Zone 2 training: impact on longevity and mitochondrial function, how to dose frequency and duration, and more | Iñigo San-Millán, Ph.D. (#201 rebroadcast)
Dr. Iñigo San-Millán, an applied physiologist, discusses Zone 2 exercise, its impact on mitochondrial function, and longevity, drawing insights from elite athletes like Tadej Pogačar. He details optimal Zone 2 training, metrics for assessment, and the role of high-intensity training for health.
Deep Dive Analysis
20 Topic Outline
Introduction to Zone 2 Exercise and Guest Iñigo San-Millán
Iñigo San-Millán's Work with Cyclist Tadej Pogačar
Physiological Metrics and Race Strategy in Elite Cycling
Transparency of Physiological Data in Professional Cycling
Defining Zone 2: Mitochondrial Function and Fat Oxidation
Measuring Metabolic Function: Indirect Calorimetry and Lactate
Lactate Kinetics and Mitochondrial Oxidation in Athletes
Bioenergetics of the Cell: Glucose, Pyruvate, Lactate, and MCT Transporters
Impact of Diet (Ketosis) on Fuel Utilization and Metabolic Testing
Glutamine and Muscle Wasting in ICU Patients
Exercise as an Insulin-Independent Glucose Transporter Mechanism
Estimating Zone 2 Without Lab Tests: RPE and Heart Rate
Optimal Zone 2 Training: Dose, Duration, and Frequency
Integrating High-Intensity Training (Zone 5) with Zone 2
Compounding Benefits of Zone 2 Exercise and Metabolic Health with Aging
Metformin and NAD Supplements: Impact on Mitochondrial Function and Longevity
Lactate as an Oncometabolite and Exercise in Cancer
Mitochondrial Dysfunction in Long COVID Patients
Limitations of VO2 Max for Exercise Prescription and Cellular Surrogates
Cellular Metabolism Alterations in Sedentary Individuals and Metabolic Syndrome
7 Key Concepts
Zone 2 Exercise
Zone 2 is the exercise intensity that maximally stresses mitochondria and oxidative capacity, primarily recruiting type 1 muscle fibers. It mobilizes the highest amount of fat for oxidation and stimulates oxidative phosphorylation, burning both fat and glucose within the mitochondria while maintaining low glycolytic flux.
Fat Max
Fat Max refers to the exercise intensity at which an individual achieves their maximum rate of fat oxidation. As exercise intensity increases, fat oxidation rises to a peak (Fat Max) before sharply declining as the body shifts to relying more on carbohydrates for fuel.
Lactate Shuttle
Discovered by George Brooks, the lactate shuttle describes how lactate, produced as a byproduct of glycolysis in fast-twitch muscle fibers, is transported to adjacent slow-twitch muscle fibers. Within these slow-twitch fibers, lactate is oxidized back to pyruvate and then used as fuel in the mitochondria.
MCT1 Transporters
MCT1 (Monocarboxylate Transporter 1) are specific transporters on the mitochondrial membrane of slow-twitch muscle fibers that facilitate the entry of lactate into the mitochondria. Well-developed MCT1 transporters enable efficient oxidation of lactate, preventing its accumulation in the blood.
Mitochondrial Pyruvate Carrier
The mitochondrial pyruvate carrier is a transporter responsible for moving pyruvate, a byproduct of glucose metabolism, into the mitochondria for complete oxidation. In sedentary individuals, this carrier can be significantly downregulated, impairing glucose metabolism even without clinical signs of diabetes.
Metabolic Flexibility
Metabolic flexibility is the body's ability to efficiently switch between using fat and carbohydrates as fuel sources depending on availability and demand. Elite athletes demonstrate high metabolic flexibility, capable of sustaining high power outputs while relying heavily on fat oxidation.
Intramuscular Triglycerides
These are fat droplets stored within muscle cells, serving as an immediate fuel source for mitochondria. In elite athletes, these are highly active and constantly turning over, whereas in individuals with type 2 diabetes or obesity, they accumulate and are high in ceramides, linking to cardiovascular disease.
10 Questions Answered
Elite athletes exhibit extremely low blood lactate levels at a given power output compared to moderately active or metabolically unhealthy individuals, indicating a superior ability to clear and oxidize lactate within the muscle rather than exporting it to the blood.
The purest way to estimate Zone 2 is via indirect calorimetry to measure fat oxidation (Fat Max), often correlated with lactate levels. However, point-of-care lactate meters and perceived exertion (RPE) are also effective surrogates.
A good subjective measure for Zone 2 is being able to maintain a conversation, but with some noticeable strain, indicating you are working hard enough that the person you're talking to would know you are exercising.
A ketogenic diet can create an artifact in indirect calorimetry measurements, making it appear that fat oxidation is much higher than it truly is due to altered gas exchange (high oxygen consumption, low CO2 production) that misleads stoichiometric equations.
Muscle contraction during exercise provides an insulin-independent pathway to translocate GLUT4 glucose transporters to the muscle surface, allowing glucose uptake into cells and lowering blood glucose levels without requiring insulin.
Ideally, Zone 2 training should be done 3-4 days a week, with each session lasting 1 to 1.5 hours. Even 30-minute sessions can initiate adaptations for those new to exercise, but longer durations are more effective for sustained improvement.
Yes, high-intensity training is necessary to stimulate glycolytic capacity, which also declines with age. It's best incorporated at the end of a Zone 2 session (e.g., a 5-minute maximal effort) to avoid blunting the fat oxidation benefits of Zone 2.
Yes, individuals in their 60s and 70s, even those who were previously unhealthy, can achieve metabolic parameters comparable to active people in their 30s through consistent Zone 2 training, demonstrating the powerful compounding benefits of exercise over time.
Preliminary pilot studies in mice suggest that NAD precursors like nicotinamide riboside could potentially increase tumor growth in aggressive cancers, raising concerns that boosting NAD levels might favor the glycolytic metabolism of undiagnosed tumors in humans.
Studies show that even previously healthy individuals with long COVID can exhibit severe mitochondrial dysfunction, resembling that of type 2 diabetes patients, characterized by significantly impaired fat oxidation and elevated lactate production, which explains their profound fatigue and exercise intolerance.
18 Actionable Insights
1. Exercise for Mitochondrial Health
Recognize exercise as the most effective ‘medication’ for improving mitochondrial function, which is crucial for metabolic health and longevity.
2. Embrace Compounded Zone 2 Gains
View Zone 2 training as a long-term investment, focusing on consistent, compounded gains over years rather than quick fixes, to achieve significant and sustainable metabolic health improvements and longevity benefits.
3. Optimal Zone 2 Training Frequency
Engage in Zone 2 training 3-4 days per week as a minimum for improvement, with 4-5 days being ideal for most individuals, and 5-6 days for maximal benefit. Less than 3 days may lead to deterioration or just maintenance.
4. Optimal Zone 2 Training Duration
Aim for 60-90 minutes per Zone 2 session for significant mitochondrial and metabolic adaptations. Beginners can start with 20-30 minutes and gradually increase duration.
5. Gauge Zone 2 by Conversation Test
Determine Zone 2 intensity by maintaining a conversation where you can talk, but it requires noticeable effort, and the person you’re speaking with would recognize you are exercising.
6. Use Lactate Meter for Zone 2
Utilize a lactate meter to identify Zone 2 by ensuring blood lactate levels remain below 2 millimoles/liter, as exceeding this indicates a transition into Zone 3.
7. Estimate Zone 2 by Heart Rate
Estimate Zone 2 heart rate by aiming for 70-80% of your realized maximum heart rate, then fine-tune based on the conversation test (RPE).
8. Combine Zone 2 with End-Session HIIT
Incorporate high-intensity intervals (e.g., a 5-minute interval) at the end of a Zone 2 session to stimulate both oxidative and glycolytic systems, without blunting the Zone 2 benefits. Avoid starting with high-intensity work.
9. Prioritize Recovery, Carb Intake for Fatigue
If experiencing fatigue (e.g., inability to reach target heart rate during exercise), prioritize recovery by taking a day off, increasing sleep, and boosting carbohydrate intake to restore glycogen stores and improve subsequent performance.
10. Manage Mental Workload for Physical Performance
Acknowledge that high mental workload and stress can significantly impact physical performance and recovery, even with low training volume. Prioritize rest, sleep, and adequate carbohydrate intake on such days to prevent overtraining and aid recovery.
11. Exercise Post-Carb Meal for Glucose Control
For individuals with insulin resistance or pre-diabetes, exercise immediately after consuming carbohydrates to leverage insulin-independent glucose uptake, helping to lower blood glucose levels.
12. Use Indoor Trainer for Consistent Zone 2
Utilize an indoor trainer for Zone 2 exercise to maintain a constant, precise intensity without interruptions from external factors like traffic, wind, or varied terrain.
13. Stimulate Glycolytic Capacity
Include high-intensity training to stimulate glycolytic capacity, which is important as it declines with age.
14. Maintain Muscle Health for Systemic Benefits
Maintain good muscle health through exercise, as it may contribute to overall metabolic health and potentially release beneficial exosomes that could counteract cancer’s glycolytic phenotype.
15. Measure Metabolic Function with Indirect Calorimetry
Undergo indirect calorimetry (metabolic cart) to precisely measure fat oxidation capacity and determine personalized training zones, especially for those with metabolic dysregulation, by starting at very low wattages (e.g., 25-50 watts).
16. Structured Exercise for Long COVID
For individuals with long COVID experiencing severe mitochondrial dysfunction (resembling Type 2 Diabetes), consider a carefully structured exercise program aimed at stimulating mitochondrial function, potentially under medical guidance.
17. Exercise Caution with NAD Precursors
Exercise caution with NAD precursor supplements (e.g., NR, NMN) due to theoretical and preliminary experimental concerns that they might potentially favor the growth of undiagnosed tumors by increasing glycolytic flux.
18. Advance Longevity Knowledge
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6 Key Quotes
When I say someone has good potential, I don't usually say that lightly of anybody.
Iñigo San-Millán
The person on the other end will know you are exercising. You will not be able to mask from them that you are exercising.
Peter Attia
The only medication that we know is exercise.
Iñigo San-Millán
The brain is the boss. The brain says, like, I don't care about your legs, but don't use up all the glycogen, because you have to give me, and the liver has to give me glycogen as well.
Iñigo San-Millán
If you were to genetically engineer a molecule, they can inject it into a tissue and transform into cancer. You would replicate an exosome.
Iñigo San-Millán
You own your own body, and you can really take ownership of that and improve it at any age.
Iñigo San-Millán
1 Protocols
Zone 2 Training Program for General Health
Iñigo San-Millán- Determine your Zone 2 intensity using a metabolic test (indirect calorimetry or lactate meter) or surrogates like heart rate and perceived exertion (RPE).
- For RPE, ensure you can maintain a conversation, but with noticeable strain, indicating you are not in Zone 1 but not too high to be breathless.
- Aim for 3 to 4 training sessions per week, ideally 4-5 days a week if possible.
- Each session should last between 1 hour to 1.5 hours. For those new to exercise, start with 20-30 minutes and gradually increase.
- Perform the exercise consistently at your determined Zone 2 intensity, avoiding significant fluctuations into higher or lower zones.
- Consider incorporating a high-intensity interval (e.g., 5 minutes maximal effort) at the very end of some Zone 2 sessions to stimulate glycolytic capacity without blunting Zone 2 benefits.