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August 5, 2024 • 2hr 6min
#312 - A masterclass in lactate: Its critical role as metabolic fuel, implications for diseases, and therapeutic potential from cancer to brain health and beyond | George A. Brooks, Ph.D.
The Peter Attia Drive
In this episode, Peter Attia interviews George A. Brooks, a renowned professor of integrative biology at UC Berkeley. Brooks is known for his groundbreaking "lactate shuttle" theory proposed in the 1980s, which revolutionized our understanding of lactate as a crucial fuel source rather than just a byproduct of exercise.
The conversation covers a wide range of topics related to lactate metabolism, from historical misconceptions to cutting-edge research on lactate's role in various physiological processes and disease states. Brooks challenges many long-held beliefs about lactate and provides insights into its importance in energy production, brain function, and potential therapeutic applications.
#312 - A masterclass in lactate: Its critical role as metabolic fuel, implications for diseases, and therapeutic potential from cancer to brain health and beyond | George A. Brooks, Ph.D.
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Key Takeaways
- Lactate is not just a waste product, but a crucial fuel source for the brain and muscles. It is the preferred fuel in many situations.
- The traditional view of lactate as a byproduct of anaerobic metabolism is incorrect. Lactate production does not require oxygen lack.
- Lactate can enter mitochondria directly and be used for energy production, contrary to conventional understanding.
- Exercise increases lactate clearance capacity, which may help reduce cancer risk by removing potentially carcinogenic lactate.
- Lactate infusion shows promise as a potential therapy for traumatic brain injury, as it can fuel the injured brain when glucose uptake is impaired.
- Metformin's effects on lactate metabolism may explain some of its benefits in diabetes treatment.
- Lactate plays important signaling roles, including effects on gene expression through "lactylation" of histones.
- Understanding lactate flux and clearance, not just concentration, is crucial for interpreting its physiological effects.
- More research is needed on lactate's role in various disease states and its potential therapeutic applications.
Introduction
In this episode, Peter Attia interviews George A. Brooks, a renowned professor of integrative biology at UC Berkeley. Brooks is known for his groundbreaking "lactate shuttle" theory proposed in the 1980s, which revolutionized our understanding of lactate as a crucial fuel source rather than just a byproduct of exercise.
The conversation covers a wide range of topics related to lactate metabolism, from historical misconceptions to cutting-edge research on lactate's role in various physiological processes and disease states. Brooks challenges many long-held beliefs about lactate and provides insights into its importance in energy production, brain function, and potential therapeutic applications.
Topics Discussed
Historical Understanding and Misconceptions (3:30)
Brooks begins by addressing common misconceptions about lactate and lactic acid:
- The body does not produce lactic acid, but rather lactate
- Early experiments by Otto Meyerhoff in the 1920s led to misunderstandings about lactate's role
- The association between lactate and oxygen lack or acidosis is incorrect
"We've been teaching glycolysis wrong for 100 years," Brooks states, highlighting how deeply ingrained these misconceptions are in scientific and medical education.
Fundamentals of Metabolism (16:15)
The discussion moves to the basics of how glucose is metabolized in cells:
- Glucose enters cells via specific transporters (e.g., GLUT4)
- Inside the cell, glucose is split into two 3-carbon molecules
- Traditionally, pyruvate was thought to be the end product of glycolysis that enters mitochondria
- Brooks reveals that lactate can actually enter mitochondria directly and be used for energy production
This revelation challenges the conventional understanding of cellular energy production taught in textbooks for decades.
Lactate's Role in Energy Production (24:00)
Brooks explains the critical role of lactate in energy production within muscles:
- Lactate is a preferred fuel source over glucose in many situations
- Lactate can enter mitochondria directly via specific transporters
- The "cell-cell lactate shuttle" allows fast-twitch muscle fibers to export lactate to slow-twitch fibers for energy use
"Lactate is important as a fuel, and as you describe, really the first articulation of a lactate shuttle was by the Coris. They showed that a dog muscle made to contract with adrenaline or otherwise will release pyruvate and lactate, which will recirculate to the liver and become glucose," Brooks explains, highlighting the interconnected nature of lactate metabolism.
Lactate as a Preferred Fuel (30:45)
The conversation delves into how lactate becomes a preferred fuel during high-energy demands:
- Lactate can inhibit fat oxidation, making it the primary fuel source in fight-or-flight situations
- In type 2 diabetes, elevated lactate levels may inhibit fatty acid oxidation, exacerbating metabolic issues
- The brain can use lactate as a fuel source, especially in injured states
Brooks emphasizes that understanding lactate flux, not just concentration, is crucial for interpreting its physiological effects.
Lactate and Traumatic Brain Injury (43:00)
Brooks discusses the potential therapeutic use of lactate in traumatic brain injury (TBI):
- Injured brains often have impaired glucose uptake
- Lactate can cross the blood-brain barrier and fuel neurons when glucose uptake is compromised
- Clinical trials have shown promising results with lactate infusion in TBI patients
"If lactate's around, it's going to suppress the BHB [beta-hydroxybutyrate]. So lactate could be the dominant fuel in the injured brain," Brooks explains, highlighting the potential importance of lactate as a therapeutic agent in brain injury.
Exercise-Induced Lactate Production (49:30)
The discussion turns to the effects of exercise on lactate production and utilization:
- High lactate levels during intense exercise are not due to lactate itself, but associated acidosis
- Lactate can suppress appetite by crossing the blood-brain barrier and inhibiting ghrelin secretion
- Exercise training increases the body's capacity to clear lactate
Metabolic Differences in Athletes vs. Insulin-Resistant Individuals (52:00)
Brooks explains the metabolic differences between highly-trained athletes and insulin-resistant individuals:
- Athletes have a greater mitochondrial mass, allowing for more efficient lactate clearance
- Insulin-resistant individuals may have impaired lactate clearance, leading to elevated levels
- The ability to clear lactate efficiently is a key factor in athletic performance
Training Effects on Lactate Utilization (58:45)
The conversation explores how training enhances lactate utilization:
- Exercise training can double mitochondrial mass in muscle cells
- Increased mitochondrial density allows for greater lactate clearance and utilization
- Training increases the expression of monocarboxylate transporters (MCTs) that facilitate lactate movement
"We've done this in animals and we've done it in looking at trained and untrained people. And we can see an increase in the abundance of the MCTs. That helps two ways, because getting lactate into the mitochondrial network requires an MCT," Brooks explains.
Recognition of Lactate's Importance (1:06:00)
Brooks discusses the growing recognition of lactate's importance in metabolism:
- The discovery of lactate transporters (MCTs) in the 1990s opened new avenues of research
- Many textbooks and researchers are still catching up to the new understanding of lactate metabolism
- There is increasing interest in lactate's role in various physiological processes
Lactate Metabolism Pathways (1:09:00)
The discussion delves into the intricate pathways of lactate metabolism:
- Isotope tracer studies have revealed complex patterns of lactate production and utilization
- Exceptional athletes are able to generate and clear large amounts of lactate efficiently
- Understanding lactate flux, not just concentration, is crucial for interpreting its effects
Lactate and Cancer (1:23:15)
Brooks touches on the role of lactate in cancer:
- Cancer cells often exhibit high rates of glycolysis and lactate production (Warburg effect)
- Lactate may stimulate the expression of certain enzymes involved in cancer progression
- Exercise-induced improvements in lactate clearance may help mitigate cancer risk
Lactate in Disease and Exercise (1:29:45)
The conversation explores lactate's role in various diseases and how exercise might mitigate its effects:
- Elevated lactate levels are associated with sepsis and other critical illnesses
- Exercise may help reduce cancer risk by improving lactate clearance
- Lactate plays a role in brain health and may be involved in neurodegenerative diseases
"If lactate is carcinogenic, by removing it, you lessen the chance for carcinogenesis," Brooks suggests, highlighting the potential protective effects of exercise.
Current Research Interests (1:37:00)
Brooks discusses his current research interests involving lactate:
- Investigating the role of enterocytes in lactate production during glucose absorption
- Exploring how the liver regulates glucose and lactate metabolism
- Studying the effects of different meal compositions on lactate production and utilization
Remaining Questions About Lactate (1:50:45)
The conversation concludes with a discussion of remaining questions about lactate:
- The role of lactate in gene expression through "lactylation" of histones
- Differences between the effects of endogenous vs. exogenous lactate
- Potential therapeutic applications of lactate in various diseases
- The need for more research on lactate flux and clearance in different physiological states
Conclusion
This wide-ranging conversation between Peter Attia and George Brooks challenges many long-held beliefs about lactate metabolism and highlights its crucial role in various physiological processes. Brooks's work has revolutionized our understanding of lactate, showing that it is not merely a waste product but a vital fuel source and signaling molecule.
The discussion emphasizes the need for further research into lactate's role in disease states, its potential therapeutic applications, and the importance of understanding lactate flux rather than just concentration. Brooks's insights open up new avenues for research in fields ranging from exercise physiology to cancer biology and neurology.
Ultimately, this conversation underscores the complexity of metabolic processes and the ongoing need to challenge established beliefs in science and medicine. As Brooks states, "We've been teaching glycolysis wrong for 100 years," highlighting the importance of continual reevaluation and investigation in scientific understanding.