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#201 – Iñigo San-Millán, Ph.D. (Pt. 2): Deep dive back into Zone 2 | The Drive With Peter Attia

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Click here for Iñigo San-Millán’s first appearance on The Drive

Key Takeaways

  • Fat oxidation, carbohydrates, and lactate are connected – lactate is the byproduct of glucose utilization
  • The capacity to transport lactate through high-intensity exercise is trainable
  • Well-trained & elite athletes have an amazing ability to oxidize lactate in mitochondria – but everyone gets to a point where the effort can’t be sustained, the difference is how long it takes you to get there
  • People with metabolic syndrome who are characterized by having poor mitochondrial function cannot do an exercise oxidized with lactate because they produce lactate but can’t oxidize the lactate (their slow-twitch muscles don’t have mitochondria to use fat so rely on glucose)
  • A reasonable measure of how zone 2 should feel: you can carry out a full conversation, maybe not as comfortably as if you weren’t exercising, but still without much strain – the other person will know you’re exercising but you are understandable
  • Zone 2 is necessary for mitochondrial health, high intensity is necessary for glycolytic efficiency (which you can improve in just a matter of months if consistent)
  • Ideal training protocol: 4 days of zone 2 training lasting 60-90 minutes + 1 day of anaerobic/high-intensity effort
  • High-intensity suggestion: keep it simple – 4 minutes high effort, near heart rate max + 4 minutes of recovery x 4-5 cycles
  • PSA: to be considered a zone 2 workout, you need to spend the entire duration in zone 2 for the benefit – not just an average of zone 2 oscillating faster and slower periods


Iñigo San-Millán, Ph.D. (@doctorinigo) is an internationally renowned applied physiologist. His research and clinical work focus on exercise-related metabolism, metabolic health, diabetes, cancer metabolism, nutrition, sports performance, and critical care  

Iñigo San-Millán returns to The Drive to take a deep dive into zone 2 training. He and Peter Attia breakdown metrics and levers of elite athletes, how to assess zone 2 threshold, training levels for optimal health, and touch on learnings gathered from studying the mitochondria of long COVID patients in the ICU.

Host: Peter Attia (@PeterAttiaMD)

Insights From Work With Tour de France Winner Tadej Pogačar

  • Tadej Pogačar’s unique characteristics: can sustain high amounts of power output over long periods of time, recovers well, highly trainable
  • Functional threshold power (FTP), lactate measurements, and watts per kilo predict performance – you really know where you stand before the race
  • The Tour de France is won and lost in minutes when your ability to put out power really sets you apart
  • Algorithms and metrics that work with the general population don’t always translate as well into professional athletes because they can mentally ignore a lot more and
  • The sport of cycling has changed over time: watts and power output have decreased from the era drug use was rampant
  • It’s feasible that the future of cycling will include real-time physiology & output metrics of riders
  • Tour de France racers like Tadej spend 70-80% of the time in zone 2 training during winter months and increase intensity as the race nears
  • Each energy system has a time in the calendar to achieve the desired output

What Is Zone 2 Training?

  • Zone 2: the exercise intensity at which you are stressing mitochondria and oxidative capacity the most
  • Tenants of zone 2 training: recruits mainly type I muscle fibers, mobilizes the highest amount of fat oxidation, and stimulates bioenergetics (fat & glucose in mitochondria)
  • Lactate is the preferred fuel for most cells in the body
  • Lactate is oxidized in the mitochondria back to energy
  • The purest way to estimate zone 2 training is indirect telemetry which will give us information about fat oxidation
  • Indirect telemetry: hook the device up to yourself then ride a bike or machine and gradually increase the intensity, measuring VO2 and VCO2
  • Consumption of oxygen production of carbon dioxide – which tells us total energy consumption (in kcal per minute),
  • Ratio of VO2 and VCO2 tells us how much energy comes from fat oxidation and how much is glycolytic
  • In a more glycolytic state of fatty oxidation state, you still consume oxygen but don’t produce as much CO2
  • As exercise intensity increases, you need more oxygen so VO2 increases then you give off more CO2 – you are recruiting type II muscle fibers, using more glucose for energy, consuming more oxygen, and produce more CO2
  • Mitochondria oxidize fuels differently at different exercise intensities – an elite athlete can still recruit slow-twitch muscle fibers at high intensities and rely on fat to produce energy while the average person fully relies on glucose (instead of fat) to sustain the effort

Nuances In Muscle Physiology, Lactate, & Fat Oxidation

  • The independent variable is workload (in watts); the dependent variable is blood lactate
  • People with metabolic syndrome have high resting lactate (almost 2 mmol) – it’s possible that resting lactate will eventually be a tracked biomarker (the same way we use blood glucose)
  • Once lactate exceeds 2 mmol you are leaving zone 2 and entering zone 3
  • A healthy person starts with lactate of about 1 mmol; an elite athlete starts at lactate of about .5 mmol
  • The fitter the individual, the higher the absolute capacity for fat oxidation
  • The metabolic stress of an elite athlete is not the same as a recreational athlete or layperson at the same blood lactate – 2 mmol of stress in an elite athlete might be higher than 2 mmol of stress in the average person because of the intensity it takes the elite athlete to get to 2 mmol in the first place
  • The lactate in the blood reflects mitochondrial oxidation: someone with high power output who needs a lot of glycolysis to produce energy will produce lactate
  • Lactate is the byproduct of glycolysis – the higher the glycolysis, the higher the lactate
  • Two routes of lactate: (1) from fast-twitch muscle fibers to slow-twitch muscle fibers; (2) export to blood
  • Every time you use glucose you produce pyruvate; every time that pyruvate will be reduced to lactate
  • No matter how fit you are, at some point, you have to produce lactate
  • When lactate can no longer be oxidized it’s transported to the blood
  • Insulin-independent glucose uptake is heavily dependent on fitness–fit type I diabetics hardly rely on insulin to transport glucose to muscle
  • Tip for type I diabetics: do not inject right before exercise because it will increase your risk of hypoglycemia

How To Identify Your Zone 2 Level

  • A reasonable measure of how zone 2 should feel: you can carry out a full conversation, maybe not as comfortably as if you weren’t exercising, but still without much strain
  • You want to know your actual maximum heart rate – zone 2 will be about 70-80% of your realized maximum heart rate
  • Zone 2 will depend on fatigue as well – heart rate variability will be lower on days you are tired or didn’t sleep well
  • Heart rate variability is actually a strong indicator of how hard you should push or backoff exercise
  • When you don’t have enough glycogen storage it’s possible that adrenergic activity is decreased
  • Hypothesis: when you have a decrease in glycogen stores, the brain needs glucose and takes over at the expense of everything else
  • Rest & recovery is key! When you’re overworked, adjust the parameters of what “success” means in your training that day

New To Zone 2 Training?

  • Zone 2 really involves steady-state, sustained cardio
  • “You can accomplish very important mitochondrial adaptations and very important metabolic adaptations by exercising one hour…3-4 days per week.” – Iñigo San-Millán
  • If you only train once per week, you will deteriorate overtime – two days per week you might maintain what you have – three days or more, we see improvements
  • Ideal parameters of zone 2: ideally train 1 hour-1.5 hours, 4x per week
  • If it’s difficult to start out with one hour, start with less and work your way up
  • If you look at the workload of an elite athlete, most sessions are in lower intensity – it’s not all about intensity and interval training

Incorporating Other Energy Systems Into Exercise

  • Four pillars of fitness: (1) stability; (2) strength; (3) “low-end aerobic” or zone 2; (4) high intensity/anaerobic capacity
  • VO2 max is highly correlated with longevity
  • Longevity is also highly correlated with mitochondrial function and metabolic health
  • High-intensity training is not sustainable over time, the same way extreme diets are not sustainable over time
  • High intensity is critical for sustaining glycolytic capacity, especially as we age – but thankfully it can be improved in just a few months
  • Ways to incorporate high-intensity training: (1) add a 5th day of exercise dedicated to high intensity (in addition to your four zone 2 days); (2) once per week add high-intensity bout after 60-90 minute zone 2 workout
  • Sample high intensity protocol: 4 minute full effort, 4 minute recovery, 4-5 cycles

Supplements & Use Of Metformin

  • Some studies point to elevated lactate levels in patients on metformin
  • Metformin carries a lot of potential long term benefits but it’s difficult to parse out effects on mitochondrial function
  • NAD levels decrease with aging, but many other metabolites are also downregulated with aging
  • “Taking NAD is not going to increase longevity, I don’t think so, that’s my opinion because longevity is not just one supplement or two or three or four or five, it’s a compendium.” – Iñigo San-Millán
  • NR &NMN are precursors to NAD – but we should be cautious when considering – a lot of fads come and go in longevity research
  • In studies, too much NAD encouraged tumor growth in cancerous mice – what if you have a tumor you weren’t aware of and supplement with NAD? It could drive cell growth and proliferation

Long COVID Patients

  • Patients with long COVID, even if previously healthy, end up looking mitochondrially like patients with type 2 diabetes in terms of fat oxidation and lactate production
  • Metabolic test results of patients with long COVID often have normal pulmonary function tests and normal cardiac function – but they struggle to go up a flight of stairs at 50 years old
  • Viruses highjack mitochondria for their benefit and reproduction – it’s possible that’s what COVID is doing (in studies now)
  • It’s suspected that COVID produces a global insult to mitochondria (maybe in skeletal muscle) and leads to severe mitochondrial dysfunction, even one year later
  • Worth noting: the patients in Iñigo San-Millán’s studies had mild alpha (original) COVID not requiring hospitalization

Observations Of ICU Patients

  • The brain dies if the liver can’t produce glucose continuously
  • “You’d much rather err on the side of hyperglycemia than hypoglycemia under a period of stress.” ­– Peter Attia
  • Muscles deplete glycogen because of high utilization but the liver has plenty of glucose because of gluconeogenesis
  • It’s plausible that muscles eat themselves to feed themselves and the rest of the body – so getting some sort of load-bearing training (even moving extremities in bed) and supplementing with amino acids could improve outcomes
  • Two main parameters that are predictors of mortality in ICU: (1) high cortisol levels; (2) high lactate levels
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