Down your daily dose of exercise with a glass of water

By Natasha Kisseroudis

Would an exercise pill be effective and is it a good idea? This article was inspired by a piece written in the New Scientist by Jo Marchant and summarises the research, concerns and hopes for exercise mimetic drugs that may help combat the health hazards of our increasingly sedentary lifestyles.

The benefits of exercise and demand for an exercise mimetic drug

If exercise were a pill, it would be the most sought-after drug, due to its vast array of benefits. Specifically,  it has been shown to lead to a faster metabolism which in turn decreases the risk of obesity and diabetes. Moreover, it improves cardiovascular health by strengthening the heart and thus, leads to a lower risk of heart attacks. Apart from physical health, exercise has also been shown to have significant mental health benefits, as well as to improve memory and cognition (Marchant, 2021). Overall, physical activity has been associated with an improved quality of life and reduced physical mortality (Vina et al., 2012). 

However, despite the known benefits of exercise, a study conducted across 100 countries has shown that 31 per cent of individuals are physically inactive (Marchant, 2021). Contrary to popular belief, this is not always a case of laziness, as many people have physical limitations and societal constraints on their activity levels (Deck et al., 2014). Therefore, the common phrase “eat less, move more” does not provide a solution, but a pill with the benefits of exercise may be the solution to individuals leading healthier, happier and, consequently, longer lives (Marchant, 2021).    This concept is unsurprising because many parallels can be drawn between exercise and a psychoactive drug, as its effects are related to dosage,it is often prescribed along with medication and can become addictive (Vina et al., 2012).  

Research into exercise mimetics

Several studies have been conducted to investigate whether exercise mimetic drugs could elicit the beneficial effects of exercise (Fan and Evans, 2017).  Ronald Evans conducted a study (2008) where he fed the exercise mimetic GW1516 to unfit mice and compared them to unfit mice that had not received the drug with respect to the distances that they could run on a wheel (Narkar et al., 2008). Results showed that the experimental group receiving GW1516 ran double the distance (Marchant, 2021). GW1516 works by targeting PPAR-delta, a hormone receptor (Berger and Moller, 2002) and increasing the expression of energy expenditure proteins, causing increased fat metabolism (Sprecher, 2007).  PPAR-delta is a ligand activated hormone receptor that acts as a transcription factor and is responsible for controlling and maintaining energy balance, uptake and transport of fatty acids, and insulin secretion. Therefore, it is believed to play a significant role in the prevention of metabolic diseases (Liu et al., 2018) and has been described as a novel therapeutic target (Reilly and Lee, 2007).

Irisin is a hormone secreted during muscle contraction that stimulates the conversion of white adipose tissue (fat) into brown adipose tissue, which burns more energy and thus leads to weight loss (Maalouf and El Khoury, 2019). A study conducted by Bruce Spiegelman (2014) showed that when given irisin, obese mice lost weight, even on a high fat diet (Wu and Spiegelman, 2014; Marchant, 2021). 

Lastly, an exercise mimetic known as compound 14 has been used by Ali Tavvasoli (2015) to investigate diabetes in mice (Asby et al., 2015). Before treatment, mice were fed a high fat diet until they showed diabetes symptoms. After a week of compound 14 treatment, results showed that the mice had not only lost weight, but their diabetes symptoms had vanished. Tavvasoli attributed these results to the ability of the drug to “reprogram” the mouse metabolism by altering gene expression in fat cells to reflect normal weight as opposed to obese mice (Marchant, 2021).  This is because compound 14 activates AMPK, a protein kinase that acts as a cellular energy sensor and has been characterised as “the master regulator of cellular energy homeostasis” (Asby et al., 2015). AMPK activation has been reported to act as an exercise mimetic in obese mice, by for example increasing the oxidation of fatty acids in muscle tissue (Fullerton et al., 2013). Moreover the researchers found that AMPK activation by treatment with compound 14 decresed glucose levels in the blood, strengthened glucose tolerance and reduced the body mass of obese mice (Asby et al., 2015).

Is it worth it?

It is impossible to synthesise a drug that is able to directly mimic all the health benefits of exercise.  This is because there are additional factors that complement the effects of exercise, such as being outdoors or in a team environment, which contribute to endorphin release and subsequent mood boost. Moreover, physical ability is subjective, meaning that each individual feels the benefits of exercise according to their own physiology. These are high demands for a pill (Marchant, 2021).  

Prolonged studies of the above mentioned compounds used on obese mice also revealed harmful side-effects. Specifically, prolonged animal studies of GW1516 showed rapid cancer development in multiple organs (Sahebkar, Chew and Watts, 2014). In addition, inflammation in the brains of obese mice treated with a drug similar to compound 14 was observed two weeks post-treatment, resulting in a decline in their cognition and performance in a maze test (Marchant, 2021). This means more research needs to be conducted, but also provokes skepticism regarding the plausibility of a pill with such a broad action and no dangerous consequences.

Concluding remarks

So far, although exercise mimetics have been shown to briefly improve health in mice, they also elicit long-term side effects. Therefore, fully substituting exercise with a pill poses a high health risk, but may prove beneficial in the short term. Consequently, researchers are optimistic that such medications could be used by obese individuals as a starting off point, until they get to a weight that allows them to exercise more easily (Marchant, 2021). 

An alternative approach supported by Bruce Spiegelman (2013) is enhancing specific benefits of exercise in a targeted fashion (Wrann et al., 2013). For example, exercise has been shown to improve neuron health and connectivity as well as stimulating the birth of new neurons in the hippocampus, where memory is believed to be localized (Marchant, 2021). Spielgman attributes this to a precursor of irisin which reaches the brain during exercise and alters expressions of genes associated with neurogenesis. The irisin precursor action generated by exercise alone has not shown any positive effects on patients with Alzheimer’s disease, but Spielgelman is optimistic that an increased dose of irisin may result in dramatic benefits (Wrann et al., 2013; Marchant, 2021). In other words, if we could recreate the benefits of exercise by harnessing and amplifying the power of specific compounds  released during exercise, we may be able to treat illnesses currently deemed untreatable.  

References

  1. Asby, D., Cuda, F., Beyaert, M., Houghton, F., Cagampang, F. and Tavassoli, A., 2015. AMPK Activation via Modulation of De Novo Purine Biosynthesis with an Inhibitor of ATIC Homodimerization. Chemistry & Biology, 22(7), pp.838-848.
  2. Berger, J. and Moller, D., 2002. The Mechanisms of Action of PPARs. Annual Review of Medicine, 53(1), pp.409-435.
  3. Deck, K., Haney, B., Fitzpatrick, C., Phillips, S. and Tiso, S., 2014. Prescription for Obesity: Eat Less and Move More. Is It Really That Simple?. Open Journal of Nursing, 04(09), pp.656-662.
  4. Fan, W. and Evans, R., 2017. Exercise Mimetics: Impact on Health and Performance. Cell Metabolism, 25(2), pp.242-247.
  5. Fullerton, M., Galic, S., Marcinko, K., Sikkema, S., Pulinilkunnil, T., Chen, Z., O’Neill, H., Ford, R., Palanivel, R., O’Brien, M., Hardie, D., Macaulay, S., Schertzer, J., Dyck, J., van Denderen, B., Kemp, B. and Steinberg, G., 2013. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nature Medicine, 19(12), pp.1649-1654.
  6. Liu, Y., Colby, J., Zuo, X., Jaoude, J., Wei, D. and Shureiqi, I., 2018. The Role of PPAR-δ in Metabolism, Inflammation, and Cancer: Many Characters of a Critical Transcription Factor. International Journal of Molecular Sciences, 19(11), p.3339.
  7. Maalouf, G. and El Khoury, D., 2019. Exercise-Induced Irisin, the Fat Browning Myokine, as a Potential Anticancer Agent. Journal of Obesity, 2019, pp.1-8.
  8. Marchant, J., 2021. Exercise pills: Should we use drugs that mimic benefits of a workout?. [online] New Scientist. Available at: <https://www.newscientist.com/article/mg25033310-900-exercise-pills-should-we-use-drugs-that-mimic-benefits-of-a-workout/&gt; [Accessed 2 May 2021]. 
  9. Narkar, V., Downes, M., Yu, R., Embler, E., Wang, Y., Banayo, E., Mihaylova, M., Nelson, M., Zou, Y., Juguilon, H., Kang, H., Shaw, R. and Evans, R., 2008. AMPK and PPARδ Agonists Are Exercise Mimetics. Cell, 134(3), pp.405-415.
  10. Reilly, S. and Lee, C., 2007. PPARδ as a therapeutic target in metabolic disease. FEBS Letters, 582(1), pp.26-31.
  11. Sahebkar, A., Chew, G. and Watts, G., 2014. New peroxisome proliferator-activated receptor agonists: potential treatments for atherogenic dyslipidemia and non-alcoholic fatty liver disease. Expert Opinion on Pharmacotherapy, 15(4), pp.493-503.
  12. Sprecher, D., 2007. Lipids, Lipoproteins, and Peroxisome Proliferator Activated Receptor–δ. The American Journal of Cardiology, 100(11), pp.S20-S24.
  13. Vina, J., Sanchis-Gomar, F., Martinez-Bello, V. and Gomez-Cabrera, M., 2012. Exercise acts as a drug; the pharmacological benefits of exercise. British Journal of Pharmacology, 167(1), pp.1-12.

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