In this Journal Club, Bob Kaplan and Pete Shaw explore cancer through a metabolic lens, focusing on the normal physiological roles of hereditary cancer syndrome (HCS) genes. Rather than viewing these genes primarily as drivers of cancer through mutation, they present them as fundamentally involved in mitochondrial function, oxidative phosphorylation (OXPHOS), and cellular energy regulation. Drawing on recent literature—including Kaplan’s 2025 paper linking hereditary cancer syndromes to oxidative phosphorylation insufficiency—their discussion suggests that disruptions in mitochondrial metabolism may precede and potentially drive many of the genetic alterations commonly associated with cancer. They also highlight evidence from exercise physiology studies showing that genes such as BRCA1 and p53 play key roles in maintaining mitochondrial performance and genomic stability during energetic stress, reinforcing the idea that these genes serve important metabolic functions under normal conditions.
Bob and Pete further critique how the naming and study of cancer genes has biased research toward mutated functions, leaving their normal physiological roles underexplored. They connect this perspective to broader frameworks such as the atavistic theory of cancer, which proposes that cancer represents a reversion to primitive metabolic programs characterized by fermentation and substrate-level phosphorylation. In this view, mitochondria act as functional tumor suppressors by sustaining differentiated cellular metabolism, and when mitochondrial capacity declines, cells compensate by shifting toward glycolytic states similar to those seen in stem cells and tumors. The discussion also touches on environmental factors—including tobacco, diet, and infections—which account for the majority of cancers, yet cancer research remains heavily centered on genetic mutation models, reflecting longstanding scientific dogma and institutional inertia that have hindered exploration of cancer’s metabolic origins.
Featured paper:
- Hereditary cancer syndromes linked to oxidative phosphorylation insufficiency:Â Kaplan et al (2025).
- Metabolic Signatures of Performance in Elite World Tour Professional Male Cyclists: Nemkov et al (2023).
- Skeletal Muscle Function Is Dependent Upon BRCA1 to Maintain Genomic Stability: Tarpey et al (2021).
- p53 improves aerobic exercise capacity and augments skeletal muscle mitochondrial DNA content: Park et al (2009).
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This Journal Club meeting summary is free for anyone to watch. BSI Medical Society Members and MetFix affiliates can access the full meeting archive in their Dashboard.
Bob Kaplan is an independent research analyst. Bob previously served as director of research at Early Medical, contributing to The Drive podcast with Peter Attia and its other properties. Kaplan was a researcher at the Nutrition Science Initiative (NuSI), and an exercise physiologist at the University of Nevada, Las Vegas. His current and previous research interests include meta-research, chronic diseases, bioenergetics, exercise physiology, and nutrition.
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Metabolic health, medical education, and the case for bringing clinicians and coaches together
At the 2026 Unbreakable Health Retreat in Miami, Emily Kaplan hosted a panel with Bob Kaplan, Professor Thomas Seyfried, and Dr. Derek Lee on what it means to treat cancer as a metabolic disease. They discussed the glucose-ketone index (GKI), nutritional ketosis, and strategies aimed at restricting the fuels cancer cells depend on while considering how metabolic therapy can fit alongside standard cancer treatment.
The conversation also addressed the practical realities patients face when trying to pursue a metabolic approach within the conventional oncology system, including questions about nutrition, repurposed drugs, inherited cancer risk, and how to evaluate different treatment options. Seyfried and Lee connected these clinical questions back to mitochondrial dysfunction, fermentation, and the metabolic vulnerabilities that may offer additional targets for cancer treatment.
An abbreviated version of this discussion is available here, for free.
At the 2026 Unbreakable Health Retreat in Miami, Professor Thomas Seyfried presented the case that cancer is fundamentally a mitochondrial metabolic disease rather than primarily a genetic one. He contrasts the dominant somatic mutation theory with a metabolic model in which impaired mitochondrial respiration drives a shift toward fermentation, dysregulated cell growth, and the mutations commonly associated with cancer.
Citing the work of Otto Warburg and research from his lab at Boston College, Seyfried explains how cancer cells rely heavily on fermentable fuels—particularly glucose and glutamine—and why mitochondrial dysfunction sits upstream of many of the genetic abnormalities seen in tumors. He also discusses reactive oxygen species, altered cellular signaling, and the role of mitochondria in regulating cell growth and behavior.
The presentation then turns to the therapeutic implications of this model. Seyfried explains strategies aimed at placing tumor cells under metabolic stress by restricting the fuels they depend on, including ketogenic metabolic therapy and approaches targeting glucose and glutamine. For Seyfried, the therapeutic target follows directly from the biology: restrict the fuels cancer cells depend on, exploit their metabolic weaknesses, and treat mitochondrial dysfunction as the central feature of the disease.
An abbreviated version of this discussion is available here, for free.
MetFix and BSI Members can view the full 54-minute video.
