ADHD and Autism

#205: Dom D’Agostino, PhD- Your Brain on Keto

by Mike Mutzel

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About Dom D’Agostino

USF Associate Professor, IHMC Scientist, devoted husband, TEDx speaker, NASA NEEMO 22 crew member.

https://ketonutrition.org

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Show Notes

01:38 The ketogenic diet can suppress glucose availability to tumor cells and suppress the pentose phosphate pathway, which causes cancer cells to make endogenous antioxidant mechanisms. With the ketogenic diet and hyperoxygenating them with hyperbaric oxygen, you are crippling the cancer cell’s ability to make oxidants, as a way to enhance oxidative stress in cancer cells to kill them. These early experiments lead to researchers developing and using ketones as a mitigation countermeasure to prevent oxygen toxicity seizures.

03:17 Nutritional ketosis has a stabilizing effect upon the brain. Nutritional ketosis and exogenous ketones activate an enzyme that makes more GABA, which is an inhibitory neurotransmitter from glutamate (which causes over-excitability). The cells of the hippocampus are selectively vulnerable to oxidative stress and energy deprivation, thus make effective study samples. It is a dynamic area for learning and memory. The hippocampus is thought to be the locus of seizure generation. Robust changes are made in response to different variables.

05:30 Acetoacetate is neuroprotective, so the ketone esters developed by his lab are high in both acetoacetate and beta hydroxybutyrate. Dr. D’Agostino’s lab has 5 different hyperbaric chambers where they do many experiments, including those on live animals, studying them in and without the presence of ketones.

08:07 Clinically, the state of nutritional ketosis is defined as an elevation of blood beta hydroxybutyrate 0.5 and above or urine ketones, which measure acetoacetate, is 15 mg/deciliter or above. This does not occur in the standard American diet. You have to fast more than 18 to 20 hours to achieve it. Athletes can achieve it easily, especially with caloric restriction.

09:54 Ketosis is mobilizing free fatty acids from adipose tissue. These fats go to the liver. Through a process of beta oxidation of fatty acids, you accumulate acetyl CoA. This feeds into the ketogenesis process. We all have different levels of ketolytic enzymes and ketogenic enzymes, these are enzymes in the liver that contribute to the production of ketones. It is a flexible metabolic system. The more we subject our livers to oxidizing fats for fuel, the greater capacity we will have over time, unless we have a fatty oxidation disorder. There is a spectrum of people who have different enzyme disorders and this effects them during ketosis.

13:34 We may have the ability to robustly increase our capacity to make ketones, as well as break down and use ketones. We all have different rates of ketone transport, getting ketones across the membranes and across the blood brain barrier, as well as different rates of ketolytic enzymes. Animal models show that this can be upregulated. After 2 weeks of stimulation of the protein for monocarboxyl acid transporter, it can be upregulated by 50%.

15:38 Ketone supplements, especially the ketone esters, have the capacity to be toxic if they are consumed in large quantities. Ketone salt products have the capacity to be toxic, but they are self-limiting by the amount of mineral load that gets in your gut. The mineral load will cause an osmotic shift and you will excrete them. You can only tolerate so much.

17:22 Ketones have been found to be neuroprotective against high levels of oxygen, reactive oxygen species, glutamate and excitotoxicity. The ketones were preserving the bioenergetics state of the cell, the resting membrane potential. Mitochondria make the ATP that dictates what the resting membrane potential of the cell will be. When ATP levels are high, the cell can maintain the resting membrane potential and not leak ions, even when hit with toxins and stress. Antioxidants deal with the problem after the fact.

21:18 The most potent anti-seizure effects found in animal models are from the elevation of both beta hydroxybutyrate and acetoacetate. His lab developed a potent and effective ketone diester, which is highly neuroprotective.

23:52 Independent of their metabolic properties, ketone molecules have potent signaling properties. A recent study has found that acetoacetate has a potent muscle building effect, enhanced IGF-1 sensitivity, had an interplay with myostatin to suppress some of its effects, and enhanced satellite cell division. Beta hydroxybutyrate has signaling properties as well: as a histone deacetylase inhibitor, and as a suppressor of the inflammasome that leads to chronic inflammation. What is observed in cell culture, is not necessarily what will be observed in a whole animal systems physiology experiment.

29:38 Acetoacetate does not have an enantiomer. Beta hydroxybutyrate does. In the liver the enzymatic pathway associated with hepatic ketogenesis primarily makes D – beta hydroxybutyrate. There is a tissue distribution of a racemic enzyme that can convert the D to the L and the L back to the D. In animal models, the L form is metabolized to acetylCoA, which can feed back and make D – beta hydroxyl butyrate. The D form may have the capacity to enhance mitochondrial metabolism. The L form may have unique properties for lowering blood glucose.

31:36 Exogenous ketones, when consumed as a bolus, can lower blood glucose levels via what appears to be a mechanism that is independent of insulin. This may have therapeutic effects. The glucose suppressing effects are far greater than you get with Metformin. 1 3 butanediol can make you drunk, but it can have anti-cancer effects, even higher than a standard ketone ester, when it is mixed with standard high carbohydrate chow.  The greatest effects were from combining the 1 3 butanediol with the ketogenic diet.

41:40 In his studies of the hippocampus in mouse models, as oxygen levels went up, there was a proportional increase in oxidative stress. Ketones mitigated this by enhancing mitochondrial energy production and reducing the leaking of electrons through the electron transport chain to molecular oxygen. It was then found that ketones function as histone deacetylase inhibitor, type 1 and type 2. It can activate various endogenous antioxidant pathways. Many other pathways can be impacted by ketones.

43:57 The suppressing effect of ketones, in particular beta hydroxybutyrate, may be a major part of protecting the brain and your system from the oxidative stress in extreme environments. Acetoacetate has does not necessarily reduce oxygen free radicals, but seems to work through other mechanisms.

44:40 Being in a state of ketosis and having your ketone levels elevated, and brain tissue levels of ketones at a certain level, improves brain energy homeostasis. This is not just energy. Making neurotransmitters is an energetic process. The activity of the enzyme, glutamic acid decarboxylase, is increased when you are in a state of nutritional ketosis and with exogenous ketones.

46:04 Exogenous ketones work through the adenosine A1 receptor. In their metabolomics study of hundreds of different metabolites in response to feeding forms of exogenous ketones, the adenosine levels were 3 to 5 times higher. Adenosine is neuroprotective, has many different effects upon the heart and is a potent vasodilator.

46:40 Being in a state of moderate ketosis can augment brain blood flow by up to 30%.

47:18 Your brain stores more creatine when you are in ketosis. Creatine is neuroprotective, even against brain injury.

48:49 Caffeine is an adenosine receptor antagonist. Adenosine has a calming effect. Taking ketones does not make you sleepy, but it increases levels of serum and brain tissue adenosine. Caffeine works through a number of different avenues. There are also altered levels of adenosine in obesity.

51:41 Unlike drugs, the ketogenic diet works across all different seizure types. It restores and makes the brain more resilient. Ketosis brings the brain back to a state of balance: energetic balance, redox balance, and probably neurotransmitter balance. This translates to more resilience and neuroprotection from environmental extremes. In ketosis, the energetic state of a cell can be preserved with less oxygen.

57:39 The ketogenic diet is being found to be effective in a number of diseases. When drugs fail to control seizures, the ketogenic diet works. Glucose transporter deficiency syndrome (GLUT1) is a deficiency of the GLUT1 transporter in the blood brain barrier. Blood levels of the cerebral spinal fluid are very low and the brain is starved for glucose. Elevating ketones provides the brain with an alternative energy substrate. Angleman syndrome is a persistent molecular pathology that can be silenced/masked with a metabolic based therapy.

01:03:32 Being in a state of ketosis, combined with a state of mild calorie restriction, quiets the brain and reduces anxiety behavior (in rodent models). This could be because of less glutamate and more GABA. You are more lucid and more receptive to the states of others. This can be achieved with fasting and nutritional ketosis with the correct food selection. Parents report that placing their child on a ketogenic style diet improves behavior.

01:06:35 Exogenous ketones can attenuate some of the rebound effect from periodic hypoglycemia, which would activate your sympathetic nervous system. Changing your metabolic physiology can have profound changes upon your sympathetic nervous system and your parasympathetic nervous system.

01:11:26 A ketogenic diet approach can be used to maintain and build muscle. Dr. D’Agostino partakes in a loose modified Atkins diet with ketone supplementation. He also does intermittent fasting a few days a week. It enables him, and his like-minded friends, to maintain and build their strength. He advises titrating more calories into your diet on workout days.

01:15:10 Your mitochondrial function will be better preserved if you live in a state of or go in and out of a state nutritional ketosis and do intermittent fasting a few times a week. Change it up. Your body adapts and will adapt better when you provide stress for it to adapt to, including eating seasonally. As we age, generally our carbohydrate tolerance goes down. It is probably in part due to the inevitable decline of our mitochondria.

01:17:02 Exercise is a huge hammer, as big as nutrition, in slowing aging. Designing resistance training for rats is a challenge. The amount of muscle you have correlates with reducing cancer rates.

01:22:11 Repeatedly in animal studies there is a decrease in weight, 5 to 15%, using a ketone ester. A bolus of caffeine can increase ketone levels by 30 to 50% by mobilizing fatty acids from your adipose, which go to your liver to make ketones. The ketogenic diet works, in part, through an appetite suppressing effect. Weight loss due to ketone supplementation are from the ketone effects upon brain energy metabolism. Larger human clinical trials are needed. Count/track your macros.

01:31:45 Dr. D’Agostino’s single favorite exercise is chin-ups. They decompress your spine, work your grip, and work your lats.

01:32:20 Dr. D’Agostino’s desert island supplement is coffee, which is full of polyphenols. When you combine MCTs with ketone salts, your ketones can be elevated higher than with either one alone and extends the pharmacokinetic profile. His lab is actively trying to deduce the optimal formula.

01:36:07 Dr. D’Agostino’s morning routine is flexible. He lets the dogs out and plays with them. His dogs are ketogenic. Two to 3 days a week he does intermittent fasting.  He drinks fatty coffee. He feels best on fasting mornings. He sets aside creative down time every day where he spends time with his wife and releases from work.

01:39:12 Dr. D’Agostino’s Elevator Pitch: Switch farm subsidies to small organic farms. This would result in shifting consumer preferences by shifting price points.

 

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