Can exercise pills help create a healthier society? | Sciences

IIn a hospital in northern Norway, just south of the Arctic Circle, a landmark experiment is underway that could change the way we treat aging in the coming years. The clinical trial, called ExPlas – exercise plasma – involves taking blood plasma from young, healthy adults who exercise regularly and injecting it into people aged 50 to 75 in the early stages of Alzheimer’s disease. It’s the first time this has been tested on humans.

The full results will be available in 2025, and will hopefully represent a new way to rejuvenate the minds and bodies of older people, and perhaps one day even all of us who live largely sedentary lives.

Scientists have long known that exercise is the best medicine of all. Studies have found that exercise can reduce the risk of dementia by up to 45%, along with maintaining strong bones, flexible blood vessels and muscle fibers that renew themselves rather than wear away.

In August 2023, a new study in British Medical Journal It 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. However, despite public health guidance, a quarter of the UK population is still classed as inactive. A survey conducted in more than 100 countries found that nearly a third of people do no exercise.

But what if the pharmaceutical industry could help alleviate this problem? From the United Kingdom to Japan, scientists have spent years searching for exercise mimics — pills or perhaps injections that could mimic some of the beneficial effects of exercise on the body. Signs indicate that we are getting closer.

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

Because scientists are still unsure which exercise hormones are most beneficial, the ExPlas trial is taking a broad approach. Injecting blood plasma from people who exercise regularly is a simple way to deliver all these hormones that may be beneficial to patients. “The Norwegian idea is to take plasma as a medicine and give it to those who need it,” says Rahn.

But another, more focused approach is also gaining momentum. In 2012, scientists discovered a hormone called irisin, which is secreted by muscles during exercise, and is a chemical messenger that communicates with different parts of the body. In November 2023, Ran and her colleagues demonstrated that irisin can reach the brain and remove toxic amyloid plaques associated with Alzheimer’s disease, a major breakthrough in understanding how exercise helps protect the brain from dementia.

Wrann and others have now created a separate company, Aevum Therapeutics, with the ultimate goal of commercializing irisin as the world’s first exercise-based therapy. Perhaps by mimicking the hormone with a drug, modifying genes so that they generate more irisin, or simply injecting more of it into the body.

It’s too early to say whether this could represent a new treatment for Alzheimer’s disease or just a widespread exercise drug, but Ran believes that if the health benefits of irisin can be proven in clinical trials, it could lead to several more exercise-based drugs. .

“(So far) no one has succeeded in translating the benefits of exercise into medicine,” Wran says. “But if it can capture, perhaps not all, but at least a significant amount of the benefits of exercise in a drug, I think it could be transformative for improving patient outcomes.”

A pill for everyone?

Can we all break free from the obligation to go to the gym next January? Andrew Bodson, a professor of neuroscience at Boston University, agrees that the idea is compelling.

“I think there’s nothing inherently wrong with the idea of ​​trying to replicate the physiologically beneficial effects of exercise,” he says. “I don’t have a problem with it. I’ve enjoyed exercising and I don’t think I’ll give it up, but on a busy day, I think it would be nice (to be able to) take medication rather than miss out on the health benefits of exercise. Completely.”

However, researchers like Ran insist that the main target group for exercise drugs is not time-poor or lazy people, but disabled and elderly patients who have become housebound or bedridden due to enforced inactivity. At Tokyo Medical and Dental University, scientists have been searching for the secret ingredient of exercise – the one that protects against osteoporosis and muscular dystrophy (loss of muscle mass and strength) – with the idea of ​​turning it into a new medicine to prevent weakness and perhaps even restore mobility.

In the fall of 2022, they announced the discovery of a chemical called lucamidazole that stimulates two signaling pathways in the body that are activated during exercise and are involved in maintaining muscle and bone. When it was given to mice as an oral supplement, it appeared to improve muscle width and function as well as promote bone formation.

But while this is encouraging, researchers are largely proceeding slowly and cautiously because of the risks of unpleasant or even dangerous side effects that have hampered many previous attempts to turn exercise into medicine.

Jonathan Long, an 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 exercise, which stimulates the removal of excess blood sugars and thus reduces the likelihood of developing type 2 diabetes. . However, the AMPK system is very complex, and its activation 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 in doing just that,” Long says. “They put these molecules in monkeys and they did exactly what you would expect them to do, which is lower blood glucose. But on top of that, they also saw that those monkeys developed dilated cardiomyopathy, which means their hearts became too big, which is dangerous.” “So that wasn’t helpful.”

Antidepressants and fat injections

The main question that 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 the pathways associated with exercise are not expected to be active.

It’s unlikely we’ll ever have a drug that universally replicates the full benefits of exercise, Rahn says. Physical activity simply involves too many biological processes, and even if it were possible to target all of them, it would probably not be safe. “I don’t think it’s realistic that one pill is going to give you 20 good things exercise does for your body,” she says.

Instead, scientists envision a future with many different treatments all based on biological pathways identified through the study of exercise, some for osteoporosis and others for brain protection. At University College London, Jonathan Roser, 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 this affects mood and motivation, in an unprecedented way. the details. One hope is that this will one day lead to an entirely new class of exercise-based antidepressants.

Long is particularly interested in whether understanding the effects of exercise on the brain could lead to new alternatives to existing obesity medications. His research group discovered a metabolite called Lac-Phe (N-lactoyl-phenylalanine) that the body produces during running or resistance training. As Lac-Phe is released into the bloodstream, it can travel to the brain, where it suppresses appetite.

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

Lac-Phe may be a valuable new tool in the fight against the modern obesity epidemic. While Ozempic and Wegovy have emerged as leading weight-loss treatments, Long points out that they come with limitations, particularly the requirement to be injected weekly to maintain benefits.

“Maybe you could combine it[with Lac-Phe]in interesting ways that would allow for more sustained appetite suppression,” he says. “Perhaps Lac-Phe could be developed as a molecule that you can take orally rather than inject.”

Others believe that simulating exercise is a way to reprogram the body’s metabolism in ways that help burn fat. Some studies in mice have shown that boosting irisin levels can convert normal fat cells into energy-burning brown fat, causing the rodents to lose weight even on a high-fat diet.

For the past 20 years, Ronald Evans, a professor at the Salk Institute for Biological Studies in San Diego, California, has been studying a protein called PPAR delta (peroxisome proliferator-activated receptor delta), a drug target that he describes as a master switch activated by endurance exercise.

PPAR-delta can help us increase the proportion of our slow-twitch muscle fibers and tell the body to switch from burning sugar to burning fat. Now, after years of research, Evans is finally convinced that he has a drug capable of flipping that switch; What is still needed is data proving that it is safe and effective in humans.

Because large funding bodies tend to be skeptical of the idea of ​​exercise drugs, Evans had to tout them as a potential new treatment for either fatty liver disease or the hereditary muscle-weaking disorder Duchenne muscular dystrophy to attract regulatory approval and funding for clinical trials.

“I hope there will be an exercise medicine in the next 10 years,” he says. “But the challenge from a scientific standpoint is that all the research that’s being done (in the United States) is sponsored by the National Institutes of Health. They give a drug that enhances the benefits of exercise, and they say, ‘Well, what do we treat? Why don’t they just exercise?’

But if evidence begins to emerge that these drugs are safe and effective in humans, experts agree that they could be the blockbuster drugs of the future. “If we can pull it off, I definitely think so,” Long says. “If we can actually do that, I think these will be really great drugs.”