#201 - Deep dive back into Zone 2 | Iñigo San-Millán, Ph.D. (Pt. 2)

Episode Summary

Executive Summary: Peter Attia and Inigo San Milan discuss elite cycling physiology through Tadej Pogacar, then use that lens to explain zone 2, lactate, fat oxidation, mitochondrial function, and exercise prescription. They argue that lactate and fat-oxidation testing are more useful than generic VO2 max or heart-rate formulas, and explore how diet, metformin, NAD, cancer, and long COVID alter mitochondrial metabolism.

Main Topics: Pogacar as a physiologic benchmark: San Milan explains how testing, training data, and metabolomics revealed Pogacar’s exceptional ability to clear lactate, sustain power, and recover, making him a model for elite endurance physiology. Zone 2 definition and measurement: They define zone 2 as the intensity that maximally stresses mitochondrial oxidative capacity and fat oxidation, then debate how best to identify it using lactate, indirect calorimetry, heart rate, and perceived exertion. Lactate, fat oxidation, and mitochondrial function: The conversation details how lactate production/clearance reflects mitochondrial health, why elite athletes can produce and clear more lactate, and why blood lactate alone can be misleading across populations. Exercise prescription for non-athletes: San Milan outlines practical training guidance: frequency, duration, and intensity for people trying to improve metabolic health, emphasizing repeated zone 2 sessions plus some high-intensity work. Diet, ketosis, and testing artifacts: They discuss how low-carb or ketogenic diets can distort indirect calorimetry estimates of fat oxidation and carbohydrate use, potentially overstating mitochondrial efficiency if lactate is not also measured. Metformin, NAD, and supplements: They examine whether metformin impairs mitochondrial function and whether NAD-boosting supplements truly improve longevity, with caution about interpreting lactate and metabolic data in users. Disease states: cancer, ICU stress, and long COVID: San Milan connects mitochondrial dysfunction to cancer metabolism, ICU catabolism, and long COVID, arguing that these conditions may share impaired oxidative metabolism and altered substrate handling.

Key Arguments: Pogacar’s low lactate at high power outputs indicates unusually strong mitochondrial oxidative capacity and lactate clearance, not just high FTP. Blood lactate thresholds are not universal; the same lactate value can represent very different metabolic stress in elite athletes versus sedentary or metabolically unhealthy people. Zone 2 is best understood as the intensity that maximizes mitochondrial stress and fat oxidation, but the exact lactate cutoff may vary by fitness level and diet. Indirect calorimetry is useful for estimating fat oxidation, but it can be confounded by ketogenic or low-carb diets, making lactate data important for interpretation. Elite athletes can oxidize more glucose and produce more lactate than recreational athletes, yet clear it so efficiently that blood lactate stays lower. For most people, zone 2 training should be frequent, sustainable, and long enough to drive adaptation; high-intensity work is useful but not a substitute for base training. Heart rate and perceived exertion are practical surrogates for zone 2 when lactate testing is unavailable, but they are imperfect and should be individualized. Metformin may raise lactate and complicate interpretation of metabolic testing; its long-term effects on mitochondrial function and longevity remain uncertain. NAD-boosting supplements are not proven longevity tools, and in cancer models NAD precursors may accelerate tumor growth by supporting glycolysis. Long COVID may involve a mitochondrial defect resembling type 2 diabetes, suggesting exercise and metabolic testing could help identify and potentially treat a subset of patients.

Data Points: Pogacar age when first tested: 19 - San Milan began working with him when he joined UAE Team Emirates in late 2018. Tour de France stage attack distance: 35 kilometers to the finish - Used as an example of Pogacar’s confidence and race strategy in the Alps. Tour de France duration: about 100 hours - Attia notes the race is roughly a 100-hour event over three weeks. Elite climbing power: about 5 watts/kg - Attia and San Milan discuss typical peloton tempo climbing intensity. Historical doping-era FTP: 6.8 to 7.1 watts/kg - Referenced as the approximate range seen in the EPO/blood transfusion era. Modern winning FTP estimate: around 6.1 watts/kg - Attia argues current Tour winners do not need doping-era numbers. Professional athlete lactate at low power: ~0.5 mmol - In the figure discussed, elite athletes start with very low resting lactate. Moderately trained individual lactate at low power: ~1 mmol - Shown in the comparative lactate curve during ramp testing. Metabolic syndrome resting lactate: ~1.5 to 3 mmol - San Milan notes elevated resting lactate in metabolically unhealthy individuals. Fat oxidation in elite athletes: up to ~6.5 g/min carbohydrate oxidation and very high fat oxidation - Elite athletes can oxidize substantially more substrate at high workloads. Recreational athlete carbohydrate oxidation: ~4 g/min max - Compared with elite athletes in indirect calorimetry testing. Elite athlete carbohydrate oxidation: ~6.5 g/min max - Used to illustrate higher glycolytic capacity in trained athletes. Long COVID cohort size: 50 patients - San Milan describes the study sample from National Jewish/Mayo-style referral pathways. Long COVID subgroup split: 25 with prior conditions, 25 previously healthy - Half the cohort had underlying conditions and half were previously healthy. Long COVID sex distribution: 35 females, 15 males - The cohort was female-predominant. Metformin-related resting lactate example: 3.5 mmol at rest - San Milan says this often prompts him to ask whether the patient is on metformin. VO2 max in San Milan: 4 L/min - He reports his current VO2 max at age 50. San Milan’s historical VO2 max: 4.5 to 4.8 L/min - He says he has declined only modestly from his cycling peak decades earlier. Zone 2 heart-rate heuristic: 70% to 80% of realized max heart rate - Attia and San Milan agree this is a practical starting range. San Milan’s own zone 2 at altitude: ~2.5 to 2.8 W/kg - He says Colorado altitude lowers his sustainable zone 2 power. Attia’s zone 2 at sea level: just under 3 W/kg - He describes his own current zone 2 threshold. Attia’s morning resting lactate range: 0.3 to 1.1 mmol - He reports 40 days of morning lactate tracking. Ketogenic test fat oxidation: 1.3 g/min - Attia describes his highest measured fat oxidation while in ketosis. Ketogenic test glucose oxidation: just under 6 g/min - Attia reports this at the end of the ramp test. ICU glucose use: about 3x resting - San Milan says ICU patients use roughly triple resting glucose for wound healing and stress metabolism. Cancer pilot study sample: 4 mice per group - NR-treated versus control mice in a triple-negative breast cancer pilot. Cancer pilot result: ~15% increase in tumor growth - Observed in the nicotinamide riboside group.

Pivotal Quotes: "This is where I saw that at a given power output, his lactate levels, blood lactate levels were extremely low." — Inigo San Milan: Explaining why Pogacar stood out physiologically during early testing. "The same blood lactate concentration does not correspond in an elite athlete, does not correspond necessarily to the same lactate concentration in a recreational athlete, the metabolic stress." — Inigo San Milan: Clarifying why lactate thresholds must be interpreted relative to fitness level. "The only medication that we know is exercise." — Inigo San Milan: Summarizing his view that exercise is the most powerful intervention for mitochondrial health and longevity.

Implications: Listeners should treat zone 2 as a personalized metabolic target, not a fixed heart-rate formula. For clinicians and athletes, lactate and fat-oxidation testing are more informative than VO2 max alone, and exercise remains the most powerful mitochondrial intervention.