Exercise Mimetics

For millennia, humanity has acknowledged the benefits of physical exercise. Hippocrates, who practised medicine around 400 years BC was one of the first physicians to prescribe exercise as a form of medicine. Today, exercise remains central to preventive healthcare, with well-documented associations between regular physical activity and improved health outcomes. While previous research established correlations between exercise and reduced risk for chronic diseases, it is only recently that science has begun to unravel how these benefits arise at the biochemical level. This understanding has led to the development of “exercise mimetics,” drugs that aim to replicate the positive effects of physical activity by targeting specific molecular pathways associated with exercise. Such drugs hold promise for individuals who cannot exercise, but they also raise ethical and cultural questions, challenging our views on health, effort, and lifestyle.

The benefits of exercise extend across various domains, from cardiovascular resilience and metabolic health to improved cognitive function and mood. Physiologically, exercise activates specific biochemical pathways that produce widespread adaptations throughout the body. For instance, the AMP-activated protein kinase (AMPK) pathway is triggered when cells experience an energy deficit, as occurs during exercise. AMPK activation encourages the body to improve fat oxidation, glucose uptake, and mitochondrial growth, supporting endurance and metabolic efficiency. AMPK was discovered in 1973, and the early research demonstrating AMPK’s role in these processes illuminated a molecular basis for exercise’s benefits, paving the way for developing drugs that could replicate these effects. This shift toward pharmacologically mimicking exercise introduces the concept of exercise mimetics as a potential therapeutic approach.

The idea of achieving exercise-like benefits through pharmaceuticals rests on the premise that if these benefits stem from specific molecular mechanisms, they might be inducible without physical exertion. Unlike traditional medications that function only while active in the body, exercise mimetics are designed to stimulate internal adaptations that persist, even after the drugs are metabolized. For example, while beta-blockers lower blood pressure only during administration, drugs like AICAR (a potential exercise mimetic) enhance vascular health more durably by stimulating nitric oxide production and reducing chronic vascular inflammation through the AMPK pathway. Similarly, whereas statins directly reduce blood cholesterol by stimulating the liver to temporarily stop producing, and start absorbing fats, compounds like SLUPP332 promote efficient fat oxidation in muscle and liver cells, supporting a more sustainable reduction in risk of diseases like coronary heart disease. Such drugs could provide preventive health benefits, particularly for individuals for whom exercise is challenging.

Not everyone stands capable of reaping the rewards of regular physical activity. Currently 31% of adults and 80% of adolescents do not meet recommended amounts of physical activity. For many individuals, particularly the elderly, those with disabilities, or patients suffering from chronic diseases such as arthritis, heart failure, or severe obesity, the very act of exercising may be impractical. These populations stand to gain most from exercise mimetics. Cardiovascular diseases (CVDs) are a leading cause of death globally, claiming approximately 17.9 million lives annually, according to the World Health Organization. Increased body fat percentage, often associated with CVD, contributes to the development of atherosclerosis and hypertension. These pharmaceutical agents could offer cardiovascular protection by promoting fat oxidation and reducing body fat, mimicking the effects of exercise. Metabolic disorders, such as type 2 diabetes and obesity, which involve dysregulated glucose and lipid metabolism, could also benefit from these drugs. AICAR, for instance, has been shown to prevent hyperglycaemia and improve insulin sensitivity in diabetic animal models, highlighting its potential for aiding individuals with metabolic disorders in managing their health without relying solely on physical activity.

Moreover, exercise mimetics could offer benefits in neurodegenerative diseases, where physical exercise has been shown to reduce inflammation and support mitochondrial health, thus protecting brain function. Drugs which appear to confer similar protective effects, could potentially delay cognitive decline in diseases such as Alzheimer’s. Furthermore, regular physical activity is known to reduce cancer risk by lowering inflammation and enhancing immune function. While some exercise mimetics have demonstrated potential to reduce tumour growth, others, such as GW501516, present carcinogenic risks, indicating a need for caution. Nevertheless, these drugs could hold promise as complementary therapies in cancer prevention and treatment, although further research is essential to assess their viability.

In addition to chronic disease management, exercise mimetics could support broader populations who face challenges in maintaining physical activity. Aging populations, for instance, often experience declines in muscle mass and mobility, which elevate their risks of falls, frailty, and metabolic issues. Exercise mimetics could potentially help these individuals preserve muscle mass and metabolic function without exertion. Likewise, individuals with temporary or permanent mobility limitations, such as those recovering from surgery or those with conditions like multiple sclerosis, could benefit from drugs that maintain muscle health and cardiovascular function during periods of immobility. While exercise mimetics are still primarily in the preclinical phase, they offer potential to improve health outcomes in populations with diverse needs.

Despite the promise of exercise mimetics, significant challenges remain, both scientifically and ethically. Much of the current research on exercise mimetics is confined to preclinical studies, with few drugs progressing to human trials due to safety concerns. For example, although AICAR has shown potential as a cancer therapy in laboratory settings, it has not been extensively tested in humans. Additionally, research on GW501516 was halted when animal studies revealed carcinogenic risks. Some drugs though seem promising in animal models, are yet to be tested in humans, leaving their effects in human physiology largely speculative. The path from animal studies to clinical applications will require rigorous testing to assess both efficacy and long-term safety.

The physiological complexity of exercise-induced adaptations also poses substantial challenges for developing effective exercise mimetics. Physical activity triggers an array of biochemical responses across nearly every organ system. Exercise-induced adaptations are systemic and multi-layered, involving numerous pathways, tissues, and organs, from the cardiovascular and musculoskeletal systems to the brain. Exercise mimetics, while able to target individual pathways, cannot replicate the broad spectrum of benefits that exercise provides. For instance, while AMPK activation may promote fat oxidation and glucose regulation, it cannot replace the mechanical stress that strengthens muscles. Developing drugs that mimic the holistic effects of exercise remains a complex challenge for researchers.

Beyond scientific hurdles, safety concerns are paramount when considering the widespread use of exercise mimetics. Although short-term benefits have been observed, the long-term impact of these drugs is not yet fully understood. Manipulating metabolic pathways carries risks. Drugs, like SR9009, which influence circadian rhythms and energy expenditure, may have unforeseen effects on liver function, or hormonal balance. Altering these pathways without a comprehensive understanding of their long-term impact could lead to adverse consequences, emphasizing the need for caution and further study before exercise mimetics become widely available.

Ethically and culturally, exercise mimetics challenge our perceptions of physical activity and its role in society. Physical exercise is more than just a vehicle for health; it serves as a source of social connection, psychological resilience, and personal accomplishment. Engaging in physical activity fosters teamwork, camaraderie, and community, qualities that cannot be replicated by a pill. Exercise also builds personal resilience, encouraging discipline, goal-setting, and stress relief—factors that enhance well-being beyond the purely physiological. The availability of exercise mimetics could shift societal attitudes toward a more sedentary lifestyle, undermining the personal and social value of physical effort.

The introduction of exercise mimetics could also disrupt the sports industry, raising concerns about fairness and equity. If exercise mimetics are used to boost endurance, strength, or recovery, they may be seen as akin to performance-enhancing drugs, creating uneven playing fields. The World Anti-Doping Agency currently bans several exercise mimetics, indicating the need for strict regulation should these drugs gain broader availability. Without careful oversight, exercise mimetics could compromise the integrity of competitive sports, creating disparities between athletes based on access to these drugs.

Despite these concerns, exercise mimetics represent an exciting frontier in preventive medicine, offering the potential to extend exercise’s health benefits to those who cannot engage in physical activity. Elderly individuals, those with chronic diseases, and people with restricted mobility could benefit from drugs that support cardiovascular health, regulate glucose levels, or maintain muscle mass. For these populations, exercise mimetics could improve quality of life and reduce the risk of serious health conditions. However, the potential benefits must be balanced against risks, including long-term side effects, the erosion of exercise culture, and the possibility of misuse in sports. A balanced approach that emphasizes physical exercise alongside responsible use of exercise mimetics is essential to harness their benefits without compromising societal values. Future research, careful regulation, and a commitment to promoting the holistic value of physical exercise will be essential to harness the potential of exercise mimetics responsibly.