise  is the single best antidote for improving your health.
  • It delays onset of chronic disease
  • Extends / Improves healthspan
  • Slows and Reverses physical and cognitive decline
  • Improves emotional health
  • About 77% of the population does not exercise.
  • Could live more than a decade longer than non-exercisers (numerous studies)
  • {wymhacks Office of  Disease Prevention and Health Promotion physical activity guidelines for Adults}
    • Move more and sit less. 
    • Do moderate intensity workouts: at least (2 hours and 30 minutes) to (5 hours) a week or
    • Do for more than 5 hours/wk for more benefits.
    • Do vigorous-intensity aerobic physical activity:  (1 hour and 15 minutes) to (2 hours and 30 minutes) a week or
    • Do an equivalent combination of moderate- and vigorous-intensity aerobic activity.
    • Aerobic activity should be spread throughout the week.
    • Do muscle-strengthening activities of moderate or greater intensity: 2 or more days a week.
    • Older Adults: Do multicomponent exercise: Incorporate a mix of balance, strength, aerobic
  • The more exercise you do , the better off you will be. 
  • Cardiorespiratory fitness measured by VO2 max – single most powerful marker for longevity
    • VO2 – max rate at which you can utilize oxygen (measured while you are exercising)
    • At rest 300 ml O2/minute  (so your body can generate ATP)
    • Go for a jog: 2,500 to 3,000 ml O2/minute
    • Run uphill as fast as you can: 4,000 to 5,000 ml O2/min
    • VO2 Max Usually expressed as Volume per kg of bodyweight per minute 
    • Elite Athlete (VO2 max in high 60s ml/kg/min)
    • Average 45 year old man (VO2 max 40 ml/kg/min)
    • Unfit: VO2 max in the high 20s ml/kg/min
    • Strong correlation to longevity (2018 JAMA study, 2022 JACC study – Peter Kokkinos et al.)
    • Fig. 9 in Attia’s book comes from the Kokkinos et al article which you can access from the link above.
    • Hazard Ratio definition:  1.4 would mean risk relative to some baseline is 40% greater (e.g. risk of death of smoker/non smoker)
    • From Fig. 9: All Cause Mortality Risk of person with below average VO2 max (relative to extremely fit VO2 Max) is TWICE that for smokers (relative to non smokers): 2.88 vs 1.4  
    • “Having a higher VO2 max is better for your overall health and longevity than having a lower VO2 max.” 
  • Austin Bradford Hill – 9 Criteria for Assessing Studies
    • Correlation does not mean Causation
    • Attia applies these criteria when assessing Causality of the 2022 Kokkinos JACC study.
  • Muscle is also correlated to longevity
    • You need muscle mass and strength.
    • Fitter you are the lower risk of death.
    • Probably better than medicinal interventions (see work of Ioannidis at Stanford).
    • Exercise improves mechanics (strengthens heart and circulatory system).
    • Exercise improves health of mitochondria.
    • It improves metabolism of glucose and fat.
    • More muscle helps support and protect body.
    • Metabolic health is improved.       
    • Muscles generate Cytokines which strengthen immune system (seems to be good and bad…immune response good; inflammation is bad)
  • Endurance exercises help body generate BDNF (Brain Derived Neurotrophic Factor)
  • Exercise “keeps brain vasculature healthy”.
  • May help “preserve brain volume”.
  • Exercise more effective at “preserving healthspan than extending lifespan”. 
  • Muscle Mass declines steeply after age 65 (less activity)..faster still by 75
  • “Continued muscle loss and inactivity” put our lives at risk.
  • In old age, more muscle is better.
  • Muscles keep bones upright and intact.
  • Muscle atrophy and sarcopenia (age related muscle loss) increase risk of falling.
  • Accidental Death from falls becomes dominant in 75+ age group.  
  • Attia lifts heavy weights at least 4 times a week

The Centenarian Decathlon

  • Attia gives his patients a long list of tasks to choose at least 10 things from
  • To be able to do in their 9th or 10th decade
  • Activities like swim 1/2 miles in 20 minutes
  • Do five pull ups etc
  • Idea being you can now tailor a series of exercises that will get you there

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Part III – Chapter 12 – Training 101

  • Need to work on cardio, strength, and stability
  • cardio (continuum from walk to sprint)
    • long steady endurance work – jogging , cycling, swimming (zone 2)
    • max aerobic effort
  • stability important – do the exercise using proper form and safely

Aerobic Efficiency – Zone 2

  • zone 1 intensity: walk 
  • zone 2: going at an intensity slow enough to be able to maintain a conversation (but fast enough that it is strained)
    • between easy and moderate
  • zone 5,6,7:  All out sprint
  • “Healthy Mitochondria fostered by zone 2 training helps keeps fat accumulation in check”
    • Mitochondria convert both glucose and fatty acids to energy (see my post: Metabolic Pathways)
    • Glucose can be metabolized for energy outside (some of it via glycolysis) or inside (most of it via Krebs and ETC) the Mitochondria.
    • Fatty Acids are converted to energy only in the Mitochondria.
{wymhacks – Picture Cellular Respiration in The Cell}

Cellular respiration in Eukaryotic Cell Cytosol and Mitochondria Mitochondrion

{wymhacks – Acetyl CoA in Central Metabolism}

  • Zone 2 training makes Mitochondria healthier allowing them to process fat more efficiently
  • 2017 Study by Brooks and Millan: Assessment of Metabolic Flexibility…
    • Professional cyclist vs Sedentary individuals on stationary bikes
    • Zone 2 endurance training is the key to keeping Mitochondria able to process fat efficiently
  • Zone 2 workouts done by slow twitch muscles which have lots of Mitochondria
  • Zone 2 is a max effort zone without accumulation of lactate.
  • You shouldn’t “feel the burn” during a zone 2 workout
  • You can measure your lactate with a lactate monitor(1.7 to 2 millimoles is a good range for Zone 2 workout says Attia)
  • Zone 2 will be about 70 to 85% of your max heart rate (e.g. if max is 160, then zone 2 range is 112 – 136)
  • Talk Test (Rate of Perceived Exertion) – can talk but not really carry on a conversation (i.e. you can uncomfortably converse)
  • Zone 2 exercise produces healthier for metabolically flexible Mitochondria (can process glucose and fat efficiently)
  • When we age, number and quality of our Mitochondria decline
  • Aerobic exercise creates new and more efficient Mitochondria. (Mitochondrial Biogenesis)
    • Other “bad” mitochondria are recycled (mitophagy aka autophagy for mitochondria)
  • Glucose uptake massively increases during exercise
    • exercise triggers Non Insulin Mediated Glucose Uptake (NIMGU)
    • can be effective in battling diabetes (body bypasses insulin resistance)
  • Zone 2: ride a stationary bike, walk or jog , swim laps
    • Check intensity – can talk in full sentences but just barely
  • Zone 2: 3 hours per week (four 45 minute sessions) to derive a benefit
  • Attia does 1 hour on stationary bike, 4x a week (at zone 2 threshold)
  • Measure your watts while you bike
    • take average wattage for workout and divide by weight: e.g. 125 watts avg / 60 kg weight = 2 watts / kg
    • 2 watts per kg for reasonably fit person
    • 3 watts per kg for very fit person
    • professional cyclist 4 and greater
  • Zone 2 will produce more BDNF also (Brain Derived Neurotrophic Factor)
  • Zone 2 workouts should be the foundation of your workouts 

Maximum Aerobic Output: VO2 Max

  • high intensity
  • hard minutes long effort 
  • aerobic combined with anaerobic
  • want to be at our max rate of O2 consumption
  • you want to work on this once you have a good zone 2 workout foundation in place
  • what is your VO2 max?. You should know.
  • have to wear a mask. Pain in the ass. Painful. 
  • Age-related Decline In VO2max (Video by Jayson Gifford)
    • VO2 max rapidly (steeply) declines with age
    • and corresponds to a reduced functional capacity (to climb stairs etc.)
{wymhacks – VO2 Max Chart}

    • Must keep you VO2 Max as high as possible so you can do basic functional stuff as you get older!
  • VO2 Max will decline roughly 10% per decade (and more when you are over 50!)
  • VO2 Max less than 18 ml/kg/min (for men; 15 for women) challenges your ability to live on your own. 
  • VO2 Max improvements will make you “functionally younger”.
  • VO2 Max can “always by improved by training”
{wymhacks: Table – VO2 Max vs Age for Women and Men} 

  • Using table above. If you are a man in your 60s
    • Lets say you are above average with VO2 Max of 29.75 (~30).
    • If you increased this to 35, its now equivalent to an average person 10 years younger
  • So, you want to do VO2 max work along with your Zone 2 workouts
  • VO2 Max workout recommendations
    • Can do the workouts on a bike, rowing machine, or treadmill, or outside on a track
    • warm up and cool down adequately
    • Go 4 minutes at a maximum pace (that you can sustain)
    • Then rest walk, jog easy for 4 minutes.
    • Repeat four to six time
    • For Attia: zone 2 is 150 watts, VO2 max training at about 200 watts
    • A single workout a weak could suffice
  • In the end you want to be :really good at going slow for a long time but to also
  • be able to run hard and fast when needed”.
  •  You have to do this now to preserve your range of functions in later years.
Strength
  • Muscle mass starts declining as early as our 30s. 
  • 80 year old will have about 40% less muscle than when he was 25. 
  • Per Andy Galpin, we lose muscle strength 2 to 3 x as fast as losing muscle mass
  • We lose power (strength x speed) 2 to 3 x faster than we lose strength.
  • Due to the “atrophy of our fast twitch type 2 muscle fibers”.
  • Extreme Muscle loss: Sarcopenia. Indicator of Frailty. 
  • Frailty: when you meet 3 of these 5 criteria
    • unintended weight loss
    • exhaustion or low energy
    • low physical activity
    • slowness in waling
    • weak grip strength
  •   Attia tracks Bone Mineral Density (BMD) – hips and lumbar spine (yearly in his patients)
    • Using DEXA
    • DEXA also measures body fat and lean mass
  • Bone density “diminishes on a parallel trajectory to muscle mass”
  • “1/3 of people over 65 who fracture their hip are dead within a year”
  • Check your BMD every few years. 
  • Attia tests for BMD in middle aged persons. If there is a problem, possible options are:
    • optimize nutrition (protein)
    • implement heavy load bearing activity (stimulates bone growth and strength) – estrogen involved.
    • Hormone Replacement Therapy (HRT)
    • Drugs to increase BMD
  • How much heavy things you can carry is important
    • dumbbells, kettlebells, sandbags
    • rucking – carry weight in a backpack or other strap on device (see Michael Easter)
  • Attia trains to improve the following
    • Grip Strength
    • Focus on both concentric (muscles shorten) and eccentric (muscles lengthen) loading (lift weight and put it back down)
    • Pulling motions
    • Hip hinging movements (deadlift and squat, step ups, hip thrusters, etc.
  • Grip Strength
    • Predicts how long your going to live
    • Farmers Carry (carry dumbbells around) – keep shoulder blades down and back
    • Dead hang from a pull up bar for as long as you can (you should be able to hang for 2 minutes)
  • Concentric and Eccentric motion
    • Concentric – Shorten (e.g. curl dumbbell to shoulder)
    • Eccentric – Lengthen (e.g. extend dumbbell back to start)
    • Step on and off an 19 inch block (with 3 second step down)
    • Eccentric strength is where you typically need work
    • For Eccentric, focus on the down phase of lifts
  • Pulling
    • Rows or pull ups
    • Rowing machine
  • Hip Hinging (bend at hips; not spine)
    • Focus on Gluteus Maximus (Butt) and Hamstring
    • start with single leg step ups (to begin)
    • split stance Romanian Deadlift with no weight or light weight (to begin)

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Part III – Chapter 13 – The Gospel of Stability

  • It’s important to move correctly during exercise and avoid injury.
  • Stability is “the subconscious ability to harness, decelerate or stop force.”
  • We are interested in “how efficiently and safely force can be transmitted through something”
  • Goal: “be strong, fluid, flexible, and agile”
  • Beth Lewis (Michael Stomsness) a good resource on Stability
  • DNS; Dynamic Neuromuscular Stabilization
    • based on moves we make when we are babies
    • developed by Czech neurologists working with kids with cerebral palsy
    • Goal: Re-train body in this natural movements
    • Michael Rintala – expert
    • rehabps.com (DNS)
    • posturalrestoration.com  (PRI)
    • {wymhacks – Functional Range Conditioning – FRC ?}
  • Attia Routine:
    • Twice a Week, 1 hour dedicated stability training
    • 10 to 15 minutes on other days
  • Stability Begins with the breath.
  • Deep , Steady breathing “activates the calming Parasympathetic Nervous System”
  • “Rapid, Ragged breathing triggers the Sympathetic Nervous System (part of flight or fight response).
  • Breath Test 
    • Lie on your back, 
    • one hand on belly and
    • other hand on chest,
    • Breath normally.
    • Notice movement of hands.
    • Both hands show move together.
    • See “Breathing on the Ground with Hands on Stomach and Chest” Video
    • ?Breath Test – Mr. Stay Puft – Upper chest breather
    • ?Breath Test – Sad Guy –  Lower chest breather?
    • ?Breath Test – Yogini – all around messed-up breather?
    • I personally did not get much out of the breathing sections except that you probably need a coach who has DNS experience
  • Breathing Exercise
    • On your back, breath in quietly, deeply
    • Exhale fully through “pursed lips” for “max. compression” ?
    • Do 5 breaths;  do 3 sets of 5
  • DNS
    • think of chest all the way to pelvis as a cylinder
    • When inflated this is IAP (intra abdominal pressure)
    • Important to pressurize properly because it stabilizes spine
    • Every day practice filling up this cylinder along its full surface and exhale
    • think of pressure stability of a cylinder full of air (with cap on when inhaling)
  • The Feet
    • we “channel force through our feet”
    • feet should be “flat, grounded, stable, and strong, to support..weight”  
  • Toe Yoga
    • See “Toe Yoga” Video
    • With foot firmly down, raise all five toes and spread out.
    • Then Raise Big Toes Only, with other downs.
    • Then Raise other four, keeping big toes down.
  • Pronation – inward pointing feet – bad
  • Supination – outward pointing feet – bad
  • Both above can cause plantar fasciitis and knee injury.
  • Foot one in front of other Balance Exercise.
    • close eyes, hold position for 10 seconds, very tough
    • ability to balance on one leg is correlated to longevity (like grip strength)
  • Spine
    • lumbar (lower back)
    • thoracic (mid back)
    • cervical (neck)
    • You should do Cat/Cow Process
    • Exhale – Flexion (Cat) – On all your fours – Head down, Back arched like top of C.
    • Inhale – Extension (Cow) – all fours – Head up, Back arched down
    • Slowly Move along one to the other smoothly each spine segment at a time
  • Shoulders
  • Hip Hinging 101
    • Step Up Video
      • 12 to 16 inch step up
      • step up (tripod of foot firmly down)
      • While inhaling , Shift body forward (head, ribs, pelvis)
      • Front knee behind toes
      • Lift back foot wile exhaling and bring it slightly ahead of other foot (should have finished exhaling also)
      • Hold for a second two. 
      • Shift forward as you bring the foot back down to the ground
      • Slow tempo (3 seconds from step off to landing)
      • 5 to 6 reps on each side
      • Only body weight first, with dumbbells later.
  • Barry Get Up Video
    • Getting up from a sitting position

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Part III – Chapter 14 – Nutrition 3.0

  • Goals for Nutrition 3.0. Are you
    • “undernourished or overnourished?”
    • “undermuscled or adequately muscled?”
    • “metabolically healthy or not”
  • Strategies for maintaining good health versus correcting bad health will be different
    • e.g. restricting diet to battle obesity versus a balanced diet in a healthy person
  • Basic Rules for Nutrition
    • control calories
    • consume sufficient protein and fats
    • get the vitamins and minerals you need
    • avoid pathogens (e.g. E. Coli) and toxins (e.g. mercury)  

What We Sort of Know About Nutritional Biochemistry

  • Nutrition knowledge comes from epidemiological studies or clinical trials
  • An epidemiological study looks at how often diseases occur in different groups of people and why.
    • A nutritional study for example would investigate the relationship between diet and health outcomes
  • Epidemiological Studies
    • Cannot distinguish between Correlation and Causation
    • Epidemiology is incapable of determining the “direction of causality”
  • Bradford Hill Criteria
    • 1950s ; Came up with 9 criteria to
    • evaluate strength of epidemiological study and
    • direction of causality 
  • Experiments
    • help understand causality.
    • Hard to do in nutrition. Easier to do for exercise studies.
  • In nutritional epidemiological studies, Effect Size (power of association) is often too low to prove causality according to Attia
  • {wymhacks – What is too low?  Is a Hazard Ratio of 1.17 too low?}
  • Quality of data in many of these studies might be low
  • {wymhacks – See articles / videos by John Ioannidis on bad epidemiological studies}
  • Confounding in epidemiological studies is a big issue
    • In epidemiology, confounding happens when a third, unmeasured factor distorts the apparent relationship between an exposure and an outcome.
    • General health can be a big confounder in these studies (Healthy User Bias)
    • e.g. People drink in older age because they are healthy (as opposed to drinking making them healthy)
    • e.g. People who drink no alcohol might have other health reasons for doing so
  • Epidemiological studies observe patterns in populations to find associations, while
  • clinical trials actively intervene to test the effects of specific treatments.
  • Clinical trails are more rigorous than Epidemiological studies but they are still flawed.
  • Controlling clinical trials is difficult.
  • Clinical trials for Mediterranean diet show a clear advantage. (PREDIMED).
  • There is a Large degree of variation among individuals in diet and nutrition studies. 
  • e.g. Diet might work for some but not others

{wymhacks – See my post Diet and Fitness Plan}

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Part III – Chapter 15 – Putting Nutritional Biochemistry to Work

Standard American Diet (SAD)

The SAD environment is

  1. Plentiful
  2. Inexpensive
  3. Preserved
  4. Palatable
  • Consumed in excess, the SAD harms us. 
  • Evolution has not prepared us for the plentiful calories from the SAD.
  • Our bodies will readily become fat as glucose spills to fat
  • Leading source of calories in SAD: grain based desserts (pie, cake etc.)
  • SAD “wages war on our metabolic health”
  • Almost all diets employ
    • Caloric Restriction (most efficient)
    • Dietary Restriction (most common)
    • Time Restriction (intermittent fasting)

CR: Caloric Restriction – Calories Matter

  • Too many calories end up as fat
  • which can spill over into our organs, viscera, and muscle (See Chapter 6)

  • Eating fewer calories lengthens lifespan (in lab animals)
  • Monkey Studies (2009 U of W Madison, 2012 NIH)
    • Eliminating junk food (avoiding diabetes etc.) helps longevity
    • Strong link between Calories and Cancer
    • Quality of Food is as important as quantity
    • A high quality diet might mean a normal diet is sufficient (no caloric restriction) to maintain health.
    • Limiting calories will help people who are metabolically unhealthy (and/or overnourished)
    • Limiting caloric intake AND improving diet quality helps

DR: The Nutritional Biochemistry Diet

{wymhacks – See my post Macro Molecules, Minerals, and Vitamins; A Primer}

Alcohol
  • 7 kcal/g (versus 9 kcal/g for fat and 4 kcal/g for protein and carbohydrates)
  • Has zero nutritional value
  • Ethanol oxidation Delays fat oxidation
  • Causes mindless eating
  • Ethanol is carcinogenic
  • Chronic drinking associated with Alzheimer’s
  • Metabolized in liver (bad for chronic drinkers)
  • Attia: Limit to 7 servings/week, no more than 2 a day
Carbohydrates
  • Carbohydrates digested to Glucose then converted to ATP
  • Extra glucose in muscles and liver as glycogen or in adipose tissue as fat
  • Insulin secreted when glucose in blood increases (to bring it back down)
  • Excess calories can cause NAFLD to insulin resistance to type 2 Diabetes (see Chapter 6)
  • Repeated blood glucose spikes could be bad in themselves
  • Correlated to longevity (mortality)
  • Different in each person (key point)
  • Continuous Glucose Monitoring (CGM) – device that tracks blood glucose levels
  • More accurate than HbA1c blood test
  • Available only by prescription (?)
  • Useful to track your food and see which ones spike your glucose
  • Goal: lower average blood glucose level and reduce variability
  • Target: keep average glucose <= 100 mg/dl (milligrams per deciliter) with a standard deviation of 15
  • 100 mg/d = HbA1c of 5.1% (pretty low)
  • Influenced by level of activity and sleep
  • Stress elevates Cortisol, causes liver to secrete glucose into blood
  • Attia will also test and track patients for weight, body composition (lean mass and fat mass)
  • Attia will also track biomarkers like lipids, uric acid, insulin and liver enzymes. 
  • Lessons from Continuous Glucose Monitoring
    • Glucose spike higher/faster for more refined Carbs.
    • Bread with fiber blunts the spikes
    • Rice and Oatmeal with cause Glucose Spikes (including brown rice)
    • Fructose not measured by CGM
    • Aerobic exercise best for removing glucose from blood
    • High intensity exercise and weight training tends to spike glucose (liver squirts glucose to feed the muscles). Attia says don’t worry about these spikes (why?)
    • Sleeping less will spike your glucose more (5 or 6 hours versus 8)
    • Stress via cortisol (especially during sleep) can spike glucose. 
    • Non-starchy veggies like spinach and broccoli wont spike glucose
    • High protein and high fat food wont spike glucose
    • Large amounts of lean protein will (chicken) slightly spike glucose
    • Protein shakes might spike your glucose depending on what’s in them (i.e. low in fat and with sugar)
    • Stacking of these things will make it worse
    • Tracking glucose might improve our eating behavior due to Hawthorne Effect (you behave because you are being watched so to say). 
Protein
  • Protein (Amino Acids) are the building blocks of life  (need for muscle and structure).
  • As we age we lose muscle faster.
  • Not a primary source of energy and isn’t stored like fat
  • Excess is excreted in urine (urea).
  • 20 amino acids are the building blocks for muscle, enzymes, hormones.
  • makes up Hair, Skin, Nails, immune system molecules, etc.
  • 9 (Essential) amino acids must be ingested via food because our bodies don’t make them.
  • Attia: Recommended Daily Allowance = .8 g/kg body weight is too low.
  • In the elderly, low protein = low muscle mass = greater mortality = worse quality of life
  • Attia: 1.6 to 2.2 g/kg body weight should be protein target.
  • For active people with normal kidney function target might be 1 gram/lb weight (2.2 g/kg)
  • So if you weigh 150 lb, that’s 150 g of protein (that is a lot of protein to eat)
  • Ideally consume it in 4 servings a day.
  • Attia’s: Why protein shake + high protein snack + two protein meals
  • Plant Protein: 60 – 70 % utilized by your body (see Don Layman)
  • Plant Protein has less essential amino acids (methionine, lysine, tryptophan)
  • So overall quality of protein from plants is significantly lower than from animal protein.
  • Layman – Leucine and Lycine (3 – 4 g/d); Methionine (at least 1 g/day)
  • Need more Leucine if you are building up muscle mass (2-3 g, four times a day)
  • Healthy Aging and Body Composition Study
  • Protein might improve insulin sensitivity and glucose control.
  • Protein helps us feel satiated, inhibiting the release of hunger inducing hormone ghrelin (we then eat few calories).
Fat
  • They are efficient fuel for oxidation (slow burning logs)
  • Building blocks for hormones (through cholesterol) and cell membranes
  • Important for health of brain (most of which is made up of fatty acids).
  • Saturated Fats (SFA)
    • saturated with hydrogen (more hydrogen)
  • Monounsaturated Fats (MUFA),
  • Polyunsaturated Fats (PUFA),
    • Omega-6
    • Omega-3 – Marine Sources (EPA, DHA) – Seafood
    • Omega -3 – Non Marine Sources (ALA) – Nuts, flaxseed
  • Trans Fats (largely removed from diets)
  • Fatty Foods always have mixtures of SFA, MUFA, PUFA
  • Attia for his patients:
    • target 50%-55% of fat as MUFA;
    • 15-20% as SFA; 
    • Remaining is PUFA
    • Try to boost EPA, DHA (for brain and cardiovascular health)
  • Test for EPA , DHA in membranes of red blood cells (specialized blood test)
  • Like to see 8 – 12% of RBC membrane composed of EPA and DHA
  • Attia patients
    • eating more olive oil, avocados, nuts
    • reducing omega-6 rich corn, soybean, sunflower oils
    • increase high omega-3 marine PUFAs
  • Studies on fats don’t overwhelmingly correlate superiority of one over the other but in general
    • MUFA is best , then PUFA, then SFA 
  • Attia uses “expanded lipid panels” with his patients to track fatty acid consumption and cholesterol and “overall lipid and inflammatory response”
  • {wymhacks – Standard Lipid Panel –
    • measures total cholesterol,
    • LDL cholesterol,
    • high-density lipoprotein (HDL) cholesterol and
    • triglycerides.}
  • {wymhacks – Two commonly used advanced lipid tests are
    • apolipoprotein B (ApoB; See Chapter 7) and
    • LDL particle number (LDL-P).}

TR: The Case for (and Against) Fasting

  • Fasting or Time Restricted (TR) eating
  • Some good things happen when we are not eating
    • Insulin drops
    • liver starts depleting fats {wymhacks: 24 hours?} 
    • Within 3 days, starvation ketosis – fat used, ketones produced
    • Longer term , mTOR turned down (see Chapter 5)
    • Autophagy accelerated (cellular recycling process)
    • Activates FOXO (cellular repair genes that may be helping Centenarians live so long) – See Chapter 4
  • Scientific Literature on the topic is still weak
  • Short Term Fasting
    • Eat food in a 6 or 8 hour window
    • Probably need a tighter window
    • Probably need 6 or 4 window
    • Mice studies probably not valid
    • Human trials don’t find much of a benefit
    • Meeting protein targets will be difficult
    • Maybe beneficial in reducing snacking (which Japanese call lonely mouth)
  • Alternate Day Fasting (ADF)
    • Studies and tests not that conclusive
    • Might lose muscle and your activity is reduced
    • Attia: neither necessary nor wise
  • Need to eat enough to maintain muscle mass and remain sufficiently active
  • Attia uses fasting for extreme cases where there are few other options
    • e.g. Patient Tom Dayspring
    • One week per month severe caloric reduction diet 

Conclusion

  • Diet and Nutrition is important but is not the strongest lever for longevity
  • “Bad nutrition can hurt us more than good nutrition can help us”
  • Must balance caloric intake with meeting your Protein needs.
  • Zone 2 Aerobic (long, steady type) enhance body’s ability to utilize glucose and fat
  • Avoid fructose sweetened drinks (sodas and fruit juices) – Safe way to get fructose is directly from fruits.
  • Diet plan improves or maintains
    • blood glucose and insulin
    • muscle mass
    • lipid level
    • weight
  • Your diet depends on your risk profile for
    • metabolic dysfunction – e.g. excess carbs leading to elevated triglycerides
    • cardiovascular disease – e.g. lipoprotein issues
  • Attia suggests (in general) that staying active and working out should be your main effort. 
  • Use your diet as an additional supporting weapon to improve your lifespan and healthspan. 

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Part III – Chapter 16 – The Awakening

  • Many studies show getting less than 7 hours a night is powerfully associated with bad health outcomes
    • get common cold easier
    • dying of a heart attach
    • increased metabolic dysfunction up to Type 2 Diabetes
    • upsets hormonal balance
    • affects our cognitive functions, memories, and emotions
  • While sleeping , your brain dreams and even cleans itself (similar to people sweeping city streets)
  • Sleep preserves our cognition as we age and perhaps staves off Alzheimer’s Disease.
  • See Mathew Walker podcasts with Attia and read his book Why We Sleep.
  • “Why would evolution allow us to spend up to a third of our lives in a state of unconsciousness?”
  • “Sleep is as fundamental to our health as stability is fundamental to strength”.
  • Many studies: Need to Sleep 7.5 to 8.5 hours a night.
  • Affects our physical and cognitive performance (even one bad night).
  • Lack of sleep increases odds of injury.
  • Lack of sleep affects ability to drive.
  • Danger is your body and mind can adapt to less (at its own peril).

Old Man Blood

  • Navy Seals bloods tests showed hormone levels and inflammatory markers more common in much older men.
  • Poor sleep “wreaks havoc on our metabolism”.
  • Multiple studies: Poor sleep can cause major insulin resistance.
  • Eve van Cauter – Sleep Scientist
  • Inadequate sleep can “tilt” us towards Metabolic Dysfunction.
  • Linked to Type 2 Diabetes
  • Longer than recommended sleep can also be bad.
  • 11 or more hours of sleep might increase risk of all cause mortality.
  • Stress has something to do with this.
  • Higher Stress can make us sleep poorly but also vice versa.
  • Poor Sleep; High Stress: Both activate the Sympathetic Nervous System (SNS).
    • Fight or Flight response
    • Releases Glucocorticoids including Cortisol.
  • Cortisol
    • Raises blood pressure.
    • Causes liver to release glucose.
    • Inhibits uptake / utilization of glucose by muscles and fat.
    • High overnight glucose on a CGM (continuous Glucose Monitor) usually means high Cortisol.
  • Food
    • Lack of Sleep (4 to 5 hours) reduces Leptin levels.
    • Leptin hormone signals to us that we are fed.
    • Lack of Sleep increases Ghrelin (hunger hormone).
    • {wymhacks: Mnemonic – Leptin Lowers Hunger,  Ghrelin Gains Hunger}
    • Coming off of a poor sleep causes you to be excessively hungry.
    • Lots of time people get this through junk food.
    • Perfect recipe for NAFLD and Insulin Resistance. 

Sleep and Cardiovascular Disease

  • Sympathetic Nervous System (SNS)
  • Threat Perception causes
    • Cortisol secretion
    • Adrenaline secretion
    • Raise heart rate 
    • Raise blood pressure
  • Lack of Sleep activates the SNS
  • Can cause higher heart rates and increases irregularities
  • So increased risk of heart attacks
  • Two studies: < 6 hr sleep associated (tougher to prove causality) with 6 to 26% increase in cardiovascular disease.
  • Study: < 6 hr sleep = 20% increase in risk of heart attack and sleeping 6 – 9 hrs reduced risk of heart attack.

Sleep and the Brain

  • Sleep important for cognitive function and long term cognitive health.
  • Some research: Chronic bad sleep causes Alzheimer’s Disease and Dementia.
  • When we Sleep
    • Heart rate slows down
    • Core temperature drops
    • Breathing becomes regular
  • Sleep Stages (analogy of a submarine)
{wymhacks – Hypnogram – Sleep Stages – Normal Healthy Adult}

    • Initial Sleep (submarine slips beneath the waves)
    • Rapid descent to Deep Sleep.
    • Deep Sleep: Non-REM or NREM (Non Rapid Eye Movement) sleep
    • Two substages: Light NREM and Deep NREM
    • Cycle between these
    • Deep NREM: Brain waves slow, reaching a very low frequency (1-4 cycles per second)
    • Dominates the first 1/2 of the night.
    • REM Sleep: Eyeballs dart around as we dream {wymhacks: we are fucking seeing things}
    • Electrical signature of REM sleep is similar to when we are awake. 
    • Difference is our bodies are paralyzed.
    • {wymhacks: Ever had one of those can’t get up or can’t escape dreams?}
  • Deep Sleep
    • Short term memories in Hippocampus cleared out or stored in Cortex.
    • Getting a good sleep is correlated with doing better on memory tests.
    • Keeps our brain healthy
    • Cerebrospinal fluid into neuron areas that sweeps away “intercellular junk”. 
    • Deep Sleep washes the brain (e.g. the Amyloid Betas and Taus – linked to neurodegeneration – See Chapter 9)
    • Studies: Chronic under sleep (<7 hrs) results in buildup of Amyloid Beta and Tau. 
  • REM Sleep
    • In youth, helps brain grow and develop
    • Developing neural networks
    • Plateaus in Adults but important for creativity and problem solving
    • Good for procedural memory (e.g. new ways of moving body)
    • Emotional memories are processed (always feel better in the morning)
    • So helps with controlling anxiety
    • Helps us maintain emotional awareness
  • Up to 1/2 people with Alzheimer’s Disease have Sleep Apnea. 
  • “Sleep disturbances may create conditions that allow Alzheimer’s to progress.”
  • “Superior sleep quality in older adults associated with a lower risk of developing MCI (Mild Cognitive Impairment) and Alzheimer’s. “
  • Irregular or fragmented sleep is bad for the brain
  • Ability to get deep sleep declines with age .
  • Possibly related to growth hormone secretion changes
  • Good sleep in middle age (40s to 60s) seems to be important for “maintaining cognitive health”.

Assessing Your Sleep

  • Morphine puts people to sleep (bad for other reasons, addictive, etc.)
  • Ambien (zolpidem) and Lunesta do not promote healthy long lasting sleep.
  • Orexin Antagonist Inhibitors (Dayvigo and Quviviq) – promising but expensive medicines for insomnia
  • Benzodiazepine Drugs (Valium, Xanax – sometimes used to treat insomnia) – typically don’t improve sleep quality.
  • Trazodone – anti-depressant – helpful for sleep and quality
  • Ashwagandha – helps with sleep quality also
  • No drug magic bullet today for sleep
  • Things to do to improve sleep

Sleeping Better

You obviously will have to address your Sleep Apnea or other specific problem more specifically, but here are some things you can do to improve your sleeping.

  • Create Environment conducive to sleeping (darkness)
    • Turn off all your shit (no lights)
    • Non natural lighting blocks release of melatonin. (darkness activated hormone that helps with sleep)
    • Similar to way that SAD (Standard American Diet) interferes with satiety hormones
    • Don’t stare at your devices before you go to bed (at least an hour before bedtime)
  • Keep the bedroom cool (65 F is optimal…{wymhacks: fuck…that’s cold , dude})
  • Cut back on Alcohol (not good for REM sleep; affects your memory)
  • Coffee – inhibits receptor for adenosine (helps us go to sleep)
  • 1/2 life (concentration drops by 1/2) of Coffee is 6 hours
  • We need to cultivate Sleep Pressure (our need or desire for sleep)
    • Napping counteracts this
    • Exercise helps with Sleep Pressure (especially Zone 2 endurance exercise)
  • Exercise with exposure to sunlight (1/2 hour dose of strong daylight helps keep our circadian cycle on track
  • Mentally prepare yourself for sleep (avoid stressful things – turn down Sympathetic Nervous System)
    • Meditate
  • How to Improve Your Sleep List
    • No alcohol (or one drink before 6 pm)
    • Dont eat inside 3 hours
    • No stimulating electronics (inside 2 hours)
    • No anxiety producing work (inside 2 hours)
    • Spend time in Sauna or Hot tube before bed
    • Cool room (mid 60s F) – use cool mattress
    • Darken room completely – use eye shade if necessary
    • Fix your wake up time – dont deviate much from it
    • Target 8 hours of sleep
    • Don’t obsess over your sleep
  • If you still can’t Sleep
    • Stop fighting it. Get up. Drink non caf tea and read a boring book.
    • Key is find something relaxing and enjoyable but serves no function
    • Check your chronotype (are you a night owl?). Adjust your sleeping.
  • If Sleeplessness Persists
    • Do Cognitive Behavioral Therapy for Insomnia  CBT-I.

Attia considers sleep a “performance enhancing substance” for physical and cognitive health. 

Your Evolution has required it so optimize it for a longer lifespan and healthspan. 

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Part III – Chapter 17 – Work in Progress

  • “Emotional health and physical health are closely intertwined”
  • Suicide obviously impacts lifespan
  • Suicide among top 10 cause of death among all age groups
  • CDC: >100,000 Americans (April 2020 to April 2021) died from drug overdoes (as much as from Diabetes)
  • Drug overdoses account for 40% of accidental deaths
  • Emotional Health: Maybe the most important component of healthspan
  • Without happiness, fulfillment, connection to others, its not worth it
  • Living alone or being lonely is linked to much higher risk of mortality. 
  • Trauma categories
    • Abuse 
    • Neglect 
    • Abandonment 
    • Enmeshment (blurring of boundaries between adult and children)
    • Witnessing tragic events
  • Most therapists diagnose people using The DSM
    • Diagnostic and Statistical Manual of Mental Disorders
  • Can always find a tidy diagnosis
  • See Podcast with Paul Conti
  • Hard to give blanket advice 
  • Problem with Medicine 2.0 today
    • Diagnose
    • Prescribe
    • Bill
  • Mental health and emotional health are not the same thing
  • Mental Health – Disease like states (clinical depression, schizophrenia)
  • Emotional Health – Much broader including how to manage emotions and interpersonal relationships
  • We should address Emotional Health earlier on
  • Must be proactive
  • Hard to recognize signs that you might need that Emotional help
  • Book: “I don’t want to talk about it” – By Terrence Real – Roots of male depression
  • Consider therapy
  • “90% of male rage is helplessness masquerading as frustration”.
  • think of relationships as a “delicate ecosystem”
  • Attia corrections
    • spend time with kids
    • check in with wife on her stuff
    • reframe things: look at a situation from someone else’s point of view
    • and why is your situation more important than theirs
    • David Foster Wallace commencement class speech (Kenyon, 2005)
  • Power of Reframing
    • “Step back, temper your reflexive actions, try to see what is actually happening. “
  • David Brooks: The Road to Character
    • Resume Virtues – your living CV
    • Eulogy Virtues – what people say about you when you die (focus on these)
  • Who cares how well you do if you are miserable all the time?
  • PCS – Psychological Counseling Services – Phoenix Arizona
  • Listing Affirmations is helpful (one positive affirmation for each year of your life)
  • Jacob Riis:
    • “When nothing seems to help, I go back and look at a stonecutter hammering away at his rock perhaps a hundred times without as much as a crack showing in it. Yet at the hundred and first blow it will split in two and I know it was not the last blow that did, but all that had gone before.” 
  • “True recovery required probing the depths of what shaped you, how you adapted to it, and how those adaptations are now serving you” (or not)
  • Be proactive. Look for problems early.
  • Dialectical Behavior Therapy (DBT)
    • Marsha Linehan
    • Cognitive Behavioral Therapy Principles
    • Clinical trials show it helps prevents suicide and self harm
    • Skills based; 
    • Specific Skills,
    • Practiced repeatedly
    • Under stress.
    • Break chain of Negative (-) Stimulus to (-) Emotion to (-) Thought to (-) Action
    • Mindful approach to deal with
    • Emotional Regulation,
    • Distress Tolerance,
    • Interpersonal Effectiveness,
    • Self Management.
  • For DBT Distress Tolerance Attia
    • Many of the practices discussed in the book help to maintain and widen this
  • Mindfulness helps with Reframing.
    • Create a gap between stimulus and response to avoid acting reflexively.
    • Suffering often not due to direct cause (more like past or future event).
    • Seneca: “We suffer more often in imagination than in reality.”
    • Listen to your self talk.
  • DBT Emotion Regulation
    • {wymhacks –  Have to dig deep and understand the real cause in order to control and regulate it.}
  • DBT Distress Tolerance
    • Use counter acting techniques that stimulate the Cranial Vagus Nerve. 
{wymhacks – Vegus Nerve}

    • Vagus Nerve controls heart rate and respiratory rate in or out of Parasympathetic (calm) or Sympathetic Mode (fight or flight) .
    • Ice water in face or take cold shower,
    • Slow Deep Breathing (4 second inhale, 6 second exhale),
    • {wymhacks – Based on link above – exercise regularly, Massage yourself (e.g. feet), Listen or Create Music}
    • Attia Rucks (walking with weighted vest or backpack) to help with emotional health.
  • DBT Opposite Action
    • Do reverse of something bad that you are about to do
    • “Changing the behavior can change the mood“.
  • Attia says that regular therapy is probably his most important tactic of all.

Concluding Remarks

To fix Emotional Issues, you have to first believe that you can change.

Believe that It’s ok to be vulnerable and to ask for help.

Paulo Coelho:

  • “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” 

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{wymhacks – Conclusion}

This article summarizes Peter Attia’s “Outlive” but also provides a human biology primer through linked supplementary explanations. 

It aims to clarify the book’s key points and enhance understanding of the related biological concepts.

My general takeaways from the book are:

  • Maximize your Healthspan!

    (i.e. Aim to die without having suffered any debilitating chronic disease or ailment)

  • Be aware of and work on your mental health.
  • As you age, it’s even more important that you exercise habitually and comprehensively.
    • Work on your balance and stability.
    • Exercise to maintain / increase your muscle mass and strength.
    • Do long endurance and short high intensity workouts periodically.
  • Work on your diet to ensure
    • you don’t cause fat spillover into your guts and organs.
    • you get enough protein (it’s imperative that you maintain your muscle mass as you age).
    • There are no one size fits all dietary or drug / supplement regimes.
  • Optimize conditions to get quality sleep  (preferably 7.5 to 8.5 hours/day).
  • Re Alcohol: Don’t drink at all or minimize alcohol consumption (Ethanol probably causes cancer)

Peter Attia Articles / Podcasts

Explore Attia’s website where you can find articles, podcasts etc. : https://peterattiamd.com/

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Disclaimer: The content of this article is intended for general informational and recreational purposes only and is not a substitute for  professional “advice”. We are not responsible for your decisions and actions. Refer to our Disclaimer Page.

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