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 Chilipad (Use code PodcastNotes25 for 25% off a ChiliPad or PodcastNotes15 for 15% off an Ooler) 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
    • When it comes to a brand of NR, we can’t recommend Elysium Basis enough (use the code “podcast45” at checkout to receive $45 off a semi/annual subscription). We, Matt and Yoni, have been researching the company and trying Basis out for the past 3 months. Basis is a proprietary formulation of crystalline NR and pterostilbene that supports cellular health by increasing and sustaining NAD+.
  • 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 Chilipad (Use code PodcastNotes25 for 25% off a ChiliPad or PodcastNotes15 for 15% off an Ooler) 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
  • For us at Podcast Notes, hands down, when it comes to a brand of NR, we can’t recommend Elysium Basis enough (use the code “podcast45” at checkout to receive $45 off a semi/annual subscription). We, Matt and Yoni, have been researching the company and trying Basis out for the past 3 months. Basis is a proprietary formulation of crystalline NR and pterostilbene that supports cellular health by increasing and sustaining NAD+ . Elysium Basis is the only NR supplement we’ve found that has run gold-standard clinical trials, owns their own supply chain (which means metals, other molecules, etc don’t get in your supplement), and they continuously test the product for stability long after it hits the “shelf.” In short, it’s effective AND safe.

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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