Iñigo San Millán, Ph.D.: Zone 2 Training and Metabolic Health (Ep. #85 Rebroadcast)
Dr. Iñigo San Millán, Assistant Professor at the University of Colorado School of Medicine, joins Peter Attia to discuss mitochondrial function, energy systems, and the six training zones. They extensively cover zone 2 training, lactate as a crucial fuel, and its role in metabolic health and exercise.
Deep Dive Analysis
16 Topic Outline
Iñigo San Millán's Athletic Background and Career Shift
Understanding Aerobic and Anaerobic Energy Systems
Iñigo's Six Zones of Exercise Training
Lactate: A Crucial Fuel, Not Just Waste Product
Zone 2 Training: Physiology, Fuel, and Lactate
Assessing Mitochondrial Function via Zone 2 Lactate
Fat Oxidation Capacity as a Mitochondrial Health Marker
Metabolic Differences: Elite Athletes vs. Diabetics
Physiology of Zone 3, Zone 4, and Lactate Threshold
Dietary Fueling Strategies and Glycolytic Function
Exercise, Insulin Sensitivity, and Type 1 Diabetes
Metformin's Effect on Exercise and Mitochondrial Function
The Concept and Risks of "Double Diabetes"
Optimal Dosing and Balancing Zone 2 Training
Lactate's Role in the Warburg Effect and Cancer
Doping and Altitude Training in Professional Cycling
9 Key Concepts
Aerobic Metabolism
Aerobic metabolism refers to the majority of physical activity where ATP is generated at a rate slow enough that all metabolic demands can be met through mitochondrial oxidation, primarily of fatty acids and glucose. It occurs in the presence of oxygen, but the key is the rate of ATP demand being met by mitochondrial capacity.
Anaerobic Metabolism
Anaerobic metabolism occurs when the demand for ATP exceeds the capacity of the mitochondria and even the cytosolic production of ATP. This forces the body to use ATP already stored in the muscles, such as during a sprint, and is characterized by a rapid, but quickly fatiguing, energy supply.
Lactate as a Fuel/Signaling Molecule
Lactate is a mandatory byproduct of glucose utilization and is considered a crucial fuel for the body, including the brain and heart. It also acts as a major signaling molecule that helps maintain homeostasis in various metabolic pathways throughout the body.
Zone 2 Training
Zone 2 training is an exercise intensity that maximally stimulates slow-twitch muscle fibers without recruiting fast-twitch fibers. It coincides with the 'fat max,' where the highest amount of fat is oxidized, and is considered optimal for improving mitochondrial function, fat burning, and lactate clearance capacity.
Fat Max
Fat max is the specific exercise intensity at which an individual oxidizes the highest amount of fat per minute. This physiological point typically occurs within Zone 2 training and is a key indicator of metabolic efficiency and mitochondrial health.
Respiratory Quotient (RQ) / Respiratory Exchange Ratio (RER)
RQ/RER is the ratio of carbon dioxide produced to oxygen consumed, measured from expired gases. A ratio of 0.7 indicates almost exclusive fat oxidation, while a ratio of 1.0 indicates exclusive glucose oxidation, serving as an indirect measure of fuel utilization.
Athlete's Paradox (Intramuscular Triglycerides)
This paradox describes how fat droplets found near mitochondria in muscle cells are associated with insulin resistance in unhealthy individuals, but in elite athletes, they represent an active, readily utilized reservoir of fuel. In athletes, these fat droplets are efficiently oxidized by mitochondria, contributing significantly to energy production.
Non-Insulin Dependent Glucose Uptake
This refers to the process where muscle contraction directly stimulates the translocation of GLUT4 glucose transporters to the muscle cell surface, allowing glucose to enter the cell without the need for insulin. This mechanism is particularly beneficial for individuals with insulin resistance and is enhanced by exercise.
Warburg Effect
The Warburg Effect describes the metabolic characteristic of cancer cells, which consume large amounts of glucose and produce significant lactate, even in the presence of oxygen. This lactate is not merely a byproduct but also acts as a signaling molecule that promotes various aspects of carcinogenesis, including proliferation and metastasis.
11 Questions Answered
The body primarily uses aerobic metabolism for most activities, even at higher intensities, with anaerobic metabolism reserved for very short, maximal efforts. The main fuels are fatty acids and glucose, which are oxidized in different muscle fiber types.
Lactate is a mandatory byproduct of glucose utilization, not a waste product, and is a crucial fuel for the brain, heart, and other cells. It also serves as a major signaling molecule that helps maintain metabolic homeostasis throughout the body.
Zone 2 training is an exercise intensity that fully stimulates slow-twitch muscle fibers and aligns with the 'fat max,' where fat oxidation is highest. It is considered the optimal intensity for improving mitochondrial function, enhancing fat burning, and increasing lactate clearance capacity.
Measuring blood lactate levels during exercise, particularly at the Zone 2 threshold, provides an indirect assessment of mitochondrial function. Higher lactate accumulation indicates that the muscle's mitochondria are less efficient at clearing or metabolizing lactate.
A poor capacity to oxidize fat, especially at rest or low exercise intensities, is a significant indicator of mitochondrial dysfunction and is commonly seen in conditions like type 2 diabetes. Conversely, high fat oxidation capacity signifies robust mitochondrial health.
The 'athlete's paradox' highlights that while intramuscular fat droplets are linked to insulin resistance in unhealthy individuals, in elite athletes, these fat deposits are highly active fuel reservoirs. These active fat droplets are efficiently oxidized by mitochondria, contributing significantly to energy during exercise.
Muscle contraction itself triggers pathways that translocate GLUT4 glucose transporters to the muscle cell surface, enabling glucose to enter cells independently of insulin. This non-insulin dependent glucose uptake is a key benefit of exercise, particularly for improving insulin sensitivity.
Double diabetes refers to individuals with type 1 diabetes who also develop insulin resistance or other characteristics of type 2 diabetes. This is a growing concern, especially given the high prevalence of type 2 diabetes and pre-diabetes in the general population.
For maintaining mitochondrial function, two days a week of Zone 2 training is generally sufficient. To significantly improve function, three to five days a week, for about one to one and a half hours per session, is recommended, especially for individuals with metabolic dysfunction.
Metformin can increase lactate levels, possibly by increasing glucose flux into cells or inhibiting mitochondrial function (specifically complex I). Some research suggests it might blunt exercise benefits, particularly in metabolically healthy individuals, by affecting mitochondrial efficiency.
The Warburg Effect describes cancer cells' tendency to consume large amounts of glucose and produce significant lactate, even with sufficient oxygen. Lactate is not just a byproduct but acts as a signaling molecule that drives various aspects of carcinogenesis, including cell proliferation, angiogenesis, and metastasis.
13 Actionable Insights
1. Maximize Mitochondrial Function
Engage in Zone 2 exercise, which stimulates slow-twitch muscle fibers to their fullest and maximizes fat oxidation, leading to significant improvements in mitochondrial function and lactate clearance capacity.
2. Identify Zone 2 by Conversation
To gauge Zone 2 intensity without equipment, exercise at the highest level of exertion where you can still comfortably carry on a conversation, indicating optimal aerobic output.
3. Zone 2 Lactate Levels
Aim for lactate levels between 1.5 to 2 millimoles during Zone 2 training, as this range signifies efficient fat oxidation and maximal mitochondrial output without significant lactate accumulation.
4. Zone 2 Training Frequency
To maintain mitochondrial function, aim for at least two days of Zone 2 training per week; to significantly improve it, increase frequency to five days a week.
5. Prioritize Mitochondrial Conditioning
Approach exercise not just as calorie burning, but as ‘mitochondrial conditioning’ or ‘reprogramming’ to enhance fuel partitioning and overall metabolic health.
6. Zone 2 Dose for Diabetics
For individuals with pre-type 2 or type 2 diabetes, aim for one to one and a half hours of Zone 2 training, four days a week, to effectively reverse metabolic dysfunction.
7. Implement Post-Exercise Cool Down
After high-intensity exercise, perform a cool-down period to help reduce post-exercise hyperglycemia, potentially eliminating the need for insulin correction in diabetic individuals.
8. Exercise Immediately After Meals
For individuals with type 2 diabetes, exercise immediately after eating to leverage muscle contraction for non-insulin dependent glucose uptake, reducing the need for insulin.
9. Adjust Metformin for Zone 2
If taking metformin and performing Zone 2 exercise, consider adjusting the timing or dose (e.g., stopping it the night before) to prevent potential blunting of exercise benefits and reduce elevated lactate levels, as observed in personal experimentation and suggested by recent papers.
10. Adopt Sustainable Health Habits
When choosing health and exercise routines, prioritize practices that you can realistically maintain for the rest of your life, rather than unsustainable extreme measures.
11. Consider Carbohydrate Restriction
For metabolically unhealthy individuals not aiming for elite athletic performance, carbohydrate restriction can be a powerful tool to improve metabolic health.
12. Incorporate Varied Fasting
Implement different types of fasting (e.g., weekly, monthly, quarterly) as a strategy to maintain metabolic balance and sustain long-term health habits.
13. Reduce Insulin Before Exercise (Type 1)
Type 1 diabetics, under clinical guidance, should consider reducing their insulin dose before exercise, as muscle contraction increases non-insulin dependent glucose uptake and insulin sensitivity, helping prevent hypoglycemia.
7 Key Quotes
Everybody sort of has a sense that all roads point to the mitochondria.
Peter Attia
In the elite athletes have the perfect metabolism. And mitochondria is at the epicenter of metabolism and health.
Iñigo San Millán
Lactate is the most important, if not the most important fuel for the body.
Iñigo San Millán
Watts is a mechanical parameter, but heart rate is a physiological parameter and responds to the physiological metabolic stress.
Iñigo San Millán
If you can't do it for the rest of your life, you have to come back to the, why am I doing this?
Peter Attia
The most potent drugs we have are food and exercise.
Peter Attia
There's no population on earth who has as many carbohydrates and simple sugars as these athletes by a landslide.
Iñigo San Millán
2 Protocols
Zone 2 Training for Mitochondrial Improvement
Iñigo San Millán- Perform Zone 2 training 3-5 days per week (2 days for maintenance).
- Each session should last 1 to 1.5 hours.
- Maintain an intensity where lactate levels are between 1.5-2 millimoles, or at a level where you can still comfortably carry on a conversation.
Cool-down Protocol for Post-Exercise Hyperglycemia
Iñigo San Millán- After high-intensity exercise, perform a cool-down period.
- This helps reduce post-exercise hyperglycemia by continuing muscle contraction, which facilitates non-insulin dependent glucose uptake.