Summary
Sarah Macklin interviews Dr. Inigo San Millan on why mitochondrial function represents the next frontier beyond VO2 max for understanding health and longevity. San Millan explains his methodology for measuring mitochondrial function non-invasively through fat oxidation and lactate clearance during graded exercise tests, validated against muscle biopsies. The conversation covers how lactate is the preferred cellular fuel -- faster to burn than glucose, ketones, or fat -- and a critical signaling molecule, not the waste product it was historically believed to be. San Millan describes how the burning sensation during exercise comes from ATP hydrolysis, not lactate. San Millan explains how he developed the zone 2 training concept by working with elite athletes for nearly 30 years and then applying the same principles to patients with type 2 diabetes, cardiac rehab, and cancer. He emphasizes that high-intensity training alone is not sustainable and that zone 2 improves mitochondrial function more than any other training intensity.
Key Points
- VO2 max measures cardiorespiratory fitness but mitochondrial function at the cellular level is the next frontier for understanding health and longevity
- Fat oxidation and lactate clearance during exercise are non-invasive proxies for mitochondrial function, validated against muscle biopsies
- Lactate is the preferred cellular fuel -- cells choose it over glucose, ketones, or fat because it burns fastest
- The burning sensation during intense exercise comes from ATP hydrolysis producing acid, not from lactate; lactate actually removes protons and buffers acidity
- Zone 2 training improves fat oxidation and lactate clearance more than any other intensity -- the same results seen in elite athletes apply to clinical populations
- High-intensity training produces results initially but is not sustainable long-term; zone 2 is both effective and sustainable
- Alzheimer's disease shares the same metabolic hallmarks as type 2 diabetes -- insulin resistance and mitochondrial dysfunction
- Training 4 days per week at zone 2 for about 90 minutes per session is sufficient to maintain mitochondrial function with aging
Key Moments
Measuring mitochondrial function without a muscle biopsy
San Millan explains his methodology for non-invasively measuring mitochondrial function using fat oxidation and lactate clearance during exercise tests, eliminating the need for muscle biopsies.
"By measuring fat oxidation, fat burning, we can indirectly have a proxy for mitochondrial function. Then lactate can only be burned in mitochondria."
Lactate is the preferred cellular fuel
San Millan describes how George Brooks' pioneering 50-year research program proved lactate is the best fuel for cells, a signaling hormone, and critical for homeostasis -- not the waste product it was believed to be.
"Lactate, without a doubt, it's an amazing biomarker that has been there in front of our eyes. Lactate, it's everywhere in the body."
ATP hydrolysis causes the burn, not lactate
San Millan debunks the lactic acid myth, explaining that the burning sensation during exercise comes from ATP hydrolysis producing acid protons, while lactate actually helps by removing protons.
"is that as we increase exercise intensity, that burning sensation that we feel, that's not from lactate. It's from the production of ATP and what we call the ATP hydrolysis, which is the burning of ATP for producing energy. And that's what liberates a lot of acid particles called protons, and they make the muscle very acidic."
Alzheimer's shares metabolic hallmarks with type 2 diabetes
San Millan connects Alzheimer's disease to the same metabolic dysfunction seen in type 2 diabetes -- insulin resistance and mitochondrial dysfunction -- and argues for developing novel biomarkers to detect metabolic issues decades before disease manifests.
"We know that no drug has been able to target that plaque and that now the new thinking in Alzheimer's is looking at brain metabolism, right? And that Alzheimer's disease is characterized by two hallmarks, insulin resistance and mitochondrial dysfunction, which are the same two hallmarks of type 2 diabetes, which is now given the name or rename it more colloquially,"
Zone 2 improves mitochondrial function more than any other intensity
San Millan describes how over 25 years of laboratory testing showed zone 2 training improved fat oxidation and lactate clearance -- surrogates of mitochondrial function -- more than any other training intensity, in both elite athletes and clinical populations.
"That was the one they improved the most. Two parameters that I mentioned earlier, fat oxidation and lactate clearance capacity, which both are surrogates of mitochondrial function. I was seeing this over 25 years ago. And then obviously working with athletes, you saw that also in the competition. That's where you saw that action, right? And so that's why the Zone 2 came along. But of course, you have"
