Today we have Dr. Dominic D’Agostino, who over the past 10 years has been a frequent guest on STEM-Talk. Today Dom joins us to give us an update on his recent research into ketogenic metabolic therapies, ketone supplements as well as hyperbaric oxygen therapy for traumatic brain injuries. Dom and his lab at the University of South Florida have published more than 20 papers since his last appearance on STEM-Talk in 2023.

Dom is an Associate Professor in the Department of Molecular Pharmacology and Physiology at South Florida’s Morsani College of Medicine. Dom has a background in neuroscience, molecular pharmacology, nutrition and physiology.

In addition to developing and testing metabolic-based therapies, Dom’s lab also investigates seizure disorders, brain cancer, neurodegenerative diseases and rare genetic-metabolic disorders.

Show notes:

[00:03:28] Dawn welcomes Dom back to the show and explaining that he has been quite busy since his last appearance, authoring or co-authoring more than 20 papers. Over the past several years, Dom has been helping to advance the science and application of ketogenic metabolic therapy (KMT) with colleagues at Moffitt Cancer Center, particularly focusing on using KMT to enhance immune-based therapies for certain types of cancers. Dawn asks Dom about this collaboration.

[00:05:04] Dawn explains that ketogenic metabolic therapy is a dietary approach that focuses on a high-fat/low-carb diet to reduce glucose availability for cancer cells, potentially slowing their growth and improving treatment outcomes. It has been explored as a complimentary treatment for a variety of cancers including gliomas by shifting the metabolism of tumor cells away from glucose. Dawn asks Dom to explain what is involved in KMT.

[00:06:58] Dawn clarifies that KMT requires less than 20-25 grams of carbohydrates per day, and that ketosis is a metabolic state in which the body switches from glucose metabolism to metabolizing fats in the form of ketones. Dawn goes on to explain that cancer cells typically consume glucose at a higher rate than normal cells. However, cancer cells are also very adaptable, and Dawn asks Dom to talk about this feature of cancer cells.

[00:09:14] Ken explains that KMT has shown the most promise in treating high-grade gliomas, or brain cancers, such as glioblastoma, which is the most aggressive primary brain tumor in adults. Ken explains that Dom was part of a massive review titled “Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma,” which proposed guidelines for the management of glioblastoma based on an understanding of cancer as a metabolic disease, particularly involving mitochondria. Ken asks Dom to talk about this review.

[00:11:21] From a patient advocacy perspective, Ken notes that the review recommends that there should be an aggressive education campaign that can arm patients with knowledge about KMT and other novel therapies. Ken asks Dom to talk about that recommendation.

[00:13:15] Ken asks about the process of cutting the review from upwards of 200 pages down to around 50 pages with 49 authors.

[00:15:04] Dawn mentions that Dom was part of another paper in 2024 titled “Targeting the mitochondrial stem cell connection in cancer treatment – a hybrid orthomolecular protocol.” Dawn explains that this paper looked at the mitochondrial stem cell connection theory (MSCC), which argues that cancer originates from chronic oxidative phosphorylation insufficiency in stem cells. This insufficiency leads to the formation of cancer stem cells and abnormal energy metabolism ultimately resulting in malignancy. There were 16 research centers and organizations involved in this paper which introduced a hybrid orthomolecular protocol to target the mitochondrial stem-cell connection. Dawn asks Dom to give an overview of MSCC.

[00:18:26] Dawn explains that in this paper Dom and his co-authors propose a protocol that would enhance oxidative phosphorylation and inhibit the primary fuels of cancer, glucose and glutamine. This would target both cancer stem cells and metastasis. Dawn asks Dom to explain why this concept is attracting so much interest as a potential therapeutic approach for cancer.

[00:20:48] Dawn asks if Dom could discuss the orthomolecular protocol, which is an approach that focuses on preventing and treating diseases by correcting nutritional balances in the body.

[00:24:41] Ken asks if the proposed dietary intervention in the orthomolecular approach is different from a standard or typical ketogenic diet.

[00:26:48] Ken shifts the discussion to talk about ketone supplements, explaining that Dom recently published a paper titled “Divergent hepatic outcomes of chronic ketone supplementation.” Ken goes on to explain that ketone salts preserve liver health, while some ketone esters and precursors appear to drive inflammation and steatosis. There is a lot of interest in ketone supplementation because they substantially elevate circulating ketones without having to restrict carbohydrates as strictly. The problem, as Ken explains, is that the long-term hepatic safety of ketone supplements remains unclear. In the aforementioned paper, Dom’s rodent study evaluated the formulation-dependent impact of chronic ketone supplementation on liver histopathology, inflammatory signaling and systemic biomarkers. Ken asks Dom to discuss this paper and its findings and to give an overview of the various ketone supplements currently available.

[00:30:49] Dawn asks Dom to dive into the methods and findings of the rodent study.

[00:34:36] Ken asks Dom what his confidence is in the rodent model used in this study, and what are the next step for further research.

[00:37:47] Regarding the two different doses given to rats in the study, Ken asks Dom how these doses correlate to doses in humans

[00:40:23] Ken mentions that Ben Bikman, who was our guest on episode 143, published a study in February which Dom helped co-author. It examined the effects of ketone supplements on liver function. Ken asks Dom to discuss this study.

[00:44:38] Dawn pivots to ask about a joint paper that Dom did with Andrew Koutnik, who was our guest on episode 185, on carbohydrates and physical performance titled “Carbohydrate ingestion on exercise metabolism and physical performance.” Dawn asks Dom to talk about this paper, which showed that a small amount of carbohydrates is sufficient to fuel athletic performance, and how additional carbohydrate intake showed diminishing returns.

[00:49:18] Ken follows up on the finding that endurance athletes who rely on carb loading can tend toward pre-diabetes.

[00:51:39] Ken asks Dom about the University of South Florida trial that Dom is an advisor for on traumatic brain injury and hyperbaric oxygen therapy.

[00:54:41] Dawn mentions that Dom recently had an editorial in Frontiers that gave an overview of the emerging applications of hyperbaric/hyperbaric-oxygen therapy in the treatment of different neurological disorders. Dawn asks Dom what the key points in that editorial were.

[00:59:06] Dawn explains that Dom recently gave a lecture at IHMC (available to view on IHMC’s YouTube page), on traumatic brain injury and the populations at greatest risk in that context. Dawn asks Dom to give an overview of how an injury to the brain can result in neurometabolic crisis.

[01:02:53] Ken asks Dom, excluding occupation demographics, what demographic is most at risk for traumatic brain injury (TBI) and why.

[01:04:45] Ken mentions that it is understandable the risk that young people face with TBI due to the activities that young people engage in. Older people, however, have increased risk of TBI from falling as well as an additional age-related biological component that young people are not subject to. Ken asks Dom to elaborate on this.

[01:07:12] Dawn mentions that several years ago, Dom and his wife bought some acreage in the countryside and started farming and asks Dom how the farm life is going.

[01:07:57] Dawn closes the interview asking how Dom’s wife is doing.