"Exercise in a Pill": The Next Biohack or a Far-off Fantasy?
"Exercise in a Pill": The Next Biohack or a Far-off Fantasy?
Encapsulating the benefits of physical activity is more complex than it seems.
Plenty of people love to exercise. If you’re reading this post, you might be one of them.
But the disheartening truth is that most people don’t enjoy exercise. A third or less of adults meet the minimum recommendations for aerobic and strength exercise each week. As a result, much of the global disease burden can be attributed to physical inactivity — 6–10% based on some estimations.
I’m an exercise scientist by training. I want everyone to be active and believe it’s one of the single most important things we can do for our health and longevity. But the rising trends of obesity, diabetes, and cardiovascular disease and the falling trend of activity levels lead me to a dark conclusion: things probably aren’t going to get any better.
We can promote exercise until we’re red in the face. But if people aren’t willing to change their behaviors, it’s a lost cause.
What are the other options?
In the last few decades, the idea of “exercise in a pill” has become the topic of vigorous debate. Otherwise known as “exercise mimetics”, these drugs could replicate many of the effects of physical activity without requiring one to engage in any actual exercise.
Spend an hour in the gym? How about just popping a pill to get bigger biceps. A strenuous high-intensity interval workout? What if you could just take an aerobic exercise supplement?
You’re probably turning your nose up at the idea — it’s just a shortcut to health for people who are too lazy to do the actual work, right?
Sure, an exercise pill could be an option for these individuals. But the applications are much more wide ranging.
Plenty of adults and children can’t exercise due to age or a musculoskeletal limitation. An exercise pill could be an incredible opportunity to maintain or build strength and fitness after surgery or illness, during which one might otherwise be bedridden or unable to perform physical activity. Think about the applications for astronauts in zero gravity environments.
Even already fit people could benefit from an exercise pill. Athletes could stack exercise supplements with real exercise to double up on the benefits. Runners and strength athletes could take a pill to get larger muscles or improve their VO2 max — replacing the types of exercise they might be lacking — just as they might with a nutritional supplement.
How out-of-this-world of an idea is an exercise pill? In the era of ‘omics’, understanding what it would take to mimic exercise isn’t that difficult. But could such a pill really be effective?
Defining an exercise pill
Experts who have commented on the idea of an exercise pill note one glaring issue: the term “exercise mimetic” is a not only a misnomer, but it’s inaccurate and misleading.
For one, drugs target single pathways or risk factors. Statins lower cholesterol. ACE inhibitors block the angiotensin-converting enzyme to reduce blood pressure.
In contrast, exercise targets several cells, tissues, and organs.
A single session of exercise causes the release of hundreds to thousands of myokines — proteins produced and released by muscle fibers during contraction. Once released, these myokines flow through the circulatory system to interact with multiple body systems, allowing for crosstalk between the muscle and other organs, including the brain, adipose tissue, bone, liver, gut, pancreas, vascular bed, and skin, as well as communication within the muscle itself.
Exercise perturbs our entire physiology, and it’s this disruption of homeostasis, integrative crosstalk, and subsequent adaptations that lead to the immense health benefits achieved through physical activity.
While an exercise pill could certainly activate one or a few of the pathways in the body that exercise does, the scope would be extremely narrow.
Second, what’s even meant by the word “exercise”? Exercise can refer to endurance training, resistance exercise training, flexibility training, and so on. Different types of exercise lead to different responses and adaptations: endurance training increases mitochondria and aerobic fitness, while resistance training builds strength and hypertrophy.
Without an appreciation of the specificity of adaptations to different exercise modes, the word “exercise mimetic” becomes meaningless. Furthermore, we’d need hundreds of separate pills to replicate an exercise training regimen.
Find a pill that can increase mitochondrial content, improve your VO2 max, increase your bench press, lower your blood pressure, and increase cognitive function, and then we can start to discuss the possibility of a exercise in a drug.
Just as there’s no generic “exercise”, there’s also no “exercise gene” or “exercise pathway” for an exercise pill to target.
Though early research in exercise physiology identified a transcription factor known as PGC-1 alpha as a “master regular” of exercise adaptation, the consensus now is that — while it’s incredibly important — PGC-1 alpha may be sufficient but not necessary for exercise-induced improvements in mitochondrial biogenesis and other beneficial adaptations.
If only it were so simple. Rather, as mentioned earlier, exercise — more specifically skeletal muscle contraction — causes the release of myokines and adipokines (from fat tissue) that promote inter-organ and inter-tissue crosstalk. These signaling molecules allow our body to communicate and integrate information about what’s happening during exercise and drive our training response.
All of this is to say that the way exercise affects our body goes several layers deep. We’re only beginning to understand the complex integrated responses that occur with exercise/exercise training. But one thing that’s easy to understand is that a single pill or drug is unlikely to replicate these complex phenomena.
Could an exercise pill have side effects?
There’s no such thing as free lunch in biology. An exercise pill would likely have tradeoffs — known or unknown.
We can’t exercise all the time — we need to allow our body the time for rest, repair and recovery.
The same would go for an exercise pill. Would maintaining a metabolic state or activating metabolic pathways similar to exercise chronically (via a pill) have deleterious effects?
Acutely, exercise is catabolic — protein synthesis is inhibited, autophagy (cellular recycling) is upregulated, and mTOR (or body’s growth-promoting protein) is inactivated. It’s only during recovery when we get bigger, faster, and stronger.
The ability to keep the switch “on”, so to speak, for exercise-related pathways doesn’t seem like the best of ideas.
There’s also the issue of dosing and overdosing. Would we want the minimum effective dose of an exercise drug, or naturally, would the ultra-competitive athletes begin to pop exercise pills like candy? Would we want to prescribe an exercise pill at a dose that would produce a response beyond that which could be achieve by actual exercise? Would combining an exercise pill with exercise lead to burnout or meltdown?
What would an exercise pill target?
To date, much of the research and discussion about “exercise mimetics” has focused on their ability to promote an increase in mitochondria in skeletal muscle.
But more mitochondria is hardly the only reason why anyone exercises. Nor should it be.
Cardiovascular diseases are the leading cause of death around the world. People aren’t dying from too few mitochondria (though that’s certainly an issue…), they’re dying from hardened arteries, a failing heart, and high blood pressure.
There’s a dearth of evidence about whether or not “exercise mimetics” could have cardiovascular benefits. This is also doubtful given what we know about how exercise affects the cardiovascular system.
Of course, exercise improves common cardiovascular risk factors like blood pressure, cholesterol, blood glucose, and it may even promote weight loss. But the benefits of exercise on morbidity and mortality can’t be fully explained by improvements in “traditional” risk factors — this is what researchers have called the “risk factor gap.”
This “risk factor gap” has been largely attributed to the effects of exercise on endothelial function, the autonomic nervous system, and the structure and function of our heart.
An exercise mimetic would also have to target these “non-traditional” risk factors. Unfortunately, this isn’t possible.
Why? Exercise improves endothelial function (our blood vessels’ ability to dilate) due to the direct stimulus of increased blood flow. When we start exercising, blood flow increases, and this leads to an increase in shear stress/shear force on the innermost wall of our arteries known as the endothelium.
Shear stress is an important stimulus for the release of nitric oxide (NO) and increasing endothelial function. Chronically, this protects us against atherosclerosis and other age-related changes in the structure and function of the blood vessels.
Our body has evolved mechanisms that sense and respond to movement (exercise). And it “rewards” us for doing so.
It’s the movement of our body and the movement of blood that directly mediate some of the benefits (and some of the key benefits I might argue) of exercise on cardiovascular health. This is akin to the direct stimulus of muscle contraction that mediates the release of myokines. It’s unlikely that any sort of pill or combination of pills could produce this type of effect — we have to move!
Research on exercise mimicking drugs: do they work?
Though I’ve largely dismissed the idea that we could encapsulate (literally) exercise, there has been research into the effects of different compounds as potential “exercise mimetics.” Here are a few examples.
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