Peter Attia MD201 - Deep dive back into Zone 2 Training | Iñigo San-Millán, Ph.D. & Peter Attia, M.D.
CHAPTERS
- 0:02 – 7:48
Iñigo's Early Work with Tadej Pogačar
Peter Attia asks Iñigo San-Millán to update listeners on his work with the UAE team and Tadej Pogačar. Iñigo explains how he started with Pogačar at 19 and what testing, training data and metabolomics showed him early on.
- •Iñigo began working with Pogačar in late 2018, when he was 19
- •Low blood lactate at a given power output stood out in Iñigo's long-used testing protocol
- •Training data, recovery feedback and trainability added to the picture
- •A metabolomics platform used at the 2019 Tour of California confirmed distinct metabolites
- 7:48 – 17:22
Lactate, Watts per Kilo, and Predicting Race Performance
The two discuss how lactate relative to watts per kilo predicts cyclists' performance and how that guides Tour de France strategy. Iñigo describes using the data to plan Pogačar's attack in the Alps, and both say they put little weight on readiness metrics like heart rate variability on race day.
- •Lactate at a given power output predicts performance and ranks riders at training camps
- •The Tour is decided by a handful of climbs and time trials
- •Team data guided the decision to attack 35 km from the finish
- •Iñigo says gut feel and the established physiological data count for more than heart rate variability algorithms on race day
- 17:22 – 26:07
Releasing Power Data and Real-Time Physiology for Viewers
Peter raises whether publishing riders' watts-per-kilo data would answer doubts about cheating in modern cycling. Iñigo shares his frustration and the team's reasons for withholding data, and they imagine Formula 1-style real-time physiology for spectators.
- •Modern numbers are well below the EPO-era figures of about 6.8 to 7.1 watts per kilo
- •Iñigo says team policy keeps the data private and some people would not believe it anyway
- •Other teams' published data lets observers gauge where Pogačar must be
- •Both would like real-time heart rate, power, lactate and glucose in broadcasts
- 26:07 – 32:19
Pogačar's Mindset at Ventoux and Seasonal Training Mix
Peter asks about Mont Ventoux, and Iñigo describes Pogačar's calm, strategic racing, including a story from the 2019 Tour of California. Peter then asks how much of his training Pogačar spends in Zone 2, and Iñigo describes how it shifts across the year.
- •On Ventoux, Pogačar stayed calm because of his gap and the long descent
- •In California he let two riders go to study the others' body language
- •About 70-80% of winter training days target the Zone 2 energy system
- •Each energy system gets its own period in the calendar
- 32:19 – 43:42
Defining Zone 2 and Measuring Fat Oxidation
Iñigo defines Zone 2 as the intensity that most stresses mitochondria and fat oxidation, recruiting mainly type 1 fibers. Peter explains how indirect calorimetry and the Weir equation yield fat and carbohydrate oxidation, and Iñigo describes the resulting metabolic map and what separates elite athletes from others.
- •Zone 2 is the intensity that most stimulates mitochondrial function, fat oxidation and lactate clearance
- •Indirect calorimetry gives VO2 and VCO2, which convert into fat and carbohydrate oxidation
- •Elite athletes oxidize more fat at a given power than people with type 2 diabetes or metabolic syndrome
- •The method can indirectly estimate mitochondrial function and metabolic flexibility
- 43:42 – 1:06:35
Reading the Fat Oxidation and Lactate Graphs
Iñigo shares figures from a 2017 paper comparing lactate and fat oxidation across metabolic syndrome, moderately active and professional groups. They discuss normalizing by weight, where fat max falls relative to the 2 mmol lactate point, and how to train someone whose two markers differ.
- •Resting lactate near 2 mmol in metabolic syndrome versus about 0.5 in professionals
- •Peter would benchmark in watts per kilo, with an aspiration of three watts per kilo for patients
- •Maximum fat oxidation tends to occur at lower power than the 2 mmol lactate point
- •Iñigo would train a moderately active person at a point between the two markers
- •Fat oxidation and lactate correlate very strongly
- 1:06:35 – 1:19:19
MCT Transporters and the Lactate Shuttle
Iñigo uses a mitochondria diagram to explain how glucose, fat and lactate enter mitochondria, and why the same blood lactate can mean different things in different people. Well-trained athletes oxidize lactate in muscle, so it does not appear in the blood.
- •Pyruvate is always reduced to lactate, which regenerates NAD for glycolysis
- •MCT4 exports lactate from fast-twitch fibers and MCT1 brings it into slow-twitch mitochondria
- •Pogačar's capacity is part genetic and part epigenetic and trainable
- •Elite athletes oxidize more glucose than others, yet little lactate reaches the blood
- 1:19:19 – 1:34:16
Ketogenic Diets, Metabolic Cart Artifacts, and ICU Glutamine
Peter asks how carbohydrate intake and ketosis confound fat oxidation readings, citing his own and another cyclist's data. Iñigo suspects a gas-exchange artifact and relies on lactate, and the talk moves to glutamine and muscle breakdown in ICU patients.
- •Peter saw fat oxidation above 1 gram per minute while in ketosis
- •Iñigo believes high values in ketosis are an artifact of how the equations read gas exchange
- •Peter notes biopsy work showing muscle glycogen persists in strict ketosis
- •ICU patients use glucose heavily and become depleted of muscle glycogen
- •Iñigo hypothesizes that muscle breakdown supplies glutamine for gluconeogenesis
- 1:34:16 – 1:41:10
Muscle Contraction, GLUT4, and Diabetes
Iñigo explains that insulin resistance blocks GLUT4 translocation, but muscle contraction offers an insulin-independent route. They discuss implications for type 1 and type 2 diabetes, and Peter notes how meals can shift his own lactate during testing.
- •Skeletal muscle oxidizes about 80% of carbohydrates and is likely the first tissue affected in diabetes
- •Contraction translocates GLUT4 without insulin
- •Active type 1 diabetics need little insulin and can become hypoglycemic if they inject before exercise
- •Iñigo suggests exercising after eating could help people with insulin resistance
- •A high-carb meal raises lactate and alters the Zone 2 lactate curve
- 1:41:10 – 1:59:37
Practical Zone 2 Surrogates: Talk Test, Heart Rate, and Overwork
They discuss how to find Zone 2 without a lactate meter, using conversational effort and a percentage of true maximum heart rate. Iñigo explains his view of heart rate variability, and both discuss glycogen, catecholamines and how work overload affects training.
- •The talk test works as a Zone 2 surrogate across fitness levels
- •Peter suggests 70-80% of realized maximum heart rate as a starting range, adjusted by perceived exertion
- •Iñigo defines heart rate variability by deviations from usual resting and exercise heart rates
- •Peter's propranolol self-experiment raised his Zone 2 power at a lower heart rate but felt terrible
- •Being overworked can hurt training performance even with low training volume
- 1:59:37 – 2:19:24
Zone 2 Dose: Frequency, Duration, and Adding High Intensity
Iñigo lays out his principles for beginners: about three to four days a week, roughly an hour to an hour and a half per session, building up gradually. They discuss why elite athletes do mostly low-intensity work and how to add high intensity, including finishing a Zone 2 session with a hard interval.
- •Four days a week of about an hour is the ideal Iñigo describes, and one day a week leads to deterioration
- •Higher frequency is likely better than fewer long sessions at the same volume
- •Elite athletes in all sports do most sessions at low intensity
- •Hard intervals go at the end of Zone 2 sessions, since high lactate early can inhibit lipolysis
- •Peter notes that up-and-down riding does not count as time in Zone 2
- 2:19:24 – 2:27:57
Aging, Compounding Gains, and Fitness at Any Age
Iñigo shares his own VO2 max and metabolic parameters at 50 and what he sees in people who take up training in their 60s and 70s, including an 81-year-old world champion cyclist. Peter ties it to the compounding nature of training.
- •Iñigo says he has the same metabolic parameters at 50 as at 40
- •Retirees who start training improve markedly in their 60s and 70s
- •An 81-year-old champion had been a smoker with hypertension before cycling in his 40s
- •Glycolytic fitness can change in months while mitochondrial function takes much longer
- •Peter likens consistent training to compounding wealth
- 2:27:57 – 2:40:16
Metformin, NAD Precursors, and Supplements
Peter asks whether metformin impairs mitochondrial function or merely raises lactate, and Iñigo says more research is needed and notes that metformin inhibits Complex 1. They then discuss NAD precursors, with Iñigo skeptical of a single-supplement longevity solution and describing a small unpublished mouse pilot on tumor growth.
- •Iñigo sees elevated resting lactate in people on metformin but mostly in already clinical patients, which makes interpretation hard
- •Peter and a partner plan to fund a study to resolve the metformin question
- •Iñigo doubts a single supplement like NAD precursors can drive longevity
- •His pilot study found about 15% faster tumor growth in four mice given nicotinamide riboside versus four controls
- 2:40:16 – 2:44:52
Lactate, Cancer, and the Role of Exercise
Iñigo describes his lab's work showing lactate acts as an oncometabolite and how chronic lactate exposure differs from the acute exposure of exercise. They discuss exosomes and whether exercise-derived signals could counter the glycolytic phenotype of cancer.
- •Lactate regulates gene expression in breast and lung cancer cells
- •Blocking lactate production halted cancer cell growth within hours
- •Acute exercise lactate acts as a signaling molecule, whereas tumors expose cells chronically
- •Muscle-released exosomes might counteract cancer's glycolytic phenotype
- •Peter says exercise looks bad acutely but is the most potent longevity tool chronically
- 2:44:52 – 2:52:58
Long COVID and Mitochondrial Dysfunction
Peter asks about Iñigo's study of long COVID patients, whose pulmonary and cardiac function were normal. Iñigo found fat oxidation and lactate profiles worse than in type 2 diabetes and discusses possible mechanisms.
- •50 patients were analyzed, including previously active people
- •Metabolic profiles were significantly worse than those of people with type 2 diabetes or metabolic syndrome
- •Viruses are known to hijack mitochondria, but the mechanism here is unknown
- •Biopsies are needed, and microperfusion problems are another possibility
- •The sample had 35 females and 15 males and predated Omicron
- 2:52:58 – 3:02:26
Why VO2 Max Is Not Enough for Exercise Prescription
Peter asks how predictable Zone 2 is from VO2 max, and Iñigo describes a study of 225 subjects showing that people with the same VO2 max can be in different metabolic states. He argues cellular surrogates like lactate and fat oxidation are better for prescribing exercise than VO2 max or METs.
- •Many exercise studies prescribe intensity as a percentage of VO2 max
- •At the same percentage of VO2 max, sedentary and elite people differ in lactate, fat and carbohydrate oxidation
- •Within groups, lactate and VO2 max correlate very poorly
- •Iñigo calls the MET concept for exercise prescription hard to swallow in today's times
- 3:02:26 – 3:15:40
Mitochondrial Dysregulation in Sedentary People and Diabetes
Iñigo describes unpublished omics work showing healthy sedentary people already have downregulated mitochondrial transporters and reduced oxidation. He extends this to intramuscular fat droplets and ceramides in type 2 diabetes and a possible mitochondrial link to cardiometabolic disease, then the conversation wraps up.
- •Sedentary individuals show reduced mitochondrial pyruvate carrier, CPT1/CPT2 and electron transport chain function
- •Iñigo argues active people, not sedentary ones, should be the reference model
- •Intramuscular fat is turned over actively in athletes but stagnant in type 2 diabetes
- •Stagnant droplets are high in ceramides, possibly linking diabetes and cardiovascular disease
- •Peter proposes a third podcast once more data are published
