383. The Zero-Minute Workout

There is strong evidence that exercise is wildly beneficial. There is even stronger evidence that most people hate to exercise. So if a pill could mimic the effects of working out, why wouldn’t we want to take it?

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:01Stephen J. Dubner?

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• 0:38Stephen J. Dubner?

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• 1:10Stephen J. Dubner?

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• 1:44Stephen J. Dubner?

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• 2:25Speaker 01

  Pedal Faster, Steven.

• 2:28Speaker 02

  Hey, this is Steven Dubner. I'm at the gym.

• 2:31Speaker 01

  Your current heart rate is 110 beats per minute. Your target rate is 130 beats per minute.

• 2:37Speaker 02

  We all know that exercise is good for us. We also know that most people don't get nearly enough. 34% of US adults are physically inactive, another 20% are insufficiently active, and, not surprisingly, almost 40% of US adults are classified as obese. To be reductive, many of us eat too much and exercise too little. Now, why don't we get more exercise?

• 3:06Speaker 02

  Let's be honest, it is hard work.

• 3:08Speaker 01

  Steven, I told you to pedal faster.

• 3:11Speaker 02

  The cost of physical inactivity is massive, not just in illness and death, but in dollars too. Researchers from the Centers for Disease Control and Emory University say the US spends about $117 billion a year on healthcare due to inadequate physical activity. And those are just the direct costs from treating cardiovascular disease, diabetes, and so on. It doesn't even include things like the loss of productivity.

• 3:39Speaker 01

  There is a big hill coming up. Steven, are you ready?

• 3:42Speaker 02

  It's strange, if you think about it. For thousands and thousands of years, our ancestors worried about not getting enough food to eat, and their daily life required physical activity. Today, food is everywhere, and cheap, and super fattening, and a lot of us have lives that require very little physical activity. Which is why I'm here, on this stupid bike.

• 4:06Speaker 01

  I am not going to take that personally.

• 4:08Speaker 02

  A lot of smart people have spent a lot of time and effort trying to get people to exercise more. Mostly, they failed. So what happens next? Wouldn't it be amazing if, instead of exercise, there was something like an exercise pill?

• 4:24Speaker 01

  I do not like that idea. I do not like that idea one bit.

• 4:37Speaker 03

  From Stitcher and Dubner Productions, this is Freakonomics Radio, the podcast that explores the hidden side of everything. Here's your host, Stephen Dubner.

• 4:55Stephen J. Dubner?

  Okay, glad that's over.

• 4:59Stephen J. Dubner?

  So, obesity started out as a problem in wealthier countries, but now it's spread to middle and low-income countries. The contributing factors are not in dispute. We consume too many calories, especially low-quality calories, and we don't burn off nearly enough calories with physical activity. Now, to be fair, burning calories through exercise is a pretty inefficient process. It takes a lot more exercise than you'd think to burn off one cheeseburger. In that regard, it'd be better to just eat less. That said, exercise is also considered a very valuable input for overall health. That's what we've been told, at least, but let's not take that for granted. Let's see if we can find some real evidence for that claim and understand why exercise

• 5:44Stephen J. Dubner?

  is supposed to be so good for us. We'll start with this man.

• 5:48Speaker 04

  My name is Michael Joyner, and I'm a physician scientist at the Mayo Clinic.

• 5:52Stephen J. Dubner?

  A physician scientist meaning what?

• 5:54Speaker 04

  I'm basically a physiologist who is also a clinical anesthesiologist.

• 5:59Stephen J. Dubner?

  So that sounds pretty impressive, a physician scientist at the Mayo Clinic. But just so you know, Michael Joyner was an unimpressive student, growing up in Arizona.

• 6:08Speaker 04

  You're correct. I was a sort of an indifferent student at Rincon High School. And I started college in 1976 and went to several schools in one year. I ended up in 1977 at the University of Arizona, where I promptly almost flunked out. And in December of 1977, I'd actually signed up to take the test to become a Tucson City fireman. And what happened is I was out running a race, a 10K race.

• 6:36Stephen J. Dubner?

  Joyner was a pretty good athlete.

• 6:39Speaker 04

  I ran track and field at the University of Arizona where I ran the 5,000 and the 10,000. I also ran a 225 marathon in the late 70s.

• 6:47Stephen J. Dubner?

  If you're not familiar with marathon times, two hours and 25 minutes for more than 26 miles, that is a very fast time.

• 6:55Speaker 04

  And then I continued to run until I was about 40.

• 6:57Stephen J. Dubner?

  He still exercises about an hour a day.

• 7:00Speaker 04

  It varies between a relatively easy day of aerobic exercise on the bike or maybe some swimming. And then on the opposite days, I do something relatively intense, which includes a warm-up and then about 30 or 40 minutes of circuit training. And because I'm 60 years old, I've done probably a little bit more strength training in the last five, 10 years because as you get older, you really want to avoid frailty, muscle loss, you don't want to slip on the ice, that sort of thing.

• 7:29Stephen J. Dubner?

  Back when Joyner was thinking about becoming a fireman and he was running that 10K race.

• 7:34Speaker 04

  A man named Eddie Coyle, who's a well-known exercise physiologist, and he was a graduate student in the lab at Tucson at the time. And he said, do you want to be a subject in a study on lactic acid? I said, it sounds good to me. So I showed up and ran in the lab and I said, man, this is unbelievable. There's actually people who do this for a living.

• 7:52Stephen J. Dubner?

  Joyner was told he could work in the lab as a student assistant if he got his grades up.

• 7:57Speaker 04

  And so then I had kind of a square wave experience with my grades and started basically getting straight A's. And I saw that if you wanted to do studies in humans where you put catheters in and do biopsies and that sort of thing, it would be facilitated if you were a physician. So unlike a lot of physicians who get interested in research in medical school residency or fellowship, I actually went to medical school with the express purpose of becoming a research-based integrated physiologist.

• 8:25Stephen J. Dubner?

  It did take Joyner a while to get into medical school.

• 8:28Speaker 04

  Because I had to kind of do a little academic rehab to make up for those first two bad two years. And then I came to Mayo in 1987 and I've been here ever since.

• 8:37Stephen J. Dubner?

  So you're a big deal in the field of physiology, exercise physiology. Can you first, just for total laypeople, define physiology for us?

• 8:45Speaker 04

  If you think about anatomy, anatomy describes the parts of the body. Physiology is really the engineering equivalent of that and says, what do these different parts do alone and in combination? And so there are all sorts of regulatory mechanisms that increase or decrease our breathing, increase or decrease our urine output. And so what we do as physiologists is study these regulatory systems and try to understand how all living forms adapt to environmental challenges.

• 9:13Stephen J. Dubner?

  Okay, so, open-ended question. Tell us what we know in a nutshell. We'll get into details as we go. But tell us what we know about the benefits of physical exercise?

• 9:23Speaker 04

  What we know in a nutshell is that people who are physically active, especially if they get somewhere between 150 and 300 minutes per week of moderately vigorous physical activity, have a large reduction in their all-cause mortality, typically about a 50% or maybe 40% reduction in their all-cause mortality. And typically, they live somewhere, depending on the study, between about four and seven years longer.

• 9:49Stephen J. Dubner?

  Wow, okay. Quickly, define for me all-cause mortality?

• 9:53Speaker 04

  It just means you could die of anything, could be cancer, heart disease, infectious disease, and so forth. And that's one of the points people need to remember. We typically think of exercise as being especially protective against death and disability and diseases associated with the cardiovascular system. But it's also protective against a number of forms of cancer and a number of things like diabetes and other diseases.

• 10:16Stephen J. Dubner?

  Okay, so you may be saying to yourself, "Michael Joyner sounds credible, and he's got great credentials." But we also know he's a bit of an exercise fanatic himself, so how can we be sure that it's exercise that's actually causing better health outcomes? What sort of baseline physiological evidence is there for that claim?

• 10:37Speaker 04

  Well, a couple of things. You know, the best evidence comes from various population cohorts. The most famous being the bus driver/bus conductor data from after World War II in London, where they showed the sedentary bus drivers had much higher rates of coronary artery disease and heart attack than the active conductors who were walking around punching tickets going up and down the stairs all day. And they showed a similar thing when they compared clerical workers to postmen. Again, all males, all members of the British Civil Servants. And that's where that, you know, 40, 50% reduction in all-cause mortality and cardiovascular mortality came from.

• 11:12Stephen J. Dubner?

  Okay, that is a neat story, the bus drivers, but that was a long time ago. Has the effect been shown more recently?

• 11:20Speaker 04

  It's been shown over and over again in every sort of cohort study. Then you come to some other things. So if you start looking at people with risk factors, people with hypertension, high cholesterol, obesity, so forth and so on, people with high levels of physical activity or cardiorespiratory fitness, their risk is markedly blunted. So I like to tell people that exercise and fitness really absolve you of other sort of risk factors since.

• 11:46Stephen J. Dubner?

  All right, fine, but a couple of things here. Cohort studies or population studies, those are not the randomized controlled trials that scientists consider their gold standard. And how do we know that people with high levels of physical activity, as Joyner is describing here, how do we know that there aren't other reasons for their good health? Maybe the kind of people who are more likely to exercise are the same people who are more likely to eat better or sleep better. Maybe they're the same people who don't smoke or who face less stress in their lives, stressors like poverty or difficult work or home environments. How does Joyner know that exercise is such a strong causal mechanism of good health?

• 12:27Speaker 04

  You get into studies in individual humans where you can take people and do very brief periods of exercise training, improve their glucose tolerance, improve the function of their blood vessels, and improve a whole lot of biomarkers which are associated with health. And then you go one step further to animal studies and you can really take a deep dive into the mechanisms behind those positive changes.

• 12:50Stephen J. Dubner?

  Okay, what are those mechanisms? A lot of Joyner's research is about how physical activity increases blood flow to skeletal muscles.

• 12:59Speaker 04

  Your heart rate goes from 60 or 70 to around 200, so you have about a threefold increase in heart rate. And then the amount of blood pumped with each heartbeat also goes up. So think about that. So at rest, a tiny amount of that blood flow, maybe 500 mls, is going to all the muscle in your body. During maximum exercise, perhaps 16 or 17 liters is going to muscle.

• 13:25Stephen J. Dubner?

  Now, why is blood flow per se important or beneficial?

• 13:29Speaker 04

  Well, the bottom line is if you're going to do prolonged exercise, you've got to get oxygen from the lungs to the skeletal muscles. So you have to have a big cardiac output. And you've then got to get it to the muscles that are actually contracting. So it's just a supply demand situation.

• 13:44Stephen J. Dubner?

  Okay, so take me from there, though. So you do vigorous exercise. It increases the blood flow a lot. What then are the longer term, I guess, physical and cognitive benefits of that increased blood flow?

• 13:56Speaker 04

  One is that the blood vessels kind of grow. They become larger in diameter. The lining of the blood vessels, the vascular endothelium, becomes more slippery and becomes more prone to relax versus constrict, which makes your blood pressure lower. And then the capillaries and small blood vessels around the skeletal muscles also grow. So because there's this large increase in cardiac output, all of the large blood vessels throughout the body become larger and the endothelial function increases. They become more elastic, less stiff, which is also a good thing. The other thing to remember is, and this is a really big finding in the last 20 years,

• 14:36Speaker 04

  is that there are hormone-like substances secreted by the skeletal muscle which have remote effects. They have effects on the liver to improve metabolism. They have effects on blood vessels everywhere. And they also release something called BD and F, brain-derived neurotrophic factor, which is good for brain growth. And people think that's at least one of the links between physical activity and cognition and preservation of cognition as you age.

• 15:03Stephen J. Dubner?

  So it sounds like the benefits of exercise are massive and widespread. And therefore, we would all be idiots to not do a lot of exercise, or at least enough exercise. So, Dr. Joyner, what share of Americans do get what you'd consider to be enough exercise?

• 15:20Speaker 04

  Oh, you see various numbers depending on whether it's survey research or tracking research. But, you know, if it's 20%, that's a generous number.

• 15:29Stephen J. Dubner?

  So do you feel that you personally have been preaching the gospel of exercise for a long time? And that people are not really buying?

• 15:38Speaker 04

  You know, I just try to point out the benefits and set a good example and be as encouraging to people as I possibly can. People really need to understand that they need to do something, do it regularly, and it's okay to take it in small bites. But until we have a wholesale change in transportation and food policy and just the way things are, I don't see a whole lot changing. Most of the population's behavior aligns with various overt and covert incentives. And I think we have a whole lot of incentives to be physically inactive and eat a lot. I mean, there's a terrific study from Toronto showing that the walkability of whatever zip

• 16:22Speaker 04

  code equivalent you're in in Toronto, the walkability of that neighborhood predicted who gained how much weight over, you know, 10 or 20 years. So I think we have a built environment problem. I think we've got an incentive problem. I think that, you know, as much as I'd like to tell everybody to go exercise, I think we've also got a transportation policy problem. When you go to places like the Netherlands or Denmark that are very biking friendly, when whole cities are built to do that, you know, you see a lot of really fit people.

• 16:54Speaker 05

  The challenge is we're endlessly pitted against the technological advances in civilization that tends to make us not move.

• 17:06Stephen J. Dubner?

  That's Ronald Evans.

• 17:08Speaker 05

  I am the director of the Gene Expression Laboratory at the Salk Institute.

• 17:13Stephen J. Dubner?

  The Salk Institute for Biological Studies is one of the most important biomedical research institutes in the world.

• 17:19Speaker 05

  And a lot of the work that we do studies the nature of genetic circuits that control metabolism.

• 17:25Stephen J. Dubner?

  Dr. Evans, like Dr. Joyner, is a big believer in the benefits of exercise.

• 17:31Speaker 05

  Exercise is a beneficial factor that burns calories, but it also activates many metabolic pathways that are pro-health.

• 17:41Stephen J. Dubner?

  But Evans is also a realist. And this, given the human propensity to eat too much and exercise too little, has turned Evans into a futurist. He wonders whether we should accept the fact that most people are never going to exercise enough and instead, think of a biomedical solution.

• 18:02Speaker 05

  Very big question, and I think it deserves a lot of thought.

• 18:07Stephen J. Dubner?

  What sort of solution is Evans working on?

• 18:10Speaker 05

  Exercise in a pill.

• 18:15Stephen J. Dubner?

  Details coming up, right after this.

• 18:25Stephen J. Dubner?

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• 19:09Stephen J. Dubner?

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• 19:27Stephen J. Dubner?

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• 20:00Stephen J. Dubner?

  Freakonomics Radio is sponsored by Progressive. Whoever says saving money is hard doesn't know that new customers who bundle and save with Progressive save hundreds because switching your home and auto insurance is better than cutting down on the things you love, like those iced lattes that help you get ready to face the day. So, switch your home and auto to Progressive and see if you could save and keep sipping away. Get your quote today at progressive.com. Progressive Casualty Insurance Company affiliates and other insurers. Not available in all states.

• 20:39Stephen J. Dubner?

  Fact one: The typical, modern human would do well to exercise more than they do. Fact two: Public health advocates and others have been urging us to exercise for many years. Fact three: Their urging doesn't seem to work. Consider fact four: In the US, more than 80% of large companies offer programs that encourage and often incentivize exercise and weight control. A randomized study of one such company, BJ's Wholesale Club, was recently published in the Journal of the American Medical Association. It found that employees in the wellness program did self-report that they were more likely to exercise and manage their weight.

• 21:22Stephen J. Dubner?

  But the data revealed there were no significant differences in actual health markers, including weight loss. And as we heard on last week's live show, a world-class team of behavioral scientists recently did an experiment over 28 days with 53 different interventions to try to increase the exercise activity of people who were already members of a gym.

• 21:44Speaker 06

  So, after our 28-day program, pretty much, we saw nothing in terms of behavior change.

• 21:49Stephen J. Dubner?

  That's Katie Milkman from the University of Pennsylvania.

• 21:52Speaker 06

  All 53 versions of the program, pretty much, nothing sticks. And that was the ultimate goal. So that was major failure.

• 21:59Stephen J. Dubner?

  With so much failure, you can understand why a lot of people look for exercise shortcuts.

• 22:04Speaker 07

  The revolutionary new Ab-Transform System is the safe, effective, and affordable way to change the way you work out and look forever.

• 22:14Stephen J. Dubner?

  But maybe there's another kind of shortcut, something a bit less hucksterish. A bit more grounded in science, which brings us back to the biologist Ronald Evans from the Salk Institute. Evans is well-known in the field for having discovered a family of hormone receptors that act as genetic switches.

• 22:32Speaker 05

  And if you think of genes as instruments in an orchestra, you can have many different kinds of sounds or many different ways to have them work together. And the conductor that makes the genes come on at the right time and orchestrate all that are regulatory factors that are called transcription factors that activate the genes. So those are genetic switches. This is really the underpinning of a lot of our body's physiology is while all cells have the same number and same set of genes, individual cells activate different sets of genes and the receptors and the hormones control gene networks. And so a lot of our physiology is about genetic control.

• 23:16Stephen J. Dubner?

  The discovery and understanding of this mechanism of genetic control has been incredibly important.

• 23:23Speaker 05

  Once you have a mechanism, then you can think of how to actually develop therapies or drugs that can control that mechanism. Everyone's familiar with hormone replacement for people. Sometimes we lose a thyroid gland for various reasons and you can replace that by finding or making the hormone and then giving it back to the person. The steroid hormones are amongst the most widely prescribed drugs on the planet.

• 23:50Stephen J. Dubner?

  And perhaps the most famous steroid hormone therapy, the birth control pill.

• 23:56Speaker 05

  And that's all about using these receptors. And in many ways, the impact of this family of receptors and pharmaceuticals have changed society.

• 24:09Stephen J. Dubner?

  Ronald Evans may be on his way to creating a new pill, which once again has the potential to change society.

• 24:15Speaker 05

  Exercise in a pill.

• 24:17Stephen J. Dubner?

  His lab is developing a pill that would mimic the effects of exercise in the absence of actual exercise. Other labs around the world are working on similar exercise mimetics, as they're called, with various mechanisms. Evans's pill works by targeting one of two key hormone receptors.

• 24:35Speaker 05

  There are two hormone receptors that we discovered that are very, very close to each other, but play exactly opposite roles and complementary roles in body physiology as well as in disease. And so one of the hormone receptors is called PPAR gamma, and it is the master regulator of adipose tissue.

• 25:00Stephen J. Dubner?

  Adipose tissue is what most of us know as fat.

• 25:03Speaker 05

  You need this genetic regulator to activate the fat network. It's critical for survival. You need to store energy in fat to survive. And then the partner for that, that's called PPR delta, which we discovered in 1995. That's the receptor that burns fat. And most of the problem with disease is too much storage and not enough burning. So one of the ways that we have approached the problem is looking at drugs that could be specifically built to target the fat burning receptor of PPR delta.

• 25:45Speaker 05

  And that's led to a number of companies producing new kinds of molecules. And one of the companies that I created a number of years ago, developed a screening technology that was licensed to Glaxo Welcome, and they built a drug called GW1516.

• 26:04Stephen J. Dubner?

  Glaxo Welcome is now known as GlaxoSmithKline. GW1516 originally had a different purpose.

• 26:11Speaker 05

  It was made to change cholesterol levels and to try to increase something called HDL. And this drug never made it into FDA approval. It had problems.

• 26:23Stephen J. Dubner?

  Problems like causing tumors in the mice it was tested on. Evans eventually began working with a less powerful version of the drug with the assumption it would be less toxic. Another difference, he wasn't looking at its effect on cholesterol.

• 26:38Speaker 05

  So, one of the surprising things that come out of studying the GW1516 compound, and it was very dramatic result, is when we gave it to sedentary mice, or obese sedentary mice, either one, for about 30 days, the GW drug progressively activated the genetic program that is normally activated by exercise.

• 26:59Stephen J. Dubner?

  I think we should hear that last bit again.

• 27:02Speaker 05

  The GW drug progressively activated the genetic program that is normally activated by exercise.

• 27:09Stephen J. Dubner?

  In other words, their physiology seemed to indicate the mice had been exercising.

• 27:15Speaker 05

  But these mice were not getting exercise, they were just getting the pill.

• 27:19Stephen J. Dubner?

  As you can imagine, this was a pretty exciting research result. But how well did the pill do in terms of giving the benefits of exercise in a general sense?

• 27:28Speaker 05

  You have to be careful when you say, does the pill give the benefits of exercise in the general sense, because exercise is 100 things. But I should say, in general, exercise, no matter how you do it, focuses on a few things. It increases energy expenditure. It tends to increase burning of lipids and fats and sugars. You get adult neurogenesis, and that enhances cognitive performance. It also improves immune fitness, lowers inflammation. So it has many benefits to the heart and other parts of the body. Now, if we go to this, what does PPR delta drug do in terms of metabolic fitness and, let's say, the brain? It does exactly the same things.

• 28:13Speaker 05

  It gives you this increased energy expenditure. You burn more lipids, you burn more sugar, and you correct your insulin. Your adipose depot starts to shrink, so you lose weight. And the drug by itself gives you adult neurogenesis.

• 28:31Stephen J. Dubner?

  The drug also seemed to boost endurance, at least in the mice. After 30 days of giving them the drug, Evans and his team put the sedentary mice on a treadmill.

• 28:41Speaker 05

  It's a mouse treadmill. It's very cute. And we compared the mice that got the drug with ones that did not get the drug. And the difference was striking, the ones that got the drug could run approximately one hour longer, continuous running, than ones that didn't.

• 28:58Stephen J. Dubner?

  And what is the mechanism for this endurance effect?

• 29:01Speaker 05

  What the actual drug does, it increases fat burning by the powerhouse of the muscle cell, which is called the mitochondria. And the mitochondria can burn sugar or fat, but what the drug says is, we want the mitochondria to burn fat specifically and convert fat into the chemical form of energy called ATP, but don't burn sugar.

• 29:24Stephen J. Dubner?

  That's because the sugar, or glucose, is needed for brain energy.

• 29:28Speaker 05

  And so, the P-pair delta drug powers the brain and powers the fat by separating out the two energetic molecules in the body for different purposes, one for the muscle and one for the brain. And by doing that, you're able to sustain your running time by an hour or an hour and a half, if you're a mouse.

• 29:54Stephen J. Dubner?

  So this sounds pretty much like a miracle drug, doesn't it? Others thought so, too. Right before the 2008 Beijing Olympics, Evans reached out to the World Anti-Doping Agency, or WADA, about the potential for athlete abuse, and he eventually helped develop a test for it. Soon after, WADA banned the drug, but in 2013, a bunch of pro cyclists were caught using it. Fast forward to today, Ronald Evans and a pharmaceutical firm he co-founded, Mitobridge, are working on a new form of the drug that's meant to minimize side effects.

• 30:30Speaker 05

  So the Mitobridge drug has been in what's called Phase 1 studies, and it's now moving on to Phase 2 studies. So the most critical is the Phase 1 to me, because that's the safety. They're now through that part. So the next part is, does it work? And it works very well in the mouse models, but we have to show that it works well in people. We know it's safe in people, but we have not to show that it works. I would say two or three years that we will have a pretty good idea if it's working in human disease in a way that could achieve FDA approval.

• 31:09Stephen J. Dubner?

  To get the drug through FDA approval, Mitobridge is targeting patients with Duchenne muscular dystrophy. That's a genetic disorder typically striking young boys who rarely survive into their twenties.

• 31:20Speaker 05

  There is no real drug to treat it. But our approach is to restore this balance of energy utilization in the muscle. And we can stimulate that muscle to actually burn fat and become activated as if it was being exercised.

• 31:40Stephen J. Dubner?

  But Evans clearly sees a much wider potential use for this drug.

• 31:43Speaker 05

  There is absolutely no way that the potential here is going to be limited to one or two diseases. It will be very high from metabolic to neuro to vascular to aging. We can think of the potential here in different ways. And maybe to the wider question, can it be used preventively in some cases just to maintain health as opposed to just treating disease? And this is not an easy issue because taking healthy people and giving them a drug is not common. Now, it does happen. A lot of people take adult aspirin for their entire life because it's thought to be helpful

• 32:26Speaker 05

  to reduce inflammation and reduce heart disease.

• 32:31Stephen J. Dubner?

  Tens of millions of Americans also take statins every day to forestall heart disease. Millions more take metformin to treat diabetes or even the onset of diabetes. We put fluoride in our water supply to prevent tooth decay.

• 32:44Speaker 05

  And so could you transition this to a society that is getting heavier and running into the problem of obesity and diabetes and the related complications? The answer is yes, but I think from a social and ethical component, it raises a big question that should be addressed. It's not unusual for scientific advances to raise social issues and questions. We have this all the time.

• 33:13Stephen J. Dubner?

  Indeed, just because a drug may soon exist that could mimic the effects of exercise does not necessarily mean we should immediately spike our water supply with it. So Evans's drug, if it does make it through FDA approval, will surely have its philosophical and ethical skeptics, but even now, it's got its physiological skeptics.

• 33:33Speaker 04

  So, an exercise mimetic.

• 33:36Stephen J. Dubner?

  That, again, is Michael Joyner from the Mayo Clinic.

• 33:39Speaker 04

  If you think about it, the main ones have been designed to try to increase the function of the mitochondria, the little organelles in skeletal muscle that burn carbohydrate and fat and are critical to the metabolic benefits of exercise. And certainly, you can stimulate those with drugs. But if you look at the broad class of things that exercise does, it goes way beyond just affecting the mitochondria. It affects, again, the blood vessels, the remote effects of training, the effects on the brain, the effects on intermediate metabolism, and all sorts of other things. So I think you can find mimetic for things that sort of look like exercise, but I don't

• 34:22Speaker 04

  think you're going to find the big picture drug or compound that can do the 10 or 15 main things that exercise does for people.

• 34:30Stephen J. Dubner?

  What would you think of, let's call it, the exercise pharmaceutical that works along the lines you're describing there on a mitochondrial level for those who can't exercise due to, let's say, physical handicap or some other condition? Do you like that idea?

• 34:43Speaker 04

  Absolutely, absolutely. You know, you start thinking about exercise is good for your lipids, exercise is good for diabetes, exercise is good for this and that. And there's a terrific idea, a very interesting paper in the early 2000s, I believe in the British Medical Journal, which said, you know, why don't we put everybody in low-dose statins, low-dose antihypertensives, everybody over 50, low-dose anti-diabetic drugs, and see what it would do to their life expectancy and all-cause mortality? So some people have argued that really this is closer to an exercise mimetic than drugs that target the mitochondria, for example.

• 35:19Stephen J. Dubner?

  But you can imagine that if a so-called exercise pill does come to market, it might provide people the license to never exercise again.

• 35:28Speaker 06

  There's been research showing that there can be licensing effects with diet behaviors. You remind me that I've been dieting well, then I maybe eat more.

• 35:37Stephen J. Dubner?

  Katie Milkman again, from the University of Pennsylvania.

• 35:39Speaker 06

  So if you give people a pill and say, this has the effects of exercise, will they feel licensed not to exercise? It's a real risk.

• 35:48Speaker 05

  I do not actually like to think of it that way, because we are designed to move.

• 35:54Stephen J. Dubner?

  And that, again, is Ronald Evans, the man behind the exercise pill.

• 35:58Speaker 05

  And so the social issue is not just, should we give the drug to everyone? It's how do we manage the intrinsic advances that are working against our health?

• 36:11Speaker 06

  He may not intend for it to replace fitness, but will people take it and then feel that they're licensed to skip workouts? And so whether that's the intent of the medication doesn't mean it won't be a nasty side effect.

• 36:26Stephen J. Dubner?

  Marcus Baumann, a physiologist at the University of Alabama Birmingham, is also not in favor of an exercise pill.

• 36:33Speaker 08

  Because there are thousands upon thousands of molecular responses to exercise that cannot be recapitulated by one pill.

• 36:43Stephen J. Dubner?

  Baumann has another idea, a sort of hybrid idea, which he feels may be necessary, given the difficulty of turning an inactive person into an active one.

• 36:53Speaker 08

  Going from true sedentary status to a regular exercise training habit or behavior, there are a lot of steps required to make that happen. And one of those, I think, that would be very tangible for people is a prescription with good guidance.

• 37:11Stephen J. Dubner?

  A prescription, meaning an individualized exercise regimen.

• 37:15Speaker 08

  It really doesn't do the patient a lot of good for a healthcare provider to just say, "Well, your blood pressure's high, your glucose is high, and you need to lose some weight, so you should do more exercise." They don't know how frequent, what intensity, what dose. Is it resistance? Is it endurance? Is it a combination?

• 37:35Stephen J. Dubner?

  Baumann and his research team at UAB have been doing research for 15 years on this idea. They started with older adults and now work specifically on patients with Parkinson's, multiple sclerosis, and epilepsy. But their idea is that everybody could benefit from an exercise prescription.

• 37:53Speaker 08

  Let's just take the individual who comes to the clinic, 45 years old. They've got a body mass index of 32.

• 38:01Stephen J. Dubner?

  For the record, that is a pretty high BMI, the equivalent of a 5'10" person who weighs more than 220 pounds.

• 38:09Speaker 08

  They've got some level of insulin resistance going on. They've got stage 1 hypertension. They've got some knee pain.

• 38:17Stephen J. Dubner?

  In a perfect world, or at least in Marcus Baumann's world, a physician would have a lot of good data on exactly what forms of exercise, at what intensity and duration, would be most useful.

• 38:29Speaker 08

  If you can then point to that data and say to that person, "The evidence is clear. This works, and now I'm going to refer you to somebody who knows how to implement this evidence-based prescription," I think that would have a major impact on whether or not somebody adopts the change.

• 38:47Stephen J. Dubner?

  But the truth is, those data on ailment-specific exercise are fairly sparse.

• 38:53Speaker 08

  In terms of which type of exercise is best for a given disease-risk cluster, the research is really void in many areas.

• 39:02Stephen J. Dubner?

  That may be starting to change. The National Institutes of Health is starting an exercise trial this summer as part of a program called the Molecular Transducers of Physical Activity Consortium.

• 39:13Speaker 08

  And that study is really comparing resistance training to endurance training and trying to understand the molecular mechanisms by which each of those modes of exercise training induces potential health benefits.

• 39:32Stephen J. Dubner?

  You could also imagine that technology, especially smart technology, has a larger role to play in helping us achieve our fitness goals, like making exercise equipment and apps that, rather than beating us up-

• 39:44Speaker 01

  Steven, I told you to pedal faster.

• 39:47Stephen J. Dubner?

  ...are a bit more encouraging.

• 39:49Speaker 01

  Well, aren't you the little champion? Five whole minutes on the bike without a break. That's your new personal best.

• 39:58Stephen J. Dubner?

  In the meantime, coming up next week on Freakonomics Radio, believe it or not, you have to be really fit to do this.

• 40:07Speaker 09

  The clear-cut weiner Kobayashi, who inhaled 50 hot dogs in 12 minutes, shattering the world record.

• 40:14Stephen J. Dubner?

  A form of eating with which you are almost certainly not familiar. How many do you think you'll eat this year? More than 72. More than 72. That's next time on Freakonomics Radio. Freakonomics Radio is produced by Stitcher and Dubner Productions. This episode was produced by Morgan Levy with help from Daphne Chen. Our staff also includes Alison Kreglo, Greg Rippon, Harry Huggins, Zach Lipinski, Matt Hickey, and Corinne Wallace. We had help this week from Nellie Osborne. Our theme song is "Mr. Fortune" by The Hitchhikers. All the other music was composed by Luis Guerra. You can subscribe to Freakonomics Radio and give it a nice rating, if you'd like, on Apple Podcasts, Google Podcasts, Spotify, or any other podcast app.

• 40:58Stephen J. Dubner?

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• 41:50Stephen J. Dubner?

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• 42:21Stephen J. Dubner?

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• 42:54Stephen J. Dubner?

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• 43:31Speaker 10

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