Could exercise pills help create a healthier society?

IA groundbreaking experiment is taking place in a hospital in Northern Norway, just south of the Arctic Circle, that could change the way we deal with aging in the coming years. Called ExPlas – exercise plasma – the clinical trial involves taking blood plasma from young and healthy adults who exercise regularly and injecting it into people between 50 and 75 years old in the early stages of Alzheimer's disease. This is the first time this has been tested in humans.

The full results will be available in 2025, and the hope is that it will provide a new way to rejuvenate the minds and bodies of older people, and perhaps one day even all of us who lead largely sedentary lives.

Scientists have long known that exercise may be the best medicine. Research has shown that exercise can reduce the risk of dementia by up to 45%, along with maintaining strong bones, flexible blood vessels and muscle fibers that replenish themselves instead of fading.

In August 2023, a new study in the British medical journal showed that even an hour and a quarter of moderate exercise per week – half the recommended amount – reduces the risk of cancer, heart disease and premature death, compared to no exercise. Despite public health guidelines, a quarter of the British population are still considered inactive. One survey of more than 100 countries found that almost a third of people do virtually no exercise.

But what if the pharmaceutical industry could help alleviate this? From Britain to Japan, scientists have spent years looking for exercise mimics – pills or perhaps injections that could mimic some of the beneficial effects of exercise on the body. The signs indicate that we are starting to get close.

“We know that exercise releases all these hormones that are in the blood,” says Christiane Wrann, an assistant professor of medicine at Harvard Medical School.

Because scientists are still unsure which exercise hormones are most beneficial, the ExPlas study takes a broad approach. Injecting blood plasma from people who exercise regularly is a simple way to transfer all these potentially beneficial hormones to patients. “The Norwegian idea is to take the plasma as medicine and give it to those who need it,” says Wrann.

But another, more targeted approach is also gaining ground. In 2012, scientists discovered a hormone called irisin that is released by the muscles during exercise – a chemical messenger that communicates with different parts of the body. In November 2023 Wrann and her colleagues showed that irisin can reach the brain and clearing the toxic amyloid plaques involved in Alzheimer's disease, a major breakthrough in understanding how exercise helps protect the brain against dementia.

Wrann and others have now formed a spin-off company, Aevum Therapeutics, with the ultimate goal of commercializing irisin as the world's first exercise-based treatment; perhaps by mimicking the hormone with a drug, modifying genes so they generate more irisin, or simply injecting more of it into the body.

It's too early to say whether this could be a new treatment for Alzheimer's disease or simply a generally beneficial exercise drug, but Wrann believes that if irisin can be shown to demonstrate health benefits in clinical trials, it could lead to many more exercise-based medicine.

“(Until now) no one has successfully translated the benefits of exercise into a drug,” says Wrann. “But if you can capture maybe not all, but at least a significant portion of the benefits of exercise in a drug, I think it could be transformative in improving patient outcomes.”

A pill for everyone?

Can we all be released from the obligation to go to the gym in January? Andrew Budson, a professor of neurology at Boston University, agrees that the idea is compelling.

“I don't think there's anything inherently wrong with the idea of ​​trying to mimic the physiologically beneficial effects of exercise,” he says. “I don't have a problem with that. I happen to enjoy my exercise and I don't think I would give it up, but on a busy day I think it would be great to (be able to) take a medication instead of the health benefits of exercise are completely missed.”

However, researchers such as Wrann emphasize that the main target group for exercise medicine is not the time-poor or lazy people, but rather disabled and elderly patients who have become homebound or bedridden due to enforced inactivity. At Tokyo Medical and Dental University, scientists have searched for the secret ingredient of exercise – the element that protects against osteoporosis and sarcopenia (the loss of muscle mass and strength) – with the idea of ​​turning it into a new drug to prevent frailty and perhaps even restore the ability to move.

They will be in the fall of 2022 announced the discovery of a chemical called locamidazole which stimulates two of the signaling pathways in the body that are activated during exercise and involved in the maintenance of muscles and bones. When given as an oral supplement to mice, it appeared to improve muscle width and function and promote bone formation.

But while this is encouraging, researchers are largely moving slowly and cautiously because of the risk of unpleasant or even dangerous side effects that have plagued several previous attempts to turn exercise into medicine.

Jonathan Long, assistant professor at Stanford University in California, gives the example of AMPK (adenosine monophosphate-activated protein kinase), an enzyme in the body that is activated by practicewhich stimulates the clearance of excess sugars in the blood and thus reduces the risk of type 2 diabetes. However, the AMPK system is very complex and activating it affects many different tissues in the body, not just blood glucose.

“People have been trying to develop AMPK activators, and a few years ago a pharmaceutical company succeeded,” says Long. “They put those molecules in monkeys and they did exactly what you would expect from them: lower blood glucose. But on top of that, they also saw that those monkeys developed a dilated cardiomyopathy, which caused their hearts to become too large, which is dangerous. So that was of no use.”

Antidepressants and fat sticks

The main question Long and others are trying to answer is whether there is a safe way to artificially stimulate the body when it is at rest and not expecting exercise-related pathways to be active.

Wrann says it's unlikely we'll ever have a drug that universally replicates the full benefits of exercise. Physical activity is simply involved in too many biological processes, and even if it were feasible to target them all, it probably wouldn't be safe. “I don't think it's realistic that a single pill would give you the 20 good things that exercise does to your body,” she says.

Instead, scientists envision a future with many different therapies, all based on biological pathways identified by studying exercise, some for osteoporosis and others for brain protection. At University College London, Jonathan Roiser, professor of neuroscience and mental health, is working on a Wellcome-funded project to measure the impact of moderate-intensity exercise on the immune system and metabolism, and how that affects mood and motivation, in unprecedented ways. detail. One hope is that this could one day lead to a whole new class of antidepressants based on exercise.

Long is particularly interested in whether understanding the effects of exercise on the brain can provide new alternatives to existing anti-obesity drugs. His research group has discovered a metabolite called Lac-Phe (N-lactoyl-phenylalanine) that the body produces during sprinting or strength training. Because Lac-Phe enters the bloodstream, it can travel to the brain, where it suppresses appetite.

“In prehistoric times, if you were exercising, you were usually running from predators,” Long says. “Your nervous system wants to turn off digestion and appetite so that all your glucose goes to your muscles to help you escape and survive.”

Lac-Phe could be a valuable new tool in the fight against the modern obesity epidemic. Although the drugs Ozempic and Wegovy have become the main weight-loss treatments, Long points out that they come with limitations, most notably the requirement to inject them weekly to maintain the benefits.

“You might be able to combine them (with Lac-Phe) in interesting ways that will suppress appetite more sustainably,” he says. “And perhaps Lac-Phe can be developed as a molecule that can be taken orally instead of injected.”

Others see exercise simulation as a way to potentially reprogram the body's metabolism in ways that promote fat burning. Some mouse studies have shown this that increasing irisin levels can convert normal fat cells into energy-burning brown fat, helping the rodents lose weight even on a high-fat diet.

For the past two decades, Ronald Evans, a professor at the Salk Institute for Biological Studies in San Diego, California, has studied a protein called PPAR delta (peroxisome proliferator-activated receptor delta), a drug target he describes as a master switch activated by endurance training.

PPAR-delta can help us increase our proportion of slow twitch fibers and tells the body to switch from burning sugar to fat. Now, after years of research, Evans is finally convinced he has a drug that can push this switch; what he still needs is the data showing it is safe and effective in humans.

Because major funding agencies tend to be skeptical of the idea of ​​exercise medicine, Evans has had to tout it as a potential new treatment for fatty liver disease or the genetic muscle-weakening disease Duchenne muscular dystrophy to gain regulatory approval and funding for clinical trials.

“I hope that in the next decade there will be a practice medicine,” he says. “But the challenge from a scientific point of view is that all the research that is done (in the US) is sponsored by the National Institutes of Health. And when they give a drug that promotes the benefits of exercise, they say, “Well, what are we treating? Why don't they just exercise?'”

But if evidence emerges that such drugs are safe and work in humans, experts agree they could be the blockbuster drugs of the future. “If we could succeed, I think absolutely,” Long said. “If we could actually do this, I think these would be really great drugs.”