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Peter Attia MD216 - Metabolomics, NAD+, and cancer metabolism | Josh Rabinowitz, M.D., Ph.D.
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CHAPTERS
- 0:02 – 10:05
From Med School Memories to Immunology PhD and Biotech
Peter and Josh reminisce about their surgical rotation, then Josh describes his PhD on the physical chemistry of T cell activation and why peptide antigens are about nine amino acids long. He explains why he chose research over clinical medicine and his early job at a drug-delivery startup.
- •Josh's PhD studied how antigen-MHC-T cell receptor kinetics determine immune responses
- •Josh thought immunological approaches to cancer held little promise at the time
- •His intuition: nine amino acids gives about 20^9 possible antigens, matching the scale of billions of immune receptors
- •He left medicine because he wanted to think differently every day rather than follow standard of care
- •He co-founded a company on rapid inhaled drug delivery, whose approved drug treats acute agitation
- 10:05 – 14:59
Starting a Metabolism Lab at Princeton
Josh explains why he built his Princeton lab around metabolism, noting that few labs were studying it. They discuss metabolism's unfashionable status and how the metabolic syndrome epidemic and the limits of genomics shifted interest.
- •Many important medications work via metabolism, yet few labs studied it
- •Initial goals: measure classic metabolites quantitatively and measure pathway activity
- •Metabolism was seen as a solved problem after Krebs even as metabolic syndrome worsened
- •Medical training helped him see the clinical relevance and start with bacteria
- 14:59 – 25:42
Metabolomics 101: Metabolites and Their Regulation
Josh defines metabolism and metabolomics, gives examples of key metabolites, and explains that roughly 1,000 metabolites have clear biological function. They discuss how tightly metabolites are regulated, mass action, and insulin's role in suppressing lipolysis.
- •Metabolism converts food into usable energy, building blocks and waste
- •Core metabolites include amino acids, acetate, fats, glycolytic and Krebs intermediates, and ATP, NADH and NADPH
- •No completely new, obviously important metabolite has been found this century
- •Important metabolites typically live in a roughly two-to-threefold range
- •Mass action is the main principle, with insulin layered on top, suppressing lipolysis as a primary function
- 25:42 – 34:43
Fluxomics and Why Glucose Only Needs to Double to Cause Disease
Josh describes metabolism as a system in action in which fast flux matters more than static levels. Using fasting glucose as the example, they discuss why a twofold rise is pathological and how production and consumption balance at different levels.
- •Metabolites are low in abundance and turn over in seconds to an hour
- •Blood glucose holds only a few grams, a few minutes of energy, and must be constantly replenished
- •Evolution pushed glucose to the highest non-problematic level, with glycosylation damage above it
- •Production and consumption balance in both healthy and diabetic people, but at different glucose levels
- 34:43 – 37:44
The Randle Hypothesis: Glucose Competes with Fat
Josh explains the Randle hypothesis, that fat and glucose compete for burning, and how it may underlie diabetes. He cites his lab's newer data that suppressing lipolysis or supplying lactate rapidly changes glucose use.
- •Fat competes with carbohydrate for oxidation, so available fat blunts glucose burning
- •Fat can mean free fatty acids, ectopic fat droplets in muscle, or lipoprotein breakdown
- •Turning off lipolysis rapidly induces glucose consumption
- •Lactate also competes with glucose and suppresses its use
- 37:44 – 51:58
Lactate as a Circulating Fuel
Peter contrasts the textbook view of lactate with Josh's view that it is a universal, fast-turnover circulating nutrient. Josh explains the redox-balance logic, why spitting out lactate is the default, and how it is distributed across tissues by mass action.
- •MCT transporters let lactate enter virtually any cell
- •The healthy fasted heart avoids glucose but burns lactate and fatty acids
- •Yeast experiments suggest spitting out redox-balanced waste is the default, with reuse later
- •The body must clear lactate internally, so lactic acidosis occurs when this fails
- •Distribution is driven by mass action, not a cell-level decision
- 51:58 – 57:17
Fasting Lactate as an Early Metabolic Marker
Peter shares his clinical interest in fasting lactate as an indicator of metabolic health and his observation that lactate rises after a carbohydrate meal. Josh says circulating lactate is an intermediary in glucose catabolism and discusses the pros and cons of lactate as a biomarker.
- •Insulin-resistant people can have fasting lactate near 2 mmol versus below 0.5 in healthy people
- •High fasting lactate suggests excess glucose use and poor lactate clearance, with lactate competing with fat
- •Lactate rising after a carbohydrate meal contradicts the med school model
- •Lactate fluctuates with stress, which limits its use as a biomarker
- •Both agree the problem is prevention more than diagnosis, and lactate may be an early canary
- 57:17 – 1:11:02
The Krebs Cycle, Electron Transport and Redox Explained
At Peter's request, Josh walks through how nutrients become two-carbon units that enter the TCA cycle, pass electrons to NAD, and drive ATP synthesis in the electron transport chain. They define oxidation and reduction and discuss why the NAD/NADH ratio matters, including cyanide.
- •Every carbon eaten ultimately leaves as exhaled CO2 made in the TCA cycle
- •The cycle passes electrons to NAD to make NADH, which feeds the electron transport chain
- •Proton pumping and a turnstile-like process combine ADP and phosphate into ATP
- •Oxidation is giving up electrons and reduction is receiving them
- •NADH buildup produces free radicals and gums up metabolism, as with cyanide
- 1:11:02 – 1:17:45
Metformin and NADPH
Josh discusses metformin as a complex I inhibitor, a mechanistic analog of cyanide whose liver specificity may make it beneficial. He then describes NADPH as a different, more electron-donating cofactor used to build fat and to manage oxidative stress.
- •Metformin slows NADH-to-NAD conversion by impairing complex I; it did so strongly in his lab
- •Liver specificity may explain why it is safe and net beneficial
- •Metformin raising lactate is consistent with a roadblock in electron disposal; long-term effects are unclear
- •NADPH has the same intrinsic energy chemistry as NADH but a more even ratio with NADP
- •NADPH builds fat and both fights and intentionally creates reactive oxygen species
- 1:17:45 – 1:31:44
NAD Decline with Aging and How IV NAD Works
Peter raises the popularity of NAD supplementation and the observed age-related decline. Josh says the decline is only about 10-20%, then explains how NAD is measured and why IV NAD, though lacking a direct transporter, may raise cellular NAD via breakdown products.
- •Josh's measurements show NAD declines with aging by only about 10-20%
- •NAD is relatively stable and measured in tissue, so biopsies are needed
- •IV NAD is likely broken down to NMN and NR, which cells can take up and rebuild into NAD
- •CD38 breaks down extracellular NMN and suppresses NAD levels
- •Peter corrects his earlier statement that IV NAD does not get into cells
- 1:31:44 – 1:38:11
Oral NR and NMN: Niacin Prodrugs?
Josh explains that oral NR and NMN are largely broken down in the gut and enter the body as niacin, and his flux data show little effect on circulating NR or NMN. He lists ways the measurements could mislead, including local gut effects, microbiome, and human versus mouse differences.
- •Oral NR and NMN are mainly absorbed as niacin and act like niacin prodrugs
- •They raise niacin in portal circulation but barely raise their own circulating levels
- •Nicotinamide, not NR or NMN, is the normal circulating precursor
- •Possible blind spots: local intestinal effects, microbiome, NR-preferring cell subsets, chronic dosing
- •The work was done in mice, not humans
- 1:38:11 – 1:51:25
Is Boosting NAD Beneficial? Evidence, HRT Digression and Next Steps
Josh is not convinced that restoring NAD would improve health, noting that medicine often proves more complicated than expected. A digression on the Women's Health Initiative follows, then they discuss what is needed: better pharmacology, single-cell NAD measurement and a targeted clinical trial.
- •Josh is not convinced by the hypothesis that restoring NAD improves health and calls for caution
- •Peter's digression: the Women's Health Initiative was misinterpreted, and the route of estrogen matters
- •Peter has found no compelling human NR or NMN studies, unlike for rapamycin
- •Josh suggests mapping NAD pharmacology and measuring NAD at cellular resolution
- •He proposes a niche trial, such as renal ischemia, where animal effects are strong and readouts quick
- 1:51:25 – 2:00:17
Cancer Metabolism and Immunotherapy: Josh's Path and Cancer's Metabolic Signature
Peter pivots to cancer metabolism, and Josh describes how a call from Craig Thompson drew him into cancer research. They discuss the intersection with immunotherapy, why cancers are glucose users, the nucleotide synthesis vulnerability, and why starving cancer is hard.
- •Antifolates were the first rational cancer therapy, targeting metabolism
- •Microbiome composition and fiber are linked to immunotherapy response
- •PI3 kinase mutations make cancers behave as if always seeing insulin, producing FDG PET positivity
- •Cancers can use many fuels, so cutting off supply is hard without harming immune cells or the brain
- 2:00:17 – 2:05:06
Making Cancer Chronic: Nucleotide Stress, Chemo and Ketogenic Diet
Josh describes strategies to exploit cancer's metabolic quirks. Hitting nucleotide synthesis creates mutations that give the immune system more targets, and pairing chemotherapy with a ketogenic diet lowers tumor glucose in mice. A clinical trial is open on the latter.
- •Nucleotide imbalance drives mutations, creating more antigens for immune response
- •Chemotherapy lowers tumor glucose, and a ketogenic diet strengthens the effect in mouse models
- •Pemetrexed and gemcitabine are current nucleotide-targeting agents, and Josh sees room for fresh development
- •Hepatitis C cure via nucleoside analogs suggests this chemistry is ripe for rediscovery
- 2:05:06 – 2:15:40
Why Pancreatic Cancer Is So Lethal
Josh explains his commitment to pancreatic cancer, noting that its poor outcomes allow fast clinical readouts and that responses to new combinations are not yet durable. They discuss early invasion and Ras-driven nutrient scavenging, the cancer's low metabolic activity, and the lymphocyte-poor, macrophage-rich environment.
- •Triple chemotherapy combinations produce regressions, but responses are not durable
- •Anatomy and early invasion make staging problematic, with portal access seeding the liver
- •Nearly all cases are Ras-driven, which instructs cells to scavenge and recycle nutrients
- •The cancer turns down the pancreas's huge protein synthesis, so it is efficient and not hypermetabolic
- •Tumors are lymphocyte deserts with many macrophages, where Josh sees a role for metabolism
- 2:15:40 – 2:23:26
Future Outlook and Nutritional Approaches to Cancer
Josh offers an optimistic view that metabolic, immune supplement and dietary interventions will make immunotherapy work for most patients. They discuss dietary levers such as fat type, fiber, and macronutrient timing, the limits of animal models, and trials such as SGLT2 inhibitors with low-carb diets.
- •Josh hopes metabolic interventions will raise immunotherapy responses from about 10% to a majority of patients
- •Matt Vander Heiden's work suggests high-saturated-fat ketogenic diets may suppress tumors in some contexts
- •Fiber and microbiome connections and macronutrient timing are promising areas
- •A single small molecule more than doubles complete responses to immunotherapy in mice
- •Josh describes acute glucose lowering during chemo and a trial of an SGLT2 inhibitor with low-carb diet to induce ketosis
- 2:23:26 – 2:27:09
Why Princeton Has No Medical School
In a closing aside, Peter asks why Princeton lacks a medical school, and Josh says it is a conscious choice to prioritize undergraduate education. They chat about Feynman, Oppenheimer and Princeton's history before wrapping up.
- •Josh says Princeton is a hybrid of college and university with undergraduate education as its priority
- •The administration repeatedly decided medicine on campus would not serve that goal
- •Princeton also has no business or law school
- •Josh mentions the Oppenheimer film shooting on campus and that his kids attended nursery school in Von Neumann's computer building
