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Peter Attia MD216 - Metabolomics, NAD+, and cancer metabolism | Josh Rabinowitz, M.D., Ph.D.
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At a glance
WHAT IT’S REALLY ABOUT
Rabinowitz Explains Metabolic Flux, Lactate, NAD Supplementation Doubts, and Cancer Metabolism
- Rabinowitz explains that metabolism is a system in motion, so measuring flux (where metabolites come from and go) is more informative than static levels.
- He argues that circulating lactate is a major fuel and intermediary in glucose breakdown, and that competition between fat, lactate and glucose helps set blood glucose, consistent with the Randle hypothesis.
- On NAD, he says age-related declines appear modest (about 10-20% in his measurements), oral NR and NMN act largely as niacin prodrugs, and IV NAD may partially raise cellular NAD but the benefit is unproven.
- In cancer, he describes glucose use, nucleotide synthesis and Ras-driven nutrient scavenging as metabolic features, and says starving tumors of fuel is very hard but metabolic stress combined with chemotherapy, diet or immunotherapy looks promising.
- He is hopeful that diet, supplements and metabolic interventions, including fiber and a small metabolite that boosts immunotherapy response in mice, could make immunotherapy work for far more patients within a decade.
IDEAS WORTH REMEMBERING
5 ideasMetabolism is about flow, not static levels
Rabinowitz says metabolites are low in abundance and turn over in seconds to an hour, so understanding where they come from and go is what reveals how metabolism works. He thinks the static textbook view helped kill interest in the field.
Lactate is a universal circulating fuel, not just a waste product
He explains that cells release lactate to solve a redox problem and other cells, such as the heart, burn it. Circulating lactate is an intermediary in glucose breakdown, which is why it rises after a carbohydrate meal.
Fuel competition helps explain elevated blood glucose
Rabinowitz supports the Randle idea that fat and lactate compete with glucose for burning, so diabetics may need higher glucose to balance production and consumption. He also sees suppression of lipolysis as perhaps the primary function of insulin.
Fasting lactate could be an early warning sign
Peter Attia proposes that high fasting lactate might flag metabolic dysfunction earlier than conventional markers, and Rabinowitz agrees, while noting lactate is more variable and stress-sensitive. He adds that the bigger problem is preventing metabolic syndrome rather than diagnosing it.
The case for NAD boosting is unproven
He finds age-related NAD declines subtle and says oral NR and NMN are broken down to niacin and don't meaningfully raise circulating NR or NMN in his mouse data. IV NAD may partly work via breakdown products, but he says more cell-level measurement and targeted trials are needed.
WORDS WORTH SAVING
5 quotesMetabolism 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, is one that kind of killed metabolism in a way as a topic of excitement.
— Josh Rabinowitz
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
Circulating lactate is an intermediary in glucose catabolism. And that's just the way the body works. It's not what we were taught in med school.
— Josh Rabinowitz
It's a mechanistic analog of cyanide, right? And so you have, like, one of the most acutely lethal substances and the most widely used drug working in a remarkably similar way.
— Josh Rabinowitz
We're gonna make immunotherapy work instead of for 10% of patients, for a majority of patients.
— Josh Rabinowitz
High quality AI-generated summary created from speaker-labeled transcript.
