Okay, so we're going to shift gears and get into the effortful part of this presentation, this talk. This requires putting in the work, right? This isn't as simple as taking a pill. At the very least, I think taking the pill is easier for a lot of people, but there are people who want to go a step further and are willing to put in the effort. So let's talk about that. We're going to talk about why I'm convinced that vigorous exercise is the most powerful longevity drug you're going to get, more than metformin, more than rapamycin, more than any of those things. If you could put into a pill what you can do with vigorous exercise, I think that would be the best longevity drug we have right now for delaying the aging process and improving healthspan and lifespan.

When I say vigorous exercise, what do I mean? Generally speaking, of course, there's a sliding scale here. You can take someone who's completely sedentary and has never really done any aerobic exercise. Vigorous exercise for them is probably closer to what light- to moderate-intensity exercise is for someone who is physically active. But generally speaking, once you adapt and get used to being physically active, vigorous exercise means getting to about 80% of your maximum or estimated maximum heart rate. That's really what I'm talking about, about 75% to 80% of your maximum heart rate.

Cardiorespiratory fitness is one of the best biomarkers for longevity, in my opinion. It is measured empirically by VO2 max, the maximum amount of oxygen you can take up during maximal exercise. I sometimes use cardiorespiratory fitness and VO2 max interchangeably in this talk, but VO2 max directly measures cardiorespiratory fitness. Cardiorespiratory fitness is associated with improved longevity. The biggest improvements come when you move from below normal or low-normal fitness for your age and sex to a higher category.

People whose VO2 max is below normal gain about 2.1 years of life expectancy when they move to the low-normal range. Moving from below normal to high normal is associated with almost a 3-year increase in life expectancy. Moving from below normal to the upper end of normal, the top 5% of the population and closer to the elite-athlete level, is associated with almost a 5-year increase. For perspective, about half of the US population has low-normal cardiorespiratory fitness, while the other half is around high normal. This mostly reflects whether people are physically active. On average, every one-unit increase in VO2 max is associated with a 45-day increase in life expectancy.

There was a really important study published in JAMA in 2018 that established there was no upper limit to the mortality reduction associated with high cardiorespiratory fitness, obviously within normal human ranges. I like these studies because they measure VO2 max empirically. A fitness test is measured directly, unlike questionnaires that ask how physically active someone was during the last week or month and extrapolate that answer over a much longer period. Questionnaires are sometimes all we have, but direct measurement helps clear up confounding and conflicting data.

Going from the bottom 25% of VO2 max to the elite level, the top 2.3%, was associated with an 80% reduction in all-cause mortality. People who moved from the high-fitness group, the top 25% of the population, to the elite group had a further reduction of about 20% in all-cause mortality. Equivalently, the elite group had about 20% lower all-cause mortality than the high-fitness group. Being in the bottom 25% for VO2 max carried a mortality risk comparable to, or greater than, the risks associated with type 2 diabetes, smoking, and heart disease. We think about those diseases as increasing early mortality risk, but poor cardiorespiratory fitness can do the same thing.

How do you improve your VO2 max and cardiorespiratory fitness? Any aerobic exercise can produce small changes, but meta-analyses have found that vigorous-intensity exercise, particularly high-intensity interval training, is especially effective. This means doing short bursts of very vigorous exercise at least around 80% of maximum heart rate, sometimes above that, followed by recovery periods.

This matters because studies have found that about 40% of people who meet the guideline of 2.5 hours of moderate-intensity aerobic exercise per week do not improve their VO2 max. It isn't really known why this non-responder effect occurs, but that is a large percentage of the population. When those people do high-intensity interval training and more vigorous exercise, they begin to respond and improve their VO2 max. To improve cardiorespiratory fitness, you have to increase cardiac output. The stronger and more intense the signal, the greater the adaptation. Your body responds by improving the delivery of oxygen to your tissues. That is why vigorous intensity, particularly high-intensity interval training, is so important for improving cardiorespiratory fitness.

Dr. Martin Gibala at McMaster University in Ontario, Canada, has studied different high-intensity interval-training protocols. If you really want to improve cardiorespiratory fitness, it appears that you need longer intervals, about 3 to 5 minutes at the maximum intensity you can sustain for that period. A well-studied example is the Norwegian 4x4 protocol. You do 4 minutes at the highest intensity you can maintain, followed by 3 minutes of recovery at light intensity. You let your heart rate come down and give yourself enough rest to repeat the effort. You repeat that sequence 4 times, which is why it's called 4x4. This is one of the best-studied protocols for improving VO2 max.

If you don't want to go into a laboratory to have your VO2 max measured, or you don't have access to that testing, one of the best evidence-based estimates is the 12-minute run or walk test, depending on your fitness level. You need a wearable device that can track distance, such as an Apple Watch or Fitbit, and a flat surface such as a running track or field. Run or walk for 12 minutes at the maximum intensity you can maintain. Record the distance you cover, then use the equation to estimate your VO2 max from that distance. Avoid hills because they reduce the distance you can cover. A flat surface makes the 12-minute test more accurate.