Farewell to the couch

Exercise: a panacea for what ails you, but also kind of sweaty. And time-consuming. And tiring. It’s not for everyone, even if the benefits are without question. Regular exercise has been linked to lower risk of cardiovascular disease, forms of cancer, diabetes, stroke, mental health conditions, low bone density, arthritis and much more.

The relationship between exercise and health is so strong Stanford Medicine’s Euan Ashley, MB ChB, DPhil, chair of the Department of Medicine, has called it, “the most powerful drug we’ve ever known.” He said, “Every single system in the body, every single organ of the body, every single disease we’ve ever looked at — there’s a benefit to exercise.”

The question is how to deliver the undeniable health benefits of exercise to more people. Could it be packaged into a less sweaty, less time-consuming pill? Barring that, could exercise be made easier to swallow? Research underway suggests a pill isn’t likely, but there are several approaches being tested for sneaking exercise into busy lives.

Impact of a workout

Answering the question of whether a drug could mimic exercise requires knowing what exercise does for and in the body. That’s the subject of a 23-center research effort funded by the National Institutes of Health called Molecular Transducers of Physical Activity Consortium (MoTrPAC), which is intended to identify how, at the molecular level, exercise improves and maintains healthy organs and tissues.

Ashley is an investigator on MoTrPAC (pronounced “motor pack”) along with Michael Snyder, PhD, the Stanford W. Ascherman, MD, FACS Professor in Genetics; Stephen Montgomery, PhD, the Stanford Medicine Professor in Pathology and a professor of genetics and of biomedical data science; and Matthew Wheeler, MD, associate professor of cardiovascular medicine.

For the initial portion of the MoTrPAC project, the group studied 344 rats running on miniature treadmills, taking samples from 19 tissues and measuring differences in every available molecule: DNA changes, differences in proteins or types of lipids present, increases or decreases in which genes are active, changes in immune cells present in the tissue. If the scientists could measure it, the molecules were in the study.

The group published six consecutive papers in spring 2024 with the initial rat data and are now turning their attention to humans at a range of life stages, sampling only easily accessible blood, fat and muscle. The results from the human studies are not yet in.

“Every single system in the body, every single organ of the body, every single disease we’ve ever looked at — there’s a benefit to exercise.”

Euan Ashley, chair of the Department of Medicine

The initial papers showed that, at least in rats on treadmills, what’s happening through exercise at the molecular level is sweeping.

“There was a whole-body response to exercise,” said Ashley, the Roger and Joelle Burnell Professor in Genomics and Precision Health and the Arthur L. Bloomfield Professor in Medicine, who is a devotee of all ball sports. His lab has a regular Friday soccer game that brings together data analysts, research fellows, software developers, graduate students and Ashley in a fast-paced yet friendly game.

“I was sport mad,” Ashley said of his childhood in Scotland. “There were days as a kid I would play a rugby game in the morning for my school, then play soccer in the afternoon for my local boys’ club, and then I’d go to a sports club in the evening. I played sport all day.”

“Basically, all tissues respond in some way, not just the obvious tissues, like muscles, heart and lungs,” Ashley said of the rats in the study “Every single organ had changed with training and changed quite dramatically.”

Looking at the molecular data, Ashley said the rats looked like completely different animals when sedentary versus after eight weeks of rodent boot camp. The changes are so systemic that both Ashley and Montgomery said it’s unlikely there can ever be a pill to replace the effects of exercise.

“I think what we learn from these studies looking at rats is that it would be very hard to mimic the benefits of exercise synthetically,” Montgomery said. “It’s not likely that we could create a synthetic exercise pill so you could be sitting in the office not doing anything and you’re going to get all of these benefits of exercise.”

“It’s not likely that we could create a synthetic exercise pill so you could be sitting in the office not doing anything and you’re going to get all of these benefits of exercise.”

Stephen Montgomery, professor of pathology, genetics and of biomedical data science

Montgomery is a self-proclaimed weekend warrior focusing on running and gym workouts. “Every day, I wake up and I’m like, how do I fit exercise in?” he said, “And many days I can’t.”

The rat data (and eventually human data) is publicly available to other groups of researchers who want to dig into their own disease, organ or molecular pathways of interest.

Those studies could help re-create the benefits of exercise at least in particular organs, tissues or diseases. For example, a more detailed understanding of how exercise influences molecules associated with a type of cancer could lead to drugs or other therapeutics that further reduce the risk in people with a family history, or it could reveal new treatments or recommendations. Or these studies could one day provide personalized exercise advice based on disease risk and life stage, Montgomery said.

Supported in part by the NIH and the Wu Tsai Human Performance Alliance, Montgomery and Ashley are exploring ways their discoveries about exercise can be used to benefit humans. The data MoTrPAC has gathered so far is available on the MoTrPAC data hub.

A prescription for exercise

If exercise acts like a drug in the body, scientists from the American College of Sports Medicine want physicians to treat it as such. They have launched a program called Exercise is Medicine, which encourages health care providers to consider physical activity as standard of care. They recommend recording a person’s physical activity levels as a vital sign and concluding appointments with exercise prescriptions. Their website offers printable prescription pads for exercise.

Shuchi Anand, MD, Stanford Medicine associate professor of nephrology, ran a pilot study with collaborators at Emory University testing the Exercise is Medicine model in people with chronic kidney disease. Doctors involved in the study wrote participants a prescription for a group exercise class they’d organized with a local provider.

Anand said people in the study were enthusiastic about the opportunity, but many still struggled to follow through on attending class. She’s now conducting a similar study called Sit Less, Interact and Move More in collaboration with researchers at the University of Utah, also in people with kidney disease. This study provides resistance training coaching to people with kidney disease, with the goal of helping people continue exercising beyond the study period.

“The magnitude of its effect is the same as some of the most expensive medicines we have for kidney disease.”

Shuchi Anand, associate professor of nephrology

“We know that exercise is beneficial for everyone with kidney disease,” Anand said. Past studies have shown that people with kidney disease who are more physically active have slower disease progression and live longer.

Anand called exercise, “a whole-body intervention,” and said, “The magnitude of its effect is the same as some of the most expensive medicines we have for kidney disease.”

The challenge, she found, is getting people to stick with it.

“When we first approach people about these studies they are excited,” Anand said. “But as time moves on, people do lose motivation.”

Anand jogs 20 minutes a day on a treadmill and has started trying to incorporate yoga and weights. “I’m a work in progress just like everyone else,” she said. She also looks to her step counter for motivation.

But the sweat …

This question of motivation remains the biggest challenge in helping more people gain the health benefits of exercise.

Marily Oppezzo, PhD, is looking at ways to overcome one barrier: the time commitment. Oppezzo, whose background is as a behavioral scientist, advocates exercise in 30-second to five-minute doses, which she and others call “exercise snacks.” These can include doing jumping jacks while lunch heats in the microwave, or a particularly adorable “pet the puppy” exercise that involves bending to pet an imaginary puppy then stepping over the imaginary puppy, on repeat. (Left out of the description is the potential mental health benefit of interacting with imaginary puppies.)

Oppezzo is an instructor of medicine at the Stanford Prevention Research Center, a personal trainer and an extremely tough power yoga teacher. “I mostly love strength training,” she said of her own exercise regimen. “I’ll do intervals because I have to, but I love strength.”

She is running several studies, each looking at ways to help people incorporate exercise snacks into their daily routines. One technique that has been shown to work is to give people something visible such as wristbands to indicate the number of times they are supposed to move.

“It takes the reminder out of your brain and onto the world,” she said. Other people use Post-it notes on their computers, or bands on their water bottles.

To make it easier for study participants, she is producing short exercise videos people can follow at work — she even has recommendations for exercises that can be done in a bathroom stall. Even with the short duration and multiple options, Oppezzo said follow-through remains the biggest challenge.

That’s where the work of Abby King, PhD, comes in. King, the David and Susan Heckerman Professor and a professor of epidemiology and population health and of medicine, has focused primarily on turning exercise into a habit. Her lab runs a program called Active Choices, which provides materials to train professional health educators and peer mentors to offer phone-based motivation to help people be active.

She has also been working with colleagues at the Stanford Institute for Human-Centered Artificial Intelligence, including doctoral student Matthew Jörke, to develop an AI model designed to mimic the role of a live Active Choices adviser.

“It’s important to find something in physical activity that you enjoy, where it doesn’t feel like a chore.”

Abby King, a professor of epidemiology and population health and of medicine

In an additional series of “human versus computer” physical activity intervention studies that King and her team have conducted over the past several decades, they have demonstrated that the Active Choices counseling method can also be effectively delivered through interactive voice menu systems, text messaging and an artificial intelligence-enabled virtual agent.

The virtual agent, named Carmen, used interactive facial expressions and, like the texting program, could communicate in both English and Spanish. Carmen provided personalized feedback and assistance with goal setting via on-screen prompts.

“We’re still not totally clear on what kinds of factors would drive someone to do better with a texting program versus a human phone program or AI program,” King said. “But we are starting to learn about that.”

King called this the “whiches” conundrum. “At the end of the day, we want to know which program for which people under which circumstances, to get which types of outcomes,” she said.

King admitted that she struggles to exercise at times, especially during a busy week, but she finds it easier when she combines it with something she enjoys such as dancing. “It’s important to find something in physical activity that you enjoy, where it doesn’t feel like a chore.”

She has conducted studies with a variety of midlife and older populations in which she has compared different approaches to motivating people to move. King said that, regardless of the population or the way people receive prompts, basic behavioral principles are at play. These include regular physical activity monitoring, goal setting, looking for role models and thinking about the benefits of following through. She added that tying the goal to a person’s values also helps.

“If your value is your family, then finding ways to be active with your family is going to satisfy that,” she said. “For many people, I don’t think that understanding health consequences alone is nearly as motivating as recognizing how being physically active can improve life in ways that truly matter to them.”

Wearable devices and fitness trackers also serve as motivational tools. Whether it’s tracking steps or watching your resting heart rate go down over time, Anand said the data can motivate people. “You look at all this information and you get all excited,” she said. “We’re very responsive to whether we get a positive or a negative effect, and that might make someone decide to walk their dog farther.”

“The problem in our society is not whether people do 70 minutes of high intensity exercise instead of 60, our problem is that people sit on the sofa and eat pizza.”

Euan Ashley

If the advice to exercise rather than wait for a pill brings heartache to those opposed to sweat — whether by preference or by physical limitations such as age, injury or disability — the researchers have some good news. Studies suggest that more exercise produces more molecular benefits, and “more” can mean relatively small increases in exercise levels.

The goal isn’t to make people feel bad if they don’t complete long bouts of hard exercise. “The problem in our society is not whether people do 70 minutes of high intensity exercise instead of 60, our problem is that people sit on the sofa and eat pizza,” Ashley said.

Even small changes can add up. “If you can just stand, if you can take a meeting walking, if you can take a walk after dinner, or if you could do any kind of exercise, that is better than sitting,” he said. “You don’t need to go to the gym, and you don’t need to sweat, you don’t need to jump in a pool in the morning if you don’t want to. Those are great things to do, and the more you can do, the better. But getting up and standing is worth something.”

King agreed that small steps matter. “Move more, sit less, is really the mantra,” she said. “For inactive people and older adults, along with people with chronic conditions, lighter types of walking intermixed with some more moderate activities work very well to help get some of those important benefits.”

Taken in small doses and linked to things you value and enjoy, exercise doesn’t have to be a hard pill to swallow. — Contact Amy Adams at medmag@stanford.edu