Peter Attia MD#85 – Iñigo San Millán, Ph.D.: Mitochondria, exercise, and metabolic health
CHAPTERS
- 0:04 – 7:51
Why the Podcast Has No Ads and Today's Guest
Peter Attia explains that the show is funded by listener support rather than ads, citing trust and his difficulty promoting things he isn't enthusiastic about. He then introduces Iñigo San Millán and his mitochondria-focused research across exercise, diabetes, cancer and critical care.
- •Subscriber model chosen over ads for trust reasons
- •Members get show notes, transcripts and AMA access
- •Iñigo studies exercise metabolism, diabetes, cancer and more through the lens of mitochondria
- •Iñigo works with professional cycling teams at Tour de France level
- 7:51 – 13:09
From Real Madrid Academy to Pro Cycling and Science
Iñigo describes growing up in Spain, playing at the Real Madrid academy, switching to cycling at 16 and racing professionally for two years. He explains why he moved into education and sports medicine, and the two discuss how far elite cyclists sit above category racers.
- •Six years at the Real Madrid academy before switching to cycling at 16
- •Two years racing professionally at a low level, mainly as a climber
- •Chose education and a sports medicine internship over chasing a pro career
- •Huge physiological gaps between category riders, domestic pros and Tour de France riders
- 13:09 – 23:02
Meeting in Abu Dhabi and the Energy Systems Explained
Peter recounts their first meeting and the VO2 max test in Abu Dhabi, then asks Iñigo to explain aerobic metabolism. Iñigo covers fuels, muscle fiber types and recruitment, and Peter reframes aerobic versus anaerobic as a matter of ATP demand rather than oxygen presence.
- •Fat and glucose are the main exercise fuels, burned in different muscle fibers
- •Type 1 fibers recruit first, with the stick-shift gear analogy for recruitment
- •Aerobic vs anaerobic reflects the speed of ATP demand, not oxygen presence
- •Lactate can be produced under fully aerobic conditions via cytosolic glycolysis (Warburg effect/aerobic glycolysis)
- 23:02 – 26:11
Elite Athletes as the Model of Perfect Mitochondria
Peter brings up the Brooks and San Millán paper comparing zone 2 in elite cyclists, recreational athletes and people with diabetes. Iñigo explains that he studies elite endurance athletes as the picture of perfect mitochondrial health in order to understand dysfunction in diseases like type 2 diabetes.
- •Study of zone 2 across world-class cyclists, recreational athletes and type 2 diabetics
- •Elite endurance athletes seen as having the healthiest mitochondria on the planet
- •Understanding perfection helps in understanding imperfect metabolism
- •Potential for diagnostics, therapeutics and prevention programs
- 26:11 – 40:09
The Six Training Zones, Zone 1, and Lactate Myths
Iñigo walks through his six-zone system built on muscle fiber recruitment, starting with zone 1 as recovery effort. The discussion moves to baseline and maximal lactate values, lactate as a fuel and signaling molecule, and the fact that hydrogen ions, not lactate, contribute to fatigue.
- •Zone 1 is minimal stimulation, mostly fat burning, such as recovery rides
- •Resting lactate is about 0.7 to 1 mmol; maximal values vary by protocol
- •Lactate is a mandatory byproduct of glucose use and a major fuel, including for the brain
- •Hydrogen ions and central fatigue, not lactate itself, impair contraction
- 40:09 – 51:51
Zone 2, Fat Max, and Lactate Clearance
The conversation turns to zone 2 as the intensity of maximal fat oxidation and maximal type 1 fiber stimulation without recruiting type 2 fibers. They discuss lactate levels around 1.5 to 2 mmol, the steady state of production and clearance, and how elite athletes oxidize lactate inside slow-twitch fibers.
- •Zone 2 coincides with Fat Max and highest stimulation of type 1 fibers
- •Lactate in zone 2 sits around 1.5 to 2 mmol with no net accumulation
- •Fast-twitch fibers export lactate to slow-twitch mitochondria, where it is oxidized
- •Elevated blood lactate signals that muscle clearance capacity is exceeded
- 51:51 – 1:06:54
Zone 2 Power as a Test of Mitochondrial Function
Peter and Iñigo discuss the paper's finding that the power at which lactate rises differs enormously between elite cyclists, recreational riders and people with type 2 diabetes. They discuss resting RQ as a red flag, the analogy to stress EKGs, and the planned muscle biopsy study.
- •Zone 2 power of about 300 W vs 200 W vs 120 W across the three groups
- •Resting RQ near 0.9 to 1.0 flags possible mitochondrial dysfunction
- •Fat oxidation and lactate curves correlate in the nineties, serving as an indirect test
- •Upcoming biopsy study with Oroboros and Seahorse, plus omics, across athletes, masters, prediabetics and diabetics
- 1:06:54 – 1:19:58
Muscle Differences: Mitochondria, Glycogen, and the Athlete's Paradox
Iñigo describes what separates the muscle of fit people from those heading toward diabetes: far more and larger mitochondria, higher glycogen storage measured via his ultrasound method, and intramuscular fat droplets that are active in athletes but inert in type 2 diabetics. Peter ties this to the idea of flux.
- •Well-trained athletes have three to four times the mitochondria in number and size
- •High-frequency ultrasound estimates muscle glycogen, with correlations of about 0.93 to 0.94 against biopsy
- •Athlete's paradox: fat droplets are an active fuel reservoir in athletes but build up unused in diabetics
- •Flux, not snapshot levels, explains similar blood free fatty acid patterns
- 1:19:58 – 1:32:46
Zone 4, Lactate Threshold, and Why Watts Are Not Watts
Iñigo explains zones 3 and 4 as the transition into glycolysis and the lactate inflection point. He presents an unpublished poster showing that at constant relative power, lactate, heart rate and VO2 climb over time, arguing that heart rate must be monitored alongside power.
- •Zone 3 is a transition; zone 4 shows the lactate inflection and RQ near 1.0
- •Constant 80% or 75% of peak power led to rising lactate, from 4 to 9 mmol
- •Heart rate is a physiological measure while watts are mechanical
- •Fatigue or carbohydrate restriction lowers maximal lactate and maximal heart rate
- 1:32:46 – 1:46:54
Ketogenic Diets, Adaptation Time, and Elite Carbohydrate Intake
The pair discuss carbohydrate restriction and athletic performance, with Peter describing his own long adaptation and Iñigo explaining why elite athletes cannot afford it. Iñigo then details the enormous carbohydrate intake of Tour de France riders and their metabolic health despite it.
- •Peter's keto adaptation took about 18 months to restore performance
- •Iñigo has never seen an elite athlete successfully adapt while competing and notes catabolic responses
- •Tour riders eat about 12 g/kg of carbohydrates, roughly 850 g per day, with much of it simple sugar
- •Peter says carbohydrate restriction is a useful tool for metabolically unhealthy non-elite people
- 1:46:54 – 2:04:19
Type 1 Diabetes, Non-Insulin Glucose Uptake, and the Cool-Down
They discuss Team Novo Nordisk, an all type 1 diabetic pro cycling team, and what it taught about insulin dosing and exercise. Topics include contraction-driven GLUT4 translocation independent of insulin, glucose falling during zone 2, post-exercise hyperglycemia after hard efforts, and the cool-down strategy.
- •Type 1 cyclists showed about 25% higher glycogen and about a third of the carbohydrate needs in Iñigo's observations
- •Muscle contraction translocates GLUT4 without insulin, and insulin secretion drops about 50% during exercise
- •Zone 2 lowers glucose while high intensity raises it
- •A cool-down helps correct post-exercise hyperglycemia, which Iñigo has taught clinicians to use
- 2:04:19 – 2:18:02
Metformin, Lactate, and a Proposed N-of-1 Experiment
Peter describes how his zone 2 lactate readings ran high while on metformin and fell when he cut back the dose. Iñigo explains possible mechanisms such as PDH saturation or reduced mitochondrial function, and they plan a biopsy-based experiment, with a brief detour into statins and the prediabetes continuum.
- •Peter's lactate dropped after cutting metformin from 14 g to 3 g per week
- •Possible mechanisms: PDH saturation acting like a fuse, and metformin inhibiting mitochondrial function
- •Iñigo guesses metformin might be detrimental for elite athletes but is not an expert on it
- •Proposed biopsy study comparing full dose, washout and water fast
- •Iñigo notes that statins affect mitochondrial function and increase diabetes risk
- 2:18:02 – 2:27:19
Zone 2 Dosing, Iñigo's Own Weight Loss, and Sustainability
Peter asks about the minimum effective dose of zone 2. Iñigo shares what he has seen with athletes and patients and tells how he lost about 50 pounds with zone 2 training after gaining weight upon quitting cycling, and the two discuss why intensity and sustainability matter more than calories burned.
- •Two days a week maintains; three to five days a week pushes adaptation
- •About one to one and a half hours, four days a week helped reverse late prediabetes in a patient
- •Iñigo lost about 50 pounds with zone 2 and without giving up foods he loves
- •Too-hard exercise burns little fat and is hard to sustain for life
- 2:27:19 – 2:39:25
Cancer, Lactate, and the Warburg Effect
Iñigo explains Warburg's discovery that cancer cells produce abundant lactate, and the acidic microenvironment that results. He describes his unpublished breast cancer cell experiment showing lactate upregulates oncogene expression, while Peter lays out competing explanations of the Warburg effect and the open questions about metformin.
- •Warburg was most struck by lactate accumulation in cancer cells
- •More aggressive cancers tend to be more glycolytic, with more lactate and acidity
- •MCF-7 cells showed 2 to 8 fold higher oncogene expression with added lactate
- •Future experiments will use more cell lines and metabolomics, and may include metformin
- 2:39:25 – 2:53:02
Cycling's Drug Era, Altitude Training, and Miguel Indurain
Peter asks about performance-enhancing drugs in cycling's history. Iñigo says times up climbs today match those of the 1980s and early 1990s and describes altitude training. The conversation ends with Indurain's extraordinary physiology and mindset, and Peter's closing thanks.
- •Iñigo argues cycling is cleaner now, citing climb times and the use of altitude
- •Altitude erodes glycolytic capacity, so a sea-level-simulating room is being built in Colorado Springs
- •Indurain's huge sweat output, heat dissipation and calm mindset
- •Iñigo praises LeMond's book and scientific approach
