#517: Dr. Peter Attia On Longevity Drugs, Alzheimer’s Disease, And The 3 Most Important Levers To Pull | Tim Ferriss Show

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Key Takeaways

  • We haven’t made much progress in cancer outcomes but liquid biopsy technology has exciting potential and scalability for early cancer detection
  • “Be attune to all of the tools: caloric restriction, dietary restriction, time restriction – the three levers…always pull one, sometimes pull two, sometimes pull three – never pull none.” – Dr. Peter Attia
  • Strength training is critical during fasting to avoid losing too much muscle mass
  • Don’t guess whether weight loss is coming from muscle or fat – get regular Dexa scans to be sure, especially if fasting or time-restricted eating as a lifestyle
  • Pillars of exercise: stability, strength, aerobic efficiency, anaerobic performance
  • Dose of Zone 2 training: 3 hours per week in 45-60 minute intervals – best completed in a steady-state such as bike, rower, treadmill
  • The lower the Apolipoprotein B (ApoB) goes, the less risk of adverse health outcomes like atherosclerosis, Alzheimer’s disease, diabetes-related mortality, all-cause mortality
  • Time and time again, rapamycin has been shown to increase lifespan and healthspan in animal studies
  • “We don’t have a meaningful biomarker of aging. That’s full stop the biggest problem in again research today – nothing else matters.” – Dr. Peter Attia
  • It’s important to read scientific journal articles and research studies with a judicious eye – learn how to break it down properly to avoid succumbing to a narrative


Peter Attia, MD (@PeterAttiaMD) is a former ultra-endurance athlete and renowned physician in the field of longevity and performance. His practice and interests lie in optimizing nutrition, sleep, exercise, physical and mental health, and pharmacology to increase lifespan and healthspan. Peter is also the host of the popular podcast, The Drive.

Tim Ferriss and Peter Attia take a dive into all things longevity – from optimizing fasting and time-restricted eating, to promising advances in cancer detection, the three levers of health, and Alzheimer’s disease. They also dissect a couple of research studies and break down the key components to understanding scientific papers.

Host: Tim Ferriss (@tferriss)

More Ways To Follow: PeterAttiaMD.com

Liquid Biopsy For Early Cancer Detection

  • Liquid biopsy draws and tests a sample of blood for early cancer detection of 50 difficult to diagnose cancers – exciting because we’ve had very little success in advancing outcomes of cancer
  • Promising company: Grail (recently acquired by Illumina) uses “cell-free DNA” and methylation patterns
  • 50% sensitivity (true positive – the probability that cancer is truly there and is detected by test) and 70-90% specificity (true negative – the probability that cancer is truly not there if not detected by the test)
  • The sensitivity seems low at a glance but if you otherwise had a low likelihood of diagnosing a tough cancer (such as pancreatic cancer) – a 50% sensitivity is high
  • Idea is to use multiple technologies to cover the blind spots of others

Metabolic Health & Exercise

  • Keys in cancer prevention: (1) not smoking and (2) being metabolically healthy
  • Exercise is one of the most potent drugs we have
  • Pillars of exercise: stability, strength, aerobic efficiency, anaerobic performance
  • Stability: the ability to safely transfer the load to the outside of the body and vice versa
  • Many people have great hamstring strength but poor control
  • Wearing shoes all days has negatively affected our gait and posture
  • Common posture problem: pelvis tilts forward, ribs flare, erector spinal muscles are locked in concentric load, hamstrings tight and long
  • “Age exposes deficiencies and eventually everyone will pay a price.” – Dr. Peter Attia
  • Dynamic Neuromuscular Stabilization (DNS) training: starting from the foundation and emphasizing breathing patterns then building up and working on progressions
  • Postural restoration institute (PRI): a school of thought to fix breathing patterns from the feet all the way up
  • Sitting has probably contributed to poor breathing and stability because it’s easier to rely on accessory movements of respiration

Zone 2 Training

  • Zone 2 training: “all day pace” where the highest level of output you can produce while maintaining below 2 millimole
  • In the presence of oxygen the body can use glucose or fat for energy during aerobic activity
    • An efficient engine can run on both glucose and fat
    • A broken engine can only run on short-term fuel (glucose)
  • As you exert yourself more, lactate rises
  • The glucose system is the first system to cave as intensity increases  
  • Bike, rowing machine, or treadmill are best for Zone 2 training because you want to be in a steady-state
  • The goal of Zone 2 training: increasing the ability of mitochondria to utilize substrate, therefore, increasing the ability of the muscle to take in more oxygen
  • Still under study but looks like the ideal dose for Zone 2 training is 3 hours per week in 45-60 minute intervals
  • Factors that affect Zone 2 training: sleep, hydration, energy, heart rate
  • Heart rate zone calculation for Zone 2:
    • Method 1: 180 – age = HR (beats per min)
    • Method 2 (for those who exercise regularly and monitor heart rate): 78% of max HR
  • The sweet spot of Zone 2 training: you should be able to carry out a conversation but wouldn’t want to

Using Fat For Energy

  • The advantage of the ketogenic diet is you can be satiated without eating a lot
  • Ketosis forces your body to use fat for energy
  • Ketosis is not automatically a weight loss diet – it only works if your body uses endogenous fat stores

The Three Levers Of Nutrition

  • Three levers of diet:
    • Time restriction: restricting when you eat but not what you eat
    • Dietary restriction: restricting content (e.g., avoiding wheat, meat, etc.)
    • Caloric restriction: restricting how much you eat
  • “Be attune to all of the tools: caloric restriction, dietary restriction, time restriction – the three levers…always pull one, sometimes pull two, sometimes pull three – never pull none.” – Dr. Peter Attia
  • If you aren’t pulling one of the levers – you are consuming the Standard American Diet and it doesn’t end well for most people  
  • Time-restricted eating: going without food for a period of hours instead of days (i.e., 16-18 hours)
  • Daily time-restricted eating has to be taken in context – it’s not always worthwhile to lose muscle mass unless you are obese or significantly overweight and dealing with metabolic syndrome
  • Ideal use of time-restricted eating: wake up, exercise, eat a big breakfast (biggest meal of the day), eat modest lunch – then stop eating
  • It’s tough to skip dinner: (1) socially tough because dinner is the meal we tend to gather; (2) it’s hard to go to bed hungry
  • Tip: Use Dexa scans to monitor muscle and fat percentages, particularly visceral fat

Avoiding Muscle Loss While Fasting   

  • Strength training is critical during fasting to avoid losing too much muscle mass
  • If you aren’t training correctly, you’ll lose weight but with more muscle loss than desirable
  • Anecdotally, many people who report losing more muscle than fat while time-restricted eating or fasting  
  • In some cases, branch chain amino acids (BCAA) can be used as a supplement to help combat muscle loss while fasting
  • Use BCAA as a supplement if your goal is fasting for weight loss (Peter’s favorite BCAAs)
  • Use of BCAAs if you are using fasting for longevity benefits may be counterproductive  
    • If using fasting to facilitate autophagy it’s probably counterproductive to use BCAA because the amino acids used in exercise are the most potent stimulators of mTor (the purpose of fasting is in part to give mTor a rest)

How To Read Scientific Articles & Case Study 1: Psilocybin  

  • Statistical significance: asking the question, “what is the probability that the differences observed between these two groups is by chance?”
    • To obtain statistical significance, you must know the anticipated (a priori or before the study) effect size between the two groups
  • Power: is the probability of avoiding a Type II error and sets the standard for the study and participant enrollment numbers; the higher the power, the higher the standard
  • Effect size: magnitude of difference between groups; if you overestimate you will underpower the study
  • Note about clinical trials in the U.S.: to be NIH funded you have to state your primary objective (e.g., not just hitting a home run but hitting a home run over that wall) – in advance of the trial and pre-register (before funding) your primary objective at clinicaltrials.gov
  • Trial of Psilocybin versus Escitalopram for Depression by Carhart-Harris, et. al.
    • The study is flawed but worthwhile because it’s a head-to-head study of pharmaceutical gold standard versus psychedelic
    • Finding: no statistically significant difference between psilocybin and pharmaceutical
    • Limitations: likely this study was underpowered
    • Though the study was presented as unsuccessful, it should actually be considered a success because while flawed the psychedelic was tied with the pharmaceutical
  • For more information about how to read scientific studies, check out the Studying Studies series by Peter Attia
  • MDMA as an antidepressant seems a little clearer:
    • Antidepressants for PTSD had a masking effect
    • MDMA is more about putting the individual in the correct state of mind to then receive the therapies and treatments needed

Our Understanding Of Cholesterol And ApoB

  • Every cell in our body makes cholesterol without it you will die in utero
  • Cholesterol makes the cell membrane of every cell & allows cells to have fluidity
  • Cholesterol is not water-soluble but needs to be transported across the body so needs more of a system – which is where lipoproteins come in
  • Lipoproteins are fat-soluble on the outside and water-soluble on the inside
  • Two families of lipoproteins: ApoB and ApoA (associated with “good cholesterol” HDL)
  • ApoB: consists of very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoprotein (LDL), and lipoprotein (a) or Lp(a)
  • The current model of cholesterol is too simplistic: in genera,l we say HDLs do not cause atherosclerosis and LDLs do – but so does anything with an ApoB on it
  • “ApoB is hands down the best biomarker we have for cardiovascular risk because it is the total concentration of all particles capable of producing atherosclerosis.” – Dr. Peter Attia
  • There’s no upside to having higher levels of ApoB
  • Benefits of low ApoB: reduces cardiac risk, reduces the risk of Alzheimer’s disease, and lowers all-cause mortality
  • A new class of drugs called PCSK9 Inhibitors inhibit LDL receptors on the liver and pull ApoB particles out of circulation and has been shown to reduce levels of ApoB with no side effects
  • PCSK9 Inhibitors are a bit cleaner than statins (though statins are well-tolerated and relatively safe)

Rapamycin, Metformin And Other Drugs For Longevity

  • Rapamycin is a naturally occurring, potent antifungal agent – which was discovered to have amazing anti-proliferating effects
  • Rapamycin was produced in 1999 for organ transplant patients to avoid rejection
  • Interventions Testing Program (NIH funded program that tests molecules aimed at enhancing longevity) tested rapamycin
  • Results: rapamycin fed late in life extends lifespan in mice
  • The protocol used by the Interventions Testing Program (ITP) has been replicated several times over with the same results
  • Other markers of healthspan (vision, hearing, heart damage) studies in mice have shown improvements with rapamycin as well
  • In human studies, rapamycin was shown to improve antibody response to the flu vaccine
  • On the flip side, Metformin has been shown to have longevity effects in people with diabetes but we’re not sure about effects in people without
  • When studied by ITP, metformin did not extend longevity
  • Acarbose has been shown to have longevity effects but is harsher to take and not likely to be as promising as metformin
  • Canagliflozin-SGLT2 Inhibitor: blocks reuptake of glucose so you pee it out and was shown to extend lifespan in mice  
  • “We don’t have a meaningful biomarker of aging. That’s full stop the biggest problem in again research today – nothing else matters.” – Dr. Peter Attia
  • Dry sauna: 4 sessions x 20 minutes at 175 degrees Fahrenheit
  • GLP1 agonist: originally for people with diabetes but was shown to lead to significant weight loss (20% body weight) in people with and without diabetes when administered once per week
    • Potential use for cycling (three months on, three months off)
  • Things that improve diabetes also improve health
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