HoldsUp

Thomas Seyfried

Boston College

Thomas Seyfried, PhD, is a professor of biology at Boston College who specializes in the metabolic origins and treatment of cancer. He is the author of "Cancer as a Metabolic Disease" and co-developed the Glucose Ketone Index. His published research focuses on ketogenic metabolic therapy, mitochondrial metabolic theories of cancer, cellular fermentation mechanisms, and repurposed drug combinations for conditions such as glioblastoma.

26 claims checked on air: 4 context 5 contradicted 3 overstated 11 supported 3 unverified

What they said on air - citing their own research

5 citing their own research

0:08:56overstatedvery lowtheir own paperEmily Kaplan and Dr. Seyfried: The oncology field must under

The Glucose Ketone Index can be used as a clinical tool to monitor and manage all major chronic diseases and cancers.

"Our big paper that just came out last week, Frontiers in Science, talks about the glucose ketone index as a tool for managing all the major chronic diseases and cancers." (said at 0:08:56)

The Glucose Ketone Index (GKI) was introduced by Seyfried and colleagues as an experimental metric to track metabolic ketosis and blood glucose in preclinical models and preliminary trials of brain tumors (such as glioblastoma). Claiming that GKI is an established clinical tool to monitor and manage 'all major chronic diseases and cancers' is a substantial overstatement. Systematic reviews show that even in brain tumors, evidence for ketogenic metabolic therapy is limited, heterogeneous, and unproven for survival outcomes, and broad clinical utility across all chronic diseases has not been validated in clinical trials.

0:10:28overstatedvery lowtheir own paperEmily Kaplan and Dr. Seyfried: The oncology field must under

Ketogenic metabolic therapy combined with targeted drugs facilitates drug delivery across the blood-brain barrier for pediatric brain cancers.

"And I think that with the big paper that we had with Purna Mukherjee a couple of weeks ago in Cell Reports Medicine, we've shown how ketogenic metabolic therapy can facilitate drug delivery to manage these different cancers. Brain can—childhood brain cancer, number one killer of little kids. We know how to manage that now effectively without toxicity." (said at 0:10:28)

Evidence for ketogenic diet acting as a metabolic vehicle to enhance drug delivery and therapeutic efficacy for pediatric brain cancers comes entirely from preclinical animal models (juvenile syngeneic mice) and in vitro cell lines, rather than clinical human trials. A recent study in Cell Reports Medicine demonstrated that a ketogenic diet combined with repurposed/targeted drugs (mebendazole and devimistat) enhanced survival and reduced tumor invasion while allowing lower drug dosing in juvenile mouse glioblastoma models, but clinical efficacy in pediatric patients remains unproven.

0:11:18needs contextvery lowtheir own paperEmily Kaplan and Dr. Seyfried: The oncology field must under

Cancer cells drive dysregulated growth through the fermentation of glutamine via substrate-level phosphorylation in the mitochondrial matrix.

"one of the mechanisms to drive dysregulated cell growth is the fermentation of glutamine. That's why you have to go back before you can talk about mebendazole, fenbendazole, and some of these others. You have to know how we made the second major discovery after Otto Warburg, which was the fermentation of an amino acid in the matrix of the mitochondria through substrate-level phosphorylation." (said at 0:11:18)

The claim accurately describes the mitochondrial metabolic theory of cancer articulated by Thomas Seyfried and colleagues, which posits that cancer cells utilize glutamine-driven mitochondrial substrate-level phosphorylation (specifically via the succinate-CoA ligase step in the TCA cycle within the mitochondrial matrix) as a fermentation mechanism to generate ATP and drive dysregulated growth when oxidative phosphorylation is impaired. However, the evidence base for this concept consists primarily of theoretical narrative reviews and in vitro preclinical experiments in glioma cell lines, rather than definitive evidence across broad human clinical malignancies.

0:12:45contradictedlowtheir own paperEmily Kaplan and Dr. Seyfried: The oncology field must under

Mebendazole targets the glutaminolysis pathway to kill parasites and can kill cancer cells via the same metabolic target.

"We just published the mechanism in Purna's paper. We clearly showed that mebendazole targets the glutaminolysis pathway to kill the parasite, and also because the cancer cell is using the same pathway in part, then you—then you manage the cancers the same way." (said at 0:12:45)

Mebendazole's primary and well-established mechanism of action against parasites is the selective binding to helminth β-tubulin and disruption of microtubule polymerization, not targeting the glutaminolysis pathway. Similarly, in oncology research, its primary antitumor mechanism is described as the inhibition of tubulin polymerization alongside anti-angiogenic and signaling pathway alterations. While isolated preclinical studies have noted downstream metabolic effects such as glycolysis and glutaminolysis inhibition in specific glioma cell lines, glutaminolysis is not the recognized parasitic target or the primary antitumor mechanism.

0:52:00needs contextvery lowtheir own paperEmily Kaplan and Dr. Seyfried: The oncology field must under

In a Greek clinical trial of 18 glioblastoma patients receiving standard radiation, those who followed a calorie-restricted Mediterranean diet had significantly improved survival and a higher rate of reaching the three-year mark.

"Even in even in our Greek trial where we had 18 patients, those individual, they were all nuked. And I hate to say it, but that's what they do... But those individuals that did a a calorie-restricted Mediterranean diet lived significantly longer. More of them made the three-year mark than the ones who didn't take the Mediterranean diet." (said at 0:52:00)

The speaker appears to be referring to a 2024 Greek clinical study of 18 patients with glioblastoma (PMID 40041752), but misidentifies the intervention. The study tested dietary ketogenic metabolic therapy (a ketogenic diet), not a calorie-restricted Mediterranean diet. In that prospective cohort of 18 patients, 6 patients adhered to the ketogenic diet for >6 months and exhibited a significantly higher 3-year survival rate compared to the 12 non-adherent patients (66.7% vs. 8.3%, p = 0.0114). However, the evidence certainty is very low due to the tiny sample size, lack of randomization, and inherent selection/adherence bias (e.g., immortal time and healthier-patient bias in those able to adhere). Furthermore, a separate cohort study specifically assessing Mediterranean-like diets in glioblastoma found no survival benefit (PMID 40690185).

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