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

• The sport of cycling has changed over time: watts and power output have decreased from the era drug use were 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.

• 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.

• 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 fibres, using more glucose for energy, consuming more oxygen, and producing more CO2.

Mitochondria oxidize fuels differently at different exercise intensities – an elite athlete can still recruit slow-twitch muscle fibres 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.

• 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 a 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 fibres to slow-twitch muscle fibres;
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.

• 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 back off exercise.

• Zone 2 really involves steady-state, sustained cardio.
• 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 of lower intensity – it’s not all about intensity and interval training.

• 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.

• 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 ageing, but many other metabolites are also downregulated with ageing
• 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.
• NR &NMN are precursors to NAD – but we should be cautious when considering – a lot of fads come and go in longevity research

• 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.
• 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.

• The brain dies if the liver can’t produce glucose continuously
• 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