AMPK (AMP-activated protein kinase) is a nutrient sensor in cells. When energy is scarce, it is activated to restore energy balance by inhibiting energy consumption and enhancing glucose and lipid metabolism. The diabetes drug metformin has become a top anti-aging candidate largely because of its ability to activate AMPK. However, as a prescription drug, it is not easily accessible to many people; meanwhile, the application and research of other AMPK activators are limited. Must we miss out on this promising target?
Recently, a European research team discovered a new AMPK activator, O304 – which has already entered Phase II human clinical trials – that can mimic the benefits of exercise. It improves hyperglycemia, insulin resistance, cardiac function, and exercise capacity in aged mice. The study was published in a Nature sub-journal on November 18[1].
Key Research Findings
With age, AMPK activity in the human body decreases, leading to energy metabolism disorders. Exercise reduces energy and glucose levels, which activates AMPK and brings multiple health benefits – making exercise particularly important for the elderly. However, many elderly people are unable to exercise due to physical limitations. Thus, researchers explored whether the AMPK activator O304 could mimic exercise benefits in older individuals.
To rule out interference from diseases like diabetes and focus on O304’s effects on aging, the study used lean, healthy aged mice as subjects. Even though these mice were not overweight, their metabolic function, cardiac volume, and vascular flexibility were still impaired by aging.
After being administered O304, the aged mice showed significant improvements similar to those from exercise:
- Cardiac function enhancement: Stroke volume, cardiac output, and end-diastolic volume increased significantly; heart rate decreased markedly.
- Metabolic improvement: Insulin levels dropped sharply, indicating reduced insulin resistance.
Additionally, O304 "tricked" the mice’s hearts into thinking the mice were exercising intensely daily, leading to exercise-induced adaptive changes: increased heart weight (relative to tibia length) and higher myocardial capillary density.
Important Considerations & Clinical Progress
It is important to note that O304 was developed by the Swedish biopharmaceutical company Betagenon, and Helena Edlund – the corresponding author of the study – is a co-founder of Betagenon, creating a potential conflict of interest. Therefore, further verification is needed to determine whether the experimental results can be translated into practical applications.
Nevertheless, with strong financial and institutional support, O304 research has progressed rapidly. It has moved beyond the laboratory and entered human clinical trials to test its efficacy in treating diseases including:
- Diabetic nephropathy
- Type 2 diabetes
- Heart failure
- Obesity
- Non-alcoholic fatty liver disease (NAFLD)
The most advanced trials focus on type 2 diabetes: Phase IIa clinical trials have been completed. Results showed that O304 effectively improved glucose homeostasis, blood pressure, and peripheral microvascular perfusion in calf muscles in diabetic patients[2]. A drawback, however, was its poor bioavailability in the trials. To address this, Betagenon developed a new formulation of O304 with improved bioavailability, which has now been approved for a clinical bridging trial[3].
Table: Diseases Targeted by O304 and Its Potential Mechanisms of Action
| Disease | Potential Mechanism of Action |
|---|---|
| Type 2 Diabetes | Maintains glucose homeostasis by enhancing glucose uptake in muscles and reducing insulin resistance. |
| Diabetic Nephropathy | Reduces proteinuria, improves glomerular filtration rate and renal fibrosis, and enhances renal function. |
| Heart Failure | Improves cardiac function by increasing stroke volume, cardiac output, and end-diastolic volume, and lowering heart rate. |
| Obesity | Increases ATGL activity (via AMPK-mediated phosphorylation of S406) to enhance lipolysis; boosts energy expenditure by increasing oxygen consumption and reducing respiratory exchange rate. |
| Non-Alcoholic Fatty Liver Disease (NAFLD) | Alleviates insulin resistance and reduces fatty liver by decreasing de novo hepatic lipogenesis and increasing fatty acid oxidation/plasma β-hydroxybutyrate. |
Figure Note: Diseases targeted by O304 and its potential mechanisms of action (Source: Betagenon official website[4]).
Conclusion
This study reveals a new possibility: in the future, we may enjoy the benefits of exercise without actually exercising – "living longer while lying down" could become a reality.
Researcher Profile
Helena Edlund
- Swedish molecular biologist, Member of the Royal Swedish Academy of Sciences, Founder and shareholder of the biopharmaceutical company Betagenon.
- Main research focus: Type 2 diabetes and pancreatic β-cell function. She has published numerous papers on β-cell differentiation, β-cell function, pancreatic development, and type 2 diabetes.
- 2000: Received the Minkowski Prize from the European Association for the Study of Diabetes (EASD) for her contributions to regulating β-cell characteristics and glucose homeostasis.
References
[1] Ericsson, M., Steneberg, P., Nyrén, R., & Edlund, H. (2021). AMPK activator O304 improves metabolic and cardiac function, and exercise capacity in aged mice. Communications Biology, 4(1). https://doi.org/10.1038/s42003-021-02837-0[2] Steneberg, P., Lindahl, E., Dahl, U., Lidh, E., Straseviciene, J., Backlund, F., Kjellkvist, E., Berggren, E., Lundberg, I., Bergqvist, I., Ericsson, M., Eriksson, B., Linde, K., Westman, J., Edlund, T., & Edlund, H. (2018). PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients. JCI Insight, 3(12). https://doi.org/10.1172/jci.insight.99114[3] Betagenon. (2018, August 17). Start of bridging pharmacokinetic and safety clinical trial of a novel solid pharmaceutical composition of AMPK activator O304. Retrieved November 25, 2021, from https://betagenon.com/wp-content/uploads/2020/08/Start-of-Bridging-PK-clinical-trial-of-O304-1-1.pdf[4] Betagenon. (2020, November 8). O304 – Our lead AMPK activator. https://betagenon.com/research-development/o304-our-ampk-activator