#216 - Metabolomics, NAD+, and cancer metabolism | Josh Rabinowitz, M.D., Ph.D.

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Aug 1, 2022

Josh Rabinowitz, a Princeton professor specializing in cellular metabolism, dives into the fascinating world of metabolomics, explaining the intricate roles of NAD+ in energy production and health. He discusses how NAD levels decline with age and evaluates the benefits of supplementation. The conversation also highlights the intersection of cancer metabolism and immunotherapy, suggesting promising avenues for future cancer treatments. Additionally, he touches on glucose regulation, lactate's role as a fuel, and the complexities of measuring key metabolites.

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INSIGHT

Insulin's Primary Role

Insulin primarily helps us survive nutrient scarcity by signaling fat storage.
It indicates sufficient carbohydrates to suppress fat burning, preserving energy.

INSIGHT

Lactate as Fuel

Lactate isn't just a waste product; it's a crucial circulating fuel.
Unlike glucose, it's readily taken up by most cells via MCT transporters.

INSIGHT

Lactate Usage

Cells utilize lactate based on mass action and substrate availability.
There's no central decision-making; it's a gradient-driven process.

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Josh Rabinowitz is a Professor of Chemistry and Integrative Genomics at Princeton University, where his research focuses on developing a quantitative, comprehensive understanding of cellular metabolism through the study of metabolites and their fluxes. In this episode, Josh focuses the discussion on three main topics: metabolomics, NAD (and its precursors), and cancer metabolism. The metabolomics discussion starts with a broad definition of metabolism, metabolites, and fluxomics before diving deep into glucose metabolism, lactate as a fuel, movement of lactate, and the regulation of these substrates. He then gives a detailed explanation of the electron transport chain and Krebs cycle and their implications with respect to both drugs and nutrition while also explaining how NAD is central to the process of energy generation. He then discusses the age-related decline in NAD and what current literature says about efforts to increase NAD through intravenous or oral supplementation with the precursors NMN and NR, including whether doing so provides any advantage to lifespan or healthspan. Finally, Josh ends the conversation talking about cancer metabolism and how one particular intersection between cancer metabolism and immunotherapy might provide a hopeful outlook on the future of cancer treatment.

We discuss:

Josh's background and unique path to becoming a research scientist at Princeton [3:30];
What sparked Josh's early interest in metabolism [11:15];
Metabolomics 101: defining metabolites and how they are regulated [16:30];
Fluxomics: metabolism as a system in action [26:00];
The Randle Hypothesis: glucose and fatty acids compete as substrates for oxidation [33:30];
The important role of lactate as an alternate fuel [36:30];
Fasting lactate levels as a potential early indicator of metabolic dysfunction [48:00];
The beauty of the Krebs cycle and the role of NAD in energy production [53:15];
How the drug metformin acts on complex I of the electron transport chain [1:05:00];
The difference between NADH and NADPH [1:08:45];
NAD levels with age, and the efficacy of supplementing with intravenous NAD [1:10:45];
The usefulness of restoring NAD levels and efficacy of oral supplementation with NAD precursors NR and NMN [1:22:15];
Exploring the hypothesis that boosting NAD levels is beneficial [1:32:30];
Cancer metabolism and the intersection with immunotherapy [1:39:00];
Making cancer a chronic disease: exploiting the metabolic quirks of cancer, augmenting the immune system, and more [1:46:15];
The challenge of treating pancreatic cancer [1:50:30];
Epithelial cancers that might respond to metabolic approaches to therapy [1:56:30];
Josh's hopeful outlook on the future of cancer treatment [1:59:00];
Nutritional approaches to cancer attenuation [2:00:15];
What makes Princeton University special [2:06:15];
More.

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