Episode 14: Dominic D’Agostino discusses the physiological benefits of nutritional ketosis

Dominic D’Agostino looks like a bodybuilder. But that doesn’t mean that he eats a diet typical for that sport; on the contrary, the research scientist—and amateur athlete—can go an entire day without eating and says his performance—both in the lab and in the gym—improves because of it.

D’Agostino is perhaps rare in the world of science in that he practices what he preaches. As associate professor in the department of molecular pharmacology and physiology at the University of South Florida, and a visiting research scientist at IHMC, D’Agostino develops and tests metabolic therapies for a range of diseases and conditions for which the ketogenic diet is the cornerstone.

The low-carb, moderate-protein, high-fat ketogenic diet is what he also follows for health and greater mental clarity.

The ketogenic diet for decades has been used, albeit perhaps sparingly in the clinic, to treat epileptic seizures. D’Agostino is working on the development of exogenous ketones in the form of ketone esters for cancer and neurological disorders as well.

For more information on D’Agostino and his research, visit: http://health.usf.edu/medicine/mpp/faculty/24854/Dominic-DAgostino.aspx or http://www.ketonutrition.org.

His IHMC bio is at http://www.ihmc.us/groups/ddagostino/; and his IHMC talk “Metabolic Therapies: Therapeutic Implications and Practical Application”: https://www.youtube.com/watch?v=gONeCxtyH18

D’Agostino is a long-time friend and colleague to STEM-Talk Host Dawn Kernagis, and the two engage in a rich, cutting-edge conversation with knowledgeable input from IHMC Director Ken Ford in this episode.

00:37: Dawn introduces D’Agostino, who goes by ‘Dom,’ and Ken Ford as co-host.

2:14: Ford reads an iTunes five-star review of STEM-Talk from “A Sweet 81,” which is entitled BAM: “Amazing podcast. It’s like candy for the brain. That is, if candy was good for your brain. So it’s like ketones for your brain.”

2:48: Dawn describes Dom’s research: He develops and tests metabolic therapies for CNS oxygen toxicity, epilepsy, neurodegenerative diseases, brain and metastatic cancer. Main research focus past five years: understanding why the ketogenic diet and ketone esters are anticonvulsant and protective to the brain.

4:15: Dom says his interest in science started in high school: He was a football player and wanted to improve his athletic performance. His honors biology teacher got on him to study hard. “I saw biology and science as a way to understand my own biology and physiology to maximize my performance.”

5:23: During his Ph.D. program in neuroscience and physiology at the Robert Wood Johnson Medical School, his mentor urged him to be an independent thinker. He describes being “thrown into the fire” when he was asked to apply basic science research to medical situations. He specifically looked at how the brain responded to hypoxia.

7:12: He did a post-doc with Jay Dean and also became a recreational diver. “Dean was the only person studying cellular and molecular mechanisms of extreme environments.”

8:36: Of Dean, he said, “The tools he created are filling gaps in the understanding of dive physiology.”

10:19: Nutritional ketosis is important for the metabolic management of diseases, especially seizures.

10:45: Nutritional ketosis works similarly to fasting: you liberate free fatty acids from the adipose tissue and break down stored glycogen levels in the liver. Once the glycogen levels reach a certain level, you start accelerating the oxidation of fatty acids in liver.

11:11: Dom explains how ketosis works: the heart (and muscles) prefers fatty acids over glucose, but they don’t readily cross the blood-brain barrier. So brain energy metabolism will transition from glucose to a fuel source called ketone bodies, which is a by-product of accelerated fat oxidation in the liver. These represent water soluble fat molecules that readily cross the BBB; they help preserve, maintain and enhance brain energy metabolism in the face of starvation.

11:54: The ketogenic diet has a macronutrient ratio that mimics the physiological state of fasting: high fat, moderate protein, and very low carbohydrate.

12:22: Nutritional ketosis has been used for over 90 years to manage drug-resistant epilepsy.

13:25: The ketogenic diet helps control seizures because it’s effective at achieving brain energy homeostasis.

14:28: The Office of Naval Research has played the key and primary role in sponsoring Dom’s research program to develop and test exogenous ketone esters for mitigation of CNS oxygen toxicity in Navy divers.

14:46: “Here was a substance that could potentially mitigate CNS oxygen toxicity; but also at the same time potentially enhance physical and cognitive performance.”

15:27: Of all the ketone esters that Dom and colleagues tested, the one that would elevate beta hydroxybutyrate and acetoacetate more or less in a one to one ratio was most efficacious in controlling seizures.

19:09: The ketone ester worked in every single experiment we did, which was remarkable.

20:20: Dom says they want to move into human studies of testing cognitive resilience under hypoxia using exogenous ketones.

21:00: Dom talks about the potential for ketones to protect against radiation in space as well as in cancer treatments. Adrienne Scheck at the Barrow Neurological Institute has done animal studies on glioblastoma showing that “If animals are in a state of nutritional ketosis, sensitizes tumors to radiation, and makes the radiation much more lethal because ketones have an anti-cancer effect.”

22:30: Basic science supports idea that nutritional ketosis could preserve cognitive and physical functions under conditions of hypoxia; and also preserve the cellular, tissue and physiology of people exposed to radiation. This is especially important for astronauts, who may suffer long-term from cancer.

23:16: Commercial break: STEM-Talk is an educational service of the Florida Institute for Human and Machine Cognition, a not-for-profit research lab pioneering ground-breaking technologies aimed at leveraging human cognition, perception, locomotion and resilience.

23:40: Dawn mentions that Dom is taking a metabolism-centric approach to so many conditions, including seizures, cancer, traumatic brain injury, Alzheimer’s Disease, ALS, and muscle wasting. “How to have traction in so many diseases?”

24:37: Dom explains that cellular metabolism relates to so many different disorders.

27:32: A lot of people are turning their attention to cancer metabolism. Cancer growth is tightly linked to insulin, and the liver creates ketones in response to decreased insulin.

30:31: The ketogenic diet abolishes those spikes in glucose/insulin. “That’s a powerful part of efficacy as a metabolic therapy for cancer/managing seizures.”

31:00: Ketone bodies were once considered a bad thing. But in the past ten years ago, they have been appreciated an efficient metabolic substrate for cells; and in the last five years, a powerful signaling molecule that can influence inflammation and endogenous anti-oxidant in cell.

38:33: Anecdotally, patients with Parkinson’s Disease have improved in nutritional ketosis.

40:00: They are also encouraged by research on the effects of nutritional ketosis on brain injury and stroke.

40:50: Nutritional ketosis can, in some cases, mitigate the consequences of traumatic brain injury.

43:08: 80-90 percent of people with brain injury will have seizures. The VA system is looking into this. “Exogenous ketones would be the way to go. Something could be developed that could be taken to the field—either orally or via IV.”

47:45: Undoubtedly cancer is a genetic disease in that certain oncogenes are activated that can cause transformation of a healthy cell to a cancer cell. We believe that the initial insult associated with genomic instability results from a decrease in mitochondrial oxidative phosphorylation. And the nucleus senses that.

48:18: Mitochondria are ultimate tumor suppressor; one way to keep them healthy is by feeding them fuels that are metabolized exclusively in mitochondria; ketones (and fatty acids) are metabolized in the mitochondria. We need to enhance our mitochondrial function and biogenesis. “The more we have, the greater bio-energetic potential the cell has for preservation under stress.”

49:20: We’re studying a bunch of disorders, including Angelman Syndrome, a rare disorder characterized by drug-resistant seizures and severely impaired motor function.

50:50: Nutritional ketosis (perhaps specifically the use of IV esters) could also avert the use of anti-seizure drugs that in children can cause developmental delays.

51:18: Brain cancer patients would be great candidates for nutritional ketosis for managing cancer.

53:34: He notes several challenges to getting ketone esters into widespread medical application: funding; IRB approval; patient recruitment. Many institutes will not run a diet trial for cancer. Metabolic-based therapies are not recognized at this time as an effective treatment for disease management. Medical school students are not taught nutrition.

56:10: Ford shares his own positive experience on the ketogenic diet, which he has been on off and on throughout his whole life and continuously for the last decade. He reports a range of physical and cognitive benefits; and is hopeful about the prophylactic potential for age-related diseases.

57:00: Dom shares his experience on the ketogenic diet, which he embraced in 2009. “I thought it was important for a strength athlete to eat six meals a day; on a carb-based diet I was hungry every few hours.” His hunger went down on the ketogenic diet.

58:30: He says making the transition from glucose to ketones was rough. He had glucose withdrawal symptoms in the brain. “I felt foggy initially; but then, there was clarity after two to three weeks. The more I followed the diet, the easier it got for me.” Specific benefits include cognitive resilience when fasting and improved sleep.

1:02:50: Fasting is the quickest way to activate AMPK; the ketogenic diet mimics caloric restriction that will activate AMPK (the suppression of insulin.) The drug metformin also activates AMPK.

1:07:38: They are also doing a lot of studies on the tissue-specific effects of metformin.

1:10:05: The ketogenic diet mimics metformin. One question is: If we use both, can we get a twofer?

1:13:09: Benefits from ketogenic diet are more beneficial (than metformin) for anti-aging. Using both may be synergistic.

1:14:12: They need to do clinical trials of metformin and ketogenic diet, in order to study the metabolic biomarkers.

1:14:35: Commercial break: STEM-Talk is an educational service of the Florida Institute for Human and Machine Cognition, a not-for-profit research lab pioneering ground-breaking technologies aimed at leveraging human cognition, perception, locomotion and resilience.

1:16:37: Dom says the data on mTOR is fascinating; and in some ways confusing and conflicting to get through it all. Ketogenic diet can cause suppression of mTOR.

1:18:18: There are studies on how the ketogenic diet impacts the immune system. Adrienne Scheck published recently a paper on how the ketogenic diet could make the immune system hyper-vigilant in seeking out cancer cells.

1:19:00: The ketogenic diet activates AMPK and decreases mTOR.  Ford and D’Agostino discuss the subtle interplay between AMPK and mTOR and the possible trade-offs between health-span and longevity, especially in the context of sarcopenia.

1:19:25: The ketogenic diet, caloric restriction, intermittent fasting, and metformin converge on these pathways that are of intense interest to pharmaceutical companies.

1:20:00: Dom recommends a ketogenic diet to anyone who has had cancer and wants to prevent its recurrence. “The emerging animal data is enough” to convince him of its efficacy; he also would recommend metformin and intermittent fasting.

1:25:00: Branch chain amino acids that work through the activation of mTOR can preserve weight in animals with cancer cachexia. Could also be useful for sarcopenia.

1:26:52: Dom’s recommendation for muscle building/maintenance: “Lift heavy stuff and eat just enough to recover.”

1:27:55: Ford calls IGF-1 a “Goldilocks hormone: low and high levels both seem problematic.”

1:29:46: Dom says it’s important to make the distinction between circulating and local IGF-1. Strenuous, low-bearing exercises can increase local IGF-1, and the ketogenic diet sensitizes the body to local IGF-1.

1:32:22: Chronically elevated IGF-1 levels are not a good thing.

1:34:00: Ford recounts a significant decrease in his own circulating IGF-1 levels as a result of the ketogenic diet.

1:34:45: Ford notes that aging athletes avoid the ketogenic diet because they think it will lower IGF-1 and therefore lower their muscle protein synthesis. “But they are not making the distinction between local and circulating IGF-1; nor the distinction between a denser collection of receptors and more sensitive receptors.”

1:35:20: Athletes who do well on the ketogenic diet include those doing distance running, cycling, rowing; weight-class restricted sports.

1:36:00: The Elite Gymnast published a study of athletes on a modified Atkins diet and the ketogenic diet; those on the latter had maintenance of strength and more significant body alteration. “The use of the ketogenic diet for performance really shines in the context of trying to make weight for a certain event.” Or where the power to weight ratio is important, such as in wrestling or cycling.

1:37:37: Dom cites study of elite-level endurance athletes by Jeff Volek and Stephen Phinney.

1:39:00: Another study showed that testosterone was 25-30 percent higher in people on the ketogenic diet (vs the Western diet); they also gained muscle strength and size.

1:41:10: We typically become increasingly carb-intolerant with age.

1:42:45: Dom would most like to see FDA approval for exogenous ketones in epilepsy patients soon.

1:43:30: “Developing metabolic-based treatments (where nutritional ketosis is the cornerstone) for neurological diseases and cancer… is the thrust of what I want to accomplish as a scientist.”

1:44:40: Dom mentions a number of people in his lab who are doing excellent work, including his wife Csilla Ari, who spearheaded work on an ALS project and is studying the effects of nutritional ketosis in behavior disorders such as anxiety. Her work showed that animals in nutritional ketosis were easier to handle.

1:48:00: Dom says ketones might have application for treating PTSD in the military.

1:49:00: Dom and Csilla have a rescue dog from the Tampa Humane Society: “He’s our recovery. We go on nightly walks; we go to the beach a lot and bring our dog with us whenever we can.” They also love international travel and visited several countries in Southeast Asia on their recent honeymoon.

1:51:00: Dom explains his optimistic outlook and good nature: “To a large extent, it’s who you surround yourself with. If you’re grateful, it’s hard to be angry.”

1:52:30: His advice to young scientists: “You really have to follow what you’re passionate about. Identify people who are doing what you want to do. Contact those people; follow their paths. If you’re really passionate, and your research is meeting a need for someone, you’re going to be happy and fulfilled.”

1:54:35: Ford calls Dom’s research “important, innovative and impactful.”

1:54:55: Dawn and Ken sign off.