Dr. Peter Attia: Fasting, Autophagy, and mTOR Inhibition – High Intensity Health

Check out the High intensity Health Episode Page & Show Notes

Key Takeaways

  • The only two interventions that really seem to offer longevity benefits are rapamycin supplementation and some degree of fasting
    • They both suppress mTOR (mechanistic target of rapamycin) and in turn increase autophagy
      • Autophagy is the process by which cells eat themselves – the dysfunctional cells (like cancer cells) tend to be “eaten” first
  • It’s currently impossible to measure the level of autophagy taking place in the body 
  • Fasting
    • Fasting is the single most potent tool in our toolbox of nutrition
    • Peter estimates that around day 3 of a prolonged water-only fast autophagy starts taking place
    • The fasting function:
      • F (x,y,z) (AKA fasting is a function of x, y, and z)
        • x = the amount you restrict calories (100% = full calorie restriction)
        • y = the duration of the fast
        • z = the frequency at which the fast is repeated
      • For example, Peter does a 7-day fast once per quarter = F (100%, 7 days, 90 days)
    • There are TONS of different fasting regimens
      • But because we can’t measure autophagy – “Anyone who says theirs is the best is either delusional or incapably of understand combinatorial mathematics”
    • During his prolonged fasts, Peter tries to lift as heavy as possible every day (to stimulate mTOR in the muscle – to prevent muscle loss)
  • What does/doesn’t break a fast largely depends on the reason you’re fasting in the first place
    • If the purpose of your fast is caloric restriction and weight loss:
      • Coffee and even eating celery wouldn’t technically break it
    • If the purpose of your fast is gut rest:
      • Coffee breaks the fast
    • If the purpose of your fast is to increase autophagy:
      • We don’t know if something like coffee would break the fast (since we can’t measure autophagy)
  • Oral NR (nicotinamide riboside) (it’s a NAD+ precursor) supplementation and intravenous NAD+ administration are both probably useless
  • “If there was one disease state that seems to benefit more from a ketogenic diet than any of the others it’s type 2 diabetes”

Products Mentioned

  • Peter frequently does Tabata workouts on his Assault Airbike
  • Peter sleeps with a Chillipad in addition to an eye mask
  • Peter took True Niagen by Chromadex for a brief period as an experiment, but didn’t notice any effects
    • It’s NR (nicotinamide riboside) which is a NAD+ precursor
  • Berberine tends to lower blood glucose levels
  • Resveratrol is a compound that has a positive effect on the sirtuin geness
    • Sirtuins are genes which protect all organisms from deterioration and disease

Intro

Lactate

  • When doing Tabata workouts on his Assault Airbike, Peter achieves a lactate level of 20 mmol
    • What’s a Tabata workout? – It’s 20 seconds of going all out (he aims to hit a power output of 8 watts/kilo) followed by 10 seconds of ease, done for 4 minutes
  • “I’ve had this theory that elite athletes just recover better” – Mike
  • That’s Peter for you  – “The worst thing that ever happened to my conditioning was going to college. I basically had to go from training 6 hours/day to training 2 hours/day.”
  • “I do believe the difference between a world-class athlete and me is the density of monocarboxylate transporters (MCTs) in their muscle”
    • What does this mean? – They’re much more efficient at getting lactate back into circulation and back to the liver 
      • The cori cycle in the liver then turns lactate back to glucose
    • You need to actually do muscle biopsies to demonstrate this (which hasn’t been done) – it’s just a hypothesis
  • Lactate tends to get a bad rep – it’s actually an amazing fuel source
    • There’s evidence that the brain can utilize lactate as well as glucose
    • (The bad rep comes from the hydrogen ion that accompanies it – lactate is buffered with a hydrogen ion that causes all the pain/discomfort you experience when you’re at all out exertion. The hydrogen ion prevents myosin actin filaments from releasing – during intense, intense workouts, you’ll actually feel like you’re losing control of your muscles.)

mTOR Inhibition Through Rapamycin Supplementation or Fasting Increases Autophagy and Enhances Longveity

  • Longevity has no clinical trials, so in order to best determine how we as humans can live a long life we can:
    • Examine the centenarians
    • Examine animal (non-human) data 
  • Looking at this data, the only two interventions that really seem to offer longevity benefits are rapamycin and some degree of fasting
    • What do these have in common? – They both suppress mTOR (mechanistic target of rapamycin) and in turn increase autophagy 
      • (When mTOR activity is turned down, the body is more likely to undergo autophagy)
      • What’s authophgy? – “Auto” means self, and “phagy” means eating
        • Autophagy is the process by which cells eat themselves – the dysfunctional cells (like cancer cells) tend to be “eaten” first
        • Said another way: Autophagy is the self eating process where a cell breaks down its own damaged components, and remakes them – this is essentially the cell rejuvenating itself

What is rapamycin?

  • Rapamycin is used for immune suppression in patients who have had organ transplants 
    • In modest daily doses, it has anti-proliferative properties, impacting T cells in the adaptive immune system (the branch of the immune system that would reject an organ)
  • In 2009, researchers began examining what would happen after administering rapamycin to older mice 
    • Males lives ~9% longer and females lived ~13% longer
    • “These results have been replicated over and over again across multiple species which is what makes, 10 years later, rapamycin the most interesting compound when it comes to longevity”
  • Recent studies in dogs show that in as little as 12 weeks, rapamycin improves cardiac function
    • Why does this matter? – Cardiomyopathy is one of the top 3 causes of death in dogs
  • There are currently no human clinical trials involving rapamycin (although some might be happening soon targeting people in the earliest stages of cognitive impairment)
  • Rapamycin is legal (anyone can acquire a prescription for it)
  • In these Podcast Notes, Peter mentioned he’s been taking 5 mg of rapamycin for the last 3 months (he doesn’t specify how often, but it sounds like every 4-7 days)
    • BUT –  Peter has never written a prescription for it (we still have no idea of the correct dose/timing)
    • Why don’t we know this? – It’s impossible (currently) to measure autophagy in the body

Fasting

  • “People are interested in it. I think it’s the single most potent tool in our toolbox of nutrition. There’s nothing more potent than not eating periodically.”
  • Peter estimates that around day 3 of a prolonged water-only fast autophagy starts taking place
  • Wearing a continuous glucose monitor, Peter has noticed a decent amount of glucose fluctuation in the first 2 days of a prolonged fast, but around the third day his glucose levels start to flat line just below 60 mg/dL and tend to only further fluctuate with exercise
    • What does this indicate? – The body has come to an equilibrium in glycogen (stored glucose in the muscles and liver)
  • The fasting function:
    • F (x,y,z) (AKA fasting is a function of x, y, and z)
      • x = the amount you restrict calories (100% = full calorie restriction)
      • y = the duration of the fast
      • z = the frequent at which the fast is repeated
    • For example, Peter fasts 7 days, once per quarter = F (100%, 7 days, 90 days)
    • Peter thinks a reasonable fasting protocol (which he’ll recommend to his patents) is F (100%, 3 days, 30 days)
    • Something like a fasting mimicking diet would be = F (75%, 5 days, 90 days)
  • So know this:
    • There are TONS of different fasting regimens
    • Because we can’t measure autophagy – “Anyone who says theirs is the best is either delusional or incapably of understand combinatorial mathematics”
  • Mike fasts ever Sunday until dinner (his last meal would have been dinner on Saturday) and also does a 5-day fast once per quarter
  • During a fast, your weight loss is slightly misleading (since you’re losing so much water)
    • (A gram of glycogen moves with 3-4 grams of water)
    • Peter estimates that during a 7-day fast, if he loses 8 lbs., at least 5 lbs. of it is accounted for by water
  • Peter has noticed his heart rate variability increases during a fast (which improves sleep)

Peter’s Routine

  • He only does his 7-day fasts while he’s in NY for work (his home base in San Diego)
  • While in California, he goes to bed at 9 PM and wakes ~5 AM. While in NY, he goes to bed at 11 PM and wakes ~7 AM.
    • This allows his body to stay on as normal a schedule as possible, mitigating jet lag
  • Peter sleeps with a Chillipad both in NY and California in addition to an eye mask
    • To add – he keeps his room as close as possible
    • Related – Mike tapes his mouth every night while he sleeps to stimulate nostril breathing

Muscle Loss and Fasting

  • During his fasts, Peter tries to lift as heavy as possible every day (to stimulate mTOR in the muscle – to prevent muscle loss)
  • “The two amino acids I think are most interesting in regards to fasting are methionine and leucine because they both play such an important role in muscle”
    • Once you start fasting, methionine levels start to drop (after a day of not eating, you’ll have unmeasurable levels)
    • Leucine levels tend to stay constant, even after 7 days of fasting
      • This tells you that the body will go to great lengths to conserve leucine (and leucine is absolutely necessary for the maintenance of muscle protein)
    • Given this – Peter estimates you don’t need methionine to maintain muscle mass, but you definitely need it to increase it

TSH, T4, and T3 – How the thyroid hormones change during a fast

  • Research has shown that T4 and T3 decrease during the first 3 days of a fast and then flat line
  • Let’s get technical:
    • The pituitary gland in the brain makes thyroid stimulating hormone (TSH) in response to the hypothalamus telling it to
    • The TSH tells the thyroid to make T4 
      • Some T4 gets converted to T3 in the brain
        • The body can also make T3 in the periphery (outside the brain)
      • The body can also turn T4 into Reverse T3 (RT3)
        • Reverse T3 is competitive to T3 (it’s a competitive antagonist – it sits in the same receptor, but doesn’t activate it)
    • And..
      • Each of the conversions is controlled by a different deiodinase enzyme (the environment is what upregulates or downregulates those enzymes)
      • In a fasted state:
        • The body upregulates the deiodinase enzyme that converts T4 into Reverse T3
        • The body downregulates the deiodinase enzyme that turns T4 into T3
      • The ratio of Reverse T3 to T3 gives you a sense of peripheral thyroid function
        • In a normal person, that ratio is usually > 0.2-0.25
  • During Peter’s fasts:
    • On the 6th or 7th day, Peter’s TSH levels are unchanged (this indicates that his brain is still seeing the same amount of T3)
    • His T3 drops 
    • His Reverse T3 drops
    • (His Reverse T3 to T3 ratio drops from 0.3 to 0.05 – meaning he’s had a complete and total peripheral shutdown of thyroid function)
      • What are some of the implications of this? – A greater sensitivity to cold temperatures
        • Although he hasn’t measured it, this indicates a significant reduction in metabolic rate (Peter estimates a ~50% reduction)
    • To add – his testosterone levels drop quite significantly
      • “Despite having the testosterone of a girl at the end of a fast, I don’t really feel like I experience a significant reduction in strength”

NAD+: Nicotinamide Adenine Dinucleotide

  • NAD exists in two forms: an oxidized and reduced form abbreviated as NAD+ and NADH, respectively.
  • “I think oral NR is somewhere between useless and maybe potentially beneficial”
    • When you take oral NR, most of it is converted to NAD+ by the liver – it’s not clear, though, how much of the desired outcome (NAD+ getting into the mitochondria) is actually happening
    • Once NAD+ is made in the liver:
      • It has to then make it to the blood plasma
      • The plasma NAD+ then has to make it into the cytoplasm of the cell
      • The cytoplasm NAD+ then has to make it into the mitochondria and alter the ratio of NAD+ to NADH 
      • (it’s just a huge stretch)
    • Peter does not take (nicotinamide riboside) NR currently (it’s a NAD+ precursor)
  • What about intravenous NAD+?
    • “I’m pretty confident that intravenous NAD+ doesn’t make any sense”
    • “I think it’s somewhere between useless and harmful” – why?
      • There really aren’t effective transporters that bring NAD+ into the cell
      • Similar to taking oral NR, for it to work:
        • The NAD+ would have to get from the blood plasma into the cell
        • The cytoplasm NAD+ would have to make it’s way into the mitochondria and alter the ratio of NAD+ to NADH

The Ketogenic Diet

  • “If there was one disease state that seems to benefit more from a ketogenic diet than any of the others it’s type 2 diabetes”
    • The ketogenic diet is kryptonite for treating type 2 diabetes
    • “But it’s probably not as effective as fasting. I would argue fasting is the single most important tool for treating metabolic disease.”
  • BUT some people seem not to do well on a ketogenic diet (their health markers seem to go in a negative direction)
    • Why? – It’s probably due to the enzymes that regulate ketogenesis

AMP-Activated Protein Kinase (AMPK) and Metfomin

  • AMPK is an enzyme that goes up when we’re void of nutrients (like during a fast)
    • It’s more sensitive to a lack of glucose (compared to something like TOR which is sensitive to amino acids)
  • Metformin activates AMPK (Why? – it causes the liver to put less glucose into circulation)
    • Metformin is drug used for treating type 2 diabetes (given at ~2 grams/day – 1g in then morning and 1g at night) (but given the above, it seems to offer benefits to people who are perfectly healthy)
    • In general – “The more metabolically ill you are, the more benefit you probably get from metformin”
  • Peter isn’t taking metformin at the moment, but has experimented with it in the past
    • He’s observed that his lactate levels tend to run higher while he’s taking it

Berberine

  • Berberine (although weaker) and metformin tend to go after the same pathway, both lowering blood glucose levels – so it wouldn’t be a good idea to combine them –
  • Berberine also weakly inhibits PCSK9 in those who overexpress PCSK9 (high PCSK9 can cause elevated LDL cholesterol)

Resveratrol

  • “In many ways the resveratrol model is more appealing to me than the NR model”
    • “It seems to me it should be easier to activate sirtuins [which resveratrol does] than trying to get NAD into mitochondria”
      • Sirtuins are genes which protect all organisms from deterioration and disease
  • For more on resveratrol and supplementing with it, check out the Podcast Notes

What does and doesn’t break a fast?

  • Peter answered this question more in depth in these Podcast Notes
  • “The definition of what breaks a fast is as subjective as the definition of, ‘What is sex?'”
  • The answer largely depends on the purpose of your fast
    • If the purpose of your fast is caloric restriction and weight loss:
      • Coffee and even eating celery wouldn’t technically break it
    • If the purpose of your fast is gut rest:
      • Coffee breaks the fast
    • If the purpose of your fast is to increase autophagy:
      • We don’t know if something like coffee would break the fast (as we can’t measure autophagy)

Peter’s Morning Routine

  • Peter gets up early and meditates using either Dan Harris’ Ten Percent Happier app or Sam Harris’ Waking Up app
  • He then makes coffee for him and his wife using a french press
  • Peter is currently trying to limit email checks to 2x per day
    • The first batch of email checking/answering happens while he waits for his kids to wake up
  • Once his kids head to school, he works out

Additional Notes

  • Peter plans to soon experiment with methylene blue (he’s just about done getting a compound pharmacy to make something he’s happy with)
    • You need to be careful sourcing methylene blue – even if there’s 1% contamination, it can be harmful
  • Peter doesn’t like to use telomere length as a marker of aging since so many other factors can influence it
  • Peter gets some his best writing done on planes
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