What nature’s experiments teach us about exercise

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In this column, we believe in randomized, double-blind, placebo-controlled trials. Others might start taking a new supplement because their friend said it made them feel good, wear the latest wearable because logic suggests the information it provides should be useful, or start doing double-threshold Norwegian workouts because Jakob Ingebrigtsen is so fast. But expect solid scientific evidence, preferably from multi-year studies with large samples synthesized in meta-analyses.

In truth, however, this approach inevitably leaves many unanswered questions. Good luck with a trial where half the participants are randomized to run 100 miles a week for the next 20 years, while the other half get no exercise at all. As a result, much of our key information about optimizing health and improving performance comes from other types of sources, including what a new article inComplete physiology call experiments of nature. Mayo Clinic physiologist Michael Joyner and his colleagues have examined some of the most important natural experiments in the history of exercise science, offering an important corrective to the cult of the randomized trial.

Joyner and his colleagues begin with a subtle distinction. Nature’s experiments, in their terminology, involve people with rare genetic or acquired conditions that shed new light on how a particular physiological system works. Natural experiments, in contrast, involve observing large populations that have been exposed to some sort of environmental or behavioral stimulus.

Nature experiments

In 1951, a British physician named Brian McArdle described a 30-year-old patient who, throughout his life, had suffered from muscle pain and weakness after just a minute or two of light exercise. Even chewing food left his jaw muscles exhausted. McArdle discovered that the patient had a rare condition, now known as McArdle’s disease, which meant he was unable to break down glycogen, the form in which carbohydrates are stored in the muscles and liver, into lactate.

If you’re trying to understand the long-controversial concept of the lactate threshold, people who don’t produce lactate at all come in handy. The initial concept of anaerobic threshold, formulated in the 1960s, was that when your muscles can’t get enough oxygen, lactate levels begin to build up in your blood, which (via some intermediate steps) causes you to start breathing more heavily. But McArdle’s patients also showed a sharp increase in respiratory rate beyond a certain threshold, even though they weren’t producing lactate at all, which forced scientists to rethink the concept.

That original 1982 study had only four subjects, the kind of study that people like me might be tempted to dismiss as too small to be meaningful. However, lead investigator James Hagberg later pointed out, at the time these four patients represented 10 percent of the total world population with McArdle disease described in the medical literature. These were insights that were only possible through nature’s little experiments.

The same goes for many other topics. Joyner and his colleagues mention Eero Mntyranta, the Finnish cross-country ski champion who had a rare genetic variant that led to sky-high hemoglobin levels (whose story I first read in David Epstein’s book The sports gene), as well as various studies of identical twins that have altered our understanding of muscle fiber types and the links between exercise and body composition. Studies of world-class athletes also fall into this category: they’re freaks of nature (and culture, of course) whose out-of-the-box physiology sheds new light on how the body works. But you can’t randomize people to become Olympic champions, and you can’t recruit 100 of them to show up at your lab for testing.

natural experiments

Joyner’s paradigmatic example of a natural experiment is the study of London transport workers, often cited as a starting point for modern research on physical activity and health. British epidemiologist Jeremy Morris collected data on 31,000 transport workers, comparing two nominally similar groups: those who rode London’s double-decker buses and those who spent their working days climbing and descending bus stairs to collect fares. The findings, published in 1953, showed that drivers were about half as likely to die of heart disease as drivers, providing some of the first large-scale data to show that exercise is good for health.

Another famous natural experiment is Harvard nutrition researcher Jean Meyer’s 1956 study of hundreds of workers at a jute-processing plant in India. He divided the workers into 13 categories ranging from sedentary clerks and supervisors to cutters, haulers and blacksmiths who perform very heavy physical work. Then he assessed their weight and their daily calorie intake.

The results, which are shown below, require some explanation. Worker classes are arranged from most sedentary (left) to most active (right). Body weight is plotted on the left axis, calorie intake on the right axis. If you only look at the right side of the graph, it all makes sense. The more physical the job, the more calories the workers eat, and their weight is roughly the same, suggesting that the increase in calorie intake balances the increase in workload.

But on the left side of the graph, things get choppy. The most sedentary employees actually eat more than anyone else, and as a result they also weigh more than anyone else. Here is the data:

(Illustration: Complete physiology)

One way to interpret this data is that your appetite will naturally prompt you to eat as much as your body needs, but only above a certain threshold of physical activity. If you’re sedentary, a situation unheard of for most of human evolutionary history, then your appetite mechanism no longer works properly. This is consistent with the idea that the link between exercise and body weight isn’t so much a matter of calories burned (you probably know the depressing statistics about how many miles you’d have to run to burn off, say, a bowl of ice cream), but instead helps ensure your appetite matches your spending.

Of course, weight loss and exercise are still controversial topics, nearly 70 years after Mayer’s jute study. His discoveries did not settle the question once and for all, and this is true of most of the natural experiments discussed by Joyner and his colleagues. But their broader point is that these kinds of nonstandard experiments add to our knowledge in ways that often wouldn’t otherwise be possible to test, and help generate hypotheses for subsequent laboratory experiments.

The value of considering different types of evidence may seem obvious, but the motivation for the article was the frustration Joyner and others felt trying to distribute convalescent plasma (antibody-rich blood from recovered patients) during the COVID pandemic. They ran into barriers with National Institutes of Health treatment guidelines, which did not approve of their use. The dispute revolved in part around the NIH’s reliance on data from large clinical trials versus data from nature’s small experiments in patients with rare conditions that make them unable to make their own antibodies.

Joyner’s criticisms of the NIH drug bureaucracy got him suspended and threatened with firing from the Mayo Clinic (your use of idiomatic language was problematic and reflects badly on the Mayo Clinic’s brand and reputation, his boss wrote in the reprimand letter). So now he’s making his case about it in more academic language in the pages of Complete physiologyand it’s a relevant message for anyone looking to optimize their training or improve their health. Of course, I’m still a proponent of clinical trials. If you travel too far along nature’s road experiments, you end up concluding that, shall we say, PowerBalance wristbands have truly made Shaquille ONeal a better basketball player. But you should weigh each piece of evidence on its own merits, not simply on which category she falls into. Good science, it turns out, is an art.


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