The Peter Attia Drive – Dr. Dom D’Agostino

Intro
The Brain and Hyperbaric Oxygen
  • We don’t have a good understanding of how our brains function in extreme environments (hyperbaric pressure, elevated oxygen etc. – so something like deep sea diving)
    • Hyperbaric = gas at a pressure greater than normal
    • This led Dom to study how cells (particularly the mitochondria) behave in extreme pressure + graded oxygen environments for his post-doc work
      • This simulates how cells would behave in a deep sea dive
    • In doing this work, Dom noticed that in the presence of hyperbaric (greater than normal) oxygen, cancer cell (in this case human U87 glioblastoma cells) death was accelerated 
      • In this case, hyperbaric = 5x atmospheric pressure
      • How did the cancer cells die? – cancer cell mitchondria started producing so much reactive oxygen species (ROS), causing them to essentially “explode”
    • Think about this in terms of deep sea diving
      • You’re under great pressure, and by using an oxygen tank, you may be getting a surplus amounts of oxygen
      • You basically replicate in a person, what you see with the above in a cell
  • In the process of growing the cancer cells for the above work, Dom noticed they don’t proliferate/grow as rapidly as they should in the presence of beta-hydroxybutyrate (BoHB -a type of ketone)
    • What’s a ketone? – see here
    • This benefit seemed to be from the addition of BoHB to the grow media (what the cells we’re grown in), not from the reduction in glucose in the media
    • In the presence of ketones and low glucose, cancer cells were more apt to die
Seizures
  • “The ketogenic diet is a very effective anti-seizure strategy, even when drugs fail”
    • About 10-15% never have seizures again while on the ketogenic diet
    • 2 out of 3 people with seizure issues respond favorably to a ketogenic diet
  • Why do these seizures occur in some divers who use oxygen rebreathers?
    • (Rebreathers don’t produce bubbles, making it easy for navy seal divers to surprise an enemy)
    • The answer is oxygen toxicity – this is the same thing that can happen with hyperbaric oxygen therapy (HBOT)
    • Even 10 minutes of diving using an oxygen rebreather, at a depth of 50 feet, can be enough to trigger oxygen toxicity
    • The high levels of oxygen are creating oxidative stress, and impeding various metabolic processes 
      • The brain becomes hyperexcitable, causing neurons to fire so many action potentials, that the cells can’t maintain their membrane potential
      • This results in “excitotoxicity” – causing the mass firing of the neurons that you see in a seizure
  • Ketone esters (explained below – like this one from HVMN) have been found to increase resistance to oxygen toxicity by 600%
    • There are many applications for HBOT, so taking ketone esters prior to HBOT, would greatly reduce the odds of oxygen toxicity/death
  • As people age, greater oxidative damage in the body is observed (due to more ROS)
    • Similarly, you’re seeing a ton of ROS when divers use rebreathers
    • If you exercise intensely, your ROS levels also rises
    • What’s going on?
      • In the presence of an oxidative stimulus, adaptive processes in our cells are triggered that allow cells to be more resilient to that oxidative stress
      • In healthy people – this happens easily
      • In older adults – this is impaired
Hyperbaric Oxygen Therapy (HBOT)
  • What does it do?
    • Stimulates the production of stem cells
    • This hones in on sites of injury, and aids in repair
    • The most promising/most utilized application of HBOT – to aid in wound healing
    • There are 14 FDA approved applications of HBOT
      • Thermal burn injury
      • Carbon Monoxide Poisoning
      • Crush Injury
      • Etc.
  • Dom wants to study traumatic brain injury (TBI) treated with HBOT combined with ketone esters
    • “The faster you restore oxygenation, the more likely you are to salvage those neurons”
  • “If you’re going to do HBOT, do it in strong ketosis” 
    • The last thing you want, if you have a brain injury, is to have a seizure – and one of the dangerous consequences of HBOT is CNS oxygen toxicity
Warbrug Effect
  • Back to biology class…
  • Our cells turn glucose into pyruvate outside the mitochondria, then, based on how quickly the body needs ATP (this is just energy)…
    • When the body needs ATP quickly (anaerobic environment) – pyruvate gets converted to ATP through the glycolytic pathway
      • This doesn’t generate much ATP, but it does so quickly in the presence of minimal oxygen
      • Lactate is a byproduct off this pathway (this is what causes muscles to “burn” during intense exercise)
    • If the body doesn’t need ATP quickly – the pyruvate gets converted to acetyl CoA, which then gets shuttled into the mitochondria, and ATP is made
      • This makes more ATP than the first method, but requires more oxygen
  • SO …the Warburg effect- even under conditions at rest, in the presence of normal oxygen, a cancer cell seems to favor the glycolytic pathway, as opposed to going into/utilizing the mitochondria to make ATP
Ketosis and the Ketogenic Diet
  • Peter and Dom discuss the George Cahill study
    • Participants fasted for 40 days (water and minerals only), and after 7 days, blood BoHB levels matched blood glucose levels 
    • Glucose levels stayed constant at 55 mg/dL after 7 days
      •  Why did they stay constant and not drop?
        • When stored body fat is converted to ketone bodies (like BoHB), a small amount of glycogen is produced as a side effect, which then gets stored in the liver, and eventually gets released into the blood stream
        • So even by not eating for 40 days, your blood will always have a small amount of glucose
  • The brain uses what’s in your blood, as far as ketones and glucose go, for fuel
    • In the carb fed state, the brain uses 100% glucose
  • Classical Ketogenic Diet – 87-90% fat, 10% protein, 1-2% carbs
  • Modified Ketogenic Diet – 65% fat, 30% protein, 5% carbs
    • This is what Dom mostly follows now
    • Dom has noticed that this modified ketogenic diet, in combination with MCT supplementation (MCT = medium chain triglyceride), raises his blood ketone levels higher than a classical ketogenic diet
  • How do we make ketones?
    • In starvation – the liver starts burning up its stored glucose (known as glycogen)
      • After 24 hours, your liver glycogen levels drop to about 25-50% of the original supply
    • As insulin levels (this is the hormone that shuttles glucose into cells – if you’re not eating any glucose/carbs, insulin levels are dropped) are suppressed – fat starts to be taken/mobilized from adipose tissue to be used as fuel
      • Fat can be used by muscle and heart cells directly for fuel (ketones don’t need to be made from the fat)
    • Fatty acids (the fat taken from adipose tissue) can’t cross the blood brain barrier, so…
      • These fatty acids are sent to the liver to create ketone bodies (like BoHB)
      • These ketone bodies are then used (just like glucose would be) to create energy (through the Kreb’s cycle) in cells that need it within their mitochondria
Medium chain triglycerides (mcts)
  • When you consume them orally, they go directly to the liver (as opposed to when you eat other fats, they have a different route of entry to the liver – they’re first packaged in molecules called chylomicrons)
    • MCTs are rapidly oxidized (more so than other fats) by mitochondria
    • MCTs are much less likely to be stored as fat
  • MCTs can be consumed on a carbohydrate based diet to boost ketone levels in the blood
  • C8 Oil (a type of MCT)
    • With 2-3ml of  pure C8, on a carb based diet, you can get blood BoHB levels to rise to about 0.5-1.0 mmol/L
    • With pure C8, you get about a 20-30% higher rise in blood ketone levels
      • Generic MCTs are a mix of C10 and C8
    • Some good C8 oils (aka the triglyceride form of caprylic acid)
  • Powdered MCT
    • Dom uses this one from Quest
    • He says it boosts his blood ketone levels more so than the oil form of MCT
    • Powdered MCTs are more tolerable on the gut, if you take too much MCT oil, just make sure there’s a bathroom nearby
  • “MCTs are the poor mans ketone ester”
  • Dom has increased his MCT oil tolerance from 30ml/day to 150ml/day
    • He says its best to incorporate them with food (like on salad)
  • Some MCTs directly enter the blood, and can cross the BBB (so they’re not converted to ketones)
    • About 20% of MCTs enter the blood directly, and are not converted to ketones – these are the ones that cross the BBB
    • The brain then utitilizes the MCTs for fuel
    • These MCTs that go directly to the brain may have anti-seizure properties
Ketones and Glucose
  • Ketones drive down blood glucose levels
  • If you take someone in ketosis, and have them do intense exercise, ketone levels drop immediately after, and glucose levels spike
    • Why? – In intense bouts of exercise, your body can only utilize glucose to create ATP/energy via anaerobic respiration. Once glucose is shuttled into the blood from the liver, ketone levels drop…. but we don’t know exactly why that is.
    • A potential answer – A glucose induced release of insulin (as glucose enters the blood stream, insulin levels rise to shuttle that glucose into cells), which lowers fat oxidation, so ketone levels drop
      • Side note – Dom has noticed that after consuming a ketone ester, his insulin levels will show a slight bump (this isn’t nearly as large of a bump from eating carbs)
      • This is why healthy normals won’t go into diabetic ketoacidosis (basically when ketone levels get too high) – your pancreas is able to normally regulate insulin levels, preventing your blood ketones levels from sky rocketing
    • Another potential explanation – insulin sensitivity is very high for people on a ketogenic diet, so any available insulin will thus have more of an effect
      • Dom has noticed that, when consuming lots of exogenous ketones over a few weeks, his insulin levels will fall below reference range
      • On a normal ketgenic diet without exogenous ketone supplementation, his insulin levels are at the low end of the reference range
  • Dom’s baseline insulin levels on the ketogenic diet are 1-2 mmol/L
Measuring Ketones
  • The Precision Xtra and the Keto Mojo are the gold standards for measuring blood BOHB levels
    • These are accurate to 10-15%
    • For the Precision Xtra use these lancets these test strips
    • The strips are included with the Keto Mojo
  • Urine ketone tests measure acetoacetate levels in the urine
    • If your urine acetoacetate levels are 40 mg/dl or more, you are likely at a BoHB of 1.0 mmol/L
The Oura Ring
  • Dom typically gets 1.5 hours of deep sleep
  • He finds 2 hours of REM sleep does him well
  • Use the code “podcastnotes” for $50 off the Oura Ring
Exogenous Ketones
  • The studies have not been done to determine if giving someone exogenous ketones on a high carb diet allows for an anti-seizure benefit
    • Dom thinks it does have an effect – it works well in animal models
  • The difference between a ketone salt and a ketone ester
    • A salt is an ionic bond between the ketone molecule (BoHB), a monovalent or divalent cation, or an alkaline amino acid
      • The easiest thing to do is bond BoHB with sodium, potassium, calcium, and magnesium
    • A ketone ester is a covalent, not an ionic bond
      • With these – “The ketogenic potency is inversely proportional to taste”
      • Check out this ketone ester from HVMN
  • The different types of BoHB
    • The dominant form of BoHB in the body is D-BoHB
      • Our body makes D-BoHB from oxidizing fat
    • 99% of all ketone supplements (ketone salts) are equal parts D-BoHB and L-BoHB – the term for this is “racemic”
      • Dom isn’t aware of any negative health side effects of taking these
    • The HVMN ketone ester is all D-BoHB
    • In Dom’s work, he’s found that pure D-BoHB doesn’t provide anti-seizure benefits
    • Inflammaition
      • Both the D- and L-BoHB forms have been shown to suppress inflammation via the NLRP3 inflammasome pathway
      • When ketone salts are taken (remember these are equal parts D- and L-BoHB), the L form tends to stick around longer and gets metabolized slower – this may result in a stronger anti-inflammatory effect
    • The racemic ketone salts have been found to lower blood glucose levels > 20-30%
      • The pure D-BoHB HVMN ketone ester has been shown to lower blood glucose levels only 20-30%
Ketone Tolerance Test
  • What does it involve?
    • Fast, take a know amount of exogenous ketones, and monitor blood ketone levels over time
    • This is similar to a glucose tolerance test
  • Dom has shown that athletes dispose of, and utilize ketones, remarkably well
    • “Fat adapted athletes are very good ketone utilizers and have a hard time elevating their blood ketone levels with the ketogenic diet”
    • In addition, keto adapted athletes clear lactate faster (this is why they tend to not feel the lactate burn associated with intense exercise – they are more efficient at shuttling lactate out of their muscle cells)
The Ketogenic Diet and Cancer
  • What would Dom advise a loved one to do, after exhausting all the standard of care treatment options, to aid in treatment of glioblastoma (GBM) and metastatic breast cancer ?
    • The 5 year survival rate for someone with GBM is almost 0
    • First, get a FDG-PET scan – this involves taking glucose labeled with a radioactive molecule, and monitoring how certain tissues absorb the glucose
      • Cancerous tissues do so more readily
    • Slow down cancer growth and proliferation by..
      • Following a calorie restricted, ketogenic diet, with intermittent fasting (with exogenous ketone supplements)
        • Ideally you want a glucose to ketone ratio of 1/2
        • At the minimum 1/1 –
          • For example – have 3mmol/L of ketones and 3mmol/L of glucose in your blood
        • How? – Eat for only 6 hours of the day, and when fasting – consume exogenous ketones (you can also consume exogenous ketones during your feeding time window)
      • Taking low dose of metformin (500-2000 mg/day)
        • This can lower insulin, and blood glucose
    • Do some form of HBOT
    • You can further enhance the oxidative stress given to the tumor by HBOT by…
      • Taking IV Vitamin C (around 25-100 grams) 
        • Note that this can drop blood glucose severely, and will require you to take some sort of oral dextrose during treatment if you are not in a state of nutritional ketosis
      • At very high concentrations, Vitamin C acts as a prooxidant (it can create oxidative stress) – at lower doses, its an antioxidant
    • Antioxidants can blunt the effects of cancer therapy
      • Many chemotherapies and radiation work by enhancing oxidative stress in the cell
        • By taking antioxidants, you’re hindering this
    • In a mouse model, being in a state of ketosis made radiation therapy much more effective in the treatment of GBM
Dom’s Fasting Experiments
  • Dom did a 7 day fast a few years ago
    • He got his ketone levels up to 4-5 mmol/L, and his blood glucose levels dropped to 3 mmol/L
    • Dom deadlifted 500 lbs. for 10 reps (his max at this time was 675 lbs. for 5 reps and 555 lbs. for 8-10 reps at the time), and 585 lbs. for 1 rep on the 7th day
    • “If you’re in a keto adapted state, your body is pretty resilient”
What does dom believe today to be true that 5 years ago he did not believe to be true?
  • 5 years ago Dom was fascinated with ketones as an alternative energy source
  • Now, he’s much more interested in utilizing ketones as a metabolite that can control gene transcription
    • For example, it’s been found that ketones are an histone deacetylase (HDAC) inhibitor
    • We’ve only just begun to scratch the surface when it comes to studying ketones (and other metabolites), and how they epigenetically control gene transcription
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