#120 - AMA with Dom D'Agostino, Ph.D., Part II of II: Ketosis for cancer and chronic disease, hyperbaric oxygen therapy, and the effect of ketosis on female health

Episode Summary

Executive Summary: This AMA sneak peek centers on Dom D’Agostino’s view of ketosis as a metabolic therapy for cancer, especially when combined with hyperbaric oxygen, radiation, fasting, and drugs that target glucose or glutamine metabolism. The discussion emphasizes “press-pulse” therapy: first weaken tumors metabolically, then apply oxidative or targeted stress to improve treatment response, while noting the evidence is largely preclinical and not medical advice.

Main Topics: Press-pulse therapy for cancer (Priority: 5/5): Dom explains the concept of using therapeutic ketosis to 'press' tumors metabolically, then applying a 'pulse' such as hyperbaric oxygen, radiation, or drugs to exploit tumor vulnerability. Ketosis, glucose restriction, and tumor metabolism (Priority: 5/5): The conversation details how lowering insulin and glucose availability may slow tumor growth, reduce glycolysis, and make cancer cells more susceptible to oxidative stress. Hyperbaric oxygen and oxidative stress (Priority: 5/5): Dom describes how hyperbaric oxygen can increase reactive oxygen species in cancer cells, especially when combined with ketosis or radiation, potentially enhancing tumor cell death. IV vitamin C as a pro-oxidant cancer adjunct (Priority: 4/5): Vitamin C is framed not as an antioxidant here but as a high-dose pro-oxidant that can antagonize glucose transport and amplify oxidative damage in tumors. Glutamine targeting and metabolic flexibility (Priority: 4/5): The discussion covers glutamine dependence in tumors, the use of DON and related inhibitors, and the idea that blocking multiple fuel pathways may improve outcomes. Preclinical models and cancer cachexia (Priority: 3/5): The VMM3 metastatic cancer model is highlighted as a powerful system for studying metastasis and cachexia, with implications for more realistic cancer research. Fasting, ketogenic diets, and case reports (Priority: 3/5): Recent case studies and mouse studies are cited suggesting fasting plus ketogenic approaches may reduce tumor burden in difficult cancers, though evidence remains early.

Key Arguments: Therapeutic ketosis may weaken tumors by lowering insulin signaling, reducing glucose availability, and limiting glycolysis-driven growth. Most cancers cannot efficiently use ketones as a fuel source, so ketosis may create a metabolic disadvantage for tumors. Hyperbaric oxygen can increase reactive oxygen species in tumor cells, and this effect may be amplified when tumors are metabolically stressed. Radiation efficacy is strongly linked to tumor oxygenation; oxygenating tumors can sensitize them to radiation. High-dose IV vitamin C may act as a pro-oxidant and glucose antagonist, making it potentially useful in metabolic cancer therapy. Tumors often have elevated free iron/heme and aberrant mitochondria, which can intensify oxidative damage when exposed to oxygen or vitamin C. Glutamine is another major tumor fuel, so combining ketogenic strategies with glutamine inhibition may be more effective than targeting glucose alone. The VMM3 metastatic model is especially valuable because it captures metastasis and cachexia better than simple tumor-shrinkage models. Much of the current press-pulse framework is still preclinical and hypothesis-driven, not established clinical therapy.

Data Points: Hyperbaric oxygen protocol: 2.5 atmospheres, 60 minutes, 3 times per week - Used in animal studies combining hyperbaric oxygen with a modified ketogenic diet Tumor burden/lifespan effect: Decreased tumor burden and extended lifespan - Observed in the VMM3 metastatic cancer model with ketogenic diet plus hyperbaric oxygen Glucose ketone index target: 1 to 2, ideally below 1 - Suggested range to create a metabolic environment less favorable to tumor growth Radiation mechanism: 80% to 90% reactive oxygen species generation - Estimated proportion of radiation’s cancer-killing effect attributed to ROS rather than direct DNA damage Tumor oxygenation effect: Radiation efficacy is directly proportional to tumor PO2 - Higher oxygenation increases radiation sensitivity Case report tumor reduction: About 90% to 96% decrease in tumor burden - Reported in a metastatic thymoma case using fasting, ketogenic diet, and other therapies Weight loss in case report: About 15 kilograms - Described during episodes of reduced oral intake in the metastatic thymoma patient Tumor size change in case report: Roughly 600 cubic centimeters to about 30 cubic centimeters - Approximate visual/volume comparison discussed for the thymoma case Mouse survival curve: No deaths through 40 days - Calorie-restricted ketogenic diet plus DON in a Kaplan-Meier curve from a mouse study Standard diet comparison: All mice dead by about 15 days - Contrasted with the ketogenic plus DON group in the same preclinical study

Pivotal Quotes: "“the lower that is, ideally in the one to two range, below one if possible”" — Dom D’Agostino: Describing the desired glucose ketone index for press-pulse metabolic therapy "“if you can cure cancer in this model system, then you’ve cured cancer”" — Tom Seyfried (as relayed by Dom): Referring to the aggressive VMM3 metastatic cancer mouse model "“I’m so into the pro-oxidant effect of vitamin C and down to the redox pathways that I don’t even think about as an antioxidant anymore”" — Dom D’Agostino: Explaining why high-dose IV vitamin C may help in cancer therapy

Implications: The episode suggests a growing but still preclinical case for combining ketosis, fasting, oxygen-based therapies, and metabolic drugs to stress tumors. For listeners, it highlights promising research directions, not proven treatment guidance.