#201 - Deep dive back into Zone 2 | Iñigo San-Millán, Ph.D. (Pt. 2)
Iñigo San-Millán, an internationally renowned applied physiologist, discusses Zone 2 training's impact on mitochondrial function and longevity, drawing insights from elite athletes like Tadej Pogačar. He covers optimal training protocols, the role of lactate and fat oxidation, and the metabolic effects of metformin, NAD, and long COVID.
Deep Dive Analysis
18 Topic Outline
Introduction to Iñigo San-Millán and Tadej Pogačar's Physiology
Physiological Metrics for Elite Cyclists and Race Strategy
Transparency of Athlete Data and Doping in Cycling
Tadej Pogačar's Race Strategy and Mental Fortitude
Defining Zone 2 Exercise and its Bioenergetic Basis
Measuring Metabolic Function: Fat Oxidation and Lactate Kinetics
The Role of Lactate and MCT Transporters in Muscle Metabolism
Impact of Diet and Glutamine on Fuel Utilization
Exercise and Glucose Transporters in Diabetes Management
Estimating Zone 2: Heart Rate and Perceived Exertion
Optimal Zone 2 Training: Dose, Frequency, and Duration
Integrating High-Intensity Training with Zone 2 for Health
Compounding Benefits of Zone 2 Exercise and Longevity
Metformin, NAD, and Supplements for Mitochondrial Health
Lactate as an Oncometabolite and Exercise in Cancer
Mitochondrial Dysfunction in Long COVID Patients
Limitations of VO2 Max and Insights from Muscle Biopsies
Cellular Metabolism Changes in Sedentary and Diabetic Individuals
6 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 efficiently within mitochondria without significant lactate accumulation in the blood.
Lactate Clearance Capacity
This refers to the body's ability, particularly in slow-twitch muscle fibers, to efficiently oxidize lactate back into pyruvate within the mitochondria for energy. Elite athletes have a superior capacity, meaning they can produce a lot of lactate during high-intensity efforts but clear it rapidly, preventing its accumulation in the blood.
MCT1 Transporters
These are monocarboxylate transporters located on the outer mitochondrial membrane of slow-twitch muscle fibers. They facilitate the transport of lactate into the mitochondria, where it can be converted back to pyruvate and used as fuel, thereby preventing lactate buildup in the muscle microenvironment and blood.
Metabolic Flexibility
This is the body's ability to efficiently switch between using fat and carbohydrates as fuel sources depending on energy demand and availability. High metabolic flexibility, often seen in elite athletes, indicates robust mitochondrial function and efficient fuel partitioning.
Mitochondrial Pyruvate Carrier
This is the transporter responsible for allowing pyruvate, a byproduct of glucose metabolism, to enter the mitochondria for oxidation. In sedentary individuals, this carrier can be significantly downregulated, impairing glucose's entry into the mitochondria and potentially leading to its reduction to lactate.
Lactate as Oncometabolite
Lactate, the byproduct of glycolysis, can act as an oncometabolite, meaning it promotes cancer growth and proliferation. High glycolytic flux in cancer cells leads to lactate accumulation, creating an acidic tumor microenvironment that drives aggressiveness and metastasis.
11 Questions Answered
Pogačar exhibits exceptionally low blood lactate levels at high power outputs and an amazing ability to clear lactate, allowing him to sustain high power for long durations. His metabolomic profile also shows distinct differences in glycolytic, oxidative, and recovery metabolites compared to other athletes.
Plotting watts per kilo against lactate production is highly predictive of success in endurance sports like the Tour de France. Elite athletes can sustain high power with very low lactate, indicating superior lactate clearance and mitochondrial function, which allows them to perform longer at high intensities.
High-fat, low-carbohydrate diets can create an artifact in metabolic cart measurements, leading to an overestimation of fat oxidation. The equations used are calibrated for high-carb diets, and low CO2 production relative to O2 consumption in ketosis can mislead the algorithm into assuming higher fat burning, even if mitochondrial function isn't exceptionally high.
Muscle contraction during exercise provides an insulin-independent pathway to translocate GLUT4 glucose transporters to the muscle cell surface. This mechanism allows glucose to enter the muscle cells without requiring insulin, effectively lowering blood glucose levels and benefiting individuals with insulin resistance or diabetes.
A reliable method is the 'talk test': you should be able to hold a conversation, but it should feel somewhat strained, indicating you are working hard enough that the person on the other end of the conversation would know you are exercising. If talking is too easy, you're likely in Zone 1; if you can't talk, you're likely in Zone 3 or higher.
A broad range of 70% to 80% of your *actual achieved* maximum heart rate is a good starting point for Zone 2. However, this range can be wide, so it should be adjusted based on perceived exertion and, if possible, lactate measurements for greater precision.
High-intensity training is necessary to stimulate glycolytic capacity, which also declines with age. It can be incorporated at the end of a Zone 2 session, for example, with a 5-minute maximal effort interval. This approach targets both oxidative and glycolytic energy systems without blunting the Zone 2 benefits.
While NAD levels decrease with aging, it's unclear if supplementing precursors directly increases longevity in humans. A pilot study in mice showed a 15% increase in triple-negative breast cancer tumor growth when given an NAD precursor, raising concerns about potentially favoring tumor metabolism if undiagnosed cancers are present.
Patients with long COVID, even those previously healthy and active, exhibit significantly worse fat oxidation and lactate production profiles compared to individuals with type 2 diabetes or metabolic syndrome. This suggests a severe mitochondrial dysfunction, which could explain their profound exercise intolerance despite normal cardiac and pulmonary function.
VO2 max primarily reflects cardiorespiratory fitness, but it doesn't always correlate well with specific cellular metabolic adaptations like lactate clearance or fat oxidation capacity. Individuals with the same VO2 max can have vastly different metabolic states, meaning exercise prescriptions based solely on VO2 max might not be optimally specific for improving mitochondrial function.
Healthy sedentary individuals, even without clinical symptoms like insulin resistance, show significant dysregulation at the mitochondrial level. Specifically, they exhibit decreased capacity in mitochondrial pyruvate carriers and fat transporters (CPT1 and CPT2), indicating impaired glucose and fat metabolism within the cell, potentially years before clinical disease onset.
16 Actionable Insights
1. Prioritize Exercise for Longevity
Recognize that exercise is the single most potent tool or agent available to impact longevity, ranking above all other interventions.
2. Zone 2 Training Frequency
Aim for 3-5 (ideally 4-5) Zone 2 training sessions per week to achieve optimal mitochondrial and metabolic adaptations, especially for those new to exercise.
3. Gauge Zone 2 by Conversation
Determine your Zone 2 intensity by your ability to talk: you should be able to maintain a conversation, but with some noticeable strain, where the person on the other end knows you are exercising.
4. Zone 2 Session Duration
Target 1 to 1.5 hours per continuous Zone 2 training session, gradually building up from shorter durations (e.g., 20-30 minutes) if new to exercise.
5. Compound Gains in Zone 2
Approach Zone 2 training with a long-term mindset, understanding that significant mitochondrial improvements are achieved through small, compounded gains over years, not months.
6. Add High-Intensity Post-Zone 2
Incorporate a high-intensity interval (e.g., a good 5-minute effort) at the end of a Zone 2 session to stimulate the glycolytic system without interfering with fat oxidation.
7. Monitor Heart Rate for Fatigue
Pay attention to your resting heart rate (if higher than normal) and your heart rate response during exercise (if it’s hard to get up) as indicators of fatigue or low glycogen stores.
8. Manage Overwork & Recovery
Recognize that mental stress and overwork can lead to fatigue and poor exercise performance, even with low physical training volume; respond by taking a day off, sleeping more, and increasing carbohydrate intake.
9. Zone 2 Heart Rate Range
As a starting point for Zone 2, aim for 70-80% of your realized maximum heart rate, then adjust based on your perceived exertion.
10. Exercise Post-Carb Meal (Diabetes)
For individuals with type 2 diabetes or pre-diabetes, consider exercising right after a carbohydrate-containing meal to utilize muscle contraction for insulin-independent glucose uptake and lower blood glucose. For type 1 diabetics, avoid injecting insulin before exercise.
11. Ensure Continuous Zone 2
Ensure your Zone 2 training is continuous and sustained within the target intensity, avoiding oscillations (e.g., from hills or stops) that dilute the metabolic effect.
12. Use Indoor Trainer for Zone 2
Utilize an indoor trainer for Zone 2 cycling to maintain consistent intensity and maximize efficiency, as it isolates variables like wind and terrain.
13. Prioritize Low-Intensity Training
Even when training for high-intensity sports, prioritize lower intensity (Zone 2) training, as elite athletes dedicate the majority of their sessions to this zone.
14. Be Wary of Longevity Supplements
Be cautious about relying on single supplements like NAD precursors for longevity, as it’s a complex process, and there’s a theoretical risk they might promote tumor growth if an undiagnosed cancer is present.
15. Interpret Metabolic Tests on Low-Carb
If on a low-carbohydrate diet, be aware that indirect calorimetry may show artificially high fat oxidation numbers due to gas exchange artifacts; lactate levels might be a more reliable indicator in such cases.
16. Maintain Good State of Mind
Cultivate a good state of mind and practice eating what you like in moderation, as these are important components for overall longevity and enjoyment of life.
6 Key Quotes
When I say someone has good potential, I don't usually say that lightly of anybody.
Iñigo San-Millán
The physiological testing we started doing right off the bat. I saw like amazing capabilities, ability to clear lactate and to put out great amount of power for long periods of time.
Iñigo San-Millán
I always tell people, if you can exercise whatever the exercise you do and maintain a conversation like you and I are doing, you're way too easy. You're probably zone one. If you can talk, but it's some form of strain, you can talk for two hours. But we're talking a little bit like that. You're just at that threshold.
Iñigo San-Millán
I think that more and more, and this is what you see in so many fields in medicine nowadays, everybody is stumbling upon mitochondria. So there's an aging process where we lose mitochondrial function, and there's like a sedentary component where we lose mitochondrial function. I wish that we could have a medication, a pill that you could take it and increase the mitochondrial function because it would increase metabolic health and longevity. But the only medication that we know is exercise.
Iñigo San-Millán
The intervention of human evolution has been becoming sedentary.
Iñigo San-Millán
The deeper I go in the rabbit hole into all things that relate to longevity, the more convinced I am that if you're going to rank order things, if you were forced to rank order things, there's nothing that ranks above exercise as the single most potent tool or agent we have to impact longevity.
Peter Attia
1 Protocols
Optimal Zone 2 Training Program for Metabolic Health
Iñigo San-Millán- Determine your personalized Zone 2 intensity using a metabolic test (indirect calorimetry for fat oxidation and lactate levels) or surrogates like heart rate (70-80% of max HR) and perceived exertion (able to talk, but strained).
- Start with a duration appropriate for your current fitness level (e.g., 20-30 minutes) and gradually increase.
- Aim for a continuous exercise duration of 1 to 1.5 hours per session once adapted.
- Perform Zone 2 training 3 to 4 days a week, ideally 4-5 days for significant improvements.
- Consider adding a short, high-intensity interval (e.g., 5 minutes maximal effort) at the end of some Zone 2 sessions to stimulate glycolytic capacity without interfering with fat oxidation.