How accurate are predictive metrics like heart rate variability for athlete readiness?

While heart rate variability (HRV) and other readiness predictors might work for the general population, elite athletes often report discrepancies. They report beating records on days flagged as 'fatigued' and performing poorly on 'top form' days, suggesting that subjective feeling and historical data often outweigh algorithm predictions at peak performance levels.

Why is the real-time physiological data of cyclists not made public?

The speaker expresses frustration that genuine data is not released, which would likely counter public skepticism about current doping in cycling. However, team policy considers it private data, and there's a belief that even if released, some people would not believe it or would accuse teams of altering the data.

How much Zone 2 training do professional cyclists do?

Professional cyclists ideally spend a significant portion of their training in Zone 2, especially during winter months, dedicating 70-80% of their training days to this intensity. This percentage adjusts as the season progresses, with increased intensity closer to races, but Zone 2 remains a foundational component.

How can I estimate my Zone 2 training intensity without expensive equipment?

A reliable surrogate for Zone 2 is the 'talk test' or 'relative perceived exertion' (RPE). If you can hold a conversation but feel some strain, meaning the person on the other end would know you're exercising, you're likely in Zone 2. If you're too comfortable, it's too easy (Zone 1); if you can't talk, it's too intense (Zone 3+).

What is the recommended frequency and duration for Zone 2 training?

Ideally, Zone 2 training should be done 3-4 days a week, with 4-5 days being optimal for significant adaptations. Each session should last approximately 1 to 1.5 hours, though even 20-30 minutes can initiate metabolic changes for untrained individuals, gradually built up over time.

Does stress or mental work impact physical training performance and energy levels?

Yes, high levels of mental work and stress can significantly deplete glycogen stores, even from the brain's high glucose demand, leading to feelings of fatigue and reduced exercise performance. This can manifest as a lower-than-normal heart rate response during workouts, indicating the need for rest and increased carbohydrate intake.

Can older adults significantly improve their metabolic health through exercise?

Absolutely. There are inspiring examples of individuals in their 60s and 70s achieving metabolic parameters comparable to active people in their 30s. This demonstrates the significant potential for improvement at any age, even for those starting later in life with no prior athletic background.

What are the concerns about Metformin for longevity and mitochondrial health?

Metformin inhibits Complex I of the electron transport chain, a crucial component of mitochondrial function. While beneficial for pre-diabetes and early diabetes, its long-term effects on mitochondrial function and longevity in healthy individuals are not fully understood, making interpretation of metabolic data challenging.

Are NAD+ boosting supplements like NR and NMN beneficial, or do they pose risks?

While NAD+ levels decrease with aging, suggesting a benefit from precursors like NR and NMN, direct evidence of human longevity benefits is lacking. A pilot study in mice observed a 15% increase in aggressive breast cancer growth with NAD+ precursors, raising concerns about potentially favoring tumor metabolism in humans with undiagnosed tumors.

What is the impact of long COVID on mitochondrial function?

Studies on long COVID patients, even previously healthy and active individuals, show significant mitochondrial dysfunction, resembling that seen in type 2 diabetes or metabolic syndrome. This metabolic impairment can explain severe exercise intolerance, even when cardiac and pulmonary functions appear normal.

How does a sedentary lifestyle affect mitochondrial function and glucose metabolism?

Sedentary individuals, even those without clinical diabetes, exhibit significant dysregulation in mitochondrial function. They show decreased capacity to oxidize glucose, fatty acids, and amino acids, reduced electron transport chain activity, and particularly, downregulation of the mitochondrial pyruvate carrier, impacting glucose metabolism and potentially preceding clinical symptoms.

Key Moments

201 - Deep dive back into Zone 2 Training | Iñigo San-Millán, Ph.D. & Peter Attia, M.D.

Peter Attia MD

Science & Technology8 min read196 min video

Mar 28, 2022|1,725,336 views|10,493|637

zone 2 training Zone 2 training zone 2 zone 2 running zone 2 cycling aerobic training zone 2 training for endurance athletes zone 2 training benefits zone 2 training explained zone 2 triathlon cycling

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TL;DR

Revolutionary insights into Zone 2 training, mitochondrial function, and its profound impact on longevity.

Key Insights

Zone 2 training is crucial for optimal mitochondrial function, fat oxidation, and lactate clearance, offering unparalleled benefits for metabolic health and longevity.

Elite athletes like Tadej Pogačar exhibit exceptional Zone 2 capacity, characterized by low lactate levels at high power outputs and superior fat oxidation, highlighting its predictive power for endurance performance.

Indirect calorimetry combined with lactate testing provides the most accurate assessment of metabolic flexibility and mitochondrial function, helping to define individualized Zone 2 training.

Sedentary individuals, even without overt clinical symptoms, show significant mitochondrial dysfunction, suggesting these changes precede the onset of diseases like type 2 diabetes.

Chronic exposure to lactate, as seen in cancer, promotes tumor growth, while acute lactate (from exercise) acts as a beneficial signaling molecule for cellular health.

Long COVID patients often exhibit severe mitochondrial dysfunction, resembling type 2 diabetes, even after mild infections, indicating a potential global insult to skeletal muscle mitochondria.

THE PHENOMENON OF TADEJ POGAČAR AND ELITE PHYSIOLOGY

Dr. Iñigo San-Millán, a renowned applied physiologist, highlights his work with cycling prodigy Tadej Pogačar, emphasizing Pogačar's extraordinary physiological capabilities. San-Millán identified Pogačar's potential in 2018 through extensive physiological testing, revealing exceptional oxidative capacity and lactate clearance. Pogačar could sustain high power output with remarkably low lactate levels, a testament to his superior mitochondrial function. This metabolic efficiency allows him to maintain effort and recover quickly, setting him apart even among elite professional cyclists. The discussion underscores how critical metrics like watts per kilogram and lactate production predict success in grueling races like the Tour de France.

DEFINING AND MEASURING ZONE 2 TRAINING

Zone 2 training is precisely defined as the exercise intensity that maximally stresses mitochondria and oxidative capacity. It primarily recruits type I muscle fibers, mobilizes the highest amount of fat for fuel, and stimulates oxidative phosphorylation. The most accurate way to measure Zone 2 is through indirect calorimetry, which assesses oxygen consumption and carbon dioxide production. This method determines fat oxidation rates across varying exercise intensities, revealing a 'fat Max'—the point of maximum fat oxidation. This test provides a 'metabolic map' crucial for understanding mitochondrial function, metabolic flexibility, and for defining individualized training zones, correlating directly with lactate levels and overall metabolic health.

UNDERSTANDING LACTATE KINETICS AND LIMITATIONS

Lactate, often misunderstood as a waste product, is a crucial fuel source for cells. Its production and clearance reflect mitochondrial health; efficient clearance indicates robust mitochondrial function. The body processes lactate through specific transporters (MCT1) into mitochondria, where it's converted back to pyruvate and oxidized for energy. While lactate levels are excellent indicators, they can vary across individuals. For instance, a 2 millimolar lactate level might signify a higher metabolic stress in an elite athlete than in a metabolically impaired individual, due to differences in lactate kinetics and clearance capacities. Training specifically enhances these lactate shuttles and mitochondrial pathways.

DIFFERENCES IN METABOLIC PROFILES: ATHLETES VS. METABOLIC SYNDROME

Comparative data reveal stark differences in metabolic profiles. Individuals with metabolic syndrome show elevated resting lactate and quickly transition to glucose as a primary fuel source at low exercise intensities, reflecting impaired mitochondrial function. In contrast, professional athletes maintain remarkably low lactate levels and high fat oxidation capacities even at high power outputs. Moderately active individuals fall in between, highlighting a spectrum of metabolic flexibility. These differences underscore the value of individualized metabolic testing to truly understand fuel partitioning and mitochondrial efficiency, rather than relying on generic fitness metrics alone. The data also emphasizes the importance of normalizing for body weight (watts per kilo) for accurate comparisons.

THE ROLE OF MUSCLE FIBER TYPES AND TRANSPORTERS

Muscle fiber types play a critical role in energy utilization. Fast-twitch fibers primarily utilize glucose rapidly, producing pyruvate and subsequently lactate. However, slow-twitch muscle fibers, abundant in endurance athletes, are adept at clearing this lactate through MCT1 transporters, oxidizing it within their mitochondria. Pogačar's low lactate levels, even during intense efforts, suggest a high density and efficiency of these MCT1 transporters, which can be enhanced through specific training. When lactate cannot be efficiently oxidized or transported, it accumulates, leading to an acidic microenvironment that can impair muscle function and contribute to fatigue, a key distinction between elite and untrained individuals.

TRAINING PROTOCOLS FOR OPTIMAL ZONE 2 ADAPTATION

For individuals looking to improve metabolic function, a structured Zone 2 training program is essential. Optimal adaptation requires specific frequency, duration, and intensity. Ideally, individuals should aim for three to four, or even four to five, one-hour to 90-minute sessions per week. Perceived exertion (ability to converse with slight strain) and heart rate (70-80% of maximum) serve as practical surrogates for individuals without laboratory access. This consistent, moderate-intensity training fosters mitochondrial biogenesis, enhances fat oxidation, and improves lactate clearance. While some high-intensity work is beneficial for overall fitness and glycolytic capacity, Zone 2 forms the foundational block for sustained metabolic health.

CHRONIC TRAINING VS. ACUTE STRESS AND RECOVERY

Consistent, long-term Zone 2 training yields compounding benefits, similar to wealth accumulation—small, daily gains over years. This is evidenced by individuals maintaining or even improving metabolic parameters into their 60s and 70s. However, acute stressors like overwork and insufficient sleep can significantly impair performance, even in well-trained individuals, by affecting fuel availability and catecholamine response. Adequate recovery, sleep, and nutrition (including appropriate carbohydrate intake) are crucial for optimizing physiological adaptations and maintaining consistent training performance. Judging performance solely by training load without considering external stressors can be misleading.

METFORMIN AND MITOCHONDRIAL FUNCTION: A COMPLEX INTERPLAY

The impact of Metformin on mitochondrial function, particularly in non-diabetic individuals using it for longevity, remains a complex and debated topic. Metformin is known to inhibit Complex I of the electron transport chain, a key component of mitochondrial function. Clinically, patients on Metformin often exhibit elevated resting lactate levels (e.g., 3.5 mM), raising questions about whether this reflects true mitochondrial impairment or is an artifact of the drug itself. Further research, including muscle biopsies in trained individuals, is needed to disentangle these effects and understand the long-term implications of Metformin on healthy mitochondrial function.

SUPPLEMENTS AND CANCER METABOLISM: THE NAD+ DILEMMA

While NAD+ precursors (NR, NMN) are popular for their touted longevity benefits, their impact on healthy cellular function and cancer metabolism requires caution. NAD+ is crucial for glycolysis, a pathway often hijacked by cancer cells for rapid growth (the Warburg effect). Pilot studies in mice suggest that boosting NAD+ levels could potentially increase tumor growth in aggressive cancers like triple-negative breast cancer. This raises a theoretical concern about whether supplementing with NAD+ precursors could inadvertently favor undiagnosed tumors or cancer recurrence. The intricate balance of cellular metabolites, rather than single-pathway enhancement, is critical for understanding overall health and disease.

EXERCISE, LACTATE, AND THE TUMOR MICROENVIRONMENT

Chronic accumulation of lactate, a hallmark of many aggressive tumors, drives cancer growth and metastasis by creating an acidic microenvironment. In contrast, acute lactate production during exercise acts as a beneficial signaling molecule, upregulating genes involved in cellular homeostasis. The critical distinction lies in the acute vs. chronic exposure to lactate. Exercise, despite transiently raising lactate, also enhances the body's capacity to clear it, potentially counteracting the chronic lactate accumulation seen in cancer. Research into muscle-derived exosomes, microvesicles released during exercise, suggests they might possess anti-cancer properties by influencing the metabolic phenotype of tumor cells, offering a promising avenue for understanding exercise's therapeutic role in cancer.

LONG COVID: A METABOLIC CRISIS

A published study revealed that individuals with long COVID, even those previously healthy and active, exhibit severe mitochondrial dysfunction, metabolically resembling patients with type 2 diabetes. These patients experience debilitating fatigue and exercise intolerance, despite normal pulmonary and cardiac function. This suggests a global insult to skeletal muscle mitochondria, potentially due to viral hijacking or disruption of mitochondrial fission/fusion processes. The majority of these cases were linked to Alpha and Delta variants. This underscores a significant and under-recognized aspect of long COVID, highlighting the need for further research, including muscle biopsies, to understand the precise mechanisms and develop targeted interventions, potentially including carefully managed exercise protocols.

THE LIMITATIONS OF V̇O2 MAX AS A SOLE PREDICTOR

While V̇O2 Max is a well-established marker for cardiorespiratory fitness and longevity, relying solely on it for exercise prescription can be misleading. Studies indicate that individuals with the same V̇O2 Max can have vastly different metabolic profiles at the cellular level, in terms of fat oxidation and lactate dynamics. Elite athletes, for instance, can significantly improve lactate clearance and metabolic flexibility without a corresponding increase in V̇O2 Max, demonstrating crucial adaptations at the cellular level. Therefore, integrating cellular surrogates like lactate and fat oxidation, alongside V̇O2 Max, offers a more precise and individualized approach to exercise prescription and health assessment, moving beyond outdated metrics.

SEDENTARY LIFESTYLE: THE PRECURSOR TO METABOLIC DISEASE

Emerging research highlights that a sedentary lifestyle, even in seemingly healthy individuals without clinical symptoms, leads to significant mitochondrial dysfunction. This includes decreased capacity to oxidize glucose, fatty acids, and amino acids, alongside impaired electron transport chain function and reduced substrate transporter expression. Notably, a downregulation of the mitochondrial pyruvate carrier (MPC), which transports pyruvate into mitochondria, is observed. This suggests that the first 'jammed door' in glucose metabolism for sedentary individuals may be at the entry of pyruvate into the mitochondria, potentially predating overt insulin resistance and clinical diabetes by years, emphasizing the importance of early intervention through regular activity.

INTRAMUSCULAR FAT AND CARDIOMETABOLIC HEALTH

Intramuscular triglycerides (IMTGs), fat droplets within muscle, present a paradox. In elite athletes, IMTGs are metabolically active, constantly turning over and contributing significantly to fat oxidation. However, in individuals with type 2 diabetes or obesity, IMTGs become stagnant, accumulating and releasing pro-inflammatory mediators like ceramides. Ceramides are known to play a key role in the atherosclerotic process, linking intramuscular fat accumulation to cardiovascular disease. This suggests that the active turnover of IMTGs in athletes contributes to metabolic health, while its stagnation in sedentary or metabolically compromised individuals contributes to cardiometabolic disease, hinting at a mitochondrial impairment as a central nexus.

Mentioned in This Episode

●Supplements

●Products

●Software & Apps

●Organizations

●Concepts

●People Referenced

Zone 2 Training for Mitochondrial Health

Practical takeaways from this episode

Do This

Aim for 3-4 days of Zone 2 training per week, ideally 4-5 days for significant adaptations.

Target 1 to 1.5 hours of continuous Zone 2 exercise per session; even 30 minutes can initiate adaptations, but more is needed for progressive improvement.

Use Relative Perceived Exertion (RPE) as a primary guide: be able to talk but with noticeable strain, such that the other person knows you're exercising.

Triangulate with heart rate: aim for 70-80% of your actual maximum heart rate as a starting point, then adjust with RPE.

If you only have limited time, perform Zone 2 first, then incorporate a short, high-intensity interval at the end of the session to stimulate glycolytic capacity without blunting aerobic benefits.

Prioritize rest and recovery, especially when experiencing high work stress or fatigue, to allow for proper physiological adaptations and glycogen replenishment.

Consider using a stationary bike (trainer) for consistent Zone 2 intensity, as outdoor cycling can be highly variable.

Avoid This

Don't rely solely on predicted maximum heart rate; know your actual maximum heart rate for accurate Zone 2 calculation.

Avoid mixing high-intensity intervals in the middle or beginning of a Zone 2 session, as high lactate levels can inhibit fat oxidation.

Don't neglect other energy systems; while Zone 2 is crucial, some high-intensity training is needed to maintain glycolytic capacity, which also declines with age.

Avoid extreme diets or training regimens that are not sustainable long-term, as consistency is key for mitochondrial adaptations.

Do not solely focus on cardiorespiratory fitness (V2 Max) as the ultimate metric for metabolic health; cellular-level markers like fat oxidation and lactate dynamics provide deeper insight.

Don't dismiss the concept of perceived exertion; it's a scientifically valid and practical surrogate for exercise intensity.

Do not take NAD+ precursors like NR or NMN if you have undiagnosed tumors or cancer, as pilot studies suggest they may favor tumor growth.

Lactate and Fat Oxidation Profiles by Fitness Level

Data extracted from this episode

Fitness Level	Resting Blood Lactate (mMol/L)	Lactate Threshold (~2mMol/L) at Watts	Max Fat Oxidation (watts)
Metabolic Syndrome	~1.8-2.0	100W	<50W (decreasing from start)
Moderately Active	~1.0	175W	~130W
Professional Athlete	~0.5	300W	~250W

Historical Cycling Power Output (FTP / Watts per Kilo)

Data extracted from this episode

Era	Athlete Status	FTP (watts/kilo)	Drug Assistance
1990s-2000s	Best of the Best	6.8-7.1	EPO, Blood Transfusions
Today	Top Contenders	6.1 (to win Tour)	None (publicly known)
Today	Short Climbs (peak)	6.3	N/A
Today	Longer Climbs (peak)	5.5-5.8	N/A

Common Questions

Elite cyclists like Pogačar show exceptional oxidative capabilities, high lactate clearance rates, and the ability to sustain high power output with extremely low blood lactate levels. Early physiological testing revealed his outstanding fat oxidation capacity and metabolic flexibility even at a young age.

Topics

Endurance Training Exercise Physiology Fat Oxidation Health & Longevity Neuroscience & the Brain Human Performance Metabolic Flexibility Mitochondrial Health Zone 2 Training Lactate Threshold

Mentioned in this video

Companies

UAE Team Emirates

Professional cycling team with whom Dr. San-Millán works, coaching athletes like Tadej Pogačar and using advanced physiological testing to predict performance and formulate race strategies.

People

Travis Nemkov

Colleague of Dr. San-Millán at the University who helped develop a metabolomics platform.

Brian Bergman

Colleague of Dr. San-Millán at the university, researching the content within fat droplets (intramuscular triglycerides), particularly ceramides and diglycerides.

Joxean Fernández Matxín

General Manager of UAE Team Emirates who introduced Dr. San-Millán to Tadej Pogačar.

George Brooks

Colleague, mentor, and friend of Dr. San-Millán, recognized for discovering the lactate shuttle and his extensive work on lactate metabolism, considered a potential Nobel Prize winner.

Michael Phelps

Legendary swimmer mentioned to illustrate that even in a sport defined by short, maximal efforts, elite athletes dedicate extensive hours to lower-intensity training, similar to endurance sports.

Tadej Pogačar

Professional cyclist known for winning the Tour de France at a young age, displaying exceptional physiological capabilities, low lactate levels at high power outputs, and remarkable trainability. He serves as a prime example of elite endurance athlete physiology, with his training and race strategies extensively discussed.

Angelo D'Alessandro

Colleague of Dr. San-Millán at the University who helped develop a metabolomics platform for analyzing hundreds to thousands of metabolites.

Otto Warburg

Scientist who observed in 1923 that cancer cells exhibit high glycolytic flux, specifically noting lactate production as a characteristic feature, forming the basis of the 'Warburg effect'.

Francis Benedict

One of the first researchers in the 1920s to study the combustion of carbohydrates and fatty acids in the body, laying the groundwork for indirect calorimetry equations.

Mauro Gianetti

CEO of UAE Team Emirates who introduced Dr. San-Millán to Tadej Pogačar.

Drugs & Medications

Propranolol

A beta-blocker discussed by Peter Attia as a way to lower heart rate during exercise, illustrating that while it can reduce heart rate, the subjective experience of exertion can be miserable, indicating the importance of perceived exertion over sole reliance on heart rate metrics.

Metformin

A medication that inhibits complex one of the electron transport chain, a key component of mitochondrial function. Its effect on lactate levels makes interpreting Zone 2 data challenging in patients taking it, especially when considering its use as a geroprotective agent.

Moderna vaccine

An mRNA COVID-19 vaccine, mentioned in the context of a higher risk of myocarditis in young males compared to the risk from COVID-19 infection itself.

Software & Apps

CPET

A medical term for physiological testing (metabolic testing) used to assess cardiac, pulmonary, and metabolic function, enabling a deeper understanding of patient limitations, including those with long COVID.

TrainingPeaks

Software used by Dr. San-Millán and his athletes to analyze training data, including power output and recovery, indicating athlete fitness and fatigue.

Supplements

NAD

A coenzyme crucial in glycolysis and redox status. Its cellular levels decrease with aging, leading to a debate about the efficacy and potential risks of supplementation with precursors like NR and NMN, especially concerning cancer growth.

Resveratrol

Mentioned as a historical example of a longevity supplement that showed significant promise in mouse studies but failed to demonstrate similar effects in humans, highlighting the caution needed when extrapolating animal research to human health.

Nicotinamide Mononucleotide

A precursor to NAD+, discussed as a longevity-boosting supplement, but with theoretical risks related to potentially favoring tumor metabolism, based on pilot studies in mice.

Nicotinamide Riboside

A precursor to NAD+, discussed as a longevity-boosting supplement, but with theoretical risks related to potentially favoring tumor metabolism, based on pilot studies in mice.

Organizations

Mayo Clinic

Mentioned in comparison to National Jewish Health as one of the top pulmonology hospitals.

National Jewish Health

A top pulmonology hospital that observed metabolic issues in long COVID patients, leading to collaboration with Dr. San-Millán for further research.

Concepts

MCT1

A transporter protein crucial for moving lactate into the mitochondria in slow-twitch muscle fibers, enabling lactate to be oxidized for energy. Its development is stimulated through specific training zones.

Weir equation

A linear equation used in indirect calorimetry to calculate total energy consumption and the proportion of energy derived from fat and carbohydrate oxidation, based on oxygen consumption and carbon dioxide production.

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