<p><a href="https://peterattiamd.com/joshrabinowitz/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=220801-pod-joshrabinowitz&utm_content=220801-pod-joshrabinowitz-podfeed"> View the Show Notes Page for This Episode</a></p> <p><a href="https://peterattiamd.com/subscribe/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=220801-pod-joshrabinowitz&utm_content=220801-pod-joshrabinowitz-podfeed"> Become a Member to Receive Exclusive Content</a></p> <p><a href="https://peterattiamd.com/newsletter/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=220801-pod-joshrabinowitz&utm_content=220801-pod-joshrabinowitz-podfeed"> Sign Up to Receive Peter's Weekly Newsletter</a></p> <p>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.</p> <p>We discuss:</p> <ul> <li>Josh's background and unique path to becoming a research scientist at Princeton [3:30];</li> <li>What sparked Josh's early interest in metabolism [11:15];</li> <li>Metabolomics 101: defining metabolites and how they are regulated [16:30];</li> <li>Fluxomics: metabolism as a system in action [26:00];</li> <li>The Randle Hypothesis: glucose and fatty acids compete as substrates for oxidation [33:30];</li> <li>The important role of lactate as an alternate fuel [36:30];</li> <li>Fasting lactate levels as a potential early indicator of metabolic dysfunction [48:00];</li> <li>The beauty of the Krebs cycle and the role of NAD in energy production [53:15];</li> <li>How the drug metformin acts on complex I of the electron transport chain [1:05:00];</li> <li>The difference between NADH and NADPH [1:08:45];</li> <li>NAD levels with age, and the efficacy of supplementing with intravenous NAD [1:10:45];</li> <li>The usefulness of restoring NAD levels and efficacy of oral supplementation with NAD precursors NR and NMN [1:22:15];</li> <li>Exploring the hypothesis that boosting NAD levels is beneficial [1:32:30];</li> <li>Cancer metabolism and the intersection with immunotherapy [1:39:00];</li> <li>Making cancer a chronic disease: exploiting the metabolic quirks of cancer, augmenting the immune system, and more [1:46:15];</li> <li>The challenge of treating pancreatic cancer [1:50:30];</li> <li>Epithelial cancers that might respond to metabolic approaches to therapy [1:56:30];</li> <li>Josh's hopeful outlook on the future of cancer treatment [1:59:00];</li> <li>Nutritional approaches to cancer attenuation [2:00:15];</li> <li>What makes Princeton University special [2:06:15];</li> <li>More.</li> </ul> <p>Connect With Peter on <a href="https://twitter.com/PeterAttiaMD">Twitter</a>, <a href="https://www.instagram.com/peterattiamd/">Instagram</a>, <a href="https://www.facebook.com/peterattiamd/">Facebook</a> and <a href="https://www.youtube.com/channel/UC8kGsMa0LygSX9nkBcBH1Sg">YouTube</a></p>
Actionable Insights
1. Combine Chemotherapy with Ketogenic Diet
In animal models, combining chemotherapy with a ketogenic diet (which lowers insulin and glucose) can be a powerful strategy for cancer treatment, as it further reduces tumor glucose and improves outcomes.
2. Consider Acute Deep Ketosis with Chemo
For cancer patients undergoing tough chemotherapy or surgery, an acute intervention with deep ketosis and pharmacotherapy (lowering glucose to near zero for 12-24 hours) at the time of chemo could significantly improve overall effects.
3. Explore SGLT2 Inhibitor + Low-Carb
A trial is investigating SGLT2 inhibitors with a low-carbohydrate diet to induce ketosis in cancer patients, aiming for a convenient way to achieve ketosis benefits while allowing some dietary flexibility.
4. Increase Fiber for Immunotherapy Efficacy
Fiber intake can promote the effectiveness of immunotherapy in cancer patients, with microbiome composition being predictive of immunotherapy success.
5. Monitor Fasting Lactate Levels
Regularly checking fasting lactate levels (first thing in the morning) can indicate metabolic health, as higher levels correlate with insulin resistance and metabolic dysfunction.
6. Understand Insulin’s Fat Storage Role
Recognize that a primary function of insulin is to signal that fat does not need to be used, thereby suppressing lipolysis and preserving fat stores when carbohydrates are available.
7. Recognize Lactate as Universal Fuel
Understand that lactate is a major, fast-turnover circulating nutrient usable by virtually any cell, providing flexible carbohydrate energy, especially when glucose uptake is heavily regulated.
8. Avoid Oral NAD Supplementation
Do not take oral NAD directly, as there is no known absorption route for it, and it is likely broken down to nicotinic acid, making it an ineffective way to increase intracellular NAD.
9. Oral NR/NMN are Niacin Prodrugs
Understand that oral Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN) are primarily converted to niacin, with their effect on boosting circulating NR/NMN levels being subtle or vanishing compared to physiological precursors.
10. Consider IV NAD for Intracellular Boost
Intravenous NAD can indirectly increase intracellular NAD levels by breaking down into precursors (like NR/NMN) in the bloodstream, which cells can then take up and reconstitute into NAD.
11. Be Skeptical of General NAD Benefits
Approach general NAD supplementation with skepticism, as age-related NAD depletion is subtle (10-20%), and historical medical interventions (like HRT) show that simple solutions often prove more complex than initially envisioned.
12. Prioritize Targeted NAD Restoration Research
Instead of broad NAD supplementation, focus on identifying specific, severely NAD-depleted cell types and developing targeted methods to restore NAD in those cells, which may yield significant health benefits.
13. Challenge ‘Starve Cancer’ Diets
Recognize that completely starving cancer cells of glucose is very difficult and potentially dangerous, as cancer cells are metabolically flexible and can use various fuels also vital for healthy cells (immune cells, brain).
14. Consider Saturated Fat Ketogenic Diet
A ketogenic diet higher in saturated fat might be more tumor-suppressive in certain cancer contexts because tumors, especially under hypoxia, may struggle to synthesize unsaturated fats.
15. Embrace Research-Driven Career Mindset
For a scientific career, prioritize opportunities to ‘do something different every day’ and ’think differently than people ever have before’ to drive novel problem-solving and research.
When studying metabolism, emphasize understanding the dynamic ‘flow’ of metabolites (origin, destination, speed) rather than just static concentrations, as this reveals how the system truly works.