Summary
Simon Hill sits down with Dr. Inigo San Millan, an assistant professor at the University of Colorado and one of the world's foremost experts on metabolic health and exercise physiology. Dr. San Millan explains why mitochondrial function sits at the epicenter of metabolic health, and how a decline in mitochondrial capacity -- driven largely by sedentary lifestyles -- precedes conditions like type 2 diabetes, cardiovascular disease, and even Alzheimer's by 10 to 25 years. The conversation walks through each exercise zone from a cellular metabolism perspective, detailing how the body shifts from fat oxidation at lower intensities to glucose-dominant energy production at higher intensities, and the critical role lactate plays as both a signaling molecule and a biomarker of mitochondrial function. Dr. San Millan makes the case that zone 2 training -- the intensity at which fat oxidation is maximized -- provides the most efficient stimulus for improving mitochondrial function based on his 30 years of laboratory data from elite athletes and clinical patients. Practical recommendations include aiming for 200 to 300 minutes of zone 2 cardiovascular exercise per week, supplemented with bursts of higher-intensity work to stimulate glycolytic capacity and lactate transporters. Dr. San Millan also addresses why resistance training alone is insufficient for metabolic health, why ketogenic diets likely produce artifacts rather than real improvements in fat oxidation, and why sustainability and consistency are essential when prescribing exercise for long-term health.
Key Points
- Mitochondrial dysfunction is the root cause of most cardiometabolic disease, and it can begin decades before clinical symptoms appear in otherwise healthy sedentary individuals
- Zone 2 exercise is defined as the intensity at which fat oxidation is maximized, and it provides the strongest stimulus for improving mitochondrial function based on 30 years of laboratory data
- Lactate is not a waste product but a critical signaling molecule and fuel source; it serves as the best non-invasive biomarker of mitochondrial function when measured during graded exercise
- At rest, about 80% of carbohydrates are metabolized in skeletal muscle, making muscle mitochondrial health essential for glucose tolerance and insulin sensitivity
- Elite athletes can produce high amounts of lactate at high intensities but clear it efficiently through robust MCT1 transporters in slow-twitch muscle fibers -- this clearance capacity is trainable
- The recommended volume is 200 to 300 minutes per week of zone 2 training, with additional high-intensity bursts in zone 4 or 5 to stimulate glycolytic enzymes and lactate transporters
- Resistance training alone does not adequately improve mitochondrial function; people who only lift weights can present with metabolic profiles similar to sedentary individuals
- Ketogenic diets appear to increase fat oxidation in metabolic testing, but Dr. San Millan argues this is likely a measurement artifact caused by depleted glycogen stores rather than genuine mitochondrial improvement
Key Moments
81-year-old transforms metabolic health through cycling
Dr. San Millan shares the story of an 81-year-old man who was obese, hypertensive, and a smoker until his early 50s, then started cycling and achieved the metabolic health of a healthy 30-year-old without any medication.
"And then, you know, 30 years later, at 81 years old, his metabolic health was that of someone in their 30s who's healthy. That's unbelievable, hard to believe."
Mitochondrial dysfunction precedes type 2 diabetes by decades
Dr. San Millan explains that mitochondrial decay from sedentary lifestyles impairs glucose metabolism inside the cell, leading to lactate buildup and hyperglycemia long before clinical diabetes is diagnosed. About 80% of carbohydrates are metabolized in skeletal muscle mitochondria.
"So during post-praneial conditions after a meal, about 80% of all carbohydrates are burned or metabolized in skeletal muscle."
Resistance training alone fails to improve mitochondrial function
San Millan explains how the lessons from elite athletes translate to general health, and reveals that people who only do resistance training can have mitochondrial profiles resembling sedentary individuals. Zone 2 cardiovascular training is essential for mitochondrial health.
"So that's again, it's at the epicenter of metabolic flexibility. So people who are metabolically inflexible, there are people who cannot metabolize fatty acids or glucose properly, right? And therefore, as we mentioned earlier, it's going to pose a metabolic challenge because you can increase glucose levels. On one hand, it's also increased the fat deposits in the muscles as well as."
Zone 2 improves fat oxidation and lactate clearance the most
Dr. San Millan describes how zone 2 training improves the two parameters most tied to mitochondrial function -- fat oxidation and lactate clearance capacity -- more than any other training intensity, based on decades of laboratory observations.
"And then you see in the laboratory at this intensity, you see that fat starts to drop significantly. There's a significant drop in fat oxidation. And there's a significant increase in glucose oxidation or utilization. And at the same time, you see also an inflection point also for lactate because lactate and glucose go together. As I was saying earlier, it's about glucose flux. The higher the glucose flux into the cell, the higher the lactate accumulation, right? So this is what's starting to happen in this zone three that I call, which is a transition zone."
Practical zone 2 prescription for the general population
San Millan recommends four days per week of zone 2 training at one to one and a half hours per session, plus two days of high-intensity work and two days of strength training for a well-rounded program targeting metabolic health and longevity.
"So if you do one hour purely at zone two, you're going to get good benefits. But if you go and go a little bit above and below or even to zone four here and there, yeah, you might want to have a longer session, which is an hour and a half, for example, whereas those 30 minutes is like when you So that's where you have the stimulation within one session. That's kind of how I see it. And it also depends on your form and your peak. Let's say that you do like a high-intensity interval in the middle of the session and you only do one hour. So if you do a high-intensity interval, you're going to have a lot of lactate."
