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

KEYPOINTS

• 01

  Zone 2 is the intensity that maximally stimulates type 1 fibers and their mitochondria.

  San-Millán defines zone 2 as the point of highest fat oxidation: mainly type 1 fibers are recruited, fat is mobilized from adipose tissue and burned in mitochondria, and pyruvate and lactate are oxidized rather than piling up. Glycolytic flux isn't very high. Training here builds mitochondrial function, fat oxidation and lactate clearance through MCT1 transporters.

• 02

  Blood lactate of about 2 mmol/L is a practical upper boundary.

  Once lactate passes about 2 mmol/L, a person is leaving zone 2 for zone 3. Indirect calorimetry measures oxygen consumed and CO2 produced to estimate fat versus carbohydrate use, and the 'FatMax' point usually lines up with this lactate marker. San-Millán has used this method for about 16–17 years and has validated it against muscle biopsies that test how fatty acids, pyruvate and glutamine are oxidized. Someone with metabolic syndrome may leave zone 2 almost immediately, already outside it by about 100 W.

• 03

  Lactate is a key fuel and signal, not waste.

  When glycolysis runs fast, converting pyruvate to lactate regenerates the NAD that glycolysis needs. Lactate is then exported or shuttled into mitochondria via MCT1 and burned, a concept San-Millán credits to George Brooks, whom he thinks may someday win a Nobel. Problems arise from the hydrogen ions that accompany lactate, which acidify muscle, and from poor clearance.

• 04

  Dose matters: aim for three to four sessions a week of about 60–90 minutes.

  In San-Millán's lab data, one day a week leads to deterioration over time, especially with age. Two days may maintain fitness but won't be enough for a beginner. Three days produce clear gains, four is ideal, and five or six is better still if you have the time. Sessions of about one to one and a half hours are on target, though beginners should build from 20–40 minutes. He notes that people who only do high-intensity work, and bodybuilders, often have very poor mitochondrial function.

• 05

  Muscle is where type 2 diabetes starts, and contraction offers a second route for glucose.

  About 80% of carbohydrate is oxidized in skeletal muscle. With insulin resistance, GLUT4 transporters can't move to the cell surface. Muscle contraction moves them in an insulin-independent way, and the fittest athletes need almost no insulin for this. That, San-Millán argues, makes zone 2 exercise a direct therapy for dysglycemia.

• 06

  Metrics for the Tour de France: watts per kilo at a given lactate.

  Discussing Tadej Pogačar, whom Attia says may become the greatest Tour rider ever, San-Millán explains that FTP alone isn't enough. A plot of watts per kilogram against lactate production is among the best predictors, and it guides race strategy alongside overnight heart rate, HRV and how the rider felt. Attia notes that decisive climbs once required about 6 W/kg clean versus about 7.1 W/kg in the EPO era. The race is decided by minutes over roughly 100 hours, at a few strategic moments.

• 07

  Mitochondrial dysfunction may explain some long COVID.

  San-Millán's study with National Jewish Health tested long-COVID patients, including previously healthy athletes who had run marathons but now struggled on stairs. Their fat oxidation and lactate profiles were significantly worse than those of people with type 2 diabetes and metabolic syndrome. He hypothesizes that the virus hijacks mitochondria, as other viruses do.

• 08

  Lactate may act as an 'oncometabolite.'

  Warburg noted in 1923 that cancer cells have high glycolytic flux, and what struck him was the lactate. San-Millán's group, with a first paper published and six or seven more in progress, found that lactate regulates the expression of key breast-cancer genes and is seeing the same in lung cancer. If cells can't clear lactate, it may drive growth and proliferation.

• 09

  Supplements and drugs that touch metabolism are unresolved.

  Attia asks whether metformin's raised lactate reflects real mitochondrial impairment or a drug artifact, which matters if metformin is used as a geroprotector. San-Millán says much more research is needed. On NAD, levels fall with age, but he cautions against simply supplementing, noting that many metabolites decline and raising one may not help. Both raise the possibility that boosting NAD could be harmful in someone with an existing cancer.