Could Fitness Tablets Really Work?

31% Proportion of adults in 122 countries who are physically inactive, rising to 43% in eastern Mediterranean and the Americas.

Exercise-mimetic drugs have long been a goal of science. As a new trial begins, it is hoped they could aid not just the sedentary, but elderly people and those with disease or disability.

In a hospital in northern Norway, near the Arctic Circle, a landmark experiment is taking place that could transform the way we treat ageing. Called ExPlas - exercised plasma - the clinical trial involves taking blood plasma from young and healthy adults who exercise regularly and injecting it into people aged between 50 and 75 in the early stages of Alzheimer's disease. The full results will be available in 2025, and the hope is that it will represent a new way of rejuvenating 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 arguably the best medicine of all. Studies have found that exercising can slash the risk of dementia by up to 45%, along with maintaining strong bones, supple blood vessels and muscle fibres that replenish themselves.

In August 2023, a study in the British Medical Journal showed that even an hour and a quarter of moderate exercise a week - half the recommended amount - reduces the risk of cancer, heart disease and premature death, compared with doing no exercise. However, a quarter of the UK population are still classed as inactive.

One survey of more than 100 countries found that nearly a third of people (31.1%) do next to no exercise.

But what if the drug industry could help mitigate this?

On a busy day, it would be great to take a drug instead of missing out on the benefits of exercise. If evidence does emerge that such medicines are safe and work in humans, experts agree that they could be the blockbuster drugs of the future.

From the UK to Japan, scientists have spent years searching for exercise mimetics-pills or perhaps injections that could replicate some of exercise's beneficial effects on the body.

"We know that exercise releases all these hormones that show up in the blood," said Christiane Wrann, an assistant professor of medicine at Harvard Medical School.

Because scientists are still unsure which exercise hormones are the most beneficial, the ExPlas trial is taking a broad approach. Injecting blood plasma from people who exercise regularly is a simple way of transferring 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.

In 2012, scientists discovered a hormone called irisin that is released by muscles during exercise. In November 2023, Wrann and her colleagues demonstrated that irisin can reach the brain and clear the toxic amyloid plaques involved in Alzheimer's disease, a big breakthrough in understanding how exercise helps shield the brain from dementia.

Wrann and others have now created a spin-off company, Aevum Therapeutics, with the ultimate aim of commercialising irisin as the world's first exercise-based treatment. If irisin can demonstrate health benefits, it could lead to more exercise-based medicines.

Researchers such as Wrann insist the main target group for exercise drugs is not the time-poor or the lazy, but rather disabled and elderly patients who have become house-bound or bed ridden through enforced inactivity.

At the Tokyo Medical and Dental University, scientists have been searching 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 for preventing frailty and perhaps even restoring the ability to move.

In autumn 2022, they announced the discovery of a chemical called locamidazole that stimulates two of the signalling pathways in the body that are activated in exercise.

While this is encouraging, researchers are proceeding cautiously because of the risk of
unpleasant or even dangerous side-effects that have waylaid previous attempts to tum exercise into a drug.

The key question scientists 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.

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 that affects mood and motivation, in unprecedented detail. One hopeis that this could one day lead to a new class of antidepressants based on exercise.

Jonathan Long, an assistant professor of pathology at Stanford University in California, is particularly interested in whether understanding the effects of exercise on the brain can yield new alternatives to existing obesity drugs. His research group has 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, your nervous system wants to shut down digestion and appetite so all your glucose goes to your muscles to help you escape and survive.

Others see mimicking exercise as a way of potentially reprogramming 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.

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 through endurance exercise.

PPAR-delta can help us increase our proportion of slow-twitch muscle fibres and tells the body to go from burning sugar to fat. Now, Evans is convinced that he has a drug capable of pressing this switch; what he still needs is the data to demonstrate that it is safe and efficacious in humans.