The Kevin Rose Show – Dr. Peter Attia on Longevity Compounds, Fasting, Supplements and More

Check out The Kevin Rose Show Episode Page & Show Notes

Key Takeaways

  • “If you look at the administration of rapamycin across about a billion years worth of evolutionary animal models, everything from yeast to worms, fruit flies to mammals (mice and dogs), this compound seems to universally increase life”
  • Rapamycin binds to a complex, called mTOR (mechanistic target of rapamycin) in our cells and inhibits its function
  • mTOR regulates autophagy
    • When mTOR activity is turned down (by taking rapamycin), the body is more likely to undergo autophagy
      • Autophagy is the process by which cells eat themselves – the dysfunctional cells (like cancer cells) tend to be “eaten” first
    • In a sense – the inhibition of mTOR mimics what happens to the body in a nutrient sparse environment
  • Peter has 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)
  • We can also suppress mTOR by fasting
  • Peter does a 1 week water only fast once per quarter, sandwiched on both sides by a week of following a ketogenic diet
    • “I think it’s really important to lift weights while fasting, because it really holds off the muscle mass loss”

Cool Products and Supplements Mentioned

  • Flite Tabs to help protect against blood clots while flying
  • Peter only trusts two branched-chain amino acid (BCAA) companies – Ajinomoto and Biosteel
  • “I think there’s really some pretty good data on curcumin’s antinflammatory benefits, and in particular some much more compelling data on a formulation of it called Theracumin
  • Peter takes Kirk Parsley’s Sleep Cocktail (a double dose) to help him fall asleep on planes
    • He’s mentioned on other podcasts that he takes it every night before bed as well

Intro

Peter’s Team of Researchers

  • What do they do? 
    • It varies from month to month
    • Right now, almost all of the effort from Peter’s team of researchers is going towards helping Peter right his upcoming book
    • ~10% of effort right now is directed to answering any clinical questions that pop up
  • ~100,000 studies make their way on to PubMed every month 
    • 60-70% of those are never cited again
    • Peter says fewer than 1% of the 100k are actually relevant
    • Peter and his team tend to focus more on research that has to do with cardiovascular disease, neurodegenerative disease, cancer, insulin resistance, NAFLD (Non-Alcoholic Fatty Liver Disease), fasting, etc.
      • Peter estimates there are about 1,000 papers per month relevant to their research interests
  • The structure
    • Peter’s head analyst – Bob Kaplan
    • Other analysts reports to Peter, but most report to Bob
  • Example questions his team of researchers might explore:
    • What’s the best way to prevent blood clots on airplanes?
      • Why is this a problem? – All these things increase the coagulability of blood:
        • The reduction in oxygen concentration
        • Dehydration (we don’t drink much water on airplanes)
        • The position we’re sitting in
      • (Through this, they actually discovered Flite Tabs – they contain molecules which very good at thinning the blood)
      • It’s actually very common for people to encounter medical problems on airplanes

Rapamycin and mTOR

  • For more on rapamycin, check out these Podcast Notes
  • An entire chapter in Peter’s upcoming book is devoted to caloric restriction and rapamycin
  • “If you look at the administration of rapamycin across about a billion years worth of evolutionary animal models, everything from yeast to worms, fruit flies to mammals (mice and dogs), this compound seems to universally increase life”
    • It seems to do it disproportionately better in females over males
  • Rapamycin binds to a complex, called mTOR (mechanistic target of rapamycin) in our cells
    • Rapamycin inhibits mTOR
  • So what does mTOR do?
    • Many things…
    • Regulates autophagy (cell death), regulates cell size and growth,  and many metabolic pathways
      • 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
      • When mTOR activity is turned down, the body is more likely to undergo autophagy

A Quick Detour – How Glucose Gets Into Cells

  • What good is glucose if it’s just floating around in your bloodstream? – None
    • Glucose in the blood needs to get into our cells…how?
      • Insulin is made in the pancreas – It binds to the surface outside the cells
      • That triggers a chemical reaction inside the cell which shoots a transporter (called GLUT4) from inside the cell, across the cell membrane, where it stays
      • Think of GLUT4 like a tube going across the membrane, and through GLUT4, glucose flows down its gradient into the cell

What the hell is mTORC1 and mTORC2??

  • mTOR organizes itself in 2 ways
    • If it organizes itself around a protein called RPTOR – it’s called mTOR Complex 1 (mTORC1)
      • RPTOR = Regulatory Associated Protein of mTOR
      • By “organized itself” – it just means “joined together with”
    • If it organizes itself around a protein called RICTOR – it’s called mTOR Complex 2 (mTORC2)
  • “It seems most of the longevity benefits happen when you inhibit mTORC1, but not mTORC2”
  • It’s the inhibition of mTORC2 that seems to produce some of the unintended consequences of rapamycin (which there’s debate about)
    • One of these is thought to be insulin resistance
    • In theory, what what you want to do is inhibit mTORC1, without inhibiting mTORC2

So why does the inhibition of mTORC1 matter?

  • “It mimics what happens to the body, when in a nutrient sparse environment”
  • mTOR is probably the best thing we have at sensing amino acids (the build block of proteins)
    • The amino acid which seems to be most sensitive to activating mTOR – leucine
    • “Leucine is so clearly essential to turn on mTOR”
  • But here’s what’s interesting – when you fast, your leucine levels don’t go down
    • “The body is so good at keep leucine levels at a regulated level, that when you fast, it will create leucine out of other amino acids”

A Quick Recap

  • mTORC needs leucine to be turned on
  • When mTOR activity is turned down, the body is more likely to undergo autophagy
  • This is why fasting suppresses mTOR (lack of nutrients and amino acids, so mTOR is inhibited)
  • Rapamycin also inhibits mTOR

A Quick Detour into BCAA Supplements

  • Peter recommends that in order to stack the odds in your favor of gaining muscle, you really need to be supplementing with leucine/adding it to the equation
  • “Most branched-chain amino acid (BCAA) supplements are actually literally just crushed up bird feather”
    • Peter only trusts two BCAA companies (that he knows of)  – Ajinomoto and Biosteel
    • Some companies do add Ajinomoto BCAAs into their product – so look for the Ajinomoto stamp on other products

What is autophagy?

  • “Auto” means self, and “phagy” means eating
    • It’s the process by which cells eat themselves – the dysfunctional cells (like cancer cells) tend to be “eaten” first
  • Almost everybody has cancer cells in their body
    • “The probability that you and I are sitting here without at least one cancer cell in our body is pretty low”
    • But virtually, all the time, your immune system is recognizing cancer cells as “non-self” and terminating them – the time that it doesn’t, is when we develop cancer

Aging = Inflammation

  • If you were to do a biopsy of your leg muscle today, and compare it to a biopsy of your leg muscle 10 years ago, you’d see MUCH more inflammation in the cells
    • You’d see much more cytokines, macrophages, and the chemical signals that inflammatory cells use to speak to each other
    • “Inflammation and aging are so tightly wound together”

What’s mitophogy?

  • When damaged mitochondria are recycled 
  • We all have ~20,000 genes in our DNA (which we got from our parents), but mitochondria have their own DNA (37 genes) as well
    • Mitochondrial DNA comes from your mom
    • This mitochondria DNA is bacterial in origin (compared to the DNA in your nucleus, which is of human origin)
  • A promising hypothesis – One of the reasons we see an increase in inflammation with aging is that as we age, we get more mitochondrial breakdown, and as more mitochondria are breaking down, perhaps that’s eliciting an immune response
    • (Since the mitochondrial DNA is bacterial in origin, once it gets out of the mitochondria into the cytoplasm, the body thinks of it “non-self”, and attackedn it )

So why not just take rapamycin every day?

  • Peter says the following 3 things need to be true, if you’re taking the correct dose of rapamycin:
    • Glycemic response will be unchaged or improved (it shouldn’t get worse, which could happen if you take too much rapamycin)
    • Immunity should get better, not worse
    • Autophagy should increase (but there’s currently no way to measure this)
  • One of the most obvious negative side effects of rapamycin is mouth sores (apthous ulcers) – Peter equates them to “super annoying canker sores”

What would be the correct rapamycin dosing?

  • In the Mannick study, the negative side effects when taking 5 mg of rapamycin once per week, compared to taking 1 mg every day, didn’t seem to be that much worse
    • But taking 20 mg once per week vs. 5 mg once per week, showed no additional immune benefit (however there were more negative side effects)
  • Matt Kaeberlein has done some studies on dogs, suggesting the optimal dosing in humans would be around 4-8 mg, in some sort of pulsatile/episodic fashion (every other day or every third day)
    • Why? – You don’t want to inhibit MTORC2 
      • If you dose with rapamycin every day, you don’t allow for TOR to be recirculated, and within a few days of consecutive dosing, you start to inhibit the creation of mTORC2
  • So in short, there’s no side effects to taking too little (just a lack of benefit), but you want to be careful about taking too much
  • If Peter were to guess the perfect dose: 4-6 mg every 4-7 days

Rapamycin Appears to Inhibit Senescent Cells

  • Senescent cells are cells which are “basically bad actors”
    • They essentially mimic other types of cells, with a less effective version
    • So inhibiting them, would be a benefit

Can anyone take rapamycin?

  • Yes – all you need is a presrciption from your doctor
    • We just need more data to indicate that we’re not taking too much/we’re taking enough

Does Peter take rapamycin?

  • Yes (for the last 3 months), but he’s never written a prescription for it
    • “I’m relatively confident that the dosing I’m using is relatively congruent with all the data I’ve assimilated over the past 4 years, and speaking with some of the smartest people in the world”
    • He’s taking 5 mg (he doesn’t say how often)
  • Why does he take it?
    • “For me and my risk appetite, I think the risk of not taking it is higher than the risk of taking it”
    • A good way to think about this – “Strong convictions loosely held”
      • Peter says, given new information/data, he’d be apt to change his mind very easily
  • Has he noticed anything?
    • For the first two months, he had very bad mouth sores…and then they stopped
    • Nothing else
  • Here’s what Peter has learned from a physician, also in NY, who regularly prescribes rapamycin – “the worse your glucose levels are starting out, the more of an improvement you can get”
    • What else is this doctor seeing? 
      • Patients are losing weight, their triglycerides are falling, insulin/glucose levels are improving as well as HA1c

Are there any cognitive benefits of taking rapamycin?

  • “It’s a bit too soon to say”
    • Peter says it’d be a very interesting research question – What happens when you give rapamycin to people in the very early stages of cognitive decline?
    • “There’s definitely preliminary data that suggests, in certain models, that rapamycin is delaying the onset of cognitive impairment”

Acarbose for preventing diabetes?

  • Acarbose is a molecule that binds to glucose in the gut, and basically prevents you from absorbing it, so it comes out in your stool
    • Kevin has noticed that when he takes it, he can eat 4 slices of pizza, and he won’t see his glucose spike at all
  • “I don’t know specifically if it’s been studied formally as a diabetes prevention agent, but it is a definitely a way to lower glucose, and it’s one of 15 drugs I’d consider super interesting”

What does Peter think of NAD?

  • NAD – Nicotinamide adenine dinucleotide
    • NAD exists in two forms: an oxidized and reduced form abbreviated as NAD+ and NADH, respectively.
  • “There really aren’t effective transporters that bring NAD+ into the cell.”
    • Peter says everybody who he knows who has gotten NAD+ administered intravenously says it feels horrible, but that doesn’t means it’s doing what you think it’s doing
    • For it to work, the NAD+ would have to get from the blood plasma, into the cell, into the mitochondria, alter the ratio of NAD+ to NADH, and activate the sirtuin– “That’s a huge stretch, and in my mind, there is no evidence for any step along that chain”
  • Peter thinks it’s more interesting to give NAD+ precursors intravenously, or through routes that can go around the liver
    • Like NR (nicotinamide riboside)
    • “What I think we know is the cell has to make its own NAD+, so you want to give it the thing it can use to make NAD+, because it can bring that into the cell”
    • 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.

Curcumin

  • “I think there’s really some pretty good data on curcumin’s antinflammatory benefits, and in particular some much more compelling data on a formulation of it called Theracumin

How does Peter manage stress?

  • This is where Peter says he needs the most improvement 
  • “I think meditation far and away is the best tool”
  • Peter is more interested in raising is stress tolerance, as opposed to trying to become less stressful
    • What lowers stress tolerance ? – A lack of sleep, bad nutrition
  • For more on how Peter thinks about meditation, check out these Podcast Notes from his episode with Sam Harris

A Talk You Need to Hear

Methylene Blue

  • It’s an industrial dye (it was created for clothing, like blue jeans)
  • It has one generally accepted medical use today – the treatment of methemoglobinemia
    • When you generate too much methemoglobin (when you have too much carbon monoxide binding to the electron transport chain) methylene blue will override the symptom and allow the mitochondria to make ATP
  • It’s in every hospital emergency room
  • It been used to treat malaria
    • Side note – Peter notes that a lot of malaria drugs used to treat malaria (he doesn’t say which) have nasty neurological side effects
      • “I had a friend from undergrad who ended up being on one of these drugs. and he never has been quite the same since”
    • Kevin agrees – He and Tim Ferriss were once going to China, and were advised to take some form of malaria medication, but ended up not taking it out of caution
  • Methylene blue has been found to improve cognitive function/overcome energy deficits in mitochondria which can lead to cognitive decline
    • One of the major drivers of Alzheimer’s Disease is an energy deficit of the neurons in the brain
  • Note – You ABSOLUTELY 100% can’t take methylene blue unless it is 100% pure
    • So don’t go Googling and order some
    • You need pharma grade methylene blue

What’s Peter’s fasting protocol?

  • Once a quarter, he’ll do a 1 week water only fast, sandwiched on both sides by a week of following a ketogenic diet
  • Peter really thinks the true benefits of fasting (autophagy etc.) start to occur around day 3 of the fast
    • But we really don’t know the true answer – it’s impossible to measure autophagy
  • “I think it’s really important to lift weights while fasting, because it really holds off the muscle mass loss”
    • The weight training is stimulating mTORC1 in the muscle, which is the place you don’t want to turn it off (it’s okay to dial it down, but you want to dial it down more so in other organs)

A Good Thought

  • Keto, plant-based, carnviore….it doesn’t matter, ANYTHING is better than the standard American diet
    • When you combine sugars, fats, and carbohydrates in the ratio that they are eaten on a standard American diet, ANYTHING is a dramatic improvement

Has Peter found any nootropics that work for him?

  • Outside ModafinIl….no
    • “Even 200 mg of ModafinIl does nothing for me”
  • Caffeine also doesn’t do much for Peter

How does Peter beat jet lag?

  • Peter describes how he recently dealt with a trip to the Middle East from California – his flight out of LAX left at 4pm (so 4am Middle East time)
    • The day of his flight, he woke up at 4am, did a very hard workout to build up some adenosine
      • “Sleep is basically about balancing adenosine, cortisol, and melatonin”
        • For a clearer explanation of why this is the case, check out these Podcast Notes
    • His goal was to be able to sleep the second the plane took off
    • He woke up 6 hours after takeoff (so 10am Middle East time)
    • Then he took 200 mg of Modafinil 
    • The flight landed at 9pm
    • He did some work, and then went to bed

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