How is glucose regulated in the body and why is a small increase significant in diabetes?

Glucose levels are tightly regulated, typically within a 2-3 fold range, as evolution pushed safe limits to allow for efficient energy delivery. A two-fold increase in circulating glucose (from 5g to 10g) signifies type 2 diabetes because it indicates a broad derangement in the body, particularly issues with fat handling, that disrupt this balance, leading to deleterious protein modifications.

What is the Randle Hypothesis and what is the latest evidence supporting it?

The Randle Hypothesis posits that fat is a preferred fuel, creating competition with carbohydrates (glucose) for burning. Recent experiments show that fat clearly suppresses glucose use in tissues. Providing alternative fuels like lactate also suppresses glucose use, supporting the idea of a competitive nutrient environment that dictates glucose clearance.

Why is lactate considered more than just a waste product in modern biochemistry?

Lactate is now understood as a major, universally available circulating nutrient that turns over very fast. While traditionally seen as a waste converted to glucose by the liver, it can be directly consumed by many tissues, including the heart, offering tremendous physiological flexibility, especially during hypoxia or burst exercise.

What do fasting lactate levels indicate about metabolic health?

Fasting lactate levels show significant variability and correlate with metabolic health: higher levels suggest less metabolic health. Elevated fasting lactate indicates excessive glucose usage converted to lactate during fasting and impaired lactate clearance, often due to competition with fat burning, feeding into diabetes syndrome.

How do oxidation, reduction, and redox pairing work with NAD+/NADH in energy production?

Oxidation and reduction are coupled electron movements: the substance losing electrons is oxidized, and the one gaining them is reduced. NAD+ is the oxidized form and NADH is the reduced, electron-holding form. NAD+ accepts electrons from TCA cycle intermediates forming NADH, which then feeds into the electron transport chain, where electrons flow to pump protons and generate ATP.

What is the scientific consensus on NAD+ levels and aging?

NAD+ levels do decline with aging, but the observed depletions are relatively subtle, typically 10-20%. This suggests that while NAD+ is metabolically central, a simple increase might not be a panacea for aging, and more targeted approaches might be needed for specific cell types.

How effective are oral NAD+ precursors like NR and NMN?

Oral NAD+ precursors like NR and NMN are largely broken down in the gastrointestinal tract, mainly entering the body as nicotinic acid (niacin). They act as niacin prodrugs, showing subtle to vanishing effects on circulating NR/NMN levels, making them unlikely to significantly boost NAD+ in most tissues in a way that competes with physiological nicotinamide.

Why is pancreatic adenocarcinoma so lethal?

Pancreatic adenocarcinoma is highly lethal due to its soft organ location, invasive nature leading to early local invasion, and immediate access to the portal system, which seeds the liver. Metabolically, it's tricky: driven by Ras oncogene mutations, it actively scavenges nutrients, reduces normal protein synthesis, and can function very efficiently even with low metabolic activity, enabling aggressive growth and metastasis.

What metabolic strategies show promise in cancer therapy, beyond just reducing insulin?

Beyond insulin reduction, promising metabolic strategies include targeting nucleic acid synthesis to induce mutations for enhanced immune response, and dietary modifications. For instance, a ketogenic diet high in saturated fat can stress tumors that struggle to make unsaturated fats in hypoxic conditions. The microbiome and timing of macronutrients also hold potential.

What role does the microbiome play in cancer immunotherapy?

Microbiome composition has been shown to predict whether immunotherapy works. For example, fiber intake can promote the effectiveness of immunotherapy. The interaction between diet, microbiota, and immune response to cancer is an incredibly important area of ongoing research.

What challenges exist in translating animal diet studies to human cancer therapy?

Good animal models for cancer are not yet high-throughput, and translating animal diets to human diets involves many challenges in isolating variables and ensuring adherence. The sheer number of dietary permutations and the difficulty of chronic adherence in humans mean that simpler, targeted interventions (like specific molecules or acute hospital-based dietary changes) might be more clinically actionable.

Key Moments

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

Peter Attia MD

Science & Technology4 min read148 min video

Aug 1, 2022|49,584 views|983|121

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Key Moments

TL;DR

Metabolomics, NAD+, and cancer metabolism explored with insights on cellular energy, nutrient utilization, and therapeutic strategies.

Key Insights

Metabolism converts food into energy and building blocks, with metabolomics quantifying these processes.

NAD+ is crucial for energy generation, declining with age, and its restoration has therapeutic potential.

Cancer cells exhibit distinct metabolic profiles, often utilizing glucose more heavily.

Lactate serves as a universal fuel and plays a complex role in metabolic health and disease.

Nutrient competition, particularly between fat and glucose, significantly impacts metabolic regulation.

Targeting cancer cell metabolism, especially nucleic acid synthesis, offers therapeutic vulnerabilities.

Dietary interventions, like ketogenic diets and fiber, hold promise in modulating cancer metabolism and immune response.

THE FUNDAMENTALS OF METABOLISM AND METABOLOMICS

Metabolism is the intricate process of converting consumed food into usable energy and the essential building blocks for growth and repair, while also generating waste. Metabolomics aims to quantify and understand these complex biochemical pathways on a large scale. The core of these metabolic processes involves approximately a hundred key metabolites, including amino acids like glutamine, fats like acetate, and intermediates from pathways such as glycolysis and the Krebs cycle. Measuring these effectively is crucial for understanding cellular function and dysfunction, forming the basis of metabolomic studies.

THE CRITICAL ROLE OF NAD+ AND REDOX BALANCE

NAD+ is a vital cofactor in cellular energy generation, acting as an electron carrier in the Krebs cycle and electron transport chain. The balance between its oxidized form (NAD+) and reduced form (NADH) is critical for maintaining redox homeostasis. As organisms age, NAD+ levels tend to decline, which may impact energy production and cellular function. While intravenous NAD+ or its precursors like NR and NMN can potentially increase intracellular NAD+ levels, the most effective delivery and the precise impact on health are still areas of active research and debate.

LACTATE: MORE THAN JUST A WASTE PRODUCT

Lactate, often perceived as a metabolic waste product of intense exercise, is increasingly recognized as a universal fuel source for various tissues, including the heart and brain. Mammalian systems are wired to use lactate efficiently, with specific transporters (MCTs) facilitating its movement. Unlike glucose uptake, lactate can readily enter numerous cell types, providing a flexible source of carbohydrate energy. Elevated fasting lactate levels can be an indicator of metabolic dysfunction, reflecting both increased glucose utilization and impaired lactate clearance.

COMPETITION FOR FUEL AND THE RANDALL HYPOTHESIS

The body's metabolic system involves a constant competition for fuel sources. The Randall hypothesis suggests that fat, when readily available, can suppress glucose utilization. This competition plays a crucial role in regulating blood glucose levels and overall metabolic health. When fat is easily accessible or glucose utilization is impaired, the body may struggle to clear glucose effectively, contributing to conditions like insulin resistance and type 2 diabetes. This interplay highlights the importance of understanding nutrient partitioning.

METABOLIC QUIRKS OF CANCER CELLS

Cancer cells often exhibit distinct metabolic profiles, characterized by a high uptake and utilization of glucose, partly due to internal signaling that mimics insulin presence. This metabolic dependency makes them visible on FDG-PET scans. Furthermore, uncontrolled cell growth requires constant nucleic acid synthesis, a vulnerability that has historically been targeted by anti-metabolite chemotherapy. Understanding these metabolic differences is key to developing targeted therapies that exploit these unique cellular pathways.

TARGETING CANCER METABOLISM FOR THERAPY

Starving cancer cells of glucose is challenging due to the body's need to maintain essential glucose levels for vital organs like the brain. However, strategies that exploit cancer's metabolic vulnerabilities are promising. Interrupting nucleic acid synthesis can induce mutations, potentially enhancing the immune system's response to the tumor. Combining therapies, such as chemotherapy with dietary interventions like ketogenic diets, may create a synergistic effect by stressing cancer cells' fuel supply and promoting greater sensitivity to treatment.

THE METABOLIC CHALLENGES OF PANCREATIC CANCER

Pancreatic adenocarcinoma is an exceptionally lethal disease, partly due to its invasive nature and early metastasis. Metabolically, it is driven by mutations like Ras, which promote nutrient scavenging and unusual uptake mechanisms. The cancer cells can adapt to utilize various fuel sources and remain highly efficient even with reduced TCA cycle activity. This metabolic perversity, coupled with anatomical challenges, makes it a formidable target for therapy, necessitating innovative approaches beyond conventional treatments.

FUTURE DIRECTIONS IN DIET AND CANCER METABOLISM

The interface between diet, metabolism, and cancer therapy holds significant promise. Beyond reducing insulin, strategies involving specific types of fats, amino acid restriction, and tailored fiber intake are being explored. The type of fat (saturated vs. unsaturated) can differentially impact tumor suppression. Furthermore, manipulating macronutrient timing and integrating dietary approaches with the microbiome could create favorable immune microenvironments. Developing simple, actionable dietary interventions that can be integrated into treatment protocols is a key goal for future research.

Mentioned in This Episode

●Supplements

●Software & Apps

●Companies

●Organizations

●Books

●Concepts

●People Referenced

Common Questions

Metabolism is the process converting food into energy, building blocks, and waste. Metabolomics aims to quantitatively measure these classic metabolites and their flow rates to understand where they come from and where they're going in the body. Roughly a thousand metabolites have clear biological function.

Topics

Cancer Metabolism Health & Longevity Neuroscience & the Brain Science & Mathematics Lactate Metabolism Insulin Sensitivity Aging Research Medicine & Clinical NAD+ Metabolism Electron Transport Chain Dietary Interventions

Mentioned in this video

Supplements

Cyanide

An electron transport chain inhibitor that rapidly leads to a backup of the system, preventing ATP synthesis and causing rapid mortality.

NADP

An important cofactor, similar to NAD+, used in different biological ways, with a more even ratio of its oxidized and reduced forms.

Nicotinamide Riboside

An oral NAD+ precursor that gets broken down in the GI tract, mainly entering the body as nicotinic acid (niacin). It's considered a niacin prodrug.

Niacin

A healthy substance and form of vitamin B3, which NR and NMN are primarily converted to upon oral ingestion. High doses can cause a 'flush'.

NAD

A famous cofactor in the electron transport chain, crucial for energy generation. Its levels decline with aging, but the change is subtle (10-20% reduction).

NADPH

The reduced form of NADP, considered a master energetic building material for fat assembly and crucial for fighting (or intentionally creating) reactive oxygen species.

SGLT2 inhibitor

A type of medication being investigated in a clinical trial combined with a low-carbohydrate diet to induce ketosis in cancer patients.

NADH

The electron-holding, reduced form of NAD+, which feeds into the electron transport chain. Its buildup can lead to free radical production and metabolic issues.

Nicotinamide Mononucleotide

An oral NAD+ precursor, similar to NR, that also primarily converts to nicotinic acid (niacin) in the gastrointestinal tract and is considered a niacin prodrug.

Nicotinamide

A form of vitamin B3, a physiological precursor that the liver normally produces to feed NAD+ to tissues. Oral NR and NMN have difficulty competing with its circulating levels.

People

Peter Attia

Host of The Drive podcast and interviewer of Josh Rabinowitz. They attended medical school together and reconnected at a cancer metabolism conference.

Steve Rosenberg

A scientist whom Peter Attia interviewed previously about the immune system and cancer.

Navdeep Chandel

A mutual friend and previous podcast guest of Peter Attia, who also studies metabolism. He discussed the previous lack of interest in metabolism research in the 1990s.

Randy Strong

A researcher associated with the ITP program at NIH.

Craig Thompson

Former head of the Penn Cancer Center (now at Memorial Sloan Kettering) who invited Josh Rabinowitz into cancer metabolism research.

Sydney Farber

Pioneer in rational cancer treatment by targeting metabolism, especially with anti-folates, memorialized at Dana-Farber Cancer Institute.

Matt Vander Heiden

Head of the Koch Institute at MIT, whose lab has done work on how higher saturated fat ketogenic diets can be tumor suppressive in some contexts.

John von Neumann

A brilliant mathematician and computer scientist who built the first computer in a building at Princeton where Josh Rabinowitz's children attended nursery school.

Max Dean

A mutual classmate of Peter Attia and Josh Rabinowitz from medical school.

Karl Deisseroth

A mutual classmate of Peter Attia and Josh Rabinowitz from medical school, who started surgical rotation with them.

Hardin McConnell

A physical chemist and Josh Rabinowitz's PhD advisor at Stanford, with whom he studied the physical chemistry of T-cell activation.

Mark Davis

An immunologist who collaborated with Hardin McConnell, also involved in Josh Rabinowitz's PhD research on T-cell activation.

Alex Zaffaroni

An early biotech entrepreneur with whom Josh Rabinowitz co-founded a company focused on fast drug delivery.

George Brooks

A researcher at Berkeley who extensively studied and recognized the ubiquitous potential for lactate as a fuel.

Jerry Reaven

A scientist Peter Attia mentions who performed an insulin suppression test on him, and whose five criteria for Syndrome X (now metabolic syndrome) included fasting glucose.

Rich Miller

A researcher associated with the ITP program at NIH.

Joe Baur

A fantastic collaborator and expert in NAD+ research, credited by Josh Rabinowitz.

Lou Cantley

A researcher who pioneered the PI3-kinase pathway, a key pathway mutated in cancers that drives glucose utilization.

Richard Feynman

A renowned physicist whose work Peter Attia admires and collects original materials from, while Josh Rabinowitz is only lightly familiar with his work.

J. Robert Oppenheimer

Physicist and 'father of the atomic bomb,' whose biography Josh Rabinowitz read and a film about whom was being shot on Princeton's campus.

Concepts

Randle Hypothesis

An old idea suggesting that fat is a preferred fuel for tissues, and there's competition between carbohydrates (glucose) and fat for burning, which can lead to diabetes when fat is available.

Cory Cycle

The metabolic pathway where lactate goes back to the liver and is turned back into glucose for export.

Metabolic Syndrome

A cluster of metabolic derangements including high fasting glucose, which Peter Attia suggests could be better indicated by dysregulated fasting lactate levels.

Ras oncogene

A common mutation (driver) in pancreatic cancer cells that instructs them to scavenge and internalize nutrients in non-standard, metabolically pernicious ways.

Krebs Cycle

A central metabolic pathway responsible for generating energy intermediates and carbon dioxide. Josh Rabinowitz explains its historical perception as a 'solved problem' and its renewed importance.

Sirtuins

A family of proteins often linked to NAD+ and aging, which Josh Rabinowitz prefers to set aside, focusing on the direct metabolic role of NAD+.

CD38

A protein thought to be designed to control NAD+ pathways, acting as a suppressor by breaking down extracellular NAD+ and NMN.

Drugs & Medications

Metformin

A widely used medication that likely works mainly by slowing the conversion of NADH back to NAD+ by inhibiting complex I of the electron transport chain, primarily in the liver.

Pemetrexed

A first-line chemotherapy treatment for lung cancer that targets nucleic acid synthesis in cancer cells.

Abraxane

An albumin-bound form of paclitaxel, used in combination therapy for pancreatic cancer, producing tumor regressions.

Rapamycin

A medication Peter Attia takes, acknowledging it has good but imperfect evidence, contrasting with his reluctance to take NAD+ precursors due to lack of compelling human data.

Gemcitabine

A chemotherapy agent used as part of the armamentarium for cancer treatment, including for pancreatic cancer.

Organizations

National Institutes of Health

The primary public funding body for health research, discussed as a potential source of funding for NAD+ research and its interest in central metabolic topics.

Dana Farber Cancer Institute

A cancer center named in honor of Sydney Farber, relevant to the history of cancer metabolism research.

Koch Institute at MIT

An institute at MIT where Matt Vander Heiden is the head.

Princeton University

The institution where Josh Rabinowitz became a faculty member and established his lab. It's noted for its focus on undergraduate education and lack of medical, business, or law schools.

Software & Apps

ITP

An NIH-funded program that rigorously tests compounds for their effects on lifespan in mice. It tested NR, which did not extend life in their model.

FDG PET scan

A metabolic imaging technique that detects most types of cancer by showing constant uptake and phosphorylation of glucose or its analogs by cancer cells.

Studies & Research

University of Pennsylvania

An institution near Princeton where Josh Rabinowitz began collaborations in biomedicine and cancer metabolism.

Companies

Alexza Pharmaceuticals

A company co-founded by Josh Rabinowitz and Alex Zaffaroni, focused on rapid, non-invasive drug delivery, which has one FDA-approved drug for acute agitation.

Books

Stryer's Biochemistry

A classic biochemistry textbook referenced by Peter Attia, which he remembers presenting metabolism in a static way.