#216 - Metabolomics, NAD+, and cancer metabolism | Josh Rabinowitz, M.D., Ph.D.
Josh Rabinowitz, Professor of Chemistry and Integrative Genomics at Princeton, discusses metabolomics, NAD, and cancer metabolism. He covers glucose, lactate, the Krebs cycle, NAD decline with age, and the efficacy of NR/NMN, concluding with how cancer metabolism intersects with immunotherapy.
Deep Dive Analysis
14 Topic Outline
Josh Rabinowitz's Background and Path to Research
Introduction to Metabolism, Metabolomics, and Fluxomics
Glucose Metabolism, Regulation, and the Randle Hypothesis
Lactate as a Universal Fuel and its Role in Metabolism
The Krebs Cycle, Electron Transport Chain, and Redox Balance
Metformin's Mechanism of Action on Complex I
NAD, NADH, NADPH: Roles and Regulation
Age-Related NAD Decline and Supplementation Efficacy
Oral vs. Intravenous NAD Precursors (NR/NMN)
Cancer Metabolism: Glucose Dependence and Vulnerabilities
Exploiting Cancer's Metabolic Quirks for Immunotherapy
Challenges and Hopes in Treating Pancreatic Cancer
Nutritional Approaches to Cancer Attenuation
The Future of Cancer Treatment and Metabolic Interventions
7 Key Concepts
Metabolism
Metabolism is the process that converts the food we eat into usable energy and the building blocks our body needs to grow or regenerate itself, producing waste along the way. It involves a core set of about a hundred metabolites that are constantly flowing and being transformed.
Metabolomics
Metabolomics is the comprehensive measurement of the hundreds of classic metabolites (like glucose, amino acids, pyruvate, lactate, ATP) that are central to cellular function. This field aims to quantitatively survey these molecules to understand their roles in biological systems.
Fluxomics
Fluxomics studies metabolism as a dynamic system in action, focusing on the rates at which metabolites flow through pathways (their derivatives with respect to time). Metabolites are intermediates that are made and used rapidly, with all the action residing in their flow, not just their static abundance.
Randle Hypothesis
This hypothesis posits that fat is a preferred fuel for tissues, and there is competition between carbohydrates (like glucose) and fat for burning. When fat is readily available, glucose tends not to be burned effectively, which can contribute to conditions like diabetes.
Lactate as a Universal Fuel
Beyond being a byproduct of anaerobic glycolysis, lactate serves as a major circulating nutrient that can be used by almost any cell in the body, including the heart and brain. It provides a universally available form of carbohydrate energy, allowing for metabolic flexibility, especially during periods of high demand or low glucose availability.
Redox Balance (NAD/NADH)
Redox refers to coupled oxidation and reduction reactions involving electron movement. NAD is the oxidized form and NADH is the electron-holding (reduced) form, crucial for energy generation. Maintaining a high NAD:NADH ratio is vital; imbalances can lead to free radical production and impaired metabolism.
Electron Transport Chain
The electron transport chain is a series of proteins in the inner mitochondrial membrane that accept electrons from NADH (and FADH2). As electrons flow, protons are pumped out of the mitochondria, creating a gradient. These protons then flow back in through ATP synthase, generating ATP.
10 Questions Answered
The body is evolved to operate at the highest safe circulating glucose levels, leaving little wiggle room for increases. Even a two-fold excursion indicates broad derangements in fat handling and competition between glucose and fat for burning, leading to deleterious protein modifications and downstream health consequences.
While insulin controls blood sugar by promoting glucose uptake and preventing its production, an equally important role is signaling that there's enough carbohydrate to prevent the release of free fat from adipose tissue, effectively saving fat stores for when nutrients are scarce.
Circulating lactate is an intermediary in glucose catabolism. Even with ample oxygen, the body processes glucose through glycolysis to pyruvate, and then converts some pyruvate to lactate as a redox-balanced waste, which is then released into circulation and consumed by other tissues.
Higher fasting lactate levels correlate with poorer metabolic health and insulin resistance. This indicates that even during fasting, the body is using too much glucose and converting it to lactate, and the lactate clearance system may be impaired due to competition with fat for fuel.
Oxidation and reduction are always coupled reactions involving the movement of electrons. The substance that gives up electrons is oxidized, and the substance that receives electrons is reduced.
Metformin primarily works by inhibiting complex I of the electron transport chain, which slows the conversion of NADH back to NAD. This leads to a buildup of NADH and can raise circulating lactate levels, likely in a liver-specific manner, making it beneficial for diabetes.
NAD and its precursors are broken down in the gastrointestinal tract, mainly to nicotinic acid (niacin), preventing direct oral absorption of NAD. Intravenous NAD bypasses the liver and breaks down into precursors like NR and NMN in the bloodstream, which can then be taken up by cells and reconstituted into NAD, indirectly boosting intracellular NAD levels.
Oral NR and NMN are largely converted to niacin in the gut and portal circulation. While they may act as niacin prodrugs, their effect on boosting circulating NR or NMN levels to compete with physiological precursors like nicotinamide, or their impact on overall tissue NAD levels, is subtle or vanishing in current observations.
Even with severe glucose restriction, the body maintains circulating glucose, and cancer cells can access internally stored glycogen, amino acids, fat, lactate, and ketone bodies as alternative fuels. Completely cutting off cancer's fuel supply without harming essential tissues like the brain or immune cells is extremely difficult.
One avenue is to interfere with cancer cells' nucleic acid synthesis, inducing nucleotide imbalances that drive mutations. These mutations can then create more antigens, enhancing the immune system's response. Another is to apply strong metabolic stress (e.g., ketogenic diet with chemotherapy) to deplete tumor glucose, making chemotherapy more effective.
16 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.
16. Focus on Metabolic Flux, Not Static Levels
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.
7 Key Quotes
Metabolism is the process that converts the food we eat into usable energy and the building blocks our body needs to grow or regenerate itself as well as waste along the way.
Josh Rabinowitz
Metabolism is a system in action. And I think this kind of static view of metabolism, which is probably never a view that Stryer ever had in his mind, but that got codified in the textbooks as one that killed metabolism in a way as a topic of excitement.
Josh Rabinowitz
There's little doubt biochemically and medically the suppression of lipolysis is a primary, perhaps the primary function of insulin.
Josh Rabinowitz
The default is to spit out the redox-balanced waste. And then you can always pick the waste up and reuse it if you need energy from the TCA cycle.
Josh Rabinowitz
It is really crazy that maybe the world's most widely used medication is at some level inhibits the electron transport chain. It's a mechanistic analog of cyanide.
Josh Rabinowitz
NAD changes we see with aging are like 10%, 20%.
Josh Rabinowitz
I think it's really interesting to me that when we were in medical school, I thought we would not see a cure in our lifetimes for hepatitis. And look at that now, huh?
Josh Rabinowitz