IIn the hospital in northern Norway, just south of the Arctic Circle, a landmark experiment is taking place that could change the way we treat aging in the coming years. Called ExPlas – exercised plasma – the clinical trial involves taking blood plasma from young and healthy adults who exercise on a regular basis and injecting it into people between the ages of 50 and 75 in the early stages of Alzheimer’s disease. This is the first time it has been tested in humans.
The full results will be available in 2025, and the hope is that it will represent 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 is probably 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, supple blood vessels and muscle fibers that replenish themselves rather than disappear.
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 doing no exercise at all. Despite public health guidelines, a quarter of the British population is still classified as inactive. One survey of over 100 countries found that almost a third of people do almost no exercise.
But what if the drug industry could help mitigate this? From the UK to Japan, scientists have spent years searching for exercise mimics – pills or perhaps injections that could replicate some of exercise’s beneficial effects on the body. The signs indicate that we are getting close.
“We know that exercise releases all these hormones that show up 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 trial 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 the drug and give it to those who need it,” says Wrann.
But another, more focused approach is also gaining traction. In 2012, scientists discovered a hormone called irisin released by muscles during exercise – a messenger chemical that communicates with various parts of the body. In November 2023, Wrann and her colleagues showed that irisin can reach the brain and removes the toxic amyloid plaques involved in Alzheimer’s disease, a major breakthrough in understanding how exercise helps protect the brain from dementia.
Wrann and others have now created 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, tweaking genes so 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 Alzheimer’s treatment or simply a generally beneficial exercise drug, but Wrann believes that if irisin can be shown to show health benefits in clinical trials, it could lead to many more exercise-based medicines .
“[So far,] no one has successfully turned the benefits of exercise into a drug,” says Wrann. “But if you can capture maybe not all, but at least a significant amount of the benefits of exercise in a medication, I think that could be transformative in improving patient outcomes.”
A pill for everyone?
Can we all be freed from the obligation to go to the gym this coming January? Andrew Budson, professor of neurology at Boston University, agrees that the idea is a compelling one.
“I think there’s nothing inherently wrong with the idea of trying to replicate the physiologically beneficial effects of exercise,” he says. “I have no 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 drug instead of missing out on the health benefits of exercise altogether.”
However, researchers such as Wrann insist that the main target group for exercise drugs is not the time-poor or the lazy, but rather disabled and elderly patients who have become housebound or bedridden through enforced inactivity. At Tokyo Medical and Dental University, scientists searched for exercise’s secret ingredient – 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.
In the fall of 2022 they have announced the discovery of a chemical called locamidazole which stimulates two of the signaling pathways in the body that are activated in exercise, and are involved in the maintenance of muscle and bone. When given to mice as an oral supplement, it appeared to improve muscle width and function, as well as promote bone formation.
But while encouraging, researchers are proceeding slowly and cautiously largely because of the risk of unpleasant or even dangerous side effects that have thwarted several previous attempts to turn exercise into a drug.
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 which is activated by exercise, which stimulates the clearance of excess sugars in the blood and thus reduces the likelihood of type 2 diabetes. However, the AMPK system is highly 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 that,” says Long. “They put those molecules into monkeys and they did exactly what you’d 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 got too big, which is dangerous. So it wasn’t helpful.”
Antidepressants and fat injections
The key 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 expect exercise-related pathways to be active.
Wrann says it’s unlikely we’ll ever have a medicine 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 all of them, it would probably not be safe. “I don’t think it’s realistic that a single pill will give you the 20 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 protecting the brain. At University College London, Jonathan Roiser, a 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 it affects mood and motivation, in unprecedented detail. One hope is that this could one day lead to an entirely new class of antidepressants based on exercise.
Long is particularly interested in whether understanding the effects of exercise on the brain can yield new alternatives to existing obesity drugs. His research group discovered a metabolite called Lac-Phe (N-lactoyl-phenylalanine) that the body produces during sprinting or resistance training. Because Lac-Phe is released into the bloodstream, it can travel to the brain, where it suppresses appetite.
“In prehistoric times, when you were exercising, you were typically running away from predators,” Long says. “Your nervous system wants to shut down digestion and appetite, so all your 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 the drugs Ozempic and Wegovy have emerged as the leading weight-loss treatments, Long points out that they have limitations, particularly the requirement to inject them weekly to maintain the benefits.
“Maybe you can combine them [with Lac-Phe] in interesting ways that will allow for more durable appetite suppression,” he says. “And maybe Lac-Phe could be developed as a molecule that you could take orally rather than inject.”
Others see mimicking exercise as a way to potentially reprogram the body’s metabolism in ways that aid fat burning. Some mouse studies 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.
Ronald Evans, a professor at the Salk Institute for Biological Studies in San Diego, California, has spent the past 20 years studying a protein called PPAR-delta (peroxisome proliferator-activated receptor-delta), a drug target he describes as a master switch activated by endurance exercise.
PPAR-delta can help us increase our proportion of slow twitch muscle fibers and tell the body to switch from burning sugar to fat. Now, after years of research, Evans is finally convinced that he has a drug capable of flipping this switch; what he still needs is the data to demonstrate that it is safe and effective in humans.
Because major funding bodies tend to be skeptical of the idea of exercise drugs, Evans had to pitch it as a potential new treatment for either fatty liver disease or the genetic muscle-weakening disorder Duchenne muscular dystrophy in order to attract regulatory approval and funding for clinical trials.
“I hope that in the next 10 years there will be an exercise drug,” 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 Institute of Health. And giving a drug that promotes the benefits of exercise says, ‘Well, what are we treating? Why don’t they just practice?’”
But if evidence does begin to emerge that such drugs are safe and work in humans, experts agree that they could be the blockbuster drugs of the future. “If we could succeed, I think absolutely,” Long said. “If we could actually do that, I think it would be really great medicine.”